Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([N:21]=[CH:22]OCC)#[N:20].[ClH:26].C(O)C>C(O)C.C(OCC)C>[ClH:26].[C:19]([NH:21][CH:22]=[N:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)#[N:20]
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCOC=NC#N
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: N#CNC=NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C

Procedure:
To a solution of 2.48 g of 3-[3-(1-piperidinylmethyl)phenoxy]-1-propanamine (prepared according to British Pat. No. 2,023,123 which is hereby incorporated by reference) in 25 ml of absolute ethanol, are added dropwise 0.98 g of ethyl N-cyano-formimidate in 15 ml of ethanol, under stirring and at room temperature. Stirring is maintained for 30 minutes, and then the ethanol is removed by underpressure distillation. An oil residue is formed, which is then dissolved in 250 ml of ethyl ether, after which 0.95 ml of 10N HCl/ethanol are added, yielding 1.4 g of N-cyano-N'-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]formamidine hydrochloride.
Reaction SMILES: [ClH:1].C([O:5][C:6]1[C:11]2[O:12][C:13]3[C:18]([C:19]4([CH2:24][CH2:23][N:22]([CH2:25][C:26]#[CH:27])[CH2:21][CH2:20]4)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)(=O)C.Cl.C(=O)(O)[O-].[Na+]>CCOCC>[ClH:1].[OH:5][C:6]1[C:11]2[O:12][C:13]3[C:18]([C:19]4([CH2:24][CH2:23][N:22]([CH2:25][C:26]#[CH:27])[CH2:21][CH2:20]4)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: C#CCN1CCC2(CC1)c1ccccc1Oc1c(OC(C)=O)cccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: C#CCN1CCC2(CC1)c1ccccc1Oc1c(O)cccc12

Procedure:
4-Acetoxy-1'-(prop-2-ynyl)xanthene-9-spiro-4'-piperidine hydrochloride (0.4 g.) is stirred with 3N hydrochloric acid (20 ml.) at room temperature for 24 hours. The solution is basified using solid sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract is dried over MgSO4 and evaporated to give a gummy residue which is dissolved in ether and treated with ethereal hydrochloric acid. The precipitate is recrystallised from ethanol-ether to give 4-hydroxy-1'-(prop-2-ynyl)xanthene-9-spiro-4'-piperidine hydrochloride, m.p. 246°-247° C.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]([NH2:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[Br:19][CH:20]([CH2:24][CH3:25])[C:21](Br)=[O:22].O>ClCCl>[Br:19][CH:20]([CH2:24][CH3:25])[C:21]([NH:11][C:8]([CH3:10])([CH3:9])[C:7]#[C:6][CH2:5][CH2:4][CH2:3][Cl:2])=[O:22]
Reactant: CCC(Br)C(=O)Br
Reactant: CC(C)(N)C#CCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC(Br)C(=O)NC(C)(C)C#CCCCCl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
The product from Step 2 (12.2 g) was suspended in dry dichloromethane (300 ml), cooled to 5° C. with stirring and dry triethylamine (18.1 ml) was added. The mixture was stirred for 0.25 hours and 2-bromobutyryl bromide (14.3 g) in dichloromethane (25 ml) was added dropwise over 0.5 hours at 10–18° C. The mixture was stirred for a further 0.5 hours then allowed to warm to ambient temperature for 2 hours and stored for 18 hours. Water was added and the organic phase was separated, washed with water (three times), dried over magnesium sulphate then evaporated under reduced pressure to give the required product as a dark yellow oil, 17.4 g, 1H NMR (CDCl3) δ: 1.04(3H, t); 1.62(6H, s); 1.96(2H, m); 2.10(2H, m); 2.38(2H, m); 3.66(2H, t); 4.12(1H, t); 6.44(1H, s).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][NH:18][CH2:19][CH2:20]O)[CH:10]=[CH:9]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].[H-].[Na+]>O1CCCC1.CN(C)C=O>[CH3:22][S:23]([CH:13]1[CH2:14][C:15]2[CH:17]=[N:18][CH:19]=[CH:20][N:8]3[C:16]=2[C:11]([CH:10]=[CH:9]3)=[CH:12]1)(=[O:25])=[O:24]
Reactant: OCCNCc1cccc2cc[nH]c12
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)C1C=c2ccn3c2=C(C=NC=C3)C1
Temperature: 25 °C

Procedure:
Add triethylamine (3.19 g, 31.56 mmol) to a solution of 2-[(1H-Indol-7-ylmethyl)amino]-ethan-1-ol (2.0 g, 10.52 mmol) in tetrahydrofuran (50 ml) at 0° C. Slowly add 1.75 mL (22.09 mMol) methanesulfonyl chloride and allow the reaction to warm to room temperature. Quench the reaction with saturated aqueous sodium bicarbonate and extract into ethyl acetate. Combine the organic layers, wash sequentially with saturated aqueous ammonium chloride, water, and saturated aqueous sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure. Add sodium hydride (0.8416 g, 21.04 mmol, 60% dispersion in mineral oil) to the resulting oil in dimethylformamide (20 ml). Quench the reaction with saturated aqueous sodium bicarbonate, concentrate to about 10 ml and extract into ethyl acetate. Combine the organic layers, wash sequentially with saturated ammonium chloride, water, and saturated aqueous sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate:hexane gradient gives the title compound as an off-white solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:14]([NH2:22])=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH2:17][CH2:16]2)=[O:12].C(OCC)(=O)C>C(O)(=O)C>[CH3:9][O:10][C:11]([C:13]1[C:14]([NH2:22])=[C:15]2[C:19](=[C:20]([Br:1])[CH:21]=1)[CH2:18][CH2:17][CH2:16]2)=[O:12]
Reactant: COC(=O)c1ccc2c(c1N)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c2c(c1N)CCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.5 %

Procedure:
Add N-bromosuccinimide (1.99 g, 11.2 mmol) to 4-amino-indan-5-carboxylic acid methyl ester (2.15 g, 11.2 mmol) (Example 48, Step 3) in acetic acid (13 mL). Stir the mixture at room temperature for 48 h. Pour the mixture into ice water and add ethyl acetate. Separate the layers and wash the organic phase with saturated NaHCO3 and brine and dry over sodium sulfate. Remove the solvent under reduced pressure to afford the title compound (3.10 g, quantitative). MS (ES+): 271 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[OH:27])=[O:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:27][C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: COc1ccc(C(C)=O)c(O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(C(C)=O)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 160 °C
Reaction time: 7 h
Yield: 30.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg), 2-hydroxy-4-methoxyacetophenone (873 mg), and 4-dimethylaminopyridine (619 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 7 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the organic layer was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (53.9 mg, yield 31%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]1[CH2:11][CH2:12][CH2:13][CH:14]=O.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:23]=[CH:22][C:21]([C@:24]23[CH2:29][C@H:28]2[CH2:27][NH:26][CH2:25]3)=[CH:20][CH:19]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:50]C(Cl)C>O>[ClH:50].[O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]1[CH2:11][CH2:12][CH2:13][CH2:14][N:26]1[CH2:27][C@H:28]2[C@:24]([C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:31])[F:30])=[CH:23][CH:22]=3)([CH2:29]2)[CH2:25]1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: CC(Cl)Cl
Reactant: N#Cc1cn(CCCC=O)c(=O)[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cl
Product: N#Cc1cn(CCCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
To a solution of 2,4-dioxo-1-(4-oxo-butyl)-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (Prep55, 70 mg, 0.34 mmol) in dichloroethane (5 mL), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 76 mg, 0.34 mmol) was added. The suspension was cooled at 0° C. and then AcOH (30 mg, 0.68 mmol) and NaBH(AcO)3 (79 mg, 0.38 mmol) were added and the mixture stirred at 0° C. for 4 hours. Water was added and the solvent was evaporated under vacuum, the residue re-dissolved in ethyl acetate and the mixture washed with aqueous saturated NaHCO3 solution. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (97-3-1) to give the title compound as a white solid (86 mg, 53% yield) as free base
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12](Cl)[CH:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22].C(N(CC)CC)C>CN(C=O)C.O>[CH3:17][O:18][C:19](=[O:23])[CH2:20][CH2:21][NH:22][C:12]1[CH:11]=[C:10]([Cl:15])[N:9]=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=1
Reactant: Clc1cc(Cl)nc(Cc2ccccc2)n1
Reactant: COC(=O)CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCNc1cc(Cl)nc(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
0.503 g (2.1 mmole) of 2-benzyl-4,6-dichloro-pyrimidine was dissolved in 10 mls of DMF. To this solution was added 0.340 g of 3-amino-propionic acid methyl ester HCl. Next 0.6 mls of triethyl amine 94.3 mmoles) was added dropwise and the reaction stirred at room temperature for 12 hours. The reaction was diluted with 10 mls of H2O and extracted with two portions of EtOAc. The combined organic layers were washed with two portions of saturated NaCl solution, dried over MgSO4, filter and evaporated under reduced pressure to yield a crude oil. This material was chromatographed on silica gel with 10% Ethyl Acetate-90% Heptane as the eluent. 3-(2-benzyl-6-chloro-pyrimidin-4-ylamino)-propionic acid methyl ester (0.531 g, 79%) was isolated a clear oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([Cl:49])[CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Si]([O:69][CH2:70][CH2:71][C:72]1[CH:79]=[CH:78][C:75]([CH2:76]Br)=[CH:74][CH:73]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O>CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([Cl:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:76][C:75]2[CH:78]=[CH:79][C:72]([CH2:71][CH2:70][OH:69])=[CH:73][CH:74]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c[nH]c12
Reactant: CC(C)(C)[Si](OCCc1ccc(CBr)cc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: OCCc1ccc(Cn2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3cccc(Cl)c32)cc1
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-7-chloro-1H-indole (0.48 g) in N,N-dimethylformamide (5 mL) was added 55% sodium hydride (37 mg) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added a solution of 4-[2-(tert-butyldiphenylsilyloxy)ethyl]benzyl bromide (0.42 g) in tetra hydrofuran (2 mL) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in tetra hydrofuran (5 mL). To the solution was added tetra(n-butyl)ammonium fluoride (1.0 mol/L tetra hydrofuran solution, 1.07 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was washed with a mixed solvent of n-hexane and ethyl acetate (5/1), and dried under reduced pressure to give the title compound (0.50 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>C1COCC1.CCOC(C)=O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH2:19][CH2:20][S:21]([N:2]([CH3:3])[CH3:1])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)CCc1cc(Cl)ccc1Br
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)CCc1cc(Cl)ccc1Br
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
To a solution of dimethylamine (1.91 mL of 2 M, 3.82 mmol) and triethylamine (386.7 mg, 532.6 μL, 3.82 mmol) in THF (8.1 mL) at room temperature was added 2-(2-bromo-5-chloro-phenyl)ethanesulfonyl chloride (405.0 mg, 1.27 mmol) and the mixture stirred for 10 min. The mixture was diluted with EtOAc and washed subsequently with water and brine, the organic layer dried (MgSO4) and concentrated to afford 2-(2-bromo-5-chlorophenyl)-N,N-dimethylethanesulfonamide as a white solid (413 mg, 99%). 1H NMR (500 MHz, d6-DMSO) δ 7.66 (1H, d), 7.60 (1H, s), 7.30 (1H, d), 3.31-3.34 (2H, m), 3.08-3.12 (2H, m).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[CH2:12]([O:14][C:15]([C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=[C:19](Cl)[N:18]=1)=[O:16])[CH3:13].O>O1CCCC1>[CH2:12]([O:14][C:15]([C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=[C:19]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([F:3])=[CH:5][CH:6]=2)[N:18]=1)=[O:16])[CH3:13]
Reactant: OCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccc(Cl)nc1C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCc2ccc(F)cc2)nc1C(=O)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of sodium hydride (55% in mineral oil, 254 mg, 0.6 mmol) and 4-fluorobenzylalcohol in tetrahydrofuran (30 mL) was heated at 60° C. for 30 min and then after cooling at 0° C. a solution of 6-chloro-pyridine-2,3-dicarboxylic acid diethyl ester (1.3 g. 0.5 mmol) in tetrahydrofuran (20 mL) was added over 10 min. The resulting mixture was kept at 0° C. for 1 h and then water was added. The mixture was then extracted with ethylacetate and the combined organic extracts washed with water, brine and then dried over sodium sulfate. Filtration and evaporation gave a residue which was purified by chromatography (SiO2, heptane-EtOAc 9:1 to 3:1) to afford the title compound (1.3 g, 74%) as a colorless oil. MS: m/e=348.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[CH:24]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:24]1([C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)C1CCCCC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3CCCCC3)cc1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxy late (50 mg, 0.16 mmol), cyclohexanecarboxylic acid (0.03 mL, 0.24 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.32 mmol,) in dichloromethane (5 mL) was added phosphorus oxychloride (0.02 mL, 0.24 mmol) via syringe below 0° C. The mixture was stirred at room temperature for 16 h under nitrogen. The solvent was removed and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 2-(4-(cyclohexane carboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 42 mg, yield: 53%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:6][CH:7]1OC(C)OC(C)O1.[CH:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=1)([CH3:17])[CH3:16].P(=O)(O)(O)O>C(O)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:24][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([CH:15]([CH3:17])[CH3:16])=[CH:19][CH:20]=1)[CH3:7]
Reactant: c1ccsc1
Reactant: CC1OC(C)OC(C)O1
Reactant: CC(C)c1ccc(C(N)=O)cc1
Agent: O=P(O)(O)O
Solvent: O=CO
Product: CC(C)c1ccc(C(=O)NC(C)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 229.4 %

Procedure:
Thiophene (42 g, 0.5 mol), paraldehyde (4.4 g, 0.033 mole) and 4-isopropylbenzamide (16.3 g, 0.1 mol) were added to a mixture of formic acid (40 ml) and 85% phosphoric acid (20 ml) and stirred at a room temperature for three hours. The reaction mixture was extracted with water (70 ml). An organic phase was washed with water (30 ml) and evaporated to dryness with a rotary evaporator. A residue was recrystallized from carbon tetrachloride/petroleum benzine (1:2) to obtain the entitled compound (20.7 g) as a colorless crystal. Yield: 75.8%. Melting point: 100° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(C)(C)C.Cl>CC(O)C.C(Cl)Cl>[NH2:7][CH2:8][CH:9]([NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NCC(NC(=O)c1ccc(-c2ccncc2)cc1)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: NCC(NC(=O)c1ccc(-c2ccncc2)cc1)c1ccccc1

Procedure:
The title compound was prepared by BOC cleavage of the compound obtained in Example 3 with HCl in 2-propanol/DCM at room temperature.
Reaction SMILES: C1(C2CCN(CC[CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])CC2)C=CC=CC=1.O=C1C2C(=CC=CC=2)C(=O)N1CCCCC[N:46]1[CH2:51][CH2:50][CH:49]([C:52]2[CH:53]=[C:54]([NH:58][C:59](=[O:63])[CH:60]([CH3:62])[CH3:61])[CH:55]=[CH:56][CH:57]=2)[CH2:48][CH2:47]1>>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:18][CH2:17][CH2:16][CH2:15][N:46]1[CH2:51][CH2:50][CH:49]([C:52]2[CH:53]=[C:54]([NH:58][C:59](=[O:63])[CH:60]([CH3:62])[CH3:61])[CH:55]=[CH:56][CH:57]=2)[CH2:48][CH2:47]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCN1CCC(c2ccccc2)CC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN3C(=O)c4ccccc4C3=O)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN3C(=O)c4ccccc4C3=O)CC2)c1
Yield: 64 %

Procedure:
The synthetic method is the same as described for 2-[6-(4-phenyl-1-piperidinyl)hexyl]-1H-isoindole-1,3(2H)-dione. N-(3-(1-[5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 614 mg (64% yield); 1H NMR (400 MHz, CDCl3) δ 7.87-7.8 (m, 2H), 7.76-7.68 (m, 2H), 7.48 (s, 1H), 7.41 (d, 1H, J=7.6 Hz), 7.21 (t, 1H, J=7.6 Hz), 6.95 (d, 1H, J=7.6 Hz), 3.69 (t, 2H, J=7.2 Hz), 3.39-3.28 (m, 2H), 3.02 (apparent d, 2H, J=11.6 Hz), 2.78 (q, 2H, J=7.2 Hz), 2.64-2.52 (m, 1H), 2.52-2.40 (m, 1H), 2.40-2.31 (m, 2H), 2.01 (dt, 2H, J=3.7, 11.1 Hz), 1.85-1.64 (m, 2H), 1.58 (q, 2H, J=7.6 Hz), 1.45-1.32 (m, 2H), 1.23 (d, 6H, J=6.9 Hz); ESMS m/e: 462.4 (M+H)+; Anal. Calc. for C28H36N3ClO3: C, 67.52; H, 7.29; N, 8.44. Found: C, 67.04; H, 7.06; N, 8.38.
Reaction SMILES: [Na].[C:2]1([P:8](Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([Si:18]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH2:17].C([SiH3])=C.C([OH:33])C>C1(C)C=CC=CC=1>[C:2]1([P:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH2:17][CH2:16][Si:18]([O:19][CH2:20][CH3:21])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])=[O:33])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([PH:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCO
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: C=C[Si](OCC)(OCC)OCC
Agent: C=C[SiH3]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCO[Si](CCP(=O)(c1ccccc1)c1ccccc1)(OCC)OCC
Product: c1ccc(Pc2ccccc2)cc1
Reaction time: 3 h
Yield: 16.7 %
Yield: 16.3 %

Procedure:
To a suspension of sodium diphenylphosphide prepared, under nitrogen in dry toluene (100 ml), from sodium (4.6, 0.2 g atom) and diphenylphosphinous chloride (22.0 g, 0.1 mol), vinyl triethoxysilane (19.0 g, 0.1 mol) is added during 45 minutes. A slight temperature rise occurs. The temperature is held at 30° C by adjusting the feed rate of the vinyl silane. After 3 hours, 5 ml anhydrous ethanol is added. The yellow color of the anion is instantly discharged. The solution is filtered to remove inorganic salts. Gas chromatographic analysis confirms the presence of diphenyl phosphine and 2-(dipenylphosphinyl)ethyl triethoxysilane. After neutralization with carbon dioxide, the liquid is distilled giving 6.3 g (16.7 percent yield) of 2-(diphenylphosphinyl) ethyl triethoxysilane and 3.0 g (16.3 percent yield) of diphenylphosphine. The H'NMR spectrum of the silane is identical to that of the product of addition of diphenylphosphine to vinyl triethoxysilane with a radical initiator.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CS([C:35]1[N:40]=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:38]=[CH:37][N:36]=1)(=O)=O.[OH2:49]>O1CCCC1>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C@@H:18]([CH3:21])[CH2:19][O:20][C:35]3[N:40]=[C:39]([O:41][C:42](=[O:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:38]=[CH:37][N:36]=3)[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](CO)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Reactant: CS(=O)(=O)c1nccc(OCc2ccccc2)n1
Reactant: O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H](COc1nccc(OC(=O)c2ccccc2)n1)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Reaction time: 16 h

Procedure:
1.05 g of (R)-3-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-2-methyl-propan-1-ol (3.02 mmol) were dissolved in 8 ml of tetrahydrofuran. At 0° C., 1.71 ml (3.37 mmol) of n-butyllithium (2 M in pentane) were added within 15 minutes. 0.85 g of 2-methylsulfonyl-4-benzyloxy-pyrimidine (3.21 mmol), dissolved in 5 ml of tetrahydrofurane, were added. Stirring continued for 16 h at room temperature. By cooling with, 2 ml of water were added. The obtained mixture was poured into 15 ml of water and extracted three times with 15 ml of diethyl ether each. The organic layers were combined, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified via silica gel chromatography with dichloromethane, dichloromethane/ethyl acetate 9:1, and dichlormethane/ethyl acetate 3:2 to yield 0.83 g of the product.