Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:8][O:9][CH3:10])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].[CH2:15]([Si:17](Cl)([CH2:20][CH3:21])[CH2:18][CH3:19])[CH3:16]>>[CH2:1]([C:5]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:6][O:7][Si:17]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:15][CH3:16])[CH2:8][O:9][CH3:10])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCCCC(CO)(CCCC)COC
Product: CCCCC(CCCC)(COC)CO[Si](CC)(CC)CC

Procedure:
According to the procedure as described in Example 1,2,2-di-n-butyl-1-methoxy-3-[(triethylsilyl)oxy]propane was prepared from intermediate 2,2-di-n-butyl-3-methoxy-1-propanol and reagent triethylsilyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:22]=[C:23]([CH:34]=O)[NH:24][C:25]=1[C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:34][C:23]4[NH:24][C:25]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])=[C:21]([CH3:20])[CH:22]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C=O)[nH]c1C(=O)N1CCOCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 87 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrol[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 4-methyl-5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (66.7 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 105 mg (87%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.16 (br s, 1H, NH), 11.74 (br s, 1H, NH), 8.78 (br s, 1H), 8.27 (s, 1H), 7.74 (dd, J=2.2 & 6.5 Hz, 1H), 7.71 (s, 1H), 7.52 (m, 1H), 7.38 (t, J=9.1 Hz, 1H), 6.74 (s, 1H), 3.65 (m, 4H, 2×CH2z), 3.54 (m, 4H, 2×CH2), 2.15 (s, 3H, CH3). MS 483 [M++1].
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([OH:9])=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[Br:16][C:17]1[CH:18]=[N:19][C:20]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)=[N:21][CH:22]=1>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:26]1[CH2:27][CH2:28][CH2:29][C@@H:24]([NH:23][C:20]2[N:19]=[CH:18][C:17]([Br:16])=[CH:22][N:21]=2)[CH2:25]1)=[O:9]
Reactant: Brc1cnc(N[C@@H]2CCCNC2)nc1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: O=C(c1ccccc1-c1ccccc1)N1CCC[C@@H](Nc2ncc(Br)cn2)C1

Procedure:
prepared by reaction of biphenyl-2-carboxylic acid with (R)-(5-bromo-pyrimidin-2-yl)-piperidine-3-yl-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][CH:12]=1)=[O:5].Cl[C:30]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:31].N1C=CC=CC=1>O1CCCC1>[C:13]1([C:10]2[N:11]=[CH:12][C:7]([NH:6][C:4]([C:3]3[CH:19]=[C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:2]=3[NH:1][C:30]([C:32]3[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=3)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:31])=[O:5])=[CH:8][N:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-amino-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide (138 mg, 0.37 mmol, 1.00 equiv) in tetrahydrofuran (6 mL) was added methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (112 mg, 0.41 mmol, 1.10 equiv) and pyridine (60 mg, 0.76 mmol, 2.00 equiv) and the resulting solution was stirred for 5 h at room temperature. The reaction progress was monitored by LCMS. The crude product was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1>C(#N)C.[F-].[K+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:16]2[C:11]([F:10])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1
Reactant: Nc1cnc(Br)cc1I
Reactant: OB(O)c1cccnc1F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cnc(Br)cc1-c1cccnc1F
Temperature: 70 °C
Yield: 39.1 %

Procedure:
A mixture of 6-bromo-4-iodo-pyridin-3-ylamine (10.0 g, 33.4 mmol), 2-fluoropyridine-3-boronic acid (5.2 g, 36.8 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (2.73 g, 3.34 mmol) in acetonitrile (150 mL) and 1N aqueous potassium fluoride solution (150 mL) was degassed with nitrogen for 20 minutes. The reaction mixture was heated at 70° C. for 2.5 h, allowed to cool to ambient temperature and then partitioned between ethyl acetate (400 mL) and water (150 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant solid residue was triturated with dichloromethane: methanol (1:1, 100 mL), collected by filtration and washed with diethyl ether (50 mL) to furnish the title compound as a brown solid (3.5 g, 39%). The filtrate was evaporated and purified by passing the resultant residue through a pad of silica eluting with ethyl acetate: cyclohexane (1:1). Collection of the appropriate fractions and evaporation to dryness afforded a solid that was then triturated with diethyl ether to afford the title compound as a brown solid (3.7 g, 42%) (combined yield—7.22 g, 81%). 1H NMR (CDCl3, 300 MHz): 8.34 (ddd, J=4.9, 2.0, 1.2 Hz, 1H), 7.99 (s, 1H), 7.85 (ddd, J=9.4, 7.4, 2.0 Hz, 1H), 7.37 (ddd, J=7.4, 4.9, 2.0 Hz, 1H), 7.22 (s, 1H), 3.75 (s, 2H). LCMS (Method B): RT=2.78 min, M+H+=268/270.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH3:12][Si](C=[N+]=[N-])(C)C.C(OCC)C>CO>[NH2:2][C:3]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC1(C(=O)O)CCOCC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1(N)CCOCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 99 %

Procedure:
To a solution of 4-amino-4-carboxy-tetrahydropyrane hydrochloride (2 g) in methanol was added dropwise a solution of 2M trimethylsilyldiazomethane-diethylether (33 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated in vacuo, and the resultant crude product was dissolved in hexane-diethylether (1 mL/1 mL), and thereto was added an aqueous 4N hydrochloric acid. The precipitates were collected by filtration to give 4-amino-4-methoxycarbonyl-tetrahydropyrane (2.13 g, yield: 99%) as white-crystals.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:7]([Cl:20])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1C)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)SCC(Cc1ccccc1C)C(=O)Cl
Reaction time: 18 h

Procedure:
To 2-acetylthiomethyl-3-(2-methylphenyl)propionic acid (1.80 g, 7.0 mmol) in toluene (50 ml) add thionyl chloride (1.25 g, 10.5 mmol). Stir 18 hr, concentrate, dilute with toluene, concentrate, and repeat to obtain 2-acetylthiomethyl-3-(2-methylphenyl)propionyl chloride, a yellow liquid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=1)([CH3:38])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH:32]1[S:37][CH2:36][CH2:35][CH2:34][S:33]1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=1)([CH3:21])[C:16](OCC)=[O:17])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:45]([C:42]1[CH:43]=[CH:44][C:39]([C:5]([CH3:38])([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH:32]2[S:33][CH2:34][CH2:35][CH2:36][S:37]2)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)([CH3:21])[CH2:16][OH:17])[CH2:4][OH:3])=[CH:40][CH:41]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: CCOC(=O)C(C)(CCCCC(CCCCC(C)(C(=O)OCC)c1ccc(CC(C)C)cc1)C1SCCCS1)c1ccc(CC(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(C)(CO)CCCCC(CCCCC(C)(CO)c2ccc(CC(C)C)cc2)C2SCCCS2)cc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
2,12-Bis-(4-isobutyl-phenyl)-2,12-dimethyl-7-([1,3]dithianyl)-tridecanedioic acid diethyl ester (5.81 g, 8.33 mmol) was dissolved in freshly distilled tetrahydrofuran (THF, 50 mL) and added to lithium aluminum hydride (1.0 g, 26.3 mmol) in THF (50 mL) at −78° C. under a nitrogen atmosphere. The solution was warmed to room temperature over four hours. The reaction was then cooled back to −78° C. and quenched with ethyl acetate (5.0 mL). After warming to room temperature, water (100 mL) was added and the product was extracted with diethyl ether (2×100 mL). The ether extracts were combined, dried with sodium sulfate, filtered, and concentrated. After drying under high vacuum for four hours, the reaction yielded 2,12-bis-(4-isobutyl-phenyl)-2,12-dimethyl-7-([1,3]dithianyl)-tridecane-1,13-diol (4.80 g, 94% yield) as a colorless oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.20 (d, 4H, J=8.0 Hz), 7.09 (d, 4H, J=8.0 Hz), 3.64 (d, 2H, J=10.7 Hz), 3.48 (d, 2H, J=10.7 Hz), 2.71 (t, 4H, J=5.1 Hz), 2.50-2.35 (m br., 2H), 2.43 (d, 4H, J=7.0 Hz), 1.90-1.80 (m, 4H), 1.80-1.68 (m, 6H), 1.58-1.42 (m, 2H), 1.38-1.25 (m, 4H), 1.30 (s, 6H), 1.26-1.10 (m, 2H), 1.10-0.95 (m, 2H), 0.89 (d, 12H, J=6.6 Hz). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 141.94, 139.39, 129.20, 126.44, 72.48, 53.30, 44.97, 43.09, 38.45, 38.18, 30.21, 26.01, 25.64, 24.84, 24.09, 22.55, 21.64. HRMS (LSIMS, nba): Calcd. for C38H61O2S2 (MH+): 613.4113, found: 613.407.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[CH3:42][N:43]([CH:45]=[O:46])[CH3:44]>>[CH3:42][N:43]([CH3:44])[C:45]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)=[O:24])[C:5]1=[O:32])=[O:46]
Reactant: NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-(tetrahydro-2-furanylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.057 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (3 mL) under nitrogen was treated with N,N-dimethyl carbonyl chloride (0.0055 mL, 0.06 mmol) (40° C. After 2½ h the reaction was cooled, concentrated in vacuo, and the resulting residue treated with 1N NaHSO4, filtered, washed with water, and dried in vacuo to provide the title compound as an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.34 (m, 1 H), 1.48-1.67 (m, 1 H), 1.67-2.12 (m, 3 H), 2.70 (s, 6 H), 3.32-3.41 (m, 1 H), 3.57 (d, J=18.81 Hz, 1 H), 3.63-3.71 (m, 1 H), 3.78-3.85 (m, 1 H), 4.00 (d, J=1.97 Hz, 2 H), 4.12 (s, 3 H), 4.26 (t, J=6.04 Hz, 2 H), 6.52-6.57 (m, 1 H), 7.14 (t, J=8.70 Hz, 2 H), 7.35-7.43 (m, 2 H), 8.28 (s, 1 H), 8.53 (s, 1 H), 10.46 (s, 1 H); ES+ MS: 512 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([OH:7])=[C:5]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15].O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([S:36](Cl)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35]>CC(C)=O>[CH3:1][C:2]1[C:6]([O:7][S:36]([CH2:32][CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])=[C:5]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CCCCS(=O)(=O)Oc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1C

Procedure:
A mixture of 2.3 g (8 mmol) of di-isopropyl 3-methyl-4-hydroxy-2,5-thiophene-dicarboxylate, 30 ml of dioxane, 60 ml of acetone, 1.6 g (120 mmol) of anhydrous potassium carbonate and 1.6 g (10 mmol) of butane-sulfonyl chloride was refluxed for about 10 hours. The mixture was then freed from dioxane and acetone by distillation in vacuo and then added with ethylether, washed with water, and dried with anhydrous magnessium sulfate. The solvent was removed by distillation and then recrystallization was effected from methanol to give 2.8 g (86%) of the desired white crystalline compound. m.p. 59°-61° C.
Reaction SMILES: Cl[C:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][C:3]=1[CH:9]=O.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19]>CN(C=O)C>[CH3:22][O:21][C:17]([C:18]1[S:19][C:2]2[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][C:3]=2[CH:9]=1)=[O:20]
Reactant: COC(=O)CS
Reactant: CC1CCC(C=O)=C(Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(s1)CC(C)CC2
Temperature: 100 °C
Yield: 69.1 %

Procedure:
769 mg of the crude 2-chloro-4-methyl-cyclohex-1-enecarbaldehyde obtained in step a) were dissolved in DMF (10 ml). Then 837 mg (6.06 mmol) of potassium carbonate and 440 μl (4.85 mmol) of methyl thioglycolate were added and the mixture was heated to 100° C. for 16 h. After cooling to RT, the solvent was removed in vacuo. Water was added to the remaining residue and the mixture was extracted with ethyl acetate. The organic extracts were then washed with 50% sodium chloride solution, dried (MgSO4) and concentrated to give 704 mg of 6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid methyl ester (containing 10% of 4-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid methyl ester) as dark brown oil. MS (ISP) 211.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].[CH3:11][Mg]Br.[Cl-].[NH4+]>CCOCC>[CH3:11][C:3]1([OH:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH2:6][C:2]1([CH3:10])[CH3:1]
Reactant: CC1(C)CCC(C)(C)C1=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)C1(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,2,5,5-tetramethylcyclopentanone (30 g, 0.215 mole) in ether (50 ml) was treated, under nitrogen, with a 3M solution of methyl magnesium bromide in ether (100 ml). The reaction mixture was stirred overnight at room temperature and saturated aqueous ammonium chloride (65 ml) then added dropwise. The mixture was stirred for 10 minutes, the ether solution decanted and the solid residue triturated with ether. The ether extracts were dried (Na2SO4) and evaporated under reduced pressure to give crude 1,2,2,5,5-pentamethylcyclopentanol (30 g) which was used without further purification.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([Cl:14])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Cl:14][C:8]1[C:9]([O:11][CH2:12][CH3:13])=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][C:7]=1[O:15][CH2:16][CH3:17]
Reactant: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCOc1cc(CO)cc(OCC)c1Cl
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 4-chloro-3,5-diethoxy-benzoic acid ethyl ester (5.0 g, 18.33 mmol, 1.0 equiv) in dichloromethane (25 mL) was added slowly over a time period of 15 min under slight cooling to −30° C. a solution of diisobutylaluminum hydride (55.0 mL, 55.00 mmol, 3.0 equiv; 1.0 M solution in THF). After 30 min, the excess hydride was quenched by cautious addition of methanol (10 mL) and water (2 mL). The mixture was stirred for 30 min, a solution of 1 M HCl was added and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure providing 4.0 g (95%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.45 (t, J=7.0 Hz, 6H), 1.93 (br s, 1H), 4.09 (q, J=7.0 Hz, 4H), 4.62 (s, 2H), 6.57 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 14.74, 64.96, 65.18, 104.30, 110.65, 140.29, 155.66. MS (ISP): 231.4 [M+H]+.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](O)([C:13]([F:16])([F:15])[F:14])[CH2:5][C:6](=[O:12])[NH:7]2.N([O-])=[O:19].[Na+]>OS(O)(=O)=O.O>[OH:19][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:13]([F:16])([F:15])[F:14])=[CH:5][C:6](=[O:12])[NH:7]2
Reactant: Nc1cccc2c1C(O)(C(F)(F)F)CC(=O)N2
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=c1cc(C(F)(F)F)c2c(O)cccc2[nH]1
Temperature: 145 °C
Yield: 83.6 %

Procedure:
To a solution of 5-amino-3,4-dihydro-4-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one (6.0 g, 24 mmol) in 100 mL 4.8 M H2SO4 was added a solution of NaNO2 (1.85 g, 26.8 mmol) in 6 mL water at 0° C. The reaction mixture became deep red. This solution was transferred to 120 mL 10M H2SO4 preheated to 145° C. The mixture was heated at 145° C. for 0.5 h, then poured into 400 g of ice water. The crude solid was adsorbed onto silica gel and eluted with 9:1 CH2Cl2:MeOH to afford 4.6 g (82%) of 5-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one, an off-white solid. 1H NMR (400 MHz, acetone-d6) δ 11.0 (broad s, 1H), 9.64 (s, 1H), 7.42 (t, 1H, J=8.1), 6.99 (d, 1H, J=8.1), 6.90 (s, 1H), 6.79 (d, 1H, J=8.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:18])[C:5]([C:15]([OH:17])=O)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:41][NH:42][O:43][CH3:44]>CN(C=O)C>[CH3:44][O:43][N:42]([CH3:41])[C:15]([C:5]1[C:4](=[O:18])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[N:6]=1)=[O:17]
Reactant: COc1cn(-c2ccncc2)nc(C(=O)O)c1=O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cn(-c2ccncc2)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a mixture of 5-methoxy-4-oxo-1-pyridin-4-yl-1,4-dihydropyridazine-3-carboxylic acid (8.2 g, 33 mmol), HOBt (7.6 g, 50 mmol) and WSC (9.5 g, 50 mmol) in DMF (160 mL) was added N,O-dimethylhydroxylamine hydrochloride (6.5 g, 66 mmol) and TEA (14 mL, 100 mmol), and the mixture was stirred at room temperature overweekend. The mixture was concentrated under reduced pressure. The residue was diluted with water, saturated with K2CO3, and extracted with AcOEt. (There were three layers.) The highest organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The middle layer was extracted with CH2Cl2 (50 mL×4), and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. Two of the residues were combined and chromatographed on basic silica gel (0/100-10/90 MeOH/AcOEt) to give the title compound (9.6 g, 100% yield) as a pale yellow oil: 1H NMR (300 MHz, CDCl3): δ ppm 3.40 (3H, s), 3.68 (3H, s), 3.98 (3H, s), 7.61 (2H, dd, J=4.8, 1.5 Hz), 8.08 (1H, s), 8.73 (2H, dd, J=4.8, 1.5 Hz).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13]([C:15]1([OH:38])[CH2:20][C@@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:18](=[CH2:29])[C@H:17]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:16]1)=O>CCOCC>[Si:22]([O:21][C@H:19]1[C:18](=[CH2:29])[C@H:17]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:16][C:15]([CH2:13][OH:12])([OH:38])[CH2:20]1)([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:24])[CH3:23]
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(C(=O)OC)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(CO)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: -24 °C
Reaction time: 1.5 h
Yield: 21.4 %

Procedure:
Diisobutylalurninum hydride (1.5 M in toluene, 2.0 mL, 3 mmol) was added to a solution of the ester 3 (215 mg, 0.5 mmol) in anhydrous ether (3 mL) at −78° C. under argon. The mixture was stirred at −78° C. for 3 h and at −24° C. for 1.5 h, diluted with ether (10 mL) and quenched by the slow addition of 2N potassium sodium tartrate. The solution was warmed to room temperature and stirred for 15 min, then poured into brine and extracted with ethyl acetate and ether. The organic extracts were combined, washed with diluted (ca. 1%) HCl, and brine, dried (MgSO4) and evaporated. The crystalline residue was purified by flash chromatography. Elution with hexane/ethyl acetate (9:1) gave crystalline diol 4 (43 mg, 24%).
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].O.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>ClCCl>[CH2:11]([NH:15][C:4](=[O:5])[CH2:3][C:2]([F:1])=[C:7]([F:9])[F:8])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: CCCCN
Solvent: ClCCl
Solvent: O
Product: CCCCNC(=O)CC(F)=C(F)F
Temperature: 0 °C
Yield: 92.4 %

Procedure:
2.5 g (0.0158 mole) 3,4,4-trifluoro-3-butenoyl chloride is added to a mixture of water (15 mL), dichloromethane (15 mL) and n-butyl amine (2.34 g, 0.032 mole) with stirring at 0° C. After stirring for 30 min, the organic layer is successively washed with 2N HCl, water, 5% sodium bicarbonate and brine, and dried. Evaporation of the solvent gave 2.85 g of title compound as a white solid, a 92% yield. m.p. 34°-36° C.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C@H:3]([N:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[N:15]=2)[C:9]1=[O:24])[C:4]([O:6]C)=[O:5].[Li+].[OH-]>O1CCCC1.O>[CH3:1][C:2]([CH3:26])([CH3:25])[C@H:3]([N:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[N:15]=2)[C:9]1=[O:24])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H](N1CCN(Cc2nc3ccccc3n2C)C1=O)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product of Example 148E (37 mg) in tetrahydrofuran (0.26 mL) and water (0.13 mL) was treated with LiOH (6.1 mg, 1.4 equivalents), stirred at 25° C. for 16 hours, quenched with 1N HCl (0.15 mL) at 0° C., and the solvents were evaporated to give the crude product to be used without further purification.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:29][CH3:30])(=[O:21])=[O:20])=[N:9][N:10]([C:12](=[O:18])[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:11]=1.[CH3:31][S:32]SC.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[Cl:6][C:7]1[C:8]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:29][CH3:30])(=[O:21])=[O:20])=[N:9][N:10]([C:12](=[O:18])[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:11]=1[S:32][CH3:31]
Reactant: CCc1cccc(C)c1S(=O)(=O)c1nn(C(=O)N(CC)CC)cc1Cl
Reactant: CSSC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cccc(C)c1S(=O)(=O)c1nn(C(=O)N(CC)CC)c(SC)c1Cl
Reaction time: 0.5 h
Yield: 35 %

Procedure:
0.11 ml of a 1.49M solution of butyllithium in hexane was added, at -78° C. and under an atmosphere of nitrogen, to a solution of 59 mg of 4-chloro-1-(diethylcarbamoyl)-3-(2-ethyl-6-methylphenylsulfonyl)pyrazole (prepared as described in Example 18) in 2 ml of dry tetrahydrofuran, and the resulting mixture was stirred for 30 minutes, after which 15 μl of methyl disulfide were added. The resulting reaction mixture was stirred for 30 minutes, and then mixed with an aqueous solution of ammonium chloride and extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, eluted with a 10:1 by volume mixture of hexane and ethyl acetate, to afford 28 mg (yield 35%) of the title compound as an oil.