Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([C@H:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:36])[N:29]([CH3:35])[CH2:30][C:31]([F:34])([F:33])[F:32])[CH2:23]3)[N:16]=[N:15]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH3:35][N:29]([CH2:30][C:31]([F:34])([F:32])[F:33])[C:28]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:22]([N:17]2[C:18]3[C:14](=[CH:13][N:12]=[C:11]4[C:19]=3[CH:20]=[CH:21][NH:10]4)[N:15]=[N:16]2)[CH2:23]1)=[O:36]
Reactant: CN(CC(F)(F)F)C(=O)N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CC(F)(F)F)C(=O)N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Yield: 52.4 %

Procedure:
A solution of racemic trans 3-[3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-1-methyl-1-(2,2,2-trifluoro-ethyl)-urea (80.0 mg, 150 μmol) and sodium hydroxide solution (1.5 mL, 1N) in methanol (1 mL) and THF (1 mL) was stirred at ambient temperature for 30 minutes. Dilute HCl was added and the mixture purified by Isolute® SCX-2 column (gradient: methanol to 2M NH3 in methanol solution). The residue obtained was purified further by trituration with DCM/diethyl ether to afford 30 mg (51%) of racemic trans 1-methyl-3-[3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-1-(2,2,2-trifluoro-ethyl)-urea as a white solid. LCMS (Method A, ESI): RT=3.40 min, m+H=382.10; 1H NMR (400 MHz, DMSO) δ: 12.36 (s, 1H), 9.00 (s, 1H), 7.61 (t, 1H), 7.00 (dd, 1H), 6.67 (d, 1H), 5.66 (m, 1H), 4.41 (m, 1H), 4.09 (q, 2H), 2.97 (s, 3H), 2.50 (m, 2H), 2.27 (m, 3H), 1.79 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:9](Cl)(=[O:18])[C:10]1[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.Cl>O>[C:9]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:18])[C:10]1[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: NCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1C(=O)NCCC(=O)O
Reaction time: 6 h
Yield: 74.7 %

Procedure:
Ten grams of β-alanine and 9 g of sodium hydroxide were dissolved in 100 mL of purified water, and 17.4 g of o-anisoylchloride were added dropwise under freezing conditions. After stirring for six hours, hydrochloric acid was added and the pH was adjusted to 2 or less. After extraction with 500 mL of ethyl acetate, the product was desiccated over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized with aqueous ethanol, and 17.0 g of the desired product was obtained (yield of 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:20][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:22][CH3:23])=[O:18])[CH:8]=2)[N:3]=1.[H-].[Na+].[CH3:36]I.O>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:36])[C:17]([N:19]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:20][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:22][CH3:23])=[O:18])[CH:8]=2)[N:3]=1
Reactant: CCC(CN(C(=O)NCCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1)OC(C)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CN(C(=O)N(C)CCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-6-{3-[3-cyclohexyl-3-(2-acetyloxybutyl)ureido]propoxy}quinoline (5.6 g) in dimethylformamide (80 ml) is added sodium hydride (60% oily, 0.8 g), and the mixture is stirred at room temperature for one hour. To the reaction solution is added methyl iodide (1.1 ml), and the mixture is stirred for one hour. To the mixture is further added methyl iodide (2 ml), and the mixture is stirred at room temperature overnight. The reaction solution is poured into water, and extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water, and dried over anhydrous magnesium sulfate. The resultant is concentrated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol=20:1) to give 2-chloro-6-{3-[1-methyl-3-cyclohexyl-3-(2-acetyloxybutyl)ureido]propoxy}quinoline (5.5 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].ClCCl.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:19][S:20]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:22])=[O:21]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(OS(C)(=O)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a 0° C. solution of dimethyl 5-hydroxyisophthalate (2.0 g, 9.5 mmol) in 3:1 dichloromethane:pyridine (100 mL) was added methanesulfonyl chloride (3.6 g, 31.4 mmol). The reaction warmed to room temperature over 18 h. The reaction mixture was concentrated in vacuo. The crude material was diluted with DCM and washed with 1N HCl, H2O (2×), brine, dried with MgSO4, filtered, concentrated and purified by flash chromatography (40 g silica, 25-40% EtOAc/hexanes) to give 1.37 g (50%) of dimethyl 5-[(methylsulfonyl)oxy]isophthalate. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.12 (s, 2H), 3.97 (s, 6H), 3.23 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:37])=[C:5]([C:28]([O:35]C)=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:32][O:31][C:30]1[C:3](=[O:2])[C:4]([CH3:37])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[C:28](=[O:35])[C:29]=1[O:33][CH3:34]
Reactant: COc1c(C)c(Cc2ccc(Oc3ccncc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccncc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 63.2 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyloxy)benzoyl]morpholine (0.042 g, 0.0827 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (0.113 g, 0.207 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate:methanol=3:6:1) to obtain the titled compound (0.025 g, 0.0523 mmol, 63%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.Br[C:22]1[CH:23]=[C:24]([C:27]#[N:28])[O:25][CH:26]=1>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:20]=[C:2]([C:22]3[CH:23]=[C:24]([C:27]#[N:28])[O:25][CH:26]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(Br)co1
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3coc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 4-bromo-2-cyanofuran generally according to the procedures described in examples 82 and 1. A white solid: mp 99-100° C.; 1H NMR (DMSO-d6): δ 10.04 (s,1H), 8.60 (s, 1H), 8.17 (s, 1H), 7.54-7.61 (m, 3H), 7.22 (d, J=8.45 Hz, 1H), 6.99 (dd, J=4.99, 3.60 Hz, 1H), 6.90 (dd, J=3.48, 1.02 Hz, 1H), 4.40, (d, J=15.42, 1H), 3.94 (d, J=15.47 Hz, 1H), 2.5 (m, 2H), 0.76 (t, J=7.02 Hz, 3H); MS (ESI) m/z 365 ([M+H]+); MS (ESI) m/z 363 ([M−H]−); Anal. calcd for C20H16N2O3S: C: 65.92; H: 4.43; N: 7.69. Found: C: 64.84; H: 4.59; N: 6.98.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:15]2OCC[O:16]2)[CH:11]=[CH:12][C:13]=1[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>S(=O)(=O)(O)O.C(OCC)C>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[F:14])[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2OCCO2)cc1Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: O=Cc1ccc(F)c(Cc2ccccc2)c1
Reaction time: 8 h
Yield: 101.6 %

Procedure:
A mixture of 2-(3-benzyl-4-fluorophenyl)-1,3-dioxolane (0.7 g) acetone (10 cm3), water (1 cm3) and concentrated sulphuric acid (5 drops) was stirred overnight. The reaction mixture was poured into diethyl ether and the organic layer washed with sodium bicarbonate solution, water and brine, then dried over anhydrous magnesium sulphate. Evaporation of the solvents under reduced pressure gave 3-benzyl-4-fluorobenzaldehyde (0.59 g), which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[H-].[Na+].CS(O[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(=O)=O>CN(C=O)C.C(Cl)Cl>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[N:3]=[CH:2][N:1]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: c1ccc(-c2c[nH]cn2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccccn3)c2)CC1
Temperature: 25 °C

Procedure:
To a solution of 2-(1H-imidazol-4-yl)pyridine (0.87 g, 6 mmol) in DMF (12 mL) at 0° C. was added sodium hydride (346 mg, 7.2 mmol). The reaction mixture was allowed to warm to room temperature and stirred for an additional 20 min. tert-Butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (1.34 g, 4.8 mmol) was added and the resulting mixture was heated at 80° C. for 48 h. The reaction was cooled to room temperature, diluted with CH2Cl2, and washed with water and brine. The combined organic layers were dried over magnesium sulfate and the solvents removed in vacuo. The residue was purified by silica gel chromatography (0%-100% MeOH/CH2Cl2) and then by HPLC (phenomenex column, 30%-100% acetonitrile/water+0.1% TFA) to afford tert-butyl 4-(4-pyridin-2-yl-1H-imidazol-1-yl)piperidine-1-carboxylate as an oil. 1H NMR (500 MHz, CD3OD) δ 8.88 (m, 1H), 8.70 (m, 1H), 8.40 (m, 1H), 8.10 (m, 1H), 8.00 (m, 1H), 7.55 (m, 1H), 4.58 (m, 1H), 4.32 (m, 2H), 3.01 (m, 2H), 2.24 (m, 2H), 2.00 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+]>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>[Cl:1][C:2]1[CH:8]=[C:7]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Sc1ccccc1
Reactant: Nc1ccc(I)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(Sc2ccccc2)cc1Cl
Reaction time: 18 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.1 15 g) was added to a deoxygenated mixture of 2-chloro-4-iodoaniline (0.507 g), thiophenol (0.214 ml) and sodium methoxide (0.227 g) in ethanol (20 ml). The mixture was further deoxygenated by evacuation and refilling with argon (3 cycles) then heated under reflux with stirring under argon for 18 hours, cooled, diluted with ether (30 ml) and filtered. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 10-15% ethyl acetate/hexane to give the title compound (0.443 g) as a solid. M.p. 59-60° C.; NMR: 5.78 (br s, 2H), 6.8 (t, 1H), 7.04 (m, 2H), 7.15 (m, 2H), 7.2-7.35 (m, 3H); EA: C12H10ClNS requires C, 61.1; H, 4.3; N, 5.9; S, 13.6%; found: C, 60.8; H, 4.4; N, 5.7; S, 13.3%.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.[S:12]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2)(=[O:15])(=[O:14])[NH2:13].N1CCCCC1>C(O)C>[S:12]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:1][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)(=[O:15])(=[O:14])[NH2:13]
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of 3-formyl-7-azaindole (1.46 g, 10 mmol), 5-sulfamoyl-2-oxindole (2,122 g, 10 mmol) and piperidine (0,255 g, 3 mmol) in absolute ethanol (50 ml) was treated for 3 h at reflux. The reaction mixture was chilled to room temperature, the precipitate filtered, the residue washed with ice-cold ethanol and dried under vacuum. Almost pure title compound was so obtained in about 70% yield. Compounds of higher purity were obtained by crystallization from ethanol.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3].C([BH3-])#[N:12].[Na+].C([O-])(=O)C.[NH4+]>CO>[CH3:1][CH:2]([CH2:4][CH:5]([NH2:12])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3]
Reactant: CCCCC(=O)CC(C)C
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCCC(N)CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
A mixture of 2-methyloctan-4-one (6.3 g, 44 mmol), sodium cyanoborohydride (3.0 g, 48 mmol), ammonium acetate (33.9 g, 0.44 mol) and 3Å molecular sieves in dry methanol (50 ml) was stirred overnight at room temperature under argon. The solvent was removed under reduced pressure and the residue taken up in chloroform (100 ml), filtered through a pad of celite and concentrated to give 2-methyl-4-aminooctane (1.6 g, 25%) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH:15]([OH:16])[C:14]([CH3:18])([CH3:17])[CH2:13][C:12](=[O:19])[C:11]([CH3:20])=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]=O>C(O)=O>[OH:16][CH:15]1[C:14]([CH3:17])([CH3:18])[CH2:13][C:12](=[O:19])[C:11]([CH3:20])=[CH:10][CH:9]1[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:21]
Reactant: C=O
Reactant: CC1=CC(NCc2ccccc2)C(O)C(C)(C)CC1=O
Solvent: O=CO
Product: CC1=CC(N(C)Cc2ccccc2)C(O)C(C)(C)CC1=O
Temperature: 90 °C
Yield: 39 %

Procedure:
The 4-benzylamino-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 1 (5.86 g, 21.5 millimoles) was dissolved in formic acid (30 ml), formalin (30 ml) was added, and the mixture was heated at 90° C. for 3 hours. The reaction solution was concentrated and alkalified with a 1% aqueous sodium hydroxide solution. The aqueous solution was subjected to extraction with benzene, washed with water, and then dried over anhydrous potassium carbonate. The benzene solution was concentrated, and the resulting residue was subjected to silica gel column chromatography with hexane-ethyl acetate (9:1) as the eluent, to obtain 2.95 g of crude product which was then recrystallized from hexane to give 2.39 g (39%) of 5-hydroxy-4-(N-methylbenzylamino)-2,6,6-trimethyl-2-cyclohepten-1-one as colorless crystals. Melting point: 78.5°~80° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH:23](O)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(=O)C.[Na+]>ClCCl.O>[C:1]([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH:6]([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(=O)C(C(c2ccccc2)c2ccccc2)C1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
1-Acetyl-4-piperidinone (77 g) was dissolved in dichloromethane (300 ml), and trimethylsilyltrifluoromethanesulfonate (200 ml) and benzhydrol (92 g) were added thereto with stirring under ice-cooling. The mixture was allowed to stand at room temperature overnight, and then water (500 ml) and sodium acetate (50 g) were added thereto and the reaction mixture was vigorously stirred. The dichloromethane layer was preparatively separated, washed with an aqueous sodium bicarbonate solution, dried, and then the solvent was evaporated under reduced pressure. The residue was treated with ethyl ether to obtain 1-acetyl-3-benzhydryl-4-piperidinone as colorless crystals (132.6 g, 86%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](C)([CH3:13])[C:11]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:17](=[O:20])([O-])[O-:18].[K+].[K+]>CO>[CH2:1]([O:8][CH2:9][C:10]([CH3:13])([CH3:11])[C:17]([OH:18])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C#N)COCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(COCc1ccccc1)C(=O)O
Temperature: 140 °C
Reaction time: 22 h
Yield: 98.8 %

Procedure:
3-Benzyloxy-2,2-dimethylpropionitrile (2.0 g, 10.6 mmol), potassium hydroxide (31.2 g, 86%, 479 mmol) and potassium carbonate (1.13 g, 82 mmol) were dissolved in methanol (340 ml), concentrated under reduced pressure. The resulting residue was heated at 140° C. (bath temperature) under nitrogen atmosphere, and stirred for 22 hours. The reaction mixture was dissolved in water, cooled in an ice-water bath, followed by controlling at pH of 1 with hydrochloric acid (36%) added thereto. The organic matter was extracted with diethyl ether, washed with saturated brine, dried on anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure to obtain the entitled compound (2.18 g, 99%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[CH:20][N:13]2[N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[I:26]I>C1COCC1>[CH2:1]([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[C:20]([I:26])[N:13]2[N:12]=1)[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: CC(OCc1ccccc1)c1nn2cncc2c(=O)[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(OCc1ccccc1)c1nn2c(I)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To a solution of compound 11 (1.2 g, 4.4 mmol) in THF (100 mL) was added n-BuLi (2.5 M, 3.5 ml) dropwise at −78° C. over 30 minutes and the resulting reaction mixture was stirred below −70° C. for another one hour. Then a solution of iodine (2.2 g, 8.8 mmol) in THF (20 mL) was added dropwise and the dark brown mixture was allowed to warm up to room temperature slowly over one hour. The reaction was quenched with saturated aqueous solution of Na2SO3 (60 mL), and then the mixture was extracted with EtOAc (200 mL×2). The organic layers were combined and dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel column (eluted with PE/EtOAc=10:1 to 2:1) to afford compound 12 (450 mg, 25% yield) as a yellow solid. LC-MS: m/z 397 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.82 (br. s, 1H), 7.94 (s, 1H), 7.36˜7.32 (m, 5H), 4.65˜4.55 (m, 3H), 1.60 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:34][C:33]1[CH:35]=[CH:36][C:30]([S:27]([O:19][CH2:18][CH2:17][C@@H:15]2[CH2:16][C@@H:14]2[CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=3)[CH2:9][CH2:10]2)(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Temperature: 0 °C

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (176 mg, 0.63 mmol) from. Step 6, Example 2 was dissolved in dichloromethane (3 mL), then added triethylamine (190 mg, 1.87 mmol), 4-dimethylaminopyridine (15.3 mg, 0.13 mmol), last tosylchloride (167 mg, 0.87 mmol), stirred under N2 for 1.5 hours. The reaction solution was poured into ice water (10 mL), extracted with dichloromethane (10 mL×2). The organic phase was combined and dried by magnesium sulfate, filtered, then concentrated and purified by column chromatography through a 24 gram RediSep Rf™ silica gel cartridge eluting with 10% ethyl acetate/hexanes to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6](Br)[CH:7]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([C:2]2[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)/C=C/c1cc(Br)cc(Br)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)/C=C/c1cc(-c2ccccc2)cc(-c2ccccc2)c1

Procedure:
The colourless solid, (E)-ethyl 3-[1,1′;3′,1″]terphenyl-5′-yl-acrylate was prepared from (E)-ethyl 3-(3,5-dibromophenyl)-acrylate and phenylboronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13]([C:15]1[S:19][N:18]=[CH:17][CH:16]=1)=O)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].N1C=CC=CC=1.Cl.[NH2:27][OH:28]>C(O)C>[CH2:1]([N:4]([CH2:12][C:13](=[N:27][OH:28])[C:15]1[S:19][N:18]=[CH:17][CH:16]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: NO
Reactant: C=CCN(CC(=O)c1ccns1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C=CCN(CC(=NO)c1ccns1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a room temperature solution of tert-butyl N-allyl-N-(2-isothiazol-5-yl-2-oxo-ethyl)carbamate (5.93 g, 21.00 mmol) in ethanol (70 mL) is added pyridine (5.94 mL, 73.50 mmol) and hydroxylamine hydrochloride (3.65 g, 52.50 mmol). The mixture is heated to reflux for 4 hours. The mixture is allowed to cool to room temperature and is then concentrated under reduced pressure. The resulting crude product is diluted with ethyl acetate (200 mL) and washed with saturated sodium bicarbonate (150 mL). The aqueous layer is re-extracted with ethyl acetate (2×100 mL). The combined organic layers are dried over sodium sulfate, filtered, and the solvent is removed under vacuum. The crude product is purified by silica gel column chromatography using a 15 minute, 0% to 20% ethyl acetate in dichloromethane gradient, to give the title compound as a mixture of E and Z isomers (5.62 g, 18.90 mmol, 90%). ES/MS (m/e): 298 (M+H).