Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[S:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[CH:11]([O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[C:7]1[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3s2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(OC(c2cccc(CO)c2)c2nc3ccccc3s2)CC1

Procedure:
A solution of 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acid ethyl ester (0.55 g, example 206) in tetrahydrofurane (10 mL) is treated with lithium aluminum hydride (76 mg) at room temperature for 1 h. Two other additions of lithium aluminum hydride (76 mg each) allow a complete conversion. The mixture is then hydrolyzed with water (178 μL), 5% sodium hydroxide (178 μL) and water (535 μL), filtered through a pad of clarcel and concentrated under reduced pressure. The residue is purified over silica gel (dichloromethane/methanol/ammonia 95/5/0.5) to afford {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol which is then converted into its oxalate salt in acetone to give {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol, oxalate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:14])[C@H:7]([C:9]([CH2:12][OH:13])([CH3:11])[CH3:10])[OH:8].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:22][C:23]([CH3:25])=O>>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C@H:7]1[C:9]([CH3:11])([CH3:10])[CH2:12][O:13][C:23]([CH3:25])([CH3:22])[O:8]1)=[O:14]
Reactant: CC(C)=O
Reactant: CC(C)(CO)[C@H](O)C(=O)NCCCO
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC1(C)OCC(C)(C)[C@H](C(=O)NCCCO)O1
Yield: 59 %

Procedure:
D-panthenol (10 mmol), anhydrous Na2SO4 (35.20 mmol) and PTSA monohydrate (0.99 mmol) was stirred in anhydrous acetone (40 mL) at room temperature during 4 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The crude was purified by chromatography on a silica gel column (eluent: CH2Cl2/CH3OH 0 to 10%) to give the expected compound as a white crystallized solid in 59% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.89 (s, 3H), 0.91 (s, 3H), 1.37 (s, 6H), 1.55 (quintuplet, J=6.52 Hz, 2H), 3.03-3.11 (m, 1H), 3.17-3.25 (m, 2H), 3.38-3.43 (m, 2H), 3.63 (d, J=11.48 Hz, 1H), 4.02 (s, 1H), 4.49 (t, J=5.18 Hz, 1H), 7.45-7.48 (m, 1H).
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13]C1(C)CCCB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: CB1CCCC(C)(C)O1
Reactant: Nc1ccc(C(F)(F)F)cc1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)ccc1N
Temperature: 100 °C

Procedure:
A mixture of 2-iodo-4-trifluoromethyl aniline (5.0 g, 17.42 mmol), trimethylboroxane (3.64 ml, 26.1 mmol), tetrakis(triphenylphosphine) palladium (1.0 g, 0.87 mmol) and potassium carbonate (4.82 g, 34.8) in DMF (10 ml) was heated to 100° C. for 48 h. The reaction was quenched with water (50 ml) and extracted with EtOAc (3×50 ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/1:9 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 7.13 (s, 1H), 7.30 (d, J=8 Hz, 1H), 6.71 (d, J=8 Hz, 1H), 3.98 (br s, 2H), 2.21 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](I)=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cc(I)cnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cccnc1Cl
Yield: 40 %

Procedure:
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80% yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130° C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55%). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40%). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1′-bis (diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92%). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95%). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25° C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74% to 95%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[NH:6][CH:5]=1.Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[Br:3][C:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:5]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(Br)c2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.205 g, 5.13 mmol) was suspended in 5 mL dimethylformamide. The mixture was stirred for 10 min and then cooled at 0° C. with an ice bath. 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 4.30 mmol) dissolved in 5 mL dimethylformamide was added dropwise and the mixture was stirred for 30 min. At the same temperature [2-(chloromethoxy)ethyl](trimethyl)silane (0.9 g, 5.4 mmol) dissolved in 5 mL dimethylformamide was added dropwise and stirred for 30 min at 0° C. The mixture was poured into water and extracted twice with ethyl acetate. The organics were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 1.18 g (76% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][N+:3]=1[O-].[OH-].[Na+]>C(O)(=O)C.[Fe]>[NH2:8][C:6]1[C:5]([CH3:11])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1c[n+]([O-])c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cnc(Cl)cc1N
Temperature: 100 °C

Procedure:
Iron (1.0 g) was added to a solution of 2-chloro-5-methyl-4-nitropyridine N-oxide (500 mg, 2.6 mmol) in glacial acetic acid (10 mL). The reaction mixture was then heated at 100° C. for 20 minutes. The suspension was poured onto aqueous NaOH (1M) and extracted with ethyl acetate. After drying over Na2SO4, the solvent was then evaporated and the title compound was isolated as a colorless solid (370 mg, 2.6 mmol, HPLC Rt 1.3 min, FIA ES+ 143.0).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[O:12]=[C:13]1[NH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[CH2:22][N:23]1[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1
Reactant: CCOC(=O)N1CCC(NCc2cnccc2NC(=O)OC(C)(C)C)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC(N2Cc3cnccc3NC2=O)CC1
Reaction time: 8 h
Yield: 46.4 %

Procedure:
Trifluoroacetic acid (0.50 mL) was a add to a solution of the material from Step A (0.24 g, 0.63 mmol) in dichloromethane (5 mL). After stirring overnight, another 0.5 mL of trifluoroacetic acid was added. After an additional 2 h, the reaction was concentrated. This material was dissolved in acetonitrile (5 mL) and carbonyldiimidazole (0.31 g, 1.89 mmol) was added at room temperature. After 2 h, the acetonitrile was evaporated in vacuo, the residue partitioned between 1N NaOH and dichloromethane, and the organic phase dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, 10 to 15% methanol in methylene chloride gradient elution), which gave the title compound (0.089 g). MS 305.3.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:47][O:48][CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[C:15]([NH:17][CH:18]2[C:45](=[O:46])[N:20]3[C:21]([C:42]([OH:44])=[O:43])=[C:22]([CH2:25][S:26][C:27]4[N:31]([CH2:32][CH2:33][NH:34]C(OC(C)(C)C)=O)[N:30]=[N:29][N:28]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1>C1(OC)C=CC=CC=1>[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:47][O:48][CH2:49][C:50]([OH:52])=[O:51])[C:15]([NH:17][CH:18]2[C:45](=[O:46])[N:20]3[C:21]([C:42]([OH:44])=[O:43])=[C:22]([CH2:25][S:26][C:27]4[N:31]([CH2:32][CH2:33][NH2:34])[N:30]=[N:29][N:28]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 47.5 %

Procedure:
Trifluoroacetic acid (12.8 ml.) was added portionwise to a chilled suspension of 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.2 g.) in anisole (3.2 ml.), and stirred at room temperature for 70 minutes. After removing the solvent from the resultant mixture in vacuo, the residue was triturated with diethyl ether. The precipitates were collected by filtration, dried and dissolved in water (40 ml.). The solution was adjusted to pH 4.8 with 10% sodium hydroxide solution under ice-cooling. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (trademark: Mitsubishi Chemical Industries Ltd.) and eluted with 20% aqueous isopropyl alcohol. The eluate was concentrated in vacuo and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.).
Reaction SMILES: [CH:1](=[N:8][CH:9]=[CH:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]=[CH:13][CH:14]=[CH2:15]>>[CH3:11][CH:10]1[CH2:4][CH:3]=[CH:2][CH2:1][CH2:15][CH:14]=[CH:13][CH2:12][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:9]1
Reactant: CC=CN=Cc1ccccc1
Reactant: C=CC=C
Product: CC1C=NC(c2ccccc2)CC=CCCC=CC1

Procedure:
In a manner analogous to that described in Example 1(a), 495 g (3.41 mols) of N-benzylidene-propenylamine is reacted with 1,3-butadiene. The reaction mixture is distilled to yield 750 g (2.97 mols) of 3-methyl-12-phenyl-1-aza-1,5,9-cyclododecatriene as a cis-trans isomeric mixture (cis:trans=65:35); b.p. 112°-113° C./1 Pa; nD20 =1.5505; m.p. (cis isomer)=57°-58° C.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[N:24]=[C:23]([F:25])[CH:22]=[CH:21][CH:20]=1)[CH2:2][CH3:3].[C:26](O)(=O)[C:27](C)=[O:28].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>[N+]([O-])([O-])=O.[Ag+].C(Cl)Cl.O>[F:25][C:23]1[N:24]=[C:19]([C:15]2[N:14]([CH2:13][C:5]3[N:4]([CH2:1][CH2:2][CH3:3])[C:8]4[CH:9]=[CH:10][N:11]=[C:12]([C:27](=[O:28])[CH3:26])[C:7]=4[N:6]=3)[CH:18]=[CH:17][N:16]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)C(=O)O
Reactant: CCCn1c(Cn2ccnc2-c2cccc(F)n2)nc2cnccc21
Agent: [Ag+]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCCn1c(Cn2ccnc2-c2cccc(F)n2)nc2c(C(C)=O)nccc21
Temperature: 40 °C

Procedure:
To the mixture of H2O (5 mL) and CH2Cl2 (5 mL) is added 1-Propyl-2-{[2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-aza-1H-benzimidazole (168 mg, 0.5 mmol), pyruvic acid (132 mg, 1.5 mmol), silver nitrate (7 mg, 0.04 mmol), (NH4)2S2O8 (342 mg, 1.5 mmol), and sulfuric acid (98%, 100 mg, 1.0 mmol). The mixture is heated to 40° C. for 2 hr, then cooled to room temperature. The aqueous solution is neutralized to pH 8 with saturated sodium bicarbonate solution and extracted with CH2Cl2. The combined organic layers are dried over Na2SO4 and solvent is removed to give a brown solid. Purification by preparative TLC provides ′1-(2-{[2-(6-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-1-propyl-1H-imidazo[4,5-c]pyridin-4-yl)ethanone as white solid. 1H NMR (CDCl3) δ 8.48 (d, 1H), 8.12 (dd, 1H), 7.88 (q, 1H), 7.44 (d, 1H), 7.23 (d, 1H), 7.11 (d, 1H), 6.88 (dd, 1H), 6.40 (s, 2H), 4.22 (q, 2H), 2.84 (s, 3H), 1.58 (m, 2H), 0.74 (t, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:39]=[CH:38][C:14]2[N:15]=[C:16]([C:18]3[C:19]([CH3:37])=[C:20]([C:24]([N:26]4[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]4)=[O:25])[NH:21][C:22]=3[CH3:23])[NH:17][C:13]=2[CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)C>[C:3]([C:11]1[CH:39]=[CH:38][C:14]2[N:15]=[C:16]([C:18]3[C:19]([CH3:37])=[C:20]([C:24]([N:26]4[CH2:27][CH2:28][CH:29]([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]4)=[O:25])[NH:21][C:22]=3[CH3:23])[NH:17][C:13]=2[CH:12]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2[nH]c(C)c(-c3nc4ccc(C(=O)c5ccccc5)cc4[nH]3)c2C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]c(C(=O)N2CCC(C(=O)O)CC2)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 100 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
A 1 N sodium hydroxide aqueous solution (16.2 ml, 16.2 mmol) was added to an ethanol (15 ml) solution of the ((4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrol-2-yl)-carbonyl)-4-ethoxycarbonylpiperidine (4.19 g, 10.8 mmol) obtained in Example 44, and stirred at 100° C. for 4 hours. The reaction mixture was allowed to cool to room temperature with stirring, and then neutralized with 6 N hydrochloric acid (12 ml, 16.2 mmol). The precipitate was collected by filtration, and dried at reduced pressure to afford ((4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrol-2-yl)-carbonyl)piperidine-4-carboxylic acid (3.02 g, 78%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[O:5][CH2:6][C:7](=[N:9]O)[CH3:8]>C(O)C.[Ni]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[O:5][CH2:6][CH:7]([NH2:9])[CH3:8]
Reactant: CC(COc1cc(C)cc(C)c1)=NO
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(C)cc(OCC(C)N)c1
Yield: 85.9 %

Procedure:
10.0 Grams (52 mmol) of 1-(3,5-dimethylphenoxy)-2-propanone oxime was dissolved in 50 ml of ethanol in an autoclave, and 1.0 g of a Raney nickel catalyst (W-2) was added. The resultant mixture was stirred under a hydrogen pressure of 5 kg/cm2G at 50° to 60° C. for 1 hour. The catalyst was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 50 ml of ethyl ether, and the mixture was subjected to extraction with a 20% hydrochloric acid aqueous solution. The extracted water layer was made alkaline with a 20% sodium hydroxide aqueous solution, and subjected to extraction with 50 ml of ethyl ether. The extracted organic layer was distilled under reduced pressure to give 8.01 g (yield 86%) of 1-(3,5-dimethylphenoxy)2-aminopropane (boiling point 113° C./3 mmHg).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][CH2:10][N:9]([C:23]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])=S)[C:8]=12)=[O:3].[H-].[Na+].CI>O1CCCC1>[O:3]=[C:2]1[N:1]=[C:23]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])[N:9]2[C:8]3[N:7]([C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=4)=[CH:11][CH2:10]2)[N:6]=[CH:5][C:4]1=3
Reactant: CCOC(=O)NC(=S)N1CC=C(c2cccc(C(F)(F)F)c2)n2ncc(C(N)=O)c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 300 mg of [[3-(amino carbonyl)-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-4(5H)-yl]-thioxomethyl]carbamic acid, ethyl ester (Example 12) in 15.0 ml of dry tetrahydrofuran cooled in an ice bath at 0° C. was added 30 mg of sodium hydride (60% dispersion in mineral oil) in one portion. After the evolution of gas ceased the mixture was stirred for an additional 30 minutes at 0° C., then 1.0 ml of methyl iodide was added and the reaction mixture was allowed to warm to room temperature with stirring for 2 hours. The mixture was quenched with water and diluted in water. The aqueous solution was extracted with chloroform. The chloroform extracts were combined and evaporated in vacuo and the residue was triturated with ether. The solid was collected by filtration to give the desired product as a white solid, m.p. 219°-220° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[C:8]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[CH:7]=1.CC1C=C(C2C=C(C=C([N+]([O-])=O)C=2)OCC(OC)=O)C=CN=1.NC1C=C(C=C(C2C=CN=C(C)C=2)C=1)OCC(OC)=O>>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[C:8]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[CH:7]=1
Reactant: Cc1cc(-c2cc(OCCN(C)C)cc([N+](=O)[O-])c2)ccn1
Agent: COC(=O)COc1cc(-c2ccnc(C)c2)cc([N+](=O)[O-])c1
Agent: COC(=O)COc1cc(N)cc(-c2ccnc(C)c2)c1
Product: Cc1cc(-c2cc(N)cc(OCCN(C)C)c2)ccn1
Yield: 93.3 %

Procedure:
This title intermediate was prepared starting from 76.A (694 mg, 2.30 mmol) according the procedure described above for conversion of 65.D to 65.E. The crude product was purified by flash chromatography on silica gel using 0-10% MeOH/CH2Cl2 for elution to provide 76.B as colorless syrup (582 mg, 93%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][CH2:2][C:3]1([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)(=[O:18])[CH3:17]
Reactant: CN1CCN(C2(CN)CCCCC2)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCC1(N2CCN(C)CC2)CCCCC1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
1-[1-(Aminomethyl)cyclohexyl]-4-methyl piperazine (10.57 g.,) was added slowly to stirred acetic anhydride (40 ml) cooled in ice and the stirring was continued for 15 mins. The mixture was heated under reflux for 1 hr.. The solution was evaporated to dryness and re-evaporated with ethanol/benzene (X2). The residue was dissolved in water, the solution made alkaline with 5NNaOH (pH = 14), extracted with chloroform (X3), dried (anhyd.Na2SO4) and evaporated. The residue was dissolved in hot petroleum ether (80°-100°) decolourised with charcoal and allowed to cool. The crystalline solid which formed was recrystallised from petroleum ether (b.p. 80°-100°) to give 1-[1-(acetamidomethyl)cyclohexyl]-4-methyl piperazine (8.3 g; 65%) m.p. 110°-111°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:16]([CH2:22][CH2:23][CH3:24])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:25](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:2]1[CH:3]=[C:4]([C@H:16]([CH2:22][CH2:23][CH3:24])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCC[C@H](CC(=O)OC)c1ccc(OCc2ccccc2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC[C@H](CC(=O)OC)c1ccc(OCc2ccccc2)c(C)c1
Temperature: 100 °C
Yield: 61.3 %

Procedure:
To a flask charged with 27.2 (0.8986 g, 2.30 mmol), tetrakis(triphenylphosphine)palladium (0) (0.265 g, 0.230 mmol), and potassium carbonate (0.635 g, 4.59 mmol) in DMF (10 mL) was added trimethylboroxine (0.959 mL, 6.89 mmol). The resulting mixture was then heated at 100° C. overnight. The reaction was allowed to cool and was then filtered and concentrated. The product was purified by silica gel chromatography (0 to 20% EtOAc/Hexanes) yielding 27.3 (0.46 g, 61% yield).
Reaction SMILES: CO[C:3](=[O:8])[C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.Cl>C1(C)C=CC=CC=1.C(Cl)Cl.CCCCCC.CCOC(C)=O>[OH:8]/[C:3](=[CH:21]\[C:20]([C:17]1[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=1)=[O:22])/[C:4]([O:6][CH3:7])=[O:5]
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)/C(O)=C/C(=O)c1ccc(SC)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
Dimethyloxalate (26 g, 180.7 mmol) was added to a stirred suspension of sodium methoxide (9.75 g, 180.7 mmol) in dry toluene (200 mL) at 0° C. The white suspension was stirred for 15 min at 0° C. A solution of 4′-(methylthio)acetophenone (15 g, 90.4 mmol) in dry toluene (150 mL) was then added drop-wise over 15 minutes giving a yellow suspension which was stirred for 2 hours at room temperature. The thick yellow suspension was transferred to a 2 liter flask and stirred vigorously with 10% HCl (250 mL) and EtOAc (200 mL) to dissolve all the solid present. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic extracts were washed with water (250 mL), dried over Na2SO4 and the solvent was evaporated under reduced pressure to give thick brown oil. The brown oil was dissolved in CH2Cl2 (25 mL) and hexane (125 mL) and left in a freezer at −20° C. for 16 hours to give the title compound (18 g, 79% yield) as orange color solid. Mp 81° C. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 6.97 (s, 1H), 3.89 (s, 3H), 2.47 (s, 3H); 13C NMR (75 MHz, CDCl3). Mass spectrum (API-TIS) m/z 253 (MH+). Anal calcd. for C12H12O4S: C, 57.13; H, 4.79; S, 12.71. Found: C, 56.85; H, 4.76; S, 12.43.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:15])[C:8](=[N:13]O)[C:9](=[O:12])[CH2:10][CH3:11])=[CH:3][CH:2]=1.Cl.CCOCC>C(O)(=O)C.[Zn]>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:15])[CH:8]([NH2:13])[C:9](=[O:12])[CH2:10][CH3:11])=[CH:3][CH:2]=1
Reactant: CCC(=O)C(=NO)C(=O)c1ccncc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCC(=O)C(N)C(O)c1ccncc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 20 ml acetic acid is dissolved 1.0 g of 1-(4-pyridyl)-1,3-diketo-2-oximinopentane with heat (50° C.). The solution is acidified with dry hydrogen chloride and 1.0 g of zinc dust is slowly added. The mixture is stirred for one hour and cooled. Dry ether is added to the mixture and the title compound precipitates from the solution as a crude solid. This may be used in subsequent steps without purification.