Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][C:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45]C(C(O)=O)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CN(C)C=O>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:21]([C:20]([NH:19][C:14]3[CH:13]=[CH:12][C:11]4[CH:10]=[C:9]([CH2:8][CH2:7][N:2]5[CH2:6][CH2:5][CH2:4][CH2:3]5)[CH2:18][CH2:17][C:16]=4[CH:15]=3)=[O:22])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
Concentrated hydrochloric acid (2 ml) was added to N-[6-[2-(1-pyrrolidinyl)ethyl]-7,8-dihydro-2-naphthalenyl]acetamide (98.0 mg, 0.345 mmol) obtained in Reference Example 103, which was stirred at 100° C. for 16 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. WSC (62.5 mg, 0.326 mmol) was added to a dimethylformamide solution (1.5 ml) of the resulting oily substance (79.0 mg, 0.326 mmol), 4′-fluoro-[1,1′-biphenyl]-4-carboxylic acid (64.6 mg, 0.326 mmol) and DMAP (39.8 mg, 0.326 mmol) under ice-cooling, which was stirred at room temperature for 1 day. Ethyl acetate was added to the reaction mixture, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resulting residue was purified by aluminum column chromatography (development solvent; ethyl acetate), powdered with ethyl acetate-isopropyl ether (1:5), to give the titled compound (75.1 mg).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=1.[NH:13]1[CH:17]=C(C#N)C=N1>>[C:17]([C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=1)#[N:13]
Reactant: O=C(O)C1(n2cc(F)cn2)CC1
Reactant: N#Cc1cn[nH]c1
Product: N#Cc1cnn(C2(C(=O)O)CC2)c1

Procedure:
The title compound was prepared by a method analogous to Intermediate 4 but using 1H-pyrazole-4-carbonitrile in Step 1. 1H NMR (400 MHz, CDCl3) δ 1.65 (m, 2H), 1.89 (m, 2H), 7.80 (s, 1H), 8.02 (s, 1H); MS (ES−) (M−H) 176.4, LCMS retention time: 1.04 minutes (Method M).
Reaction SMILES: C([O:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=O)C.C([O-])([O-])=O.[K+].[K+].O>CO>[OH:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1
Reactant: CC(=O)OC1CCCc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 8-acetoxy-5,6,7,8-tetrahydroquinoline (99.2 g) in methanol (450 mL) was added K2CO3 (144 g, 1.04 mol) and the mixture was stirred at room temperature overnight. The mixture was poured into water (500 mL) and extracted with CHCl3 (3×500 mL) and the combined organic extracts were dried (Na2SO4), and concentrated to provide 71.6 g of 8-hydroxy-5,6,7,8-tetrahydroquinoline as a brown oil. A purified sample (silica gel, 25:1 CH2Cl2-CH3OH) exhibited the following spectral properties: 1H NMR (CDCl3) δ 1.75-1.89 (m, 2H), 1.96-2.06 (m, 1H), 2.25-2.33 (m, 1H), 2.74-2.90 (m, 2H), 4.23 (br s, 1H, OH), 4.72 (dd, 1H J=7.8, 6.3 Hz), 7.12 (dd, 1H, J=7.5, 4.8 Hz), 7.41 (d, 1H, J=7.5 Hz), 8.41 (d, 1H, J=4.8 Hz); 13C NMR (CDCl3) δ 19.60, 28.84, 31.27, 68.87, 122.74, 132.19, 137.40, 147.06, 158.50. ES-MS m/z 150 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:27][C:28]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([O:21][Si:31]([C:28]([CH3:30])([CH3:29])[CH3:27])([CH3:33])[CH3:32])[CH2:17][CH2:16]1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CC1CCC(O)CC1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of the (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-hydroxycyclohexyl)propanoate (96.56 g, 0.32 mol) in CH2Cl2 (500 mL) was added imidazole (43.52 g, 0.64 mol), followed by TBSCl (72 g, 0.48 mol) at 0° C. After addition, the mixture was allowed to stir at rt overnight. The reaction mixture was treated with water and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered, and evaporated to give (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-(tert-butyldimethylsilyloxy)cyclohexyl)propanoate (133 g, yield 100%). 1H NMR: (CDCl3, 400 MHz) δ 0.08 (d, 6H), 0.89 (d, 9H), 1.45 (s, 9H), 1.51 (m, 4H), 1.58 (m, 1H), 1.68 (t, 4H), 1.85 (d, 1H), 3.71 (d, 3H), 3.91 (m, 1H), 4.34 (m, 1H), 4.86 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[C:2]1=[O:10]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1
Reactant: O=C1Cc2cccnc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ncccc43)ncnc2cc1OCCn1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of 7-azaoxindole (165 mg, 1.23 mmol), (prepared as described for the starting material in Example 2), in DMF (3 ml) was added dropwise to a suspension of sodium hydride (50 mg, 1.23 mmol, prewashed with hexane) in DMF (3 ml). After stirring for 30 minutes at ambient temperature, 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (125 mg, 0.41 mmol) in DMF (3 ml) was added. The mixture was heated at 65° C. for 30 minutes. After cooling the mixture was partitioned between saturated aqueous ammonium chloride and methylene chloride. The precipitate was collected by filtration, dried and purified by flash chromatography eluting with methylene chloride/methanol (8/2). After evaporation of the solvent, the solid was dissolved in methylene chloride/methanol and 2.2 M hydrogen chloride in ether was added. After stirring for 10 minutes at ambient temperature, the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(7-azaoxindol-3-yl)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (110 mg, 53%).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Se](=O)(O)[OH:13].O1CCOCC1>O>[CH:8]([C:9]([CH:10]=[O:13])=[O:11])=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[Se](O)O
Reactant: CC(=O)C=Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)C=Cc1ccccc1

Procedure:
A solution containing 100 parts of 4-phenyl-3-buten-2-one, 106 parts of selenous acid, 160 parts of dioxane and 20 parts of water is heated to the reflux temperature. After the initial vigorous reaction has subsided, the mixture is heated at that temperature for an additional 30 minutes. The supernatant is then decanted from the metallic selenium and is concentrated under reduced pressure. Distillation of the residue under reduced pressure affords, as a yellow oil, styrylglyoxal, boiling at about 120° at 2.5 mm. pressure.
Reaction SMILES: C(OC([N:8]1[C@@H:16]2[C@H:11]([C@H:12]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])=[C:21]([F:36])[CH:20]=3)[CH2:13][S@:14](=[O:17])[CH2:15]2)[O:10]C1(C)C)=O)(C)(C)C>C(Cl)Cl>[CH2:29]([O:28][C:26](=[O:27])[NH:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:12]2[C@H:11]([OH:10])[C@@H:16]([NH2:8])[CH2:15][S@@:14](=[O:17])[CH2:13]2)=[CH:20][C:21]=1[F:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]2C[S@@](=O)C[C@@H](Cc3ccc(NC(=O)OCc4ccccc4)c(F)c3)[C@@H]2OC1(C)C
Solvent: ClCCl
Product: N[C@H]1C[S@@](=O)C[C@@H](Cc2ccc(NC(=O)OCc3ccccc3)c(F)c2)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3aR,5S,7S,7aS)-7-(4-benzyloxycarbonylamino-3-fluoro-benzyl)-2,2-dimethyl-5-oxo-hexahydro-1-oxa-5lambda*4*-thia-3-aza-indene-3-carboxylic acid tert-butyl ester (11.0 g, 20.1 mmol) in CH2Cl2 (80 mL) was slowly added under cooling TFA (15.5 mL, 201 mmol) and the reaction mixture was stirred for 3 h at 25° C. The reaction mixture was evaporated to dryness and the dried residue was titurated with diisopropylether. The title compound was obtained after filtration and drying as a light yellow solid: UPLC RtD=1.077 min; RtE=0.990 min; ESIMS [M+H]+=407; 1H NMR (400 MHz, CD3OD): δ 7.76 (m, 1H), 7.35 (m, 5H), 7.05 (m, 2H), 5.19 (s, 2H), 3.64 (dt, 1H), 3.41 (t, 1H), 3.34 (m, 1H), 3.25 (m, 2H), 2.82 (t, 1H), 2.57 (m, 2H), 2.01 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:36]2[CH:37]=[CH:38][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=S(=O)(Oc1ccc(-c2c(Cc3ccccc3)oc3ccccc23)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
To a stirred solution of the triflate (from example 10) (9.35 g, 21.6 mmol) and tetrakis-(triphenylphosphine)palladium(0) (750 mg, 0.65 mmol) in toluene (70 mL) was added a solution of 4-formylphenylboronic acid (4.06 g, 27.05 mmol) in ethanol (20 mL) and 2N sodium carbonate (21.6 mL, 43.2 mmol). The resulting suspension was stirred at 100° C. for 4 hrs (TLC control). The reaction was cooled, diluted with water (50 mL) and extracted with diethyl ether (3×100 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting brown solid was redissolved in tetrahydrofuran (50 mL). 2N Hydrochloric acid (10 mL) was added and the resulting solution was stirred at room temperature for 1 hour, and then diluted with water (50 mL) and extracted with diethyl ether (3×100 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 20% ethyl acetate in heptane as eluent, afforded the title compound as a white solid (7.34 g, 88%).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[C:10]1=[N:11][NH:12][C:13](=[O:15])[CH2:14][CH:9]1[CH2:8]2)(=O)C.C(O)C>O.NN>[NH2:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[C:10]1=[N:11][NH:12][C:13](=[O:15])[CH2:14][CH:9]1[CH2:8]2
Reactant: CC(=O)Nc1ccc2c(c1)CC1CC(=O)NN=C21
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CC1CC(=O)NN=C21
Yield: 33 %

Procedure:
7-Acetamido-4,4a-dihydro-[5H]-indeno[1,2-c]pyridazin-3[2H]-one (1.50 g) was suspended in hydrazine hydrate (30 ml ) and heated under reflux with ethanol (5 ml ) for 2 hours. The solution was filtered through diatomaceous earth, allowed to cool, then extracted into chloroform. The combined organic extracts were dried over magnesium sulphate and concentrated. Recrystallisation of the crude product from n-propanol gave 7-amino-4,4a-dihydro-[5H]-indeno[1,2-c]pyridazin-3[2H]-one (0.41 g, m.p. 244°-245° C.) as a pale yellow powder; ν(Nujol mull) 3400, 3320, 3220, 1652, 1635, 1600, and 1580cm-1 ; δ(DMSO-d6) 2.50 (3H,m,4-H,5-H2), 3.05 (1H,m,4a-H), 5.67 (2H,s(br),NH2), 6.55 (2H,m,6,H-H), 7.27 (1H,d,9-H).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH3:14][C:15]1[C:20]([CH3:21])=[C:19]([Cl:22])[C:18]([F:23])=[CH:17][N+:16]=1[O-].[OH-].[Na+]>ClCCl>[OH:4][CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([Cl:22])[C:18]([F:23])=[CH:17][N:16]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(Cl)c(F)c[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(CO)ncc(F)c1Cl
Reaction time: 16 h

Procedure:
Trifluoroacetic anhydride (9.7 ml) in dichloromethane (20 ml) was added dropwise to a solution of 2,3-dimethyl-4-chloro-5-fluoropyridine-N-oxide (4.0 g) in dichloromethane (35 ml) at 10°-15°. After 16 hours at room temperature, the mixture was poured onto ice and stirred for 15 minutes. After basifying (NaOH) to pH 13, the dichloromethane was separated, dried (K2CO3) and evaporated to dryness to yield 2-hydroxymethyl-3-methyl-4-chloro-5-fluoropyridine which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[C:15]([NH2:16])=[CH:14][C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12]2)[CH:6]=1)[CH3:2].[Cl:22][C:23]([Cl:47])([Cl:46])[CH2:24][O:25][C:26](=[O:45])NC1N(C2C=CC=C(CO)C=2)N=C(C(C)(C)C)C=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[C:15]([NH:16][C:26]([O:25][CH2:24][C:23]([Cl:47])([Cl:46])[Cl:22])=[O:45])=[CH:14][C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12]2)[CH:6]=1)[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CO)c2)n1
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2N)c1
Product: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1

Procedure:
The title compound was prepared from Intermediate 29a using an analogous procedure to that described for Intermediate 29c. LCMS (Method 3): Rt 4.67 min, m/z 462, 464 [MH+].
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH:13](O)=[O:14]>>[CH3:1][N:2]([CH2:3][CH:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:13]=[O:14]
Reactant: O=CO
Reactant: CCCCCC(CCC)CNC
Product: CCCCCC(CCC)CN(C)C=O
Temperature: 60 °C

Procedure:
A total amount of 846 g (4.81 moles) of N-methyl-N-(2-propylheptyl)-amine was added to a 2 l round bottomed flange flask equipped with a condenser. Formic acid was charged into a dropping funnel in an amount of 223.3 g (4.80 moles) and added drop wise to the round bottomed flange flask over a time period of 1 hour during heating and stirring with a magnetic stirrer. The final temperature was set to 180° C., while the boiling point of the initial reaction mixture was ˜125° C. Water was distilled off and collected in a round bottomed receiver flask and thereby removed from the reaction medium. During the reaction the boiling point of the reaction medium rose continuously. The reaction was performed at atmospheric pressure for a total time of 3.5 hours. Titration of remaining amine was performed to monitor the reaction. When the amine value did not decrease anymore, the remaining unreacted material was removed by gently pulling vacuum to 100 mbar for two hours. The reaction mixture was cooled to 60° C. before breaking the vacuum.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.[C:16]1([CH:22]([NH2:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]([C:10](=[O:12])[NH:33][CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[CH3:13])=[O:7])=[CH:14][CH:15]=1
Reactant: NC(c1ccccc1)c1cccc(C(F)(F)F)c1
Reactant: C[C@H](NC(=O)c1ccc(F)cc1)C(=O)O
Product: C[C@H](NC(=O)c1ccc(F)cc1)C(=O)NC(c1ccccc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from (S)-2-(4-fluoro-benzoylamino)-propionic acid (CA [214629-12-6]) and rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92-1]).
Reaction SMILES: [C:1](=NO)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(C1C=CC(SC2C=C(C3(OC)CC[O:36]CC3)C=C(F)C=2)=CC=1)C>>[C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)Cl)cc3)c2)CCOCC1
Reactant: ON=C(c1ccccc1)c1ccccc1
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 38 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reactants were heated to 60° C. for 2 hours, benzophenone oxime was reacted with 4-{3-[4-(1-chloroethyl)phenylthio]-5-fluorophenyl}-4-methoxytetrahydropyran to give benzophenone O-}4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyl}oxime as an oil in 38% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:24])[C:8]([CH2:22][CH3:23])=[C:9]([C:20]#[N:21])[C:10]=1B1OC(C)(C)C(C)(C)O1)=[O:5])[CH3:2].Br[C:26]1[CH:41]=[CH:40][CH:39]=[CH:38][C:27]=1[O:28][CH2:29][CH2:30][NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:24])[C:8]([CH2:22][CH3:23])=[C:9]([C:20]#[N:21])[C:10]=1[C:40]1[CH:41]=[CH:26][C:27]([O:28][CH2:29][CH2:30][NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])=[CH:38][CH:39]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(B2OC(C)(C)C(C)(C)O2)c(C#N)c(CC)n1C
Reactant: CC(C)S(=O)(=O)NCCOc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(OCCNS(=O)(=O)C(C)C)cc2)c(C#N)c(CC)n1C
Yield: 99.2 %

Procedure:
Prepare the title compound in a manner analogous to the procedure set forth in Example E-281, using 4-cyano-5-ethyl-1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (478 mg, 1.4 mmol, prepared in preparation 50), N-[2-(bromo-phenoxy)-ethyl]-i-propanesulfonamide (385 mg, 1.2 mmol, prepared in preparation 82), aqueous sodium carbonate (3.0 mL, 6.0 mmol, 2N), and [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II) complex with methylene chloride (1:1) (30 mg, 0.04 mmol) to give 533 mg (99%) of the title compound. Mass spectrum (ES+)=446.1 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:12]2[CH2:16][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[N:14]=[CH:13]2)=[C:6]2[CH:10]=[C:9](Cl)[O:8][C:7]=12.CC1(C)C(C)(C)OB([C:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43]#[N:44])=[CH:40][CH:41]=3)[NH:36][CH:35]=2)O1>>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[CH:16]=[C:12]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[C:7]4[O:8][C:9]([C:34]5[C:42]6[C:37](=[CH:38][C:39]([C:43]#[N:44])=[CH:40][CH:41]=6)[NH:36][CH:35]=5)=[CH:10][C:6]=34)[CH:13]=[N:14]2)[CH2:18][CH2:19]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCC(N2CC(c3cnc(N)c4oc(Cl)cc34)C=N2)CC1
Reactant: CC1(C)OB(c2c[nH]c3cc(C#N)ccc23)OC1(C)C
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5c[nH]c6cc(C#N)ccc56)cc34)cn2)CC1
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield from 1-{4-[4-(7-amino-2-chloro-furo[2,3-c]pyridin-4-yl)-4,5-dihydro-pyrazol-1-yl]-piperidin-1-yl}ethanone and 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-6-carbonitrile by a procedure analogous to Example 213. 1H NMR (600 MHz, CD3OD): δ 1.99-2.02 (m, 2H), 2.12 (s, 3H), 2.14-2.24 (m, 2H), 2.84-2.88 (m, 1H), 3.29-3.38 (m, 1H), 4.07-4.11 (m, 1H), 4.52-4.54 (m, 1H), 4.67-4.70 (m, 1H), 7.25 (s, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.84 (s, 1H), 7.89 (s, 1H), 7.92 (s, 1H), 8.15 (s, 1H), 8.25 (s, 1H), 8.39 (d, J=8.0 Hz, 1H); MS (ESI): 466 [M+H]+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[N+:10]([C:13]1[CH:14]=[C:15]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH2:25]O)[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11].CS([Cl:31])(=O)=O.O>ClCCl>[Cl:31][CH2:25][C:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cccc(C2=C(CO)CCCC2)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(C2=C(CCl)CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (3.64 mL) was added to a solution of [2-(3-nitrophenyl)cyclohex-1-enyl]methanol obtained in Preparation Example 4-(2) (1.67 g) in dichloromethane (109 mL) in an ice bath. Then, methanesulfonyl chloride (668 μL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.56 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18](O)[N:17]=1.C(N(CC)CC)C>ClCCl>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[N:17]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cc2ccccc2cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1cc2ccccc2cn1)C(F)(F)F
Reaction time: 0.67 h
Yield: 96.4 %

Procedure:
Add trifluoromethanesulfonic anhydride (383 μL, 2.3 mmol) dropwise to a suspension of isoquinolin-3-ol (274 mg, 1.89 mmol) and triethylamine (524 μL, 3.8 mmol) in dichloromethane (12 mL). Stir for 40 min, then load onto a silica column and elute with dichloromethane to give trifluoro-methanesulfonic acid isoquinolin-3-yl ester as a white solid (505 mg, 97%).
Reaction SMILES: [C:1]([N:4]([CH2:24][C@@H:25]1[O:29][C:28](=[O:30])[N:27]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]3)=[C:33]([F:45])[CH:32]=2)[CH2:26]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:23])[C@H:11]([NH:15]C(OC(C)(C)C)=O)[CH:12]([CH3:14])[CH3:13])=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.C1COCC1.[ClH:59]>O1CCOCC1>[ClH:59].[C:1]([N:4]([CH2:24][C@@H:25]1[O:29][C:28](=[O:30])[N:27]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:42][CH2:41][S:40](=[O:43])(=[O:44])[CH2:39][CH2:38]3)=[C:33]([F:45])[CH:32]=2)[CH2:26]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:23])[C@H:11]([NH2:15])[CH:12]([CH3:13])[CH3:14])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: COc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@H](N)C(C)C
Yield: 51 %

Procedure:
Following general procedure G, 2(R)-tert-Butoxycarbonylamino-3-methyl-butyric acid (acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamoyloxy)-methyl ester (12d) (0.89 g, 1.35 mmol), anisole (0.12 mL), THF (25 mL), and 4 M HCl in dioxane (10 mL) gave the title compound in 51% yield (0.41 g). 1H NMR (400 MHz, DMSO): δ 8.52 (br s, 3H), 7.47 (dd, 1H), 7.39 (t, 1H), 7.28 (dd, 1H), 5.98 (d, 1H), 5.93 (d, 1H), 4.80 (m, 1H), 4.14 (m, 2H), 4.03 (d, 1H), 3.90 (dd, 1H), 3.82 (dd, 1H), 3.39 (m, 2H), 3.20 (tt, 1H), 3.10 (m, 2H), 2.47 (s, 3H), 2.17 (m, 3H), 2.04 (m, 2H), 0.98 (d, 3H), 0.96 (d, 3H), MS-APCI (m/z+): 558.