Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CS(N1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=O)=O>>[NH:35]1[C:36]2[C:37](=[C:4]([C:2]3[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:5]=[CH:6][CH:8]=2)[CH:33]=[CH:34]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Via 2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared from 1-methanesulfonyl-piperazine
Reaction SMILES: [O:1]([C:8]1[CH:24]=[CH:23][C:11]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1OC2C=CC(C=O)=CC=2O1.C1C=CC(OC2C=CC(N)=CC=2)=CC=1.O>C1C=CC=CC=1>[O:1]([C:8]1[CH:24]=[CH:23][C:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=Nc1ccc(Oc2ccccc2)cc1)c1ccc2c(c1)OCO2
Agent: Nc1ccc(Oc2ccccc2)cc1
Agent: O=Cc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(Oc2ccc(NCc3ccc4c(c3)OCO4)cc2)cc1

Procedure:
The starting material used for catalytic hydrogenation, 4-phenoxy-(3,4-methylenedioxy-benzylidene)-aniline, is prepared as follows: the solution of 75 g of 3,4-methylenedioxy-benzaldehyde (piperonal) and 92.5 g of 4-aminodiphenyl ether in 500 ml of benzene is refluxed, with separation of water, for 8 hours. After the water has been completely separated, the reaction mixture is concentrated by evaporation; the crystals precipitated after cooling to about +5° C. are filtered off under suction; the crystal mass is recrystallised firstly in anhydrous benzene and subsequently in acetonitrile to thus obtain pure 4-phenoxy-(3,4-methylenedioxybenzylidene)-aniline, M.P. 89°-91° C.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.O.[NH2:21][NH2:22]>CCO>[N+:17]([C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:22][N:21]=[C:4]2[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:19])=[O:18]
Reactant: NN
Reactant: O=C(Nc1ccccc1)c1cc([N+](=O)[O-])ccc1F
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]nc(Nc3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
2-Fluoro-5-nitro-N-phenyl benzamide (100 mg, 0.38 mmol) was suspended in EtOH (10 mL) and the mixture heated to 50° C. To the resulting solution was added hydrazine monohydrate (0.1 mL, 1.9 mmol). The mixture was heated at reflux for 30 minutes, at which time LC-MS showed complete conversion to the aryl hydrazine (ES+m/e=273). The mixture was allowed to cool to room temperature, concentrated and the residue partitioned between EtOAc and saturated ammonium chloride solution. The layers were separated and the organic phase was dried over sodium sulfate and concentrated to a yellow foam. The residue was dissolved in phosphorous oxychloride (5 mL) and the mixture heated at 90° C. for 30 minutes, then allowed to cool to room temperature and stirred overnight. The reaction mixture was concentrated and the residue partitioned between EtOAc and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated to afford the title compound as a red solid (80 mg, 83%); 1H NMR (400 MHz, DMSO) 6.88 (1H, t), 7.31 (2H, t), 7.51 (1H, d), 7.74 (2H, t), 8.17 (1H, dd), 9.24 (1H, s), 9.42 (1H, s), 12.74 (1H, s); MS (ES+) m/e=255.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]=[CH:9][C:5]2=[N+:6]([O-])[CH:7]=1.[C:13](#[N:15])C.C(N(CC)CC)C.C[Si](C#N)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]=[CH:9][C:5]2=[N:6][C:7]=1[C:13]#[N:15]
Reactant: Cn1ccc2c1cc(Br)c[n+]2[O-]
Reactant: CC#N
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ccc2nc(C#N)c(Br)cc21
Temperature: 10 °C
Reaction time: 10 h
Yield: 77.1 %

Procedure:
A solution of 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine 4-oxide (42.8 kg, 188 mol) in DCM from the previous step was distilled at 45° C. to a volume of about 85 L. Acetonitrile (100 kg) was added and the mixture was distilled at 45° C. to a volume of about 110 L (2.5 L/kg). More ACN (80 kg) was added and the mixture was again distilled at 45° C. to a volume of about 110 L. Triethylamine (80 kg, 791 mol) was added. The mixture was cooled to 10±5° C. and trimethylsilyl cyanide (81.6 kg, 822 mol) was added over the course of 15 minutes while maintaining the temperature of the mixture below 25° C. The reaction mixture was gradually heated to 70±5° C. After stirring for 10 hours at this temperature, the starting material was consumed. The reaction mixture was cooled to 10±5° C. A 20% aqueous K2CO3 solution (260 kg) was added and the mixture was stirred at 10±5° C. for 1 hour. The resulting precipitate was filtered. The reactor was rinsed with a 2.3% aqueous K2CO3 solution (133 kg). The rinse was used to wash the filter cake, which was slurried in water (180 kg) for 30 minutes and filtered. The filter cake was again slurried in water (180 kg) for 30 minutes and filtered. The filtered solids were dispersed in a solution of DCM (1166 kg) and THF (156 kg). The mixture was stirred for 2 hours at 30±5° C. Activated carbon (7.0 kg, 0.16 kg/kg) was added and the mixture was stirred at 30±5° C. for 2 hours and filtered through a pad of Celite under pressure. The reactor was rinsed with DCM (200 kg) and the rinse was used to wash the filter cake. The combined filtrate was distilled at 40±5° C. to a volume of about 170 L. Next, n-heptane (120 kg) was added to the mixture, which was concentrated by distillation at 40±5° C. to a volume of about 170 L. More n-heptane (238 kg) was added to the mixture. The slurry was cooled to 5±5° C. and stirred for 1 hour. The resulting precipitate was filtered under pressure and the filter cake was washed with n-heptane (68 kg) from the reactor rinse. The wet cake was dried under vacuum at 40° C. for 20 hours to give the title compound as an off-white solid (34.2 kg).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[NH:19]1[CH:18]=[C:17]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH:21]=[N:20]1
Reactant: O=Cc1cnc(Br)s1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1cnc(-c2cn[nH]c2)s1
Temperature: 70 °C
Yield: 53.7 %

Procedure:
To a solution of 2-bromothiazole-5-carbaldehyde (500 mg, 2.6 mmol) in toluene (15 mL) and ethanol (7 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (606 mg, 3.1 mmol), 2M sodium carbonate solution (7.3 mL) and Pd(PPh3)4 (30 mg, 0.02 mmol). The reaction mixture was purged with argon for 15 min and the resulting mixture was heated at 70° C. for 4 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered and concentrated to under vacuum to obtain crude product. The crude product was purified by flash chromatography (60-120μ; 50% ethyl acetate in hexane) to afford 2-(1H-pyrazol-4-yl)thiazole-5-carbaldehyde as yellow solid (250 mg, 54% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.49 (br s, 1H), 10.00 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 8.09 (s, 1H); LC-MS m/z calculated for [M+H]+180.02. found 180.1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=1>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]CCCCCCCCc1ccccc1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2CCCCCCCCc2ccccc2)=N1
Reaction time: 24 h

Procedure:
To 8-phenyloctylmagnesium bromide (from 24.25 mmoles of 8-phenyloctyl bromide and 21.27 mmoles of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmoles) [A. I. Meyers et al., J. Org. Chem., 43, 1372 (1978)] in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmoles) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 76.5°-78° C.). To an ice cold solution of the iodide (9.46 mmoles) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmoles). The reaction mixture was allowed to stir for 30 minutes and was then quenched with 5 percent sodium hydroxide (50 ml). The reaction mixture was extracted with diethyl ether (2×50 ml) and the extract was washed with brine (50 ml) and dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate afforded an oil which was dissolved in acetone (50 ml), and 3N hydrochloric acid (10 ml) was added. The mixture was flushed with argon and stirred for 16 hours at ambient temperature. The volatiles were removed under vacuum and the residue partitioned between diethyl ether (50 ml) and water (50 ml). The aqueous phase was extracted with more diethyl ether (50 ml). The combined organic phase was washed with brine (50 ml) and dried over anhydrous magnesium sulfate. Evaporation of the organic phase yielded an oil which was purified by flash chromatography over silica gel with 2 percent ethyl acetate in hexane as eluant to afford the desired product as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:39])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]3[O:33][CH2:32]3)[CH:24]=2)[CH:20]=1)=[O:13]>>[CH3:39][N:8]([CH3:7])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]([OH:33])[CH2:32][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:24]=2)[CH:20]=1)=[O:13]
Reactant: C1COCCN1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC2CO2)c1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(O)CN2CCOCC2)c1
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 29, morpholine was reacted with N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-(2,3-epoxypropoxy)-benzamide to give the title compound in 64% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 2.44 (m, 4H), 2.94 (s, 6H), 3.15 (m, 1H), 3.55 (t, 4H), 3.96 (m, 2H), 4.06 (m, 1H), 4.89 (m, 1H), 6.9 (m, 1H), 7.14 (m, 1H), 7.21 (m, 3H), 7.32 (t, 1H), 7.42 (t, 1H), 7.56 (m, 31H), 7.79 (d, 1H), 9.88 (br s, 1H), 10.08 (br s, 1H); Mass Spectrum: M+H+ 533.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](=[S:16])[NH:7][C:6]=2[CH:17]=1.O1CCOC[CH2:19]1.[OH-].[K+].S([O-])(OC)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8]([S:16][CH3:19])=[N:7][C:6]=2[CH:17]=1
Reactant: CN1c2ccc(Cl)cc2NC(=S)c2cscc21
Reactant: C1COCCO1
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSC1=Nc2cc(Cl)ccc2N(C)c2cscc21
Reaction time: 3 h

Procedure:
To a stirred suspension of 1.1 g. of 7-chloro-4-methyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-thione in 15 ml. of dioxane is added dropwise and simultaneously at 30°-40° C., a solution of 1.3 g. of potassium hydroxide in 15 ml. of methanol and 1.1 g. of methyl sulfate. After addition is complete, the mixture is stirred for 3 hours, diluted with methanol and filtered. The filtrate is concentrated to 20 ml., diluted with water and the precipitate is collected. Recrystallization from methanol-water gives deep yellow crystals, m.p. 156°-158° C.
Reaction SMILES: C[Mg+].[Br-].[F:4][C:5]([F:15])([F:14])[C:6]1[CH:13]=[CH:12][C:9](C#N)=[CH:8][N:7]=1.CC[O:18][CH2:19][CH3:20]>>[F:4][C:5]([F:15])([F:14])[C:6]1[N:7]=[CH:8][C:9]([C:19](=[O:18])[CH3:20])=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(C(F)(F)F)nc1
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Product: CC(=O)c1ccc(C(F)(F)F)nc1
Reaction time: 2 h

Procedure:
A 3 M solution of MeMgBr in Et2O (7.2 mmol) was added to a stirred solution of 6-(trifluoromethyl)nicotinonitrile (0.82 g, 4.8 mmol) in ether (16 mL) dropwise over a 30 minute period. The reaction was stirred for 2 hours then the mixture was quenched with aqueous 1N HCl and extracted with Et2O. The organics were combined and washed with brine and dried over anhydrous MgSO4. The solvent was removed in vacuo yielding 530 mg of a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:29][CH2:28][C:27](=[N:32][OH:33])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reactant: NO
Agent: Cl
Solvent: CO
Product: ON=C1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1

Procedure:
A mixture of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-piperidin-4-one 7A-96 (75 mg, 0.17 mmol) and hydroxylamine hydrochloride (11.9 mg, 0.17 mmol) in methanol (0.3 ml) was stirred overnight at room temperature. The reaction was then extracted from saturated aqueous sodium bicarbonate, the combined organic layers were dried (Na2SO4) and concentrated to afford title compound 32A-1 (75 mg, 97%) as a solid: +ESI MS (M+1) 453.4; 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.28 (s, 1H), 7.70 (dd, J=7.7, 1.5 Hz, 1H), 7.53–7.41 (m, 5H), 7.31 (d, J=8.7 Hz, 2H), 4.45–4.18 (v br s, 4H), 2.61 (t, J=6.0 Hz, 2H), 2.39 (t, J=5.8 Hz, 2H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-]=C=O.[NH2:13][C:14]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[CH2:18][N:17]=[C:16]2[O:27][CH:28]=[CH:29][C:15]=12>>[NH2:13][C:14]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH:21]=2)[CH2:18][N:17]=[C:16]2[O:27][CH:28]=[CH:29][C:15]=12
Reactant: O=C=Nc1ccccc1
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Agent: [N-]=C=O
Product: NC1=c2ccoc2=NCN1c1cccc(NC(=O)Nc2ccccc2)c1

Procedure:
The compound was prepared following the procedure described in Example 232(b), using phenyl isocyanate as the isocyanate of choice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 346 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2C=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:29](=O)CCC.C[C@H]1CC[C@H](N)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH2:21]([N:7]([C@H:1]1[CH2:6][CH2:5][C@H:4]([CH3:29])[CH2:3][CH2:2]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CCCC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: C[C@H]1CC[C@H](N)CC1
Product: CCCCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using butyraldehyde, trans-4-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:11]([CH:32]([CH3:34])[CH3:33])=[C:12]([NH:19][C:20](=[O:31])[CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)[C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=1.[CH3:35][S:36]SC>>[CH:32]([C:11]1[C:10]([S:36][CH3:35])=[CH:15][CH:14]=[C:13]([CH:16]([CH3:17])[CH3:18])[C:12]=1[NH:19][C:20](=[O:31])[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1)([CH3:34])[CH3:33]
Reactant: CC(C)c1ccc(N)c(C(C)C)c1NC(=O)CN1CCN(CCO)CC1
Reactant: CSSC
Agent: CC(C)CCON=O
Product: CSc1ccc(C(C)C)c(NC(=O)CN2CCN(CCO)CC2)c1C(C)C
Temperature: 110 °C
Yield: 68 %

Procedure:
Isoamyl nitrite (1 ml) was slowly dropped into a solution of N-[3-amino-2,6-diisopropylphenyl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide (500 mg) in dimethyl disulfide (10 ml) with heating and stirring at 110° C. followed by stirring at the same temperature for 20 minutes. The reaction solution was allowed to cool and concentrated. The resulting residue was purified by a silica gel column chromatography (developing solvent, chloroform:methanol=20:1) to provide 370 mg (yield 68%) of N-[2,6-diisopropyl-3-(methylthio)phenyl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([O:15][C:16]([NH:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CCO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:23]1[CH2:22][CH2:21][CH2:20][CH:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccccc2[N+](=O)[O-])C1
Yield: 85 %

Procedure:
The method of Example 1 was followed using 1-fluoro-2-nitrobenzene (1.0 eq), 3-N-Boc-aminopiperidine (1.0 eq), and DIEA (2.0 eq) in EtOH at 50° C. for 48 hours yielding tert-butyl 1-(2-nitrophenyl)piperidin-3-ylcarbamate (85%). LCMS (m/z): 322.2 (MH+); LC Rt=3.23 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[Cl:23][C:24]1[C:29](F)=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:26][N:25]=1>O>[Cl:23][C:24]1[C:29]([O:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:27]=[CH:26][N:25]=1
Reactant: Fc1c(C(F)(F)F)ccnc1Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottom flask charged with 3,5-dichlorophenol (1.23 g, 7.52 mmol) and potassium carbonate (1.04 g, 7.52 mmol) was added N-methylpyrrolidinone (5 mL). To this suspension under N2 was added 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (1.50 g, 7.52 mmol) and the reaction mixture was placed in an oil bath at 120° C. After 60 minutes, the reaction mixture was allowed to cool to room temperature, water (20 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (3×25 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 80 gram column, eluting with 0-75% CH2Cl2 in hexanes to afford the title compound. 1H NMR (DMSO-d6) δ 8.52 (d, J=4.5 Hz, 1H), 7.60 (d, J=4.6 Hz, 1H), 7.14-7.10 (m, 1H), 6.72-6.68 (m, 2H). HRMS (M+1)=341.9465.
Reaction SMILES: [BH4-].[Na+].[CH:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH2:6][CH2:5][N:4]=1.[ClH:16]>CO.C(O)(C)C>[ClH:16].[CH2:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH2:6][CH2:5][NH:4]1
Reactant: C1=NCCc2c1oc1ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: c1ccc2c3c(oc2c1)CNCC3
Temperature: 20 °C
Reaction time: 20 h

Procedure:
9.2 g (240 mmol) of sodium borohydride are added in small portions and in the space of 3 h to a suspension of 8.2 g (47.8 mmol) of 3,4-dihydrobenzofuro[2,3-c]pyridine in 350 ml of methanol. The mixture is stirred for 20 h at 20° C. and the solvent then evaporated off under reduced pressure. The residue is washed with water and the 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine extracted by means of ethyl acetate. The organic phase is separated off after settling has taken place, dried over sodium sulphale and evaporated under reduced pressure, and the residue is treated with one equivalent of 0.1N hydrochloric acid in isopropyl alcohol. The hydrochloride is isolated and recrystallized in a mixture of isopropyl alcohol and ethanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>CCOCC>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]1[CH:43]=[CH:44][C:45]([C:46]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:47])=[CH:49][CH:50]=1
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NCCCCCCCCCCCCCCCCBr)cc1)N1CCCCC1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 4-(16-bromohexadecylamino)benzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with 100 ml. portions of water and dried over magnesium sulfate. The solvent is removed in vacuo and the solid is recrystallized in 50 ml. of diethyl ether to yield the product.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:24][CH3:25])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]([CH3:22])[S:20][CH:21]=2)[C:12]1=[O:23])[C:4]([O:6]C(C)(C)C)=[O:5].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[CH3:1][C@@H:2]([CH2:24][CH3:25])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]([CH3:22])[S:20][CH:21]=2)[C:12]1=[O:23])[C:4]([OH:6])=[O:5].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2csc(C)n2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2csc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution containing the product from Example 11C (2.0 g, 5.4 mmol) in dichloromethane (14 mL) was treated with trifluoracetic acid (7 mL), stirred at 25° C. for 3 hours and concentrated to give the title compound as a trifluoroacetic acid salt.