Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[NH:4](C(OC(C)(C)C)=O)[C@H:5]([C:11]([O:13]C(C)(C)C)=[O:12])[CH2:6][CH2:7][C:8](=[O:10])O.Cl.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:38][C:39]1[CH:40]=[C:41]([Cl:50])[C:42]([CH3:49])=[C:43]([S:45]([OH:48])(=[O:47])=[O:46])[CH:44]=1>FC(F)(F)C(O)=O.C1COCC1>[Cl:50][C:41]1[CH:40]=[C:39]([NH:38][C:8](=[O:10])[CH2:7][CH2:6][C@@H:5]([C:11]([OH:13])=[O:12])[NH2:4])[CH:44]=[C:43]([S:45]([OH:48])(=[O:47])=[O:46])[C:42]=1[CH3:49]
Reactant: Cc1c(Cl)cc(N)cc1S(=O)(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cl)cc(NC(=O)CC[C@H](N)C(=O)O)cc1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After 1 ml of methylene chloride and 1 ml of THF were added to 303 mg (1 mmol) of Boc-Glu-OtBu hydrochloride and 180 mg (1.1 mmol) of CDI, 221 mg of 5-amino-3-chloro-2-methylbenzenesulfonic acid was further added to mixture. The mixture was stirred at room temperature overnight and then purified in accordance with the purification step A to give the protected product. The protected product obtained was dissolved in 5 ml of trifluoroacetic acid. The solution was stirred for 2 hours. The solvent was distilled off and the mixture was purified in accordance with the purification step A to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.Cl[CH2:14][CH2:15][N:16]=[C:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:7][C:5]1[N:6]=[C:2]([N:1]2[CH2:14][CH2:15][NH:16][C:17]2=[O:18])[S:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: O=C=NCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Yield: 71 %

Procedure:
To a solution of ethyl 2-amino-4-methylthiazole-5-carboxylate (9.31 g, 49.99 mmol) in tetrahydrofuran (200 mL) was added 2-chloroethyl isocyanate (5.50 mL, 64.0 mmol) at ambient temperature. The resulting reaction mixture was heated to reflux for 7 hours, followed by the addition of potassium carbonate (8.30 g, 60.0 mmol) and tetra-n-butylammonium iodide (0.50 g, 1.35 mmol) and the resulting mixture was heated to reflux for 23 hours. The solvent was removed in vacuo, and the residue was washed with water (200 mL) and ethyl acetate (50 mL) to afford the title compound in 71% yield (9.10 g): mp 197-199° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.83 (s, 1H), 4.20-3.93 (in, 4H), 3.49-3.43 (m, 2H), 2.46 (s, 3H), 1.20 (t, J=6.9 Hz, 3H); MS (ES+) m/z 256.3 (M+1).
Reaction SMILES: C([NH:9][C:10]1[CH:20]=[C:19]([NH:21]C(=O)C2C=CC=CC=2)[C:13]2[O:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:12]=2[CH:11]=1)(=O)C1C=CC=CC=1.Cl>C(O)C>[NH2:9][C:10]1[CH:20]=[C:19]([NH2:21])[C:13]2[O:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:12]=2[CH:11]=1
Reactant: Cc1oc2c(NC(=O)c3ccccc3)cc(NC(=O)c3ccccc3)cc2c1C
Agent: Cl
Solvent: CCO
Product: Cc1oc2c(N)cc(N)cc2c1C

Procedure:
To a suspension of 5,7-bis(benzoylamino)-dimethylbenzo[b]furan (2.5 g) in ethanol (18 ml) was added conc. hydrochloric acid (9 ml) and the mixture was refluxed for 36 hours. The reaction mixture was cooled and evaporated in vacuo. The residue was dissolved in water and the solution was washed with ethyl acetate. The aqueous layer was neutralized with aqueous saturated sodium bicarbonate and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo to give 5,7-diamino-2,3-dimethylbenzo[b]furan.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[C:13]=2[F:22])=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[C:23]([Cu])#[N:24]>CN1C(=O)CCC1.C(Cl)Cl>[F:22][C:13]1[C:14]([O:20][CH3:21])=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=1[C:9]1[C:8]2[N:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:2]([C:23]#[N:24])=[CH:11][CH:10]=1
Reactant: N#C[Cu]
Reactant: COc1cc(OC)c(F)c(-c2ccc(Br)c3nccnc23)c1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1cc(OC)c(F)c(-c2ccc(C#N)c3nccnc23)c1
Temperature: 160 °C
Reaction time: 6.5 h
Yield: 62 %

Procedure:
A mixture of 5-bromo-8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline (Step 94.3) (3.09 g, 8.5 mmol) and CuCN (918 mg, 10.2 mmol, 1.2 equiv) in NMP (30 mL) was stirred for 6.5 h at 160° C., under an argon atmosphere. The reaction mixture was allowed to cool to rt, diluted with DCM/(10% aqueous solution of ethylenediamine) (200 mL, v/v 1:1), filtered through celite and the filtrate extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in DCM to provide 1.63 g of the title compound as a white solid: ESI-MS: 310.1 [M+H]+; tR=4.41 min (System 1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(C1C=CC=C(CC=C)C=1[OH:24])C=C.C1(O)C=CC=CC=1.C(N(CC)CC)C>C(N(CC)CC)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:24])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C=CCc1cccc(CC=C)c1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Oc1ccccc1
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
Triethylamine (4 ml) and 4-toluenesulfonyl chloride (3.80 gm, 0.02 mol) were diluted with 1,2-dichloromethane (50 ml) and 2,6-diallylphenol (3.48 gm, 0.02 mol), dissolved in 1,2-dichloromethane (10 ml), was added drop wise to the phenol-triethylamine solution at room temperature and then refluxed for 1 hr. The reaction mixture was cooled, washed with water and dried over MgSO4, filtered and evaporated to give 4-toluenesulfonic acid: 2,6-diallylphenyl ester as an oil. Purification was carried out via filtering a hexane solution of the ester through silica gel. MS m/z 328 (M+ calcd for C19H20O3S=328). H NMR (300 MHz, CDCl3) d 2.50 (s, 3, CH3), 3.25–3.35 (d, 4, CH2), 4.95–5.10 (m, 4, CH2 vinyl), 5.75–5.90 (m, 2, CH, vinyl), 7.10–7.25 (m, 3, aromatic), 7.85–7.95 (m, 2, aromatic). Oxidation of product as described in Example 1 gave 4-toluenesulfonic acid 2,6-di(2,3-epoxypropyl)phenyl ester. MS m/z 360 (M+ calcd for C19H20O5S=360. H NMR (300 MHz, CDCl3) d 2.45–2.55 (m, 2, CH2 epoxypropyl), 2.50 (s, 3, CH3), 2.35–2.95 (m, 6, CH2 epoxypropyl), 3.21–3.35 (m, 2, CH epoxypropyl), 7.25–7.45 (m, 5, aromatic), 7.85–7.95 (d, 2, aromatic).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[C:5]=1C.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:16][O:15][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[C:7]=1[O:13][CH3:14])[CH2:3][OH:2]
Reactant: CCCc1cc(C(=O)OC)c(C)c(OC)c1OC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCc1cc(CO)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
To a stirred solution of methyl 3,4-dimethoxy-5-propylbenzoic acid methyl ester (Example 1, Step 4, 6.0 g, 25.2 mmol) in DCM (400 mL) at −78° C. was added DIBAH (1.0 M in toluene, 76 mL, 76 mmol). The reaction mixture was stirred at −78° C. for 30 min then quenched with EtOAc (50 mL). The quenched reaction was warmed to room temperature then treated with 1:1 saturated aqueous potassium tartrate/saturated aqueous sodium bicarbonate (400 mL). The biphasic mixture was stirred vigorously for 30 min then the layers separated. The aqueous layer was extracted with EtOAc (300 mL), then the combined organic layer was dried over MgSO4, and concentrated to give 3,4-dimethoxy-5-propylbenzylalcohol (5.42 g, 100% yield). The product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=1.[OH:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][CH:32]=1>>[O:30]=[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([C:2]2[CH:7]=[C:6]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=4)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=3[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=2)[CH:33]=[CH:32]1
Reactant: Oc1ccnc2ccccc12
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Br)c2)c1C(=O)OC
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(-n3ccc(=O)c4ccccc43)c2)c1C(=O)OC

Procedure:
1-(2-Bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene and 4-hydroxyquinoline are treated in the same manner as in Example 6-(2) to give 1-[2-(4-oxo-1,4-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:19])[CH:8]=2)[N:3]=1.Cl[CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([CH3:30])=[CH:24][N:23]=1>>[CH3:29][O:28][C:26]1[C:25]([CH3:30])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:19])[CH:8]=3)[N:3]=2)[CH:27]=1
Reactant: COc1cc(CCl)ncc1C
Reactant: Cc1ccc2nc(S)n(-c3ccccc3)c(=O)c2c1
Product: COc1cc(CSc2nc3ccc(C)cc3c(=O)n2-c2ccccc2)ncc1C
Yield: 32.9 %

Procedure:
The title compound was prepared in a yield of 32.9%, using 2-mercapto-6-methyl-3-phenyl-4(3H)-quinazolinone in place of 2-mercapto-3-phenyl-4(3H)-quinazolinone and 2-chloromethyl-4-methoxy-5-methylpyridine in place of 2chloromethyl-4-methylpyridine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:28])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[C:6]=2[CH:40]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]([OH:28])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[C:6]=2[CH:40]=1
Reactant: Cc1ccccc1CC(=O)c1ccc(C(=O)N2CCCC(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccccc1CC(O)c1ccc(C(=O)N2CCCC(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cc1
Reaction time: 2 h
Yield: 100.6 %

Procedure:
7-Chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-{4-[2-(2-methylphenyl)acetyl]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.06 g) is dissolved in a mixture of methylene chloride (20 ml) and methanol (20 ml), and thereto is added with stirring sodium borohydride (0.28 g) under cooling over an ice-bath. The mixture is stirred for two hours over an ice-bath, and the mixture is evaporated to remove almost of the solvent. To the residue is added water, and the mixture is extracted with methylene chloride. The organic layer is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol=20˜10:1) to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-{4-[2-(2-methylphenyl)-1-hydroxyethyl]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.08 g) as colorless amorphous.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH2:22][C:23]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:25][O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)=[O:14])[CH2:7]1)C.O.[OH-].[Li+]>C1COCC1.O.CO.Cl>[CH3:28][C:27]1[O:26][N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]=1[CH2:22][O:21][C:18]1[N:17]=[CH:16][C:15]([C:13]([NH:12][CH:8]2[CH2:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:35])=[O:3])[CH2:7]2)=[O:14])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CN1CCCC(NC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid ethyl ester (538 mg, 1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (420 mg, 83%) which was obtained as an off white solid. MS: m/e=449.0 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[N+:18]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])([O-:20])=[O:19].CO.C([O-])(O)=O.[Na+]>COCCO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Solvent: CO
Product: COc1cc2ncc(C#N)c(Nc3cccc([N+](=O)[O-])c3)c2cc1OC
Yield: 68.5 %

Procedure:
A solution of 0.500 g (2.00 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile and 0.332 g (2.41 mmol) of 3-nitroaniline in 6 mL of methyl cellosolve was refluxed under N2 for 8 hr. Methanol was added, followed by satd NaHCO3 (pH 8) and volatile material was removed. The residue was slurried with water, collected by filtration and dried. Recrystallization from ethanol gave 0.480 g of 6,7-dimethoxy-4-(3-nitrophenylamino)quinoline-3-carbonitrile as yellow crystals: mass spectrum (electrospray, m/e): M+H 351.0.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:5]=1[C:6]#[N:7].Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:5]=1[C:6](=[N:15][OH:16])[NH2:7]
Reactant: N#Cc1c(F)cccc1OC(F)F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1c(F)cccc1OC(F)F
Temperature: 75 °C
Reaction time: 20 h

Procedure:
A mixture of 6.4 g of 2-difluoromethoxy-6-fluorobenzonitrile and 3.1 g of hydroxylamine hydrochloride, 2.6 g of sodium carbonate, 7 ml of water and 35 ml of ethanol was stirred for 20 hours at 75° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN1CCOCC1.[N:18]1([C@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>ClC(Cl)C.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:25]2[CH2:26][CH2:27][C@H:23]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:24]2)=[O:8])=[CH:9][CH:10]=1
Reactant: C1CCN([C@H]2CCNC2)C1
Reactant: O=C(O)c1ccc(F)cc1
Solvent: CN1CCOCC1
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)N1CC[C@H](N2CCCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A solution of 4-fluorobenzoic acid (1.5 g, 10.71 mmol) in dichloroethane:DMF (4:1) was treated with O-benzotriazol-1-yl-N,N,N′N′-tetramethlyuronium tetrafluoroborate (4.13 gm 12.85 mmol) and N-methylmorpholine (5.41 g, 53.55 mmol) followed by a solution of (3′S)-1,3′-bipyrrolidine (2.52 g, 11.77 mmol) in dichloroethane:DMF (4:1). The reaction mixture was stirred at room temperature for 3 h and quenched with saturated sodium hydrogen carbonate. The phases were separated. The aqueous phase was extracted with ethyl acetate. The organic phase and the extracts were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash column chromatography to provide (3′S)-1′-(4-fluorobenzoyl)-1,3′-bipyrrolidine (57%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@@H:7]([C:14]([OH:16])=O)[CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].[NH:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20]>>[CH2:1]([O:3][C:4]([NH:6][C@@H:7]([C:14]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)=[O:5])[CH3:2]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCOC(=O)N[C@H](CC1CCCC1)C(=O)O
Product: CCOC(=O)N[C@H](CC1CCCC1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 70.5 %

Procedure:
2.43 g (10.5 mmol) of ethoxycarbonyl-3-cyclopentyl-D-alanine (Example 4, Step B) is treated according to the method described in Example 1, Step E, using proportional quantities of reagents and solvents. The resulting 2,4,5-trichlorophenylester is coupled with 1.15 g (10 mmol) of L-proline which yields 2.3 g (71%) of an oily product. Rf(6)=0.53.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])[C:7]=1[CH3:28])=[O:5])C.FC(F)(F)C1C=CC=CC=1N.C(OC(=O)C(C(=O)C)CC(C1C=CC(F)=CC=1)=O)C.FC1C=CC(N)=CC=1.[CH3:67][S:68]([C:71]1[CH:76]=[CH:75][C:74]([NH:77]C(C2C=C(C3C=CC(F)=CC=3)N(C3C=CC(F)=CC=3)C=2C)=O)=[CH:73][CH:72]=1)(=[O:70])=[O:69].CS(C1C=CC(N)=CC=1)(=O)=O>>[CH3:67][S:68]([C:71]1[CH:76]=[CH:75][C:74]([NH:77][C:4]([C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])[C:7]=2[CH3:28])=[O:5])=[CH:73][CH:72]=1)(=[O:69])=[O:70]
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(F)cc2)n1-c1ccc(F)cc1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccccc2C(F)(F)F)c1C
Agent: CCOC(=O)C(CC(=O)c1ccc(F)cc1)C(C)=O
Agent: CS(=O)(=O)c1ccc(N)cc1
Agent: Nc1ccc(F)cc1
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(F)cc2)n1-c1ccccc1C(F)(F)F

Procedure:
In a manner similar to that described for Examples 16C-D, the title compound was prepared from 5-(4-fluorophenyl)-2-methyl-1-(2-trifluoromethylphenyl)-1H-pyrrole-3-carboxylic acid ethyl ester, which was synthesized from 2-trifluoromethyl-aniline and 2-acetyl-4-(4-fluorophenyl)-4-oxobutyric acid ethyl ester using the procedures described in WO 03/027069. 1H-NMR (CDCl3): δ 7.92-7.84 (5H, m), 7.77-7.69 (2H, m), 7.63-7.60 (1H, m), 7.42 (1H, d), 7.07-7.03 (2H, m), 6.88-6.84 (2H, m), 6.60 (1H, s), 3.05 (3H, s), 2.33 (3H, s). MS (ESI): 517 (MH+). B. In a manner similar to that described for Example 20A, but replacing 2-trifluoromethyl-aniline with 4-fluoroaniline, the following compound was prepared: 1,5-bis-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylic acid (4-methanesulfonyl-phenyl) amide; 1HNMR (CDCl3): δ 7.93-7.80 (5H, m), 7.25-7.11 (4H, m), 7.09-7.01 (2H, m), 6.93-6.87 (2H, m), 6.56 (1H, s), 3.04 (3H, s), 2.45 (3H, s). MS (ESI): 467 (MH+). C. In a manner similar to that described for Example 20A, but replacing 4-methanesulfonyl-aniline with the appropriate amines in the last step, the following compounds were prepared:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:21]=[CH:20][C:10]2[N:11]3[CH2:19][CH2:18][CH2:17][C:12]3=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1.O>C(Cl)Cl>[CH2:19]1[N:11]2[C:12](=[N:13][S:14](=[O:15])(=[O:16])[C:9]3[CH:8]=[C:7]([OH:6])[CH:21]=[CH:20][C:10]=32)[CH2:17][CH2:18]1
Reactant: COc1ccc2c(c1)S(=O)(=O)N=C1CCCN12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=S1(=O)N=C2CCCN2c2ccc(O)cc21
Reaction time: 24 h

Procedure:
A solution of BBr3 (68.75 mmol) in 25 ml of methylene chloride is added dropwise to a solution, cooled to 0° C., of 27.5 mmol of 7-methoxy-2,3-dihydro-1H-pyrrolo[2,1-c]-[1,2,4]benzothiadiazine 5,5-dioxide in 350 ml of methylene chloride. Stirring is carried out at ambient temperature for 24 hours. The reaction mixture is poured into a mixture of ice and water, and the suspension is stirred for 30 minutes. The precipitate is filtered off, rinsed several times with water, filtered under suction and dried in vacuo to yield the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:17])[C:14]=1[CH2:15][OH:16])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:17])[C:14]=1[CH2:15][O:16][S:26]([CH3:25])(=[O:28])=[O:27])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(F)c(CO)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(F)c(COS(C)(=O)=O)c(F)c1
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a stirred solution of tert-butyl 3,5-difluoro-4-(hydroxymethyl)benzoate (1.9 g, 7.78 mmol) in DCM was added Et3N (3.27 mL, 23.4 mmol, 3 eq) and methanesulfonylchloride (0.72 mL, 9.3 mmol, 1.2 eq) successively at 0° C. After the reaction was stirred for 30 min, it was extracted with CH2Cl2C and water. Organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=4:1) to give tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (2.25 g, 89% yield) as a ivory solid.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[Br:26]Br.O>ClCCl>[Br:26][CH:9]([C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13]
Reactant: O=C(CCCC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)C(Br)CCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
To a solution of 11.5 g. of 1-(4-benzoylbutyryl)-L-proline (Example 41) in 115 ml. of acetic acid is added dropwise a solution of 6.4 g. of bromine in 25 ml. of acetic acid. The mixture is stirred for 18 hours, reduced to 1/3 its volume, poured into ice and water and extracted with dichloromethane. The organic extract is washed with water and saline, dried over magnesium sulfate and evaporated in vacuo to a yellow gum. This gum is dissolved in dichloromethane, placed on a 11/2"×24" column of silica gel which has been wet with dichloromethane and eluted with ethyl acetate:acetic acid (1:1) taking 100 ml. cuts. Cut number 7 gives 2.1 g. of solid which is dissolved in dichloromethane, filtered through celite and evaporated to dryness giving the desired product as 2.0 g. of an orange gum.
Reaction SMILES: Cl[CH:2]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:3]([O:7][C:8](=[O:14])[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[N:4][O:5][CH3:6].[P:22]([O-:30])([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:23].[K+].[I-].[K+]>C(C(C)=O)C>[P:22]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])([O:30][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:3]([O:7][C:8](=[O:14])[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[N:4][O:5][CH3:6])=[O:23]
Reactant: CCN(CC)C(=O)OC(=NOC)C(Cl)c1ccc(Cl)cc1
Reactant: CCOP(=O)([O-])OCC
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(OCC)OC(C(=NOC)OC(=O)N(CC)CC)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
1-Chloro-1-(4-chlorophenyl)-2-(N,N-diethylcarbamoyloxy)-2-methoxyiminoethane (16.6 grams; 0.05 mole), methyl ethyl ketone (100 ml), potassium O,O-diethyl phosphate (9.6 grams; 0.05 mole) and a few crystals of potassium iodide are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 12 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove inorganic salts. The salts are washed with acetone and the washings combined with the filtrate. The resulting solution is stripped of solvents in a rotary evaporator. The remaining residue is dissolved in ether and the ether solution is washed with water and dried over anhydrous magnesium sulfate. The dried solution is filtered and stripped of ether to yield the desired product O-[1-(4-chlorophenyl)-2-(N,N-diethylcarbamoyloxy)-2-methoxyiminoethyl] O,O-diethyl phosphate.