Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:23][C:24](=O)[CH:25]=[C:26]1[CH2:31][CH:30]([CH2:32][CH3:33])[CH2:29][CH2:28][C:27]1=O)C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]1[C:27]2[C:26]([CH2:31][CH:30]([CH2:32][CH3:33])[CH2:29][CH:28]=2)=[CH:25][C:24]1=[O:23]
Reactant: Cc1cccc(Cl)c1N
Reactant: CCOC(=O)C=C1CC(CC)CCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1CC=C2C(=CC(=O)N2c2c(C)cccc2Cl)C1
Temperature: 22 °C

Procedure:
3.45 g of 2-Chloro-6-methyl-aniline are dissolved in 26 ml of toluene. 0.227 g of p-toluene-sulfonic acid (mono hydrate) are added and the mixture is heated to reflux. A solution of 5.0 g of (5-Ethyl-2-oxo-cyclohexylidene)-acetic acid ethyl ester in 13 ml of toluene is added drop-wise during 75 minutes and the water formed is collected by the means of a water separator. The reaction mixture is heated to reflux for 15 hours, during which time the condensing solvent is frequently removed and replaced by fresh toluene. For work-up, the mixture is cooled to 22° C. and is treated with 70 ml of saturated aqueous sodium bicarbonate solution under rigorous stirring. The layers are separated and the toluene phase is washed with a 5% aqueous solution of citric acid and finally with a 10% solution of sodium chloride in water. The aqueous phases are extracted with 70 ml of toluene and the toluene phases are combined. The solvent is evaporated in vacuo to yield 7.1 g of the crude product as a highly viscous oil. An analytical sample of the crude product can be purified by chromatography on silica gel using toluene/ethyl acetate (9:1) as eluent to yield pure 1-(2-Chloro-6-methyl-phenyl)-5-ethyl-1,4,5,6-tetrahydro-indol-2-one.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[N:18]([CH2:19][CH2:20]O)[CH:13]([CH2:14][CH2:15]2)[CH:12]=1.CS([Cl:26])(=O)=O.CCN(CC)CC.C(Cl)Cl>O>[Cl:26][CH2:20][CH2:19][N:18]1[CH:16]2[CH2:15][CH2:14][CH:13]1[CH:12]=[C:11]([C:2]1[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=1)[CH2:17]2
Reactant: OCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: ClCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Yield: 50 %

Procedure:
2-[3-(2-Naphthyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]ethanol (0.95 g, 3.40 mmol), 0.42 g (3.70 mmol) MsCl, 0.71 mL (515 mg, 5.10 mmol) Et3N and 20 mL CH2Cl2 are stirred at 23 C in for 12 h. The reaction mixture is poured into 200 mL of H2O and extracted with 3×50 mL CH2Cl2. The combined organics are washed with H2O (3×100 mL,) brine (1×100 mL), dried over MgSO4, filtered, and the volatiles are evaporated. Flash chromatography on SiO2 gel, eluting with EtOAc/MeOH (20/1 to 10/1), gives 0.50 g (1.68 mmol, a 50% yield) of the title compound as a tan solid. mp: 122-123° C.; MS (ES) m/z 298 (MH)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]2[NH:41][CH:40]([C:42](O)=[O:43])[CH2:39][S:38]2)[CH:32]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][C:42]([CH:40]2[CH2:39][S:38][CH:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[NH:41]2)=[O:43])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Reactant: NCCNCCCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCNCCCc1ccccc1)C1CSC(c2cccnc2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of 200 mg of 3-phenylpropylethylenediamine and 81 mg of N-methylmorpholine in 5 ml of dimethylformamide, there were added in sequence 120 mg of 1-hydroxybenzotriazole, 180 mg of dicyclohexylcarbondiimide and 170 mg of 2-(3-pyridyl)thiazolidine-4-carboxylic acid. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. After addition of 0.5N aqueous sodium hydroxide, the residue was extracted with ethyl acetate. The organic layer was extracted with 1N hydrochloric acid, and the aqueous layer was adjusted to pH 10 with potassium carbonate and extracted again with ethyl acetate The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to alumina column chromatography (20 g). Elution with methanol-ethyl acetate (1:10) gave 160 mg of N-(3-phenylpropylaminoethyl)-2-(3-pyridyl)thiazolidine-4-carboxamide. The NMR and MS data for this compound were in agreement with those given in Examples 115.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].O[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCCCCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: O=Cc1cccc(O)c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1oc(-c2ccccc2)nc1CCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
2-(5-methyl-2-phenyloxazol-4-yl)ethanol (1.02 g), 3-hydroxybenzaldehyde (0.73 g) and triphenylphosphine (1.57 g) were dissolved in dichloromethane (10 ml) and thereto was added 1,1′-(azodicarbonyl)dipiperidine (1.74 g) at 0° C. and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added hexane and the solid was filtered off. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (methanol:chloroform=1:100) to give the title compound (1.30 g) having the following physical data.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].ClCCl.[OH:9][CH2:10][C@@H:11]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][N:13]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)=[O:23])[CH2:12]1>C(N(CC)CC)C>[CH3:1][S:2]([O:9][CH2:10][C@@H:11]1[C@@H:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][N:13]([C:22]([O:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:30]=2)=[O:23])[CH2:12]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(OC(=O)N2C[C@H](CO)[C@@H](c3ccccc3)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](COS(C)(=O)=O)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A 0.84 ml portion of methanesulfonyl chloride was added dropwise to a 30 ml dichloromethane solution of 3.5 g of 4-(methoxycarbonyl)phenyl (3R,4S)-3-(hydroxymethyl)-4-phenylpyrrolidine-1-carboxylate and 2.75 ml of triethylamine, and stirred at room temperature for 2Hours. Thereafter, its work-up was carried out in the standard method to obtain 4.3 g of 4-(methoxycarbonyl)phenyl (3R,4S)-3-{[(methylsulfonyl)oxy]methyl}-4-phenylpyrrolidine-1-carboxylate as a colorless amorphous substance. EP: 434.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)=[O:9])[CH:3]=1.FC(F)(F)C(O)=O>>[ClH:1].[NH2:13][CH2:12][CH2:11][NH:10][C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc(Cl)ccn1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNC(=O)c1cc(Cl)ccn1

Procedure:
10.6 g of t-butyl [2-(4-chloropyridine-2-carboxamido)ethyl]carbamate were reacted with trifluoroacetic acid in an analogous manner to that described in Example 3, paragraph 2. The residue was converted into the hydrochloride which was recrystallized from methanol/ether, whereby there was obtained N-(2-aminoethyl)-4-chloropyridine-2-carboxamide hydrochloride as beige crystals, m.p. 228°-229°.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([S:19][CH3:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[OH:34].[Na+].[OH2:38]>CC(C)=O>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([S:19]([CH3:20])(=[O:34])=[O:38])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C([O-])O
Reactant: CSc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: O
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1

Procedure:
A solution of Oxone (trade mark)(potassium peroxymonosulphate) (44 g, 71.7 mmol) in water (200 ml) was added dropwise over 2 hours to a solution of N-(2,2-diphenylethyl)-2-(methylsulfanyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (Preparation 3) (25 g, 56.2 mmol) and sodium hydrogencarbonate (20 g, 238 mmol) in acetone (1000 ml) and water (250 ml). The resultant mixture was stirred at room temperature for 24 hours, filtered and the residue washed with acetone. The acetone was removed from the filtrate under reduced pressure and the resulting aqueous residue extracted with ethyl acetate and then dichloromethane. The combined organic layers were washed with brine, dried with anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was triturated with diethyl ether, filtered, washed with diethyl ether and pentane and then dried to afford the title compound as a white solid (20.32 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[NH:31][C:30]([CH3:35])=[CH:29]4)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[NH:31][C:30]([CH3:35])=[CH:29]4)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCCc4cc(F)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2cc(-c3nc4ccc(C(=O)O)cc4nc3N3CCCc4cc(F)ccc43)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of methyl 3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate (118 mg, 0.25 mmol) in methanol (20 ml) and water (1.0 ml) was added sodium hydroxide (40 mg, 1.00 mmol). The reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (20 mL) and adjusted to pH 4 with hydrogen chloride (3 N). The solids were collected by filtration to afford 3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylic acid as a light yellow solid (81 mg, 71%).
Reaction SMILES: [H-].[Na+].[H][H].Br[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([S:19]([N:22](C(OCC(C)C)=O)[C:23]3[C:28]([O:29][CH3:30])=[N:27][C:26]([CH3:31])=[CH:25][N:24]=3)(=[O:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:39][OH:40]>>[CH3:39][O:40][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([S:19]([NH:22][C:23]3[C:28]([O:29][CH3:30])=[N:27][C:26]([CH3:31])=[CH:25][N:24]=3)(=[O:20])=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: CO
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Product: COCc1ccc(-c2ncccc2S(=O)(=O)Nc2ncc(C)nc2OC)cc1

Procedure:
Oil-free sodium hydride (240 mg) was added to methanol (20 ml) with stirring. When evolution of hydrogen ceased, 2-(4-bromomethylphenyl)-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (549 mg) was added and the mixture was stirred for 2 hours. Volatile material was removed by evaporation and saturated ammonium chloride solution (10 ml) was added to the residue. The mixture was extracted with ethyl acetate (3×20 ml) and the extracts were dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (13:7 v/v), to give 2-(4-methoxymethylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (170 mg), m.p. 129-130° C. (after trituration with ether); microanalysis found: C, 56.9; H, 4.9; N, 13.9%; C19H20N4O4S requires: C, 57.0; H, 5.0; N, 14.0%.
Reaction SMILES: [Br:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:11])[C:4](=[O:12])[O:3]1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[Br-:1].[Cl:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:2]([P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[O:3][C:4]2=[O:12]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1OC(Br)c2c(Cl)cccc21
Solvent: C1CCOC1
Product: O=C1OC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c2c(Cl)cccc21
Product: [Br-]
Yield: 78 %

Procedure:
3-bromo-4-chloroisobenzofuran-1(3H)-one (100) (14 g, 56.57 mmol) and triphenylphosphine (14.84 g, 56.57 mmol) were dissolved THF (200 mL) and heated at reflux for 2 hours. The reaction was cooled and filtered, the filtrate was evaporated to the desired compound as a yellow gum (22.5 g, 78% yield); 1H NMR (400.132 MHz, CDCl3) δ 7.54-7.51 (2H, m), 7.65-7.59 (7H, m), 7.79-7.74 (3H, m), 8.07-8.02 (6H, m), 10.41 (1H, s); m/z (LC-MS, ESI+), RT=2.09 (M+H not detected).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([P:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Br:23][CH2:24][CH2:25][CH2:26][OH:27].P(=O)(O)(O)O>C1(C)C=CC=CC=1>[Br-:23].[OH:27][CH2:26][CH2:25][CH2:24][P+:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=1)([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Reactant: OCCCBr
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc([P+](CCCO)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Product: [Br-]
Temperature: 40 °C

Procedure:
Into a 50 milliliter glass reactor equipped with a thermometer connected to a temperature controller, a heating mantle, a condenser and a magnetic stirring bar, is charged 5.19 gms (0.0171 mole) of tri-p-tolyl phosphine and 23 gms of toluene. The slurry is heated to 40° C., then 2.85 gms (0.0205 mole) of 3-bromo-1-propanol is added. This reaction mass is heated to 40° C. in 1.2 hours, then increased the temperature to 80° C. and maintained at that temperature for 1 hour, then increased the temperature to 100° C. and maintained at that temperature for 1.75 hours, then cooled to 30° C., and then separated. The salt is washed with 10 gms of toluene, decanted and then vacuum dried. There is obtained 5.24 gms of an oily catalyst which has a chemical shift of 23.3 ppm (phosphoric acid reference).
Reaction SMILES: F[O-].[C:3]([C:7]([O:10]C(C(Cl)(Cl)F)Cl)([F:9])[F:8])([F:6])([F:5])[F:4].C(C(OC(C(F)Cl)(Cl)Cl)(F)F)(F)(F)[F:18]>>[C:3]([C:7]([O:10][F:18])([F:9])[F:8])([F:6])([F:5])[F:4]
Reactant: FC(Cl)(Cl)C(Cl)OC(F)(F)C(F)(F)F
Reactant: FC(Cl)C(Cl)(Cl)OC(F)(F)C(F)(F)F
Agent: [O-]F
Product: FOC(F)(F)C(F)(F)F
Reaction time: 3 h

Procedure:
The reaction is carried out for 3 hours. The raw product (65.0 g) is analyzed by GLC/MS. The hypofluorite conversion is 100% and the selectivity in the two reaction products CF3CF2O—CHCl—CFCl2 and CF3CF2O—CCl2—CHClF is equal to 61%.
Reaction SMILES: [Br-].[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]2)=[CH:38][CH:37]=1)#[N:35].O>COC(C)(C)C.O1CCCC1>[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH:14]=[C:45]2[CH2:46][CH2:47][CH:42]([C:39]3[CH:40]=[CH:41][C:36]([C:34]#[N:35])=[CH:37][CH:38]=3)[CH2:43][CH2:44]2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC[C@H]1CC[C@H](CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: N#Cc1ccc(C2CCC(=O)CC2)cc1
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CC=C2CCC(c3ccc(C#N)cc3)CC2)CC1
Reaction time: 0.17 h

Procedure:
A suspension of 10.6 g of 2-(trans-4-pentylcyclohexyl)ethyl-triphenylphosphonium bromide in 100 ml of dry t-butyl methyl ether was treated portionwise under an inert gas atmosphere at 5°-10° C. with 2.2 g of potassium t-butylate and the mixture was stirred for a further 10 minutes. Subsequently, a solution of 3.5 g of 4-(p-cyanophenyl)cyclohexanone in 50 ml of tetrahydrofuran was added dropwise over a period of 30 minutes to the orange suspension. The mixture was stirred at room temperature overnight and then treated with 50 ml of water. The aqueous phase was separated and extracted with diethyl ether. The combined organic phase was washed neutral with water, dried over sodium sulphate and concentrated. The residue was chromatographed on silica gel with hexane/ethyl acetate (vol. 95:5), thereby obtaining 3.8 g of p-[4-[2-(trans-4-pentylcyclohexyl)ethylidene]cyclohexyl]benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](OC)[CH:7]=1.N1C=CC=CC=1.[C:16]1([O:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C[O:29][CH2:28]C1>>[CH3:28][O:29][C:5]1[N:4]=[CH:3][C:2]([NH:1][C:23](=[O:24])[O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cncc(N)c1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)Oc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
3-Amino-5-methoxy-pyridine (5.00 g, 40.3 mmol) was dissolved in THF (80 mL), cooled to 0° C., treated with pyridine (4.07 mL, 50.4 mmol) followed by phenylchloroformate (5.32 mL, 42.3 mmol). The reaction mixture was slowly warmed to RT over several hours and stirred an additional 12 h. The mixture was partitioned between water and EtOAc. The organic layer was separated and the aqueous layer was extracted again. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the product as a reddish solid (9.45 g, 96%), which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:15](=[O:16])[N:11]2[CH2:12][CH2:13][CH2:14][N:10]2[C:9]=1[C:17]1[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=1)=[O:7].O[O:30][S:31]([O-:33])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[C:43]([O-])(O)=O.[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:15](=[O:16])[N:11]2[CH2:12][CH2:13][CH2:14][N:10]2[C:9]=1[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:31]([CH3:43])(=[O:33])=[O:30])[N:18]=1)=[O:7]
Reactant: O=C([O-])O
Reactant: CSc1nccc(-c2c(C(=O)NCc3ccccc3Cl)c(=O)n3n2CCC3)n1
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1nccc(-c2c(C(=O)NCc3ccccc3Cl)c(=O)n3n2CCC3)n1

Procedure:
To a solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-1-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylic acid 2-chloro-benzylamide, 15, (0.20 g, 0.48 mmol) in THF/MeOH (8 mL of 1:1 mixture) was added dropwise a solution of Oxone® (potassium peroxymonosulfate) (in H2O (8 mL). After stirring the reaction for 1.5 h at room temperature, the solution was poured into aqueous saturated NaHCO3. The aqueous phase is extracted with CHCl3 (×3). The combined organic phases are dried (MgSO4), filtered and concentrated in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1.CCOC(C)=O>[C:13]1([S:19][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCCc2cc(F)ccc21
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCCc2cc(Sc3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A solution of 6-fluoro-3,4-dihydro-2H-naphthalen-1-one (5.51 g, 33.56 mmol), benzenethiol (4.07 g, 3.79 mL, 36.92 mmol) and K2CO3 (9.28 g, 67.12 mmol) in 50 mL of N-methyl pyrrolidinone (NMP) was heated to 80° C. under argon and stirred at 80° C. for 2 hours. The reaction mixture was poured int 500 mL of water and diluted with 300 mL of EtOAc. The layers were separated and the aqueous layer was extracted twice with 250 mL of EtOAc. The combinded organic layers were washed with water, saturated brine, and then dried over MgSO4. The solvent was removed under reduced pressure to yield an oil which was eluted through silica gel using hexanes/EtOAc (9:1). Removal of solvent under reduced pressure provided 8.05 g (31.65 mmol, 94.31%) of 6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one as a pale yellow oil. MS: 255 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10]C)=[CH:4][C:3]=1[F:12].[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)C>C(Cl)Cl>[F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(F)c(F)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(F)c(F)cc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a solution of 1,2-difluoro-4,5-dimethoxybenzene (5 g, 28.71 mmol, Aldrich) in methylene chloride (300 mL) cooled to 0° C. was added aluminum chloride (14.16 g, 106.2 mmol, Fluka) in several portions. At the end of the addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 12 hours. Water was added to quench the reaction. Diethyl ether (200 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (50 mL). The combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 10% ethyl acetate in hexanes) yielded 4,5-difluoro-2-methoxy-phenol as dark oil (3.75 g, 82%).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([Cl:24])=[O:23]>>[ClH:24].[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=3)=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2ccc(N3CCN4CCC3CC4)cc2)c1
Product: Cl

Procedure:
Was prepared by Method G from 4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenylamine and 3-methoxybenzoyl chloride. Mp. 260° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH2:3]1.Cl[C:18]1[N:23]([CH3:24])[C:22](=[O:25])[CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:19]=1.C(N(CC)CC)C>O1CCCC1>[CH3:24][N:23]1[C:22](=[O:25])[CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:19]=[C:18]1[N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH2:3]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: O=C(Nc1ccccc1)C1CCCNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCCC(C(=O)Nc3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 91.6 %

Procedure:
A solution of 3-piperidinecarboxanilide hydrochloride (96.0 mg, 0.40 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (66.0 mg, 0.30 mmol) and triethylamine (0.33 ml, 2.50 mmol) in tetrahydrofuran (3 ml) was stirred at room temperature for 3 hours. The whole reaction mixture was evaporated in vacuo and the precipitate was washed with water and diethyl ether to give the title compound (107 mg, 92%).