Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH:7]([CH3:9])[CH3:8])[CH:3]=1.Cl.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][C:23](=[NH:26])OC)=[CH:16][CH:15]=1)([O-:13])=[O:12].NO.Cl.NO.C[O-].[Na+]>CO>[CH3:8][CH:7]([C:4]1[CH:3]=[C:2]2[N:6]([NH:26][C:23]([CH2:22][CH2:21][CH2:20][C:17]3[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=3)=[N:1]2)[N:5]=1)[CH3:9]
Reactant: CC(C)c1cc(N)[nH]n1
Reactant: COC(=N)CCCc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CC(C)c1cc2nc(CCCc3ccc([N+](=O)[O-])cc3)[nH]n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
5-Amino-3-(1-methylethyl)pyrazole (12.5 g) was dissolved in methanol (40 ml) and to the resulting solution was added methyl 4-(p-nitrophenyl)butaneimidate hydrochloride (25.9 g) and the resulting mixture was stirred for 2 hours at room temperature. To this mixture was further added a methanol solution of hydroxylamine prepared by hydroxylamine hydrochloride (6.95 g) and a 28% methanol solution of sodium methoxide (19.3 g), and the resulting mixture was left to stand overnight at room temperature. After the solvent was distilled off under reduced pressure, the residue was added to water and extracted by ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (200 ml), and triethylamine (12.0 ml) was added and the resulting mixture was stirred in a water bath. p-Toluenesulfonic acid chloride (16.0 g) was gradually added to the mixture, and the resulting mixture was stirred for 1 hour without water bath. The insoluble matter was filtered off, and the filtrate was concentrated. The residue was dissolved in methanol (600 ml) and heated under refluxing for 3 hours. The methanol was distilled off under reduced pressure, and the residue was poured into water (1,000 ml) and extracted by ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was separated by the silica gel column chromatography (eluate: chloroform/ethyl acetate=5/1). The eluate containing the intended Compound (C) was concentrated, and the residue was recrystallized from ethyl acetate to obtain 6.2 g (20%) of 6-(1-methylethyl)-2-[3-(4-nitrophenyl)propyl]-pyrazolo[1,5-b][1,2,4]triazole (C) as pale yellow crystals (m.p.: 188°-189° C.).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][C:14]=2[O:27]CC2C=CC=CC=2)[CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3]>CO.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[OH:27])[CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)COC(=O)N1CCC(c2ccc(O)cc2O)C1
Reaction time: 18 h
Yield: 74.8 %

Procedure:
In a 25 ml round-bottomed flask, 0.22 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid isobutyl ester is dissolved in 6 ml of methanol in the presence of 0.1 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 18 hours under a hydrogen atmosphere. The reaction mixture is filtered and the residue is then chromatographed on silica gel (1/1 heptane/ethyl acetate). 0.1 g of 3-(2,4-dihydroxyphenyl)pyrrolidine-1-carboxylic acid isobutyl ester is obtained. Yield=75%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([O:18]C)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1nnn(Cc2ccc(Cl)c(Cl)c2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)nnn1Cc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a mixture of methyl 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylate (Intermediate 7) (9 g, 0.03 mol) in methanol (200 mL) was added NaOH (2.4 g) and water. The mixture was stirred overnight. Water was added and the solvent was evaporated. The residue was extracted with DCM (twice). The aqueous phase was adjusted to pH=2 with a 2N HCl solution. The formed precipitate was filtered to give the title compound as a white solid (7.29 g, 84%). LC/MS: m/z 287 (M+H)+, Rt: 2.52 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1>C(OCC)(=O)C.C(O)C.[C].[Pd]>[NH2:14][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:13]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C1CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(N)cc1C1CC1
Yield: 76.7 %

Procedure:
To a mixture of methyl 2-bromo-4-nitrobenzoate (871 mg), bis(tricyclohexylphosphine)palladium(II)dichloride (136 mg), tripotassium phosphate (3.98 g) and cyclopropylboronic acid (863 mg) were added toluene (10 mL) and water (0.4 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, and the obtained residue was purified by column chromatography (ethyl acetate:hexane) to give methyl 2-cyclopropyl-4-nitrobenzoate (285 mg). The obtained methyl 2-cyclopropyl-4-nitrobenzoate (285 mg) was dissolved in a solution of ethyl acetate and ethanol, and catalytic hydrogenation was performed using palladium carbon to give methyl 4-amino-2-cyclopropylbenzoate (189 mg). Using the obtained methyl 4-amino-2-cyclopropylbenzoate (189 mg) and 3-chloropropane-1-sulfonyl chloride (0.156 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (168 mg) was obtained.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:32])[C:7]([N:9]1[CH2:31][CH2:30][CH2:29][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:27]=[C:26]2[N:17]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=32)[N:16]=1)=[O:12])=[O:8])(=O)C>N>[SH:4][CH2:5][CH:6]([CH3:32])[C:7]([N:9]1[CH2:31][CH2:30][CH2:29][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:27]=[C:26]2[N:17]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=32)[N:16]=1)=[O:12])=[O:8]
Reactant: CC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)OCc1cc2c3ccccc3[nH]c(=O)n2n1
Agent: N
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)OCc1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
A mixture of 4.56 g (0.01 M) of (S)-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-L-proline, (5,6-dihydro-5-oxopyrazolo[1,5-c]-quinazolin-2-yl)-methyl ester and 200 cc 1.25 N of methanolic ammonia is stirred at room temperature under nitrogen for 2 hours. A clear solution forms after about 10 minutes. The solution is concentrated to dryness at 15 mm and 30° and the residue (4.4 g) dissolved in 250 cc 50% CHCl3 --CH2Cl2, washed with 2×150 cc H2O (to remove acetamide) and dried over MgSO4. The solution is concentrated to yield 3 g (75%) product, m.p. 140°-142° d.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(N(C)C)=O.CCOC(C)=O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH3:15])[CH:18]=1)=[N:1]2
Reactant: COc1cccc(C=O)c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1cccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Temperature: 140 °C
Yield: 69 %

Procedure:
A mixture of 2-amino-4,6-dimethoxybenzamide (0.0600 g, 0.306 mmol), 3-methoxybenzaldehyde (0.306 mmol), NaHSO3 (94%, 0.0474 g, 0.428 mmol), and p-TsOH.H2O (0.0175 g, 0.0918 mmol) in DMA (3.06 mL) was heated at 140° C. for 20 hours. The mixture was diluted with EtOAc (300 mL), washed with water (3×75 mL), then brine (75 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified on silica gel (40 g, CH2Cl2/MeOH) and the product was freeze-dried from MeCN/H2O to provide the title compound (69%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 12.04 (s, 1H), 7.82-7.70 (m, 2H), 7.43 (t, J=7.98 Hz, 1H), 7.13 (dd, J=8.19, 2.46 Hz, 1H), 6.76 (d, J=2.19 Hz, 1H), 6.55 (d, J=2.19 Hz, 1H), 3.92-3.82 (m, 9H); MS (APCI) m/z 313 [C17H16N2O4+H]+.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:5].[OH2:17].[OH-].[Na+]>CO>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:7]1[CH2:8][CH:6]1[C:4]([OH:17])=[O:5]
Reactant: O
Reactant: CON(C)C(=O)C1CC1c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1c1ccccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-(2-chloro-phenyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH (40 mL) was refluxed for 3 h. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was acidified by 6 N HCl followed by extraction with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (7.8 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[S:34][C:35]=1[CH3:36].O>CN(C)C=O>[CH3:36][C:35]1[S:34][C:33]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[N:32][C:31]=1[CH2:30][O:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)sc3C)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-5-methyl-2-phenylthiazole (336 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (690 mg, yield: 86%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: CC(C)[C@H](N1CC2C(=CC(C3C=CC(NS(C4C=CC=CC=4)(=O)=O)=CC=3)=CC=2)C1=O)C(O)=O.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)(=[O:44])=[O:43])=[CH:38][CH:37]=1)#[N:35]>>[C:34]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:50][CH:51]=2)(=[O:44])=[O:43])=[CH:38][CH:37]=1)#[N:35]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(C#N)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(C#N)cc4)cc3)cc2C1=O
Yield: 93 %

Procedure:
The compound of example 80 was prepared analogous to compound of example 78 by hydrolysis of compound of example 79.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.C1C(=O)N([Cl:21])C(=O)C1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH2:13][Cl:21])[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2cc(Cl)c(Cl)cc2n1
Product: ClCc1ccc2cc(Cl)c(Cl)cc2n1

Procedure:
MS (ESI) 246 (M+H)+. Prepared from 6,7-dichloro-quinaldine and NCS in place of NBS.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([O:24][CH2:25][CH:26]([F:28])[F:27])[CH:23]=[C:18]3[N:17]([CH2:29][CH3:30])[C:16]2=[O:31])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[F:28][CH:26]([F:27])[CH2:25][O:24][C:22]1[CH:23]=[C:18]2[N:17]([CH2:29][CH3:30])[C:16](=[O:31])[N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:19]2=[N:20][CH:21]=1
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(OCC(F)F)cc21
Agent: [Pd]
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(OCC(F)F)cc21
Reaction time: 8 h

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-(2,2-difluoroethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) and 10% Pd—C (37.5 mg) in EtOH (10 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 6-(2,2-difluoroethoxy)-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a colorless solid. To a solution of this product and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (153 mg) in DMF (5 ml) was added sodium hydride (34.1 mg) at 100° C., and the mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was quenched with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with sat. NaHCO3 aq. and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 15%-50% AcOEt in hexane) to give 6-(2,2-difluoroethoxy)-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (264 mg) as a colorless solid. The solid was crystallized from AcOEt-hexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][CH2:18][NH2:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:21][C:22]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:10]=[C:11]([CH2:17][CH2:18][NH:19][C:24]([C:23]2[C:22]([CH3:21])=[N:30][C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=3)=[CH:28][CH:27]=2)=[O:25])[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1cc(CCN)cc(OC)c1
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Product: CCOC(=O)C(C)(C)Oc1cc(CCNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc(OC)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-5-methoxy-phenoxy]-2-methyl-propionic acid ethyl ester was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-[3-methoxy-5-(2-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.Br[C:40]1[CH:41]=[C:42]([S:46]([NH:49][C:50]([CH3:54])([CH3:53])[CH2:51][OH:52])(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=1.CCCCCCC>C1(C)C=CC=CC=1>[OH:52][CH2:51][C:50]([NH:49][S:46]([C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=4)[N:12]=3)[CH:10]=2)[CH:41]=1)(=[O:48])=[O:47])([CH3:54])[CH3:53]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(CO)NS(=O)(=O)c1cccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.503 g, 0.7 mmol), 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (Example H.4) (0.237 g, 0.77 mmol), tetrakis(triphenyl-phosphine)palladium (0.040 g, 0.030 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (268 mg, 66%). MS (ISP) 585.2 [(M+H)+]; mp 150° C. (dec.).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[NH:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=1>O1CCOCC1.C(O)(=O)C>[Br:1][C:11]1[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:14][C:10]=1[CH3:9]
Reactant: CCOC(=O)c1[nH]c(C)cc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]c(C)c(Br)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
N-Bromo succinimide (1.40 g, 7.87 mmol) was added to a solution of ethyl 5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (1.5 g, 6.55 mmol) in a mixture of dioxane (10 mL) and acetic acid (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. The reaction mixture was warmed to room temperature and stirred for another 15 min. The mixture was quenched with 2N NaOH solution and the organic layer was separated, washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give ethyl 4-bromo-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (1.68 g, 84%) as a solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)=O.[CH3:15][C:16]1[C:17]([NH2:22])=[N:18][CH:19]=[CH:20][CH:21]=1>C(#N)C>[CH3:15][C:16]1[C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[S:12][C:11](=[O:13])[NH:10][C:9]=4[CH:14]=3)[N:22]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(CBr)c1ccc2sc(=O)[nH]c2c1
Reactant: Cc1cccnc1N
Solvent: CC#N
Product: Cc1cccn2cc(-c3ccc4sc(=O)[nH]c4c3)nc12
Yield: 65.2 %

Procedure:
A solution of 5-bromoacetyl 2-benzothiazolinone (1.75g) and 3-methyl-2-aminopyridine [2.07 g] in acetonitrile [100 ml] was refluxed for 4 hours and the reaction mixture was evaporated in vacuo. To the residue was added a mixture of water, ethyl acetate and tetrahydrofuran. The resulting mixture was adJusted to pH 8.0 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo to afford a crystalline residue, which was recrystallized from a mixture of tetrahydrofuran and diethyl ether to give 5-(8-methylimidazo-[1,2-a]pyridin-2-yl)-2-benzothiazolinone (1.18 g). mp. 272° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH3:27][S:28]([CH2:31][C:32](O)=[O:33])(=[O:30])=[O:29].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.O1CCCC1.O.CN(C)C=O>[CH3:27][S:28]([CH2:31][C:32]([O:26][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])=[O:33])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(OC(=O)CS(C)(=O)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.6 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (150 mg, 0.365 mmol), (methylsulfonyl)acetic acid (81.6 mg, 0.59 mmol), triethylamine (0.11 mL, 0.789 mmol) and 4-dimethylaminopyridine (48.0 mg, 0.39 mmol) in tetrahydrofuran (5.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (136 mg, 0.709 mmol) at room temperature. The mixture was stirred at room temperature for 3 days. (Methylsulfonyl)acetic acid (82.0 mg, 0.59 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg, 0.73 mmol), triethylamine (0.11 mL, 0.789 mmol) and N,N-dimethylformamide (10 mL) were added to the reaction mixture at room temperature. The mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on NH-silica gel eluting with a 40-70% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/diisopropyl ether to give the title compound (68.9 mg, 0.13 mmol, 36%) as colorless crystals.
Reaction SMILES: [CH:1]1([N:6]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:7](=O)[O:8]C)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[CH:1]1([N:6]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7]2=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)N(CCc1ccc(OC)cc1)C1CCCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(=O)N(C1CCCC1)CC2
Yield: 94.8 %

Procedure:
To a solution of methyl cyclopentyl(4-methoxyphenethyl)carbamate (0.830 g, 3 mmol) in POCl3 (10 mL) was added P2O5 (0.852, 6 mmol). The reaction mixture was heated at reflux for 2 h. Excess POCl3 was removed under reduced pressure and quenched with ice water. The mixture was neutralized with Na2CO3, extracted with ethyl acetate and dried over Na2SO4. Concentration of the solvent followed by chromatographic separation (silica gel, 30% EtOAc:Hexanes) afforded 2-cyclopentyl-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (0.698 g, 95%). 1HNMR (400 MHz, CDCl3): δ 7.60 (s, 1H), 7.05 (d, 1H, J=8.6 Hz), 6.93 (d, 111, J=8.6 Hz), 5.19-5.15 (m, 1H), 3.83 (s, 3H), 3.40 (t, 211, J=6.1 Hz), 2.85 (t, 2H, J=6.1 Hz), 1.90-1.89 (m, 2H), 1.72-1.53 (m, 6H). LC-MS (ESI) Calcd for C15H19NO2 [M+H]+: 246.14. Found: 246.00.