Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:3]=1[CH:26]([CH2:31][CH2:32][CH3:33])[C:27]([O:29]C)=[O:28].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=2)[C:3]=1[CH:26]([CH2:31][CH2:32][CH3:33])[C:27]([OH:29])=[O:28]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(OC(F)(F)F)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(OC(F)(F)F)cc1)CCCC3
Temperature: 60 °C
Yield: 3.8 %

Procedure:
To a solution of methyl [2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.271 g; 0.568 mmol) in methanol (5.7 mL) was added a solution of sodium hydroxide 5 N (1.1 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 1) furnished 0.010 g (4%) of the title compound as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[NH2:9][CH2:10][CH2:11][CH2:12][OH:13].C([O-])(O)=O.[Na+].C(O)(CC)(C)C>C(Cl)Cl>[OH:13][CH2:12][CH2:11][CH2:10][NH:9][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: [O-][n+]1ccccc1Cl
Reactant: NCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)(C)O
Solvent: ClCCl
Product: [O-][n+]1ccccc1NCCCO
Temperature: 67 °C
Reaction time: 23 h
Yield: 80.3 %

Procedure:
A mixture of 2-chloropyridine-N-oxide (16.6 g, 100 mmoles), 3-amino-1-propanol (15.3 ml, 200 mmoles), NaHCO3 (42 g, 0.5 mole), and tert-amyl alcohol (100 ml) was heated to reflux. After 23 hours, the reaction was cooled, diluted with CH2Cl2 (300 ml), and filtered to remove insoluble materials. The filtrate was concentrated to afford a brown oil. The oil was dried under vacuum overnight. Ether (100 ml) was added to give a brown solid. The ether was decanted and the solid was washed further with ether/acetonitrile (3/1). The resulting solid was heated at 67° C. under vacuum to give the desired product (13.5 g). 1H NMR was consistent with the proposed structure.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]3[N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[N:19][C:15]=3[CH:14]=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[H-].[Na+].I[CH3:33]>O1CCCC1>[CH3:33][N:4]([C:5]1[CH:6]=[C:7]([C:11]2[C:16]3[N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[N:19][C:15]=3[CH:14]=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[C:1](=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)Nc1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)c1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Temperature: 40 °C
Yield: 36.1 %

Procedure:
To a solution of 7-(3-acetamidophenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.35 g, 0.88 mmol) in anhydrous tetrahydrofurane (5 ml) was added sodium hydride (0.09 g 60% dispersion in mineral oil, 2.2 mmol). The resultant mixture was stirred for one hour at ambient temperature, whereafter iodomethane (0.44 ml, 7 mmol) was added and the temperature was raised to 40° C. for 30 min. The cooled mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The concentrate was eluted through silica gel with a mixture of dichloromethane and methanol (97:3, v/v). Removal of solvent from the eluate afforded the title product (0.13 g, 36%) m/z, 410.1 (M+H)+.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>CO>[CH:1]([N:14]1[CH2:18][CH:17]([OH:19])[CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: ClCC1CO1
Solvent: CO
Product: OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.8 %

Procedure:
A mixture of benzhydrylamine (25.0 g, 136 mmol), epichlorohydrine (12.6 g, 136 mmol) in MeOH (55 mL) was stirred for 3 days at room temperature. Then the mixture was stirred under reflux for 2 days. After cooling, the solvent was evaporated in vacuo and the resulting solid was washed with acetone (30 mL). Then the solid was suspended in Et2O (500 mL) and washed with aqueous 6N NaOH (100 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford a product (13.6 g, 42%). This compound was used for the next reaction without further purification.
Reaction SMILES: [CH:1](=[C:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)[CH3:2].[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[CH2:15].S(=O)(=O)(O)O>CCCCCC>[C:13]([O:18][C:3]1([CH2:1][CH3:2])[CH:4]2[CH2:12][CH:8]3[CH2:7][CH:6]([CH2:11][CH:10]1[CH2:9]3)[CH2:5]2)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: CC=C1C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Temperature: 80 °C

Procedure:
70 g of 2-ethyl-2-adamantanol was dissolved in toluene, 1 g of p-toluenesulfonic acid was added, and water was removed by distillation by use of a Dean and Stark dehydrator under heating so as to obtain 2-ethylideneadamantane. To 50 g of the obtained 2-ethylideneadamantane, 500 g of methacrylic acid and 0.1 ml of concentrated sulphuric acid were added, and the resulting mixture was heated at 80° C. for 5 hours. After hexane was added to the obtained reaction mixture, the mixture was washed with water, a 5% sodium hydroxide solution, and water in turn, and it was confirmed that the pH of an aqueous phase became 8. After the washed organic phase was concentrated, unreacted 2-ethylideneadamantane was partially removed by sublimation so as to obtain crude 2-ethyl-2-adamantyl methacrylate containing 80% by weight of 2-ethyl-2-adamantyl methacrylate.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[C:18](Cl)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([N:7]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc2c(c1)N(C(C)=O)c1ccccc1S2
Temperature: 0 °C

Procedure:
30 g (0.118 mol) of 2-acetylphenothiazine and 9.28 g (1 eq.) of acetyl chloride are introduced into a 500 ml flask containing 150 ml of toluene. The reaction mixture is heated to reflux for 45 minutes before the introduction of a new portion of 4.6 g (0.5 eq.) of acetyl chloride. Stirring is maintained under heating at reflux for another 2 hours. The reaction medium is then poured onto approximately 200 g of ice. After stirring, the organic phase is decanted and washed successively with 100 ml of water and 100 ml of salt water. The organic solution is dried over sodium sulphate, filtered and concentrated to dryness using a rotary evaporator. A yellow solid (33 g; 100%) is obtained which is used in the following stage without additional purification.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:44])([F:43])[C:4]1[CH:5]=[C:6]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]=CC2C=CC=CC=2O)[CH2:11][C@H:10]1[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:8].C(OCC)(=O)C.CO>O1CCOCC1>[ClH:1].[ClH:1].[NH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:7](=[O:8])[C:6]2[CH:5]=[C:4]([C:3]([F:43])([F:44])[F:2])[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=2)[C@H:10]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)[CH2:11]1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCN=Cc2ccccc2O)C[C@H]1Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: NCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
Hydrochloric acid (0.22 ml) was added to a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[N-(2-hydroxybenzylidene)-2-aminoethyl]-2-(1H-indol-3-yl-methyl)piperazine (0.80 g), ethyl acetate (12 ml) and methanol (6 ml) at room temperature. The mixture was stirred at 50° C. for 4.5 hours and then concentrated in vacuo to give an oil. The oil was treated with 4N hydrogen chloride in dioxane solution (0.33 ml) to afford (2R)-4-(2-aminoethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine dihydrochloride (0.57 g).
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Cl:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3](=[O:9])[CH2:2][O:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(CCl)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CCl)C(=O)COc1ccc(Cl)cc1
Reaction time: 15 h
Yield: 80.4 %

Procedure:
213 g (1 mol) of 1-bromo-4-chloro-3,3-dimethyl-butan-2-one were added dropwise to a boiling suspension of 128.5 g (1 mol) of 4-chlorophenol and 140 g (1 mol) of potassium carbonate in 1,000 ml of absolute acetone. The mixture was stirred for 15 hours under reflux and was then allowed to cool, and the inorganic residue was filtered off and rinsed with acetone. The filtrate was concentrated by distilling off the solvent in vacuo and the residue was taken up in 1,000 ml of methylene chloride, washed three times with 250 ml of water at a time, dried over sodium sulphate and distilled. 210 g (80.7% of theory) of 4-chloro-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one of boiling point 125°-127° C./0.1 mm Hg were obtained.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7]([N:16]=[C:17]=[O:18])[CH:8]=[CH:9][C:10]=1[O:11][S:12]([CH3:15])(=[O:14])=[O:13]>ClC1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([NH:16][C:17]([N:2]([CH3:3])[CH3:1])=[O:18])[CH:8]=[CH:9][C:10]=1[O:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CNC
Reactant: CS(=O)(=O)Oc1ccc(N=C=O)cc1Cl
Solvent: Clc1ccccc1
Product: CN(C)C(=O)Nc1ccc(OS(C)(=O)=O)c(Cl)c1

Procedure:
120 g of dimethylamine were introduced into a solution of 620 g of 3-chloro-4-methylsulfonyloxyphenylisocyanate (alternative name: methanesulfonic acid 2-chloro-4-isocyanatophenyl ester) in 2.5 liters of chlorobenzene at a temperature of 5°-22°C, whilst cooling. The crystals which thereupon formed were filtered off and dried. Yield: 714 g of N-(3-chloro-4-methylsulfonyloxyphenyl)-N',N'-dimethylurea, of melting point 130°-132°C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:12]([C:13]([O:15]CC)=[O:14])=[C:11]([OH:18])[C:10]2[C:5](=[CH:6][C:7]([C:19]([F:22])([F:21])[F:20])=[CH:8][CH:9]=2)[N:4]=1.[OH-].[Na+]>C(O)C>[F:23][C:2]([F:1])([F:24])[C:3]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([OH:18])[C:10]2[C:5](=[CH:6][C:7]([C:19]([F:22])([F:20])[F:21])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1O
Reaction time: 7 h
Yield: 94.8 %

Procedure:
A mixture of 21.38 g of the product of Step D, 300 ml of ethanol and 60.5 ml of sodium hydroxide solution was refluxed with stirring for 7 hours and the ethanol was then distilled under reduced pressure at 40° C. The residue was taken up in about 300 ml of water and the pH was adjusted to 1 by addition of 20% hydrochloric acid. The mixture was vacuum filtered and the recovered product was washed with water and was taken up in 350 ml of ether. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure to obtain 18.65 g of 2,7-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid melting at 240° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18](#[N:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[C:12]1([NH:11][C:18](=[NH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N=C(Nc1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
To NaHMDS (49 mL, 48.5 mmol, 1.0 M solution in THF) was added dropwise a solution of aniline (compound 11a, 4.5 mL, 48.5 mmol) in anhydrous THF (10 mL) under N2. After 20 min, a solution of benzonitrile (compound 21, 5.0 mL, 48.5 mmol) in anhydrous THF (10 mL) was slowly added. The reaction mixture was stirred for 12 hrs, poured into cold water and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[NH:17][C:18](=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C.CCCCCCC>CN(C=O)C>[CH3:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:15])[CH2:10][C:11]1[O:13][N:25]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:17]=1
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: N=C(NO)c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(Cc1nc(-c2ccccc2)no1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 15 h
Yield: 67.5 %

Procedure:
A solution of 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid (2.75 g, 12.7 mmol) and N,N′-carbonyldiimidazole (CDI; 2.05 g, 12.7 mmol) in DMF (20.0 mL) was stirred at RT under nitrogen atmosphere for 5 h. N-Hydroxybenzamidine (1.72 g, 12.7 mmol) was added and the reaction mixture was heated to 100° C. and stirred for 15 h. The crude reaction mixture was concentrated in vacuo, poured into ethyl acetate (100 mL) and extracted with water (3×100 mL). The combined aqueous layer was back-extracted with ethyl acetate (100 mL). The combined organic layer was dried over MgSO4, concentrated in vacuo and purified by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) to yield the product as white solid (2.72 g, 8.57 mmol, 67.5%). MS: M=318.1 (M+H)+
Reaction SMILES: C/C(/CC/C=C(\C)/CCC=C(C)C)=C\[CH2:4][CH2:5][C:6](OC(C)(C)C)=[O:7].Cl[CH2:25][CH:26]=[C:27]([CH3:39])[CH2:28][CH2:29][CH:30]=[C:31]([CH3:38])[CH2:32][CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.C(OCC)C>[CH3:39][C:27]([CH2:28][CH2:29][CH:30]=[C:31]([CH3:38])[CH2:32][CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])=[CH:26][CH2:25][CH2:4][CH2:5][CH2:6][OH:7]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCl
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(=O)OC(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCCCO
Reaction time: 1 h

Procedure:
A solution of 37.5 mL (20.3 mmol, 5.1 eq.) of a 0.54 M solution of Grignard reagent (Part (2)) in tetrahydrofuran and 9 mL of hexamethylphosphoramide at room temperature under argon was treated over 10 minutes with a solution of 955.5 mg (3.97 mmol) of farnesyl chloride (Part (1)) in 5 mL of tetrahydrofuran. After one hour, the reaction mixture was diluted with a mixture of 1:1 diethyl ether:hexane and quenched with 1 M HCl. The organic phase was washed with three 25 mL portions of saturated NaHCO3, three 25 mL portions of H2O, and 25 mL of brine, dried over MgSO4 and evaporated to obtain 995.0 mg of crude product. Purification required two chromatographies. The first was run on 70 g of silica gel, eluting with 1:99 ethyl acetate:CH2Cl2 to provide 484.3 mg of impure material and 307.7 mg of pure title compound. The second chromatography, of the impure fractions, on 50 g of silica gel eluted with 0.75:99.25 ethyl acetate:CH2Cl2 gave 117.2 mg of slightly impure material and 302.8 mg of pure title compound. Combination of pure material from both columns gave a yield of 610.5 mg (58%) of pure desired title isomer.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[S:10][C:11]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:28])=[O:27])[N:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1>O1CCCC1.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[S:10][C:11]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:28])=[O:27])[N:21]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)c1nccc(-c2sc(Cl)nc2-c2ccccc2)n1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2nc(-c3ccccc3)c(-c3ccnc(S(C)=O)n3)s2)CC1
Temperature: 25 °C

Procedure:
A solution of N-methylpiperazine (0.6 g, 6.0 mmol) in tetrahydrofuran (5 ml) is added to a well stirred solution of 4-(2-chloro-4-phenyl-thiazol-5-yl)-2-methylsulfinyl-pyrimidine (1.0 g, 3.0 mmol) in tetrahydrofuran (20 ml) at +5° C. The reaction mixture is allowed to warm to room temperature over night. Evaporation of the solvent leaves a crystalline residue that is suspended in water, filtered with suction, washed with diethyl ether and dried under vacuum. The product 4-[2-(4-methylpiperazin-1-yl)-4-phenyl-thiazol-5-yl]-2-methylsulfinyl-pyrimidine shows a m.p. of 166–169° C.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:21]([Cl:22])=[CH:20][C:17]([CH2:18]O)=[CH:16][C:15]=3[Cl:23])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:24]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1>C(#N)C>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:21]([Cl:22])=[CH:20][C:17]([CH2:18][Br:24])=[CH:16][C:15]=3[Cl:23])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(CO)cc3Cl)cc12
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(CBr)cc3Cl)cc12

Procedure:
Analogously to the procedure of Example VII, 4.8 g (12.66 mmol) of benzyl alcohol derivative from Example XVII are reacted with 6.95 g (16.46 mmol) of dibromotriphenylphosphorane and 1.6 g (20.26 mmol) of pyridine in 80 ml of acetonitrile.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[F:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[NH:36][CH:35]=[C:34]2[C:38]1[CH2:39][CH2:40][NH:41][CH2:42][CH:43]=1>CS(C)=O>[F:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[NH:36][CH:35]=[C:34]2[C:38]1[CH2:39][CH2:40][N:41]([CH2:12][CH:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)[CH2:42][CH:43]=1
Reactant: Fc1cccc2c(C3=CCNCC3)c[nH]c12
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC=C(c2c[nH]c4c(F)cccc24)CC1)O3
Temperature: 75 °C

Procedure:
(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzene sulfonate (0.55 g, 1.4 mmole) and 7-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.80 g, 3.7 mmole) were combined in 10 mL of DMSO. The mixture was heated at 70-80° C. under nitrogen for 6 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed, washed with 400 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was column chromatographed on silica gel using 0-2% methanol/chloroform. The product fractions were concentrated in vacuum to give 0.39 g of the (S)-enantiomer of the title compound as a pale yellow solid (m.p. 205-210° C.), which retains 0.25 equivalents of chloroform.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10]/[CH:11]=[C:12](/[CH:14]=[CH2:15])\[CH3:13])/[CH3:8])[CH3:3]>[Pd]>[CH3:15][CH2:14][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13]
Reactant: C=C/C(C)=C/C/C=C(\C)CCC=C(C)C
Agent: [Pd]
Product: CCC(C)CCCC(C)CCCC(C)C
Yield: 91.8 %

Procedure:
α-Farnesene (204 g, 1 mole, 255 mL) was added to a 500 mL Parr high pressure vessel containing 10% Pd/C (5 g, 5% by weight of α-farnesene). The reaction vessel was sealed and evacuated under house vacuum for 5 minutes after which time the reaction mixture was pressurized with H2 to 35 psi at 25° C. The reaction mixture was shaken until no further drop in the H2 pressure was observed (approximately 16 hours). The excess H2 gas was removed under house vacuum followed by venting to a N2 atmosphere. Thin layer chromatography (“TLC”, Rf=0.95, hexane, p-anisaldehyde stain or iodine) indicated the complete disappearance of the reactant. The reaction contents were vacuum filtered over a silica gel (60 Å from Aldrich) pad followed by washing of the silica gel with hexane (2 L). The filtrate was concentrated on a rotary evaporator. The isolated product was further dried under high vacuum to remove any residual hexane to afford farnesane as a colorless liquid (195 g, 244 mL, 95%). 1H-NMR (CDCl3, 500 MHz): δ 1.56-1.11 (m, 17H), 0.88-0.79 (overlapping t&d, 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].F[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([O:28][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccccn1
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1CCCCC(Oc2ccccn2)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 138, 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide, NaH, and 2-fluoropyridine are reacted to give the product after flash chromatography with CH2Cl2-MeOH. LC-MS: 480 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 8.0 (m, 2H), 7.60 (m, 1H), 7.45 (d, 1H), 6.85 (m, 2H), 6.75 (d, 1H), 6.05 (d, 1H), 5.20 (m, 1H), 4.10 (m, 1H), 3.75 (m, 4H), 3.25 (m, 4H), 2.28 (m, 1H), 2.10 (m, 3H), 1.85 (m, 2H), 1.70 (m, 1H), 1.40–1.60 (m, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5]2[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:3]=[C:2]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9](=[O:11])[CH2:8]1
Reactant: Nc1ccccc1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccn3)c2C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2c(Nc3ccccc3)cn(-c3ccccn3)c2C1
Yield: 43.4 %

Procedure:
A suspension of 3-bromo-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one (50 mg, 0.16mmol), aniline (17 μL, 0.19 mmol), sodium tert-butoxide (18 mg, 0.19 mmol) tris(dibenzylideneacetone)dipalladium (7.2 mg, 0.008mmol) and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1-binaphthyl (9.8 mg, 0.016 mmol) in toluene (3 mL) was heated at reflux for 3 h. The toluene was evaporated and the residue chromatographed on silica gel, eluting with isohexane: EtOAc (9:1→4:1). The title compound (23 mg, 43%) was isolated as a yellow solid. mp 135-138° C. Found: C, 73.98; H, 6.10; N, 12.33%. C21H21N3O0.0.45(H2O): C,74.29; H, 6.50; N, 12.38%. 1H NMR (360 MHz, d6-DMSO) δ 1.07 (6H,s), 2.37 (2H,s), 3.03 (2H,s), 6.81 (1H,t, J=7.4 Hz), 7.08 (2H,d, J=7.7 Hz), 7.25-7.29 (2H,m), 7.41 (1H,dd, J=7.2 and and 4.9Hz), 7.72 (1H,d, J=8.1 Hz), 8.01 (1H,d of t, J=7.6 and 1.8 Hz), 8.16 (1H,s), 8.57-8.60 (1H,m). MS (ES+) 332 (M+1).