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: Oc1ccc(F)cc1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
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 (25.0g, 116 mmol), 4-fluorophenol (8.70g, 77.6 mmol), potassium carbonate (21.5g, 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 (15.4g, 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: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18].C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O>[CH3:18][C:17]1[O:16][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14][C:13]=1[CH2:12][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:3]([CH:2]=[O:1])[C:4]=2[CH:5]=[CH:6]1
Reactant: Cc1oc(-c2ccccc2)nc1Cn1ccc2c(CO)cccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1oc(-c2ccccc2)nc1Cn1ccc2c(C=O)cccc21
Reaction time: 0.5 h

Procedure:
There were dissolved, in 14 ml of dimethylsulfoxide, 700 mg of 4-hydroxymethyl-1-[(5-methyl-2-phenyloxazol-4-yl)methyl]indole prepared in Example 29 and 890 mg of triethylamine, followed by addition of 700 mg of sulfur trioxide-pyridine complex to the solution and stirring for 30 minutes. The reaction solution was added to 100 ml of a 10% ammonium chloride aqueous solution, followed by extraction with ethyl acetate (50 ml×3). The resulting organic phase was washed, in turn, with water (50 ml×2) and 50 ml of a saturated common salt solution and dried over anhydrous sodium sulfate. After removal of the solvent through distillation under reduced pressure, the resulting residue was crystallized in 50 ml of ether to thus give 640 mg of 1-[(5-methyl-2-phenyloxazol-4-yl)methyl]indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 84%.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:11](=[O:12])[CH2:10][NH:9][C:8](=[O:13])[C:5]21[CH2:7][CH2:6]2.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH3:3][N:4]1[C:11](=[O:12])[CH2:10][N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](=[O:13])[C:5]21[CH2:7][CH2:6]2
Reactant: CN1C(=O)CNC(=O)C12CC2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CN(Cc2ccccc2)C(=O)C12CC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.8 %

Procedure:
Sodium hydride (302 mg, 12.62 mmol) was taken up in DMF (10 mL) and cooled to 0° C. for 30 min. Then a mixture 4-methyl-4,7-diazaspiro[2.5]octane-5,8-dione (1.769 g, 11.47 mmol) in DMF (5 mL) was slowly added over 10 min. This mixture was allowed to stir for 45 min, and then benzyl bromide (4.08 mL, 34.41 mmol) was added, and the reaction was stirred for 45 min further. The mixture was carefully diluted with water (10 mL) and concentrated in vacuo. The resulting crude product was purified via reverse phase HPLC to provide 4-methyl-7-(phenylmethyl)-4,7-diazaspiro[2.5]octane-5,8-dione (1.535 g, 54%). LCMS: (M+H)+: 245.1.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:13]([OH:15])=O)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH3:16][C:17]1[S:18][C:19]([S:22][CH2:23][C:24]2[CH2:31][S:30][CH:29]3[N:26]([C:27](=[O:33])[CH:28]3[NH2:32])[C:25]=2[C:34]([OH:36])=[O:35])=[N:20][N:21]=1>>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:10]([OH:12])=[O:11])[C:13]([NH:32][CH:28]2[C:27](=[O:33])[N:26]3[CH:29]2[S:30][CH2:31][C:24]([CH2:23][S:22][C:19]2[S:18][C:17]([CH3:16])=[N:21][N:20]=2)=[C:25]3[C:34]([OH:36])=[O:35])=[O:15])=[CH:7][CH:8]=1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)s1
Reactant: O=C(O)C(C(=O)O)c1ccc(CCl)cc1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(C(=O)O)c4ccc(CCl)cc4)C3SC2)s1

Procedure:
When in the above procedure appropriate amounts of an acid derivative and acephalosporin derivative listed in the following Table X are substituted respectively for p-chloromethylphenylmalonic acid and 3-[(2-methyl-1,3,4-thiadiazol-5-ylthio)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in the above procedure, the respective products listed in the following Table X are obtained.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]Br)[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:12]
Reactant: CCCNc1ccccc1
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)CN(CCC)c1ccccc1
Temperature: 125 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A mixture of N-propylaniline (24 parts), 2-ethylhexyl bromide (58 parts), anhydrous potassium carbonate (42 parts) and dry N,N-dimethylformamide (50 parts) was stirred at 125° C. for 16 hours. The cooled reaction mixture was poured into water (250 parts), the organic phase separated and washed with water (2×200 parts) and dried at 90° C. and 15 mmHg to yield N-(2-ethylhexyl)-N-propylaniline (49 parts, 89%). Acetic anhydride was added to this to make a total of 69.5 parts.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])[CH3:20]>>[CH:19]([N:22]1[CH2:27][CH2:26][N:25]([CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:24][CH2:23]1)([CH3:21])[CH3:20]
Reactant: CC(C)N1CCNCC1
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(N3CCN(C(C)C)CC3)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (INTERMEDIATE 18) and 1-isopropylpiperazine. m/z 363.
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[C:21]#[N:22])C=[CH:13]1>ClCCl>[CH:6]([C:7]1[C:15]2[C:20](=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][CH:16]=2)[NH:12][CH:13]=1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cccc2c(C=O)c[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
DMF (0.539 mL) in dry dichloromethane (30 mL) was added dropwise to a solution of oxalyl chloride (0.610 mL) in dry dichloromethane (30 mL) at 0° C. The resulting solution was stirred at 0° C. for 15 min. A solution of 1H-indole-7-carbonitrile (D2) (0.90 g) in dry dichloromethane (5 mL) was added to the reaction mixture. The reaction mixture was warmed to RT and stirred for 30 min. The solvent was evaporated. THF (20 mL) was added, followed by addition of aqueous NaOH (0.5 M, 50 mL). The biphasic mixture was allowed to stand for 10 min. EtOAc (100 mL) and water (70 mL) was added. The organic fraction was separated and was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 3-formyl-1H-indole-7-carbonitrile (D3) as a light cream solid (0.75 g, 70%). δH (DMSO-d6, 400 MHz): 7.42 (1H, t), 7.79 (1H, dd), 8.43 (1H, dd), 8.48 (1H, s), 10.00 (1H, s), 13.02 (1H, br s). MS (ES): C10H6N2O requires 170; found 171.2 (M+H+).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1C[O:12][C:13]1[CH:14]=[C:15]([CH:28]=[C:29]([N+:31]([O-])=O)[CH:30]=1)[C:16]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17].CCO>[Pd].CN(C=O)C>[OH:12][C:13]1[CH:14]=[C:15]([CH:28]=[C:29]([NH2:31])[CH:30]=1)[C:16]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17]
Reactant: O=C(NNC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1)c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1cc(O)cc(C(=O)NNC(=O)c2ccccc2)c1
Reaction time: 1.5 h

Procedure:
A mixture of 1-{3-[(2-naphthyl)methoxy]-5-nitrobenzoyl}-2-benzoylhydrazine (0.34 g, 0.77 mmol), Pd/C (10%, 0.35 g), EtOH (10 mL), and DMF (10 mL) was hydrogenated in Parr apparatus (H2 pressure—30 psi) at room temperature for 1.5 h. Catalyst was filtered off, and filtrate concentrated in vacuo to give a slurry of white needles, which were filtered and washed with EtOH (3×25 mL). Yield 0.20 g (96%). 1H NMR (DMSO-d6, 400 MHz), δ: 10.37 (s, 1H); 10.12 (s, 1H); 9.20 (s, 1H); 7.91 (d, J=7.0 Hz, 2H); 7.62-7.48 (m, 3H); 6.54 (s, 1H); 5.46 (s, 1H); 6.19 (s, 1H); 5.18 (br.s, 2H).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].C([Mg]Br)C.[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1>C1COCC1>[OH:21][C:18]1([C:3]#[C:2][CH2:1][O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: O=C1CCOCC1
Reactant: C#CCOC1CCCCO1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: OC1(C#CCOC2CCCCO2)CCOCC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
Tetrahydro-2-(2-propynyloxy)-2H-pyran (21 g, 150 mmol) was converted to the corresponding magnesium anion by deprotonation with ethyl magnesium bromide (75 mL of a 2M solution, 150 mmol) according to the method described in Org. Synth., 60: 81, 7 (1981). The resulting anion was cooled to -20° C. and tetrahydro-4H-pyran-4-one (14.8 g, 148 mmol) in dry THF (30 mL) was added dropwise and the resulting solution stirred for three hours. The reaction was quenched by addition of crushed ice and saturated aqueous NH4Cl. The resulting two-layered mixture was extracted with ether (3×150 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (200 g, 20% ethyl acetate: hexanes) provided 4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)prop-1-ynyl]tetrahydropyran(31.4 g, 88%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[N:17]=1>ClCCl.CN(C)C=O>[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)=[O:9])[N:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ccc(SCc2csc(N)n2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ccc(S(=O)Cc2csc(N)n2)cc1
Yield: 86.3 %

Procedure:
A solution of 3-chloroperbenzoic acid (4.9 g) in dichloromethane (100 ml) was dropwise added to a solution of 2-amino-4-(4-aminophenylthiomethyl)thiazole (5.1 g) in a mixture of dichloromethane (200 ml) and N,N-dimethylformamide (10 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 1.5 hours with stirring. The precipitates were collected by filtration, washed with ethyl acetate and dried in vacuo to give solid. The solid was recrystallized from ethanol to give 2-amino-4- (4-aminophenylsulfinylmethyl)thiazole (4.70 g, yield: 86.3%).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C([O-])=O.[CH:34]1([NH:37][C:38]([CH:40]2[O:45][CH2:44][CH2:43][NH2+:42][CH2:41]2)=[O:39])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:42]3[CH2:43][CH2:44][O:45][C@@H:40]([C:38]([NH:37][CH:34]4[CH2:35][CH2:36]4)=[O:39])[CH2:41]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(NC1CC1)C1C[NH2+]CCO1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCO[C@@H](C(=O)NC4CC4)C3)ccc2n1CC1CCC(F)(F)CC1
Reaction time: 1 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (1.1 g, 2.7 mmol) was added to a solution of 2-[(cyclopropylamino)carbonyl]morpholin-4-ium trifluoroacetate (0.92 g, 3.2 mmol) (see the following step B for preparation) and DIPEA (1.5 mL, 8.1 mmol) in DCE at 80° C. The reaction mixture was stirred for 1 h and washed with saturated NaHCO3 solution, water and brine. The solvent was concentrated to provide the racemic title compound as white solid. The enantiomers were separated by chiral preparative HPLC to provide the title compounds.
Reaction SMILES: [C:1](/[C:3](=[C:12](/OCC)\[CH3:13])/[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:19]=1[NH2:20]>C(O)C>[C:1](/[C:3](=[C:12](/[NH:20][C:19]1[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:18]=1[CH3:17])\[CH3:13])/[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: Cc1cccc(C)c1N
Reactant: CCOC(=O)NC(=O)/C(C#N)=C(/C)OCC
Solvent: CCO
Product: CCOC(=O)NC(=O)/C(C#N)=C(/C)Nc1c(C)cccc1C

Procedure:
α-Cyano-β-ethoxy-N-ethoxycarbonylcrotonamide (0.05 mol) is reacted with 2,6-dimethylaniline (0.05 mol) in hot ethanol using the procedure of Example 1 to yield α-cyano-β-(2,6-dimethylanilino)-N-ethoxycarbonylcrotonamide, which is cyclized by heating in tetralin to yield 5-cyano-1-(2,6-dimethylphenyl)-6-methyl-uracil, m.p. 302°-303°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.F[B-](F)(F)F.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1([C:48]([O:50][CH3:51])=[O:49])[CH2:47][CH2:46]1)#[CH:38].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:51][O:50][C:48]([C:45]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:37]#[C:38][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:3]=2)[CH2:47][CH2:46]1)=[O:49]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccccc1C1(C(=O)OC)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CC1
Temperature: 120 °C
Yield: 86.5 %

Procedure:
A solution of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K3) (262 mg, 0.574 mmol), PdCl2(PPh3)2 (20 mg, 0.029 mmol,) t-Bu3PH.BF4 (8 mg, 0.03 mmol), CuI (5 mg, 0.03 mmol) and methyl 1-(2-ethynylphenyl)cyclopropanecarboxylate (K2) (138 mg, 0.689 mmol) in DMF (5.0 mL) was degassed with nitrogen for 10 minutes. Et3N (1.0 mL) was added and the resulting mixture heated under microwave irradiation for 20 minutes at 120° C. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound A3 as a yellow solid (308 mg, 86%); 1H NMR (400 MHz, d6-DMSO) δ 10.37 (s, 1H), 8.79 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.60 (dd, J=7.6, 1.0 Hz, 1H), 7.54-7.38 (m, 3H), 7.21 (d, J=8.6 Hz, 2H), 4.07 (d, J=11.6 Hz, 2H), 3.52 (s, 3H), 2.80 (s, 2H), 2.65 (J m, 1H), 1.74 (d, J=12.4 Hz, 2H), 1.64 (q, J=4.0 Hz, 2H), 1.49 (td, J=12.6, 4.1 Hz, 2H), 1.42 (s, 9H), 1.29 (q, J=4.2 Hz, 2H). LCMS-A: rt 7.083 min; m/z 619 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)[CH2:30][CH2:29]1
Reactant: Cc1cc(/C(C[C@H](c2ccc(Br)cc2)c2ccccc2C)=N/O)ccn1
Reactant: OC1CCNCC1
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCC(O)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 39, from (E,R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one oxime (example 142, step 1) and 4-hydroxypiperidine was prepared the title compound as a yellow foam, MS (ESI+): m/z=430.2 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.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>[N:13]1[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:4]2[CH:3]=[C:2]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH:7]=[CH:6][CH:5]=2)=[CH:11][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Brc1cccc(C#Cc2ccncc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C(#Cc1cccc(-c2cnccn2)c1)c1ccncc1
Yield: 39.6 %

Procedure:
To a solution of 4-[(3-bromophenyl)ethynyl]pyridine (387 mg, 1.50 mmol) in toluene (10 mL) is added tetrakis(triphenylphosphine)palladium (87 mg, 0.075 mmol) and 2-(tributylstannyl)pyrazine (1.45 g, 3.75 mmol) at room temperature. After refluxing for 24 h, the reaction mixture is cooled and diluted with EtOAc (100 mL), washed with saturated NaHCO3 (2×30 mL), brine (30 mL), dried over MgSO4 and concentrated on a rotary evaporator. The crude material is purified by chromatography (silica gel, EtOAc/hexane: 40/60 to give the title compound (153 mg, 40%) as solid. mp: 94-95° C. MS(+) ES: 258 (M+OH)+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([OH:31])[CH2:26]2)[C:21]([C:32]#[N:33])=[CH:20][N:19]=1>CS(C)=O>[CH:1]1([NH:7][C:18]2[N:23]=[C:22]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([OH:31])[CH2:26]3)[C:21]([C:32]#[N:33])=[CH:20][N:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: N#Cc1cnc(Cl)nc1N[C@@H]1CCC[C@H](O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1cnc(NC2CCCCC2)nc1N[C@@H]1CCC[C@H](O)C1
Temperature: 70 °C
Yield: 88 %

Procedure:
A solution of cyclohexanamine (0.181 mL, 1.583 mmol) in DMSO (5 mL), 2-chloro-4-((1R,3S)-3-hydroxycyclohexylamino)-pyrimidine-5-carbonitrile (0.200 g, 0.791 mmol; synthesis described herein) and DIEA (0.276 ml. 1.583 mmol) was heated at 70° C. overnight. After completion of reaction as indicated by LCMS and TLC the reaction mixture was allowed to cool to room temperature and concentrated. The resulting crude was purified by silica gel chromatography using a gradient of 0%-70% ethyl acetate (containing 10% ammonia saturated methanol) in hexanes. The desired product fractions were combined and concentrated to yield 2-(cyclohexylamino)-4-((1R,3S)-3-hydroxycyclohexylamino)-pyrimidine-5-carbonitrile (0.220 g, 88% yield, 98.1% pure) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.08-8.21 (m, 1H), 7.08-7.56 (m, 2H), 4.74 (d, J=3.90 Hz, 1H), 3.93-4.13 (m, 1H), 3.44-3.77 (m, 2H), 1.83-2.02 (m, 2H), 1.65-1.82 (m, 6H), 1.58 (d, J=14.84 Hz, 1H), 1.32-1.45 (m, 2H), 1.08-1.30 (m, 7H); MS (ESI) m/z 316.4 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2].[OH-].[K+].[CH:23](Br)([CH3:25])[CH3:24].Cl>C(O)C.O>[C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[C:15]([O:17][CH:23]([CH3:25])[CH3:24])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: CC(C)Br
Reactant: O=C(O)c1ccc2c(c1)CCc1ccc(O)cc1C2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc2c(c1)C(=O)c1ccc(C(=O)O)cc1CC2

Procedure:
0.82 G. of 2-carboxy-7-hydroxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene was dissolved in 30 ml of ethanol and a solution of 1.0 g of potassium hydroxide in 5 ml of water was added, followed by 2.0 ml of isopropyl bromide. The reaction was refluxed for 3 hours, then diluted with water and acidified with dilute hydrochloric acid. The product was filtered off and recrystallized from aqueous dimethylformamide to give 2-carboxy-7-isopropoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene, m.p. 174°-177°. By substituting other alkylbromides or iodides such as ethyl bromide, m-propyl bromide, isobutyl bromide, n-amyl bromide, n-hexyl bromide and the like, the corresponding 2-carboxy-7-alkoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptenes are obtained. The 8- and 9- alkoxy compounds are similarly prepared.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:14][CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.N12CCN(CC1)CC2.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>ClCCl>[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([NH:1][CH2:2][CH2:3][C:4]2([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)=[O:20])[CH2:14][CH2:13]3)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCNS(=O)(=O)c4ccc(C)cc4)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.9 %

Procedure:
To a solution of N-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (synthesized in Example 18) (228 mg) in dichloromethane (3 mL) were added 1,4-diazabicyclo[2.2.2]octane (108 mg) and p-toluenesulfonyl chloride (120 mg) successively. The solution was stirred at room temperature for 6 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7:3 to 1:2)] to give the title compound (265 mg).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][CH:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-phenylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=447.