Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[C:10]([Cl:18])[CH:11]=[C:12]2[Cl:17])=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[C:3]([C:2]([NH:1][C:26](=[S:27])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=1)([CH3:19])[CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[C:10]([Cl:18])[CH:11]=[C:12]2[Cl:17])=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: COc1c2c(Cl)cc(Cl)cc2nn1CC(C)(N)C#N
Product: COc1c2c(Cl)cc(Cl)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (30 mg, described in Example 116) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (42 mg, 83%). MS (ES): M/Z [M+H]=503. 1H NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 4.12 (s, 3H), 4.94 (d, J=6.5 Hz, 2H), 7.17 (d, J=1.2 Hz, 1H), 7.62 (d, J=1.1 Hz, 1H), 7.86-7.91 (m, 2H), 7.93-7.99 (m, 2H) and 9.03 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH:10]=[O:11])[S:8][CH:9]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:5]1[CH:6]=[C:7]([CH:10]=[O:11])[S:8][CH:9]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: OB(O)c1ccco1
Agent: OBO
Product: O=Cc1cc(-c2ccco2)cs1

Procedure:
4-(furan-2-yl)thiophene-2-carbaldehyde was prepared using the general boronic acid coupling procedure with 4-bromothiophene-2-carbaldehyde and furan-2-ylboronic acid (26 mg, 93 mg theoretical, 28.0%). LC-MS m/z 179 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:6]=[CH:5][N:4]=1.[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([C:32](O)=[O:33])[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18]>>[CH3:1][N:2]([CH3:15])[C:3]1[N:4]=[CH:5][N:6]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:32]([C:22]3[CH:21]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:25]=[CH:24][C:23]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:33])[CH2:11][CH2:10]2)[N:8]=1
Reactant: CN(C)c1ncnc(N2CCNCC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Product: CN(C)c1ncnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3-c3ccccc3)CC2)n1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from Dimethyl-(4-piperazin-1-yl-[1,3,5]triazin-2-yl)-amine (Example X) and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 467.4 MH+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1)#[N:10].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:9]([C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=2)[CH:14]=[CH:13][CH:12]=1)#[N:10]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=c1cc(Cl)cn[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2cn[nH]c(=O)c2)c1
Yield: 59.7 %

Procedure:
To a mixture of 5-chloropyridazin-3(2H)-one (2.0 g, 15.3 mmol) and 3-cyanophenyl boronic acid (2.71 g, 18.4 mmol) in anhydrous toluene (20 ml) was added dichloro-(1,4-bis(diphenylphosphino)-butane)palladium (0.1 g, 0.16 mmol), and saturated aqueous sodium carbonate solution (5.0 ml) and the mixture was irradiated in a Milestone microwave reactor at 120° C. for 15 minutes. The resulting suspension was filtered and the solid was washed with isopropanol (20 ml) and dried on the sinter to give 5-(3-cyanophenyl)pyridazin-3-one (1.8 g, 50%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH:4]([NH:21][C:22]1[N:27]=[CH:26][C:25]([C:28]([O:30]C)=O)=[CH:24][N:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[Li+].[OH-].Cl.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(C(C)C)CC)(C)C.[NH2:57][C:58]1[NH:62][N:61]=[N:60][N:59]=1>O1CCCC1>[CH3:32][CH:2]([CH3:1])[CH2:3][CH:4]([NH:21][C:22]1[N:27]=[CH:26][C:25]([C:28]([NH:57][C:58]2[NH:62][N:61]=[N:60][N:59]=2)=[O:30])=[CH:24][N:23]=1)[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1cnc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Reactant: Nc1nnn[nH]1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(Nc1ncc(C(=O)Nc2nnn[nH]2)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 4.5 %

Procedure:
To a solution of methyl 2-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)pyrimidine-5-carboxylate (Example 1.4, step A) (0.220 g, 0.496 mmol) in anhydrous tetrahydrofuran (8 mL) was added 2M LiOH (8 mL) slowly at 0° C. The mixture was heated to 50° C. and stirred for 48 hours. The mixture was neutralized with 1N HCl and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylformamide (20 mL) and 1,1′-carbonyldiimidazole (123 mg, 0.757 mmol) and diisopropylethylamine (113 mg, 0.873 mmol) were added. The mixture was stirred for 30 minutes at 80° C. 5-Aminotetrazole (148 mg, 1.75 mmol) was then added to the reaction mixture. The resulting mixture was stirred overnight at 80° C. The mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by preparative HPLC gave (+/−)-2-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)-N-(1H-tetrazol-5-yl)pyrimidine-5-carboxamide (11 mg, 3.8%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.87 (s, 2H), 7.78 (d, 2H), 7.26 (d, 2H), 7.64 (d, 2H), 7.51 (d, 2H), 5.32-5.26 (m, 1H), 1.95-1.89 (m, 1H), 1.78-1.65 (m, 2H), 1.01 (d, 3H), 0.99 (d, 3H) ppm. MS (M+1): 495.1.
Reaction SMILES: [CH3:1][C:2]([C:11]1[O:15][N:14]=[C:13]([NH2:16])[CH:12]=1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C1COCC1>[CH3:10][C:2]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:24](=[O:25])[O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=1)([CH3:1])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(CN1CCOCC1)c1cc(N)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(CN1CCOCC1)c1cc(NC(=O)Oc2ccccc2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 637 %

Procedure:
To a stirred mixture of 5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-amine (20 mg, 0.010 mmol) and potassium carbonate (25 mg, 0.181 mmol) in THF (6 mL) at 0° C., was added dropwise phenyl chloroformate (0.010 mL, 0.08 mmol). The reaction mixture was warmed to rt and stirred for a further 15 h. The reaction mixture was filtrated and the filtrate washed with saturated aqueous sodium carbonate, then brine, and concentrated under reduced pressure. The residue was dissolved in dichoromethane and dried over sodium sulfate then filtrated. The filtrate was concentrated under reduced pressure to give the crude product. Purification via recrystallization from a mixture of diethyl ether and hexanes, afforded phenyl 5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-ylcarbamate (22 mg) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]=[C:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(OC(C1CC(C(OCC)=O)=C(C)NC=1C)=O)C.C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=C3SC(=O)NC3=O)cn2)cc1Cl
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(CC3SC(=O)NC3=O)cn2)cc1Cl
Temperature: 90 °C
Yield: 57.5 %

Procedure:
A suspension of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-pyrazin-2-yl]-propionamide (150 mg, 0.28 mmol), 2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester (92.5 mg, 0.37 mmol), and silica gel (450 mg) in anhydrous toluene (12 mL) was heated at 90° C. for 12 h. The reaction mixture was then allowed to cool to 25° C. and then was acidified to pH=2 with acetic acid. The silica gel was removed by filtration and washed with a small amount of methanol. The product was then extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/9 to 7/3 ethyl acetate/hexanes) afforded the 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,4-dioxo-thiazolidin-5-ylmethyl)-pyrazin-2-yl]-propionamide (86.5 mg, 57%) as a white solid: LC-MS m/e 537 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][N:10]=1)=[O:8])C.CO.O.O[Li].O>C1COCC1>[C:14]1([C:12]2[NH:11][N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:20])=[O:3])=[O:8])[CH:13]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reaction time: 2 h
Yield: 38.8 %

Procedure:
To a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid (1.25 g, 0.00665 mol) in DMF (3 mL) was added DIPEA (4.296 g 0.03324 mol), HOBt (1.123 g, 0.00831 mol) and EDCI.HCl (1.593 g, 0.00831 mol) at ambient temperature. After 2 minutes glycine acid ethyl ester hydrochloride (0.928 g, 0.00665 mol) was and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.76 g (42% of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid ethyl ester. LCMS: 274.11 (M+1)+, 96.7%. To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid ethyl ester (0.615 g, 0.0025 mol) in a mixture of THF (10 mL), methanol (5 mL) and H2O (5 mL) was added LiOH.H2O (0.283 g, 0.00675 mol) at ambient temperature. The reaction mixture was stirred at the same temperature for 2 hours. Volatiles were evaporated and the residue was diluted with water, acidified with 10% HCl solution. The resulting precipitate was isolated by filtration, washed water followed by hexane and to afford 0.238 g (38%) of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid. LCMS: 246.08 (M+1)+, 95.60%
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30](O)=[O:31])[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:42][O:43][C:44]1[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=1[NH2:46]>>[CH3:42][O:43][C:44]1[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=1[NH:46][C:30](=[O:31])[CH2:29][CH2:28][O:27][C:17]1[C:16]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=2)(=[O:12])=[O:13])[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:18]=1
Reactant: COc1ccccc1N
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Product: COc1ccccc1NC(=O)CCOc1nc(N2CCOCC2)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy] propionic acid and 2-methoxyaniline, to thereby obtain the title compound as a colorless oil.
Reaction SMILES: [C:1]1(=[O:34])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:28])[C:14](=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[C:15]([CH3:17])=O)[C:4](=[O:29])[C:3]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:2]12.[CH3:35][O:36][C:37](=[O:42])/[CH:38]=[C:39](\[NH2:41])/[CH3:40]>>[CH3:40][C:39]1[NH:41][C:15]([CH3:17])=[C:14]([C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]2[C:4](=[O:29])[C:3]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:2]3[C:1]2=[O:34])=[O:28])[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[C:38]=1[C:37]([O:36][CH3:35])=[O:42]
Reactant: CC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)OCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)/C=C(/C)N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN2C(=O)c3ccccc3C2=O)C1c1ccccc1[N+](=O)[O-]
Yield: 34.5 %

Procedure:
Prepared by a method analogous to that of Example 7(a) from 23.0 g (50 mmol) of 2-(2-nitrobenzylidene)-aceto acetic acid-(6-phthalimidohexyl)ester and 5.7 g (50 mmol) of 3-amino-crotonic acid methyl ester. 9.7 g (35%) of a dark yellow oil obtained after column chromatographic purification on silica gel with dichloromethane/methanol (98:2) as solvent.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:21]=[O:22].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]([C:3]1[CH:4]=[C:5]([O:6][C:7]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH:19]=[CH:20][C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(Br)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(-c2ccccc2)c(C=O)c1
Yield: 98.9 %

Procedure:
To a mixture of 2-(4-bromo-3-formyl-phenoxy)-4-trifluoromethyl-benzonitrile (1.76 g, 4.76 mmol) and Pd(dba)3 (21.8 mg, 5 mole %) in dimethoxyethane (15 ml) was added a solution of phenylboronic acid (609 mg, 5 mmol), triphenylphosphine (15 mg, 12 mole %) and sodium carbonate (530 mg, 5 mmol) in water (10 ml). The mixture was refluxed for 3 h. The solvent was evaporated off and the aqueous layer was extracted with dichloromethane. The extracts were dried with MgSO4 and filtered through silica. Evaporation yielded a brown solid (1.73 g, 99%).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1)=[O:14])=O)C1C=CC=CC=1>[Pd]>[NH2:11][CH2:12][C:13]([NH:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)OCc2ccccc2)C1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1

Procedure:
To a flask containing tert-butyl 3-(2-(((benzyloxy)carbonyl)amino)acetamido)azetidine-1-carboxylate (9.26 g, 25.5 mmol) and a stirbar, was added 10% Pd/C (1.356 g, 1.27 mmol). The flask was evacuated and back filled with argon. Methanol (100 mL) was carefully added via syringe and the flask was evacuated with stirring. It was then back filled with hydrogen and stirred 2 days under a hydrogen balloon. After evacuation with stirring and back filling with argon, the catalyst was removed by filtration over Celite 521 and concentrated in vacuo to afford the product.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([CH:13]1[S:17][C:16](=[O:18])[NH:15][C:14]1=[O:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[S:17]1[CH:13]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:9][CH:8]=2)[C:14](=[O:19])[NH:15][C:16]1=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: O=C1NC(=O)C(Cc2ccccc2)S1
Product: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)Cl)cc2)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Chlorosulfonic acid (5 ml) was cooled to 0° C. and the 5-benzyl-2,4-thiazolidinedione prepared above (9.6 mmol, 2.0 g) was added portionwise. The reaction mixture was stirred at room temperature for 0.5 hour and poured into ice (25 g). The solution was extracted with methylene chloride (2×50 ml) and the organic layers were dried (Na2SO4) and solvent removed in vacuo to afford title product which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[CH2:24]([N:31]1[CH:35]=[N:34][C:33]([C:36](O)=[O:37])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:36]([C:33]1[N:34]=[CH:35][N:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:32]=1)=[O:37])[CH3:2]
Reactant: O=C(O)c1ncn(Cc2ccccc2)n1
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Product: CCOC(=O)C(C(=O)c1ncn(Cc2ccccc2)n1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1

Procedure:
The title compound, a colorless oil (1.1 g, 50%), was prepared in analogy to intermediate 8A by reaction of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) with 1-benzyl-1H-[1,2,4]triazole-3-carboxylic acid. MS: 517.2 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:16]1([CH2:22][CH2:23][NH:24][C:25](N2C=CN=C2)=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:22][CH2:23][NH:24][C:25]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(NCCN1CCCCC1)n1ccnc1
Reactant: NCCNC(=O)OCc1ccccc1
Agent: Cl
Product: O=C(NCCNC(=O)OCc1ccccc1)NCCN1CCCCC1

Procedure:
Prepared from benzyl 2-aminoethylcarbamate hydrochloride and N-[2-(1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (Preparation 18) by a similar procedure to Preparation 50. The title compound was obtained as a yellow oil.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].N1C=CC=CC=1.[C:27](Cl)([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].O>C(Cl)Cl>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
In a two neck round bottom flask, 1-(naphthalene-2-ylsulfonyl)piperazine hydrochloride (compound 4, 0.72 mmoles, 0.200 g) and pyridine (7.22 mmoles, 2 mL) were charged in DCM (20 mL) at 0° C. CBZCl (1.08 mmoles, 0.30 g) was added slowly at the same temperature and then allowed the reaction mixture to stir for 3 h at room temperature. After completion of the reaction, water (10 mL) was added and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by Column Chromatography (Silica gel 60-120, MeOH/DCM) to obtain the title compound (0.150 g, 50.6%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:20])[CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:20][Br:21])[CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2oc3ccc(C)cc3c(=O)c12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc2oc3ccc(CBr)cc3c(=O)c12
Temperature: 25 °C
Yield: 44.8 %

Procedure:
Brominating agents include N-bromosuccinimide, bromine, complexed bromine such as pyridinium bromide, and the like can be used to convert 7-methyl-9-oxoxanthene-1-carboxylic acid methyl ester 40 to 7-bromomethyl-9-oxoxanthene-1-carboxylic acid methyl ester 41. Solvents include chlorinated hydrocarbons, dipolar aprotic solvents, and various ethers. Temperature can range from 0-100 C. For example, a suspension of 7-methyl-9-oxoxanthene-1-carboxylic acid methyl ester (0.1 mol), N-bromosuccinimide (0.12 Mol) and benzoylperoxide (10 mg) in dry carbon tetrachloride (300 mL) is stirred at 60 C for 6 hours. The mixture is filtered, and the solid is washed successively with small amounts of chloroform, water and ether, and then dried to leave a desired product as white solid. For example, to a solution of compound 40 (1.97 g, 7.4 mmol) in carbon tetrachloride (400 mL) was added N-bromosuccinimide (1.44 g, 8.1 mmol) and a catalytic amount of benzoyl peroxide (45 mg, 3%). The reaction mixture was heated to reflux for 6 h and cooled to room temperature. The white precipitate was filtered out. The solvents were removed and the residue was recrystallized from EtOAc and hexanes. The crude product (2.05 g) was obtained and further recrystallization gave a pure white solid product 41 (1.15 g, 45%). 1H NMR (400 MHz, CDCl3) of 2: 8.27 (d, J=2.5 Hz, 1H), 7.80-7.72 (m, 2H), 7.57 (dd, J=8.5 and 1.1 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.33 (dd, J=7.0 and 1.1 Hz, 1H), 4.57 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[N:3]=[N:4][C:5]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nn1
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccc(Br)nn2)c([N+](=O)[O-])c1
Yield: 61.2 %

Procedure:
3.0 g of 3,6-dibromopyridazine was dissolved in 15 ml of dimethyl sulfoxide. To this solution, a mixture of 2.0 g of 4-amino-2-nitrophenol, 3.6 g of potassium carbonate and 10 ml of water was added and, after flushing with nitrogen, the mixture was reacted at a temperature of from 100° to 110° C. for 2 hours. After the completion of the reaction, the reaction product was cooled and poured into water, and then extracted with methylene chloride. The extract layer was washed with an aqueous sodium hydroxide solution and then with water, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, whereby 2.4 g of 4-(6-bromo-3-pyridazinyloxy)-3-nitroaniline was obtained. (2) 1.0 g of 4-(6-bromo-3-pyridazinyloxy)-3-nitroaniline obtained in the above step (1) was dissolved in 20 ml of dioxane. To this solution, 8 ml of a dioxane solution containing 0.62 g of 2-nitrobenzoyl isocyanate was added, and the mixture was reacted at room temperature for 15 hours. After the completion of the reaction, the reaction product was poured into water and collected by filtration. The obtained solid was dried and, after the addition of methylene chloride, again subjected to filtration, whereby 1.0 g of the desired product having a melting point of from 222° to 225° C. was obtained.