Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[CH:25]=[CH:26][C:21]([I:20])=[CH:22][CH:23]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Oc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(I)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (7.0 g) synthesized in Example 4 and 4-iodophenol (5.08 g) were dissolved in tetrahydrofuran (100 mL), triphenylphosphine (6.06 g) and diethyl diazodicarboxylate (4.02 g) were added under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1) to give the title compound (7.5 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[C:11]([CH2:17][CH2:18][CH3:19])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:34]1([CH2:37][NH:38][C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([N:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)=[O:49])=[CH:44][CH:43]=2)=[O:40])[CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:34]1([CH2:37][NH:38][C:39]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([C:48]([N:50]3[CH2:55][CH2:54][N:53]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:5])([F:6])[F:7])[C:2]([F:21])([F:20])[F:1])=[CH:10][C:11]=4[CH2:17][CH2:18][CH3:19])[CH2:52][CH2:51]3)=[O:49])=[CH:46][CH:47]=2)=[O:40])[CH2:35][CH2:36]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CN1CCN(C(=O)c2ccc(NC(=O)NCC3CC3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-(hydroxymethyl)-3-propylphenyl)propan-2-ol (0.509 mmol, 161 mg) was dissolved in dichloromethane (4 mL) and triethylamine (1.527 mmol, 155 mg) was added. The mixture was cooled to 0° C. before the addition of methanesulfonyl chloride (0.611 mmol, 70.0 mg). The mixture was stirred at 0° C. for 1 hour before warming to room temperature and stirring for 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×10 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (4 mL) and 1-(cyclopropylmethyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea (0.510 mmol, 154 mg) was added followed by potassium carbonate (1.529 mmol, 211 mg). The mixture was heated to reflux for 16 hours. The mixture was cooled, diluted with dichloromethane (50 mL) and washed with water (2×20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC and treated with strong cation exchange column chromatography to afford the title compound (63 mg). MS (ESI) m/z 601.3 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].FC(F)(F)C(O)=O.[CH3:22][C:23]([CH3:25])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:13]([C:3]1[C:2]([NH:1][CH:23]([CH3:25])[CH3:22])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:14]
Reactant: CC(C)=O
Reactant: COC(=O)c1cc(N)c(C#N)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(NC(C)C)c(C#N)cc1C
Temperature: 25 °C
Yield: 76.2 %

Procedure:
Methyl 5-amino-4-cyano-2-methylbenzoate (synthesized in reagent preparation 41, step 4) (240 mg, 1.26 mmol) was dissolved in 1,2-dichloroethane (7 mL) and was treated with trifluoroacetic acid (0.6 mL, 7.57 mmol), acetone (0.28 mL, 3.79 mmol), and sodium triacetoxyborohydride (802 mg, 3.78 mmol) at 45° C. for 20 min. The reaction mixture was cooled to ambient temperature and quenched with saturated aqueous sodium bicarbonate and was partitioned with dichloromethane. The aqueous portion was extracted with dichloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, then filtered and concentrated to afford a yellow oil which was purified by column chromatography (silica gel, 10% dichloromethane in hexanes) to afford methyl 4-cyano-5-(isopropylamino)-2-methylbenzoate (224 mg, 0.96 mmol, 76% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.25 (s, 1H), 7.16 (s, 1H), 4.28 (d, 1H), 3.91 (s, 3H), 3.77-3.74 (m, 1H), 2.40 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H); MS (EI) for C14H16N2O2: 233 (MH+).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[C:11]1([C:17](=[O:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].Cl>CN(C=O)C.O>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:18][C:17](=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=O)CC(=O)c1ccccc1
Temperature: 0 °C
Yield: 42.6 %

Procedure:
Diethyl oxalate (7.23 g, 49.47 mmol) was added to a stirred solution of 1-phenyl-ethanone (5.0 g, 41.6 mmol) in DMF (40 mL) at room temperature. The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in oil, 2.0 g, 83.3 mmol) was added. The resulting mixture was maintained at 0° C. for 30 minutes, stirred for a further hour at room temperature and then slowly heated to 50° C. and stirred for a further 30 minutes. Chilled water was then added, the mixture was acidified with 2.4 N HCl and the resulting precipitate was filtered to afford 2,4-dioxo-4-phenyl-butyric acid ethyl ester in 42.6% yield. LC-MS purity: 85.2%.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[CH3:29][C:30]1([CH3:44])[CH2:34][C:33]2[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41](O)=[O:42])[CH:37]=[CH:38][C:32]=2[O:31]1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:41](=[O:42])/[CH:40]=[CH:39]/[C:36]4[CH:37]=[CH:38][C:32]5[O:31][C:30]([CH3:29])([CH3:44])[CH2:34][C:33]=5[CH:35]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: CC1(C)Cc2cc(/C=C/C(=O)O)ccc2O1
Agent: Cl
Product: CC1(C)Cc2cc(/C=C/C(=O)N3CCC(C(NC4CCC(c5c[nH]c6ccccc56)CC4)C(N)=O)CC3)ccc2O1

Procedure:
The title compound was prepared from the product of Example 1, step J, and (2E)-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)prop-2-enoic acid, by the method of Example 1, step K, giving a yellow solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C33H40N4O3: 541 (M+H). Found: 541
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:26]#[N:27].[Cl:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[S:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1)[NH2:32].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Cl:28][C:29]1[CH:30]=[C:31]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([N:15]4[CH2:20][CH2:19][CH:18]([N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH2:17][CH2:16]4)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:26]#[N:27])[CH:33]=[CH:34][C:35]=1[S:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1
Reactant: N#Cc1cnc2cc(N3CCC(N4CCCC4)CC3)c([N+](=O)[O-])cc2c1Cl
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c([N+](=O)[O-])cc23)cc1Cl
Temperature: 105 °C
Yield: 60.9 %

Procedure:
A mixture of 0.5 g (1.45 mmol) of 4-chloro-6-nitro-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile, 0.38 g (1.6 mmol) of 3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]aniline and 0.17 g of pyridine hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at 105° C. for 1 hour. After cooling to room temperature, the mixture is stirred with 15 mL of saturated solution of sodium bicarbonate. The resulting solid is collected by filtration and washed with water. Some of the product dissolves in water, which is recovered by extracting the aqueous layer with solution of 95:5 methylene chloride/methanol. The organic layer is evaporated to provide crude product. The combined solids are purified by silica gel chromatography (gradient 95:5methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 0.52 g of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-nitro-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as an orange solid, mp 220-230° C.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1.Cl[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]>C1COCC1>[N+:15]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[O:7][CH:5]1[CH2:6][O:3][CH2:4]1)([O-:17])=[O:16]
Reactant: OC1COC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnccc1OC1COC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
NaH (164.0 mg, 4.100 mmol) was added portionwise to a stirred solution of oxetan-3-ol (280.4 mg, 3.785 mmol) in THF (10.00 mL) to form a white suspension. The reaction mixture was stirred at ambient temperature for 10 mins then was added dropwise to a suspension of 4-chloro-3-nitro-pyridine (500 mg, 3.154 mmol) in THF (3 mL). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction was quenched with water (20 mL) and partitioned with ethyl acetate (3×20 mL). The combined organics were washed with brine, dried (MgSO4), filtered and evaporated to dryness to afford the desired product as a beige solid (499 mg, 81%). LC-MS (M+H)+ 198.1; 1H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.66 (d, J=5.9 Hz, 1H), 7.09 (d, J=5.9 Hz, 1H), 5.60 (tt, J=6.0, 4.7 Hz, 1H), 4.99 (ddd, J=7.9, 6.0, 1.1 Hz, 2H), 4.61 (ddd, J=7.7, 4.7, 1.1 Hz, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:23][CH2:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]([C:38]#[N:39])[CH:29]=1)=O)(=[O:22])[CH3:21].C[Si]([N:44]=[N+:45]=[N-:46])(C)C>C1COCC1.CCOC(C)=O>[C:20]([O:23][CH2:24][C:25]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]([C:38]#[N:39])[CH:29]=2)[N:46]=[N:45][N:44]=1)(=[O:22])[CH3:21]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OCC(=O)Nc1ccc(C(F)(F)F)c(C#N)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1nnnn1-c1ccc(C(F)(F)F)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 138.1 %

Procedure:
Triphenylphosphine (2.29 g, 8.73 mmol) and diisopropylazodicorboxylate (1.76 g, 8.70 mmol) were added to a solution of 2-{[3-cyano-4-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 38, 1.0 g, 3.49 mmol) in THF (20 mL), at 0° C. The reaction mixture was stirred for 30 min at 0° C. and trimethylsilyl azide (1.01 g, 8.77 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, and then heated to reflux for 4 h. The reaction mixture was diluted with EtOAc and washed with ice water, followed by saturated brine solution. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude compound. This was purified by column chromatography (100-200 mesh silica gel), eluting with 10%-50% EtOAc/pet.ether, to give the title compound (1.5 g, impure).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH:16]=[C:15]([CH3:22])[C:14]=2[C:13]=1[C:23]([O:25]C)=[O:24])(=[O:10])=[O:9].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>C(#N)C.C(N(CC)CC)C>[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH:16]=[C:15]([CH3:22])[C:14]=2[C:13]=1[C:23]([OH:25])=[O:24])(=[O:9])=[O:10]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(C)=CCC2
Reactant: CN(C)CCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1=CCCc2ccc(NS(=O)(=O)c3ccccc3NCCN(C)C)c(C(=O)O)c21
Yield: 103.3 %

Procedure:
A mixture of Example 275E (50 mg, 0.133 mmol), N,N-dimethylethylenediamine (117 μl, 1.06 mmol), and triethylamine (56 mL, 0.4 μmol) in 0.5 mL of acetonitrile was heated to 200° C. for 1200 seconds in a microwave oven. The obtained reaction mixture containing a crude product was purified by reverse phase column chromatography to provide 59 mg of the desired product. MS (ESI(+)) m/e 430 (M+H)+; MS (ESI(−)) m/e 428 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.48 (dd, 1H), 7.42 (d, 1H), 7.06 (d, 1H), 6.93 (d, 1H), 6.66-6.76 (m, 2H), 6.10 (t, 1H), 5.99 (t, 1H), 5.75 (s, 3H), 3.59-3.64 (m, 2H), 3.25-3.30 (m, 2H), 2.85 (m, 6H), 2.54-2.56 (m, 2H), 1.96-2.09 (m, 5H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[CH2:7][C:8](=[O:18])[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)[CH3:4].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>C1COCC1.[Cl-].[Na+].O>[CH2:3]([O:5][C:6](=[O:19])[CH:7]([C:8]([CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:14]1)=[O:18])[CH2:21][C:22](=[O:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:4]
Reactant: CCCC1CCC(C(=O)CC(=O)OCC)CC1
Reactant: O=C(CBr)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCC(C(=O)C(CC(=O)c2ccccc2)C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 115.5 %

Procedure:
To a stirred slurry of 0.92 g (23 mmol) NaH, 60% dispersion in mineral oil, in 30 mL anhydrous THF, cooled 0° C. in ice, 5.12 g (21.3 mmol) 3-oxo-3-(4-propyl-cyclohexyl)-propionic acid ethyl ester from Step 2 was added dropwise over the course of 60 min. The reaction was stirred at 0° C. for 1 hr. 2-bromoacetophenone (5.57 g, 28 mmol) in 12 mL anhydrous THF was then added dropwise at 0° C. and the reaction was allowed to stir at room temperature over 5 days. The reaction was poured into brine, extracted with ethyl acetate, dried over MgSO4, and concentrated to afford 8.85 g (24.6 mmol, 115% yield) 4-oxo-4-phenyl-2-(4-propyl-cyclohexanecarbonyl)-butyric acid ethyl ester as an oil. The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([O:13]C(N(C)C)N(C)C)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[O:13])[N:3]=1
Reactant: Cc1cccc(F)n1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccc(F)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Fluoro-6-methylpyridine (14.4 g, 0.13 mol) and tert-butoxybis(dimethylamino)methane (Bredereck's reagent; 34.9 g, 0.20 mol) are heated at 140° C. for 24 h. The reaction is cooled and diluted with THF (100 mL). Sodium periodate (75 g) in water (400 mL) is added at 0-5° C., and the reaction mixture is then stirred for 24 h at room temperature. The precipitate is filtered through celite, and the filtrate extracted 5× with diethyl ether. The combined ether layers are washed with water, brine, and dried (MgSO4). Most of the solvent is removed by concentration at 0° C. (by keeping ice in the bath) to provide 2-Fluoropyridine-6-carboxaldehyde.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([OH:26])[C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=1.[ClH:28].O1CCOCC1>CO>[ClH:28].[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([OH:26])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)(O)c1ccc(OCc2nc3ccc(OC)cc3n2C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2nc(COc3ccc(C(C)(O)C(=O)O)cc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactate (0.2 g), methanol (5 ml) and 4N hydrogen chloride/dioxane (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crystals. The crystals were washed with a mixture of methanol and ether to afford the title compound (0.2 g, mp 193-195° C.).
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].[Li][CH3:16].[BH4-].[Na+].Cl>CO.C1COCC1>[NH2:12][CH:11]([C:10]1[CH:9]=[CH:8][C:7]([C:3]2([C:1]#[N:2])[CH2:6][CH2:5][CH2:4]2)=[CH:14][CH:13]=1)[CH3:16]
Reactant: [Li]C
Reactant: N#Cc1ccc(C2(C#N)CCC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1ccc(C2(C#N)CCC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
4-(Cyanocyclobutyl)benzonitrile (335 mg, 1.84 mmol) is mixed with THF (10.0 mL) and cooled to −78° C. under N2 gas. MeLi (1.15 mL, 1.84 mmol, 1.60M in Et2O) is added, and the mixture is stirred at −78° C. for 15 minutes. A mixture of NaBH4 (70.0 mg, 1.84 mmol) in MeOH (10.0 mL) is added, and the solution is warmed to 0° C. for 1 hour. 1N HCl (40.0 mL) is added, and the solution is concentrated to dryness on the rotovaporator. The product is purified by HPLC: Gilson prep pumps, flow rate: 30 ml/min, column: Synergi Gemini (5u) 21.2×50 mm (high pH), mobile phase: A=water (10 mM NH4CO3) B=MECN, (95.0 mg, 0.475 mmol, 26%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.23 (d, J=6.64 Hz, 3H) 1.90-2.06 (m, 1H) 2.16-2.35 (m, 1H) 2.52-2.64 (m, 2H) 2.64-2.78 (m, 2H) 4.00 (q, J=6.64 Hz, 1H) 7.36 (d, J=8.59 Hz, 2H) 7.42 (d, J=8.20 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:27]=1.[C:28]([C@:30]1([OH:37])[CH2:34][CH2:33][N:32]([CH3:35])[C:31]1=[O:36])#[CH:29]>>[OH:37][C@@:30]1([C:28]#[C:29][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([NH:20][CH:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:27]=2)[CH2:34][CH2:33][N:32]([CH3:35])[C:31]1=[O:36]
Reactant: NC(=O)c1nc2n(c1C(=O)NC1CCOCC1)CCOc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)C1=O
Yield: 11 %

Procedure:
10-bromo-2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-3-carboxylic acid was reacted with tetrahydro-pyran-4-ylamine hydrochloride similarly to as described in example 2 with non-critical modifications to afford 117 mg (63%) 10-bromo-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. 10-bromo-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 14 mg (11%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[C:11]=2[C:12]#[N:13])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[Na+]>COCCOCCOC.Cl.O>[NH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([S:9][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[C:11]=1[C:12]#[N:13]
Reactant: Cc1cc(C)cc(Sc2cccc([N+](=O)[O-])c2C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Product: Cc1cc(C)cc(Sc2cccc(N)c2C#N)c1
Yield: 64 %

Procedure:
2-[(3,5-Dimethylphenyl)thio]-6-nitrobenzonitrile (Example 5) (1.0 g, 0.0035 mol) was dissolved in 50 ml of diglyme. A solution of stannous chloride-2H2O (3.16 g, 0.014 mol) in 15 ml of concentrated HCl was added dropwise with stirring. After stirring 1 h and 15 min, the reaction mixture was poured into a solution of 12 g NaOH in 100 ml of water with ice added to bring the total volume to 300 ml. The mixture was stirred for 1 h and the solid was collected by vacuum filtration. Chromatography on silica gel (flash; Hex/EtOAc 1:1) provided 0.57 g (64%) of 2-amino-6-[(3,5-dimethylphenyl)thio]benzonitrile: mp 124°-125° C.; NMR (Me2SO-d6, 300 MHz) δ 2.23 (s, H), 6.17 (br, 2H), 6.24 (apparent d, 1H), 7.00 (m, 3H), 7.09 (apparent t, 1H); mass spec (CI) 255 (M+ +1, 100%). Anal. Calc. for C15H14N2S: C, 70.83; H, 5.55; N, 11.01; S, 12.61. Found: C, 70.84; H, 5.60; N, 10.98; S, 12.53.
Reaction SMILES: C1(C)C=CC(S(O[C:11]2[C:22]3=[C:23]4[N:18]([CH2:19][CH2:20][CH2:21]3)[CH:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15](=[O:27])[C:14]4=[CH:13][CH:12]=2)(=O)=O)=CC=1.[F:29][C:30]([F:38])([F:37])[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CS(C)=O.Cl>O>[F:29][C:30]([F:38])([F:37])[N:31]1[CH2:36][CH2:35][N:34]([C:11]2[C:22]3=[C:23]4[N:18]([CH2:19][CH2:20][CH2:21]3)[CH:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15](=[O:27])[C:14]4=[CH:13][CH:12]=2)[CH2:33][CH2:32]1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c(=O)c(C(=O)O)cn4c3c2CCC4)cc1
Reactant: FC(F)(F)N1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cn2c3c(c(N4CCN(C(F)(F)F)CC4)ccc3c1=O)CCC2
Yield: 52.4 %

Procedure:
A mixture of 3.4 g of 8-(p-toluenesulfonyloxy)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of 1-trifluoromethylpiperazine and 200 ml of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 150° to 160° C. for 18 hours under nitrogen gas flow at a pressure of 10 atms. After completion of the reaction, the solvent and excessive piperazine compound were removed by distillation under reduced pressure and a mixture of methanol and ethanol was added to the residue. The precipitates formed were collected by filtration and washed with ether. The crystals obtained were suspended in a mixture of 200 ml of water and 40 ml of a 10% aqueous hydrochloric acid solution and insoluble substances were removed by filtration. The filtrate was rendered neutral with saturated aqueous solution of sodium bicarbonate and purified through column chromatography using Amberlite LH-20 (a trade name for a product of Tokyo Organic Chemical Industries Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 1.7 g of 8-(4-trifluoromethyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300° C. or more.