Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[CH:17]=[O:18])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]([OH:26])=[O:18])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc(CNC(=O)OCc2ccc([N+](=O)[O-])cc2)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NCc1cccc(C(=O)O)c1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
To 3-(p-nitrobenzyloxycarbonyl)aminomethylbenzaldehyde (1.5 g) in acetone (30 ml) was added Jones' reagent with ice-cooling, and the mixture was stirred for 2 hours. After addition of methanol (1.5 ml), the mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated to give 3-(p-nitrobenzyloxycarbonyl)aminomethylbenzoic acid
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.[CH3:18][NH2:19]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:19][CH3:18])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
To a mixture of 5-bromo-2-fluorobenzoic acid (200 mg, 0.91 mmol) in dichloromethane (5 mL) was added oxalyl chloride (0.16 mL, 1.8 mmol), followed by 1 drop of N,N-dimethylformamide. The reaction was stirred at room temperature for 1.5 hours. The reaction was concentrated and the resulting residue was dissolved in dichloromethane (3 mL) and cooled to 0° C. Methylamine (2.3 mL, 5 mmol, 2 M in tetrahydrofuran) was added and the reaction was allowed to stir at 0° C. for 30 minutes. The reaction was quenched with water and the mixture was concentrated. The residue was diluted with water and the resulting solids were filtered, rinsed with water, and dried under vacuum to give the title compound (196.6 mg, 93%) as a white solid. +ESI (M+H+1) 234.1; 1H NMR (400 MHz, CDCl3, δ); 8.22 (dd, J=6.83, 2.73 Hz, 1H), 7.55 (ddd, J=8.68, 4.49, 2.63 Hz, 1H), 7.00 (dd, J=11.32, 8.58 Hz, 1H), 6.67 (br. s., 1H), 3.02 (dd, J=4.88, 1.17 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:16](I)=[C:15]([CH3:18])[O:14][N:13]=1.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[C:12]([CH3:11])=[N:13][O:14][C:15]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1I
Reactant: OB(O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1ccc(Br)cc1
Temperature: 80 °C
Yield: 85 %

Procedure:
A mixture of 4-bromophenylboronic acid (1 g, 5 mmol), 3,5-dimethyl-4-iodoisoxazole (0.93 g, 4.2 mmol), bis(triphenylphospine)palladium(II) chloride (59 mg, 2 mol %), NaHCO3 (1.06 g, 12.6 mmol) in DME (5 mL) and H2O (5 mL) was heated to 80° C. under N2 for 18 h. The reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (5% EtOAc in hexanes) to give the title compound as a white solid (0.9 g, 86%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]1(C)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1([Li])C=CC=CC=1.O>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]([OH:11])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Cc1ccccc1
Agent: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccc2)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (10.00 g, 45.40 mM) in dry tetrahydrofuran (50 ml) was cooled to −78° C., a toluene solution of phenyllithium (49.94 mM) was dropped into this solution, and the resultant mixture was stirred at that temperature for 5 hours. Water was added to the solution obtained, the solution was warmed to room temperature and extracted with diethyl ether, the extract was dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo to obtain a crude product of α-(3-cyclopentyloxy-4-methoxyphenyl)benzyl alcohol 13.56 g as a yellow oil. The crude product thus obtained of α-(3-cyclopentyloxy-4-methoxyphenyl)benzyl alcohol in an amount of 10.00 g was dissolved in dry methylene chloride (110 ml), manganese dioxide (16.00 g) was added to the solution, and the solution was vigorously stirred at room temperature for 2 days. The undissolved material in the solution obtained were removed by filtration through Celite, and the filtrate was concentrated in vacuo to obtain a residue as a yellow solid. The residue was purified by flash chromatography (SiO2: eluted with 20% ethyl acetate/hexane). The solvent was removed in vacuo and the product was dried to obtain 3-cyclopentyloxy-4-methoxybenzophenone 9.20 g (yield 92.6%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[C:11]([CH2:17][CH2:18][CH3:19])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH2:34][C:35]([CH3:56])([CH3:55])[CH2:36][NH:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[CH:43][C:42]=1[F:54])=[O:39].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH2:34][C:35]([CH3:56])([CH3:55])[CH2:36][NH:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH:48]2[CH2:53][CH2:52][N:51]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:20])([F:1])[F:21])=[CH:10][C:11]=3[CH2:17][CH2:18][CH3:19])[CH2:50][CH2:49]2)=[CH:43][C:42]=1[F:54])=[O:39]
Reactant: CC(C)(N)CNC(=O)Nc1ccc(CC2CCNCC2)cc1F
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CN1CCC(Cc2ccc(NC(=O)NCC(C)(C)N)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 5.7 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-(hydroxymethyl)-3-propylphenyl)propan-2-ol (0.474 mmol, 150 mg) was dissolved in dichloromethane (5 mL) and triethylamine (1.423 mmol, 144 mg) added. The mixture was cooled to 0° C. before the addition of methanesulfonyl chloride (0.611 mmol, 70.0 mg). The mixture was stirred at 0° C. for 90 min. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×10 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (4 mL) and 1-(2-amino-2-methylpropyl)-3-(2-fluoro-4-(piperidin-4-ylmethyl)phenyl)urea (0.341 mmol, 110 mg) was added followed by potassium carbonate (1.023 mmol, 141 mg). The mixture was heated to reflux for 16 hours. The mixture was cooled, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC and treated with strong cation exchange column chromatography to afford the title compound (12 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[C:13]([CH3:33])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:26]=[N:27][C:28](F)=[CH:29][C:30]=3[CH3:31])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1.O>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]([CH3:33])[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([N:3]4[C@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[N:27][CH:26]=3)=[O:24])[CH2:21][CH2:22]2)=[N:15][CH:16]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2C(=O)OC[C@H]2C)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of (R)-4-methyloxazolidin-2-one (222 mg) described in Preparation Example 25 in DMF (4 mL) was added sodium hydride (84 mg) at 10° C., and the mixture was stirred for 30 min. Furthermore, [4-(5-bromo-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (447 mg) described in Preparation Example 113 was added, and the mixture was stirred at 80° C. for 3 hr and at 100° C. for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give (R)-3-{5-[4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}-4-methyloxazolidin-2-one (260 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:10][N:11]([CH2:13][CH2:14]Cl)[CH3:12].CN(CCOC1C=CC(Br)=CC=1)C>>[CH3:10][N:11]([CH2:13][CH2:14][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:12]
Reactant: CN(C)CCCl
Reactant: Oc1cccc(Br)c1
Agent: CN(C)CCOc1ccc(Br)cc1
Agent: Cl
Product: CN(C)CCOc1cccc(Br)c1
Yield: 73.7 %

Procedure:
3-Bromophenol (5.0 g, 28.9 mmol) and 2-(N, N-dimethylamino)ethyl chloride, hydrochloride (6.24 g, 43.3 mmol) were reacted by the general procedures as described in the preparation of N,N-dimethyl-2-(4-bromophenoxy)ethylamine. The residue was chromatographed on silica gel (dichloromethane/methanol 100:0 to 90:10) to give the title compound (5.2 g, 74%) as a pale yellow liquid.
Reaction SMILES: CO.Cl.O[NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1>[Fe].O>[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 70 °C

Procedure:
To a mixture of 600 parts of methyl alcohol, 200 parts of water and 70 parts of a 35% aqueous hydrochloric acid there was added with stirring 50 parts of 1-hydroxylaminoanthraquinone and the resulting mixture was heated to 70°C. After addition of 17 parts of metallic iron in the form of ribbon little by little over 1 hour, the reaction mixture was maintained at 70°C for additional 4 hours, then cooled to 25°C and filtered. The residue was washed with water, then dissolved in 500 parts of dimethylformamide and filtered to remove residual metallic iron. Dimethylformamide in the filtrate was removed by distillation under reduced pressure to obtain 42.0 parts of 1-aminoanthraquinone of a purity of 92%.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1)=[O:11])([CH3:8])[CH2:6][CH3:7])C.[OH-].[Na+]>C1COCC1.CO>[C:31]([N:28]1[CH2:27][CH2:26][CH:25]([CH2:24][O:23][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]([Cl:22])=[CH:21][C:12]=2[C:10]([NH:9][C:5]([CH3:8])([CH2:6][CH3:7])[C:4]([OH:34])=[O:3])=[O:11])[CH2:30][CH2:29]1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(C)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)(NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(C)=O)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
A solution of 70 mg of 2-{[1-(1-acetyl-piperidin-4-ylmethoxy)-4-chloro-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester in 4 mL THF and 1 mL MeOH was treated with 4 mL of 2 M aqueous sodium hydroxide. The reaction mixture was stirred at room temperature overnight. The organic solvent was removed in vacuo. The residue was taken up in 6 mL of water and washed with ethyl acetate. The aqueous phase was treated with 2 M hydrochloric acid to pH 4, then extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate and concentrated to give 30 mg of 2-{[1-(1-acetyl-piperidin-4-yl-methoxy)-4-chloro-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18][N:19](C)[CH3:20])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.C(O)(=O)C.C(N)=[NH:30].C(N)=O>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:30]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Reactant: N=CN
Solvent: NC=O
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cncnc1-2

Procedure:
A mixture of 90.5 g (0.25 mol) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepine-5-one, 100 g (0.96 mol) of formamidine acetate and 1.0 L of formamide was heated on a steam bath for 16 hr. The mixture was cooled to 0° and the resulting precipitate collected by filtration. The precipitate was washed with water and dried to constant weight to give off-white crystals mp 120°-121° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH:7]([CH2:11][C:12]1([C:18](=[O:34])[NH:19][CH:20]([C:30](=[O:33])[NH:31][CH3:32])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].[O:36]=[C:37]1[C:45]2[CH:44]=[C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]3=[CH:41][C:40]=2[C:39](=[O:50])[NH:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:35])[CH:7]([CH2:11][C:12]1([C:18](=[O:34])[NH:19][CH:20]([C:30](=[O:33])[NH:31][CH3:32])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][CH2:9][N:38]1[C:39](=[O:50])[C:40]2[CH:41]=[C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]3=[CH:44][C:45]=2[C:37]1=[O:36])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1NC(=O)c2cc3ccccc3cc21
Reactant: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCO)C(=O)OC(C)(C)C)CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCN2C(=O)c3cc4ccccc4cc3C2=O)C(=O)OC(C)(C)C)CCCCC1
Reaction time: 72 h

Procedure:
To a solution of 4-hydroxy-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)-ethylcarbamoyl]cyclohexylmethyl}butyric acid tert-butyl ester (490 mg, 1.0 mmol) in dry tetrahydrofuran (20 mL) was added 1,3-dioxo-1,3-dihydrobenzo[f]isoindole (394 mg, 2.0 mmol), triphenylphosphine (524 mg, 2.0 mmol) and diethylazodicarboxylate (0.31 mL, 2.0 mmol). The resulting mixture was stirred for 3 days. The solvent was evaporated under vacuum and the residue was chromatographed on silica gel eluting with 40% ethyl acetate in hexane. Fractions containing the two diastereomeric products were combined and evaporated to leave a white solid which was recrystallized from ethyl acetate to afford 4-(1,3-dioxo-1,3-dihydrobenzo [f]isoindol-2-yl)-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)-ethylcarbamoyl]cyclohexylmethyl}butyric acid tert-butyl ester (diastereomer A) as a white solid, 105 mg (16%). The mother liquor from the recrystallization was concentrated under vacuum to afford an oil highly enriched in diastereomer B, 140 mg (21%).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)([OH:26])[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:11][C:6]=2[O:5][CH2:4]1.I[CH3:37]>C1COCC1>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)([O:26][CH3:37])[CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)(c2ccc3c(c2)OCO3)c2ccc3c(c2)OCO3)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc2c(c1)OCO2)(c1ccc2c(c1)OCO2)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a slurry of NaH (88 mg, 2.2 mmol, 60% in mineral oil) in dry THF (5.0 mL) was added tert-butyl 4-(bis(benzo[d][1,3]dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate (100 mg, 0.22 mmol). After 30 min, iodomethane (468 mg, 143 mmol) was added and the reaction mixture was stirred for an additional 2 h. The reaction was quenched by the addition of a saturated solution of NH4Cl (30 mL) and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by SiO2 flash chromatography (20% EtOAc/hexanes) to give tert-butyl 4-(bis(benzo[d][1,3]dioxol-5-yl)(methoxy)-methyl)piperidine-1-carboxylate as a clear viscous oil (94 mg, 91%): 1H NMR 600 MHz (CDCl3) δ 6.79-6.74 (m, 6H), 5.96-5.95 (m, 4H), 4.08 (bs, 2H), 2.86 (s, 3H), 2.76-2.65 (m, 2H), 2.48-2.43 (m, 1H), 1.76 (d, J=13.2 Hz, 3H), 1.38 (s, 9H), 0.94-0.81 (m, 2H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][C:27](=[O:31])[NH:28]3)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:30]=[C:29]3[C:25]([C:26](=[CH:11][C:8]4[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=4[CH3:13])[C:27](=[O:31])[NH:28]3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc(CCC(=O)O)c2C)cc1
Yield: 58.7 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.5 mg), 120 mg 6-(4-methoxyphenyl)-2-oxindole and 3 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 118 mg (59%) of the title compound as a brown solid.
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:16])([F:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]([CH3:36])[N:34]=[C:33]([C:37]3[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:44])[N:32]=2)=[CH:27][C:26]=1[Cl:45]>O>[Cl:44][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]([F:43])[C:37]=1[C:33]1[N:32]=[C:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][O:14][C:11]3[CH:10]=[CH:9][C:8]([C:7]([F:15])([F:16])[F:6])=[CH:13][CH:12]=3)=[C:26]([Cl:45])[CH:27]=2)[N:35]([CH3:36])[N:34]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To 30 ml of N,N-dimethylformamide are added 4-trifluoromethyl phenol (0.77 g) and potassium carbonate (0.72 g) and 5-(4-bromomethyl-3-chlorophenyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (1.60 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 1 hour. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with toluene. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 1.50 g of desired compound (refractive index: 1.5961).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=O)[CH2:19][C:20](=O)[C:21]([O:23][CH3:24])=[O:22])=[N:16][CH:17]=1.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[Cl:2])[N:10]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=2)=[N:16][CH:17]=1
Reactant: COC(=O)C(=O)CC(=O)c1ccc(Br)cn1
Reactant: NNc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(Br)cn2)n(-c2ccccc2Cl)n1
Temperature: 120 °C
Yield: 12.7 %

Procedure:
A mixture of (2-chlorophenyl)hydrazine hydrochloride (1.1 g, 6.1 mmol) and methyl 4-(5-bromopyridin-2-yl)-2,4-dioxobutanoate (1.7 g, 6.0 mmol) in MeOH (30 mL) was divided into two microwave reaction vessels. Each reaction vessel was then heated in the microwave at 120° C. for ten minutes. LC/MS analysis at this time showed the reaction to be essentially complete. The solutions were concentrated under reduced pressure to afford a dark brown semi-solid. This material was taken up in EtOAc and saturated aqueous NaHCO3. The layers were separated and the basic aqueous was extracted with EtOAc (3×). Combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford a dark oil. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc in hexane to afford methyl 5-(5-bromopyridin-2-yl)-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylate (300 mg, 13% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:22]([CH3:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[C:22]([CH3:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:32])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(C)c(C)cc43)cc2s1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc2ncn(Cc3ccc4nc(S(C)=O)sc4c3)c2cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred solution of 6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (450 mg, 1.32 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (270 mg, 1.32 mmol) in DCM (3 mL). After stirring for 2 h at 0° C., the reaction solution was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (460 mg, 98%) as a colorless solid which was not purified further. 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.37 (m, 1H), 7.02 (s, 1H), 5.48 (s, 2H), 3.06 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H); LCMS (ESI) m/z 356 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:33])[NH:20][C:21]4[CH:27]=[C:26]([N:28]5[CH:32]=[CH:31][CH:30]=[CH:29]5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[N:10]=1)=O)C.[NH3:34]>>[O:33]=[C:19]1[CH2:18][C:17]([C:13]2[CH:12]=[C:11]([C:9]3[N:10]=[C:6]([C:4]([NH2:34])=[O:3])[S:7][CH:8]=3)[CH:16]=[CH:15][CH:14]=2)=[N:23][C:22]2[CH:24]=[CH:25][C:26]([N:28]3[CH:32]=[CH:31][CH:30]=[CH:29]3)=[CH:27][C:21]=2[NH:20]1
Reactant: CCOC(=O)c1nc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)cs1
Reactant: N
Product: NC(=O)c1nc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)cs1

Procedure:
A sample of 4-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-thiazole-2-carboxylic acid ethyl ester (Example 28) (0.07 g) was reacted with ammonia in an analogous manner to the procedure described in Example 27 to give the title compound (0.05 g) as a light-yellow solid.