Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:34][C:35]1[C:39]([Cl:40])=[C:38]([CH2:41][OH:42])[S:37][N:36]=1.[C:43](O)(=[S:45])[CH3:44]>C(OCC)(=O)C.C1COCC1>[C:43]([O:42][CH2:41][C:38]1[S:37][N:36]=[C:35]([Cl:34])[C:39]=1[Cl:40])(=[S:45])[CH3:44]
Reactant: CC(O)=S
Reactant: OCc1snc(Cl)c1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=S)OCc1snc(Cl)c1Cl
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a THF (50 ml) solution of 2.85 g (10.9 mmol) of triphenylphosphine was added, under ice-cooling, 2.2 g (10.9 mmol) of diisopropyl azodicarboxylate, followed by stirring for 30 minutes. To the solution was added a THF (5 ml) solution of 1.0 g (5.43 mmol) of (3,4-dichloroisothiazol-5-yl)methanol and 0.83 g (10.9 mmol) of thioacetic acid, followed by stirring at room temperature for 5 hours, to give rise to a reaction. After the completion of the reaction, ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 0.42 g (yield: 32%) of (3,4-dichloroisothiazol-5-yl)methyl thioacetate as a light red oily substance (refractive index: 1.5855).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])=[CH:20][CH:19]=2)[C:7](=[O:16])[N:8]([CH:10]([C:12](=[O:15])[NH:13][CH3:14])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[NH:32]1C=N[N:34]=[N:33]1>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:7](=[O:16])[N:8]([CH:10]([C:12](=[O:15])[NH:13][CH3:14])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(C(C)C(=O)NC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: c1nnn[nH]1
Solvent: ClCCl
Product: CCCCc1nn(C(C)C(=O)NC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
The conversion of 5-n-butyl-2,4-dihydro-2-[1-(N-methylcarbamoyl)ethyl]-4-[(2'-cyanobiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one to the corresponding tetrazole was accomplished by the procedure of Example 9, Step E, except that the mixture was stirred at 120° C. for 2 days. After work-up, the residue was taken up in CH2Cl2 and flash chromatographed over silica gel (15 mL for 0.19 mmole, gradient elution using 5-30% MeOH/CH2Cl2 to give the desired compound as a white powder in 43% yield, homogeneous by TLC in 30% MeOH/CH2Cl2, mass spectrum (FAB) 461 (M+1)+, mp 153°-155° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[CH:49]=[CH:48][C:39]([C:40]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:41])=[CH:38][CH:37]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:49]=[CH:48][C:39]([C:40]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[O:41])=[CH:38][CH:37]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C(c1ccc(CCl)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(C(=O)N3CCOCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-[4-(chloromethyl)benzoyl]morpholine (0.87 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.16 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12]2)[N:4]=1.CO.[O-][Cl:24].[Na+]>ClCCl>[Cl:24][C:11]1([C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[O:12]1
Reactant: [O-]Cl
Reactant: COc1cc(OC)nc(C2OC(=O)c3ncccc32)n1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)nc(C2(Cl)OC(=O)c3ncccc32)n1

Procedure:
A mixture of 490 mg of 5-(4,6-dimethoxy-2-pyrimidinyl)furo[3,4,b]-pyridine-7(5H)one and 50 ml of methanol is heated at 55° for 1/2 hour or until a homogenous solution is formed. 2.6 g of NaOCl (common house bleach) is added dropwise. The mixture is taken up in dichloromethane an the organic phase separated and evaporated to dryness to yield the title compound, mp 146°-148° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[C:12]1[O:13][C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=1>C(OCC)C>[CH3:2][CH:1]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:12]1[O:13][C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:15]([C:17]([F:19])([F:18])[F:20])[N:16]=1)[CH3:3]
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Reactant: CC(C)Nc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1oc(N(c2ccccc2)C(C)C)nc1C(F)(F)F
Yield: 21.5 %

Procedure:
By the procedure of Example 15, 2.59 g (0.019 mol) of N-isopropyl aniline was reacted neat with 2.32 g (0.0095 mol) of ethyl 2-chloro-4-trifluromethyl-5-oxazolecarboxylate at 140°-150° C. for 4 hours. The product mixture was slurried in ethyl ether, washed with 25% sulfuric acid and water, dried and concentrated. The residue was distilled and the distillate was recrystallized from methylcyclohexane to yield 0.7 g of a white-powder product (m.p.=66°-68° C.) identified in Table 1.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:4]=1.[H-].[Na+].[CH3:27][O:28][CH2:29][C:30](OC)=O>O1CCCC1.C(OCC)(=O)C>[CH3:19][C:18]([CH3:20])([CH3:21])[CH2:17][CH2:16][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:4]=[C:3]([C:2]3[N:1]=[C:30]([CH2:29][O:28][CH3:27])[O:24][N:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:10][CH2:11]1)=[O:22]
Reactant: COCC(=O)OC
Reactant: CC(C)(C)CCC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1nc(-c2ccnc(N3CCN(C(=O)CCC(C)(C)C)CC3)c2)no1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
1-{4-[Amino(hydroxyimino)methyl]pyridin-2-yl}-4-(4,4-dimethylpentanoyl)piperazine (62 mg) was dissolved in tetrahydrofuran (2 mL), then oily sodium hydride (13 mg) was added thereto, stirred at 60° C. for 20 minutes, and methyl methoxyacetate (0.028 mL) was added thereto and heated under reflux for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 44.3 mg of the entitled compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:31])([F:30])[F:29])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1.[NH:35]([CH3:37])[CH3:36]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:35]([CH3:37])[CH3:36])=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:29])([F:30])[F:31])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)Cl)ccc2Cl)n1
Reactant: CNC
Solvent: C1CCOC1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)N(C)C)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A round bottom flask was mixed with 4-chloro-3-(3-{[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-1,2,4-oxadiazol-5-yl)benzoyl chloride (Example 295B) (0.037 g, 0.07 mmol) and Me2NH (2.0 mL), and THF (5.0 mL). The mixture was stirred at rt for 2 h and concentrated to dryness. The resulting solid was crystallized with Et2O, filtered in vacuo and dried under high vacuum to afford a pure solid (0.025 g, 66% yield): MS (ES) m/z 515 (M+).
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH2:17][C:18]#[N:19])=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][N:5]=1.[CH2:20](N)[CH2:21][NH2:22]>C(O)C.ClCCl>[CH3:2][S:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH2:17][C:18]3[NH:22][CH2:21][CH2:20][N:19]=3)=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][N:5]=1
Reactant: COc1cc2c(SC)ncnc2cc1OCC#N
Reactant: NCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COc1cc2c(SC)ncnc2cc1OCC1=NCCN1
Temperature: 4 °C
Reaction time: 20 h
Yield: 16 %

Procedure:
Excess anhydrous hydrochloric acid in ethanol (1 ml) was added to a solution of 4-(methylthio)-6-methoxy-7-(cyanomethoxy)quinazoline (300 mg, 1.15 mmol) in dichloromethane (20 ml) and the reaction was stirred for 20 hours at 4° C. The solvent was evaporated, ethylene diamine (280 mg, 8.15 mmol) in ethanol (10 ml) was added to the residue, and the mixture was refluxed for 2 hours. Solvent evaporation in vacuo and purification by flash chromatography on silica gel, eluting with 5% methanol in dichloromethane, yielded 4-(methylthio)-6-methoxy-7-((4,5-dihydro-2-imidazolyl)methoxy)quinazoline (56 mg, 22% yield) as a white solid:
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[CH3:17])(=O)=O.CC1C([N+]([O-])=O)=CC=C(C)C=1CCl.[H-].[Na+].O[C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[N:42]=[C:41]([CH3:44])[CH:40]=[CH:39]2>CN(C)C=O.O>[CH3:17][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=1[CH2:6][O:5][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[N:42]=[C:41]([CH3:44])[CH:40]=[CH:39]2
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1COS(C)(=O)=O
Agent: Cc1ccc([N+](=O)[O-])c(C)c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(C)ccc([N+](=O)[O-])c3C)c2n1
Reaction time: 0.25 h

Procedure:
To a mixture of 2,6-dimethyl-3-nitrobenzyl methanesulfonate and 2,6-dimethyl-3-nitrobenzyl chloride obtained above in N,N-dimethylformamide (13 ml) was added sodium hydride (60% in oil, 335 mg) under ice-bath cooling, and the mixture was stirred for 15 minutes. To the mixture was added 8-hydroxy-2-methylquinoline (1.27 g), and the mixture was stirred for 1 hour at ambient temperature. Water was added thereto, and the resulting precipitate was collected by filtration to give 8-(2,6-dimethyl-3-nitrobenzyloxy)-2-methylquinoline (2.53 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:11]([Cu])#[N:12]>CN(C=O)C.CCOC(C)=O>[C:11]([C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1)#[N:12]
Reactant: COc1ncc(Br)cc1C
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncc(C#N)cc1C
Temperature: 25 °C
Yield: 91.8 %

Procedure:
To a solution of 5-bromo-2-methoxy-3-methyl-pyridine (1.0 g, 5.0 mmol) in DMF (10 ml) was added CuCN (0.534 g, 6.0 mmol) and the resulting mixture is heated at reflux for 28 h. After cooling to room temperature the mixture is diluted with EtOAc and washed with 10% ammonia solution followed by water and brine solution. The organic layer was separated, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc/Hexane) to give 5-cyano-2-methoxy-3-methyl-pyridine (36) (0.68 g, 93%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.N([O-])=O.[Na+].[ClH:18]>C(O)(=O)C.O>[Cl:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1
Reactant: Nc1ccccc1Sc1ncc[nH]1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccccc1Sc1ncc[nH]1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 5.6 g (29.3 mmoles) of the product from Example 32 in 50 ml of 3N hydrochloric acid and 50 ml of glacial acetic acid (cooled in an ice bath), was added dropwise over 20 minutes, a solution of 2.0 g (29.3 mmoles) of sodium nitrite in 8 ml of water. After stirring for 10 minutes, the mixture was added to a cold solution of 8.7 g (80 mmoles) cuprous chloride in 80 ml of 6N hydrochloric acid. After stirring at room temperature for 5 hours, the mixture was concentrated and the residue made alkaline with ammonium hydroxide. The product was extracted with dichloromethane which was washed with saturated sodium chloride, dried and concentrated. The residue was dissolved in hot dichloromethane and filtered through silica gel using dichloromethane/ethyl acetate (1:1 by volume) as the eluent. The fractions containing the product were concentrated to give 4.9 g (79%) of the product which was crystallized from dichloromethane to give colorless rods, mp 138°-141° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[N:7]2[CH2:13][CH:14]=O.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[N:7]2[CH2:13][CH2:14][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]1
Reactant: O=CCn1c(=O)ccc2c(F)cc(F)cc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
(5,7-Difluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (2.1 g; 9.4 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (2.82 g; 14.1 mmol) were dissolved in a 1:1 mixture of chloroform and MeOH (60 ml:60 ml) and stirred at rt for 1 h. This was then treated with NaBH(OAc)3 (8.92 g; 42.3 mmol) and stirred for a further 1 h. More 1,1-dimethylethyl 4-piperidinylcarbamate (470 mg; 2.35 mmol) was added and the reaction stirred under the same conditions for 20 mins, this was then treated with NaBH(OAc)3 (1.98 g; 9.4 mmol) and stirred for 25 mins. More 1,1-dimethylethyl 4-piperidinylcarbamate (470 mg; 2.35 mmol) was then added and the reaction stirred for 20 mins. More NaBH(OAc)3 (500 mg; 2.38 mmol) was then added to the reaction and it was stirred overnight at rt. The solvents were then removed and the crude residue purified by column chromatography on silica gel using a 0-15% MeOH/DCM gradient to give the desired product (2 g; 52%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([NH2:22])=[N:3]1.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=O.[BH4-].[Na+].O>C(O)C>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([NH:22][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][OH:23])=[N:3]1
Reactant: O=CCCCCO
Reactant: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1cccc(OCCCNc2nc(NCCCCCO)nn2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Methyl-N5 -[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (1.0 g) and 5-hydroxypentanal (1.9 ml) were heated at reflux in ethanol (30 ml) for 5 h. The solution was cooled at 5° and treated with sodium borohydride (0.76 g). The resulting suspension was stirred at room temperature for 16 h, treated with water and reduced in volume in vacuo. The aqueous solution was extracted with ethyl acetate, and the organic extracts were distilled to give the title compound as a pale yellow oil (0.47 g) b.p. 250°/0.5 mm. TLC silica; ethyl acetate:isopropanol:water: 0.88 ammonia 25:15:8:2, Rf 0.6.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[NH:9][CH2:8][NH:7][C:6]=2[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:24][CH2:25][CH2:26]Br.C(C(Br)C([O-])=O)C1C=CC=CC=1>>[Br:24][CH2:25][CH2:26][N:9]1[CH2:8][NH:7][C:6]2[CH:13]=[C:2]([Cl:1])[C:3]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:4][C:5]=2[S:10]1(=[O:12])=[O:11]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)NCNS2(=O)=O
Reactant: BrCCBr
Agent: O=C([O-])C(Br)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: NS(=O)(=O)c1cc2c(cc1Cl)NCN(CCBr)S2(=O)=O

Procedure:
Treat 6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine with Cs2CO3 and substitute 1,2-dibromoethane for benzylbromoacetate in the procedure of Example 7, step A to obtain 2-(2-bromoethyl)-6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH2:13][CH:14]([OH:16])[CH2:15][C:11]=2[C:10]([C:17]#[N:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[CH2:22][CH3:23]>CN(C=O)C>[CH2:1]([N:8]1[C:12]2[CH2:13][CH:14]([O:16][CH2:21][CH2:22][CH3:23])[CH2:15][C:11]=2[C:10]([C:17]#[N:18])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1nn(Cc2ccccc2)c2c1CC(O)C2
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOC1Cc2c(C#N)nn(Cc3ccccc3)c2C1

Procedure:
To a solution of 1-benzyl-5-hydroxy-1,4,5,6-tetrahydrocyclo-penta[c]pyrazole-3-carbonitrile-(see Example 9.7, 30 mg, 0.125 mmol) in anhydrous DMF (2 mL) was added sodium hydride (6 mg, 0.15 mmol, 60% dispersion in oil). After stirring for 3 minutes propyl bromide was added (14 μL, 0.15 mmol) and the resulting mixture stirred for an hour. At the end of this time sodium hydride (6 mg, 0.15 mmol, 60% dispersion in oil) and propyl bromide were added. After 30 minutes the reaction was quenched by adding saturated NH4Cl (3 mL). The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by PTLC (SiO2) using 15% ethyl acetate-hexanes to give the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16](Cl)=[N:17][OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:16]1[CH:21]=[C:20]([C:22]2[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=2)[O:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1cccc(OCc2ccccc2)c1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3cccc(OCc4ccccc4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-benzyloxy-phenyl)-acetohydroximoyl chloride (200 mg, 0.724 mmol) described in Manufacturing Example 61-1-4 and 3-ethynyl-pyridin-2,6-diamine (61.5 mg, 0.462 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (252 μL, 1.81 mmol). This mixture was stirred for 4 hours at room temperature. This mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (138 mg, 51%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:48]([N+:52]1[N:56]=[C:55]([CH3:57])[S:54][C:53]=1[CH3:58])[CH2:49][CH2:50][CH3:51]>>[CH2:48]([N:52]1[N:56]=[C:55]([CH3:57])[S:54]/[C:53]/1=[CH:58]\[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:13])[CH2:49][CH2:50][CH3:51]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-naphthoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.93 (t, 3 H) 1.32-1.41 (m, 2 H) 1.75-1.83 (m, 2 H) 2.50 (s, 3 H) 4.28 (t, 2 H) 6.90 (s, 1 H) 7.93-8.00 (m, 2 H) 8.04-8.08 (m, 1 H) 8.10-8.15 (m, 1 H) 8.61 (s, 1 H); MS (ESI) m/z 325 (M+H)+.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][C:3]=1[O:10][CH3:11].BrC[C:14]([NH:16]C1C=CC(Br)=CC=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].C(#N)CC>C(OCC)(=O)C>[O:10]([CH2:11][C:14]([NH2:16])=[O:15])[C:3]1[CH:2]=[CH:9][CH:8]=[CH:5][CH:4]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(CBr)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC#N
Product: NC(=O)COc1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 190 %

Procedure:
To 4-hydroxy-3-methoxybenzaldehyde (2.02 g, 13.3 mmol), 2-bromo-N-(4-bromophenyl)acetamide (3.00 g, 10.2 mmol) and potassium carbonate (2.12 g, 15.4 mmol) was added propionitrile (10 ml), and the mixture was stirred at 80° C. for one day. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate), and powderized with ethyl acetate-diisopropyl ether (1:5) to give a phenoxyacetamide derivative (2.93 g). The title compound was obtained by similar operations as in Reference Example 43 and Example 6 and using this compound.
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].O>CN(C)C=O>[O:14]=[C:3]1[C:4]2[C:9](=[CH:8][C:7]([O:11][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:6]([Cl:12])[C:5]=2[Cl:13])[CH2:10][C:2]1([CH3:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (9.2 g., 0.03 mole), potassium carbonate (8.29 g., 0.06 mole) and tert-butyl bromoacetate (6.44 g., 0.033 mole) in dimethylformamide (30 ml.) is stirred at 25° C. for two hours. The reaction mixture is poured into cold water (150 ml.) and the tert-butyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetate which separates is filtered, rinsed with water and dried.