Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([CH2:29]Cl)=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C.[I-].[K+]>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([CH2:29][S:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.1 %

Procedure:
Add sodium hydride (25 mg, 0.62 mmol, 60% dispersion in mineral oil) to benzenethiol (0.06 mL, 0.51 mmol) in anhydrous DMF (2 mL). Stir the mixture under nitrogen for 5 min and then add 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (198 mg, 0.51 mmol) in anhydrous DMF (2 mL) followed by catalytic potassium iodide (1 mg). Stir the reaction at 45° C. for 12 h then cool to room temperature and partition between EtOAc/water. Wash the organic phase with brine. Dry the organic phase over MgSO4, filter and concentrate in vacuo to give a yellow oil. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-butoxycarbonyl-7-chloro-6-phenylthiomethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (200 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2)[C:10]([F:13])([F:12])[F:11].[CH2:27]([O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:27]([O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:26][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:25])[C:9]([OH:24])([C:14]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:15]=3[CH:16]=[CH:17][N:18]=[CH:19]4)[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:33][CH:32]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cccc2cnccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(COc2ccc(C(C)C(O)(c3cccc4cnccc34)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-2-isoquinolin-5-yl-1-methyl -propyl)-phenol (40 mg) in N,N-dimethylacetamide (1 ml) were added ethyl-4-(bromomethyl)benzoate (18 mg) and cesium carbonate (23 mg). The mixture was stirred for 1 h at room temperature. Ice water was added and the mixture was extracted with EtOAc. The organic phase was washed with water and dried (MgSO4). The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>0:1) to give the title compound (28 mg) as an off-white solid. MS (m/e)=544.2 [M+H+].
Reaction SMILES: [CH:1]([O:4][C:5]([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=[O:6])([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>ClCCl.N1C=CC=CC=1>[CH:1]([O:4][C:5]([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([Cl:19])=[O:11])=[O:6])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)OC(=O)Oc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Oc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.8 %

Procedure:
5 g (22 mmol) of 2-(isopropoxycarbonyloxy)benzoic acid are dissolved in 50 ml of dichloromethane with a few drops of pyridine. 1.95 ml (27 mmol) of thionyl chloride are added dropwise and the mixture is stirred at ambient temperature for 18 h and then concentrated to dryness. 5.7 g of 2-(isopropoxycarbonyloxy)benzoyl chloride are obtained with a quantitative yield.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CON(C)[C:8](=[O:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:8](=[O:19])[CH2:1][CH3:2])=[CH:12][CH:13]=1
Reactant: CC[Mg]Br
Reactant: COc1ccc(CCC(=O)N(C)OC)cc1
Solvent: C1CCOC1
Product: CCC(=O)CCc1ccc(OC)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
Ethylmagnesium bromide (10.8 mL, 10.8 mmol, 1M soln in THF) was added to a cooled −78° C. solution of N-Methoxy-3-(4-methoxy-phenyl)-N-methyl-propionamide (2 g, 8.96 mmol, from Step 1) dissolved in THF (20 mL). The reaction mixture was stirred for 60 min. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed brine, dried over Na2SO4 and concentrated to a clear oil. The residue was purified by silica gel chromatography (5% EtOAc in hexanes) to give the title compound as a clear oil (0.87 g, 50%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13]([Li])[CH2:14][CH2:15][CH3:16]>O1CCCC1.[Cl-].[NH4+]>[CH2:13]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH2:14][CH2:15][CH3:16]
Reactant: [Li]CCCC
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC1(O)CCN(C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, to a solution of ethyl 4-oxo-1-piperidinecarboxylate (1.00 g) in anhydrous tetrahydrofuran (5 mL) was added n-butyl lithium (1.56M hexane solution, 5.62 mL) at −40° C. The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was poured in saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified with column chromatography on silica gel (hexane:ethyl acetate=7:3) to give the title compound (269 mg) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([CH:22]=[C:23]2[S:27][C:26](SC)=[N:25][C:24]2=[O:30])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][O:41][CH:40]([CH2:44][NH2:45])[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][O:41][CH:40]([CH2:44][NH:45][C:26]2[S:27][C:23](=[CH:22][C:20]3[CH:19]=[CH:18][C:4]([O:5][C:6]4[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=4[C:14]([F:17])([F:15])[F:16])=[C:3]([O:2][CH3:1])[CH:21]=3)[C:24](=[O:30])[N:25]=2)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Reactant: COc1cc(C=C2SC(SC)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Product: COc1cc(C=C2SC(NCC3CN(C(=O)OC(C)(C)C)CCO3)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
2-({5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-methyl)-morpholine-4-carboxylic acid tert-butyl ester was prepared using 4-[2-Methoxy-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile and 2-aminomethyl-morpholine-4-carboxylic acid tert-butyl ester as described in Example 5C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:15])[N:5]([C:7]2[CH:12]=[N:11][N:10]([CH3:13])[C:9](=[O:14])[CH:8]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]#[CH:50])[CH:44]=1>[Cu]I>[Cl:42][C:43]1[CH:44]=[C:45]([C:49]#[C:50][C:2]2[N:3]=[C:4]([CH3:15])[N:5]([C:7]3[CH:12]=[N:11][N:10]([CH3:13])[C:9](=[O:14])[CH:8]=3)[CH:6]=2)[CH:46]=[CH:47][CH:48]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: Cc1nc(I)cn1-c1cnn(C)c(=O)c1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cnn(C)c(=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
A solution of 8 mg bis(triphenyl-phosphine)palladium dichloride in 3 ml of DMF was degassed with argon. Then 52 mg (0.165 mmol) 5-(4-iodo-2-methyl-imidazol-1-yl)-2-methyl-2H-pyridazin-3-one, 1 mg (0.03 mmol) of triphenylphosphine, 0.046 ml (0.33 mmol) triethylamine were added and the mixture was stirred for 5 min at room temperature. Then 1 mg (0.005 mmol) of copper(I) iodide and 0.042 ml (0.33 mmol) of 1-chloro-3-ethynyl-benzene were added and the mixture was stirred for 2 h at 50° C. The mixture was evaporated to dryness in vaccuo, taken up in 5 ml of ethyl acetate. Then ca. 1 g of silicagel was added and the suspension was evaporated to dryness. The silicagel containing adsorbed product was loaded onto a 20 g flash chromatography column. The product was eluted with ethyl acetate. The pure fractions were concentrated to yield 36 mg (0.111 mmol, 67%) of the title compound as a light yellow crystalline solid, MS: m/e=325.2, 327.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[N:28]=[C:29]=[O:30]>>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[NH:28][C:29](=[O:30])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=Nc1ccc2ccccc2c1
Product: O=C(Nc1ccc2ccccc2c1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 2 (2), but with 2-naphthylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (14.4 mg, 55%) having the following characteristics.
Reaction SMILES: C(O[C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1OC(=O)C)(=O)C.[CH2:17]1[CH2:37][O:36][C:19]2([C:28]3[C:27](=[O:29])[CH:26]=[CH:25][C:24](=[O:30])[C:23]=3[CH2:22][C:21]([OH:35])([C:31]([O:33][CH3:34])=[O:32])[CH2:20]2)[O:18]1.C(OCC)C>C1(C)C(C)=CC=CC=1>[CH2:37]1[CH2:17][O:18][C:19]2([C:28]3[C:27](=[O:29])[C:26]4[C:25](=[CH:6][C:7]5[C:8]([CH:5]=4)=[CH:9][CH:10]=[CH:11][CH:12]=5)[C:24](=[O:30])[C:23]=3[CH2:22][C:21]([OH:35])([C:31]([O:33][CH3:34])=[O:32])[CH2:20]2)[O:36]1
Reactant: COC(=O)C1(O)CC2=C(C(=O)C=CC2=O)C2(C1)OCCO2
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: COC(=O)C1(O)CC2=C(C(=O)c3cc4ccccc4cc3C2=O)C2(C1)OCCO2
Yield: 74.6 %

Procedure:
A solution of 200 mg of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 100 mg of methyl rac-4,4-ethylenedioxy-1,2,3,4,5,8-hexahydro-2-hydroxy-5,8-dioxonaphthalene-2-carboxylate in 10 ml of xylene was stirred and heated under reflux for 1.5 hours under an atmosphere of nitrogen. The solution was evaporated to give a bright yellow crystalline residue. Trituration of this residue with diethyl ether gave 100 mg (74.5%) of methyl rac-4,4-ethylenedioxy-1,2,3,4,5,12-hexahydro-2-hydroxy-5,12-dioxonaphthacene-2-carboxylate in the form of yellow crystals of melting point 207°-209° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[CH:18]=O)[C:15]2[CH2:20][CH2:21][CH2:22][CH2:23][C:14]=2[S:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.[OH-].[K+]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[CH:18]=[N:33][NH:32][C:24]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:31])[C:15]2[CH2:20][CH2:21][CH2:22][CH2:23][C:14]=2[S:13]3)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1c(-c2ccc([N+](=O)[O-])cc2)nc2sc3c(n12)CCCC3
Reactant: NNC(=O)c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(NN=Cc1c(-c2ccc([N+](=O)[O-])cc2)nc2sc3c(n12)CCCC3)c1cccnc1

Procedure:
Next, 0.33 g of 5,6,7,8-tetrahydro-2-(4-nitrophenyl)-3-formylimidazo[2,1-b]benzothiazole, 0.15 g of nicotinohydrazide, and 0.1 g of potassium hydroxide were heated and stirred in 20 ml of methanol at 90° C. for 1.5 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was extracted with chloroform. The extract was washed with water and dried, then the solvent was distilled off and the residue was crystallized from methanol to obtain the desired substance in an amount of 0.25 g (yield of 55.6%).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+].I[CH2:32][CH:33]([OH:36])[CH2:34][OH:35].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[CH3:28][Si:2]([CH3:1])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])=[O:23])=[CH:25][CH:26]=1
Reactant: OCC(O)CI
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 7.17 g. of 4-[14-(trimethylsilyl)tetradecylamino]benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield the product as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[N:12][C:13]#[N:14])SC)[CH:2]=1.[CH2:15]([NH2:17])[CH3:16]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([NH:17][CH2:15][CH3:16])=[N:12][C:13]#[N:14])[CH:2]=1
Reactant: CCN
Reactant: CSC(=NC#N)NCc1cccnc1
Product: CCNC(=NC#N)NCc1cccnc1
Temperature: 80 °C

Procedure:
6.2 g of N-pyrid-3-ylmethyl-N'-cyano-S -methylisothiourea are stirred together with 30 ml of ethylamine (70% in water) for one hour at 60° C. and then heated for 30 minutes at 80° C. The product that crystallises out when the mixture is cooled is washed with cold water and corresponds to the title compound of formula ##STR10## having a melting point of 177°-179° C. (compound No. 1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:10]#[N:11].[Na+]>[Cu]>[C:1]([C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: [C-]#N
Agent: [Cu]
Agent: [Na+]
Product: N#CC(=O)c1ccccc1
Reaction time: 4.5 h
Yield: 57.2 %

Procedure:
Using apparatus and a procedure such as was used in Example 1, 140.5 grams (1.0 mole) of benzoyl chloride, 55.0 grams (1.1 moles) of sodium cyanide and 20.0 grams of copper filings were charged to a flask and heated under nitrogen, with stirring, to reflux temperature. The reaction mixture was maintained at a temperature ranging from 190° C. to 200° C. for about 4.5 hours. The reaction mixture was then cooled, diluted with 100 ml. toluene and suction filtered. The filtrate was then distilled to produce 75.0 grams (57.3% yield) of benzoyl cyanide having a boiling point of 48° C. at 0.01 mm. Hg. The distilled product became a semi-solid material at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[C:36]([CH3:40])=[CH:35][C:34]=1[S:41](Cl)(=[O:43])=[O:42]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:34]4[CH:35]=[C:36]([CH3:40])[C:37]([Cl:39])=[CH:38][C:33]=4[Cl:32])(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(C)c(Cl)cc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,4-dichloro-5-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=644.6)=82%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=O)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CSc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ccc(-c2cc3ccccc3c(Cl)n2)cc1

Procedure:
The resulting 3-(4-methylthiophenyl)isoquinolin-1-one (0.73 g) was reacted with phosphorus oxychloride (5 ml) according to the method of Example 10-2, to give 1-chloro-3-(4-methylthiophenyl)isoquinoline. Then, N-ethylpiperazine (10 ml) and potassium carbonate (0.36 g) were added to the resulting product as it was. The resulting mixture were reacted at 100° C. overnight. The reaction solution was evaporated, and the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.95 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:8]3[N:9]2[CH:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1.[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][SH:29])[CH3:22].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][S:29][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:8]3[N:9]2[CH:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1)[CH3:22]
Reactant: Ic1ccc2c(-c3ccccc3)cc3nncn3c2c1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(-c3ccccc3)cc3nncn3c2c1
Temperature: 60 °C

Procedure:
8-Iodo-5-phenyl-[1,2,4]triazolo[4,3-a]quinoline (900 mg, 3.0 mmol), 3-mercaptopropionic acid 2-ethylhexyl ester (660 mg, 3.0 mmol), iPr2NEt (1.1 mL, 6.3 mmol), Pd2dba3 (69 mg, 0.05 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (87 mg, 0.15 mmol) were dissolved in 1,4-dioxane (15 mL) and degassed for 10 minutes with N2. The reaction was then sealed and heated to 60° C. for 1.5 hours, followed by cooling to room temperature and concentration. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 11c.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]=[C:14]1[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]1.Cl.Cl.[Cl:23][C:24]1[C:25]([CH2:30][NH2:31])=[N:26][CH:27]=[CH:28][N:29]=1.C(N(C(C)C)CC)(C)C>C1COCC1.C(Cl)Cl>[Cl:23][C:24]1[C:25]([CH2:30][NH:31][C:18]([CH:16]2[CH2:15][C:14](=[CH2:13])[CH2:17]2)=[O:20])=[N:26][CH:27]=[CH:28][N:29]=1
Reactant: NCc1nccnc1Cl
Reactant: C=C1CC(C(=O)O)C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1CC(C(=O)NCc2nccnc2Cl)C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
1,1′-Carbonyldiimidazole (CDI) (8.24 g, 50.81 mmol) and 3-methylenecyclobutanecarboxylic acid (5.70 g, 50.81 mmol) were dissolved in anhydrous THF (100 mL) and allowed to stir at 60° C. for 4 h. A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride (10.0 g, 46.19 mmol) and diisopropylethylamine (DIPEA) (32.30 mL, 184.76 mmol) in anhydrous CH2Cl2 (150 mL) was added to the mixture and the reaction was allowed to stir at rt for 24 h. The mixture was concentrated in vacuo, the residue dissolved in EtOAc and the resulting solution washed with saturated NaHCO3 (aq.) water H2O and Brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude product, which was purified by chromatography over silica gel eluting with 50-70% EtOAc/hexane to yield desired product. 1H NMR (400 MHz, CDCl3) δ ppm 2.92-2.94 (2 H, m), 3.05-3.14 (2 H, m), 4.60 (2 H, d, J=4.24 Hz), 4.80-4.84 (2 H, m), 6.75 (1 H, brs), 8.33 (1 H, d, J=4.22 Hz) and 8.45 (1 H, d, J=2.54 Hz). MS (ES+): m/z 238 and 240 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:23][CH:24]([CH3:26])[CH3:25])=[C:4]([C:17]([CH3:22])=[C:18]([F:21])[CH2:19][OH:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].ClC1C(OC(C)C)=C(/C(/C)=C(/F)\CO)C=C2C=1OC(C)(C)C=C2C(C)C.C([N+](CCC)(CCC)CCC)CC.C[N+]1([O-])CCOCC1>>[Cl:1][C:2]1[C:3]([O:23][CH:24]([CH3:26])[CH3:25])=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH:19]=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CC(=C(F)CO)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C
Agent: C/C(=C(\F)CO)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: C/C(=C(\F)C=O)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure M, 3-(8-chloro-7-isopropoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-but-2-en-1-ol (Compound 156,0.74 g, 1.9 mmol), tetrapropylammonium perrunthenate (TPAP, 0.034 g, 0.101 mmol), and 4-methylmorpholine N-oxide (NMO, 0.34 g, 2.9 mmol) were reacted to give the title compound as a pale yellow solid after purification by flash chromatography (silica gel column, 20% ethyl acetate in hexanes).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]1([S:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:27]3[NH:32][C:31](=[O:33])[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)=[O:26])=[CH:21][CH:20]=2)[CH2:17][CH2:16]1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH:15]1([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([OH:26])[C:27]3[NH:32][C:31](=[O:33])[C:30]([C:34]([F:36])([F:35])[F:37])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16]1
Reactant: O=C(c1ccc(SC2CC2)cc1)c1ccc(C(F)(F)F)c(=O)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(C(O)c2ccc(SC3CC3)cc2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
Sodium triacetoxyborohydride (125 mg) was added to a solution of 6-{[4-(cyclopropylsulfanyl)phenyl]carbonyl}-3-(trifluoromethyl)pyridin-2(1H)-one (110 mg) in chloroform (3 mL), and the mixture was stirred at room temperature overnight. An ammonium chloride solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate only) to give 6-{[4-(cyclopropylsulfanyl)phenyl](hydroxy)methyl}-3-(trifluoromethyl)pyridin-2(1H)-one (40 mg, 36%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([O:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=1.[F:20][C:21]([F:32])([F:31])[C@@H:22]1[CH2:27][CH2:26][C@H:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[Cl:3][C:4]1[CH:5]=[C:6]([O:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:28]([C@H:25]2[CH2:24][CH2:23][C@@H:22]([C:21]([F:20])([F:31])[F:32])[CH2:27][CH2:26]2)=[O:29])[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=1
Reactant: NC(=O)c1ncc(Cl)cc1OC[C@H]1CCCN1
Reactant: O=C(O)[C@H]1CC[C@@H](C(F)(F)F)CC1
Agent: Cl
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: NC(=O)c1ncc(Cl)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 3 using (R)-5-chloro-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (EXAMPLE 29 Step 5) and cis-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.