Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1([NH:15][C:16]([C:18]2([NH:21][C:22]([C:24]3[N:28]4[C@@:29]([CH2:42][C:43]5[CH:48]=[CH:47][C:46]([C:49]#[N:50])=[CH:45][CH:44]=5)([CH3:41])[C:30](=[O:40])[N:31]([C:32]5[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=5)[C:27]4=[N:26][CH:25]=3)=[O:23])[CH2:20][CH2:19]2)=[O:17])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C>Cl.O1CCOCC1.CCOCC>[ClH:38].[NH:9]([C:10]([C:12]1([NH:15][C:16]([C:18]2([NH:21][C:22]([C:24]3[N:28]4[C@@:29]([CH2:42][C:43]5[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[CH:47][CH:48]=5)([CH3:41])[C:30](=[O:40])[N:31]([C:32]5[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=5)[C:27]4=[N:26][CH:25]=3)=[O:23])[CH2:20][CH2:19]2)=[O:17])[CH2:14][CH2:13]1)=[O:11])[NH2:8]
Reactant: CC(C)(C)OC(=O)NNC(=O)C1(NC(=O)C2(NC(=O)c3cnc4n3[C@](C)(Cc3ccc(C#N)cc3)C(=O)N4c3cc(Cl)cc(Cl)c3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(C(=O)NN)CC4)CC3)n21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 108.6 %

Procedure:
N′-{1-[(1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarbonyl)-amino]-cyclopropanecarbonyl}-hydrazinecarboxylic acid tert-butyl ester (0.30 g, 0.42 mmol) was dissolved in 4 N HCl in dioxane (3 mL) and allowed to stir at room temperature for 40 min. The resulting white suspension was diluted with Et2O and the precipitate was collected by filtration. The solid was washed twice with Et2O to give (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo-[1,2-a]imidazole-3-carboxylic acid [1-(1-hydrazinocarbonyl-cyclopropylcarbamoyl)-cyclopropyl]-amide hydrochloride (0.15 g, 52%) as a white powder, m/z 621.7 [M+1]+.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)=[O:28])=[CH:22][CH:21]=2)O1>>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=4)=[O:28])=[CH:24][CH:25]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Clc1ccn2c(I)cnc2c1
Reactant: CC1(C)OB(c2ccc(CC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Product: O=C(Cc1ccc(-c2cnc3cc(Cl)ccn23)cc1)Nc1cccc(C(F)(F)F)c1

Procedure:
Couple 3-iodo-7-chloro-imidazo[1,2,a]pyridine (655 mg, 2.35 mmol) and 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-acetamide (1.00 g, 2.47 mmol) using a procedure similar to Preparation 99B. MS(ES), m/z 430 (M+1).
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:61][CH3:62])[C:44]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[OH:60])=[N:45][C:46]=1[CH:47]1[CH2:49][CH2:48]1>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:61][CH3:62])[C:44]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[O:60][CH2:2][CH3:3])=[N:45][C:46]=1[CH:47]1[CH2:49][CH2:48]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-6-cyclopropyl-3-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: MS (ESI+) for C27H30ClN3O2 m/z 465 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.C1(C)C=CC=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[CH3:35])=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(Br)nc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)cn1

Procedure:
To a stirred slurry of 1.75 g (3.35 mmol) of (S)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-bromo-pyridin-3-yl)propanoate and 913 mg (6.70 mmol, 2 eq.) of 2-methylphenylboronic acid in 50 mL of 1:1 isopropanol/toluene was added 25.0 mL of 2 M aqueous sodium carbonate solution. The reaction mixture was purged twice with argon and evacuated and then 124 mg (0.167 mmol, 0.05 equivalents) of bis(tricyclohexylphosphine)palladium (II) chloride was added and the mixture again purged with argon and evacuated.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])SC)(=[O:3])[CH3:2].[N-:12]=[N+:13]=[N-:14].[Na+]>O1CCOCC1.O>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:8]([SH:11])=[N:14][N:13]=[N:12]1)(=[O:3])[CH3:2]
Reactant: CSC(=S)NCCNC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NCCn1nnnc1S
Yield: 43.2 %

Procedure:
To a solution of methyl N-(2-acetamidoethyl)dithiocarbamate (12.6 g.) in dioxane (40 ml.) was added a solution of sodium azide (6.4 g.) in water (40 ml.), and the mixture was heated under reflux for 4 hours. After dioxane was removed from the resultant mixture under reduced pressure, the residue was washed with ether (350 ml.) and adjusted to pH 1 with 10% hydrochloric acid. After the resultant solution was extracted with ethyl acetate (1.5 l.), the extract was dried over magnesium sulfate and the solvent was evaporated to dryness to give 1-(2-acetamidoethyl)-1H-tetrazole-5-thiol (5.3 g.) having m.p. 137.5° to 139.5° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N:16]([O-])=O.[Na+]>O.Cl.CC#N>[ClH:1].[NH:2]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)[NH2:16]
Reactant: Nc1ccc(C(=O)O)c2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NNc1ccc(C(=O)O)c2ccccc12
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
2.4 g of 4-amino-1-naphthalenecarboxylic acid hydrochloride are mixed at 0° C. with 80 ml of concentrated HCl. A solution of 0.89 g of sodium nitrite in 19 ml of water is added and the mixture is left stirring for 2 hours at 2-3° C. It is cooled to -10° C., and a solution of 9.7 g of stannous chloride dihydrate in 90 ml of concentrated HCl is added slowly. The temperature is allowed to rise to RT and the mixture is kept stirring for 30 minutes. 200 ml of water are added, the mixture is left stirring for 30 minutes and the solid formed is drained. The solid is taken up in MeCN, drained, washed with ether and dried. 2.2 g of the expected product are obtained, m.p.=190° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH3:31])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:13]1[C:11]2[O:12][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:32])=[O:3])=[CH:9][C:10]=2[CH:16]=[CH:15][CH:14]=1)[CH3:31]
Reactant: CCOC(=O)C=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC)c2o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1c(-c2cccc3cc(C(C)=CC(=O)O)oc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[7-(2-Ethoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid was isolated as a white solid. 1H-NMR (CDCl3), δ: 7.65 (d, J=7.5 Hz, 1H, Ar—H), 7.56 (d, J=7.7 Hz, 1H, Ar—H), 7.33 (d, J=2.0 Hz, 1H, Ar—H), 7.29 (t, J=7.6 Hz, 1H, Ar—H), 7.16 (d, J=2.0 Hz, 1H, Ar—H), 7.11 (s, 1H, furan-H), 6.60 (s, 1H, C═C—H), 3.43 (m, 3H, CH3—CH—CH3, O—CH2—CH3), 2.95 (m, 1H, CH3—CH—CH3), 2.57 (s, 3H, C═C—CH3), 1.31 (d, J=6.9 Hz, 12H, CH3—CH—CH3), 0.97 (t, J=7.0 Hz, 3H, O—CH2—CH3).
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:17])([F:16])[C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][CH:13]=1.B(OC)(OC)[O:19]C.N>CCCCCC.O1CCCC1.CN(C)CCN(C)C>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:16])([F:17])[F:6])[C:9]=1[OH:19]
Reactant: COc1cccc(C(F)(F)F)c1
Reactant: COB(OC)OC
Agent: CN(C)CCN(C)C
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C(F)(F)F)c1O
Temperature: -78 °C

Procedure:
A solution containing 160 ml of 1.6 molar butyllithium in hexane, 300 ml of tetrahydrofuran and 40 ml of N,N,N',N'-tetramethylethylenediamine was cooled to -78° C. and 43.3 g of 3-trifluoromethylanisole was added with stirring under nitrogen atmosphere. The solution was allowed to warm up to room temperature and cooled then again to -78° C. after which 35 ml of trimethyl borate was added. The solution was warmed up to 20° C. and 50 ml of conc. ammonia solution was added. The solvents were evaporated in reduced pressure and to the residue 60 ml of 98-100% formic acid followed with 25 ml of 35% hydrogen peroxide were added. The solution was extracted with ether-petroleum ether (1:1). The organic phase was separated and the product was extracted with 2.5 N NaOH-solution. The aqueous phase was acidified with hydrochloric acid and the product was extracted in dichloromethane. The solvent was removed for the most part in vacuo after which petroleum ether was added. The crystalline product was filtered, yield 8.5 g (18%), m.p. 51°-53° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C:13]2([C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)Cl)=[CH:4][CH:3]=1.[N:25]#[C:26][NH2:27]>O1CCOCC1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C:13]32[C:17]2=[N:18][CH:19]=[CH:20][N:21]2[C:26]([NH2:27])=[N:25]3)=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: COc1cc(F)c2c(c1)C(Cl)(c1ncc[nH]1)c1cc(Br)ccc1O2
Solvent: C1COCCO1
Product: COc1cc(F)c2c(c1)C1(N=C(N)n3ccnc31)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To 2-(7-bromo-9-chloro-4-fluoro-2-methoxy-9H-xanthen-9-yl)-1H-imidazole (10 g, 24.41 mmol) was added a solution of cyanamide (1.539 g, 36.6 mmol) in dioxane (244 mL). The solution was stirred at RT for 30 minutes. The solution was then heated at reflux for 6 hrs until only a product peak was seen by LCMS. The solution was concentrated under vacuum. The solution was quenched with 500 ml of saturated sodium bicarbonate and 500 ml of water, and sonicated for 30 minutes. The product was then collected by filtration. The solid was then triturated with DCM and dried under vacuum to afford 7′-bromo-4′-fluoro-2′-methoxyspiro[imidazo[1,5-a]imidazole-7,9′-xanthen]-5-amine (10 g, 24.4 mmol) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[N:18]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C(Cl)Cl>[CH3:42][S:39]([O:16][CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:5]2[CH:4]=[C:3]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[N:18]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:14][CH2:13]1)(=[O:41])=[O:40]
Reactant: OC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round-bottom flask containing (trans-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methanol (obtained following example 2) (102 mg, 0.231 mmol) at 0° C. was added DCM (2 ml) and triethylamine (0.048 ml, 0.347 mmol), followed by dropwise addition of Mesyl Chloride (0.023 ml, 0.301 mmol). The ice bath was removed and the reaction mixture was stirred at rt for 2 hr. The reaction mixture was diluted with DCM and washed with sat NaHCO3 and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to yield (trans-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methyl methanesulfonate (110 mg, 92% yield), LCMS (m/z): 519.2 (MH+), retention time=0.80 min. The resulting residue was used in next step without further purification.
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[N:5]=1)=O.[OH-].[K+:18]>C(O)C>[NH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[O:16])[C:11]([O-:13])=[O:12])[N:5]=1.[K+:18]
Reactant: CCOC(=O)C(=O)c1nccc(NC=O)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccnc(C(=O)C(=O)[O-])n1
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)glyoxylate and its monohydrate obtained in Preparation 6-(1) was dissolved in ethanol (30 ml.) and thereto was added dropwise 1 N ethanol solution of potassium hydroxide (11 ml.) under ice-cooling with stirring, and then stirring was continued for 2 hours at ambient temperature. The reaction mixture was filtered and the filtered precipitates were washed successively with a small amount of ethanol and diethyl ether and then dried to give a brown powder of potassium 2-(4-aminoprimidin-2-yl)glyoxylate (0.4 g.). The filtrate and washings were combined together and concentrated to the volume of about 15 ml, and to the residue was added diethyl ether (20 ml.). The precipitates were collected by filtration and washed successively with a small amount of ethanol and diethyl ether to give further a pale brown powder of a mixture of potassium 2-(4-aminopyrimidin-2-yl)glyoxylate and its monohydrate (0.8 g.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([S:20](Cl)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:21])=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: NCCCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
8-Aminooctanoic acid (1.0 g, 0.006 mol) was treated with 3,4-dichlorobenzenesulphonylchloride (1.54 g, 0.006 mol), according to the method described in Example 4, to give the title compound which was recrystallised from 2-propanol/water (1.2 g, m.p. 115°-6° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][C:3]=1[S:15](=[O:18])(=[O:17])[NH2:16].O1CCCC1.ClC(OCC)=O.[CH3:30][NH2:31]>C(N(CC)CC)C>[OH:14][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:4]=2)[N:31]([CH3:30])[C:11](=[O:12])[CH2:10][CH2:9]1
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1S(N)(=O)=O
Reactant: CN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C2(O)CCC(=O)N2C)cc1S(N)(=O)=O

Procedure:
9.4 g of 4-(4-methyl-3-sulfamoylphenyl)-4-oxobutanoic acid are reacted analogously to the instructions indicated in Example 1 using 64 ml of absolute tetrahydrofurane, 6.7 ml of triethylamine, 4.7 ml of ethyl chloroformate and 90 ml of 40% strength aqueous methylamine solution to yield 5-hydroxyl-1-methyl-5-(4-methyl-3-sulfamoylphenyl)-2-oxopyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@:10]([OH:18])([CH:15]([CH3:17])[CH3:16])[CH2:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH3:19][C@H](N)C1C=CC=CC=1>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C@@:10]([OH:18])([CH:15]([CH3:16])[CH3:17])[CH2:11][C:12]([OH:14])=[O:13])=[C:6]([CH3:19])[CH:7]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)[C@@](O)(CCc1ccc(F)cc1)CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1CC[C@](O)(CC(=O)O)C(C)C
Temperature: 25 °C

Procedure:
Compound G-16 (enriched—62% (S)-enantiomer/38% (R) enantiomer) (11.1 g, 41.5 mmol) was dissolved in 120 mL EtOAc and treated with (S)-α-methylbenzylamine (6.52 g, 53.79 mmol). The resulting suspension was heated to reflux until all solids dissolved, at which time the solution was allowed to cool to room temperature overnight. The reaction flask was cooled to 0° C. for 1 hour. The resulting solids were filtered off and washed with cold Et2O. HPLC analysis of isolated solid (as the free acid): (AS chiralpak column, 0.8 mL/min., 98% Hexanes/2% IPA/+0.1% Formic acid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.[S:16](=O)(=[O:19])([OH:18])[OH:17]>>[NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][CH2:13][O:14][S:16](=[O:18])(=[O:17])[OH:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1cccc(S(=O)(=O)NCCO)c1
Solvent: O
Product: Nc1cccc(S(=O)(=O)NCCOS(=O)(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
216 g of 3-amino-N-(2-hydroxyethyl)-benzenesulphonamide are stirred into 0.4 liter of sulphuric acid monohydrate at 0°-5° C., whilst cooling. The mixture is subsequently stirred, first at 0°-5° C. for 1 hour and then at 15°-20° C. for 3 hours. The solution is then discharged onto about 2.5 liters of ice-water, the temperature being kept below 5° C. The resulting precipitate is allowed to settle, the sulphuric acid solution is largely distilled off, the reaction product is filled up to a volume of about 1 liter with ice-water, the mixture is neutralised by adding 45.0% strength sodium hydroxide solution dropwise, whilst cooling, and the resulting precipitate is filtered off. It is washed with a little water and can be employed in the subsequent diazotisation reaction as a moist paste. If the precipitate is dried, about 200 g of sulphuric acid mono-N-(3-amino-phenylsulphonyl)-2-aminoethyl ester are obtained. ##STR17##
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([Cl:19])[C:5]=1[C:6]([O:8]CC)=[O:7]>O.C(O)C>[Cl:3][C:4]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:11]([Cl:19])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 71.7 %

Procedure:
A solution of sodium hydroxide (41.6 g) in water was added to a solution of ethyl 2,6-dichloro-4-trifluoromethylbenzoate (96.3 g) in ethanol. The mixture was heated at reflux for 2.5 hours then cooled and evaporated. It was diluted with water and extracted with ether. The aqueous layer was acidified to pH1 and extracted with ether, washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with n-hexane and filtered to give 2.6-dichloro-4-trifluoromethylbenzoic acid (62.3 g) as a white solid mp 138.5°-139° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[Li]CCCC.CN([CH:20]=[O:21])C.Cl>O1CCCC1.O>[CH:20]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[O:21]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a stirred solution of 3-bromo-4-methylbenzoic acid (2.14 g, 10.00 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) under nitrogen at −78° C. was added n-BuLi (10 mL, 2.5 M in THF, 2.50 equiv) dropwise. After stirring for 1 h below −70° C., DMF (5 mL) was slowly added. The resulting solution was warmed slowly to room temperature and stirred for 1 h. After carefully quenching the reaction by slowly adding 50 mL of water, the pH was adjusted to ˜3-4 using aqueous HCl (6 M). The resulting mixture was extracted with 2×50 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1.6 g (98%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[O:9].[CH3:11][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]([OH:9])[CH3:11]
Reactant: C[Mg]Br
Reactant: O=Cc1c(Cl)cncc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)cncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 3-Bromo-5-chloro-pyridine-4-carbaldehyde (440 mg, 2 mmol) in THF (8 mL) was added methylmagnesium bromide (3M solution in THF, 2 mL, 6 mmol) at −36° C. After 1 h, the resulting mixture was warmed to 0° C., and saturated NH4Cl solution was added. The mixture was extracted with ethyl acetate, and washed with brine. The combined extracts were separated, dried over MgSO4 and concentrated. The residue was passed though a pad of silica gel and eluted with EtOAc/Heptane (v/v, 1:1). After concentration, 370 mg of title compound was obtained without further purification. ESI-MS m/z: 237.8 [M+1]+, Retention time 1.20 min. 1H-NMR (CDCl3, 400 MHz) δ 1.56 (d, J=6.8 Hz, 3H), 5.43 (q, J=6.8 Hz, 1H), 8.40 (1H), 8.52 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34](=[O:40])[NH:35]2>>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1/[C:33](=[CH:21]/[C:3]1[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:7](=[O:20])[C:6]=3[C:2]=1[CH3:1])/[C:34](=[O:40])[NH:35]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 80.9 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d obtained from step 3 of Example 6 as starting materials to obtain (Z)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 33 (51 mg, yield 80.9%) as a yellow solid.