Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[CH3:1])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 2-methyl-4-nitroaniline (2.03 g, 13.3 mmol), triethylamine (2.00 ml, 14.6 mmol) and benzoyl chloride (1.70 ml, 14.6 mmol) were heated in toluene (50 ml) at reflux for 2 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature overnight, causing precipitation of a white solid. The solid was collected by suction filtration, washed with toluene (3×50 ml), dissolved in dichloromethane (100 ml) and washed with water (3×50 ml). Drying of the organic layer over magnesium sulphate, followed by solvent evaporation in vacuo, yielded N-benzoyl 2-methyl-4-nitroaniline (3.06 g, 90% yield) as a white solid:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:18]2[CH2:20][CH2:19]2)[CH:13]=[C:14]([F:17])[CH2:15][OH:16])=[CH:8][CH:7]=1.O>C1C=CC=CC=1.N1C=CC=CC=1>[C:1]([O:16][CH2:15][C:14]([F:17])=[CH:13][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=1)[CH:18]1[CH2:19][CH2:20]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCC(F)=CC(c1ccc(Cl)cc1)C1CC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC(F)=CC(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
Acetyl chloride (1.2 ml) was slowly added to a stirred solution of 4-(4-chlorophenyl)-4-cyclopropyl-2-fluorobut-2-enol (Example 6) (0.51 g) in benzene (30 ml) and pyridine (0.24 ml) at 0° C. and stirring was continued for 24 hours while the mixture warmed to room temperature. Water (2 ml) was added, and the mixture was extracted with diethyl ether (3×20 ml). The combined organic layers were washed with water (3×10 ml), dried and evaporated under reduced pressure. The residual oil was chromatographed on silica gel using diethyl ether/hexane (1:4) to yield 4-(4-chlorophenyl)-4-cyclopropyl-2-fluorobut-2-enyl acetate (0.46 g, 78%).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][CH:18]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CO.O.O[Li].O>C1COCC1>[F:33][C:31]([F:32])([F:34])[C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][CH2:22][C:21]([NH:20][CH:18]1[CH2:17][N:16]([CH:13]2[CH2:14][CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH2:19]1)=[O:36])=[O:35]
Reactant: COC(=O)c1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(C(=O)O)cc3)CC2)C1
Temperature: 50 °C

Procedure:
A solution of 4-(4-{3-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-azetidin-1-yl}-cyclohexyl)-benzoic acid methyl ester (less polar fraction from Example 9, 250 mg, 0.48 mmol) in THF (1 mL), MeOH (1 mL) and H2O (1 mL) was treated with LiOH.H2O (50 mg, 1.2 mmol) at room temperature. The reaction was then heated to 50° C. for 2 hours. The reaction was allowed to cool and solvent was removed in vacuo. 1 N HCl solution was added to adjust the solution to pH=6˜7. The white precipitate was collected by filtration and washed with water. The solid was dried in vacuo, re-dissolved in ethyl acetate and re-crystallization to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3cccnc3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (340 mg), 1 N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (2 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (260 mg, yield: 82%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 120–121° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[N:8]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[C:19]([N:28]3[CH:32]=[N:31][N:30]=[N:29]3)[CH:18]=2)[S:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[OH2:33]>C(OCC)(=O)C>[OH:33][C:25]([CH3:27])([CH3:26])[CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[S:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:6])[N:8]=2)=[CH:18][C:19]=1[N:28]1[CH:32]=[N:31][N:30]=[N:29]1
Reactant: O
Reactant: CCOC(=O)c1sc(-c2ccc(OC=C(C)C)c(-n3cnnn3)c2)nc1C
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)(C)O)c(-n3cnnn3)c2)nc1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution was prepared by dissolving 33.1 mg of ethyl 2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate in 1.0 mL of dimethylformamide. A reaction mixture solution prepared by adding 20.7 mg of potassium carbonate and 16.2 mg of 3-bromo-2-methylpropene to the solution was heated under stirring at 100° C. for 4 hours. The reaction mixture solution was cooled to room temperature and then 3 mL of water and 4 mL of ethyl acetate were added under stirring, followed by concentrating the organic phase to obtain 34.1 mg of ethyl 4-methyl-2-{4-[(2-methylpropen-1-yl)oxy]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate. (2) A reaction mixture solution prepared by adding 1.0 mL of 35% sulfuric acid aqueous solution to 34.1 mg of ethyl 4-methyl-2-{4-[(2-methylpropen-1-yl)oxy]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate was heated under stirring at 80° C. for 4 hours. The reaction mixture solution was cooled to room temperature and then 3 mL of water and 4 mL of ethyl acetate were added under stirring, and the organic phase was concentrated and purified using a conventional method to obtain 9.9 mg of ethyl 2-[4-(2-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([NH:20][C@H:21]([C:25](O)=O)[C@@H:22]([CH3:24])[OH:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>O1CCOCC1.CCOC(C)=O.C(=O)(O)[O-].[Na+]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:25]([C@@H:21]([NH:20][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C@H:22]([OH:23])[CH3:24])=[N:12][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-tert-butyl-1,2-diaminobenzene (375 mg, 2.28 mmol) in dioxane (4 mL) was added a solution of N-Boc-L-threonine (500 mg, 2.28 mmol) in dioxane (4 mL) followed by triethylamine (636 μL, 456 mmol) and T3P (1520 mg, 2.40 mmol). The reaction was stirred at room temperature for 10 minutes followed by heating to 100° C. for 18 hours. The reaction was cooled and diluted with EtOAc (50 mL) and saturated aqueous sodium bicarbonate solution (40 mL). The organic layer was collected, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 15-100% TBME in heptanes to afford tert-butyl [(1R,2R)-1-(5-tert-butyl-1H-benzimidazol-2-yl)-2-hydroxypropyl]carbamate.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:4][CH3:5].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=3)=[N:26][N:25]=[N:24]2)C=CC=CC=1>CN(C=O)C>[CH2:3]([O:6][C:7]1[N:8]([CH2:40][C:37]2[CH:38]=[CH:39][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:35][CH:36]=2)[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:4][CH3:5]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCOc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.24 g) was added to a stirred solution of 2-propoxybenzimidazole (0.71 g) in DMF (10 ml) under ice-cooling. The mixture was stirred for 20 minutes, to which was added N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl) tetrazole (2.3 g), followed by stirring at room temperature for 5 hours. To the reaction mixture was added ice-water, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was dissolved in methanol (50 ml), to which was added 1N-HCl (15 ml), followed by stirring at 60° C. for 2 hours. The reaction mixture was concentrated, to which were added water (15 ml) and ethyl acetate (15 ml). The mixture was made alkaline with 1N NaOH and shaken. The aqueous layer was adjusted to pH 3-4 with 1N-HCl and then extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by column chromatography on silica gel to yield crystals. Recrystallization from ethyl acetate-methanol gave colorless crystals (0.58 g, 35%), m.p. 177-179° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br[C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:16]=1[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>[N+](C1C=CC=CC=1)([O-])=O.[Cu]=O>[C:17]([C:16]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:15]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:2]([CH3:1])=[N:3]1)([OH:19])=[O:18]
Reactant: COc1cccc(Br)c1C(=O)O
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: COc1cccc(-n2nc(C)c3ccc([N+](=O)[O-])cc32)c1C(=O)O
Yield: 75.9 %

Procedure:
3-Methyl-6-nitroindazole (5.31 g), 6.93 g of 2-bromo-6-methoxybenzoic acid, 4.71 g of potassium carbonate and 0.218 g of copper (II) oxide were stirred in 60 ml of nitrobenzene at 180° C. for 50 minutes. After cooling, 300 ml of water was added to the reaction mixture, and the insoluble substance was removed by filtration. The resulting solution was washed with chloroform. The aqueous layer was decolored with active charcoal and filtered, and 40 ml of 1 N hydrochloric acid aqueous solution was added to the filtrate. The crystals precipitated were separated by filtration and dried under reduced pressure to obtain 7.45 g (75.9%) of 1-(2-carboxy-3-methoxyphenyl)-3-methyl-6-nitroindazole.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:5][N:4]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:3]1=[O:27].Br[CH:29]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(OCC)(=O)C>C(Cl)Cl>[CH2:33]([O:32][C:30]([CH:29]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:5][N:4]([CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C:3]1=[O:27])[CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccc3ccccc3c2)SCC(N)C1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccc3ccccc3c2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
0.85 g of t-butyl α-[6-amino-2-(2-naphthyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above] was subjected to N-alkylation with 1.08 g of ethyl 2-bromo-4-phenylbutyrate in the same manner as described in Example 36(h). The reaction product was subjected to silica gel column chromatography, using a 1:30 by volume mixture of ethyl acetate and methylene chloride, to separate it into two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:43]([O:45][C:46]1[CH:67]=[CH:66][CH:65]=[CH:64][C:47]=1[O:48][C@@H:49]1[CH2:54][CH2:53][CH2:52][N:51]([C:55]2[N:60]=[CH:59][C:58]([C:61](O)=[O:62])=[CH:57][N:56]=2)[CH2:50]1)[CH3:44]>C1COCC1.CS(C)=O>[CH2:43]([O:45][C:46]1[CH:67]=[CH:66][CH:65]=[CH:64][C:47]=1[O:48][C@@H:49]1[CH2:54][CH2:53][CH2:52][N:51]([C:55]2[N:60]=[CH:59][C:58]([C:61]([NH:2][CH2:3][C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])=[O:62])=[CH:57][N:56]=2)[CH2:50]1)[CH3:44]
Reactant: COC(=O)c1cccc(CN)c1
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cccc(C(=O)OC)c3)cn2)C1
Temperature: 15 °C
Reaction time: 4 h
Yield: 74.5 %

Procedure:
To a 500-mL 3-neck flask was added methyl 3-(aminomethyl)benzoate hydrochloride (12.9 g, 64.1 mmol) followed by DMSO (26 mL). The solution was cooled to 15° C. N-Methyl morpholine (27 mL, 240 mmol) was added followed by EDCl (13 g, 68 mmol) and HOBT (4.09 g, 30 mmol), maintaining the temperature at 15° C. A solution of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (20.94 g, 60.98 mmol) in THF (100 mL) was added dropwise over 10 min. The reaction mixture was warmed to 20-25° C. and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water (200 mL) and pentane-ethyl acetate (1:2, 300 mL). The aqueous phase was further extracted with ethyl acetate (2 times with 100 mL). The combined organic extracts were rinsed sequentially with water (200 mL), saturated aqueous sodium bicarbonate solution (2 times with 100 mL), and brine (2 times with 25 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated to afford (R)-methyl 3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoate (22.3 g). MS (ES+) 491.3 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:6]([CH:7]=[CH:8][C:9]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:18][CH:17]=[C:11]4[NH:12][C:13](=[O:16])[C:14]=2[C:10]=34)=[C:5]([N+:26]([O-])=O)[CH:4]=[CH:3]1.[Cl-].[NH4+].O>O1CCCC1.C(O)C.[Zn]>[NH2:26][C:5]1[CH:4]=[CH:3][N:2]([CH3:1])[C:15]2[C:6]=1[CH:7]=[CH:8][C:9]1[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:18][CH:17]=[C:11]3[NH:12][C:13](=[O:16])[C:14]=2[C:10]=13
Reactant: CN1C=CC([N+](=O)[O-])=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccccn1
Yield: 88.5 %

Procedure:
A mixture of Example 82c (0.09 g, 0.241 mmol), zinc dust (0.236 g, 3.62 mmol) and ammonium chloride (0.129 g, 2.411 mmol) in tetrahydrofuran (2.6 mL), ethanol (1.3 mL), and water (0.65 mL) was stirred at ambient temperature for 1 hour and then filtered to remove the solid. The filtrate was concentrated and then slurried in water. The solid was collected by filtration and dried in a vacuum oven at 70° C. to give 0.0732 g (88%) of the title compound as an impure mixture.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([CH3:17])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:18](=O)[CH3:19].[CH3:21][C:22]1[N:23]=[C:24]([C:30]2S[CH:32]=[CH:33][CH:34]=2)S[C:26]=1[C:27](=O)[CH3:28].[NH3:35]>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([CH3:17])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:18]1[CH:19]=[CH:18][C:3]2[C:2](=[CH:32][CH:33]=[C:34]([CH2:30][CH2:24][N:23]3[CH2:28][CH2:27][CH2:26][C@H:22]3[CH3:21])[CH:4]=2)[N:35]=1
Reactant: CC(=O)c1sc(-c2cccs2)nc1C
Reactant: N
Reactant: CC(=O)c1cnn(-c2cc(C(F)(F)F)cc(C)n2)c1C
Product: Cc1cc(C(F)(F)F)cc(-n2ncc(-c3ccc4cc(CCN5CCC[C@H]5C)ccc4n3)c2C)n1

Procedure:
The title compound was prepared using the procedure described in Example 1G using 1-[5-methyl-1-(6-methyl-4-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-ethanone (Maybridge Chemical Company Ltd., catalog number CD 11385) for 1-(4-methyl-2-thiophen-2-yl-thiazol-5-yl)-ethanone. 1H NMR (300 MHz, CDCl3) δ 1.15 (d, J=6.10 Hz, 3H), 1.49 (m, 1H), 1.79 (m, 2H), 1.96 (m, 1H), 2.27 (m, 1H), 2.43 (m, 2H), 2.68 (s, 3H), 3.05 (m, 2H), 3.11 (s, 3H), 3.15 (m, 1H), 3.32 (m, 1H), 7.30 (s, 1H), 7.61 (m, 3H), 8.01 (s, 1H), 8.03 (d, J=8.48 Hz, 1H), 8.12 (d, J=8.14 Hz, 1H), 8.14 (s, 1H); MS (DCI-NH3) [M+H]+ at 480.
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]([F:16])([F:15])[C@:5]([C:9]1[S:13][C:12]([SH:14])=[N:11][CH:10]=1)(O)[CH2:6][CH3:7].Br[C:18]1[CH:27]=[C:26]2[C:21]([C:22]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][C:24](=[O:28])[O:25]2)=[CH:20][CH:19]=1>CO.CN1C(=O)CCC1>[OH:1][CH2:7][CH2:6][C@@H:5]([C:9]1[S:13][C:12]([S:14][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:23][C:24](=[O:28])[O:25]3)=[CH:20][CH:19]=2)=[N:11][CH:10]=1)[C:4]([F:16])([F:15])[F:3]
Reactant: [OH-]
Reactant: CC[C@](O)(c1cnc(S)s1)C(F)(F)F
Reactant: O=c1cc(-c2cccnc2)c2ccc(Br)cc2o1
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: O=c1cc(-c2cccnc2)c2ccc(Sc3ncc([C@H](CCO)C(F)(F)F)s3)cc2o1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
KOH (0.223 g, 3.97 mmol) was added to a solution of (2R)-1,1,1-trifluoro-2-(2-mercapto-1,3-thiazol-5-yl)butan-2-ol (0.966 g, 3.97 mmol) in dry MeOH. When a solution was obtained, the reaction mixture was concentrated to dryness. Dry toluene was then added and the mixture was concentrated to dryness again. The residue was dissolved with 7-bromo-4-pyridin-3-yl-2H-chromen-2-one (1.0 g, 3.31 mmol) in NMP, and the resulting mixture was stirred at 120° C. for 16 h. Once cooled, the mixture was directly applied onto a column of silica gel and chromatographed (acetone/toluene; 5:95 to 15:85), affording the title compound. 1H NMR (400 MHz, CDCl3): δ 8.81 (dd,1H), 8.72 (dd, 1H), 7.82 (dt, 1H), 7.78 (s, 1H), 7.51-7.59 (m, 2H), 7.33-7.40 (m, 2H), 6.42 (s, 1H), 2.88 (br s, 1H), 2.12 (q, 2H), 0.99 (t, 3H).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1>CO>[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1](=[O:10])[O:2]2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccncc1
Reactant: O=C1OCc2ccccc21
Solvent: CO
Product: O=C1OC(=Cc2ccncc2)c2ccccc21

Procedure:
In accordance with the procedure described in Lombardino, J.O.C. Vol. 32, pp. 1988-1992 (1967), a solution of isobenzofuran-1-one (13.4 g, 0.1 mol) and 4-pyridine carboxaldehyde (10.7 g, 0.1 mol) in 100 ml dry methanol are refluxed for 2 hours. The solvent is evaporated, and the product (3-(4-pyridylmethylene)isobenzofuran-1-one is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A flame dried flask charged with (S)-2-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 5 mmol), dichloromethane (DCM) (20 mL) and triethylamine (0.70 mL, 5.2 mmol) is cooled to 0° C. under N2 is added a solution of methanesulfonylchloride (0.38 mL, 5 mmol) in DCM (5 mL) dropwise over 10 minutes. The reaction is stirred for 1 hour. After addition of DCM (100 mL), the reaction mixture is washed with brine, dried and concentrated in vacuo. The residue is purified by chromatography on SiO2 (5% EtOAc/Hexanes) to give 1.38 g of methanesulfonate ester (P) as a clear colorless oil: LCMS (ES) 280.10 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[Cl:51][C:52]1[CH:62]=[CH:61][C:55]([O:56][CH2:57][CH2:58]CO)=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:58][CH2:57][O:56][C:55]2[CH:61]=[CH:62][C:52]([Cl:51])=[CH:53][CH:54]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OCCCOc1ccc(Cl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCOc4ccc(Cl)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 63.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (115 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-chlorophenoxy)-1-propanol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (84 mg, yield 60%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.C(O)(=O)C.[Br:37]Br.C(O)(=O)C>O>[Br:37][C:7]1[C:2]([OH:1])=[C:3]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[C:4]2=[N:5][CH:6]=1
Reactant: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(O)ccnc32)CC1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c2ncc(Br)c3O)CC1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of the title compound from Example 263 (0.34 grams) and glacial acetic acid (10 mL) was added a 0.7 M bromine-acetic acid solution (4 mL) at 25° C. under N2. After 10 minutes, water was added and the resulting solid was filtered and washed with water several times and dried to give the title compound (Yield 0.31 grams, 67%, MH+ 527).