Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][NH2:12])=[CH:4][C:3]=2[O:2]1.[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])([CH3:19])[CH3:18]>CCCCCC>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][NH:12][C:30]([NH:29][C:21]3[C:20]([CH:17]([CH3:18])[CH3:19])=[CH:25][CH:24]=[CH:23][C:22]=3[CH:26]([CH3:28])[CH3:27])=[O:31])=[CH:4][C:3]=2[O:2]1
Reactant: CCCCC(CN)c1ccc2c(c1)OCO2
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCCCCC
Product: CCCCC(CNC(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To 4.8 g (21.7 mmol) of (+)-2-(3,4-methylenedioxyphenyl)hexylamine ([α]D21 =+2.64°, c=0.957, in ethanol), was added 46 ml of a hexane solution (0.472 M) of 2,6-diisopropylphenyl isocyanate, and the mixture was stirred for one hour at room temperature. The precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 2.89 g of (+)- 1-(2-(3,4-methylenedioxyphenyl)hexyl)-3-(2,6-diisopropylphenyl)urea (Yield: 31%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.[OH-].[NH4+]>C(O)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:5]1[C:4]([NH2:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cnc(Nc2ccccc2F)c([N+](=O)[O-])c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc([N+](=O)[O-])cnc1Nc1ccccc1F

Procedure:
A mixture of the product from Step A (1.0 g.) 15 ml. of ethanol and 5 ml. of concentrated ammonium hydroxide was warmed to 70° C. and hydrogen sulfide was bubbled in for 20 minutes. After cooling, the precipitate was collected and recrystallized from ethanol to give 2-(2-fluoroanilino)-3-amino-5-nitropyridine, m.p. 171°-172° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:17]1(C)C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:14][CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: c1ccc(CN2CCC3(CC2)CO3)cc1
Temperature: 80 °C
Yield: 93 %

Procedure:
18.9 g (0.1 mol) of 1-benzyl-4-piperidone, 24.2 g (0.11 mol) of trimethylsulfoxide iodide salt, 0.5 g of tetrabutyl ammonium bromide and 200 mL of toluene were added to a 500 mL round bottom flask, and slowly added dropwise at room temperature with 60 mL of (15%) sodium hydroxide solution. Then the reaction was heated to 80° C., reacted for 8 h, and then cooled to room temperature. The toluene layer was separated, and the water layer was extracted with toluene (50 mL×3). The toluene layer was combined, washed with water, saturated sodium chloride solution in sequence, dried with anhydrous sodium sulfate, and distilled under reduced pressure to recovery solvent to obtain light yellow oily liquid N-benzyl-1-oxa-6-azaspiro[2,5]-octane 19 g, yield: 93%. 1H-NMR (CDCl3, ppm) δ: 7.31-7.33 (5H, m), 3.56 (2H, s), 2.64 (2H, s), 2.53-2.62 (4H, m), 1.52-1.86 (4H, m).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][C@@H:9]1[CH2:21][OH:22])=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:6][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C@@H:9]1[CH2:21][OH:22]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CO)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(C)[C@@H](CO)C1
Temperature: 0 °C
Yield: 62.3 %

Procedure:
(R)-2-hydroxymethyl-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (6.24 g, 19.7 mmol) was dissolved in THF (10 mL) and cooled to 0° C. 2M LiAlH4 in THF (30.0 mL, 60.0 mmol) was added. The reaction mixture was stirred at reflux for 4 hours and then cooled to 0° C. and quenched with the drop-wise addition of 1M sodium hydroxide solution (20 mL). The reaction mixture was diluted with THF (50 mL), filtered and the filtrate was concentrated in vacuo to give 1,4-dimethyl-(R)-2-hydroxymethyl piperazine (1.77 g, 62%) as a colourless oil which was used without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH3:34])[C:14]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4C(=O)C5=CC=CC=C5C4=O)[CH2:18][CH2:17]3)=[N:15][C:11]=2[CH:10]=1)=[O:8])([OH:3])=[O:2].CN>>[NH2:23][CH2:22][CH:19]1[CH2:18][CH2:17][CH:16]([C:14]2[N:13]([CH3:34])[C:12]3[CH:35]=[CH:36][C:9]([C:7]([NH:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[O:8])=[CH:10][C:11]=3[N:15]=2)[CH2:21][CH2:20]1
Reactant: Cn1c(C2CCC(CN3C(=O)c4ccccc4C3=O)CC2)nc2cc(C(=O)NCCC(=O)O)ccc21
Agent: CN
Product: Cn1c(C2CCC(CN)CC2)nc2cc(C(=O)NCCC(=O)O)ccc21

Procedure:
Prepared from 5-[(2-carboxy-ethyl)-aminocarbonyl]-1-methyl- 2-(4-phthalimidomethyl-cyclohexyl)-benzimidazole by treating for 20 hours with 40% aqueous methylamine solution at ambient temperature.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][CH2:17]2)=[O:15])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30])#[N:23].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:9]1[CH:8]=[C:7]([C:6]2[S:5][C:4]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])=[CH:3][C:2]=2[C:26]2[CH:27]=[CH:28][C:29]([F:30])=[C:24]([C:22]#[N:23])[CH:25]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)s2)CN1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Product: N#Cc1cc(-c2cc(C(=O)N3CNC(=O)C3)sc2-c2cccc(Cl)c2)ccc1F
Temperature: 100 °C

Procedure:
Under argon, 61.0 mg (0.16 mmol) of the compound from Example 24A are provided in 3 ml of 1,2-dimethoxyethane, and 26.1 mg (0.16 mmol) of 3-cyano-4-fluorophenylboronic acid, 155 mg (0.47 mmol) of cesium carbonate, 5.3 mg (0.01 mmol) of dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane and 1.1 mg (0.005 mmol) of palladium(II) acetate are added. The mixture is heated in a closed glass vessel at 100° C. under microwave irradiation for 30 minutes. The reaction mixture is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient). 23.0 mg (34% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([NH2:24])=[CH:16][C:15]=2[NH2:25])[C:9](=O)[O:10]CC)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:24][C:17]1[CH:18]=[C:19]([C:20]([F:21])([F:22])[F:23])[C:14]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:9](=[O:10])[NH:25][C:15]=2[CH:16]=1
Reactant: CCOC(=O)N(c1cccc(Cl)c1)c1c(N)cc(N)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1cccc(Cl)c1
Yield: 29.3 %

Procedure:
Ethyl 3-chlorophenyl[2,4-diamino-6-(trifluoromethyl)phenyl]carbamate (80.2 mg) was dissolved in ethanol (1 ml), and to the solution was added sodium hydride (8.6 mg). The reaction mixture was heated at reflux for 2.5 hours. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by preparative TLC (2 mm, 20×20 cm, CHCl3-methanol=10:1) to give the title compound (20.6 mg, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.CCOCC.C(OCC)(=O)C.CCCCCC>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[N:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: COc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(N=Cc2ccc(O)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-4-hydroxybenzaldehyde (vanillin, 1 g, 6.57 mmol) was dissolved in methanol (30 ml). To this solution was added p-anisidine (0.810 g, 6.57 mmol) and the resultant reaction solution was stirred overnight under nitrogen at room temperature. The reaction solution was taken to dryness in vacuo with the application of heat. The resultant solid was azeotropically mixed with methanol (2x), ether (1x), and again with methanol (2x) to yield yellow crystals. The crystals were triturated with hot ether to yield the title product: 1H NMR (300 MHz, CDCl3); δ 8.36 (S, 1H), 7.60 (S, 1H), 7.30-7.17 (m, 3H), 7.05-6,91 (m, 3H), 6.10 (S, 1H), 3.97 (S, 3H), 3.83 (S, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([Li])CCC.[CH3:14][O:15][CH2:16][C:17](=[O:19])[CH3:18]>>[OH:19][C:17]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([CH3:18])[CH2:16][O:15][CH3:14]
Reactant: COCC(C)=O
Reactant: Oc1ccccc1Br
Agent: [Li]CCCC
Product: COCC(C)(O)c1ccccc1O

Procedure:
2-(2-hydroxy-1-methoxypropan-2-yl)phenol was prepared according to the procedure described for 417a using 2-bromophenol (400 μL, 3.4 mmol), n-butyllithium in hexanes (1.6 M, 5.0 mL, 7.9 mmol) and methoxyacetone (412 uL, 4.48 mmol). 1H NMR (400 MHz, CDCl3) ppm 1.64 (s, 3H), 3.45 (d, J=9.3 Hz, 1H), 3.47 (s, 3H), 3.77 (d, J=9.3 Hz, 1H), 6.85 (m, 1H), 6.90 (m, 1H), 7.04 (m, 1H), 7.20 (m, 1H), 9.22 (s, 1H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])[CH:12]=1.[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:40])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)O)c3)c(C)c2)cc1C)CC
Reaction time: 4 h
Yield: 94.9 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.22 mL) was added to a solution of [5-(4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 82-(1); 37.1 mg, 0.07 mmol) in methanol (1.2 mL), and the mixture was stirred for four hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (33.2 mg, 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[Zn]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnccc1OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1cnccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture containing 4-(benzyloxy)-3-nitropyridine (7.2 g, 31.3 mmol) and zinc powder (6.1 g, 91.0 mmol) was added acetic acid (7.2 mL, 7.5 mmol). The mixture was stirred for 6 h at room temperature, filtered and concentrated. The resultant residue was dissolved in ethyl acetate (300 mL), washed with aqueous, saturated ammonium chloride (3×100 mL), washed with brine (100 mL), dried over MgSO4, filtered and concentrated to afford 4-(benzyloxy)pyridin-3-amine as an orange oil which was used without further purification. 1H NMR (500 MHz, DMSO-D6) δ ppm 7.91 (s, 1H), 7.72 (d, J=5.49 Hz, 1H), 7.50 (d, J=7.63 Hz, 2H), 7.41 (t, J=7.32 Hz, 2H), 7.34 (s, 1H), 7.03 (d, J=5.49 Hz, 1H), 5.24 (s, 2H), 5.13 (s, 2H). LCMS: retention time: 1.372 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 201 (MH−).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH4-].[Na+]>C(#N)C>[CH2:1]([N:9]1[CH2:10][CH:11]=[CH:12][CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: C1=CCN(Cc2ccccc2)CC1
Temperature: 71 °C

Procedure:
2.4 mL of benzyl bromide (20 mmol) was added dropwise over an hour to a solution of 1.6 mL of pyridine in 5 mL of acetonitrile. Then reaction mixture was heated at 70 to 72° C. for 3 hours. Solvent was removed under reduced pressure and the residue was dissolved in 16 mL of ethanol. 1.1 g of sodium borohydride (30 mmol) was added in small portions over 30 minutes. After stirring for 24 hs reaction mixture was carefully quenched with 50 mL of water and solvents were removed in vacuo. The residue was portioned between ethyl acetate and 2M NaOH solution. Organic extracts were washed with brine, dried over MgSO4 and evaporated to afford crude 3.36 g of crude 1-benzyl-1,2,3,6-tetrahydropyridine which was used in the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)([OH:18])[CH2:14][CH2:13]3)[CH2:8]2)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][CH:7]([CH2:11][N:12]1[CH2:13][CH2:14][C:15]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)([OH:18])[CH2:16][CH2:17]1)[CH2:8]2
Reactant: Cc1ccc(CC2(O)CCN(CC3=Cc4ccc(O)cc4C3)CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(CC2(O)CCN(CC3Cc4ccc(O)cc4C3)CC2)cc1
Yield: 91.1 %

Procedure:
1-(6-Hydroxy-1H-inden-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (256 mg, 0.732 mmol) and Pd/C 10% (50 mg) in EtOAc (15 ml) was stirred vigorously under a hydrogen atmosphere for 24 hr at RT. Removal of the catalyst and evaporation of the solvent afforded (RS)-1-(5-hydroxy-indan-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol as a colourless oil (235 mg, 0.667 mmol, 91%), MS m/e=352.2 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:13]2[C:9]([CH2:10][CH2:11][CH2:12]2)=[C:8](C(O)=O)[C:7]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(=O)=O>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:13]2[C:9](=[CH:8][C:7]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH2:10][CH2:11][CH2:12]2
Reactant: O=C(O)c1c(-c2ccncc2)c(-c2cccs2)n2c1CCC2
Agent: O=C=O
Solvent: ClCCl
Product: c1csc(-c2c(-c3ccncc3)cc3n2CCC3)c1

Procedure:
3-(2-Thienyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylic acid (example 7, 0.2 g, 0.64 mmol) is heated under argon in a 10 ml flask by immersing in a metal bath at 250° C. Evolution of CO2 takes place immediately, and the substance melts and turns black. After cooling, the solidified, glassy melt is taken up in CH2Cl2 (10 ml) and filtered through Al2O3 (TSC, Baker). The filter cake is eluted with diethyl ether. The eluate is concentrated and crystallizes from ether/diisopropyl ether in the cold: white crystals 0.04 g.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[S:14]([NH2:24])(=[O:23])([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[O:15]>C(O)C>[S:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:10][CH:11]=[CH:12][CH:13]=3)=[CH:5][CH:4]=2)=[CH:18][CH:17]=1)(=[O:15])(=[O:23])[NH2:24]
Reactant: O=Cc1ccc(-c2ccco2)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CCO
Product: NS(=O)(=O)c1ccc(N=Cc2ccc(-c3ccco3)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-formylphenyl)furan (0.335 g, 1.95 mmol, prepared according to the method of Heterocycles, 1990, 31, 1951), sulfanilamide (0.336 g, 1.95 mmol) in ethanol (8 mL) was heated at reflux temperature for 2.5 hour. After cooling to room temperature, the crystals which collected by filtration and washed with ethanol to give the subtitle compound (0.378 g).
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[F:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: C[C@@H](CCl)COc1cccc(F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{[(2R)-3-chloro-2-methylpropyl]oxy}-3-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([SH:20])[CH2:17][CH2:18][CH3:19].O>CC(N(C)C)=O>[CH2:16]([S:20][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCS
Reactant: N#Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCSc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a well-stirred suspension of 41.27 g (0.3 mol) of 4-chlorobenzonitrile, 58.05 g (0.42 mol) of potassium carbonate and 200 ml DMA a solution of 27.06 g (0.3 mol) of 1-butanethiol in 50 ml of DMA are added under an atmosphere of nitrogen. The resulting mixture is heated to 80° C. and stirred at this temperature for 24 hours. Then, the reaction mixture is cooled to room temperature and poured into 750 ml of water. The crude product is extracted with 300 ml of ethyl acetate, washed with water, dried over MgSO4. Thereafter, ethyl acetate is removed. Then, fractional distillation yields 52.88 9 (80.4%) of colorless liquid 4-n-butylthio-benzonitrile.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[CH3:12])=[CH:3][CH:2]=1.C([O:16][C:17]([C:19]1[CH:42]=[CH:41][C:22]2[N:23]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:24]([C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([CH:33]=O)[CH:27]=3)=[N:25][C:21]=2[CH:20]=1)=[O:18])C.[OH-].[K+].Cl>C(O)C>[N:32]1[C:29]2[C:28](=[CH:27][C:26]([C:24]3[N:23]([CH:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]4)[C:22]4[CH:41]=[CH:42][C:19]([C:17]([OH:18])=[O:16])=[CH:20][C:21]=4[N:25]=3)=[CH:31][CH:30]=2)[CH:33]=[CH:12][C:11]=1[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: CC(=O)c1ccnc2ccccc12
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C=O)c1)n2C1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccnc5ccccc45)ccc3c1)n2C1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
(1-Quinolin-4-yl-ethanone (43 mg, 0.25 mmol) and 2-(4-amino-3-formyl-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (98 mg, 0.25 mmol) were dissolved in 500 μL ethanol and 500 μL 10% ethanolic KOH were then added. The reaction was stirred at 75° C. overnight. The reaction was acidified with 4N hydrochloric acid, extracted three times with ethyl acetate, and the organic extracts were dried with sodium sulfate and then evaporated. Purification via reverse-phase HPLC gave 24 mg product.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=3)[N:3]=[CH:4]2)[CH:12]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(I)c3)n2)cc1
Product: Nc1ncc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.23) (0.525 g, 1.09 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.287 g, 1.3 mmol) according to the general procedure VI. Obtained as a yellow solid (0.100 g, 24%). MS (ISP) 451.1 [(M)+]; mp>250° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:15][CH:16]([CH3:22])[CH2:17][CH2:18][C:19](O)=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl>CCOCC>[CH2:7]([O:15][C@@H:16]([CH3:22])[CH2:17][CH2:18][CH2:19][OH:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCOC(C)CCC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCCCCCO[C@@H](C)CCCO
Temperature: 23 °C
Reaction time: 12 h

Procedure:
Into 210 ml of dry ether, 10 g of LiAlH4 was added, and under stirring, a solution of the above carboxylic acid in 70 ml of ether was added dropwise in 70 min. while keeping a temperature of 2°-6° C. after the addition, the mixture was raised in temperature to 23° C. and stirred for 3 hours. After standing for 12 hours, 5% hydrochloric acid was added to acidify the mixture while keeping a temperature of below 15° C., and the product was extracted with ether and washed successively with water, 5% NaOH aqueous solution and water, followed by drying with anhydrous MgSO4. By distilling off the solvent and effecting vacuum distillation, 10 g of (S)-4-octyloxypentanol was obtained as a fraction at 150° C./5 mmHg. The product showed the following IR data.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[CH2:17]([O:19][C:20]1[CH:21]=[CH:22][C:23]([F:38])=[C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([C:34](OC)=[O:35])[CH:27]=2)[CH:25]=1)[CH3:18].CCO>C1COCC1>[CH2:17]([O:19][C:20]1[CH:21]=[CH:22][C:23]([F:38])=[C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([CH:34]=[O:35])[CH:27]=2)[CH:25]=1)[CH3:18]
Reactant: CCOc1ccc(F)c(-c2cc(OC)nc(C(=O)OC)c2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1ccc(F)c(-c2cc(C=O)nc(OC)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1M DIBAL in toluene (7.53 mL, 7.53 mmol) was added dropwise over 10 mins to a stirred solution of methyl 4-(5-ethoxy-2-fluoro-phenyl)-6-methoxy-pyridine-2-carboxylate (which may be prepared as described in Description 131) (1.15 g, 3.77 mmol) in dry THF (20 mL) at −75° C. The reaction was stirred at this temp for 2 h then EtOH (175 μL) was added to quench. After 1 min the reaction mixture was poured into saturated Rochelle salt solution (100 ml) and water (50 ml). The mixture was warmed to ambient temperature then extracted with EtOAc (3×50 ml). Filtration under suction through celite was necessary to clear the emulsion. The combined organic extracts were dried (MgSO4) and evaporated to 4-(5-ethoxy-2-fluoro-phenyl)-6-methoxy-pyridine-2-carbaldehyde (D132) a slightly coloured oil (970 mg);