Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:13]2[CH2:12][S:11][N:10]=[C:9]([N:14](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:8]3=[N:29][N:30]([CH2:32][C:33]4[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=4)[N:31]=[C:6]([C:7]=23)[CH2:5]1.[CH3:43]N(C)C=O.CI>O>[CH3:43][O:3][CH:4]1[C:13]2[CH2:12][S:11][N:10]=[C:9]([NH2:14])[C:8]3=[N:29][N:30]([CH2:32][C:33]4[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=4)[N:31]=[C:6]([C:7]=23)[CH2:5]1
Reactant: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1c(C)cnc(CN2N=C3CC(OC)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
Sodium hydride (6.7 mg) was added to a mixture of di-tert-butyl {8-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 32 (40 mg) and dehydrated N,N-dimethylformamide (1 mL), and then the mixture was stirred at room temperature for one hour. Methyl iodide (6.5 μL) was added to the reaction mixture, followed by stirring for 1.5 hours. Then, water (20 mL) was added. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reversed phase liquid chromatography to obtain the title compound (4.8 mg, 18%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[BH4-].[Na+]>C(O)C>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:10][CH2:9][CH2:8][CH2:7][N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[C:4]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cn(CCCN)c(-c2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cn(CCCNCc2ccc(Cl)cc2)c(-c2ccccc2)n1

Procedure:
3-(4-Methyl-2-phenylimidazol-1-yl)propylamine (5.5 g) and 4-chlorobenzaldehyde (3.6 g) were stirred in absolute ethanol (70 ml) for 16 hours. Sodium borohydride (2.0 g) was added and the mixture heated under reflux for 7 hours. Work-up as described in Example 42 gave N-(4-chlorobenzyl)-3-(4-methyl-2-phenylimidazol-1-yl)propylamine. Glc indicated that the product contained 13% (approx) of N-(4-chlorobenzyl)-3(5-methl-2-phenylimidazol-1-yl)propylamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][CH2+:39]1SC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N:16]=[C:39]2[N:38]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:42](=[O:43])[C:41](=[C:44]3[N:48]([CH3:49])[C:47]4[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=4[S:45]3)[S:40]2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(=O)OC(C)(C)C)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4-ethylamino-3-nitrobenzoic acid tert-butyl ester was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.69 (1H, dd), 7.61 (1H, d), 7.52 (1H, dd), 7.45–7.49 (2H, m), 7.27–7.37 (4H, m), 7.18 (1H, m), 7.06 (1H, d), 6.51 (1H, d), 5.19 (2H, s), 4.11 (1H, br t), 3.79 (3H, s), 3.04 (2H, m), 1.57 (9H, s), 1.04 (3H, t); MS(ESI): 573 (MH+).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:5].C(NCC)C.Cl[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>>[CH2:16]([CH2:5][C:4]([CH:6]=[C:7]([CH3:9])[CH3:8])=[O:3])[CH:17]=[C:18]([CH3:20])[CH3:19]
Reactant: CC(C)=CCCl
Reactant: CC(=O)C=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCNCC
Product: CC(C)=CCCC(=O)C=C(C)C
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
To a well stirred mixture of 60 g of 96% sodium hydroxide and 600 g of mesityl oxide was added 3 g of diethylamine, followed by 105 g of 94% 1-chloro-3-methyl-2-butene. The mixture was then heated to 70° C. over a 10 minute period, and the external heat source immediately removed. The mass continued to rise in temperature to 80° C. over a 10 minute period, and was then maintained at between 79° and 82° C. over a 2.3 hour period, with either heating or cooling, as needed. After cooling to 30° C., the mixture was quenched with 250 ml of water and stirred vigorously. The organic phase was then separated and the aqueous layer extracted four times with 20 ml portions of benzene. The organic phases were combined and dried overnight over sodium sulfate. The dried oil phase was then treated with 2 ml of acetic acid prior to distillation. The yield was 123.7 g of the mixture of prenyl mesityl oxide isomers.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]2[NH:9][C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:18]=1.[BH4-].[Na+].[ClH:29].C(=O)(O)[O-].[Na+]>O1CCCC1>[ClH:29].[OH:1][C:2]1[CH:3]=[C:4]([CH:19]([OH:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]2[NH:9][C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:18]=1
Reactant: CCOC(=O)CC(=O)c1cc(O)cc2nc(CCc3ccccc3)[nH]c12
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1cc(O)cc2nc(CCc3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of ethyl 3-(6-hydroxy-2-(2-phenylethyl)benzimidazol-4-yl)-3-oxopropanoate (800 mg) obtained in Inventive Example 42 in anhydrous tetrahydrofuran (16 mL), while cooling in an ice bath, was added sodium borohydride (26 mg) and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ice water (10 mL) and adjusted to pH 1 with 4 N hydrochloric acid. This was neutralized with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate and then washed with brine. The organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The desired fraction was concentrated and dissolved in hydrochloric acid/ethanol. The solvent was replaced by ether and then ether was evaporated to obtain the title compound as colorless crystal (350 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][C:15]=2[CH2:26][NH:27][CH2:28][CH3:29])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][C:15]=2[CH2:26][N:27]([C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])[CH2:28][CH3:29])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(-c2cnn(C)c2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3cnn(C)c3)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-ethylaminomethyl-6-methoxy-4′-(1-methyl-1H-pyrazol-4-yl)-biphenyl-3-yl]-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: C([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[S:11][C:10]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:18])C1C=CC=CC=1.O>ClCCl>[OH:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[S:11][C:10]=1[C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)=[O:18]
Reactant: COc1ccc(C(=O)c2sc(C(C)C)cc2OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2sc(C(C)C)cc2O)cc1
Temperature: 22 °C
Reaction time: 1.5 h

Procedure:
1.00 g of (3-benzyloxy-5-isopropyl-thiophen-2-yl)-(4-methoxy-phenyl)-methanone was dissolved in 20 ml of dichloromethane. 2.73 ml of a 1 molar solution of boron tribromide-dimethyl sulfide complex in dichloromethane were added to the reaction solution. The solution was stirred at 22° C. for 1.5 h. The reaction mixture was poured into 50 ml of water, and the mixture was extracted twice with 30 ml of dichloromethane each time. The combined organic phase was extracted twice with 30 ml of saturated sodium bicarbonate solution each time and washed one with 50 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/n-heptane=1:4).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][C:22]4(OCC[O:23]4)[CH2:21][CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>CC(C)=O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:29]([OH:31])=[O:30])[CH2:20][CH2:21][C:22](=[O:23])[CH2:27][CH2:28]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC1(C(=O)O)CCC2(CC1)OCCO2)OCC1c2ccccc2-c2ccccc21
Solvent: CC(C)=O
Product: O=C1CCC(NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
187 mmol (79 g) of 8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-1,4-dioxaspiro[4,5]decane-8-carboxylic acid is taken up in 3.51 of acetone/0.1 M HCl 1:1 and stirred for 4 hours at room temperature. The acetone is drawn off in a rotary evaporator, and the precipitated product is filtered off, rewashed with water and dried. Yield: 68.7 g of 2.
Reaction SMILES: [I:1]I.[F:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[NH2:7]>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[F:3][C:4]1[C:5]([I:1])=[C:6]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[NH2:7]
Reactant: Nc1cc(F)c(F)c(F)c1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1cc(F)c(F)c(F)c1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
Iodine (0.621 g; 2.45 mmol) was added to a stirred mixture of silver sulphate (0.763 g; 2.45 mmol) and 3,4,5-trifluoroaniline (0.360 g; 2.45 mmol) in ethanol (5 mL). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulfate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to afford 0.279 g (42%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:28][N:29]([CH2:37][CH2:38][CH2:39][NH:40][CH3:41])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:40]([CH3:41])[CH2:39][CH2:38][CH2:37][N:29]([CH3:28])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:6]
Reactant: CNCCCN(C)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCN(C)C(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
2-Fluoro-4-nitrobenzoic acid (150 mg, 0.810 mmol) was dissolved in methylene chloride (8 mL), triethylamine (0.135 mL, 0.972 mmol) and pivaloyl chloride (0.100 mL, 0.810 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. A solution of tert-butyl methyl[3-(methylamino)propyl]carbamate (described in J. Med. Chem. 1990, 33, 97-101) (164 mg, 0.810 mmol) in methylene chloride (4 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:2→0:100, v/v) to give the title compound (300 mg; yield, 100%) as a yellow oily substance.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=O.[OH:20][CH2:21][C:22]1[C:23](=[O:29])[N:24]=[C:25]([SH:28])[NH:26][N:27]=1>C(O)C>[C:11]([C:9]1[CH:10]=[C:5]([C:3]2[N:26]3[N:27]=[C:22]([CH2:21][OH:20])[C:23](=[O:29])[N:24]=[C:25]3[S:28][CH:2]=2)[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: O=c1nc(S)[nH]nc1CO
Solvent: CCO
Product: CC(C)(C)c1cc(-c2csc3nc(=O)c(CO)nn23)cc(C(C)(C)C)c1O

Procedure:
14.4 g (0.044 mol) of 2-bromo-1-(3,5-di-tert.butyl-4-hydroxyphenyl)-ethanone (Example 1a1) and 7.0 g (0.044 mol) of 6-hydroxymethyl-3-mercapto-2H-1,2,4-triazin-5-one from step (a1) were heated to boiling for 4 hours in 300 ml of ethanol. The reaction mixture, evaporated under reduced pressure, was dissolved in 300 ml of chloroform and treated with 100 ml of saturated sodium hydrogen carbonate solution. The chloroform phase was finally separated off, dried and evaporated. Chromatography of the crude product over silica gel using ethyl acetate/methanol (99:1) as eluent gave colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:29][C:28]1[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1OCc1ccccc1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)c2cc(Br)ccc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5.57 g of ethyl 5-bromo-3-(phenylmethoxy)indole-2-carboxylate and 2.9 mL of 4-fluorobenzyl bromide in 40 mL of DMF at 0° C. was added 887 mg of a NaH suspension (60% in oil) and the resulting reaction mixture was warmed slowly to room temperature with continuous stirring. After 0.5 hour, the reaction was quenched with saturated aqueous NH4Cl and extracted twice with ethyl acetate/ether 1:1. The organic phase was washed with water (4×), brine and dried over anhydrous Na2SO4. Flash chromatography (toluene) and recrystallization from hexane yielded 5.99 g of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH:11]([F:13])[F:12])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[F:14][C:15]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:12][CH:11]([F:13])[O:10][C:4]1[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([C:19]2[CH:20]=[C:21]([CH2:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[CH:22]=[CH:23][C:18]=2[O:17][C:16]2[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:15]=2[F:14])[CH:3]=1
Reactant: Cn1cc(Br)cc(OC(F)F)c1=O
Reactant: CCS(=O)(=O)Cc1ccc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Cc1ccc(Oc2ccc(F)cc2F)c(-c2cc(OC(F)F)c(=O)n(C)c2)c1
Temperature: 70 °C
Yield: 24 %

Procedure:
A mixture of 5-bromo-3-(difluoromethoxy)-1-methylpyridin-2-one (50 mg, 0.20 mmol), 2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (79 mg, 0.18 mmol), Pd(dppf)Cl2 (11 mg) and K3PO4 (76 mg, 0.36 mmol) in dioxane (5 mL) and water (5 drops) was purged with nitrogen, capped, and heated to 70° C. for 8 h. After the mixture was filtered, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (21 mg, 22%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.62 (d, J=2.0 Hz, 1H) 7.54 (d, J=2.0 Hz, 1H) 7.40 (d, J=2.0 Hz, 1H) 7.29 (d, J=2.0 Hz, 1H) 7.09-6.96 (m, 3H) 6.93-6.88 (m, 1H) 6.78 (m, 1H) 4.21 (s, 2H) 3.70 (s, 3H) 2.97 (q, J=7.6 Hz, 2H) 1.43 (t, J=7.6 Hz, 3H). LCMS (M+H)+=486.
Reaction SMILES: [Br:1][C:2]1[C:7]([Br:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[C:4]([F:12])[C:3]=1[CH2:13][C:14]#[N:15].O.O.[Sn](Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.CCCCCC.C(OCC)(=O)C>C(O)C>[NH2:9][C:6]1[CH:5]=[C:4]([F:12])[C:3]([CH2:13][C:14]#[N:15])=[C:2]([Br:1])[C:7]=1[Br:8]
Reactant: N#CCc1c(F)cc([N+](=O)[O-])c(Br)c1Br
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CCc1c(F)cc(N)c(Br)c1Br
Temperature: 75 °C

Procedure:
Twenty-four grams of a mixture containing (2,3-dibromo-6-fluoro-4-nitro-phenyl)-acetonitrile was dissolved in ethanol (500 mL) and tin (II) chloride dihydrate (85 g) was added. The mixture was stirred and heated at 75° C. for 5 h. 10 g more tin chloride was added and the mixture was heated at reflux for 30 additional minutes. The solution was cooled and most of the ethanol was removed in vacuo. The reaction mixture was diluted to a volume of 600 mL with ethyl acetate and 100 mL water was added. With stirring, sodium bicarbonate (75 g) was slowly added. The ethyl acetate layer was separated and the aqueous layer extracted a second time with ethyl acetate. The combined organic extracts were dried and the solvent removed in vacuo to afford 22.8 g of crude product. The title compound (3.8 g) was obtained from the crude mixture by column chromatography (hexane-ethyl acetate; then hexane-methylene chloride mixtures).
Reaction SMILES: [CH3:1][C@@H:2]([O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].BrBr.[Br:20]C1C=CC(OC[C@@H](C)CC)=C(C=1)C#N>C(Cl)(Cl)Cl>[Br:20][C:15]1[CH:16]=[CH:17][C:10]([O:9][C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CC[C@H](C)COc1ccc(Br)cc1C#N
Reactant: CCCCCC[C@@H](C)Oc1ccccc1C#N
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCCC[C@@H](C)Oc1ccc(Br)cc1C#N

Procedure:
Quantities: compound 40 (12.34 g, 0.054 mol), bromine (17.15 g, 0.0107 mol), chloroform (100 ml). The experimental procedure was as described for the preparation of compound 41. The crude product was purified by column chromatography (20% petrol/dichloromethane) to give a fawn oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[NH:12][C:13]2[CH:19]=[C:18]([C:20](O)=[O:21])[CH:17]=[CH:16][C:14]=2[N:15]=1)([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=2)[NH:27][N:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:23][O:24][C:25]1[C:33]2[C:28](=[CH:29][C:30]([NH:34][C:20]([C:18]3[CH:17]=[CH:16][C:14]4[N:15]=[C:11]([NH:10][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[CH:1]([CH3:2])[CH3:3])[NH:12][C:13]=4[CH:19]=3)=[O:21])=[CH:31][CH:32]=2)[NH:27][N:26]=1
Reactant: COc1n[nH]c2cc(N)ccc12
Reactant: CC(C)c1ccccc1Nc1nc2ccc(C(=O)O)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1n[nH]c2cc(NC(=O)c3ccc4nc(Nc5ccccc5C(C)C)[nH]c4c3)ccc12

Procedure:
2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid (0.3 mmol; see Example 66) was coupled with aforementioned 3-methoxy-1H-indazol-6-ylamine (0.3 mmol) using HBTU as described in general procedure D to afford the desired product, 2-(2-isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid (3-methoxy-1H-indazol-6-yl)-amide. MS: m/z 441 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][N:7]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CCNC1CCCC1C
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A solution of 2.2 g (0.011 mole) of (rac)-3-(2-methyl-cyclopentylamino)-propanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 2.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-92:8) gave 3.3 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-57).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[CH3:15][N:16](C)P(=O)(N(C)C)N(C)C>>[CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:15]#[N:16])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CNC(=O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Product: CNC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 55.2 %

Procedure:
2 g (6.53 mmol) N-methyl-4-iodo-3-nitrobenzamide (Compound VII-1), 0.09 g (10.0 mmol) cuprous cyanide and 10 ml hexamethylphosphoric triamide were added into a reaction flask. The mixture was heated to 100° C. and reacted for 40 minutes, and after completing the reaction, the mixture was cooled to room temperature, and then extracted with ethyl acetate. The organic layer was washed with water for three times, dried over anhydrous sodium sulfate, decolorized with activated charcoal, filtered, and the filtrate was concentrated to dryness, recrystallized from ethyl acetate to obtain 0.74 g N-methyl-4-cyano-3-nitrobenzamide (Compound I-27), yield 55.2%.