Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].N#N>CCOCC.N1C=CC=CC=1>[N+:9]([C:4]1[CH:3]=[C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[CH3:8])([O-:11])=[O:10]
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 63.1 %

Procedure:
4-Bromo-2-nitrotoluene (25.0 g, 116 mmol), 4-fluorophenol (8.70 g, 77.6 mmol), potassium carbonate (21.5 g, 156 mmol) and pyridine (75 mL), were combined under N2 atmosphere and heated at 90° C. for 30 min. The reaction mixture was cooled to ambient temperature, CuO (15.4 g, 194 mmol) was added under a stream of N2, and the resulting dark-brown suspension was heated at reflux for 17 hours. The reaction mixture was cooled to ambient temperature and diluted with ether. The solids were removed by filtration through celite. The ethereal solution was washed with 1.0M aqueous NaOH, 1.0M aqueous HCl and brine, dried over Na2SO4, filtered and concentrated in vacuo to give a dark-brown oil. The crude product was purified by chromatography on silica gel to give 2-nitro-4-(4-fluorophenoxy)-toluene (12.1 g, 63%).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22])([O-])=O>C(O)C.O>[NH2:9][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[OH:22]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(C(F)(F)F)ccc1O
Temperature: 55 °C
Yield: 39.9 %

Procedure:
Sodium dithionite (97.0 g, 0.5 mole) was added in portions over a period of 6 hours to a solution of 2-nitro-4-trifluoromethylphenol (31 g, 0.15 mole) in a mixture of ethanol (120 ml) and water (90 ml), the solution being heated, with stirring, at a temperature of 55° C. during the addition. The mixture was filtered, the filtrate retained, and the collected solid was triturated with ethanol and refiltered. The solvent was removed from the combined filtrates by distillation under reduced pressure to give a yellow solid. The solid was dissolved in water, the aqueous solution extracted with diethyl ether (4×100 ml) and the combined ethereal phases were washed with brine. The ethereal phase was dried over anhydrous magnesium sulfate and the solvent evaporated to give a yellow solid which was recrystallised from petroleum ether (700 ml, bp 100°-120° C.) to give the title compound as a pale yellow solid (10.6 g).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1>[CH2:1]([N:6]1[C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2=[N:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]2[C:28]1=[O:29])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCCNc1nc[nH]c1-c1nc(-c2ccccc2)n[nH]1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2nc(-c3ccccc3)nc2c2[nH]cnc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
N-pentyl-5-(3-phenyl-1H-1,2,4-triazol-5-yl)-1H-imidazol-4-amine (50 mg, 0.17 mmol) and N,N-carbonyldiimidazole (50 mg, 0.3 mmol) were dissolved in THF (10 mL) and stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative LCMS (method B) to yield the desired product (25 mg, 45% yield). LCMS calculated for C17H19N6O(M+H): 323.2. found 323.1.
Reaction SMILES: [C:1]([C:9]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(O)(=O)C(O)=O>CCOCC>[CH3:11][N:12]1[C:16]([C:1]([C:9]#[N:10])([OH:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)Cc1cccn1C
Reactant: N#CC(=O)c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Product: COC(=O)Cc1ccc(C(O)(C#N)c2ccccc2)n1C
Reaction time: 144 h
Yield: 12 %

Procedure:
Benzoyl cyanide, 0.67 g (0.005 mole) and methyl 1-methylpyrrole-2-acetate, 0.76 g (0.005 mole) were stirred together in ether (2 ml) containing oxalic acid (0.04 g). The reaction was run in the dark at room temperature. After six days, the reaction mixture was placed in the freezer overnight, filtered, and washed with cold ether to yield 0.17 g (12 percent) of methyl 1-methyl-5-(cyanohydroxyphenylmethyl)pyrrole-2-acetate, mp 137°-8°. The solid state IR spectrum was identical to authentic material.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C@@H:20]([OH:21])[C:19](=[O:22])[N:18]([CH2:23][CH2:24][N:25]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:26])[C:17]3[CH:34]=[CH:35][C:36]([CH3:38])=[CH:37][C:16]=3[S:15]2)=[CH:10][CH:9]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>N1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C@@H:20]([O:21][C:39](=[O:41])[CH3:40])[C:19](=[O:22])[N:18]([CH2:23][CH2:24][N:25]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:26])[C:17]3[CH:34]=[CH:35][C:36]([CH3:38])=[CH:37][C:16]=3[S:15]2)=[CH:10][CH:9]=1
Reactant: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 100 °C

Procedure:
10.7 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one perchlorate is converted to its free base, and 80 ml of acetic anhydride and one ml of pyridine are added thereto. The mixture is heated at 100° C. for 4 hours. The mixture is evaporated under reduced pressure to remove acetic anhydride and pyridine. Benzene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. 10.37 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-methyl- 2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: C(OC1C=C(C=CC=1OC)C=O)C1C=CC=CC=1.[Cl:19][C:20]1[C:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:26]([O:36]C)[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>>[Cl:19][C:20]1[C:27]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[C:26]([OH:36])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]
Reactant: COc1ccc(C=O)c(Cl)c1OCc1ccccc1
Agent: COc1ccc(C=O)cc1OCc1ccccc1
Product: O=Cc1ccc(O)c(OCc2ccccc2)c1Cl

Procedure:
Proceeding as in example 62, but replacing for 3-benzyloxy-4-methoxybenzaldehyde an equivalent quantity of 2-chloro-3-benzyloxy-4-methoxybenzaldehyde (obtained as described in example 84) and purifying the reaction raw product by chromatography on a silica gel column, eluting with methylene chloride/petroleum ether (b.p. 30°-70° C.)=1/1, 2-chloro-3-benzyloxy-4-hydroxybenzaldehyde was obtained, m.p. 149°-150° C. (from methylene chloride/petrolum ether, b.p. 30°-70° C.=1/2).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[N:10][C:4]=2[CH:3]=1.C([O:19][C:20]1[C:23](=[O:24])[C:22](=O)[C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:27]1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]([C:22]3[C:23](=[O:24])[C:20](=[O:19])[C:21]=3[N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:28]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:27]3)[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1CN(c2c(OCC)c(=O)c2=O)CCN1c1ccccc1
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1O2
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1CN(c2c(N3Cc4ccccc4Oc4ccc(Cl)cc43)c(=O)c2=O)CCN1c1ccccc1
Yield: 43.8 %

Procedure:
A mixture of 8-chloro-dibenz[b,f][1,4]oxazepine (1.02 g) and the product of Example 3 (0.26 g) and diphenyl ether (3 mL) was heated to reflux for 1.75 hours. The mixture was rapidly filtered thourough a small column of silica gel and the filtrate was concentrated. The residue was purified by chromatography on silica gel to obtain the title compound (0.173 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][CH:3]=1.[CH3:11][CH:12]([C:18]([CH3:20])=O)[C:13](OCC)=[O:14]>C(O)C>[CH3:11][C:12]1[C:13](=[O:14])[NH:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:8][C:18]=1[CH3:20]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Cc1ccc(C(=N)N)cc1
Solvent: CCO
Product: Cc1ccc(-c2nc(C)c(C)c(=O)[nH]2)cc1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
To a solution of 4-methylbenzamidine (4.4 g) in 30 ml of ethanol was added ethyl 2-methylacetoacetate (6.1 g), and the mixture refluxed for 4 hours, giving a precipitate. The mixture was cooled to 0° C., the solid filtered off, washed with ethanol, and dried under reduced pressure, yielding 6 g of 5,6-dimethyl-2-(4-methylphenyl)-3H-pyrimidin-4-one, m.p. 250° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.C(N(C(C)C)CC)(C)C.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:39])[N:31]([CH3:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:10][C:2]([CH3:1])([CH2:3][C:4](=[O:5])[NH:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30](=[O:39])[N:31]([CH3:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:27][CH:28]=1)[CH2:8][C:7]([OH:6])=[O:9]
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Reactant: CC1(C)CC(=O)OC(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(CCNC(=O)CC(C)(C)CC(=O)O)cc1)c1ccccc1
Yield: 95 %

Procedure:
A solution of 3,3-dimethylglutaric anhydride (0.3 mmol), diisopropylethylamine (0.30 mmol) and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol) in CH2Cl2 (3 mL) was stirred 1 h at rt. The mixture was washed with water and brine, dried and evaporated to give the title compound in 95% yield as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:5](O)=[O:6].[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:5](=[O:6])[CH:4]=[C:3]([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)C=C(C(F)(F)F)C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C=C(C(F)(F)F)C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 4,4,4-trifluoro-3-trifluoromethylbut-2-enoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (45.4% yield). 1H NMR (CDCl3) δ 8.07, 7.97, 7.10, 7.01, 3.87-3.74, 3.58-3.50, 1.54-1.47, 0.78-0.68, 0.48-0.42, 0.10-0.05.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[NH:20][C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:17][CH2:18][CH:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:20]2)=[O:15])[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN1CCN(C(=O)C2CC=C(c3cccnc3)N2)CC1
Solvent: O
Product: CCCCCCCN1CCN(C(=O)C2CCC(c3cccnc3)N2)CC1
Yield: 43.6 %

Procedure:
1-Heptyl-4-[2-(3-pyridyl)-2-pyrrolin-5-ylcarbonyl]piperazine (570 mg) was catalytically reduced in 20 ml of water plus 20 ml of ethanol in the presence of platinum oxide as the catalyst until cessation of the absorption of hydrogen. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (5 g). Elution with methanol ethyl acetate (1:10, v/v) gave 250 mg of 1-heptyl-4-[5-(3-pyridyl)pyrrolidin-2-ylcarbonyl]piperazine. This product was converted to its trihydrochloride (180 mg) in the same manner as in Example 54. Melting point 138°-143° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Cl.Cl.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].C(OC1C=CC(/C=C2/C(=O)N(CCC)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: ClCc1ccccn1
Agent: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccccn3)C2=O)cc1

Procedure:
The title compound 28j was prepared from compound 2 (75 mg, 0.30 mmol), 2-picolyl chloride.HCl (54 mg, 0.33 mmol), sodium iodide (45 mg, 0.30 mmol) and potassium carbonate (104 mg, 0.75 mmol) in a manner similar to that described for 28d in 97.5% (99 mg) yield as a white solid.
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[C:10]1([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C(OCC)C>[CH2:20]([O:19][C:17]([O:18][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:21]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCOC(=Cc1ccccc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
Methyllithium in diethyl ether (0.25 mol, 140 ml of 1.8 M solution) was added dropwise to a solution of 27.6 g (0.27 mol) of diisopropylamine in 40 ml of diethyl ether. The reaction mixture was cooled to -78° C. and 26.3 g (0.16 mol) of ethyl phenylacetate were added dropwise. The reaction mixture was warmed to 0° C. and 46 ml (0.36 mol) of chlorotrimethylsilane were added rapidly. The reaction mixture was stirred overnight at 25° C., filtered to remove LiCl, and then distilled under reduced pressure to give 24.91 g (66% yield) of β-ethoxy-β-trimethylsiloxystyrene as a colorless liquid: bp 92° C. (0.7 mm); 1H NMR (CFCl3) δ 0.0 ppm (s, 9H), 0.94 ppm (t,J=7 Hz, 3H), 3.44 and 3.63 ppm (qs, J=7 Hz, 25:75, 2H), 4.17 and 4.36 ppm (ss, 25:75, 1H) and 6.57-7.20 ppm (m, 5H). Anal. Calcd. for C13H20O2Si: C, 66.05; H, 8.53; Found: C, 66.26; H, 8.88.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[CH3:47][N:48]([CH3:53])[CH2:49][C:50](O)=[O:51]>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH:19][C:50](=[O:51])[CH2:49][N:48]([CH3:53])[CH3:47])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.9 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (30 mg, 0.0734 mmol) obtained in Example 63 were added triethylamine (12 μl, 0.0881 mmol), 4-dimethylaminopyridine (5 mg, 0.0367 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17 mg, 0.0881 mmol) and N,N-dimethylglycine (9 mg, 0.0881 mmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and then, concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=1:4 eluate was concentrated under reduced pressure to give the title compound (21 mg, 0.0425 mmol, 58%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+].O>CO.C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc(C2CCCCN2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCCC2c2ccccc2)CC1
Reaction time: 20 h
Yield: 3 %

Procedure:
N-tert-Butyloxycarbonyl-4-piperidone (5 g), 2-phenylpiperidine (4.03 g) and titanium isopropoxide (8.9 ml) were stirred at room temperature under a nitrogen atmosphere for 3 h. The resulting orange solution was diluted with methanol (40 ml), treated with sodium cyanoborohydride (1.6 g), and stirred for 20 h. Water (50 ml) was added to give a granular precipitate which was removed by filtration through celite. The filtrate was partitioned between water-ethyl acetate, the organic phase separated, dried (MgSO4) and concentrated. The residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of citric acid. The aqueous phase was basified to pH10 using 4N sodium hydroxide, and extracted into ethyl acetate. The organic phase was dried (MgSO4) and concentrated. The residue was chromatographed using ethyl acetate-petroleum ether (20:80 to 50:50) to afford a partially purified mixture, which was dissolved in ethyl acetate. The organic phase was washed with a saturated aqueous solution of citric acid. The aqueous phase was separated, basified to pH10 using 4N sodium hydroxide and extracted with ethyl acetate. The organic phase was dried (MgSO4) and concentrated to give the product in 3% yield. δH (250 MHz, CDCl3) 1.16-1.79 (19H, m), 2.21-2.29 (2H, m), 2.41-2.50 (2H, m), 2.90-3.04 (1H, m), 3.36-3.44 (1H, m), 3.92-4.10 (2H, m), 7.16-7.40 (5H, m).
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16](CC3C=CC=CC=3)[C@@:10]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:11][C@H:12]2[CH2:24][OH:25])C1C=CC=CC=1.C1CC=CCC=1>C(O)C.[Pd]>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[NH:16][C@@:10]1([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:11][C@H:12]2[CH2:24][OH:25]
Reactant: OC[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: N[C@@H]1CC[C@@H]2N[C@@]1(c1ccccc1)C[C@H]2CO
Yield: 75.5 %

Procedure:
(1R*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-6-hydroxymethyl-1-phenyl-8-azabicyclo[3.2.1]octane (Description 19; 220 mg, 0.53 mmol) was dissolved in ethanol (5 mL) and treated with 10% palladium on activated charcoal (100 mg), followed by 1,4-cyclohexadiene (1.5 mL). The suspension formed was heated at reflux for 24 hours, then cooled and filtered. The filtrate was concentrated in vacuo, and the oil remaining purified by silica chromatography to yield the title compound as a gum (92 mg, 0.4 mmol).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([CH:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:13]=2[CH:21]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)c1nc2ccc(F)cc2n1-c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A mixture of [1-(6-fluoro-1-pyridin-4-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (210 mg, 0.59 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound (120 mg, 79%) as a yellow solid. LCMS (Method C): RT 1.63 min [M+H]+ 257.15.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[CH2:14]([Mg]Cl)[CH3:15].CCOCC.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:14][CH3:15])=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60 %

Procedure:
To a solution of 6-chloro-N-methoxy-N-methyl nicotinamide (6.0 g, 30 mmol) (produced as disclosed in Perner, R. J. J. Med. Chem. 2003, 46, 5249) in THF (100 mL) was added a 3M solution of ethyl magnesium chloride in ether (15 mL, 45 mmol). The reaction mixture was heated under reflux for 4 hours and then stirred at approximately 25° C. for 14 hours. The reaction mixture was treated with a saturated aqueous solution of ammonium chloride (100 mL) and then extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography over silica gel, eluting with 10 percent ethyl acetate in hexane to give product as a white solid. (2.8 g, 60 percent yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[Cl:12].[NH:13]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1>>[Cl:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:6]=[CH:7][C:2]=1[N:13]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1
Reactant: CCOC(=O)CCC1CCNC1
Reactant: FC(F)(F)c1cccc(Br)c1Cl
Product: CCOC(=O)CCC1CCN(c2cccc(C(F)(F)F)c2Cl)C1
Yield: 13 %

Procedure:
The title compound (895 mg, yield 13%) was obtained from 1-bromo-2-chloro-3-(trifluoromethyl)benzene and ethyl 3-(pyrrolidin-3-yl)propanoate obtained in Reference Example 12 by a method similar to that in Reference Example 1.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1.C(C1C=C(B(O)O)C=CC=1)=O.BrC1C=CC=CN=1>>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[N:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Brc1ccccn1
Agent: O=Cc1cccc(B(O)O)c1
Product: O=Cc1ccc(-c2ccc([N+](=O)[O-])cn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 11 by substituting 4-formylphenylboronic acid and 2-bromo-5-nitropyridine for the 3-formylphenylboronic acid and 2-bromopyridine, respectively, of Reference Example 11. MS 229 (M+H)+.