Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[CH:13][C:12]([C:25]([O:27]CC)=[O:26])=[N:11]2)[CH:7]=[CH:8][CH:9]=1.Cl>CO.O>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[CH:13][C:12]([C:25]([OH:27])=[O:26])=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
8.5 g (152 mmol) of potassium hydroxide are added to a solution of 6 g (15.2 mmol) of ethyl 1-(3-chlorophenyl)-5-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate from example 4A in 80 ml of methanol and the mixture is stirred for 30 minutes under reflux. The reaction mixture is diluted with water and rendered acidic using 1 molar hydrochloric acid. The mixture is extracted with ethyl acetate. The organic phase is washed with a sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue obtained is crystallized from diethyl ether/pentane. The crystals are collected by suction filtration, washed with a little pentane and dried. 5.2 g (14.2 mmol, 93% yield of theory) of product are obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([O:10]C)=O.[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([NH:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1)=[O:10]
Reactant: COC(=O)C1=C(O)c2ccsc2S(=O)(=O)C1
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nccs1)C1=C(O)c2ccsc2S(=O)(=O)C1
Temperature: 5 °C
Yield: 21.3 %

Procedure:
A mixture of methyl 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate 7,7-dioxide (5.2 g, 0.02 mole), 2-aminothiazole (3.0 g, 0.03 mole) and xylene (175 ml) is warmed and filtered from the polymeric products. The filtrate is refluxed for 30 min. when some more polymeric product is formed. It is filtered again, and the filtrate refluxed for 1.5 hrs. The mixture is cooled to 5° C. in an ice-bath, and the resulting crystalline product is collected. It is dissolved in THF, treated with charcoal and filtered. The filtrate is concentrated to give the desired product (1.4 g, 21%), m.p. 215-216° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CS([C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[N:22]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:21]=2)[C:17]([C:43]#[N:44])=[CH:16][N:15]=1)(=O)=O.[Cl:45][C:46]1[N:51]=[CH:50][C:49]([CH:52]([NH2:54])[CH3:53])=[CH:48][CH:47]=1>O1CCCC1>[Cl:45][C:46]1[N:51]=[CH:50][C:49]([C@H:52]([NH:54][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:27]=4)[N:22]([S:33]([C:36]4[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=4)(=[O:35])=[O:34])[CH:21]=3)[C:17]([C:43]#[N:44])=[CH:16][N:15]=2)[CH3:53])=[CH:48][CH:47]=1
Reactant: CC(N)c1ccc(Cl)nc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)c4ccc(Cl)nc4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 110 °C
Yield: 58 %

Procedure:
Diisopropylethylamine (730 μl, 4.2 mmol) was added to a mixture of 2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (330 mg, 2.1 mmol) and 1-(6-chloropyridin-3-yl)ethanamine (described in the literature: EP 375907 (B1))(500 mg, 1 mmol) in tetrahydrofuran (3 mL). The reaction mixture was heated under microwave irradiation at 110° C. for 15 minutes. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as a wax (345 mg, 58% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2].[H][H]>C(O)C.N.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(C#N)cn1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc(CN)cn1

Procedure:
A 1.00 g portion of 5-cyano-2-methoxypyridine was dissolved in 30 ml of ethanol and 10 ml of 28% aqueous ammonia, mixed with 1 g of Raney nickel and then stirred at room temperature for 4 hours at atmospheric pressure in a stream of hydrogen. After filtration through celite, the solvent was evaporated to obtain 962 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH3:8])[NH:5][C:6]=1[Br:7].[H-].[Na+].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([CH3:8])[N:5]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[C:6]=1[Br:7]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1nc(Br)c(Br)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
4,5-Dibromo-2-methylimidazol (4.91 g) was dissolved in N,N-dimethyl-formamide (50 ml) and 60% sodium hydride (901 mg) was gradually added under ice-cooling. The mixture was stirred for 1 hr at room temperature, and 2-(trimethylsilyl)ethoxymethyl chloride (3.75 g) was gradually added dropwise under ice-cooling and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and ethyl acetate was added to the residue. The residue was washed with a saturated aqueous sodium hydrogencarbonate solution, and then with brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give the objective compound (7.6 g) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34]>>[CH3:29][O:30][CH2:31][CH2:32][N:33]([CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7])[CH3:34]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Reactant: CNCCOC
Product: COCCN(C)Cc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Temperature: 60 °C

Procedure:
2-Chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide (240 mg, 0.55 mmol) is dissolved in N-(2-methoxyethyl)-methylamine (1.0 g, 12 mmol) and the mixture heated to 60° C. for 1 h. The volatile components are removed in vacuo and the residue chromatographed over SiO2 eluting with dichloromethane/methanol 19/1. The title compound was obtained as yellow crystals (170 mg, 71% yield). MS: m/e=472(M+H+). Following the general method of example 46 the compounds of examples 47-62 were prepared.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)(O)[CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:38][S:35]([C:32]1[CH:33]=[CH:34][C:29](/[C:21](/[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=2)=[CH:22]\[CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)=[CH:30][CH:31]=1)(=[O:36])=[O:37]
Reactant: COc1cnc2c(c1)cc(C(O)(CC1CCCO1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cnc2[nH]c(/C(=C/C3CCCO3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 62.7 %

Procedure:
A solution of 1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-ethanol (110 mg, 0.20 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 2.0 mL, 2.0 mmol) was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (150 mL), and washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo the residue was treated with methanol to afford 2-[(E)-1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (50 mg, 64.1%) as a light yellow solid: LC/MS m/e calcd for C21H22N2O4S [M+H]+ 399.48, observed 399.3; 1H NMR (400 MHz, CD3OD) δ ppm 8.05-8.09 (m, J=8.1 Hz, 2H), 7.94 (d, J=2.5 Hz, 1H), 7.60-7.64 (m, J=8.1 Hz, 2H), 7.43 (d, J=2.5 Hz, 1H), 6.46 (d, J=9.1 Hz, 1H), 5.86 (s, 1H), 4.11-4.24 (m, 1H), 3.97 (q, J=7.0 Hz, 1H), 3.85 (s, 3H), 3.73-3.81 (m, 1H), 3.22 (s, 3H), 2.03-2.13 (m, 2H), 1.79-1.97 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:4]=[C:5]2[C:14]3[CH:13]=[C:12]4[CH:15]=[CH:16][CH:17]=[CH:18][C:11]4=[CH:10][C:9]=3[NH:8][C:7](=[O:19])[C:6]=12.C(=O)([O-])[O-].[Cs+].[Cs+].[C:33]([O:37][C:38](=[O:44])[NH:39][CH2:40][CH2:41][CH2:42]Br)([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C>[C:33]([O:37][C:38]([NH:39][CH2:40][CH2:41][CH2:42][N:8]1[C:9]2[CH:10]=[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]3=[CH:13][C:14]=2[C:5]2=[N:4][N:3]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:2]([CH3:1])=[C:6]2[C:7]1=[O:19])=[O:44])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Cc1c2c(=O)[nH]c3cc4ccccc4cc3c2nn1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c2c(=O)n(CCCNC(=O)OC(C)(C)C)c3cc4ccccc4cc3c2nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of tert-butyl 3-methyl-4-oxo-4,5-dihydro-2H-benzo[g]pyrazolo[4,3-c]quinoline-2-carboxylate (1-6) (0.1 g, 0.29 mmol, 1.0 equiv) and cesium carbonate (0.50 g, 1.5 mmol, 5.4 equiv) in DMF (5 ml) was added N-(3-bromopropyl)carbamic acid tert-butyl ester (0.12 g, 0.50 mmol, 1.8 equiv) and the reaction was stirred at room temperature. After 20 hours LC/MS indicated the reaction was 55% complete so an additional 120 mg of alkylating agent was added and the reaction was stirred at room temperature for an additional 24 hours. LC/MS indicated the reaction was complete, and the reaction was filtered to remove the base and purified by reverse phase liquid chromatography (H2O/CH3CN gradient w/0.05% NH4OH present) to yield tert-butyl 5-{3-[(tert-butoxycarbonyl)amino]propyl}-3-methyl-4-oxo-4,5-dihydro-2H-benzo[g]pyrazolo[4,3-c]quinoline-2-carboxylate (1-7) as a white solid. LRMS m/z (M+H) 507.6 found, 507.3 required.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.[NH2:43][C@H:44]1[CH2:49][CH2:48][C@H:47]([OH:50])[CH2:46][CH2:45]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:43][C@H:44]5[CH2:49][CH2:48][C@H:47]([OH:50])[CH2:46][CH2:45]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H]2CC[C@H](O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.13 mL (0.72 mmole) of ethyldiisopropyl amine and 0.030 g (0.20 mmole) of trans-4-amino-cyclohexanol hydrochloride in 2.0 mL of dimethylformamide was added 0.085 g (0.2 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.077 g of trans-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-hydroxy-cyclohexyl)-3-methoxy-benzamide (I-69) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=2)([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[N+:32]([O-:34])=[O:33].Cl>N1C=CC=CC=1>[S:2]([O:28][C:25]1[CH:26]=[CH:27][C:22]([C:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[C:8]([N+:32]([O-:34])=[O:33])[CH:9]=2)([C:18]([F:21])([F:19])[F:20])[C:14]([F:16])([F:15])[F:17])=[CH:23][C:24]=1[N+:29]([O-:31])=[O:30])([CH3:1])(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1cc(C(c2ccc(O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(C(c2ccc(OS(C)(=O)=O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 85 %

Procedure:
11.5 g (0.1 mol) of methanesulfonyl chloride are added dropwise, at a reaction temperature of 0-5° C., to a mixture of 21.3 g (0.05 mol) of 2,2-bis-(4-hydroxy-3-nitrophenyl)-hexafluoropropane and 100 ml of pyridine. Stirring is continued for 1 hour at 5° C. and overnight at room temperature. The reaction mixture is then acidified, first with dilute hydrochloric and then with half-concentrated hydrochloric acid; the precipitate which is deposited is filtered off with suction and washed with water until neutral. The crude product (29.3 g) is then recrystallized from toluene, resulting in 24.8 g of analytically pure 2,2-bis-(4-mesyloxy-3-nitrophenyl)-hexafluoropropane to be isolated. Yield 85%; m.p. 119-121° C.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([C:5]1[O:6][C:7]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc2nc(C(C)(C)C)oc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nc2cccc(C(=O)O)c2o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.6 %

Procedure:
A mixture of methyl 2-tert-butylbenzoxazole-7-carboxylate (0.41 g, 1.77 mmol), lithium hydroxide monohydrate (222 mg, 5.30 mmol) and tetrahydrofuran/water (5:1, 6 mL) was stirred at room temperature for 17 h. The reaction mixture was cooled to 0° C., adjusted to pH 2 using 1 N HCl, and then extracted with dichloromethane (2×200 mL). The combined organic phase was washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated to afford the desired 2-tert-butylbenzoxazole-7-carboxylic acid (336 mg, 86%) as a pink solid: 1H NMR (300 MHz, DMSO-d6) δ 13.20 (br s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 1.45 (s, 9H); MS (ESI+) m/z 220 (M+H).
Reaction SMILES: [I:1][C:2]1[C:6]([CH:7]=O)=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1.[CH3:15][N:16]([CH2:24][CH2:25][NH:26][CH3:27])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.ClCCl>[I:1][C:2]1[C:6]([CH2:7][N:26]([CH3:27])[CH2:25][CH2:24][N:16]([CH3:15])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1
Reactant: O=Cc1cn(C2CCCCO2)nc1I
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A mixture of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carbaldehyde (21.5 g, 70.24 mmol, 1.00 equiv), tert-butyl N-methyl-N-(2-(methylamino)ethyl)carbamate (20 g, 106.23 mmol, 1.51 equiv) and NaBH(OAc)3 (29.8 g, 137.98 mmol, 1.96 equiv) in dichloroethane (300 mL) was stirred for 1 h at room temperature. The reaction was diluted with 300 mL of dichloromethane and then washed with 3×300 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-7% methanol in dichloromethane to give 31 g (92%) of tert-butyl (2-(((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.62 (s, 1H), 5.34-5.30 (m, 1H), 4.06-4.02 (m, 1H), 3.68-3.62 (m, 1H), 3.42-3.38 (m, 4H), 2.85 (s, 4H), 2.62-2.53 (m, 2H), 2.47-2.46 (m, 2H), 2.13-1.97 (m, 3H), 1.74-1.69 (m, 3H), 1.46 (s, 9H) ppm. LCMS (method A, ESI): RT=1.17 min, m/z=479.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:12][O:13][C:14](=[O:29])[C:15]([CH3:28])([CH3:27])[CH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([CH:24]=O)=[C:19]([CH3:26])[CH:18]=1.OOS([O-])=O.[K+].O>CN(C=O)C>[CH3:12][O:13][C:14]([C:15]([CH3:28])([CH3:27])[CH2:16][C:17]1[CH:18]=[C:19]([CH3:26])[C:20]([C:24]2[NH:1][C:2]3[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=3[N:8]=2)=[C:21]([CH3:23])[CH:22]=1)=[O:29]
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.6 g of 3,4-diaminobenzenoic acid was stirred in 120 ml of DMF at room temperature. It was treated with 12.4 g of 3-(4-formyl-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid methyl ester (the intermediate A in Example 1-62) followed by an addition of a slurry of 15 g of Oxone in 60 ml of DMF. The reaction was stirred at room temperature for 3 h and 60 mL of water was added and the pH was adjusted to 6. Additional 150 mL of water was added and the resulting precipitates were collected by filtration. The collected precipitates were washed with water and dried under vacuum to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11]([CH3:28])=[C:10]2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:5][CH:4]=1)#[N:2].[Br:34]Br>C(Cl)(Cl)Cl>[Br:34][CH2:28][C:11]1[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:13]2[N:14]([N:15]=[N:16][N:17]=2)[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[C:10]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nnnn2C1c1ccc(C#N)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)c2nnnn2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyl 7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (30 mg, 66.1 μmol; Example 70) was dissolved in chloroform (1 ml), and a solution of bromine (3×11.6 mg, 3×72.6 μmol, 3.3 eq.) in chloroform was added a little at a time at 0° C. The mixture was then stirred for 12 h, during which time it slowly warmed to RT. The mixture was then diluted with chloroform and washed with 10% strength sodium thiosulfate solution. The organic phase was separated off, dried over sodium sulfate and, after filtration, concentrated on a rotary evaporator. The crude product was reacted further without further purification (35.3 mg, 87% pure according to LC-MS, 87% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14]O)=[C:5]2[O:16][CH3:17].S(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14][Cl:20])=[C:5]2[O:16][CH3:17]
Reactant: O=S(Cl)Cl
Reactant: COc1c(CO)n(C)c(=O)c2ccc(Cl)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(CCl)n(C)c(=O)c2ccc(Cl)cc12
Yield: 89.4 %

Procedure:
To a solution of 6-chloro-3-hydroxymethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone (0.76 g, 3 mmol) in tetrahydrofuran (20 ml) was added thionyl chloride (0.26 ml, 3.6 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-chloro-3-chloromethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone (0.73 g, 90.1%) as crystals.
Reaction SMILES: FC(F)(F)C([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.OO.[F:16][C:17]([F:41])([C:37]([F:40])([F:39])[F:38])[C:18]([F:36])([F:35])[C:19]([F:34])([F:33])[C:20]([F:32])([F:31])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([I:26])([F:25])[F:24]>FC(F)(F)C(O)=O>[F:8][C:7]([F:10])([F:9])[C:6]([O:11][I:26]([O:5][C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])[C:23]([F:25])([F:24])[C:22]([F:28])([F:27])[C:21]([F:30])([F:29])[C:20]([F:32])([F:31])[C:19]([F:33])([F:34])[C:18]([F:36])([F:35])[C:17]([F:41])([F:16])[C:37]([F:38])([F:39])[F:40])=[O:5]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Solvent: O=C(O)C(F)(F)F
Product: O=C(OI(OC(=O)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reaction time: 1.5 h
Yield: 66 %

Procedure:
1.3 ml (9.3 mmols) of trifluoroacetic anhydride was dissolved in 3.3 ml of trifluoroacetic acid, and 0.175 ml of a 30% hydrogen peroxide solution (H2O2, 1.71 mmol and H2O, 7.55 mmols) was added dropwise thereto while cooling in an ice bath. After completion of the addition, the mixture was stirred for 1.5 hour and 1.55 mmol of heptadecafluoro-n-octyl iodide was added and the mixture was allowed to react at 0° to 5° C. for 18 hours to obtain di(trifluoroacetoxy)iodoheptadecafluoro-n-octane in 66% yield.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH:11]1([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[C:29](F)[CH:28]=[CH:27][C:26]=3[N+:32]([O-:34])=[O:33])[CH:22]=2)=[O:16])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[C:29]([N:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]4)[CH:28]=[CH:27][C:26]=3[N+:32]([O-:34])=[O:33])[CH:22]=2)=[O:16])[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (13) in the portion of Example 1 which is concerned with the preparation of starting materials, 1-(methylsulfonyl)piperazine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[4-(methylsulfonyl)piperazin-1-yl]-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.64 (m, 4H), 2.31 (s, 3H), 2.84 (m, 1H), 2.93 (s, 3H), 3.26 (m, 4H), 3.64 (m, 4H), 7.13 (m, 2H), 7.29 (d, 1H), 7.58 (d, 1H), 7.98 (s, 1H), 8.08 (t, 1H), 8.37 (d, 1H), 9.95 (s, 1H); Mass Spectrum: M−H+ 500.