Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22].C(N(CC)CC)C>C(Cl)Cl>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oleyl alcohol (26.8 grams) is placed in a three-neck flask under a blanket of nitrogen. The entire reaction contents are cooled in an ice bath. Methacryloyl chloride (10.5 grams) dissolved in about 50 mL of methylene chloride is added slowly to the cooled oleyl alcohol with vigorous stirring in about 2 hours. Triethylamine (11.5 g) dissolved in 25 mL of methylene chloride is subsequently added in about an hour. After addition of triethylamine, the solution is allowed to warm to ambient temperature and is stirred for another 4 hours in order to complete the reaction. The precipitated triethylammonium chloride is removed by filtration, and the filtrate is washed with brine solution (saturated NaCl) followed by washings with dil. NaOH and dil. HCl. The organic layer is dried with anhydrous magnesium sulfate and the solvent is removed in vacuo to yield oleyl methacrylate in good yields. Oleyl methacrylate is stabilized from polymerization by addition of approximately 10 ppm hydroquinone. The structure of the product is verified by 1H and 13C NMR spectroscopy.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][CH2:10][CH2:11][N:5]2[CH2:4]1.FC(F)(F)C(O)=O.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([OH:39])=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[C:22]([Cl:40])[C:21]=1[Cl:41].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[ClH:1].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH2:2][C@H:3]4[O:8][CH2:7][C@@H:6]5[CH2:9][CH2:10][CH2:11][N:5]5[CH2:4]4)=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[C:22]([Cl:40])[C:21]=1[Cl:41]
Reactant: ClC[C@@H]1CN2CCC[C@H]2CO1
Reactant: COc1cc2c(Nc3ccc(Br)c(Cl)c3Cl)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Br)c(Cl)c3Cl)ncnc2cc1OC[C@@H]1CN2CCC[C@H]2CO1
Product: Cl
Temperature: 130 °C
Reaction time: 36 h
Yield: 33.9 %

Procedure:
(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (115 mg, 0.655 mmol) and 4-[(4-bromo-2,3-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetic acid salt (347 mg, 0.655 mmol) were dissolved in dimethylacetamide (0.8 mL) and potassium carbonate (452 mg, 3.28 mmol) was added. The mixture was stirred at 130° C. for 36 h. The mixture was cooled to room temperature and the mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate and the combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil which was purified by column chromatography (ethyl acetate-ethanol 1:1). The purified material was dissolved in ethanol and treated with 4M solution of HCl in 1,4-dioxane (0.25 mL) and the mixture was concentrated in vacuo. The residue was dissolved in water and lyophilized to afford N-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride as a brown solid (131 mg, 0.222 mmol, 34% yield). 1H NMR (400 MHz, d6-DMSO): 11.9-11.5 (m, 2H), 8.79 (s, 1H), 8.34 (s, 1H), 7.96 (d, 1H), 7.54 (d, 1H), 7.41 (s, 1H), 4.47-4.25 (m, 4H), 4.03 (s, 3H) 3.96-3.00 (m, 6H), 2.18-1.88 (m, 3H), 1.73-1.57 (m, 1H); MS (EI) for C23H23N4O3Cl2Br: 553 (MH+).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[CH:9]=[C:10]([OH:28])[C:11]2[CH:12]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:14]=[N:15][C:16]=2[CH:17]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CCCCCC.C(OCC)(=O)C>[C:29]([O:28][C:10]1[CH:9]=[C:8]([CH3:7])[CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[N:14]=[N:15]2)(=[O:31])[CH3:30]
Reactant: Cc1cc(O)c2cc(-c3cccc(C(F)(F)F)c3)nnc2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Oc1cc(C)cc2nnc(-c3cccc(C(F)(F)F)c3)cc12
Yield: 36 %

Procedure:
To a pyridine solution (2 mL) of 7-methyl-3-(3-trifluoromethylphenyl)cinnolin-5-ol (60 mg, 0.2 mmol) obtained in Example 70 was added acetic anhydride (3 mL), followed by reaction at room temperature over night. The reaction liquid was concentrated under reduced pressure, followed by adding distilled water (1 mL), extraction with ethyl acetate and purification of residue obtained after concentration of an organic layer under reduced pressure, with HPLC column chromatography (hexane/ethyl acetate=3/1) to obtain an objective compound (25 mg, 36%) as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH2:40]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:40][NH:39][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:19])=[CH:15][CH:14]=2)=[O:10])=[CH:22][CH:23]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
Into a solution of 4-({[4-(methoxycarbonyl)benzoyl]amino}methyl)benzoic acid (1.0 g, 3.19 mmol) and N-methyl morpholine (420 μL, 3.83 mmol) in anhydrous THF (25 mL) at 0° C. was added isobutyl chloroformate (455 μL, 3.51 mmol) then tert-butyl hydrazine carboxylate (1.12 mg, 7.66 mmol). After stirring at 0° C. for 1 hr and overnight at rt, the reaction mixture was quenched with HCl (1N, 25 mL). Extraction with EtOAc (2×25 mL), drying over MgSO4 and evaporation under vacuo gave a residue. Purification by flash chromatography (SiO2, EtOAc) gave the title compound (773 mg, 55%) as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:22])/[C:5](/[CH3:21])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)C.O[Li].O>CO.O>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[C:5](\[CH3:21])/[C:4]([OH:22])=[O:3])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc(/C=C(\C)C(=O)O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
A suspension of (E)-3-(3-cyclopentoxy-4-methoxyphenyl)-2-methyl-acrylic acid ethyl ester (30 g, 98.6 mmol) and LiOH.H2O (lithium hydroxide hydrate) (5.0 g, 119.2 mmol, 1.2 equiv.) in methanol-water (4:1, 100 mL) was stirred at room temperature for 24 hours. Methanol was removed under reduced pressure and the resulting residue was dissolved in water (100 mL), washed with three 100 mL portions of ethyl acetate, neutralized with 1.0 N HCl (hydrochloric acid) (100 mL), and extracted with two 150 mL portions of ethyl acetate. The extract was washed with brine, dried over anhydrous Na2SO4 (sodium sulfate), and concentrated under reduced pressure to afford the desired product as a light yellow powder (18.2 g, 66% yield). 1H NMR (300 MHz, CDCl3) δ(ppm): 12.4 (br. s, 1H, COOH), 7.56 (s, 1H, olefinic), 7.04 (m, 3H, aromatic), 4.81 (m, 1H), 3.78 (s, 3H, OCH3), 2.06 (s, 3H, CH3), 1.91-1.57 (m, 8H, cyclopentyl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16](C=O)=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1.OO.S(=O)(=O)(O)[OH:29].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([OH:29])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(C=O)ccc12
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(O)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Step 2 A solution of crude 4-(2-fluorophenyl)-7-formyl-9H-carbazole-1-carboxamide (25.2 mg, 0.076 mmol) in methanol (2 mL) at 0° C. was treated with 30% aqueous hydrogen peroxide (0.039 mL, 0.379 mmol) and sulfuric acid (0.020 mL, 0.379 mmol). After 1.5 h, additional hydrogen peroxide (0.100 mL) and sulfuric acid (0.050 mL) were added and the mixture was stirred at rt overnight. After 16 h, 1 M aqueous sodium hydroxide (2 mL) was added and the mixture was stirred for 1 h. The pH was adjusted to ca. 4 and the organic solvent was removed under vacuum. The aqueous residue was diluted with water and the precipitate was collected by filtration, washed with water and dried. The residue was purified by preparative HPLC to provide 4-(2-fluorophenyl)-7-hydroxy-9H-carbazole-1-carboxamide as tan solid after lypholization (5.1 mg, 21%). 1H NMR (400 MHz, methanol-d4) δ 7.81 (1H, d, J=7.70 Hz), 7.45-7.64 (2 H, m), 7.21-7.42 (2 H, m), 7.03 (1 H, d, J=7.92 Hz), 6.90-6.99 (2 H, m), 6.45 (1 H, dd, J=8.58, 2.20 Hz). Mass spectrum m/z 321.0 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:9]=[C:10]([C:19]([OH:21])=[O:20])[CH:11]=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14][CH2:13]2)([O-:7])=[O:6].[CH3:22]O>>[N+:5]([C:8]1[CH:9]=[C:10]([C:19]([O:21][CH3:22])=[O:20])[CH:11]=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14][CH2:13]2)([O-:7])=[O:6]
Reactant: CO
Reactant: O=C1CCc2cc(C(=O)O)cc([N+](=O)[O-])c2N1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2c(c([N+](=O)[O-])c1)NC(=O)CC2

Procedure:
7 ml of thionyl chloride was added to a solution of 15 g of 8-nitro-6-carboxy-3,4-dihydrocarbostyril in 150 ml of methanol with ice-cooling. The mixture was refluxed by heating, for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 12.8 g of 8-nitro-6-methoxycarbonyl-3,4-dihydrocarbostyril as a light yellow powder.
Reaction SMILES: CCOCC.C1([Mg]Br)CC1.[CH3:11][O:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](I)=[CH:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[C:34]1(=[O:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1>[CH3:11][O:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:34]3([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Agent: Br[Mg]C1CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3(O)CCCCC3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
Via addition funnel slowly add over 0.5 hours the 2M EtOEt solution of cyclopropyl magnesium bromide (2.16 g, 6.23 ml, 12.46 mmol, 1.1 eq) to the −78° C. THF solution (30 ml) of 4-(3-Iodo-indole-1-sulfonyl)-benzoic acid methyl ester (5 g, 11.33 mmol, 1.00 eq). Stir for 2 hours and then warm to 0° C. Stir for 0.5 hours. Recool to −10° C. and then slowly add a THF solution (3 ml) of cyclohexanone (1.298 g, 13.03 mmol, 1.15 eq). Stir for 15 min and warm to room temperature. Stir for 1.5 days. Quench reaction with saturated aqueous ammonium chloride, remove organics on rotovap, and add EtOAc to crude mix. Extract product into organics, separate organics, dry over MgSO4, and concentrate on rotovap to give crude product as an oil. Purify by silica gel chromatography to give 4-[3-(1-Hydroxy-cyclohexyl)-indole-1-sulfonyl]-benzoic acid methyl ester (948 mg, 20% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Cl)c(Cl)cc1N
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(Cl)c(Cl)cc1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a stirring solution of 4,5-dichloro-2-ethylbenzenamine (600 mg, 3.15 mmol) in DMF at 0° C., NaH (150 mg, 3.78 mmol) was added in portions. After stirring for 30 min, ethyl 2-bromoacetate (789 mg, 4.74 mmol) was added to the mixture. The resulting mixture was stirred at 120° C. for 16 h. The mixture was allowed to cool to room temperature, poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=5:1) to afford the desired product (380 mg, 44.7% yield) as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC#N>[ClH:1].[CH2:10]([NH:17][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: ClCCN1CCOCC1
Solvent: CC#N
Product: Cl
Product: c1ccc(CNCCN2CCOCC2)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
A solution of 100 mg of N-(2-chloroethyl)morpholine and 575 mg of benzylamine in 5 mL of CH3CN was refluxed for 2 h. The mixture was cooled to 25° C. and partitioned between dichloromethane and an aqueous sodium bicarbonate solution. The organic extracts were dried and the solvent was evaporated. The residual solvent was removed at high vacuum and the residue was dissolved in a large excess of methanolic HCl. The solvent was evaporated to give 60 mg of the product.
Reaction SMILES: BrCC1C=C(C=C(F)C=1)C#N.N[C:13](=[N:32]O)[C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:17][N:18]([CH3:27])[CH2:19][C:20](OC(C)(C)C)=O.CNCC[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[C:13]([C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:17][N:18]([CH3:27])[CH2:19][CH2:20][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])#[N:32]
Reactant: CNCCC(=O)OC(C)(C)C
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cc(F)cc(C(N)=NO)c1
Agent: N#Cc1cc(F)cc(CBr)c1
Product: CN(CCC(=O)OC(C)(C)C)Cc1cc(F)cc(C#N)c1

Procedure:
The title compound was prepared according the general procedure 10, starting from 3-(bromomethyl)-5-fluorobenzonitrile (Intermediate 24 Step 1, 750 mg, 3.5 mmol) and tert-butyl N-methyl-beta-alaninate (670 mg, 4.2 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a pale yellow oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.73 (ddd, J=8.6, 2.6, 1.4 Hz, 1H), 7.61 (s, 1H), 7.56-7.45 (m, 1H), 3.53 (s, 2H), 2.60 (t, J=6.7 Hz, 2H), 2.38 (t, J=6.7 Hz, 2H), 2.12 (s, 3H), 1.40 (s, 9H). LC/MS (Method B): 293.3 (M+H)+. HPLC (Method A) Rt 2.61 min (Purity: 96.2%).
Reaction SMILES: [F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([CH2:16]O)[S:13]/[C:12]/3=[N:18]\[C:19](=[O:23])[N:20]([CH3:22])[CH3:21])=[CH:10][C:4]=2[O:3]1.COCCN(S(F)(F)[F:35])CCOC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([CH2:16][F:35])[S:13]/[C:12]/3=[N:18]\[C:19](=[O:23])[N:20]([CH3:22])[CH3:21])=[CH:10][C:4]=2[O:3]1
Reactant: CN(C)C(=O)/N=c1\sc(CO)cn1-c1ccc2c(c1)OC(F)(F)O2
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(=O)/N=c1\sc(CF)cn1-c1ccc2c(c1)OC(F)(F)O2
Reaction time: 4 h

Procedure:
A solution of N′-[(2Z)-3-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-(hydroxymethyl)-1,3-thiazol-2(3H)-ylidene]-N,N-dimethylurea (Example 87, 0.2 g, 0.56 mmol) in dry CH2Cl2 (10 mL) was treated with bis(2-methoxyethyl)aminosulfur trifluoride (0.148 g, 0.67 mmol). After 4 hours at room temperature, the mixture was neutralized by dropwise addition of a saturated solution of sodium bicarbonate. The mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified over silica using CH2Cl2 as mobile phase. 1H NMR (CDCl3) δ ppm 3.00 (6H), 5.20 (1H), 5.38 (1H), 7.00 (1H), 7.30 (2H), 7.38 (1H); MS (ESI) 360(M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:12]4[N:13]([CH:20]=[N:21][CH:22]=4)[CH:14]=[CH:15][C:16]=3[C:17]([OH:19])=O)=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH2:55][O:56][C:57]([CH3:61])([CH3:60])[CH2:58][OH:59]>CN(C=O)C>[OH:59][CH2:58][C:57]([CH3:61])([CH3:60])[O:56][NH:55][C:17]([C:16]1[CH:15]=[CH:14][N:13]2[CH:20]=[N:21][CH:22]=[C:12]2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]=1[F:23])=[O:19]
Reactant: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Reactant: CC(C)(CO)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CO)ONC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.9 %

Procedure:
A suspension of 8-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (0.11 g, 0.35 mmol), EDCI (0.081 g, 0.42 mmol), HOBt (0.057 g, 0.42 mmol), DIPEA (0.085 mL, 0.88 mmol) and 2-aminooxy-2-methyl-propan-1-ol hydrochloride (0.055 g, 0.39 mmol) in DMF (1.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (5 mL) and saturated aqueous NaHCO3 (5 ml). The organic layer was washed with water (5 mL), followed by brine (5 mL), then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 40%, ethyl actetate in DCM) to give a yellow solid, which was further purified by preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to afford the title compound as a yellow solid (11 mg, 8%). LCMS (method A): RT=7.57 min, [M+H]+=399. 1H NMR (DMSO-d6): 10.37 (1H, s), 8.28 (1H, s), 7.79 (1H, dd, J=7.35, 0.95 Hz), 7.14 (1H, s), 7.02-6.93 (1H, m), 6.91 (1H, d, J=8.28 Hz), 6.82 (1H, s), 6.27 (1H, s), 1.99-1.90 (1H, m), 1.15 (6H, s), 0.99-0.92 (2H, m), 0.73-0.67 (2H, m).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:19])[CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[CH3:28]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[CH3:28])=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:19])[CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C(C)=O)cccc2c1Cl
Reactant: Cc1cc(O)ccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C(C)=O)cccc2c1Nc1ccc(O)cc1C
Yield: 24.7 %

Procedure:
A solution of 3-butyryl-4-chloro-8-acetylquinoline (2.0 g) and 4-amino-3-methylphenol (1.23 g, 10 mmol) in 1,4-dioxan (25 ml) was warmed briefly to reflux, then the dioxan evaporated. Chromatography (silica, 4-6% methanol in dichloromethane) and recrystallisation from ethyl acetate gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-acetylquinoline (0.65 g), m.p. 183°-185°.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]1[CH2:19][CH:18]([OH:20])[CH2:17][NH:16][C:15]2[C:14](=[O:21])[C:13](=[O:22])[C:12]1=2)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>ClCCCl.O>[OH:20][CH:18]1[CH2:17][NH:16][C:15]2[C:14](=[O:21])[C:13](=[O:22])[C:12]=2[N:11]([CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])[CH2:19]1
Reactant: CCOP(=O)(CCN1CC(O)CNc2c1c(=O)c2=O)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClCCCl
Product: O=c1c2c(c1=O)N(CCP(=O)(O)O)CC(O)CN2

Procedure:
To a solution of [2-(4-hydroxy-8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid diethyl ester (2.5 g, 7.5 mmol) in dry 1,2-dichloroethane (100 mL) under nitrogen, was added bromotrimethylsilane (9.2 mL, 60 mmol). The reaction mixture was refluxed for 20 min and then concentrated in vacuo to yield a yellow-orange foam, which was dissolved in water (100 mL). The water was washed with ether (3×100 mL) and then concentrated in vacuo to yield a solid which was recrystallized from water in isopropanol to yield [2-(4-hydroxy-8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid one sixth hydrate as a pale yellow solid (1.79 g, 86%, mp 268°-270° C. dec); IR (KBr, cm-1): 3480, 3220, 1820; MS (-FAB): 275 (M-H, 22), 148 (100); 1H NMR (DMSO 1 drop of DCl, 400 MHz): δ 3.90 (m, 1H), 3.85-3.74 (m, 2H), 3.46 (d, J=13 Hz, 1H), 3.34 (d of d, J=13 and 7 Hz, 1H), 3.28 (m, 2H), 1.98-1.89 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([F:24])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19]([F:22])([F:21])[F:20])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:23]=1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C@:31]([OH:35])([C:33]#[CH:34])[CH3:32])[CH:27]=1>>[F:24][C:3]1[C:2]([C:34]#[C:33][C@@:31]([OH:35])([C:28]2[CH:27]=[C:26]([CH3:25])[O:30][N:29]=2)[CH3:32])=[CH:23][C:6]2[C:7]3[N:8]([C:13]([C:19]([F:20])([F:22])[F:21])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[CH:9]3[CH2:12][CH:11]([C:5]=2[CH:4]=1)[CH2:10]3
Reactant: NC(=O)c1nc2n(c1C(F)(F)F)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2F)C2CC(C2)n2c-3nc(C(N)=O)c2C(F)(F)F)no1
Yield: 46 %

Procedure:
10-bromo-9-fluoro-3-(trifluoromethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 38 mg (46%) of (R)-9-fluoro-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-3-(trifluoromethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:29][C:30]([F:39])([F:38])[C:31](N1C=CN=C1)=[O:32]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:18])[CH:16]([CH3:17])[C:31](=[O:32])[C:30]([F:29])([F:38])[F:39])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(n1ccnc1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C(=O)c1ccc(OCc2ccccc2)cc1)C(=O)C(F)(F)F
Temperature: -60 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4′-benzyloxypropiophenone (6.0 g) in THF (120 ml) at −60° C. was added 38 ml of 1N lithium bis(trimethylsilyl)amide (LiHMDS), and the mixture was stirred at under −60° C. for 45 mins. 1-(Trifluoroacetyl)-imidazole (3.4 ml) was added and the mixture was stirred at −60° C. for 1 hour and at 0° C. for 30 min. The raction mixture was quenched with 0.5N HCl, the mixture was poured into EtOAc and water, and the EtOAc layer was separated, washed with brine, died over MgSO4, and concentrated to give 1-[4-(benzyloxy)phenyl]-4,4,4-trifluoro-2-methyl-1,3-butanedione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Yield: 27.7 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)pentanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (665 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.9 ml) and 1-methyl-2-chloropyridinium iodide (1.05 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)pentanamide (387 mg).