Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31])#[N:24]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
1-(4-Fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2.1 g), 5-amino-2-neopentyloxybenzonitrile (1.3 g), triethylamine (1.7 g) and diethyl cyanophosphate (1.3 g) were added to dimethylformamide (10 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (0.2 g), melting point: 126–127° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][CH2:15][CH2:16][C:17](O)=[S:18])=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH2:20]1[CH2:30][CH2:29][N:28]2[C:23](=NC[CH2:26][CH2:27]2)[CH2:22][CH2:21]1.ClC(OCC(C)C)=O.C(NC1CCCCC1)C>O1CCCC1>[CH2:27]([N:28]([CH:23]1[CH2:22][CH2:21][CH2:20][CH2:30][CH2:29]1)[C:17](=[S:18])[CH2:16][CH2:15][CH2:14][C:13]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[N:10]=[N:11][N:12]=1)[CH3:26]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCc1ccc(-n2nnnc2CCCC(O)=S)cc1
Agent: CC(C)COC(=O)Cl
Agent: CCNC1CCCCC1
Solvent: C1CCOC1
Product: CCc1ccc(-n2nnnc2CCCC(=S)N(CC)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
4-[1-(4-Ethylphenyl)-1,2,3,4-tetrazol-5-yl]thio-butyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml), and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmol) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise N-ethyl-cyclohexylamine (54 mmole), and the mixture is further stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure and the resulting residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and then dried over anhydrous sodium sulfate. Chloroform is distilled off and the resulting residue is subjected to column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-ethyl-N-cyclohexyl-4-[1-(4-ethylphenyl)-1,2,3,4-tetrazol-5-yl]thio-butyramide (yield: 43%), colorless liquid, nD19 =1.5533.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][S:19](Cl)(=[O:21])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][C:31]([Cl:57])([Cl:56])[CH2:32][O:33][C:34]([N:36]1[C:48]2[CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45][CH2:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35]>CCCCCCC.C(OCC)(=O)C>[Cl:57][C:31]([Cl:30])([Cl:56])[CH2:32][O:33][C:34]([N:36]1[C:48]2[CH2:47][N:46]([S:19]([CH2:18][CH:17]([CH:14]3[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12][CH2:13]3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:21])=[O:20])[CH2:45][CH2:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35]
Reactant: CC(C)(C)OC(=O)C(CS(=O)(=O)Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)C(CS(=O)(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 71.9 %

Procedure:
Prepared from 4-(1-tert-butoxycarbonyl-2-chlorosulfonyl-ethyl)-piperidine-1-carboxylic acid benzyl ester (640 mg) and 3,4-dihydro-1H-β-carboline-2,9-dicarboxylic acid 2-tert-butyl ester 9-(2,2,2-trichloro-ethyl) ester (500 mg) to give, after chromatography (SiO2, 2:1 heptane-ethyl acetate), the title compound (608 mg, 61%) as a white solid.
Reaction SMILES: [CH3:1][O-].[Na+].CO.[OH:6][C:7]1[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=1>CN(C=O)C>[CH3:1][O:6][C:7]1[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ncccc1O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cccnc1C
Reaction time: 5 h

Procedure:
A mixture of sodium methoxide (prepared from sodium metal) (10.2 g) and methanol (175 ml), 3-hydroxy-2-methylpyridine (43.0 g) phenyltrimethylammonium chloride (81.9 g) and DMF (400 ml) was boiled under reflux with stirring for 5 hours under nitrogen. The mixture was filtered and distilled. The fraction boiling at 167°-195° C. was collected and purified by flash chromatography on silica using dichloromethane and then IMS as the mobile phase to give 3-methoxy-2-methylpyridine which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[N:13][CH:14]=1)C1C=CC=CC=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>>[CH3:24][S:21]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[N:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=2)[CH2:16][CH2:17]1)(=[O:23])=[O:22].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]
Reactant: CS(=O)(=O)N1CCN(c2ncc(OCc3ccccc3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCN(c2ncc(O)cn2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
5-(benzyloxy)-2-[4-(methylsulfonyl)piperazin-1-yl]pyrimidine (57.9 g, 0.17 mol) was dissolved in TFA (600 mL) and the reaction heated to reflux, with stirring, for 7 hours then cooled to room temperature. The TFA was then in vacuo and the residue azeotroped with toluene (2×300 mL). The resulting solid was triturated with DCM, filtered off, washed with ether and dried to give 2-[4-(methylsulfonyl)piperazin-1-yl]pyrimidin-5-ol as a pale yellow solid (54.4 g, 0.15 mol, 88%, TFA salt).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10]C)=[O:9])[CH2:3][CH2:2]1.[CH3:12][C:13]([CH3:15])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.Cl>[CH:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1)([CH3:15])[CH3:12]
Reactant: COC(=O)CC1CCNCC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCC(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-piperidineacetate (0.6 g, 3.82 mmol) was dissolved in methylene chloride (20 mL), acetone (1 mL), acetic acid (0.26 mL) and sodium triacetoxyborohydride (1.21 g, 5.73 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated, and work-up according to a conventional method gave a crude product. The obtained crude product was dissolved in 6 N aqueous hydrogen chloride solution, and the mixture was stirred overnight at 80° C. The solvent was evaporated to give the title compound, which was used for the synthesis of A-22.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[S:12][C:11](=[O:13])[NH:10][C:9]1=[O:14]>O1CCCC1.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]1[S:12][C:11](=[O:13])[NH:10][C:9]1=[O:14]
Reactant: O=C1NC(=O)C(=Cc2ccccn2)S1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(Cc2ccccn2)S1
Reaction time: 16 h
Yield: 16 %

Procedure:
To a solution of 5-pyridin-2-ylmethylene-thiazolidine-2,4-dione (5.0 g, 0.024 mol, prepared in a similar way as described in J. Med. Chem. 41 (10), 1619–1630 (1998)) in tetrahydrofuran (300 ml) was added 10% palladium on carbon (1 g) and the resulting mixture was hydrogenated. After 50 ml of hydrogen was consumed and additional portion of 10% palladium on carbon (5 g) was added and the hydrogenation was continued at 50 psi for 16 hours. The mixture was filtered and the filtrate evaporated in vacuo. The residue was subjected to flash column chromatography (1 I silicagel) using a mixture of ethyl acetate/hexane (1:1) as eluent. Semi pure fractions were collected and the solvent evaporated in vacuo affording 0.8 g (16%) of 5-pyridin-2-ylmethyl-thiazolidine-2,4-dione as a solid.
Reaction SMILES: N[C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH:29]1[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]1)[C:5](=[O:28])[NH:6]2.[I-:40].[Cs+].II.N(OCCC(C)C)=O>COCCOC.[Cu]I>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]2[N:8]=[C:7]3[C:3]([N:4]([CH:29]4[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:30]4)[C:5](=[O:28])[NH:6]3)=[C:2]([I:40])[N:10]=2)=[N:12]1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CC(n2c(=O)[nH]c3nc(-c4nn(Cc5ccccc5F)c5ncccc45)nc(N)c32)C1
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC(n2c(=O)[nH]c3nc(-c4nn(Cc5ccccc5F)c5ncccc45)nc(I)c32)C1
Temperature: 60 °C

Procedure:
1.788 g (3.364 mmol) of the compound from example 96A were initially charged in 20 ml of 1,2-dimethoxyethane and then admixed at RT with 873 mg (3.364 mmol) of cesium iodide, 426 mg (1.682 mmol) of iodine and 192 mg (1.009 mmol) of copper(I) iodide. After addition of 2.961 ml of isopentyl nitrite, the mixture was heated to 60° C. overnight. After cooling, a precipitate was filtered off and washed with ethyl acetate. Subsequently, water was added to the precipitate, the mixture was stirred and then the precipitate was again filtered off with suction and washed with a little water and acetonitrile. 0.373 g (17% of theory) of the title compound were obtained after drying under high vacuum.
Reaction SMILES: CN(C)C=O.[CH2:6]([C:9]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH2:7][CH3:8].[Br:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>O>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][O:18][C:17]1[C:9]([CH2:6][CH2:7][CH3:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:23]([F:26])([F:24])[F:25])([C:19]([F:20])([F:21])[F:22])[O:12][CH2:11]2
Reactant: CCCc1c(O)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCBr)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Yield: 19.9 %

Procedure:
A N,N-Dimethylformamide (10 mL) solution of 4-propyl-1,1-bis(trifluoromethyl)-1,3-dihydroisobenzofuran-5-ol (800 mg, 2.55 mol), 1,4-dibromobutane (2.75 mL, 12.73 mmol) and potassium carbonate (528 mg, 3.82 mmol) was stirred at room temperature overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The obtained residue was purified by silica-gel column chromatography (hexane:ethyl acetate=50:1) and the title compound (1.136 g, 99%) was obtained as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:4][CH:3]=1.CS(O[CH:32]([C:34]1[CH:38]=[CH:37][O:36][N:35]=1)[CH3:33])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH:21]3[CH2:26][CH2:25][N:24]([CH:32]([C:34]4[CH:38]=[CH:37][O:36][N:35]=4)[CH3:33])[CH2:23][CH2:22]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:6][CH:7]=1
Reactant: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNCC2)n1
Reactant: CC(OS(C)(=O)=O)c1ccon1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(C(C)c3ccon3)CC2)n1

Procedure:
A mixture of 4-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazol-5-yl]-N-methylpyrimidin-2-amine (C8, which can be prepared by the method of J. Sisko, U.S. Pat. No. 6,239,279 B1, May 29, 2001) (75 mg, 0.21 mmol), 1-isoxazol-3-ylethyl methanesulfonate (C7) (60 mg, 0.31 mmol) and cesium carbonate (139 mg, 0.43 mmol) in acetonitrile (2 mL) was heated at 70° C. for 24 hours. Removal of solvent under reduced pressure provided a residue, which was purified by silica gel chromatography (Eluants: 0%, then 5%, then 15% methanol in ethyl acetate). The resulting colorless oil was dissolved in ethyl acetate/heptane, then concentrated in vacuo to provide the product as a white solid. Yield: 57 mg, 0.13 mmol, 62%. APCI m/z 448.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.46 (d, J=6.9 Hz, 3H), 1.93-2.07 (m, 2H), 2.12-2.24 (m, 4H), 2.98-3.08 (m, 2H), 3.02 (d, J=5.0 Hz, 3H), 3.94 (q, J=6.9 Hz, 1H), 4.59 (br m, 1H), 5.14 (br d, J=5 Hz, 1H), 6.35 (d, J=1.7 Hz, 1H), 6.40 (d, J=5.0 Hz, 1H), 7.00 (dd, J=8.8, 8.8 Hz, 2H), 7.46 (dd, J=9.0, 5.5 Hz, 2H), 7.77 (s, 1H), 8.15 (br d, J=5 Hz, 1H), 8.38 (dd, J=1.7, 0.6 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:11][CH:10]([CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]1[CH2:31][CH2:32][CH:33]([O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[H][H]>C(O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:11][CH:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]1[CH2:31][CH2:32][CH:33]([O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: [H][H]
Reactant: CCCCCC(CCC1C(C=CC=CC=CC(=O)OCC)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(CCC1C(CCCCCCC(=O)OCC)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Yield: 92.6 %

Procedure:
Ethyl 7-{3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentyl}hepta-2,4,6-trienoate (6.1 g.) [prepared as described in (n) above] was dissolved in ethanol (100 ml.) and catalytically hydrogenated using a 5% palladium on charcoal catalyst, with a hydrogen pressure of 15 kg./cm2, at room temperature. The catalyst was then filtered off and the ethanol removed in vacuo to give ethyl 7-{3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentyl}heptanoate (5.7 g.), which was used as starting material in the following preparation (p) of ethyl 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoate without further purification.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=2)[CH:13]=[C:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:28]=1.C(N(CC)CC)C>CS(C)=O>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([N:17]2[CH2:16][CH2:15][C:14](=[CH:13][C:12]3[CH:20]=[CH:21][CH:22]=[C:10]([O:9][C:8]4[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:25])[F:26])=[CH:24][CH:23]=4)[CH:11]=3)[CH2:19][CH2:18]2)=[O:35])[N:28]=1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: FC(F)(F)COc1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(OCC(F)(F)F)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(3-(4-(2,2,2-trifluoroethoxy)phenoxy)benzylidene)piperidine (40 mg, 0.110 mmol; Example 99, Step 5), phenyl pyridazin-3-ylcarbamate (24 mg, 0.110 mmol), and triethyl amine (55 mg, 0.55 mmol) in DMSO (2.5 mL) was stirred at room temperature for overnight. The reaction was quenched with water, extracted with EtOAc, dried over sodium sulfate, concentrated, and purified by column chromatography (50% acetone/hexane) to yield the title compound. (45 mg, 80%). 1H NMR (500 MHz, CDCl3): δ ppm 8.76 (s, 1H), 7.52 (s, 1H), 7.02 (m, 2H), 6.95 (m, 2H), 6.83 (m, 2H), 6.78 (s, 1H), 6.37 (s, 1H), 4.37 (m, 2H), 3.72 (s, 2H), 3.63 (s, 2H), 2.63 (s, 2H), 2.58 (s, 2H), m/z (485.1 MH+); HPLC: 98.33%.
Reaction SMILES: C(OC(CO[CH2:8][C:9]1[N:13](CC2C=CC(OC)=CC=2)[C:12]([SH:23])=[N:11][N:10]=1)=O)C.C([O:26][C:27](COCC(NN)=O)=[O:28])C.[OH-].[Na+]>>[C:27]([CH2:8][C:9]1[N:13]=[C:12]([SH:23])[NH:11][N:10]=1)([OH:28])=[O:26]
Reactant: CCOC(=O)COCc1nnc(S)n1Cc1ccc(OC)cc1
Reactant: CCOC(=O)COCC(=O)NN
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1n[nH]c(S)n1

Procedure:
By employing a procedure similar to that described in Example XVI, Part A, 3-(ethoxycarbonylmethoxymethyl)-4-(p-methoxybenzyl)-1,2,4-triazole-5-thiol was prepared from ethoxycarbonylmethoxyacetohydrazide. The ethoxycarbonyl group was then hydrolyzed to the free acid using aqueous 2 N sodium hydroxide, and the p-methoxybenzyl blocking group was thereafter removed by using trifluoroacetic acid in a manner similar to that earlier described in Example XVI, Part B to finally give pure 3-(carboxymethoxymethyl)-1,2,4-triazole-5-thiol, m.p. 180°-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:14][NH:13][C:12](=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:10][CH2:11][CH2:12][NH:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCC(CCCOC2CCOCC2)(c2ccc(Cl)c(Cl)c2)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc(C2(CCCOC3CCOCC3)CCCNC2)cc1Cl
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Piperidone (6) (42.9 g, 0.111 mol) in dry THF (300 mL) was added to a suspension of LAH (8.4 g, 0.222 mol) in dry THF (500 mL), which was then heated under N2 at 60° C. in an oil bath for 5 hours, then cooled and stirred at room temperature overnight (20 hours). The reaction was quenched by H2O (8.5 mL), 4N NaOH (8.5 mL), and H2O (0.5 mL), respectively. White solid was filtered and washed with Et2O. The filtrate was concentrated, and the crude oil was purified by flash chromatography (CH2Cl2—MeOH/95:5) to give a colorless oil (37.94 g 91.8%).
Reaction SMILES: [F:1][CH:2]([F:23])[CH2:3][N:4]1[C:9]2[N:10]=[CH:11][S:12][C:8]=2[C:7]([OH:13])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[I:20])[S:5]1(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]#[CH:32]>CN(C=O)C>[F:23][CH:2]([F:1])[CH2:3][N:4]1[C:9]2[N:10]=[CH:11][S:12][C:8]=2[C:7]([O:13][CH2:32][C:31]#[CH:30])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[I:20])[S:5]1(=[O:21])=[O:22]
Reactant: O=S1(=O)C(c2ccccc2I)=C(O)c2scnc2N1CC(F)F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOC1=C(c2ccccc2I)S(=O)(=O)N(CC(F)F)c2ncsc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
150 mg (0.3 mmol) of 1-(2,2-difluoroethyl)-3-(2-iodophenyl)-1H-[1,3]thiazolo[4,5-c][1,2]thiazin-4-ol 2,2-dioxide (compound I-a-14) were dissolved in 3 ml of DMF, and 85 mg of potassium carbonate were added at RT. The reaction mixture was stirred at RT for 5 min, and then 0.035 ml (0.46 mmol) of propargyl bromide was added dropwise. The reaction mixture was stirred at 90° C. for 4 h, then poured onto water and extracted repeatedly with ethyl acetate. The combined organic phases were dried (sodium sulfate) and concentrated to dryness. The residue was purified by means of preparative HPLC(C18—SiO2, gradient acetonitrile/water 20:80 to 100:0). This gave 51 mg of compound I-h-3.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN
Product: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CNC(=O)Oc1ccccc1

Procedure:
From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid ( 3-methylbutyl)amide (precursor 5 c) and phenyl chloroformate, according to the general working procedure followed by extraction with EA and purification by flash chromatography 55 mg of 2′-(phenoxycarbonylaminomethyl)biphenyl-2-carboxylic acid (3-methylbutyl)amide were obtained as a resin. MS (ES+): m/e=417 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[Br:13]Br.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH:7]([Br:13])[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: BrBr
Reactant: O=C1CCCc2nc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc(Cl)nc2CCC1Br
Reaction time: 1 h

Procedure:
3-Aminocyclohex-2-enone (ex Aldrich) was reacted with methyl propiolate (ex Lancaster) to give 7,8-dihydro-2,5-quinoline-dione according to Speckamp et al J. Trav. Chem. Pays. bas., 91 157 (1972). The latter was converted to 2-chloro-7,8-dihydro-5-quinolinone by analogy with Example VI. The latter compound (2 g) was dissolved in chloroform (200 ml) and treated with bromine (0.53 ml) dropwise at room temperature. After 30 min solid potassium carbonate was added, the mixture was stirred for 1 hour, filtered and solvent removed to give 2-chloro-6-bromo-7,8-dihydro-5-quinolinone (2.86 g). This compound was heated at 110° C. with anhydrous lithium chloride (1.4 g) and dimethylformamide (45 ml) for 3 hours. The mixture was diluted with water, worked-up in conventional fashion and purified by column chromatography on silica (eluting with ether-hexane) to give 2-chloro-5-hydroxyquinoline (0.77 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23](=O)[CH2:24][CH3:25])[CH2:17][CH2:16]1.Cl.O>O1CCOCC1>[CH2:24]([C:23]1([CH2:22][CH2:21][N:18]2[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]2)[C:6]2[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11][CH2:12][O:13]1)[CH3:25]
Reactant: COc1ccc(CCO)cc1OC
Reactant: CCC(=O)CCN1CCN(C)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCC1(CCN2CCN(C)CC2)OCCc2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A mixture of 34,8 g of 3,4-dimethoxybenzeneethanol and 32 g of crude 1-(4-methylpiperazinyl)pentane-3-one in 400 ml of dioxane, which is saturated with anhydrous hydrochloric acid, was stirred at ambient temperature for 24 h. After addition of water the mixture was extracted with dichloromethane. The organic phase was washed, dried and evaporated to yield 41,5 g (68,5%) of crude 1-[2-(1-ethyl-3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-methylpiperazine.