Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10].O>C(Cl)Cl>[N:7]([C:1]1([O:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: ON=C1CCCCC1
Solvent: ClCCl
Solvent: O
Product: O=NC1(OCc2ccc([N+](=O)[O-])cc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of cyclohexanone oxime (2.66 g, 23.51 mmol) in methylene chloride (50 mL) was added dropwise with stirring to a solution of LTA (10.42 g, 23.51 mmol) and 4-nitrobenzoic acid (39.29 g, 235.1 mmol) in methylene chloride (300 mL) at 0° C. A blue color gradually appeared with the addition of the oxime. After 1 h at 0° C., the reaction mixture was warmed to room temperature. After 3 h at room temperature, water (50 mL) was added and the organic layer was extracted with water (2×50 mL) and 3% sodium bicarbonate solution (2×50 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the residue was recrystallized in diethyl ether/petroleum ether (1:1) in a −5° C. freezer to give 1-Nitroso-1-para-nitrobenzoxycyclohexane as bright blue crystals (20-25% yield): Rf 0.55 (pentane/ethyl acetate=20:1); 1H NMR (300 MHz, Benzene-d6) δ 1.17-2.04 (m, 10H), 7.38-7.98 (d, 4H); 13C NMR (300 MHz, Benzene-d6) δ 22.1 (2CH2), 25.0 (CH2), 29.7 (2CH2), 123.8 (2Ph-CH), 125.3 (O—C—N), 131.1 (2Ph-CH), 135.3 (Ph-C), 151.1 (Ph-C), 162.6 (C═O).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:7](=[O:16])[N:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[CH:4]=1)[NH2:2].[CH3:21][N:22]=[C:23]=S.CO>CN(C=O)C>[CH3:21][NH:22][C:23]1[C:4]2[C:5](=[O:20])[N:6]([CH2:17][CH2:18][CH3:19])[C:7](=[O:16])[N:8]([CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[C:3]=2[NH:1][N:2]=1
Reactant: CCCn1c(=O)cc(NN)n(Cc2cccnc2)c1=O
Reactant: CN=C=S
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccnc2)c1=O
Reaction time: 14 h

Procedure:
A solution of 6-hydrazino-1-(3-pyridylmethyl)-3-propyluracil (0.7 g, 2.66 mM) and methyl isothiocyanate (0.7 ml, 10.3 mM) in DMF (10 ml) was heated at 90° C. for 14 hours and then at 110° C. for 14 hours. To the reaction solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/ethanol/water afforded colorless needles (0.5 g, 60%), m.p. >300° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[C:23]1([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:32]2[CH2:33][CH2:34][C:29]([OH:35])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:30][CH2:31]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1
Temperature: 65 °C

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.106 g, 0.301 mmol, from Example 47, Step 2), 4-phenylpiperidin-4-ol (0.0641 g, 0.362 mmol), palladium acetate (1 mg, 0.006 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6 mg, 0.009 mmol), and cesium carbonate (0.274 g, 0.843 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the desired product. LCMS calculated for C22H22ClN2O2(M+E)+: m/z=381.1; Found: 380.9.
Reaction SMILES: CO[C:3](=[O:22])[NH:4][C:5]1[C:10]2=[CH:11][N:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[N:13]=[C:9]2[CH:8]=[CH:7][N:6]=1.ClC1C=CC=C(Cl)[C:25]=1[N:31]1C=C2C(N)=NC=CC2=N1.CN=C=O>>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[N:12]1[CH:11]=[C:10]2[C:5]([NH:4][C:3]([NH:31][CH3:25])=[O:22])=[N:6][CH:7]=[CH:8][C:9]2=[N:13]1
Reactant: COC(=O)Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Reactant: Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Agent: CN=C=O
Product: CNC(=O)Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Yield: 78 %

Procedure:
Following the procedure described for [2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]carbamic acid methyl ester, 2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-ylamine and methyl isocyanate were reacted to afford the title compound as a white solid (78% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.06 (br s, 1H), 9.75-9.70 (m, 1H), 9.04 (d, J=0.9 Hz, 1H), 7.85 (d, J=6.5 Hz, 1H), 7.83-7.76 (m, 2H), 7.70 (dd, J=9.0, 7.3 Hz, 1H), 7.17 (dd, J=6.5, 0.9 Hz, 1H), 2.84 (d, J=4.6 Hz, 3H). LCMS (Method B): RT=2.69 min, m/z: 336 [M+H+].
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[C:3]([OH:5])=[O:4].C(O)(=O)C>O>[O:11]=[C:9]1[NH:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][CH2:8]1
Reactant: N[C@@H](CCCC(=O)O)C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC[C@@H](C(=O)O)N1
Yield: 45 %

Procedure:
A mixture of (S)-2-amino-hexanedioic acid (50 g, 310.25 mmol), acetic acid (100 mL), and water (400 mL) water was refluxed for 3 h. The unchanged starting amino acid was filtered off (24 g) and the filtrate evaporated, dissolved in hot water (50 mL) and then cooled. A crystalline precipitate formed which was filtered to provide the title intermediate (20 g, 45% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH2:12])=[N:9]2)=[N:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[NH2:18].CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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>[CH3:25][O:24][C:20]1[CH:19]=[C:17]([NH:18][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([NH2:12])=[N:9]3)=[N:4][CH:3]=2)[CH:16]=[C:15]([O:14][CH3:13])[C:21]=1[O:22][CH3:23]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Nc1ccc2ncc(Br)cc2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Nc2cnc3ccc(N)nc3c2)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 24 h
Yield: 17.2 %

Procedure:
Under argon atmosphere, 200 mg (892 μmol, 1 eq) of 7-bromo-1,5-naphthyridin-2-ylamine, 196.3 mg (1.07 mmol, 1.2 eq) of 3,4,5-trimethoxyaniline, 2 mg (2.3 μmol, 0.0025 eq) tris(dibenzylideneacetone)dipalladium, 4 mg (6.7 μmol, 0.0075 eq) 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl and 120 mg (1.24 mmol, 1.4 eq) of sodium terbutoxide were introduced in 6 mL of toluene. The mixture was stirred at 80° C. for 24 h. The mixture was allowed to reach it and water was added. Aqueous layer was extracted with methylene chloride. Organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography using methylene chloride/ethanol: 96/4 as eluent. The solvent was evaporated to dryness to afford 50 mg of yellow powder with 17% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.CCOCC.[BH4-].[Na+]>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: CN1CCC(Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 1946.8 %

Procedure:
To a solution of 4-chloroaniline (4.59 g, 30×1.2 mmol) and 1-methyl-4-piperidone (3.39 g, 30 mmol) in benzene (12 ml) is added Molecular Sieve 4A (6 g), and the resultant mixture is heated under reflux over a period of 20 hours. After cooling, the reaction mixture is mixed with ether and filtered to remove the Molecular Sieve. The filtrate is concentrated in vacuo, and the residue is dissolved in 95% ethanol (50 ml). Sodium borohydride (0.6 g, 15 mmol) is added to the solution, which is stirred at room temperature over a period of 5 hours. The reaction mixture is mixed with water and the ethanol is evaporated therefrom. The aqueous residue is shaken with methylene chloride, and the methylene chloride layer is dried over anhydrous potassium carbonate and concentrated in vacuo. The residue is distilled to give crude product (5.89 g) b.p. 130°-150° C./1 mmHg. This substance is recrystallized from ether-petroleum ether to give 4 -(4-chloroanilino)-1-methylpiperidine (5.25 g) as crystals melting at 91° to 92° C. The yield is 78%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH:20]1[CH2:23][N:22]([C:24]([N:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH:33]3[CH2:36][CH2:35][CH2:34]3)[CH2:28][CH2:27]2)=[O:25])[CH2:21]1)(=O)=O>CN(C=O)C.ClCCl>[CH:33]1([N:29]2[CH2:30][CH2:31][CH2:32][N:26]([C:24]([N:22]3[CH2:23][CH:20]([O:1][C:2]4[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=4)[CH2:21]3)=[O:25])[CH2:27][CH2:28]2)[CH2:34][CH2:35][CH2:36]1
Reactant: Cc1ccc(O)cn1
Reactant: CS(=O)(=O)OC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Temperature: 90 °C
Reaction time: 72 h
Yield: 35 %

Procedure:
3-Hydroxy-6-methylpyridine (24 mg, 0.22 mmol) and K2CO3 (33 mg, 0.24 mmol) were stirred in DMF (1 ml) for 30 minutes and 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl methanesulfonate (66 mg, 0.20) was added. The reaction was stirred at 90° C. for 3 days and then diluted with dichloromethane (30 ml) and washed with saturated NaHCO3 (3×15 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) to give the title product as off-white solid (24 mg, 35%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:22].Cl.[NH2:24][CH2:25][CH2:26][O:27][NH2:28].N1C=CC=CC=1>C(O)C>[ClH:22].[ClH:22].[NH2:24][CH2:25][CH2:26][O:27][N:28]=[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH2:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCCCn1ccnc1)c1ccc(C(F)(F)F)cc1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCCn1ccnc1)c1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 39.8 %

Procedure:
A mixture of 5-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-pentanone (11.5 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (5.78 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 3.3 g (20%) of product, mp 115°-120° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH:14]([N:18]=[C:19]=[O:20])([CH2:16][CH3:17])[CH3:15]>CN(C)C=O>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:19]([NH:18][CH:14]([CH2:16][CH3:17])[CH3:15])=[O:20])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: CCC(C)N=C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CN(C)C=O
Product: CCC(C)NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 53.9 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (200 mg, 0.90 mmol) and sec-butyl isocyanate (102 μL, 0.90 mmol) in 1.5 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (40/60, v/v), gave the desired product (156 mg, 54%). LC-MS 322.2 (M+).
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>CN(C=O)C.O>[N:16]1([C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ncccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncccc1-n1cncn1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of 2-cyano-3-fluoro-pyridine (2.99 g, 24.49 mmol, preparation described in case 20443, filed Jun. 4, 1999) in DMF (30 ml) is added cesium carbonate (2.03 g, 29.39 mmol) and 1,2,4-triazole (2.03 g, 29.39 mmol) and the reaction mixture is stirred at 65° C. for 4 h. After cooling to room temperature, the mixture is diluted with water and extracted with EtOAc 3 times. The aqueous layer is saturated with LiCl and further extracted with EtOAc. The combined organic layer is dried on sodium sulfate, concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, 2% MeOH containing 10% NH4OH in CH2Cl2 to 6%) to give 3-[1,2,4]Triazol-1-yl-pyridine-2-carbonitrile. 1H NMR (CDCl3, 400 MHz) δ 8.95 (s, 1H); 8.8 (d, J=4 Hz, 1 H); 8.24 (s, 1H); 8.22 (d, J=8.5 Hz, 1 H); 7.75 (dd, J=4, 8.5 Hz, 1 H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(CNC(=O)Oc1ccccc1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
Phenyl chloroformate (1.73 g.) was added to a vigorously stirred solution of 2,2-dimethoxyethylamine (1.05 g.) and potassium carbonate (1.39 g.) in water (20 ml.), and the mixture stirred at room temperature for 2 hours. The mixture was extracted with ether, and the ether extract dried and evaporated to dryness to give phenyl N-(2,2-dimethoxyethyl)carbamate (1.5 g.) which was used without further purification.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[C:14]2O)=[CH:9][CH:8]=1.N>>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[C:14]2[Cl:3])=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nccc2ccc(Br)cc12
Agent: N
Product: Clc1nccc2ccc(Br)cc12
Temperature: 100 °C
Yield: 114.3 %

Procedure:
To phosphorus oxychloride (46.6 mL, 0.5 mol) at room temperature was added, portionwise, 7-bromo-1-hydroxyisoquinoline (11.2 g, 0.05 mol). The mixture was heated to 100° C. for 90 min with rapid stirring. On cooling to room temperature, the mixture was poured, cautiously onto ice/water (200 mL). Dropwise addition of aqueous ammonia raised the pH=8 and the resulting precipitate was collected by filtration, washing with cold water. The solid was dried under reduced vacuum at 45° C. for 12 h. 13.86 g (115%) Beige solid isolated. 1H NMR (DMSO-d6) δ 8.4 (s, 1H), 8.34-8.38 (d, J=6 Hz, 1H), 8.03-8.07 (m, 2H), 7.91-7.96 (d, J=6 Hz, 1H); HPLC: 96%; LCMS: 242, 244, 246.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.C(N(C(C)C)C(C)C)C>ClCCl>[OH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:15]1
Reactant: OCC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (7.88 ml) was added over ten minutes to an ice-cold solution of 3-hydroxymethyl piperidine (5.76 g) and ethyldiisopropylamine (9.58 ml) in dichloromethane (300 ml). The reaction mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction was then diluted with dichloromethane (500 ml), washed with 1N aqueous hydrochloric acid (200 ml), dried over magnesium sulphate, and evaporated to afford benzyl 3-(hydroxymethyl)-1-piperidinecarboxylate as an oil (12.4 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][CH2:10][C:11]([NH2:14])([CH3:13])[CH3:12]>CCOCC>[NH2:14][C:11]([CH3:13])([CH3:12])[CH2:10][NH:9][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: CC(C)(N)CN
Reactant: O=C(Cl)c1ccco1
Solvent: CCOCC
Product: CC(C)(N)CNC(=O)c1ccco1
Reaction time: 0.5 h

Procedure:
A solution of 2-furoyl chloride (12.0 g.) in dry ether (1.50 ml.) was stirred during the dropwise addition over 30 minutes of a solution of 1,2-diamino-2-methylpropane (9.63 ml.) in dry ether (58 ml.). The reaction mixture was stirred for a further 30 minutes. The solid precipitate was collected by filtration and washed with ether. The residual solid was suspended in hot water (250 ml.) and basified to pH 10 with powdered sodium carbonate. The cooled mixture was extracted with chloroform (3×100 ml.). The combined extracts were dried (MgSO4) and evaporated to give N-(2-amino-2-methylpropyl)furan-2-carboxamide (10.68 g.) as an oil, which was used without purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:8]([CH:9]=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>S([O-])([O-])(=O)=O.[Cu+2].C(Cl)Cl>[CH3:13][C:14]([S@:17]([N:19]=[CH:9][C:8]1[CH:7]=[N:6][CH:5]=[CH:4][C:3]=1[C:2]([F:12])([F:11])[F:1])=[O:18])([CH3:16])[CH3:15]
Reactant: O=Cc1cnccc1C(F)(F)F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N=Cc1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 68 h

Procedure:
To a the solution of 4-(trifluoromethyl)nicotinaldehyde from above was added DCM (10 mL), (R)-2-methylpropane-2-sulfinamide (1.553 g, 12.81 mmol; See Table 1, footnote 1) (AK Scientific) and copper sulfate (4.09 g, 25.6 mmol) (Aldrich, anhydrous). The suspension was stirred at rt under N2 for 68 h. The suspension was then filtered through Celite® brand filter agent, and the solid was washed with DCM (2×20 mL). The filtrates were concentrated and purified by ISCO (40 g, SiO2, 10-50% EtOAc/hexane) to give (R)-2-methyl-N-((4-(trifluoromethyl)pyridin-3-yl)methylene)propane-2-sulfinamide as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10](=O)C(F)(F)F)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].IC>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1
Reactant: O=C(Nc1nc(Cl)cc(Cl)n1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: CNc1nc(Cl)cc(Cl)n1
Reaction time: 12 h
Yield: 85.7 %

Procedure:
To a mixture of N-(4,6-dichloro-pyrimidin-2-yl)-2,2,2-trifluoro-acetamide (4.6 g, 17.7 mmol) and potassium carbonate (4.9 g, 35.4 mmol) in acetone (100 ml) was added iodomethane (1.3 ml, 21.2 mmol). After stirring for 12 hours, the mixture was filtered through a pad of celite under suction. The filtrate was concentrated under reduced pressure and the residue was treated with methanol (150 ml) tetrahydrofuran (30 ml), and a solution of potassium carbonate (5.0 g, 51 mmol) in water (15 ml). After stirring for 1 hour, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (150 ml) and saturated aqueous sodium chloride solution (100 ml). The organic phase was dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:6 followed by 1:4) to give N-(4,6-dichloro-pyrimidin-2-yl)-methyl-amine (2.7 g, 85% yield). 1H NMR (CDCl3) δ 3.04 (d, 3H, J=5.1 Hz, CH3), 5.50 (br s, 1H, NH), 6.63 (s, 1H, Ar).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6]2([CH2:11][CH2:10][N:9](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:7]2)[O:5][C:4](=[O:22])[NH:3]1>[Pd].C(O)C>[CH3:1][C:2]1([CH3:23])[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][C:4](=[O:22])[NH:3]1
Reactant: CC1(C)NC(=O)OC12CCN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CCO
Product: CC1(C)NC(=O)OC12CCNCC2
Reaction time: 1 h
Yield: 100.9 %

Procedure:
A mixture of 4.54 g 4,4-dimethyl-8-carbobenzyloxy-1-oxa-3,8-diazaspiro[4.5]decan-2-one, 75 ml ethanol and 1 g 5% palladium on carbon is hydrogenated at 60 psi and 50° for one hour. Filtration and evaporation affords 2.65 g 4,4-dimethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 238°-240°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:17][CH2:18][CH2:19]CS([O-])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:19][CH2:18][F:17])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=S(=O)([O-])CCCF
Reactant: O=Cc1cc(O)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc(OCCF)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of 3-chloro-5-hydroxybenzaldehyde (8.2 g, 52.5 mmol; see Preparation A(ii) above) and potassium carbonate (9.4 g, 68.2 mmol) in DMF (10 mL) under nitrogen was added a solution of (2-monofluoroethyl) methanesulfonate (9.7 g, 68.2 mmol; see step (i) above) in DMF (120 mL) dropwise at room temperature. The mixture was heated to 100° C. for 5 h and then stirred overnight at room temperature. The reaction was cooled to 0° C., poured into ice-cold 2N HCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The brown oil was chromatographed on silica gel eluting with Hex:EtOAc (4:1) to afford the sub-title compound (7.6 g, 71%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:7]1[N:8]=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29]Cl)=[CH:17][C:15]=3[CH:16]=2)[S:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C-:31]#[N:32].[Na+].[I-].[K+]>CO.[Cl-].[Na+].O>[CH2:1]([C:7]1[N:8]=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:31]#[N:32])=[CH:17][C:15]=3[CH:16]=2)[S:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1csc(-c2cc3cc(OCc4ccccc4CCl)ccc3o2)n1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCCc1csc(-c2cc3cc(OCc4ccccc4CC#N)ccc3o2)n1
Yield: 84.3 %

Procedure:
A mixture of 4-hexyl-2-[5-(2-chloromethylphenylmethoxy)benzofuran-2-yl]thiazole (0.80 g), sodium cyanide (0.16 g) and potassium iodide (0.13 g) in methanol (10 ml) was refluxed for 2 hours. After being cooled, the mixture was poured into brine, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and chloroform (1:33). The fractions containing object compound were combined and concentrated under reduced pressure to give an oil of 4-hexyl-2-[5-(2-cyanomethylphenylmethoxy)benzofuran-2-yl]thiazole (0.66 g).