Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5].[F:18][C:19]1[CH:20]=[C:21]([Mg]Br)[CH:22]=[C:23]([F:25])[CH:24]=1.CCOCC>C1COCC1>[F:18][C:19]1[CH:20]=[C:21]([CH:22]=[C:23]([F:25])[CH:24]=1)[C:4]([CH:6]1[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:9]1)=[O:5]
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(C(=O)c2cc(F)cc(F)c2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1.19 g (4.87 mmol) of tert-butyl 3-{[methoxy(methyl)amino]carbonyl}azetidine-1-carboxylate in 15 mL of THF was added to a solution of 14.6 mL (7.31 mmol) of 3,5-difluorophenylmagnesium bromide (0.5M in THF). The reaction mixture was stirred for 2 h at 0° C., then poured into 100 mL of ether and washed with 10 mL of water. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound. 1NMR (CDCl3) δ 1.48 (s, 9H), 4.08 (m, 1H), 4.24 (m, 4H), 7.36 (m, 1H), 7.38 (m, 2H).
Reaction SMILES: [OH-:1].[Na+].[NH2:3][C:4](C#N)=[C:5]([NH:8][CH:9]=[NH:10])[C:6]#[N:7].Cl>O>[CH:9]1[NH:8][C:5]([C:4]([NH2:3])=[O:1])=[C:6]([NH2:7])[N:10]=1
Reactant: N#CC(N)=C(C#N)NC=N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)c1[nH]cnc1N

Procedure:
Water (50 ml) and an aqueous solution of 25% NaOH (43.0 g) were added to 8 g of N-(2-amino-1,2-dicyanovinyl) formamidine (hereinafter abbreviated as AMD), and reacted under reflux for 2 hours. This aqueous solution was cooled to room temperature or below and adjusted the pH to 7 by adding 35% hydrochloric acid. The reaction solution was concentrated and exsiccated under reduced pressure followed by adding ethanol, and subsequently insoluble sodium chloride was filtrated and removed. The filtrate was treated with activated carbon and then concentrated to afford an ethanol solution of AICA. To lower the pH to 3 or less, 35% hydrochloric acid was added to this, cooled to 10° C. or less, and subsequently generated crystal was filtrated. This crystal was dried to yield 8.1 g of 4(5)-aminoimidazole-5-carboxamide (hereinafter abbreviated as AICA) hydrochloride (yield: 84%).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:20]([F:21])=[CH:19][N:18]=[C:17]([Cl:22])[N:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:23]I>CN(C=O)C>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:23])[C:15]1[C:20]([F:21])=[CH:19][N:18]=[C:17]([Cl:22])[N:16]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1nc(Cl)ncc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCO[Si](C)(C)C(C)(C)C)c1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
Sodium hydride (0.4 g, 16.76 mmol) was added to a solution of N-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-chloro-5-fluoro-4-pyrimidinamine (Example 81, 2.68 g, 8.38 mmol) in DMF (41.90 mL). The resulting mixture was stirred at rt for 30 minutes. Methyl iodide (2.09 mL, 33.51 mmol) was added. The mixture was stirred at rt for additional 18 h, then quenched with water, and extracted with ether. The combined ether extracts were washed with water (25 mL), brine (40 mL), dried over magnesium sulfate, filtered, and concentrated. The title compound (2.76 g, 99%) was obtained after column chromatography (67% hexanes in EtOAc). 1H NMR (300 MHz, CD2Cl2) δ 7.78 (d, 1H), 3.64-3.59 (m, 4H), 3.24 (d, 3H), 1.82-1.73 (m, 2H), 0.84 (s, 9H), 0.001 (s, 6H).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (337 mg, 1.0 mmol) and commercially available 3-bromobenzene-1-sulfonamide [CAS 89599-01-9](307 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (150 mg, 31%). MS (ISP) 493.0[(M+H)+]; mp 246–247° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([N:14]1[CH:19]=[CH:18][C:17](=[O:20])[CH2:16][C@H:15]1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:13])[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[N:6]=[C:5]2[CH3:38].FC(F)(F)C(O)=O>CSC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([N:14]1[CH:19]=[CH:18][C:17](=[O:20])[CH2:16][C@H:15]1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:13])[NH:7][N:6]=[C:5]2[CH3:38]
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(NC(=O)N4C=CC(=O)C[C@H]4c4ccc(F)cc4)cc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: Cc1n[nH]c2cc(NC(=O)N3C=CC(=O)C[C@H]3c3ccc(F)cc3)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
(S)-2-(4-Fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid [5-bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-yl]-amide (40 mg, 0.07 mmol) was dissolved in dimethylsulfide (5 ml) at room temperature. Trifluoroacetic acid (1 ml) was added and the mixture was allowed to stir at room temperature overnight. The solution was concentrated in vacuo, and the residue was purified by flash chromatography (gradient 9:1 to 1:1 Hexanes/Ethyl Acetate) to give (S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (5-bromo-3-methyl-1H-indazol-6-yl)-amide 30 mg (90.0%) of an off-white foam. MS (ES+) m/z 443 (M+H).
Reaction SMILES: [CH:1]1([N:4]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[S:33][C:34]2[CH2:61][CH2:60][CH2:59][CH2:58][C:35]=2[C:36]=1[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48]2[CH:57]=[CH:56][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:50][CH:49]=2)=[CH:42][CH:41]=1)=[O:38]>CN(C=O)C.ClCCl.N1C=CC=CC=1>[CH:1]1([N:4]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH:31][C:32]2[S:33][C:34]3[CH2:61][CH2:60][CH2:59][CH2:58][C:35]=3[C:36]=2[C:37]([NH:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:56][CH:57]=3)=[CH:44][CH:45]=2)=[O:38])=[O:12])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: CCOC(=O)CCCN(C1CC1)S(=O)(=O)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C1CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of 3.00 g of 3-[cyclopropyl(4-ethoxy-4-oxobutyl)sulfamoyl]benzoic acid, 0.70 mL of oxalyl chloride, 33 mL of dichloromethane, and one drop of DMF was stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure. A mixture of the obtained crude product and 33 mL of dichloromethane was added to a mixture of 0.70 mL of pyridine, 3.33 g of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, and 33 mL of dichloromethane, followed by stirring at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform) and column chromatography (ethyl acetate) using NH silica gel in this order. The obtained solid was washed with ethanol to obtain 4.82 g of methyl 4-{2-[4-({[2-({3-[cyclopropyl(4-ethoxy-4-oxobutyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:37]=[N:38][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:41]=3)=[CH:32][C:31]=2[C:46]2[CH:51]=[CH:50][N:49]=[N:48][CH:47]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.O1CCOCC1>Cl>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:37]=[N:38][C:39]([C:42]([F:43])([F:45])[F:44])=[CH:40][CH:41]=3)=[CH:32][C:31]=2[C:46]2[CH:51]=[CH:50][N:49]=[N:48][CH:47]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)nc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccc(C(F)(F)F)nc3)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(2-(pyridazin-4-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)phenoxy)-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 58, 250 mg, 0.329 mmol) was dissolved in a 4M solution of HCl in 1,4-dioxane (0.9 mL, 3.29 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The resulting residue was purified by reverse phase chromatography on the ISCO system using acetonitrile:water0.1% formic acid to afford the title compound (160 mg, 80%) as a white solid.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[N:8][S:7]1(=[O:14])=[O:13]>C(O)C>[OH:3][CH:4]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[NH:8][S:7]1(=[O:13])=[O:14]
Reactant: COc1cc2ncnc(N3CCC(C(=O)CN4C=CC(C)=NS4(=O)=O)CC3)c2cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc2ncnc(N3CCC(C(O)CN4CCC(C)NS4(=O)=O)CC3)c2cc1OC

Procedure:
Sodium borohydride (40 mg) was added at 0° to a stirred solution of 2-{2-oxo-2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]ethyl}-5-methyl-1,2,6-thiadiazine-1,1-dioxide (0.4 g) in ethanol (10 cm3). After 2 hours the volatile material was removed in vacuo and the residue was partitioned between water (10 cm3) and dichloromethane (20 cm3). The dried organic extract was evaporated to give a solid which was chromatographed on silica ("Merck" 60.9385) eluting with methanol:chloroform, 1:19, to give a foam which was crystallised from ethyl acetate to afford 2-{2-hydroxy-2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]ethyl}-5-methyltetrahydro-1,2,6-thiadiazine-1,1-dioxide as microcrystals, m.p. 189°-193° (0.30 g).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:25])[CH2:18][CH:19]([CH3:24])[CH2:20][C:21](O)=[O:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].O>C1COCC1>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:25])[CH2:18][CH:19]([CH3:24])[CH2:20][CH2:21][OH:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)O)ccc21
Solvent: O
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CCO)ccc21
Reaction time: 14 h
Yield: 53.6 %

Procedure:
To a solution of the compound obtained in Step 1 (1.0 g, 2.96 mmol) in THF (10 mL) was added a THF (5.91 mL, 5.91 mmol) solution of 1M borane-tetrahydrofuran complex at room temperature, and the mixture was stirred for 14 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxy-3-methylpentanamide (0.514 g, 1.586 mmol, 53.7%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])=[N:10][C:11]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)=[C:12]([CH:17]=2)[C:13]([O:15]C)=[O:14])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])=[N:10][C:11]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)=[C:12]([CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a dried round bottom flask was added methanol (12 mL), the product of Example 84 (0.630 g; 1.21 mmol), and 3N aq. NaOH (2.42 mL, 7.26 mmol). The reaction mixture was heated at 50° C. and stirred for 2 hours. The reaction mixture was allowed to cool to room temperature. The methanol was removed in vacuo. The pH of the reaction mixture was adjusted with 2N aq. HCl solution to pH=5-6, and it was extracted with methylene chloride (5×). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford the desired product: m/e=508 (M+3); Rt=4.29 min on LCMS.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([NH2:30])[C:23]([NH2:29])=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N:38]([O-])=O.[Na+]>C(O)(=O)C.O>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:22]3[NH:30][N:38]=[N:29][C:23]3=[CH:24][CH:25]=4)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N)c(N)ccc4c3=O)cc2)CCC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nn[nH]c54)c3=O)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a suspension of {1-[4-(7,8-diamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (80 mg, 0.16 mmol) in glacial acetic acid (2 mL) and water (1 mL) at 0° C. was added NaNO2 (14 mg, 0.20 mmol). The resulting mixture was stirred at 0° C. for 30 mins, before allowing to warm to RT. After 16 hours, further NaNO2 (14 mg, 0.20 mmol) was added and the reaction mixture stirred at RT for a further 3 hours. The resultant mixture was poured onto water and the aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with NaHCO3 (2×30 mL), brine, dried (NaSO4), filtered, and the solvent removed in vacuo to give the title compound as a brown solid (51 mg, 63%). LCMS (Method G): RT=3.76 min, [M+H]+=509.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].[CH3:36][S:37](Cl)(=[O:39])=[O:38].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:28]1([N:27]([CH2:26][C@H:13]2[CH2:14][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]2[C:9]2[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:34])[F:35])=[CH:11][CH:10]=2)[S:37]([CH3:36])(=[O:39])=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNc2ccccc2)cc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN(c2ccccc2)S(C)(=O)=O)cc1)C(F)(F)F
Reaction time: 15 h
Yield: 29.6 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-((phenylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.100 g, 0.190 mmol, Example 203) in CH2Cl2 (3.0 mL) was added 4-dimethylaminopyridine (0.0046 g, 0.038 mmol), methanesulfonyl chloride (0.044 g, 0.381 mmol) and Hünig's base (0.135 mL, 0.774 mmol). After 15 h at room temperature, the solvent was removed and the crude product was purified by column chromatography (24 g of silica gel, 10 to 40% acetone in hexanes) to give N-phenyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide (0.034 g) as a mixture of two isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:12]2[C:15]3[C:4]=1[CH2:5][CH2:6][CH:7]([CH2:16][NH:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])[C:8]=3[CH:9]=[CH:10][CH:11]=2.[H-].[Na+].S(OC)(O[CH3:29])(=O)=O>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:12]2[C:15]3[C:4]=1[CH2:5][CH2:6][CH:7]([CH2:16][N:17]([CH3:29])[C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])[C:8]=3[CH:9]=[CH:10][CH:11]=2
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc2cccc3c2c1CCC3CNC(=O)C1CC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2cccc3c2c1CCC3CN(C)C(=O)C1CC1

Procedure:
The compound obtained in Example 3 is reacted in the presence of NaH (1.5 eq) and dimethyl sulphate (1.2 eq). The reaction is monitored using TLC. When all the starting material has disappeared, the reaction mixture is hydrolysed and then extracted. After evaporating off the solvents, the title product is isolated by flash chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.[CH3:19][C:20]1([CH3:28])[O:27][C:25](=[O:26])[CH2:24][C:22](=[O:23])[O:21]1.N1CCCCC1>C(O)(=O)C>[CH3:19][C:20]1([CH3:28])[O:27][C:25](=[O:26])[C:24](=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:22](=[O:23])[O:21]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC1(C)OC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)C(=O)O1
Reaction time: 5 h
Yield: 69.7 %

Procedure:
To 4-nitrobenzaldehyde (15.1 g) were added a toluene (180 mL) solution, Meldrum's acid (14.4 g), piperidine (300 μL) and acetic acid (300 μL) at room temperature, and the mixture was stirred for 5 hr. Insoluble material was collected by filtration, and the obtained solid was washed with ethyl acetate (80 mL). The resulting precipitate was collected by filtration to give the title compound (19.3 g) as a pale-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][CH2:28][CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:22])[NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[CH2:29][CH2:28][CH2:27]4)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3ccc4c(c3)CCC4)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(4-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (918 mg, 3 mmol) and 5-aminoindan (399 mg, 3 mmol) in methylene chloride (30 mL) was added EDCI (580 mg, 3 mmol) and DMAP (20 mg, 0.16 mmol). The mixture was stirred at room temperature overnight and then extracted with methylene chloride (50 mL) and aqueous hydrochloric acid (1N, 20 mL). The organic layer was washed with water, then sodium hydroxide solution and finally with water and brine. The solution was dried over sodium sulfate and filtered. Solvents were evaporated and the residue was crystallized from ethyl acetate (40 mL) to give 4-[4-(indan-5-ylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester. This intermediate was dissolved in methylene chloride (5 mL) and trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 1 hr and solvents were evaporated. The residue was extracted with methylene chloride and 1N sodium hydroxide solution. The organic layer was washed with brine and dried over sodium sulfate. The product, N-indan-5-yl-4-piperazin-1-yl-benzamide was obtained after solvent evaporation (450 mg, Yield: 47%). LCMS calc for C20H23N3O (m/e) 321.42, obsd 322.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:48])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44](Br)=[CH:43][CH:42]=1)[CH3:36]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:35]([O:37][C:38](=[O:48])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:23][CH:22]=2)=[CH:43][CH:42]=1)[CH3:36]
Reactant: CCOC(=O)CCc1ccc(Br)cc1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, 3-(4-bromo-phenyl)-propionic acid ethyl ester, and bis(triphenylphosphine)palladium(II) dichloride were reacted to provide 3-(4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-propionic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]([N:17]=[C:18]=[O:19])([Cl:16])[Cl:15]>C(OCC)(=O)C>[Cl:13][C:14]([Cl:16])([Cl:15])[NH:17][C:18](=[O:19])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C=NC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1csc(NC(=O)NC(Cl)(Cl)Cl)n1
Yield: 49.7 %

Procedure:
To a solution of ethyl 2-aminothiazol-4-ylacetate (1.86 g.) in dried ethyl acetate (37 ml.) was dropwise added trichloromethylisocyanate (1.6 g.) with stirring under ice-cooling. The mixture was stirred for 2 hours at room temperature, and trichloromethylisocyanate (0.32 g.) was further added thereto, and then the mixture was further stirred for 1 hour at room temperature. After the reaction, the reaction mixture was filtered. The filtrate was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and then the solvent was distilled off therefrom. The residue was pulverized in diethyl ether to give colorless crystals of ethyl 2-(3-trichloromethylureido)thiazol-4-ylacetate (1.72 g.).