Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].COCCOCCN(CCOCCOC)CCOCCOC.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32].Cl[CH:34]([F:36])[F:35]>C1C=CC=CC=1>[F:35][CH:34]([S:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[F:25])[F:36]
Reactant: Fc1ccccc1S
Reactant: FC(F)Cl
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Fc1ccccc1SC(F)F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Powdered NaOH (31.2 g), tris(2-(2-methoxyethoxy)ethyl)amine (5 mL) and 2-fluorobenzene thiol (33.6 mL) in benzene (400 mL) was saturated with chlorodifluoromethane, stirred at 80° C. for 30 minutes and filtered through diatomaceous earth (Celite®). The filtrate was washed with saturated NaHCO3 and the water layer was extracted with diethyl ether. The extracts were combined and dried (MgSO4), filtered and concentrated.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:25]=[C:24]([NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH:23]=[CH:22][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)=[O:6].[CH3:37]I>>[ClH:2].[Cl:2][C:3]1[CH:25]=[C:24]([N:26]([C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[CH3:37])[CH:23]=[CH:22][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: CI
Reactant: O=C(Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1)OCc1ccccc1
Agent: Cl
Product: CN(C(=O)OCc1ccccc1)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1

Procedure:
In a manner analogous to that described in Example 5, the 1-[2-chloro-4-(N-benzyloxycarbonylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine hydrochloride obtained in accordance with Example 17 is methylated with 0.8 g of methyl iodide, yielding 1-[2-chloro-4-(N-benzyloxycarbonyl-N-methylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine hydrochloride.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].[CH3:7][S:8](Cl)(=[O:10])=[O:9].Cl>>[CH3:7][S:8]([N:4]([CH3:3])[N:5]([S:8]([CH3:7])(=[O:10])=[O:9])[CH3:6])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: CNNC
Agent: Cl
Product: CN(N(C)S(C)(=O)=O)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.4 %

Procedure:
1,2-Dimethylhydrazine dihydrochloride (2.6 g, 0.02 mol) was suspended in ice-cold dry pyridine (6 ml) and the mixture was stirred for 10 minutes. Methanesulfonyl chloride (5.0 g, 0.043 mol) was added in portions to this mixture, while maintaining the temperature between 0° and 10° C. After an additional 1 hour of stirring at 0° to 5° C., the reaction mixture was left in a freezer (-10° C.) overnight. The pH of the reaction mixture was adjusted to pH 1 with cold dilute hydrochloric acid. The solid that separated was filtered and recrystallized from ethanol (Norit A) to give 1.4 g (32%) of the title compound: m.p. 168°-169° C.; anal. (C4H12N2O4S2) C,H,N; 1H NMR (CDCl3) δ 3.1 [2s, 12H, 2(CH3SO2NCH3)].
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N:4]1([CH2:3][CH2:2][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCN2CCCC2)cc1
Temperature: 60 °C
Yield: 54.5 %

Procedure:
A mixture of 1-(2-chloroethyl)pyrrolidine (1.19 g, 8.83 mmol), 4-hydroxybenzaldehyde (1.02 g, 8.33 mmol), and potassium carbonate (2.30 g, 16.7 mmol) in DMF (5 mL) was heated at 60° C. overnight. The reaction mixture was diluted with H2O and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed (50 mL brine), dried over Na2SO4, and concentrated. The crude material was purified on a silica gel column to yield 4-(2-(pyrrolidin-1-yl)ethoxy)benzaldehyde (996 mg, 53%). 1H NMR (CDCl3): δ 9.90 (s, 1H), 7.85 (d, 2H), 7.03 (d, 2H), 4.22 (t, 2H), 2.96 (t, 2H), 2.69 (m, 4H), 1.82 (m, 4H).
Reaction SMILES: CO[C:3](=[O:14])[CH:4]=[C:5]1[CH2:11][CH:10]2[N:12]([CH3:13])[CH:7]([CH2:8][CH2:9]2)[CH2:6]1.[CH2:15]([Mg]Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C:3]([OH:14])([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:4]=[C:5]1[CH2:6][CH:7]2[N:12]([CH3:13])[CH:10]([CH2:9][CH2:8]2)[CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COC(=O)C=C1CC2CCC(C1)N2C
Product: CN1C2CCC1CC(=CC(O)(Cc1ccccc1)Cc1ccccc1)C2

Procedure:
The title compound was prepared from (8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-acetic acid methyl ester and benzylmagnesium chloride by following the experimental procedures in Example 1 (31% yield): LCMS (ES) m/z 348 (M+H)+; 1H-NMR(CDCl3) δ 0.90 (m, 1H), 1.25 (m, 1H), 1.61 (m, 1H), 1.81 (m, 3H), 2.20 (s, 3H), 2.40 (m, 1H), 2.70 (m, 1H), 2.87 (m, 1H), 2.97 (m, 2H), 3.08 (m, 1H), 3.42 (s, 2H), 5.24 (s, 1H), 7.26 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH2:15]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:16]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(NC(=O)CCCNC(=O)OC(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 114.7 %

Procedure:
To a solution of 3-amino-9-ethylcarbazole (500 mg, 2.38 mmol), 4-(tert-butoxycarbonylamino)butyric acid (483 mg, 2.38 mmol) and DIEA (1.246 mL, 7.13 mmol) in DMF (12 mL) was added HATU (1085 mg, 2.85 mmol), and the mixture was stirred at room temperature for 3 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 75% ethyl acetate/hexane) to give crude tert-butyl 4-(9-ethyl-9H-carbazol-3-ylamino)-4-oxobutylcarbamate (1080 mg, 2.73 mmol, 115%) as a pale-yellow powder.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:20][CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[O:19])[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)O)nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CCCc2cn(COC(=O)C(C)(C)C)nn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 4-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)butanoic acid (1.63 g, 6.05 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (1.212 g, 6.05 mmol) in DMF (10 mL) was added Huenig's Base (3.17 mL, 18.16 mmol) followed by T3P® 50% in DMF (7.07 mL, 12.11 mmol) at RT. The reaction mixture was allowed to stir at RT for 20 hours. The DMF was removed under reduced pressure and the residue dissolved in EtOAc and washed with a saturated solution of sodium bicarbonate, a saturated solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product;
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=O)[O:7]C(=O)[NH:9][C:4]=2[CH:3]=1.[CH3:14][NH2:15]>>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:13]=[CH:12][C:5]=1[C:6]([NH:15][CH3:14])=[O:7]
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: CN
Product: CNC(=O)c1ccc(F)cc1N
Temperature: 110 °C
Yield: 62 %

Procedure:
A microwave vial was charged with 7-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione (750 mg, 4.14 mmol) and methyl amine 40% aqueous solution (19.8 mL, 22.8 mmol, 5.5 eq). The reaction was stirred and heated in the microwave for 6 min at 110° C. The aqueous solution was extracted with methylene chloride (3×). Organic layers were combined and washed with 5% NaHCO3 solution and brine, dried over sodium sulfate, then concentrated to give a pale yellow oil that was used without further purification (434 mg, 62% yield). MS: M(C8H9FN2O)=168.17, (M+H)+=169 and (M+H−NHMe)+=138.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][N:12]([CH3:17])[CH2:13]4)[CH2:9][CH2:8]3.B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:17][N:12]1[CH2:13][C:14]23[CH:7]([CH2:8][CH2:9][CH:10]2[CH2:11]1)[C:6]1[CH:18]=[CH:19][C:3]([OH:2])=[CH:4][C:5]=1[CH2:16][CH2:15]3
Reactant: COc1ccc2c(c1)CCC13CN(C)CC1CCC23
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CN1CC2CCC3c4ccc(O)cc4CCC23C1
Temperature: -78 °C
Reaction time: 5 h
Yield: 31.7 %

Procedure:
2-Methoxy-8-methyl-5,6,6a,7,8,9,10,11-octahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrole (Example 1B) (190.0 mg, 0.74 mmol) and tetrabutylammonium iodide (300 mg, 0.81 mmol) were dissolved in CH2Cl2 (20 mL) and cooled to −78° C. BCl3 (1.85 mL, 1M in CH2Cl2) was added dropwise. The mixture was stirred at 0° C. for 5 hrs. It was then quenched with aq. satd. NaHCO3, extracted with CH2Cl2 (15 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5% methanol in dichloromethane, providing 57.1 mg (31.8%) of the title compound 1C.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.C([C:10]1[CH:15]=[CH:14][C:13]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=1)=O.N1CCCCC1>N1C=CC=CC=1>[CH3:20][S:17]([O:16][C:13]1[CH:12]=[CH:11][C:10](/[CH:3]=[CH:2]/[C:1]([OH:7])=[O:6])=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Oc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CS(=O)(=O)Oc1ccc(/C=C/C(=O)O)cc1
Temperature: 90 °C
Yield: 57.4 %

Procedure:
Malonic acid (7.80 g, 74.92 mmol) was added to a solution of the crude methanesulfonic acid 4-formylphenyl ester (10 g, 49.95 mmol), which was synthesized in the preceeding step, and piperidine (0.7 ml, 7.09 mmol) in pyridine (50 ml). The reaction mixture was heated to 90° C. for 2.5 h. It was cooled to room temperature. Concentrated hydrochloric acid/ice (400 ml/100 ml) was added. The precipitation was filtered off and washed with a 10% aqueous solution of acetic acid (200 ml). It was dried in vacuo to give 6.95 g of (E)-3-(4-(methanesulfonyloxy)phenyl)acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3](C#N)=[N:4][C:5]([Br:9])=[CH:6][C:7]=1[Br:8].O.[C:13](=[O:16])(O)[O-:14].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:3]([C:13]([OH:14])=[O:16])=[N:4][C:5]([Br:9])=[CH:6][C:7]=1[Br:8]
Reactant: N#Cc1nc(Br)cc(Br)c1N
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Nc1c(Br)cc(Br)nc1C(=O)O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-amino-4,6-dibromo-pyridine-2-carbonitrile (158 mg) was dissolved in concentrated sulfuric acid (1.5 mL) and stirred for 1 h at 100° C. The reaction mixture was cooled to room temperature and water (1.5 mL) was slowly added. The reaction mixture was warmed again to 100° C. and stirred at this temperature for 2 h. Water was added after cooling to room temperature, the pH was adjusted to −10 by addition of solid sodium bicarbonate and the aqueous solution was washed 2× with MTB-ether. The aqueous layer was then adjusted to pH ˜2 by addition of 2 M hydrochloric acid and extracted 3× with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum to afford 123 mg of the title compound of the formula
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:17][CH3:18])=[O:16])[N:14]=2)[N:11]=1.[CH3:22][N:23]1[C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]([CH3:31])=[N:24]1.O>CN(C)C(=O)C>[CH3:22][N:23]1[C:27]([C:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([NH:17][CH3:18])=[O:16])[N:14]=3)[N:11]=2)=[O:29])=[CH:26][C:25]([CH3:31])=[N:24]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: CNC(=O)c1cn2nc(Oc3cccc(N)c3)ccc2n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cn2nc(Oc3cccc(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution of 6-(3-aminophenoxy)-N-methylimidazo[1,2-b]pyridazine-2-carboxamide (250 mg, 0.88 mmol) in N,N-dimethylacetamide (2.5 mL) was added 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (253 mg, 1.59 mmol). After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained residue was washed with water, acetonitrile and diethyl ether to give the title compound (262 mg, 73%) as a white powder.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (59.6 mg, 0.187 mmol) and triphenylphosphine (49.1 mg, 0.187 mmol) in methylene chloride (468 μL) was cooled to 0° C. and then treated with N-bromosuccinimide (36.7 mg, 0.206 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The orange reaction mixture was then treated with 2-aminopyridine (35.2 mg, 0.374 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining residue was diluted with ethyl acetate (50 mL). The organic layer was washed sequentially with a 10% aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and water (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-pyridin-2-yl-2(-4-trifluoromethylsulfanyl-phenyl)-propionamide (25.0 mg, 34%) as a cream solid: mp 101-102° C.; EI-HRMS m/e calcd for C20H21F3N2OS (M+) 394.1327, found 394.1321.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:24]=[C:23]([C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[C:21]([CH3:33])[C:16]=1[O:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:19][CH2:18][O:17][C:16]2[C:15]([CH3:14])=[CH:24][C:23]([C:25](=[O:32])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][C:21]=2[CH3:33])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: Cc1cc(C(=O)c2ccccc2)cc(C)c1OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2ccccc2)cc(C)c1OCCSc1cnn(C(C)(C)C)c(=O)c1Cl
Temperature: 25 °C
Yield: 94.1 %

Procedure:
In 50 ml of N,N-dimethylformamide were dissolved 6.6 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 10 g of 2-(2',6'-dimethyl-4'-benzoylphenoxy)ethyl bromide, and thereto was added 5 g of anhydrous sodium carbonate. The solution was stirred at room temperature for seventeen hours. The resulting solution was poured into water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure to give a crude product. The crude product thus obtained was purified by means of column chromatography (on silica gel, eluting with benzene) and crystallization (from 50 ml of n-hexanediethyl ether (4:1)) to give 13.3 g of the intended compound. m.p. 94.6°~96.2° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16]([CH2:20][C:21]4[C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[NH:23][N:22]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:30])=[CH:8][C:7]([Cl:31])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[C:9]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16]([CH2:20][C:21]4[C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[NH:23][N:22]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:30])=[CH:8][C:7]([Cl:31])=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3Cc2n[nH]c3ncccc23)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3Cc2n[nH]c3ncccc23)c1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2,5-dichloro-3-{[5-chloro-1-(1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-1H-1,2,3-benzotriazol-4-yl]oxy}benzonitrile (283 mg, 0.601 mmol) was dissolved in dry THF (30 mL), cooled to 0° C., and LAH solution (1.20 mL, 1.20 mmol) in THF (1.2 mL) was added. The reaction mixture was allowed to warm to room temperature, and after 2 hours the mixture was cooled to 0° C. and quenched with EtOAc (50 mL). To this mixture was added saturated aqueous Na2SO4 (3 mL), followed 5 minutes later by the addition of water (5 mL). This mixture was stirred for 5 minutes after which excess solid Na2SO4 was added. The mixture was then filtered and solvent removed under reduced pressure. The resulting residue was purified by reverse phase chromatography eluting with 5-95% MeCN/H2O+0.1% TFA to yield the title compound. 1H NMR (DMSO-d6) δ 8.53 (d, J=4.5 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.98 (s, 2H), 7.89 (d, J=9.0 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.48 (s, 1H), 7.20 (dd, J=8.0 Hz, J=4.5 Hz, 1H), 6.91 (s, 1H), 6.38 (s, 2H), 4.21 (s, 2H). HRMS (M+1)=476.0363.
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.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[CH3:20][N:19]([CH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([NH:22][C:23](=[O:25])[CH3:24])[N:5]=1)[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(NCCCOc2cccc(CN(C)C)c2)n(C)n1
Reaction time: 12 h
Yield: 96.7 %

Procedure:
A mixture of 1-methyl-N5 -[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (1.0 g), acetic anhydride (0.35 g) and pyridine (50 ml) was stirred at 25° for 12 h. The pyridine was removed and the residue was dissolved in ethyl acetate. The organic solution was washed with aqueous sodium carbonate and evaporated to give the title compound as a pale yellow oil (1.1 g). TLC silica, methanol/0.88 ammonia 80:1, Rf 0.49. NMR (CDCl3) 1.42 brs (1H); 2.81 m (1H); 3-3.4 m (3H); 5.34 t (1H); 5.98 t (2H); 6.52 s (3H); 6.65 s (2H); 6.5 m (2H); 7.8 s (6H); 7.5-8.1 m (2H); 7.9 s (3H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:22])[CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=1.CCOCC>ClCCl>[N:12]1[CH:17]=[CH:16][C:15]([C:18]([CH2:19][CH2:20][CH3:21])=[O:22])=[CH:14][CH:13]=1
Reactant: CCCC(O)c1ccncc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC(=O)c1ccncc1
Reaction time: 0.08 h

Procedure:
Pyridinium chlorochromate (4.27 g, 19.84 mmol) was suspended in dry dichloromethane (50 ml) in a round-bottom flask under an atmosphere of N2. After stirring for 5 min, 1-(4-pyridyl)-1-butanol (2.0 g, 13.23 mmol) in dry dichloromethane (10 ml) was added. The reaction was followed by t.l.c. and once complete (˜2 h) anhydrous ether (70 ml) was added. The supernatant was decanted and the residual black gum was washed with anhydrous ether (4×100 ml). The combined organic fractions were concentrated in vacuo, and the black tar-like substance was purified by flash chromatography [EtOAc as eluant] to give a brown oil. The product was then purified by silica gel column chromatography [3:1 EtOAc:hexanes as eluant] to give n-propyl 4-pyridyl ketone [Registry No. 1701-71-9] as a yellowy-green oil (520 mg, 27%). 1H NMR (300 MHz, CDC3): δ 1.01 (3H, t, J=7.5 Hz, CH3), 1.78 (2H, sxt, J=7.4 Hz, —CH2—), 2.95 (2H, t, J=7.2 Hz, CH2—CO), 7.72 (2H, d, J=5 Hz, H-3, H-5), 8.81 (2H, d, J=5 Hz, H-2, H-6) ppm.
Reaction SMILES: [C:1]([C:5]1[C:10]2[S:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16](O)(=[O:20])[CH2:17][CH2:18][CH3:19]>>[C:1]([C:5]1[C:10]2[S:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC(=O)O
Reactant: CC(C)(C)c1cccc2c1SCC2(C)C
Product: CCCC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CS2

Procedure:
Substantially the method described in Example 1 is employed for the reaction between 7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]thiophene and butanoic acid, to provide 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]thiophen-5-yl)-butan-1-one as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([OH:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of 6-bromo-3,4-dihydronaphthalen-1(2H)-one (1.0 g, 4.4 mmol) in ethanol (10 mL) was added sodium borohydride (0.8 g, 21 mmol). The reaction mixture was stirred at room temperature for 0.5 hour. After the reaction, the mixture was poured into water (100 mL) and the mixture was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the pure product 6-bromo-1,2,3,4-tetrahydronaphthalen-1-ol (1.0 g, 100%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:25])[C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=2[OH:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH4+].[Cl-]>[Fe].C(O)(C)C>[NH2:21][C:19]1[CH:18]=[CH:17][C:16]([OH:24])=[C:15]([CH:20]=1)[C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:26])[F:27])[CH:4]=1)=[O:25]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc([N+](=O)[O-])ccc1O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Product: Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
N-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-5-nitro-benzamide (400 mg, 1.4 mmol) prepared in step 1 was dissolved in 4.2 . of isopropanol (IPA), to which 3 g of iron powder and 3 . of NH4Cl saturated solution were added.