Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([O:16][C:15]([F:14])([F:24])[F:25])=[CH:18][CH:19]=1)=[O:8])=[O:5]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C=NC(=O)c1cc(F)ccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1cc(F)ccc1Cl)Nc1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
2.99 g (0.015 mol) of 2-chloro-5-fluoro-benzoyl isocyanate are added to 2.66 g (0.015 mol) of 4-trifluoromethoxyaniline in 30 ml of dry toluene, at 60° C., in the absence of moisture. The mixture is stirred for one hour at 80° C. and cooled to 20°-25° C. The precipitated product is filtered off under suction and dried in vacuo at 100° C. 5.6 g (100% of theory) of 1-(2-chloro-5-fluoro-benzoyl)-3-(4-trifluoromethoxyphenyl)-urea of melting point 199° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)C(C2C=CC=CC=2)C)=[CH:4][CH:3]=1.[S].[C:19]([OH:22])(=[O:21])[CH3:20].CNC>>[CH:4]1[C:5]([CH2:8][CH2:20][C:19]([OH:22])=[O:21])=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: CC(C(=O)c1ccc(O)cc1)c1ccccc1
Reactant: CC(=O)O
Agent: CNC
Agent: [S]
Product: O=C(O)CCc1ccc(O)cc1

Procedure:
To a one gallon autoclave reactor is charged 420 g (2.8 mol) of 4'-hydroxyphenylpropiophenone, 116.5 g (3.6 mol) of sulfur, 84 g (1.4 mol) of acetic acid and 189 g (4.2 mol) of dimethylamine. The procedure described in Example 1 is followed and 4'-hydroxyphenylacetic acid product containing less than 100 ppm of total sulfur is obtained.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=1.O>CN(C)C=O>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
Using the procedure reported in Chem. Pharm. Bull. 40(2), 351-6, 1992, sodium hydride (60% suspension in mineral oil, 1.26 g, 44 mmol) was added to 40 mL of dimethyl formamide (DMF) at 0° C., and a solution of benzenethiol (2.25 g, 22 mmol) in 5 mL of DMF was added dropwise over five minutes, followed by stirring for 30 minutes. A solution of 4-chloro-2-methoxy-1-nitro-benzene (3.25 g, 20 mmol) in 25 mL of DMF was then added dropwise to the reaction mixture over 30 minutes, after which stirring was continued for another hour. Sixty mL of water was added to the reaction mixture, and a solid precipitated and was collected and dried under vacuum to yield 4.63 g (17.7 mmol, 89%) of 2-methoxy-1-nitro-4-phenylsulfanyl-benzene. MS: 262 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1>>[CH:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:17])[N:2]([NH:1][C:27](=[O:28])[CH2:26][C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=3)[N:11]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(C2CCCC2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(C2CCCC2)c2ccccc2c1=O

Procedure:
The product of Example 71A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58-11.61 (bs, 1H), 8.33 (dd, J=7.9, 1.3 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.98-8.02 (m, 1H), 7.87-7.92 (m, 1H), 7.09-7.22 (m, 3H), 3.74-3.75 (m, 2H), 3.70 (d, J=7.8 Hz, 1H), 1.97-2.11 (m, 2H), 1.59-1.94 (m, 6H); MS (ESI) m/z 384 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[N:33]=[C:34]([CH3:37])[S:35][CH:36]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1nc(Br)cs1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1nc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3c(c2)ncn3C2CC2)cs1
Temperature: 100 °C

Procedure:
To a microwave tube equipped with a stifling bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (120 mg, 0.292 mmol), 4-bromo-2-methylthiazole (103.9 mg, 0.584 mmol), 1,2-dimethoxyethane (3 mL), 1 N Na2CO3 aqueous solution (0.96 mL, 0.96 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (33.7 mg, 0.029 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give white solids, 9.0 mg. 1H NMR (300 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.13 (s, 1H), 7.59 (s, 1H), 7.41 (d, J=1.2 Hz, 1H), 7.14 (d, J=1.3 Hz, 1H), 4.74 (p, J=6.0 Hz, 1H), 3.72 (tt, J=7.2, 3.9 Hz, 1H), 3.45-3.35 (m, 1H), 3.23-3.14 (m, 1H), 2.82 (m, 1H), 2.60 (s, 3H), 2.43-2.19 (m, 2H), 1.32 (d, J=6.0 Hz, 3H), 1.11 (m, 2H), 1.08-0.98 (m, 2H) ppm; MS (ESI+) m/z 384.24 (M+H).
Reaction SMILES: CI.[C:3](=[O:6])([O-])[O-].[K+].[K+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1O>O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:6][CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(F)cccc1Cl
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Methyl iodide (850 μl, 13.646 mmol) and potassium carbonate (943 mg, 6.824 mmol) were added to 2-chloro-6-fluorophenol (1.0 g, 6.824 mmol) in tetrahydrofuran (10 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between diethyl ether (50 ml) and water (50 ml). The organic phase was extracted and further washed with water (2×20 ml) then dried over sodium sulphate and concentrated in vacuo to afford the title compound as a colourless liquid in 94% yield, 1.03 g.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[SH:30][CH2:31][CH2:32][OH:33]>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:28][CH3:29])=[N:3][C:2]([S:30][CH2:31][CH2:32][OH:33])=[CH:7][N:6]=1)(=[O:10])=[O:11]
Reactant: OCCS
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Product: COc1nc(SCCO)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.2 g) and 2-mercaptoethanol (0.2 g). After removal of the SEM (2-[trimethylsilyl]ethoxymethyl) group the title compound was purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.015 g
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].C1COCC1.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])=[CH:40][CH:39]=1>CCOC(C)=O.CCCCCC>[CH2:29]([N:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:37][C:38]4[CH:39]=[CH:40][C:41]([CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])=[CH:42][CH:43]=4)[C:4](=[O:31])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])=[CH:27][C:26]([CH3:28])=[N:25]1)[CH3:30]
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CCCC(=O)O)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 69, 100 mg, 0.2401 mmol) and THF (3.0 mL). To the resulting solution was added 4-(4-Amino-phenyl)-butyric acid (43 mg, 0.24 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜50 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜5 mL) to afford the title compound in 29% yield (0.040 g, 0.0692 mmol).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[C:4](=[O:36])[CH2:3]1.IC.[C:39](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]=[C:2]1[NH:8][C:7]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH3:39])[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])=[CH:21][CH:22]=2)[C:4](=[O:36])[CH2:3]1
Reactant: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c2ccc3c(c2N1)CCCC3
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 71.7 %

Procedure:
N-[4-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahydro-naphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitro-benzenesulfonamide (150 mg, 0.30 mmol) obtained in Example 151, iodomethane (22 μL, 0.36 mmol), and potassium carbonate (45 mg, 0.33 mmol) were stirred in anhydrous DMF (3 mL) for 16 hours. After the disappearance of the starting materials was confirmed, a post-treatment was performed in a conventional manner to obtain the title compound (112 mg, yield 73%).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Br:11][C:12]1[C:13]([NH2:20])=[C:14]([NH2:19])[CH:15]=[C:16]([Br:18])[CH:17]=1.C>[OH-].[Na+]>[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[C:14]2[C:13]=1[NH:20][C:2](=[O:4])[C:1](=[O:8])[NH:19]2
Reactant: Nc1cc(Br)cc(Br)c1N
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2cc(Br)cc(Br)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.19 g, 15.0 mmol) and 3,5-dibromo-1,2-diaminobenzene (400 mg, 1.50 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the pale brown shiny solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 264 mg (55%). A portion of this solid (150 mg) was taken and dissolved in 20 mL 1N NaOH with heating. The solution was treated with activated charcoal and filtered through a pad of Celite. The resulting solution was carefully acidified with 2N HCl (pH=1 ). Pale yellow needles slowly formed in the solution and were collected by vacuum filtration, rinsed with 20 mL of H2O and dried under vacuum (0.1 torr, 78° C.) to yield 50.0 mg of powdery white solid, mp 356°-358° C. (dec). 1H NMR (d6 -DMSO) δ 7.21 (d, 1H, J=2.1, H-8), 7.53 (d, 1H, J=2.1, H-6), 11.1 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/z 322 (M+4, 51.3), 320 (M+2, bp), 318 (M +, 53.9), 294 (32.2), 292 (62.6), 290 (28.7), 185 (24.3), 183 (25.2). EIHRMS calc. for C8H4Br2N2O2 317.8641, found 317.8642.
Reaction SMILES: C(N[C@H](C(O)=O)CC1C=CC(O)=CC=1)(=[O:3])C.C(#N)C.ON1C(=O)CCC1=O.[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(OCC)(=O)C>[C:35]([NH:34][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)([NH:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:3]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C

Procedure:
N-Acetyl-L-tyrosine (1.68 g, 7.53 mmol) was taken up in 94 mL of ethyl acetate/26 mL of acetonitrile and stirred at room temperature. N-Hydroxysuccinimide (NHS, 0.87 g, 7.56 mmol) was added and the resulting solution cooled to 0° C. under N2 (g) in an ice-water bath. To the cold, stirring solution was then added dicyclohexylcarbodiimide (DCC, 1.55 g, 7.52 mmol) predissolved in 3 mL of ethyl acetate. The reaction mixture was stirred at 0° C. for 2 hours and then allowed to warm to room temperature overnight with continued stirring. The insoluble dicyclohexylurea (DCU) was removed by filtration and the resulting filtrate concentrated to a solid residue under reduced pressure. Trituration of this residue with warm ethyl acetate and subsequent storage at 4° C. then afforded a white solid. This was isolated by vacuum filtration, washed with cold ethyl acetate and dried in vacuo to yield the product in greater than theoretical yield (due to contamination with residual DCU). 1H-NMR (300 MHz, CDCl3): δ 2.00 (s, 3H); 2.87 (s, 4H); 3.22 (m, 2H); 4.05 (m, 1H); 5.80 (d, 1H, J=7.2 Hz); 6.96 (AB quartet, 4H, J=8.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]([N:9]=[N+]=[N-])[CH3:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([CH:7]([NH2:9])[CH3:8])=[CH:4][CH:3]=1
Reactant: CC(N=[N+]=[N-])c1ccc(Cl)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1ccc(Cl)s1
Temperature: 60 °C
Yield: 75.5 %

Procedure:
A mixture of 1-(5-chloro-2-thienyl)ethyl azide (991 mg, 5.3 mmol) and triphenylphosphine (1.4 g, 5.3 mmol) in THF (10 mL) and water (0.4 mL) was heated to 60° C. for 1 h. After cooling to rt, the solution was concentrated in vacuo. The resulting residue was purified by flash chromatography (90% DCM:10% methanol) to provide the desired 1-(5-chloro-2-thienyl)ethanamine (646 mg, 4.0 mmol, 75% yield) as a pink liquid. 1H NMR (400 MHz, CDCl3): 6.71 (d, 1H), 6.64 (d, 1H), 4.26 (q, 1H), 1.64 (br s, 2H), 1.44 (d, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[NH:10]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:11]1=[O:12]>ClCCl>[Cl:1][CH2:2][C:3]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[NH:10][C:11](=[O:12])[CH:13]=[CH:14]2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=c1ccc2ccccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc2[nH]c(=O)ccc2c1
Yield: 50.1 %

Procedure:
To a solution containing 467 g of chloroacetyl chloride in 400 ml of dichloromethane was added 735 g of aluminum chloride by way of one-third portion thereof in three times, at below 30° C., with stirring, then 200 g of the carbostyril was added to the mixture at the same temperature under stirring. Then the reaction mixture was refluxed for 6 hours. After the reaction was completed, the reaction mixture was poured into ice-concentrated hydrochloric acid and the crystals formed were collected by filtration, and washed with a hot methanol to obtain 153 g of 6-chloroacetylcarbostyril. The mother liquor was concentrated to dryness and the residue was purified by a silica gel column cromatography. Recrystallized from methanol to obtain 35.41 g of 8-chloroacetyl-carbostyril. Light yellow needle-like crystals. Melting point: 177.5°-179° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH3:10])=[O:4].C1C(=O)N([Br:18])C(=O)C1.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[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][Br:18])=[O:4]
Reactant: COC(=O)c1sccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1sccc1CBr
Yield: 89.1 %

Procedure:
3-Methyl-thiophene-2-carboxylic acid methyl ester (1 g, 6.4 mmol) is dissolved in CCl4 (15 mL), and NBS (1.19 g, 6.7 mmol) and benzoyl peroxide (15 mg) are added. The reaction mixture is refluxed for 6 hours, then water is added and the mixture is extracted with EtOAc (3×). The organic layers are dried over MgSO4, filtered and concentrated. The crude product is purified by silica gel column chromatography eluting with 98:2 petroleum ether-EtOAc to give the title compound (1.34 g, 27%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].Cl.Cl.[NH2:20][C:21]1[C:36]([Cl:37])=[CH:35][C:24]([C:25]([NH:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:26])=[C:23]([O:38][CH3:39])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:20][C:21]1[C:36]([Cl:37])=[CH:35][C:24]([C:25]([NH:27][CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:11](=[O:12])[C:10]4[C:9](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]3=[O:17])[CH2:33][CH2:34]2)=[O:26])=[C:23]([O:38][CH3:39])[CH:22]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN2C(=O)c3ccccc3C2=O)CC1
Reaction time: 8 h
Yield: 57.9 %

Procedure:
N-(5-Bromopentyl)phthalimide (60 g) was added to a solution of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (75.1 g) and potassium carbonate (112 g) in dimethylformamide (800 ml), and the mixture was stirred at 75°-80° C. for 8 hr. Insoluble matter was filtered off and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 60.2 g of 4-amino-5-chloro-N-(1-(5-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)pentyl)piperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1c(Cl)cccc1Cl

Procedure:
From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=417.2, tR (minutes, Method f))=0.89
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[N:5]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])[N:4]=1>C(OCC)(=O)C.[Pd]>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3]([O:2][CH3:1])=[N:4][N:5]2[CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(Cn2nc(OC)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2nc(OC)c3ccc(N)cc32)c(OC)c1
Reaction time: 3 h
Yield: 34 %

Procedure:
Palladium-on-carbon (5% w/w, 0.24 g.) was added to a solution of indazole (U) (0.48 g.) in ethyl acetate (25 ml.). The mixture was hydrogenated at 1.1 bars for 3 hours. The catalyst was removed by filtration through diatomaceous earth, and the filtrate evaporated. The residue was recrystallized from a hot ethyl acetate/petroleum ether mixture to give methyl 4-(6-amino-3-methoxyindazol-1-ylmethyl)-3-methoxybenzoate (S) (0.15 g., 34%), as a pale-yellow solid, m.p. 188°-193° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([N:40]3[CH2:39][CH2:38][N:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[O:30][CH3:29])[CH2:42][CH2:41]3)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: COc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3cccc(F)c3)noc2C)CC1
Yield: 80.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (586 mg, 1.48 mmol, 81%) was obtained.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[N:12]=[C:10]3[S:11][C:7]=2[CH:6]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].Br>O>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([C:13]2[N:12]=[C:10]3[N:9]([CH:14]=2)[C:8]2[CH:22]=[CH:23][C:5]([NH2:2])=[CH:6][C:7]=2[S:11]3)=[CH:20][CH:19]=1
Reactant: Cc1ccc(-c2cn3c(n2)sc2cc([N+](=O)[O-])ccc23)cc1
Agent: Br
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2cn3c(n2)sc2cc(N)ccc23)cc1
Yield: 22 %

Procedure:
To a suspension of 7-Nitro-2-p-tolyl-imidazo[2,1-b]benzothiazole hydrobromide salt (128 mg, 0.328 mmol) in water at 80° C. were added 4 portions (10 eq.) of sodium dithionite over 30 minutes whereupon the suspension become clear and decolorized to give 7 in 22% yield: mp>210° C. (dec.); 1H-NMR (DMSO-d6) 2.32 (s, 3H), 6.80 (dd, 1H), 7.13 (d, 1H), 7.23 (d, 2H), 7.65 (d, 1H), 7.72 (d, 2H), 8.53 (s, 1H); HR-MS (EI) m/z 279.0821 (M+); Anal. calculated for C16H13N3S. 7/3 HBr: C, 41.05; H, 3.30; N, 8.98; found; C, 41.81; H, 2.86; N, 6.10.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[CH3:9][N:10]([CH3:15])[S:11](Cl)(=[O:13])=[O:12]>O1CCCC1.[Cl-].[NH4+]>[CH3:9][N:10]([CH3:15])[S:11]([N:7]1[CH:8]=[C:4]([Br:3])[N:5]=[CH:6]1)(=[O:13])=[O:12]
Reactant: Brc1c[nH]cn1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cnc(Br)c1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Sodium hydride (55% in oil, 0.31 g) was added to a stirred solution of 4-bromo-1H imidazole (1.02 g) in dry tetrahydrofuran (20 mL) at room temperature under N2. After 10 minutes, dimethylsulfamoyl chloride (0.81 mL) was added. After stirring for 5 hours, the mixture was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL). The extract was dried over Na2SO4, filtered and concentrated. The white solid was rinsed with diethyl ether and dried to give 1-(dimethylaminosulfonyl)-4-bromoimidazole (1.53 g, 87%). MS (ES+) 256, 254 ([MH]+). Step 2: 1-(Dimethylaminosulfonyl)-4-(4-fluorophenyl)imidazole