Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:37]1([CH2:42][CH2:43]O)[CH2:41][CH2:40][CH:39]=[CH:38]1>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:43][CH2:42][CH:37]3[CH2:41][CH2:40][CH:39]=[CH:38]3)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Reactant: OCCC1C=CCC1
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCCC2C=CCC2)cc1

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-cyclopent-2-enyl-1-ethanol in place of 2-ethyl-1-hexanol (yield: 95 mg, 48%). mp 126–127° C. 1H NMR (300 MHz, DMSO-d6) δ 1.30 (m, 1H), 1.57 (sextet, J=7 Hz, 1H), 1.69 (sextet, J=7 Hz, 1H), 1.87 (m, 2H), 2.57 (m, 1H), 3.30 (s, 3H), 4.45 (m, 2H), 5.60 (m, 1H), 5.68 (m, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 473 (M+H)+; (APCI−) m/z 507 (M+Cl)−. Anal. calc. for C24H22F2N2O4S: C, 61.00; H, 4.69; N, 5.92. Found: C, 60.76; H, 4.65; N, 5.80.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21]>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2([OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CSc1ccccc1Br
Product: CSc1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 66.3 %

Procedure:
With 15.0 g of 1-bromo-2-(methylthio) benzene and 10.3 g of 5-chloroisatin as starting materials, 11.5 g of the title compound (orange red solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Zn+])=[CH:17][CH:16]=1.O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: Fc1ccc(C[Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)cnc1Cc1ccc(F)cc1
Temperature: 60 °C
Yield: 88 %

Procedure:
To a stirred solution of methyl 2,5-dichloronicotinate (Journal of Chemical and Engineering Data 1981, 26, 332, 350 mg, 1.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (196 mg, 0.17 mmol) in tetrahydrofuran (6 mL) was added a 0.5 M solution of 4-fluorobenzylzinc chloride in tetrahydrofuran (4.08 mL, 2.04 mmol) at 0° C. under nitrogen. The resulting mixture was heated at 60° C. for 16 h. The mixture was poured into water (50 mL) and the aqueous mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (6/1) to afford 416 mg (88%) of the title compounds as colorless oil: 1H-NMR (CDCl3) δ 8.64 (1H, d, J=2.6 Hz), 8.17 (1H, d, J=2.6 Hz), 7.24–7.20 (2H, m), 6.96–6.90 (2H, m), 4.50 (2H, s), 3.89 (3H, s).
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].Cl[CH2:8][CH:9]([OH:12])[CH2:10][OH:11]>O>[OH:12][CH:9]([CH2:10][OH:11])[CH2:8][S:1]([O-:4])(=[O:3])=[O:2].[Na+:5]
Reactant: O=S([O-])[O-]
Reactant: OCC(O)CCl
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CC(O)CO

Procedure:
Sodium sulfite (120 g, 924 mmol, content: 97.0%, produced by Wako Pure Chemical Industries, Ltd.) was dissolved in water (400 mL), and 3-chloro-1,2-propanediol (107.2 g, 970 mmol, produced by Wako Pure Chemical Industries, Ltd.) was added thereto. The solution was refluxed by heating for 1 hour. After completion of the reaction, the reaction solution was concentrated, thereafter methanol (750 mL) was added to the concentrated residue. The crystal formed was filtered, and the resultant crystal was dried, to obtain sodium 2,3-dihydroxypropanesulfonate relevant to the above-described general formula [2] (202.6 g, content: 67.2%, yield: 82.7%) as a white crystal. It should be noted that content of sodium 2,3-dihydroxypropanesulfonate was obtained by 1H-NMR using the internal standard method. In addition, it was confirmed that the above-described white crystal contained crystal of sodium chloride as a by-product. Measurement results of 1H-NMR are shown below.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29][N:30](C)C)#[N:2].N[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[C:37]#[N:38]>ClCCl.CO>[C:37]([C:36]1[CH:35]=[C:34]([NH:2][C:1]2[C:3]3[C:4](=[CH:5][C:6]([O:11][CH2:12][C:13]4[CH:14]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:16]=[CH:17][CH:18]=4)=[C:7]([O:9][CH3:10])[CH:8]=3)[N:28]=[CH:29][N:30]=2)[CH:41]=[CH:40][CH:39]=1)#[N:38]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Reactant: N#Cc1cccc(N)c1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4cccc(C#N)c4)c3cc2OC)c1
Yield: 71 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (100 mg, 0.22 mmol) with 3-aminobenzonitrile (31 mg, 0.26 mmol) and chromatography (silica gel, dichloromethane/methanol: 4/1) gives the desired product in 71% yield (82 mg).
Reaction SMILES: [CH3:1][C:2]1[O:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:4]=2[N:3]=1.Br[C:18]1[S:22][C:21]([C:23]#[N:24])=[CH:20][C:19]=1[CH3:25]>>[CH3:1][C:2]1[O:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7]([C:18]3[S:22][C:21]([C:23]#[N:24])=[CH:20][C:19]=3[CH3:25])[CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: Cc1cc(C#N)sc1Br
Reactant: CC1=Nc2ccc(Br)cc2C2(CCCC2)O1
Product: CC1=Nc2ccc(-c3sc(C#N)cc3C)cc2C2(CCCC2)O1

Procedure:
The title compound was prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,1-benzoxazine-4,1′-cyclopentane] and 5-bromo-4-methyl-2-thiophenecarbonitrile. A yellowish solid: mp 58-60° C.; 1H-NMR (DMSO-d6) δ 7.79 (s, 1H), 7.16 (d, 1H, J=1.9 Hz), 7.12 (dd, 1H, J=8.4, 2.2 Hz), 6.66 (s, 1H), 6.63 (d, 1H, J 8.4 Hz), 4.75 (m, 1H), 2.26 (s, 3H), 2.14 (m, 1H), 1.87 (m, 1H), 1.4-1.7 (m, 6H), 1.32 (d, 3H, J=5.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:5]=2[N:6]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:12][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:3][C:4]=2[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2c(F)cc(F)cc2s1
Product: O=C(Nc1nc2c(F)cc(F)cc2s1)c1ccccc1

Procedure:
Using 2-amino-4,6-difluoro-benzothiazole and benzoyl chloride the title compound was prepared as a beige solid (82% yield), MS: m/e=290 (M+).
Reaction SMILES: [OH:1][C:2]1([CH3:18])[CH:8](Br)[CH:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:6][C:4](=[O:5])[CH2:3]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[OH:1][C:2]1([CH3:18])[CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(O)CC(=O)OC(CCc2ccccc2)C1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC(CCc2ccccc2)C1
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of 200 mg of 3-hydroxy-3-methyl-4-bromo-7-phenyl-5-heptanolide in 2 ml of anhydrous tetrahydrofuran was added 500 mg of tri-n-butyltin hydride and the mixtue was allowed to stand overnight at room temperature. After completion of the reaction, tetrahydrofuran was evaporated and n-hexane was added to the residue to precipitate an oily substance, which was pruified by a thin layer chromatography (silica gel) affording 82 mg of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:17][C:18](=O)[CH2:19][CH:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[CH2:21][C:22]([OH:24])=[O:23])([O-])=O.Cl.[C:34]([O-])(O)=O.[Na+].C(OCC)(=O)C>CO.Cl.[Fe]>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:20]([CH2:19][C:18]2[NH:1][C:4]3[CH:9]=[C:8]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:7]=[CH:6][C:5]=3[N:17]=2)[CH2:21][C:22]([O:24][CH3:34])=[O:23])=[CH:26][CH:27]=1
Reactant: O=C(O)CC(CC(=O)Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-])c1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC(Cc1nc2ccc(Oc3ccccc3)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-Nitro-4-phenoxyphenyl)-3-(4-chlorophenyl)glutaramic acid (0.72 g) is dissolved in methanol (8 ml). Iron powder (0.88 g) is added and the suspension is heated to reflux. Conc. HCl (10 drops) was added carefully and refluxing was continued for 1 h. Then further conc. HCl (4 ml) was added and the greenish-yellow solution was stirred at reflux for additional 20 h. After cooling to rt the solution was poured into a mixture of sat. NaHCO3 solution (60 ml) and ethyl acetate (50 ml). The inorganic precipitates were removed by suction filtration and subsequently washed with ethyl acetate. From the filtrate the organic layer was separated and the aqueous layer extracted with ethyl acetate (50 ml). The combined organic layers were dried (sodium sulfate), concentrated and dried in vacuo. The residue (0.61 g of brownish oil) was purified by flash chromatography (dichloromethane/2% methanol/1% triethyl amine) on silica gel to give methyl 3-(4-chlorophenyl)-4-(5-phenoxy-2-benzimidazolyl)butanoate (0.46 g) as a colourless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([NH:10]C(=O)OC(C)(C)C)=[CH:9][C:2]=12>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([NH2:10])=[CH:9][C:2]=12
Reactant: CC(C)(C)OC(=O)Nc1cc2nccnc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2nccnc2s1
Yield: 80.6 %

Procedure:
A red solution of tert-butyl thieno[2,3-b]pyrazin-6-ylcarbamate (5.09 mmol, 1.28 g) in 66% TFA in CH2Cl2 25 mL was stirred overnight at room temperature The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, washed with NaHCO3 solution, brine, dried and evaporated to give thieno[2,3-b]pyrazin-6-amine 106 (620 mg, 81%). NMR (400 MHz, DMSO-d6) 5.98 (s, 1H), 7.17 (br s, 2H), 7.93 (d, J=2.7 Hz, 1H), 8.20 (d, J=2.7 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][CH2:7][CH2:8][OH:9])([CH3:5])[CH3:4].[CH2:10](Br)[C:11]#[CH:12]>O1CCCC1>[CH:3]([O:6][CH2:7][CH2:8][O:9][CH2:12][C:11]#[CH:10])([CH3:5])[CH3:4]
Reactant: CC(C)OCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCCOC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 60% suspension of sodium hydride in mineral oil (2.3 g, 57.6 mmol) in tetrahydrofuran (65 mL) was added 2-isopropoxyethanol (3.0 g, 28.8 mmol) dropwise at about 0 C. The mixture was stirred for about 30 min, then propargyl bromide (3.2 mL, 28.8 mmol) was added dropwise and the mixture was stirred overnight while being allowed to warm to room temperature. The reaction was quenched by addition of water and the product was extracted with diethyl ether. The combined organic extracts were dried (MgSO4), filtered and the organic solvents were carefully distilled off at atmospheric pressure. The residue was purified by flash chromatography on silica gel using diethyl ether/n-pentane (1:6) as eluent to provide Example 613. 1H NMR (500 MHz, CDCl3): δ 1.17 (d, J=6.0 Hz, 6H), 2.42 (t, J=3.0 Hz, 1H), 3.57-3.76 (m, 5H), 4.21 (d, J=3.0 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:11]=12)[NH2:5].[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:29](=[O:31])[CH3:30])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:11]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Oc2ccnc3c2ccn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3.02 g (7.60 mmol) of 3-fluoro-4-({1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)aniline are dissolved in 30 ml of acetic anhydride and stirred at 50° C. for one hour. Volatile components are then removed under reduced pressure and excess reagent is repeatedly removed azeotropically using toluene. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 1:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].Cl.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(CCC(=O)O)cc1F

Procedure:
A mixture of 5.0 g. of 3-fluoro-4-nitrocinnamic acid and 100 mg. of 10% palladium-on-carbon in 200 ml. of ethanol containing 5 drops of 5.5 N ethanolic hydrogen chloride is treated with hydrogen in a Parr apparatus at room temperature for 3 hours. The mixture is then filtered through Celite and the filtrate is concentrated, affording 3-fluoro-4-aminohydrocinnamic acid.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:11])[CH2:4][S:5][CH2:6][C:7](OC)=[O:8].[H-].[Na+]>O1CCCC1>[CH3:1][CH:2]1[C:3](=[O:11])[CH2:4][S:5][CH2:6][C:7]1=[O:8]
Reactant: CCC(=O)CSCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1C(=O)CSCC1=O
Reaction time: 3 h
Yield: 76.3 %

Procedure:
A solution of 101.3 g (0.57 mole) of methyl 2-(3-methylacetonylmercapto)acetate in 2.3 liter of dry tetrahydrofuran is added dropwise over a period of 3 hours to a stirred suspension of 0.57 mole of sodium hydride (27.4 g of 50% mineral oil suspension) in 1.1 liter of dry tetrahydrofuran at room temperature under nitrogen. Stirring is continued for an additional 3 hours. The resulting yellow reaction mixture is concentrated to a small volume at temperature below 40° C under reduced pressure, poured into ice-cold water and then extracted with ether. The aqueous layer is acidified at pH 2 - 3 with dilute hydrochloric acid and extracted several times with chloroform. The extracts are washed with a small portion of an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue is crystallized from methylene chloride - ether to give 62.7 g (75.6% yield) of 4-methyltetrahydrothiopyran-3,5-dione, mp. 131° - 133° C. Recrystallization from acetone - ether gives an analytical specimen, mp. 132.5 - 133° C. IR: νmaxCHCl3 cm-1 : 1735, 1705, 1631; νmaxNujol cm-1 : 1635, 1553. UV: λmax95 %EtOH mμ (ε): 275 (9500), 315 (2400); λmaxN--HCl mμ (ε): 272 (9900); μmaxN--NaOH mμ (ε): 289 (11600), 316 (12900). NMR: ppm (CDCl3): 1.28 (doublet, 3H, J = 7, Me), 3.44 (singlet, 4H, 2-H2 and 6-H2), 3.73 (quartet, 1H, J = 7, 4-H); ppm (CD3OD): 1.69 (broad singlet, 3H, vinyl-Me), 3.34 (broad singlet, 4H, 2-H2 and 6-H2). Anal. Calcd. for C6H8O2S (%): C, 49.98; H, 5.59; S, 22.24. Found (%): C, 50.17; H, 5.50; S, 22.14.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:36]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:41]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[O:17][C:18]5[C:23]([C:24](=[O:26])[CH:25]=4)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=5[N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)N1CCCC1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)N5CCCC5)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available 1-pyrrolidinecarbonyl chloride (Aldrich) via the parallel synthesis described above. MS—base peak at m/z=575 by positive ion Cl.
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11](Cl)=[O:12].[CH:19]1([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[CH:19]1([CH2:25][NH:26][C:11](=[O:12])[C:10]2[CH:9]=[C:8]([F:7])[C:16]([F:17])=[C:15]([F:18])[CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NCC1CCCCC1
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCCC1)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To 10 ml of ethyl acetate were added 0.50 g of 3,4,5-trifluorobenzoyl chloride, 0.32 g of cyclohexylmethylamine and 0.50 g of triethylamine and the mixture obtained was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. Crystals obtained were washed with a mixture of hexane and MTBE to obtain 0.70 g of N-cyclohexylmethyl-3,4,5-trifluorobenzamide. N-cyclohexylmethyl-3,4,5-trifluorobenzamide:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:20]([N:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[S:9]1(=[O:12])=[O:11])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=S1(=O)NCc2cccc(Cl)c21
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCN1Cc2cccc(Cl)c2S1(=O)=O

Procedure:
A suspension of 10.2 g of 7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide, 8.3 g of potassium carbonate and 7.7 ml of 1-iodopentane was refluxed in 50 ml of ethanol for 28 hours, cooled, concentrated and added to 200 ml of water. The mixture was extracted with n-BuCl, the extract washed with water and brine, dried over MgSO4 and concentrated to give 13.3 g of an amber oil which was triturated with hexane to give 11.4 g of the title compound as a tan powder, m.p. 46°-48° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]3)=[N:15][N:16]=2)[CH:3]=1.[CH3:27][O:28][C:29]1[C:34]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:11][N:8]1[C:9]2[C:5](=[C:4]([C:12]3[O:13][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]4)=[N:15][N:16]=3)[CH:3]=[C:2]([C:32]3[CH:33]=[C:34]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])[C:29]([O:28][CH3:27])=[N:30][CH:31]=3)[CH:10]=2)[CH:6]=[N:7]1
Reactant: CC(C)N1CCN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)CC1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3nnc(CN4CCN(C(C)C)CC4)o3)c3cnn(C)c3c2)cc1NS(C)(=O)=O
Temperature: 110 °C
Reaction time: 18 h
Yield: 38.9 %

Procedure:
6-Bromo-1-methyl-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1H-indazole (40 mg, 0.095 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (31.3 mg, 0.095 mmol), sodium carbonate (30.3 mg, 0.286 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (6.98 mg, 9.54 μmol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 15 mins. The reaction mixture was evaporated under a stream of nitrogen and the residual solid was dissolved in DMSO (1 ml), filtered through a frit and purified by Mass Directed Automated Preparative HPLC (Method B). The solvent was evaporated under a stream of nitrogen and the residue was dissolved in 1,4-dioxane (1 ml) and water (1 ml), frozen in a cardice bath and placed on the freeze-drier for 18 h to afford the title compound as a white solid (20 mg).
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[CH3:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[CH3:11]>>[CH3:4][C:5]1[CH:6]=[CH:7][C:8]([CH:2]([CH3:3])[CH3:1])=[CH:9][C:10]=1[CH3:11]
Reactant: C=CC
Reactant: Cc1ccccc1C
Product: Cc1ccc(C(C)C)cc1C

Procedure:
o-xylene is reacted with propene to give 1,2-dimethyl-4-isopropylbenzene,
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4](=[O:21])[CH:5]2[CH2:20][C:8]3([C:19]=1[C:18]1[CH:17]=[CH:16][C:15]4[NH:14][N:13]=[CH:12][C:11]=4[C:10]=1[CH2:9]3)[CH2:7][CH2:6]2>C(O)C.CO>[F:22][C:2]([F:1])([F:23])[C:3]1[C:4](=[O:21])[C@H:5]2[CH2:20][C@@:8]3([C:19]=1[C:18]1[CH:17]=[CH:16][C:15]4[NH:14][N:13]=[CH:12][C:11]=4[C:10]=1[CH2:9]3)[CH2:7][CH2:6]2
Reactant: O=C1C(C(F)(F)F)=C2c3ccc4[nH]ncc4c3CC23CCC1C3
Solvent: CCO
Solvent: CO
Product: O=C1C(C(F)(F)F)=C2c3ccc4[nH]ncc4c3C[C@@]23CC[C@@H]1C3

Procedure:
Racemic (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one (260 mg) was dissolved in ˜4/1 ethanol/methanol and resolved by chiral HPLC on a 2.0×25 cm Daicel Chiralcel OJ column (elution with 25% EtOH:Heptane at 7.5 mL/min, fractions monitored at 340 nm). The fractions containing the first enantiomer to elute (enantiomer A) were combined and concentrated to a clear oil which had a positive rotation. The pure fractions containing the second enantiomer to elute (enantiomer B) were combined, concentrated, and lyophilized from benzene to give (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a -methanoazuleno[2,1-e]indazol-7(8H)-one as a white solid which had a negative rotation.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[C:10]([Cl:16])[CH:9]=1.[BH4-].[Na+].[OH2:22]>O1CCCC1.[OH-].[Na+]>[CH3:19][Si:2]([CH3:1])([CH3:18])[CH2:3][CH2:4][O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:22])[CH3:15])=[C:10]([Cl:16])[CH:9]=1
Reactant: O
Reactant: C=Cc1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(O)c1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl
Reaction time: 15 h

Procedure:
(3-Chloro-4-vinyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (2.6 g) is added to a solution of mercuric acetate (3.48 g) in water (7 mL) and tetrahydrofuran (5.25 mL) and the mixture is stirred for approximately 15 hours. 3N Aqueous sodium hydroxide (8.7 mL) and a 0.5 M solution of sodium borohydride in 3N aqueous sodium hydroxide (8.7 mL) are then added and stirring is continued for 6 hours. The solution is then saturated with sodium chloride and extracted with ethyl acetate. These organic extracts are then washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white solid.