Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29](Cl)[CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2cccc(Cl)c2)C1
Reactant: C1CCNC1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2cccc(N3CCCC3)c2)C1

Procedure:
The title compound, MS: m/e=547.4 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(3-chloro-phenyl)-4-phenyl-piperidin-1-yl]-methanone, pyrrolidine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:25])[CH2:13][C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](O)=[O:21])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)[Cl:27]>O1CCCC1.S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:25])[CH2:13][C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([Cl:27])=[O:21])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: CC(Cc1ccc(OCC(=O)O)cc1)NS(=O)(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(Cc1ccc(OCC(=O)Cl)cc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
1.15 g 4-[2-(4-chlorophenyl)sulfonylaminopropyl]phenoxyacetic acid are dissolved in a mixture of 7 ml of methylene chloride and 7 ml of tetrahydrofuran, and 2.2 ml of thionyl chloride are added thereto. After the mixture is refluxed for 2 hours, the solvent is distilled off to give 4-[2-(4-chlorophenyl)sulfonylaminopropyl]phenoxyacetyl chloride as ocherous oil. The product obtained above is dissolved in 10 ml of tetrahydrofuran. The solution and 6 ml of 0.6N an aqueous sodium hydroxide solution are added dropwise to a mixture of 787 mg of 6-aminohexanoic acid, 11 ml of 0.6N an aqueous sodium hydroxide solution, 20 ml of ethanol and 10 ml of ether under stirring at the same time. After the mixture is stirred at room temperature overnight, 50 ml of water and 50 ml of ether are added thereto. The aqueous layer is made acidic with 10% hydrochloric acid, extracted with ethyl acetate, washed, dried, filtered, and evaporated to remove the solvent. Thus obtained pale yellow caramel is purified by silica gel column chromatography (solvent; chloroform, then chloroform: methanol=9:1) to give 1.50 g of 6-{ 4-[2-(4-chlorophenyl)sulfonylaminopropyl]phenoxyacetylamino}-n-hexanoic acid as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([CH2:13][OH:14])[CH2:5]2.CCN(C(C)C)C(C)C.[C:24]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:30][CH2:29]1)(=[O:27])[CH:25]=[CH2:26].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:14][CH2:13][CH:6]1[CH2:5][C:4]2[C:9](=[N:10][CH:11]=[C:2](/[CH:26]=[CH:25]/[C:24]([N:28]3[CH2:33][CH2:32][CH:31]([CH2:34][O:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH2:30][CH2:29]3)=[O:27])[CH:3]=2)[NH:8][C:7]1=[O:12]
Reactant: O=C1Nc2ncc(Br)cc2CC1CO
Reactant: C=CC(=O)N1CCC(COc2ccc(F)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ncc(/C=C/C(=O)N3CCC(COc4ccc(F)cc4)CC3)cc2CC1CO
Temperature: 100 °C
Reaction time: 48 h
Yield: 5.8 %

Procedure:
To a suspension of 6-bromo-3-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (10 mg, 0.039 mmol; which may be prepared as described in Step 2) in DMF (200 μL) and proprionitrile (200 μL) under Argon were added DIPEA (8 μL, 0.047 mmol), 1-acryloyl-4-[(4-fluorophenoxy)methyl]piperidine (14 mg, 0.053 mmol; which may be prepared as described in Step 1), tri(o-tolyl)phosphine (2 mg, 0.008 mmol) and palladium acetate (1 mg, 0.004 mmol). The mixture was stirred at 100° C. for 2 days, then was allowed to come back to room temperature, filtered through Celite pad. The residue obtained after concentration of the filtrate was purified by preparative TLC (eluent: DCM/MeOH 9/1) to give the title compound as a white solid (1 mg, 6%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH3:27])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:24](=[O:25])[CH:23]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH:16]=[CH:15][N:14]=[CH:13]3)[CH3:27])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(tert-butyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 347 (M+H)+; MS (ESI−) m/z 345 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.56 (d, J 7.1, 3H), 4.22 (d, J 6.1, 2H), 4.57 (q, J 7.1, 1H), 7.10 (d, J 8.5, 2H), 7.29 (d, J 8.5, 2H), 7.98 (t, J 7.5, 1H), 8.13 (d, J 7.1, 1H), 8.34 (d, J 7.8, 1H), 8.56 (d, J 6.8, 1H), 8.69 (m, 2H), 9.78 (s, 1H); Anal. Calcd for C23H26N2O+1.1HCl: C, 71.46; H, 7.07; N, 7.25. Found: C, 71.13; H, 7.17; N, 7.02.
Reaction SMILES: N[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH2:16][C@@H:17]([C:28]([OH:30])=[O:29])[CH2:18]C1C2C(=CC=CC=2)NC=1.C([O-])(=O)C(C)=O>>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][C:2](=[O:29])[C:13]([O-:15])=[O:14])=[CH:5]1.[NH2:16][C@@H:17]([C:28]([OH:30])=[O:29])[CH3:18]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CC(=O)C(=O)[O-]
Product: C[C@@H](N)C(=O)O
Product: O=C([O-])C(=O)Cc1c[nH]c2ccccc12

Procedure:
In a specific embodiment, L-tryptophan is converted to D-tryptophan using a tryptophan racemase. D-tryptophan then reacts with pyruvate via a broad specificity D-aminotransferase to produce indole-3-pyruvate and D-alanine. Indole-3-pyruvate then reacts with an R-specific aldolase and pyruvate to form R-α-keto acid monatin (R-MP). R-MP then reacts with a broad specificity D-aminotransferase and D-alanine to produce R,R monatin and pyruvate.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[N:4]([CH3:10])[C:3]1=[O:11].ClC1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>[Cl-].[Zn+2].[Cl-].CCOC(C)=O>[C:19]([C:6]1[C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[N:2]([CH3:1])[C:7]=1[CH3:8])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)c2ccccc2)c(=O)n(C)c(=O)n1C
Temperature: 110 °C

Procedure:
1,3,6-Trimethylpyrimidine-2,4(1H,3H)-dione (step 1) (5 g, 32.4 mmol) and chlorobenzene (50 mL) were charged to a 3 necked flask, and the vessel evacuated with nitrogen. Benzoyl chloride (commercial) (11.2 mL, 97 mmol) was added followed by zinc (II) chloride (5 g, 36.7 mmol) in one portion and the reaction was heated to 110° C. for 16 h. The reaction was cooled to RT then poured into water (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous extracted with EtOAc (2×150 mL). The combined organics were washed with water (100 mL) and dried (Na2SO4), filtered under reduced pressure and evaporated to leave an orange solid. The solid was washed with hexane followed by hot diethyl ether, affording the product as an off white solid. The mother liquors were further purified by chromatography on silica, eluting with 10%-100% EtOAc/hexane. The title product was obtained as a pale orange solid.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH3:23])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][N:22]([CH3:23])[C:34]([NH:33][S:30]([C:27]3[CH:26]=[CH:25][C:24]([CH3:36])=[CH:29][CH:28]=3)(=[O:31])=[O:32])=[O:35])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN(C)C(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.6 %

Procedure:
To a solution of N-{2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}-N-methylamine (step 1, 523 mg, 1.7 mmol) in dichloromethane (10 mL) and triethylamine (2 mL) was added p-toluenesulfonyl isocyanate (400 mg, 2.0 mmol). The resulting reaction mixture was stirred at room temperature for 6 h. After removal of solvent, the residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (10:1) to afford 358 mg (42%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.93 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.4 Hz), 6.92 (1H, s), 3.66-3.49 (2H, m), 3.51 (3H, s), 2.93-2.70 (4H, m), 2.65 (3H, s), 2.50 (3H, s), 2.38 (3H, s), 1.24 (3H, t, J=7.2 Hz).
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([O:18][CH3:19])=[CH:10][C:11]=2[CH:15]([CH3:17])[CH3:16])[S:4]1(=[O:6])=[O:5].[CH3:20][O:21][C:22]1[C:27]2[CH:28]=[CH:29][O:30][C:26]=2[C:25]([O:31][CH3:32])=[C:24]([OH:33])[C:23]=1[C:34](=[O:36])[CH3:35].CN1NCCCCCCC(C2CCCCCCCCC=2)=N1.Cl>C(#N)C>[CH3:20][O:21][C:22]1[C:27]2[CH:28]=[CH:29][O:30][C:26]=2[C:25]([O:31][CH3:32])=[C:24]([O:33][CH2:2][N:3]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][C:9]([O:18][CH3:19])=[CH:10][C:11]=3[CH:15]([CH3:17])[CH3:16])[S:4]2(=[O:6])=[O:5])[C:23]=1[C:34](=[O:36])[CH3:35]
Reactant: COc1c(C(C)=O)c(O)c(OC)c2occc12
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: CN1N=C(C2=CCCCCCCCC2)CCCCCCN1
Agent: Cl
Solvent: CC#N
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1c(C(C)=O)c(OC)c3ccoc3c1OC)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
2-Chloromethyl-4-isopropyl-6-methoxysaccharin (0.5 g) was added with stirring at room temperature to a solution of 4,7-dimethoxy-5-acetyl-6-hydroxybenzofuran (0.39 g) and methyltriazabicyclodecene (0.28 g) in acetonitrile (20 mL). The mixture was stirred overnight at room temperature. Since thin layer chromatography showed unreacted 4,7-dimethoxy-5-acetyl-6-hydroxybenzofuran, more 2-chloromethyl-4-isopropyl-6-methoxysaccharin and a drop of base were added, stirring was continued for a total of 24 hours, and the reaction mixture was poured into ice-water containing hydrochloric acid. The resulting golden solid was partially purified using dichloromethane as eluant. The reaction was repeated with stirring overnight at 35°-40° C. instead of room temperature. The product and the partially purified product of the first reaction were combined and purified by column chromatography on silica gel affording 2-(4,7-dimethoxy-5-acetylbenzofuran-6-yl)oxymethyl-4-isopropyl-6-methoxysaccharin (0.4 g, 24% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:12]([O:17]C(=O)CCC)(=O)[CH2:13][CH2:14][CH3:15].[N+:23]([O-])([OH:25])=[O:24].[OH-].[Na+]>O>[C:12]([NH:1][C:2]1[C:11]([N+:23]([O-:25])=[O:24])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:17])[CH2:13][CH2:14][CH3:15]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccccc1N
Reactant: CCCC(=O)OC(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(=O)Nc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
[step 1] To methyl 2-aminobenzoate (1.5 g, 9.92 mmol) was added butyric anhydride (4.9 mL, 29.76 mmol), and the mixture was stirred at room temperature for 2 hr. Under ice-cooling, fuming nitric acid (1.6 mL) was added dropwise to the mixture, and the mixture was stirred at 0° C. for 20 min. The mixture was adjusted to pH 7 with water and 4 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate (150 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40) to give methyl 2-butyramido-3-nitrobenzoate (1.26 g, 48%). [step 2] Methyl 2-butyramido-3-nitrobenzoate (1.65 g, 6.2 mmol) obtained in step 1 was dissolved in methanol (34 mL), and the mixture was stirred in the presence of 10% palladium carbon (413 mg) under a hydrogen atmosphere at room temperature for 6 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give methyl 3-amino-2-butyramidobenzoate (1.46 g, 100%). [step 3] To methyl 3-amino-2-butyramidobenzoate (1.46 g, 6.2 mmol) obtained in step 2 was added acetic acid (9.0 mL), and the mixture was stirred at 80° C. for 1.5 hr. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (300 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 50/50) to give the title compound (1.18 g, 87%).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[N:24][N:23]([CH2:34][CH2:35]O)[C:22](=[O:37])[CH:21]=2)=[CH:16][CH:15]=1.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.[K+].[Br-]>N1C=CC=CC=1.O>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[N:24][N:23]([CH2:34][CH2:35][N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[C:22](=[O:37])[CH:21]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2cc(=O)n(CCO)nc2-c2ccc(OC)cc2)cc1
Reactant: CN1CCNCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Br-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2cc(=O)n(CCN3CCN(C)CC3)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of para-toluenesulfonyl chloride (357 mg, 4 eq) in pyridine (0.5 ml), a solution of 5,6-bis(4-methoxyphenyl)-2-(2-hydroxyethyl)-2H-pyridazin-3-one (165 mg, 0.47 mmol) in pyridine (1.0 ml) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed successively with water and a brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off, and N-methylpiperazine (0.15 ml, 3 eq) was added to the residue. The resulting mixture was stirred at 90-100° C. for 2 hours. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and ethanol was added to the residue. The resulting mixture was azeotropically boiled three times with ethanol to drive off water. The thus-obtained residue (256 mg) was separated and purified by chromatography on a silica gel column [silica gel: 8 g, chloroform/methanol (20/1)], whereby a yellow oil (165 mg, 81%) was obtained. The oil was left over in a refrigerator. Precipitated crystals were washed with a mixed solvent of methanol and diethyl ether, whereby the title compound (65 mg, 32%) was obtained as pale yellow prisms. Melting point: 109.7-110.8° C. 1H-NMR (CDCl3) δ: 2.29(3H,s), 2.46(4H,brs), 2.64(4H,brs), 2.87(2H,t,J=6.83 Hz), 3.80(3H,s), 3.81(3H,s), 4.40(2H,t,J=6.84 Hz), 6.79(2H,d,J=9.03 Hz), 6.81(2H,d,J=8.78 Hz), 6.87(1H,s), 7.02(2H,d,J=8.79 Hz), 7.12(2H,d,J=9.03 Hz). IR (KBr) cm−1: 1659,1608,1513,1295,1250,1177,1013.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[CH2:22][C:23]1[C:31]2[C:26](=[C:27]([Br:38])[CH:28]=[C:29]([CH2:32][S:33]([NH:36][CH3:37])(=[O:35])=[O:34])[CH:30]=2)[NH:25][CH:24]=1)=O)C1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1.O>[Br:38][C:27]1[CH:28]=[C:29]([CH2:32][S:33]([NH:36][CH3:37])(=[O:35])=[O:34])[CH:30]=[C:31]2[C:26]=1[NH:25][CH:24]=[C:23]2[CH2:22][C@H:18]1[CH2:19][CH2:20][CH2:21][N:17]1[CH3:15]
Reactant: CNS(=O)(=O)Cc1cc(Br)c2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)Cc1cc(Br)c2[nH]cc(C[C@H]3CCCN3C)c2c1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
To a chilled suspension of lithium aluminium hydride (47.89 g) in tetrahydrofuran (938 mL), (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-7-bromo-5-(methylaminosulfonylmethyl)-1H-indole (262.7 g) in tetrahydrofuran (1250 mL total) was added slowly dropwise. The reaction mixture was stirred at ambient temperature and then warmed to 40° C. until conversion was complete. Then, the mixture was cooled and quenched by slow addition of industrial methylated spirit (160 mL), followed by 4M aqueous sodium hydroxide solution (45 mL), then water (142 mL). The mixture was then filtered (through Arbacel). The filtered solids were reslurried in hot industrial methylated spirit (1600 mL) then refiltered. The filtered solids were then washed with a further portion of industrial methylated spirit (200 mL) and then again reslurried from hot industrial methylated spirit (1600 mL). The resultant slurry was again refiltered. The combined filtrates and washings were evaporated in vacuo to give a crude oil which was stirred in mixed water (1000 mL) / ethyl acetate (1000 mL). The aqueous phase was separated and washed with ethyl acetate (500 mL)(then the aqueous discarded) and then the ethyl acetate extracts combined and diluted with water (1000 mL) and the whole acidified (by addition of concentrated hydrochloric acid). The aqueous phase was separated and the organic phase washed with water (500 mL). These two aqueous phases were combined and made basic (by addition of 40% aqueous sodium hydroxide solution) and the product re-extracted with ethyl acetate (2×1000 mL), then again at pH9 with further ethyl acetate (500 mL). The combined ethyl acetate extracts were evaporated to an oil then re-evaporated from acetone (250 mL) to give the title compound (200.7 g) as a semi-solid mass. TLC (diethyl ether/ethyl acetate/methanol/diethyl amine 50:50:5:5): Rf =0.26. 1H NMR (d6DMSO) δ11.05 (s, 1H), 7.5 (s, 1H), 7.3 (s, 1H), 7.2 (s, 1H), 6.85 (q, 1H), 4.35 (s, 2H), 2.95 (m, 2H), 2.55 (d, 3H), 2.5 (m, 1H), 2.35-2.3 (m, 1H and s, 3H), 2.1 (m, 1H), 1.75-1.4 (m, 4H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][C:33](=[O:35])[CH3:34])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OC(C)=O
Yield: 73 %

Procedure:
4-Methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl) carbonylthiochroman-1,1-dioxide was used as a starting material (XIH). And, 0.40 g (1.1 mmol) thereof was dissolved in 4 ml of methylene chloride, and 0.22 g (2.2 mmol) of triethylamine as a base and 0.17 g (2.2 mmol) of acetyl chloride as a reaction reagent (XII) were added. The resultant mixture was allowed to react at room temperature for 8 hours. A saturated sodium carbonate aqueous solution was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate, and its organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant oil was purified with flush column chromatography (Wako Gel C-300: hexane/ethyl acetate=1:2) to give 0.33 g (yield 73%) of 4-methoxy-5-methyl-6-(1-ethyl-5-acetoxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 51) as an end compound which comes under the general formula (XI). Table 18 shows the structures of the starting material (XIH) and the reaction reagent (XII), and the structure and the yield of the end product (XI).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1ccccc1Br
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccccc1OCC1CCCCC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
5.00 ml of 2-bromophenol was dissolved in 90 ml of N,N-dimethylformamide, 7.21 ml of (bromomethyl)cyclohexane and 7.15 g of potassium carbonate were added thereto, and the mixture was stirred at 100° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with n-hexane. The organic layer was washed with water, 5N-sodium hydroxide and brine, and then dried over anhydrous magnesium sulfate. The mixture was filtered through alumina, and the solvent was evaporated, to give 10.47 g of the title compound as a slight yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH2:24][C:25](O)=[O:26])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH2:24][C:25]([NH2:38])=[O:26])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:35])[CH3:36])=[CH:30][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)c1ccc(-c2nc3c(-c4ccccc4)nn(CC(=O)O)c3c(=O)n2-c2ccc(Cl)cc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)c1ccc(-c2nc3c(-c4ccccc4)nn(CC(N)=O)c3c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the crude [6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetic acid prepared from previous step, HATU (41.1 mg, 0.108 mmol) and iPr2NEt (37.6 μL, 0.216 mmol) in DMF (0.5 mL) is stirred at room temperature for 1 hour before transferred dropwise into 7 N ammonia in methanol solution (1.0 mL) at 0° C. The resultant reaction mixture is stirred at room temperature for 1 hour before removal of the solvent under reduced pressure. The residue is purified by preparative LC/MS to provide the title compound; HPLC-MS calculated for C28H24ClN5O2 (M+H+) 498.2. Found 498.2.