Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:10][C:11]1[C:16]([CH:17]=[O:18])=[C:15](Cl)[N:14]=[C:13]([S:20][CH3:21])[N:12]=1.O>CS(C)=O.CCOC(C)=O>[Cl:10][C:11]1[C:16]([CH:17]=[O:18])=[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:14]=[C:13]([S:20][CH3:21])[N:12]=1
Reactant: Nc1ccccc1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc(Cl)c(C=O)c(Nc2ccccc2)n1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of aniline (550 microliter (hereinafter “μL” or “uL”), 6 millimoles (hereinafter “mmol”), 1.2 equivalents (hereinafter “eq”)) in dry DMSO (100 mL) was added NaH as a 60% suspension in mineral oil (240 milligrams (hereinafter “mg”), 6 mmol, 1.2 eq) and the reaction mixture was stirred for 1 hour (hereinafter “h”). To the red solution was then added 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (1.11 grams (hereinafter “g”), 5 mmol) [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445-45] dissolved in anhydrous DMSO (20 milliliters (hereinafter “mL”)). The reaction mixture turned yellow and was stirred 2 h at 23°, H2O (250 mL) was added followed by EtOAc (500 mL). The layers were separated; the organic layer was washed with saturated (hereinafter sat'd) aq. NaCl, dried (MgSO4) and filtered. The organic layer was evaporated and the crude residue was dissolved in isopropanol (50 mL) and heated to 60°, H2O (50 mL) was added and the solution was cooled slowly to 23°. The product was isolated by filtration and dried in vacuo to afford 1.06 g (76% yield) of pure 4-chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde. 1H-NMR δ 2.59 (s, 3H), 7.21 (m, 1H), 7.44 (m, 2H), 7.68 (m, 2H), 10.37 (s, 1H), 11.38 (br s, 1H). LC MS (m/e)=280 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:42])[C@H:4]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:5]([Cl:15])[NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C(O)C.O.[NH4+].[OH-]>>[Cl:15][CH:5]([C@@H:4]([NH:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)=[CH:24][CH:25]=1)(=[O:18])=[O:19])[C:3]([OH:42])=[O:2])[NH:6][C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(Cl)NC(=O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC(Cl)[C@@H](NS(=O)(=O)c1ccc(OCCC2CCNCC2)cc1)C(=O)O)c1ccccc1
Yield: 36.2 %

Procedure:
Utilizing the procedure for convening 9-5 to 9-6, 15-5 (275 mg, 0.46 mmol) gave 15-6 (85 mg) after flash chromatography (silica, 10:1:1 ethanol/H2O/NH4OH). Rf 0.39 (silica, 10:1:1 ethanol/H2O/NH4OH).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[N:20]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:21]([C:24]2[O:25][C:26]([CH3:29])=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[C:6]([CH3:34])[CH:5]=1.Cl.C(OCC)(=O)C.O>O1CCOCC1.[OH-].[Na+].CO>[CH3:34][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=1[N:20]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:21]([C:24]1[O:25][C:26]([CH3:29])=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]([OH:35])=[O:2]
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2N(CC(C)C)S(=O)(=O)c2ccc(C)o2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)c2cc(C)c(C)cc2OCc2ccc(C(=O)O)cc2C)o1
Temperature: 25 °C
Reaction time: 30 h
Yield: 91.4 %

Procedure:
To a solution of 3-methyl-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid methyl ester prepared in Example 1 (850 mg) in dioxane (10 ml), 2N aqueous sodium hydroxide (2.5 ml) and methanol (4 ml) were added, and the mixture was stirred for 30 hours at room temperature. To the mixture, 2N hydrochloric acid was added, then ethyl acetate-water (30 ml-15 ml) was also added. The organic layer was washed, dried and concentrated under reduced pressure. The residue was dissolved in hot ethanol (40 ml) and added by hot water (40 ml), then allowed to cool. Precipitation was filtrated, and dried to give the title compound (755 mg) having the following physical data.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:11](=[O:19])OC3C=CC=CC=3)[CH:9]=[C:4]2[CH:3]=[N:2]1.[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=[C:29]([C:35]([F:38])([F:37])[F:36])[N:28]=2)[CH2:23][CH2:22]1>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:20][CH:21]1[CH2:22][CH2:23][N:24]([C:27]2[C:32]([CH2:33][NH:34][C:11]([NH:10][C:8]3[CH:9]=[C:4]4[CH:3]=[N:2][NH:1][C:5]4=[N:6][CH:7]=3)=[O:19])=[CH:31][CH:30]=[C:29]([C:35]([F:38])([F:36])[F:37])[N:28]=2)[CH2:25][CH2:26]1
Reactant: O=C(Nc1cnc2[nH]ncc2c1)Oc1ccccc1
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CN)CC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)Nc2cnc3[nH]ncc3c2)CC1
Temperature: 50 °C
Yield: 71.5 %

Procedure:
To a solution of phenyl 1H-pyrazolo[3,4-b]pyridin-5-ylcarbamate (C) (84 mg, 0.329 mmol) in acetonitrile was added DMAP (40 mg, 0.329 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (D) (90 mg, 0.329 mmol) at room temperature. The reaction mixture was heated to 50° C. for 15 h. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic part was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography to give pure 1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)urea (example compound 5) (102 mg, 71%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.[H][H]>CO.[Pd]>[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[F:1])[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(=O)O)ccc1F

Procedure:
4-Fluoro-3-nitrobenzoic acid (270 mg, 2 mmol) and 10% Pd/C (80 mg) in MeOH (10 mL) was hydrogenated with a hydrogen balloon for 6.0 h. LC-MS indicated a completion of reaction. The mixture was filtered and the filtrate was concentrated to give 19A. 1H NMR (400 MHz, CDOD3) δ ppm 7.00 (dd, J=10.99, 8.79 Hz, 1H) 7.27-7.36 (m, 1H) 7.49 (dd, J=8.79, 2.20 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[C:26]#[CH:27])[CH3:23].ClC1N=C(NCCNC(=O)OC(C)(C)C)C(C#CC(OCC)OCC)=CN=1>>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]([C:27]#[C:26][CH:25]([O:28][CH2:29][CH3:30])[O:24][CH2:22][CH3:23])=[CH:7][N:6]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Reactant: C#CC(OCC)OCC
Agent: CCOC(C#Cc1cnc(Cl)nc1NCCNC(=O)OC(C)(C)C)OCC
Product: CCOC(C#Cc1cnc(Cl)nc1NC(C)(C)CNC(=O)OC(C)(C)C)OCC

Procedure:
tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamate is synthesized by treating tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate with 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddba using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4 yl]amino]ethyl]carbamate LCMS (ESI) (M+H) 427.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].P([O-])(O)(O)=[O:16].[Na+].S(N)(=O)(=O)O.Cl([O-])=O.[Na+].Cl>O1CCOCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[C:7]([OH:16])=[O:8])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CCOc1cc(C=O)cc(OC)c1O
Agent: Cl
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(C(=O)O)cc(OC)c1O
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 3-ethoxy-4-hydroxy-5-methoxybenzaldehyde (578 mg), sodium dihydrogenphosphate (1.41 g), and amidosulfuric acid (429 mg) in dioxane (6 mL)-water (10 mL) was added an aqueous solution (3 mL) of sodium chlorite (400 mg) under ice-cooling. The mixture was stirred for 2 hours under ice-cooling. Hydrochloric acid was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous sodium thiosulfate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (586 mg).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][C:7]([CH3:12])([CH3:11])[C:8](=O)[CH3:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:6][C:7]([C:8]([CH3:9])=[C:2]([C:1]#[N:5])[C:3]#[N:4])([CH3:12])[CH3:11]
Reactant: CC(=O)C(C)(C)C
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=C(C#N)C#N)C(C)(C)C
Yield: 68.4 %

Procedure:
A solution of 9.9 g of malononitrile, 26.25 g of 3,3-dimethyl-2-butanone, 1.45 g of ammonium acetate and 2.25 g of acetic acid dissolved in 100 ml of toluene was refluxed for about 16 hours with the aid of a Dean-Stark Trap. The reaction mixture was diluted with 120 ml of toluene and washed with 200 ml water. The organic phase was collected, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The resulting residue was distilled under vacuum to afford 15.2 g of 2-(1,1-dimethylethyl)-1,1-dicyano-1-propene as an oil. Yield 68%.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6](=[O:17])[C:7]([N+:14]([O-:16])=[O:15])=[C:8]1[NH:13][CH2:12][CH2:11][CH2:10][S:9]1.[Cl:23]N1C(=O)CCC1=O.[O-][Si]([O-])=O.[Mg+2]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:23][N:13]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[C:7]([N+:14]([O-:16])=[O:15])[C:6](=[O:17])[CH2:5][O:4][C:3]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=1[Cl:1]
Reactant: O=C(COc1ccc(Cl)cc1Cl)C(=C1NCCCS1)[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(COc1ccc(Cl)cc1Cl)C(=C1SCCCN1Cl)[N+](=O)[O-]

Procedure:
3.6 g of 1 and 2.1 g of N-chlorosuccinimide were combined in 150 ml of carbon tetrachloride and the mixture was refluxed for 1 hour. The resulting mixture was filtered through Celite and the solvent was evaporated to give a liquid, which was triturated in ether, decolorized with activated charcoal and filtered through Celite and stripped of solvent to give a yellow cloudy liquid. This was passed through Florisil, using methylene chloride as eluent; then stripped to give an oil, which was kept in a refrigerator over a week-end. Part of the oil crystallized. On scratching, more crystals formed. Separation of the crystals gave 2, as bright yellow crystals, m.p. 103°-105°.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH2:4]1.[H-].[Na+].I[CH3:23]>CN(C=O)C>[CH3:23][O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])[CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](CO)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
Racemic trans 2-(3-hydroxymethyl-cyclohexyl)-isoindole-1,3-dione (0.37 g, 1.427 mmol) was dissolved in DMF (7 mL) and cooled to 0° C. At that temperature, NaH (60%, 0.136 g, 3.424 mmol) was added, followed by iodomethane (0.54 mL, 8.676 mmol) about 10 minutes later. After another 10 minutes the ice bath was removed, and the reaction mixture was heated to 38° C. After 3 hours, another 6 equivalents of iodomethane were added and the reaction mixture was stirred at 38° C. overnight before being cooled, quenched by addition of saturated aqueous NH4Cl, and extracted times with Et2O. The organic layers were combined, dried (Na2SO4), filtered, and evaporated. The remaining orange oil was purified by SiO2 chromatography (24 g SiO2, hexanes/EtOAc 0 to 10% EtOAc) to give 0.21 g of racemic trans 2-(3-methoxymethyl-cyclohexyl)-isoindole-1,3-dione as white crystalline solid (54% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][C:15]1([CH3:29])[C:20](=[O:21])[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16]1>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]2([OH:21])[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:16][C:15]2([CH3:29])[CH3:14])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
A solution of 4-bromochlorobenzene (136.6 g, 0.71 mol) in anhydrous THF (1000 mL) was cooled to −78° C., and then treated dropwise with a 1.6 M solution of n-butyllithium in hexanes (466 mL, 0.75 mol) at a rate which maintained the internal temperature below −60° C. The resulting mixture was stirred at −78° C. for 1.5 hours, during which a precipitate was observed. The resulting suspension was treated dropwise with a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (73.7 g, 0.32 mol) in anhydrous THF (400 mL) at a rate which maintained the internal temperature below −60° C. The mixture was stirred at −78° C. for 2 hours, during which a clear solution was observed. The reaction mixture was quenched with saturated ammonium chloride (300 mL) and the resulting mixture was allowed to come to room temperature. The aqueous and organic layers were separated, and the organic phase was concentrated in vacuo to yield a residue. The aqueous phase was extracted 2× with ethyl acetate (300 mL). The combined extracts were added to the residue from the original organic phase, and the resulting mixture was diluted to 1200 mL with ethyl acetate. The resulting solution was washed 2× with water (300 mL), once with brine, dried over sodium sulfate, and concentrated in vacuo to yield a residue. The residue was digested with boiling hexanes (300 mL), and the resulting suspension was cooled to room temperature. Once at the prescribed temperature, white solids were collected by filtration, and washed 2× with hexanes and then air dried to yield the title compound as a powder (93.7 g, 85% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](O)(=[O:14])=[O:13])=[CH:4][C:3]=1[N:16]=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][S:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([N:16]=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:4]=1)(=[O:14])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cc(N=Nc2ccccn2)c(O)c2ccccc12
Product: O=S(=O)(Cl)c1cc(N=Nc2ccccn2)c(O)c2ccccc12
Temperature: 25 °C

Procedure:
A mixture consisting of 10 g of 4-hydroxy-3-(2-pyridylazo)-1-naphthalenesulfonic acid prepared by the process of Japanese patent application (OPI) No. 35533/78 (the term "OPI" as used herein means "unexamined published patent application"), 100 ml of sulforan, and 15 ml of phosphorous oxychloride was heated at an inner temperature of from 55° to 65° C. for 3 hours while stirring. The reaction mixture was cooled to room temperature and poured into 1 l of ice-water. The precipitated crystals were collected by filtration, washed with water, and air-dried to obtain 10.1 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:20][N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](Cl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:22](=[O:23])[N:21]([CH3:20])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:15][CH:14]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2nc(-c3ccc(Cl)cc3)cs2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(-c2nc(-c3ccc(Cl)cc3)cs2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-[4-(4-chloro-phenyl)-thiazol-2-yl]-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (59%, white crystals). HPLC-MS m/z=421.1 (M+1), Rt: 5.85 min
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:9]#[N:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NC(=O)c1nc(Br)cnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
3-amino-6-bromo-pyrazine-2-carboxamide (500 mg, 2.304 mmol) was dissolved in pyridine (5 mL) and treated with POCl3 (666 μL, 7.145 mmol) dropwise at 0° C. After the addition was complete the reaction was allowed to warm to ambient temperature and stirred for 1.5 hours. The solvent was removed in vacuo and the reaction carefully treated with NaHCO3 to basify. The mixture was diluted with EtOAc and the layers separated. The aqueous layer was further extracted with EtOAc (1×) and the combined organics washed with brine (1×), 0.1 M HCl (1×) and water (1×), dried (MgSO4), filtered and concentrated to furnish the product as a brown solid (197 mg, 43% Yield). 1H NMR (DMSO) d 7.62 (2H, br s), 8.45 (1H, s) ppm
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Cl:9][C:10]1[CH:24]=[CH:23][C:13]([O:14][CH:15]([F:22])[C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:12][CH:11]=1>CS(C)=O.C1COCC1>[C:17]([C:16]1([CH:15]([O:14][C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:24][CH:23]=2)[F:22])[CH2:2][O:21]1)([CH3:19])([CH3:20])[CH3:18]
Reactant: CC(C)(C)C(=O)C(F)Oc1ccc(Cl)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C1(C(F)Oc2ccc(Cl)cc2)CO1

Procedure:
43 g of trimethyloxosulfonium iodide were added in portions to a dispersion of 5.28 g of 80% sodium hydride in 300 ml of absolute DMSO under a nitrogen atmosphere, while stirring. When the exothermic reaction had subsided, the mixture was stirred for a further 1 h, a solution of 40 g of 1-(4-chlorophenoxy)-3,3-dimethyl-1-fluoro-2-butanone in 100 ml of THF was then added dropwise at RT and the mixture was stirred at RT for a further 2 h. The reaction solution was then poured onto ice-water and extracted several times with diethyl ether. The combined extracts were washed with water, dried over sodium sulfate and filtered and the filtrate was concentrated. Yield of crude product: 41.5 g in the form of a yellow-brown oil, which can be either purified by column chromatography or further processed without purification.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:18][CH2:17]1)[CH3:3].[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][C:39]=1[C:40](O)=[O:41].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>ClCCl.CO.ClCCl>[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][C:39]=1[C:40]([N:27]1[CH2:28][CH2:29][C:25]([CH2:24][CH2:23][N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:8]3[N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:17][CH2:18]2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)=[O:41]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(O)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: O
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(O)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.53 g, 1.0 mmol), 2-methoxy-5-hydroxybenzoic acid (0.17 g, 1.0 mmol), 1-hydroxybenzotriazole hydrate (0.13 g, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.19 g, 1.0 mmol), and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol) in dichloromethane-(10 mL). After 18 hours, dilute the reaction mixture with dichloromethane and extract with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 3% methanol/dichloromethane, 5% methanol/dichloromethane, 7% methanol/dichloromethane, and then 10% methanol/dichloromethane to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].Cl>ClCCl.O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (5.93 g, 48.56 mmol) and triethylamine (10 mL) in 50 mL of dichloromethane was added tosyl chloride (11.8 g, 61.89 mmol). The reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with water, acidified with 1 N HCl, and extracted into methylene chloride. The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (9:1 hexanes:ethyl acetate to 5:1 hexanes:ethyl acetate) to afford 9.50 g (71%) of the title compound of Step A. 1HNMR (CDCl3): δ 9.81 (s, 1H), 7.69 (d, 2H, J=8.8 Hz), 7.57 (d, 2H, J=8.4 Hz), 7.19 (d, 2H, J=8.4 Hz), 7.03 (d, 2H, J=8.4 Hz), and 2.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12]1([SiH:18]2[CH2:23][CH2:22][C:21](CCC=CC)([CH:24]3[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)C=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C@H:27]2[CH2:26][CH2:25][C@H:24]([CH:21]3[CH2:20][CH2:19][SiH:18]([CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:23][CH2:22]3)[CH2:29][CH2:28]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1F
Reactant: CC=CCCC1(C2CCC(O)CC2)CC[SiH](c2ccccc2)CC1
Product: C=CCCC[SiH]1CCC([C@H]2CC[C@H](OC(=O)c3ccc(Cl)cc3F)CC2)CC1

Procedure:
The general procedure of Example 31 was repeated using 4-chloro-2-fluorobenzoic acid and 4-(4-phenyl-(3-pentenyl)-4-silacyclohexyl)cyclohexanol, thereby obtaining the intended product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]#[N:22])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:7]([N:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH2:22])[CH2:18][CH2:19]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CCN1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: NCCN1CCN(Cc2ccccc2)CC1
Yield: 89.2 %

Procedure:
To a suspension of lithium aluminum hydride (5.0 g) in anhydrous THF (150 ml) was added a solution of (4-benzyl-1-piperazinyl)acetonitrile (11 g) obtained in Example 95a) in anhydrous THF (50 ml) under ice-cooling. The reaction solution was refluxed for 3 hours, to the reaction solution was then added sodium sulfate decahydrate (420 g) under ice-cooling, and mixed for 15 hours. The reaction solution was diluted with THF, the precipitate obtained by decantation was filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound as pale yellow liquid (10 g, 95%).