Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].C(N(CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:26]1[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([N:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]3)=[CH:37][CH:38]=2)[N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 89 %

Procedure:
To a nitrogen de-gassed solution of methyl 2-(2-ethynylphenyl)acetate (14: prepared according to the procedure of Peng, C. et al; Adv. Synth. Catal. 2008, 350, 2359-2364 or as detailed below) (0.114 g, 0.653 mmol) in dry DMF (6 mL) were added triethylamine (0.280 mL, 2.01 mmol) followed by tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.230 g, 0.502 mmol), triphenylphosphine (0.020 g, 0.075 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.035 g, 0.050 mmol) and CuI (0.014 g, 0.075 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes and then concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-80% EtOAc in cyclohexane) to give the title compound (I5) (0.267 g, 89% yield) as an orange glassy solid; 1H NMR (400 MHz, d6-DMSO) δ 10.27 (br s, 1H), 8.76 (s, 1H), 7.65-7.49 (m, 4H), 7.49-7.38 (m, 2H), 6.95 (d, J=9.1 Hz, 2H), 3.94 (s, 2H), 3.61 (s, 3H), 3.51-3.42 (m, 4H), 3.09-3.00 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.67 min; m/z 596.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>O1CCCC1>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[S:3][C:4]=2[CH:10]=1)[CH3:13]
Reactant: C1CNCCN1
Reactant: CCOc1ccc2nc(Cl)sc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 160 °C

Procedure:
A mixture of 1.36 mmol 2-chloro-6-ethoxy-benzothiazole (CA=[79071-17-3]), 3.00 mmol of piperazine and 3.00 mmol of triethylamine in 5 ml of tetrahydrofuran in a sealed tube was heated at 160° C. for 5 min under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([CH2:10][C:11]([O:13]CC)=O)[NH:9][C:5]=2[CH:4]=1.[C:19](#[N:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH2:22]>>[CH3:18][N:2]([CH3:1])[C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([CH2:10][C:11]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]#[N:27])=[O:13])[NH:9][C:5]=2[CH:4]=1
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)Cc1nc2ccc(N(C)C)cc2[nH]1
Product: CN(C)c1ccc2nc(CC(=O)Nc3ccccc3C#N)[nH]c2c1

Procedure:
The title compound was synthesized as described in Example 9, Method B using ethyl 2-[5-(dimethylamino)benzimidazol-2-yl]acetate and anthranilonitrile. LC/MS m/z 320.2 (MH+), Rt 1.68 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1>C1COCC1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([O:8][C:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Reactant: CC1(C)CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCC(Oc2ncnc3c([N+](=O)[O-])cccc23)CC1
Reaction time: 0.33 h
Yield: 48.4 %

Procedure:
To a solution of 4,4-dimethylcyclohexanol (140 mg, 1.097 mmol) in THF (2 mL) was added NaH (43 mg, 1.097 mmol, 60% in mineral oil) at 0° C. Then the reaction mixture was stirred at that temperature for 20 min and 4-chloro-8-nitroquinazoline (Intermediate-7, step 2, 115 mg, 0.549 mmol) was added to the reaction mixture. Then the reaction mixture was stirred at 0-5° C. for 4 h and then at rt for 12 h. Then the reaction mixture was quenched with water and was extracted with chloroform. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography using chloroform to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.89 (s, 1H), 8.49-8.46 (d, J=7.8 Hz, 1H), 8.45-8.42 (d, J=7.8 Hz, 1H), 7.86-7.80 (t, J=8.4 Hz, 1H), 5.41 (m, 1H), 1.94 (m, 2H), 1.82-1.79 (m, 2H), 1.54 (m, 2H), 1.37-1.34 (m, 2H), 0.99 (s, 3H), 0.67 (s, 3H); MS (m/z): 301.93 (M+H)+.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:4]=1.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:12]1[CH:11]=[C:10]([NH:9][C:5]2[CH:4]=[C:3]([NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:8]=[CH:7][N:6]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: NC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1cccc(Nc2cc(NC3CCCCC3)ncn2)c1
Temperature: 200 °C
Yield: 71 %

Procedure:
71 mg of 6-chloro-N-(3-chlorophenyl)pyrimidin-4-amine hydrochloride, 29 mg of cyclohexylamine and 84 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using PE:EtOAc 1:1. N4-(3-Chlorophenyl)-N6-cyclohexylpyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:21].CN(C)C=O>O>[CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:32][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[O:10][CH:11]=[CH:12][CH:13]=3)[O:6][C:7]=2[CH3:8])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:21]
Reactant: COC(=O)c1cc(C=O)ccc1O
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (7.13 g), potassium carbonate (3.84 g), methyl 5-formyl-2-hydroxybenzoate (5.0 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give methyl 5-formyl-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate as pale-brown crystals (8.67 g, 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.I[CH2:11][C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].P(=O)(O)(O)O>C(OCC)(=O)C.O>[C:12]([CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([OH:14])=[O:13]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(O)CI
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(OCC(=O)O)cc1
Temperature: 60 °C

Procedure:
To a solution of p-hydroxybenzaldehyde (49 g, 0.40 mol) were added iodoacetic acid (75 g, 0.40 mol) and potassium carbonate (anhydrous, 120 g), and the magnetically stirred mixture was warmed at 60° C. for three days. The resulting solid was dispersed mechanically in a mixture of ethyl acetate (400 ml) and water. The mixture was neutralized cautiously with phosphoric acid. After the dissolution of the solid mass, the neutral aqueous layer was withdrawn. The organic layer was extracted repeatedly with a concentrated solution of dibasic sodium phosphate, to remove additional acidic organic material. The aqueous extracts were combined, filtered through glass wool, and acidified to pH 1 using 6N HCl. This solution was placed in the refrigerator overnight, and a product of tan crystals (21.85 g) was collected. Unreacted p-hydroxybenzaldehyde was recovered upon evaporation of the organic layer. Yield based on recovery of starting material was 60%. Mp 191°-193° C. Analysis (C9H8O4): calc. 60.00% C, 4.48% H; found 59.66% C, 4.37% H.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[C:16]([O:20][CH3:21])(=[O:19])[CH2:17]O.N1C=CC=CC=1>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][CH2:17][C:16]([O:20][CH3:21])=[O:19])(=[O:3])=[O:2]
Reactant: COC(=O)CO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)COS(=O)(=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 67.5 %

Procedure:
To a solution of triflic anhydride (3.7 ml, 20.0 mmol) in methylene chloride (10 ml) at -5° C. under argon, was added dropwise over 30 minutes a solution of methyl glycolate (1.8 g, 20.0 mmol), pyridine (1.55 ml, 20.0 mmol), and anhydrous methylene chloride (5 ml). The reaction was allowed to stir at between 0°-5° C. for 1.5 h. The mixture was then washed with water several times. The organic extract was then washed with water, brine, and dried (MgSO4). After removing the solvent under reduced pressure, flash chromatography of the residue (silica gel, methylene chloride) afforded the title compound as a colorless oil (3.0 g, 68%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:16][CH2:17]CC.IC>C1COCC1>[CH2:16]([C:11]1[S:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:17]
Reactant: [Li]CCCC
Reactant: O=C(O)c1cc(-c2ccccc2)cs1
Solvent: C1CCOC1
Solvent: CI
Product: CCc1sc(C(=O)O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At −78° C., a solution of 4-phenylthiophene-2-carboxylic acid (800 mg, 3.92 mmol) in THF (10 mL) is treated with tert.-BuLi (8 mL, 1.6 M in pentane). The mixture is stirred at −70° C. for 40 min before iodomethane (1 mL) is added. Stirring is continued for 5 h at −78° C., then the reaction mixture is allowed to warm to rt overnight. The reaction is quenched with sat. aq. NH4Cl and extracted with EA. The organic extract is dried over MgSO4, the solvent is removed and the crude product is purified by CC on silica gel eluting with DCM containing 3% of methanol to give 5-ethyl-4-phenyl-thiophene-2-carboxylic acid (340 mg) as a red solid; LC-MS: tR=0.95 min, [M+1+MeCN]+=274.15; 1H NMR (CDCl3): δ 7.79 (s, 1H), 7.46-7.31 (m, 5), 2.92 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]([CH3:18])=[O:17].O>C(O)C>[CH3:14][CH2:13][O:12][C:5]([C:6]([CH2:15][C:16]([CH3:18])=[O:17])=[O:8])=[O:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 125 ml of ethanol were dissolved 14.2 g of sodium ethoxide, followed by the dropwise addition of a mixed liquid of 25 ml of diethyl oxalate and 13.5 ml of acetone over 20 minutes. The resulting mixture was stirred at room temperature for 3 hours. After the completion of the reaction, water was added to the reaction mixture. Ethanol was then evaporated under reduced pressure. The residue was extracted with chloroform. After the chloroform layer was washed with water, it was dried over anhydrous magnesium sulfate. The solvent was then evaporated, whereby ethyl acetopyruvate (1) was obtained (O. S., Coll. Vol. 1, 238(1958)).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2O.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Cl:30][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[C:7]([CH3:12])[C:6]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: Cc1nc2ccc(I)cc2c(O)c1S(C)(=O)=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: Cc1ccc(N(C)C)cc1
Product: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Reaction time: 9.5 h
Yield: 77.6 %

Procedure:
6-Iodo-3-methanesulfonyl-2-methyl-quinolin-4-ol (example C.2) (14.7 g, 40.5 mmol) and N,N-dimethyl-p-toluidine (11.7 mL, 81 mmol) were dissolved in toluene (150 mL) and heated under argon to reflux. Then phosphorous oxychloride (4.1 mL, 44.5 mmol) was added and heating at reflux continued for 9.5 h. The thick suspension became gradually a dark solution. The reaction mixture was allowed to cool and then extracted with dichloromethane (not soluble in toluene), cold 1 N HCl (2×), and sat. NaCl (2×). The product was crystallized from heptane/dichloromethane. One obtained 12 g (78%) of white crystals. MS: m/z=381 (M).
Reaction SMILES: [O:1]=[C:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][C:10]([CH3:15])([CH2:13]O)[CH2:11][OH:12].B(F)(F)F.CCOCC>C(#N)C>[CH3:8][C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:12][CH2:11][C:10]([CH3:15])([CH3:13])[CH2:9][O:1]1
Reactant: CCOC(=O)C(C)=O
Reactant: CC(C)(CO)CO
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)C1(C)OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
To a solution of ethyl 2-oxopropanoate (0.581 g, 5 mmol) and 2,2-dimethylpropane-1,3-diol (0.521 g, 5.00 mmol) in acetonitrile (5 mL) cooled to 0° C. was added BF3.OEt2 (0.063 mL, 0.500 mmol), and the mixture was allowed to warm to rt and stirred at rt for 18 h. The reaction mixture was quenched with sat. NaHCO3 (5 mL) and diluted with ether/hexane (1:1, 20 mL). The organic layer was washed with water, brine and dried (MgSO4). The solvent was evaporated to yield ethyl 2,5,5-trimethyl-1,3-dioxane-2-carboxylate as a clear oil (681 mg). 1H NMR (500 MHz, CDCl3) δ ppm 4.31 (2H, q, J=7.07 Hz), 3.48-3.58 (4H, m), 1.55 (3H, s), 1.35 (3H, t, J=7.17 Hz), 1.22 (3H, s), 0.69-0.75 (3H, m). Ethyl 2,5,5-trimethyl-1,3-dioxane-2-carboxylate (90 mg) was saponified (1 N NaOH, MeOH-THF) to afford Cap P-24 (69 mg). 1H NMR (500 MHz, CDCl3) δ ppm 3.53-3.64 (4H, m), 1.63 (3H, s), 1.23 (3H, s), 0.78 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([C:4]2[C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[C:3]=2[OH:10])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:14][CH:13]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: COC(=O)CCCCC[C@H](O)c1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)cc(C)c(C)c1O
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of 2,3,5-trimethylphenol (0.80 g, 5.9 mmol), methyl (S)-7-(4-fluorophenyl)-7-hydroxyheptanoate (0.30 g, 1.2 mmol) and triphenylphosphine (0.46 g, 1.8 mmol) in 1,2-dichloroethane (20 ml) was added at 10° C. a solution of 95% DEAD (0.54 ml) in 1,2-dichloroethane (5 ml) taking 30 minutes. The mixture was stirred for one hour at the same temperature range, then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography to give 0.15 g of methyl (R)-7-(4-fluorophenyl)-7-(2-hydroxy-3,4,6-trimethylphenyl)heptanoate.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]([NH2:19])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17](=[S:29])[NH2:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CC(N)=S
Yield: 105.6 %

Procedure:
To a solution of the compound 67 (9.50 g) in methylene chloride (133 mL) was added Lawesson's reagent (6.71 g) at 0° C. and the solution was stirred for 3 Hours. To the reaction solution was added an aqueous saturated sodium bicarbonate solution and ethyl acetate and then the solution was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate:methanol=60:40:033:67:00:90:10) to give the title compound (5.30 g) having the following physical data.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:19]([O:18][C:16]([NH:1][CH:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:7]([OH:9])=[O:8])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 817.3 %

Procedure:
To a solution of L-tert-leucine (1) (50.0 g, 38.0 mmol) and NaHCO3 (96.0 g, 114 mmol) in ice (500 g) and water (500 ml) was added benzyl chloroformate (65.0 ml, 74.0 mmol) and the reaction stirred at 0° C. for 3 hours then at room temperature for 18 hours. 0.1N Na2CO3 was added until the oily layer dissolved and the solution was washed with 10% EtOAc in hexanes (2×500 ml). The iced aqueous phase was acidified to pH 1 using 12N HCl then extracted using EtOAc (3×350 ml). The combined organic extracts were dried over Na2SO4, filtered and evaporated to give the title compound as a colorless oil (82.4 g, 81.5% yield):
Reaction SMILES: [NH2:1][C:2]1[N:29]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([CH:24]5[CH2:26][CH2:25]5)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:27][CH3:28])[N:9]=[CH:10][C:5]=2[C:4](=[O:35])[C:3]=1[C:36]([NH2:38])=[O:37].CC[Cl:41]>C(Cl)Cl.CCOCC>[ClH:41].[NH2:1][C:2]1[N:29]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:19][CH2:20][N:21]([CH:24]5[CH2:25][CH2:26]5)[CH2:22][CH2:23]4)=[CH:14][C:13]=3[O:27][CH3:28])[N:9]=[CH:10][C:5]=2[C:4](=[O:35])[C:3]=1[C:36]([NH2:38])=[O:37]
Reactant: CCCl
Agent: COc1cc(C2CCN(C3CC3)CC2)ccc1Nc1ncc2c(=O)c(C(N)=O)c(N)n(CC(C)(C)O)c2n1
Solvent: ClCCl
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 0.137 g (0.26 mmol) of the product prepared in step 21.1 in 5 mL of CH2Cl2 are added 1.05 mL (1.05 mmol) of 1.0 M hydrochloric ether. The mixture is stirred for 5 minutes at room temperature and then diluted with ether. The precipitate is drained by suction, rinsed with ether and with pentane, and dried under vacuum. 0.12 g of the expected product is obtained in the form of a yellow solid. Yield (dihydrochloride)=77%. m.p.=206°C. (decomposition). M+H+=568
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH3:28][O:29][C:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([C@H:44]3[CH2:49][CH2:48][C@H:47]([CH:50]=O)[CH2:46][CH2:45]3)[CH2:40][CH2:39]2)[CH2:34][CH2:33]1)=[O:31].O>C1COCC1>[CH3:28][O:29][C:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:39][CH2:40][C@H:41]([C@H:44]3[CH2:49][CH2:48][C@H:47]([CH:50]=[CH2:2])[CH2:46][CH2:45]3)[CH2:42][CH2:43]2)[CH2:34][CH2:33]1)=[O:31]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](C=O)CC3)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](C(=O)OC)CC3)CC2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 30.2 g (74.7 mmol) of methyltriphenylphosphonium iodide and 400 ml of THF was cooled to -50° C. To this mixture was added 9.23 g (82.2 mmol) of t-BuOK and the resulting mixture was stirred for one hour. To this mixture was added dropwise a solution of 20.0 g (59.8 mmol) of trans-4-(trans-4-(trans-4-formylcyclohexyl)cyclohexyl)cyclohexane carboxylic acid methyl ester in 500 ml of THF, while maintaining a temperature at below -50° C. After the dropwise addition, the reaction temperature was gradually allowed to rise up to room temperature. After 300 ml of water was added to the reaction mixture, the reaction mixture was extracted with 1000 ml of toluene. The organic layer was washed three times with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to a silica gel column chromatography (a developing solvent: heptane) to give 9.90 g of crude trans-4-(trans-4-(trans-4-ethenylcyclohexyl)cyclohexyl)-cyclohexane carboxylic acid methyl ester.
Reaction SMILES: C1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[C:8]2C2C=CC=CC=2)C=CC=CC=1.[O:43]1CCO[CH:44]1CCCCN1CCC(C2C=C(NC(=O)C(C)C)C=CC=2)CC1.Cl.COC1C=CC(NN)=CC=1>>[CH3:44][O:43][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[NH:7][CH:8]=[C:9]2[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Agent: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]cc(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1
Yield: 42 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide, N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide (23.5 mg, 0.0628 mmol) and 1-(4-methoxyphenyl)hydrazine hydrochloride (13.2 mg, 0.0774 mmol) provided N-(3-{1-[3-(5-methoxy-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide (11 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.45 (s, 1H), 7.32 (d, 1H, J=8.4 Hz), 7.28–7.21 (m, 2H), 7.10 (s, 1H), 7.05 (d, 1H, J=2.3 Hz), 7.00–6.91 (m, 2H), 6.85 (dd, 1H, J=2.7, 9.0 Hz), 3.87 (s, 3H), 3.06 (d, 2H, J=11.6 Hz), 2.75 (t, 2H, J=7.2 Hz), 2.55–2.42 (m, 4H), 2.08–1.90 (m, 4H), 1.88–1.74 (m, 49), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 434.2 (M+H)+.