Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C(C)C)=[C:19]([I:27])[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([I:27])[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCCOc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1Cl
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of the product of Step B (0.2 g, 0.4 mmol) in anhydrous CH2Cl2(2 ml) 1M BCl3 in CH2Cl2 (3 ml) was added drop wise at rt. After 1 h, more of 1M BCl3 in CH2Cl2 (1 ml) was added and this was stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with CH2Cl2 (20 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrates was evaporated to dryness and the residue was crystallized from MeOH to give the title compound (0.145 g, 79%), as colourless solid. 1H-NMR (CDCl3) 8.47 (d, 1H, J=1.95 Hz); 8.21 (d, 1H, J=2.1 Hz); 8.06-8.04 (m, 1H); 8.03-8.02 (m, 1H); 7.07 (d, 1H, J=8.49 Hz); 7.00 (d, 1H, J=8.7 Hz); 4.08 (t, 2H, J=6.45 Hz); 1.94-1.87 (m, 2H); 1.09 (t, 3H, J=7.44 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:28]2[NH:29][C:30]([CH3:32])=[CH:31][C:27]=2[C:25]([N:22]2[CH2:23][CH2:24][C@H:20]([N:19]([CH3:18])[CH3:35])[CH2:21]2)=[O:26])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.9 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(3-Chloro-phenyl)-3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (70 mg, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])=[N:6][CH:7]=1.[C:14]([O:19][CH2:20][CH3:21])(=[O:18])[C:15]([CH3:17])=O.B(F)(F)F.CCOCC>C(#N)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:10][O:11][C:15]([CH3:17])([C:14]([O:19][CH2:20][CH3:21])=[O:18])[O:13][CH2:12]2)=[N:4][CH:3]=1
Reactant: OCC(CO)Nc1ncc(Br)cn1
Reactant: CCOC(=O)C(C)=O
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)C1(C)OCC(Nc2ncc(Br)cn2)CO1
Reaction time: 24 h
Yield: 75.8 %

Procedure:
2-[(5-bromopyrimidin-2-yl)amino]propane-1,3-diol (100 mg, 0.40 mmol), ethyl pyruvate (80 μL, 0.72 mmol) and acetonitrile (2 mL) were combined at rt. An aliquot of borontrifluoride etherate (100 μL, 0.80 mmol) was added to the reaction mixture and stirring was continued at rt for 24 hrs. A further portion of borontrifluoride etherate (100 μL, 0.80 mmol) was added to the reaction mixture, which was stirred at rt for a further 24 hrs. The reaction mixture was loaded directly onto a column for flash chromatography (12 g silica column), eluting with 0-100% EtOAc gradient in n-heptane, to give desired product (105 mg, light brown oil). m/z 345.9/347.9 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.[H-].[Na+].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](Br)([F:39])[F:38])=[CH:33][CH:32]=1>CN(C=O)C>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:38])[O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Reactant: FC(F)(Br)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OC(F)(F)c3ccc(Br)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a cooled (0° C.) solution of the title compound from Example 1 Step B (515 mg, 1.37 mmol) in DMF (5 mL) was added NaH (35.0 mg, 1.46 mmol). The reaction vessel was then allowed to warm to ambient temperature for 25 min, followed by addition of 1-bromo-4-[bromo(difluoro)methyl]benzene (445 mg, 1.56 mmol, synthesized according to U.S. Pat. No. 6,939,990) and heated at 60° C. After 24 h, the reaction mixture was cooled, quenched by addition of 2 N HCl and extracted with hexane-EtOAc. Purification by silica gel flash chromatography (5% EtOAc in hexanes to 10% EtOAc in hexanes) yielded the title compound: LCMS m/z 564.1 [M−F]+; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.88-7.82 (m, 2H), 7.78 (d, J=7.1 Hz, 1H), 7.57 (dd, J=7.8, 0.7 Hz, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.46-7.41 (m, 2H), 7.39-7.32 (m, 3H), 4.37 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([CH:7]([NH:22][C:23]([C:36]2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8][NH:9][C:10](=O)[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=CC=2OC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:42](O)=[O:43]>C(Cl)Cl>[CH3:42][O:43][C:16]1[CH:17]=[CH:18][CH:13]=[CH:12][C:11]=1[CH2:10][N:9]1[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:22]=[C:23]1[CH3:36]
Reactant: COc1ccccc1CCC(=O)NCC(NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: O=CO
Solvent: ClCCl
Product: COc1ccccc1CN1CC(c2ccccc2)N=C1C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
The 1-phenyl-1-(tritylamino)-2-[N-(2-methoxybenzyl)acetylamino]ethane, prepared as described in Preparation 1, supra, was detritylated and cyclized by dissolving the intermediate (8.0 g, 14.8 mmol) in 250 ml of methylene chloride and cooling this solution to 0° C. under a nitrogen atmosphere. Formic acid (5.7 ml, 148 mmol) was then added and the reaction mixture was warmed to room temperature and then stirred for 2.5 hours. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([OH:20])=[O:19])=[N:10]2)=[CH:5][CH:4]=1.[CH:21](N(C(C)C)CC)(C)[CH3:22].C(O)C>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1cc(C(=O)O)nn1-c1ccc(OC)cc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.9 %

Procedure:
A solution of 1-[(4-methoxy)phenyl]-5-(methoxycarbonyl)pyrazole -3-carboxylic acid (7.50 g, 27.1 mmol) in 50 mL of thionyl chloride was stirred at 80° C. for 1 h. The volatiles were then removed and the residue was azeotroped with 20 mL of toluene and dried in vacuo. The residue was dissolved in 100 mL of tetrahydrofuran and then there was added diisopropylethylamine (11.8 mL, 67.9 mmol) and absolute ethanol (3.2 mL, 54.3 mmol). The reaction mixture was allowed to stir at ambient temperature for 24 h. The volatiles were removed and the residue was dissolved in ethyl acetate. This solution was filtered through a pad of silica gel and was concentrated in vacuo to afford 3.7 g (45%) of the title compound which was used without purification. LRMS (DCI): 305.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][NH:11]2)=[C:7]([NH:14][CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:6]=1)=[O:4].[H-].[Na+].CC([O:34][C@H:35]1[CH:39]=[CH:38][C@@H:37](O)[CH2:36]1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:38]2[CH2:39][C@H:35]([OH:34])[CH:36]=[CH:37]2)=[C:7]([NH:14][CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:6]=1)=[O:4]
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-(2,2-Diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (Intermediate DA) (10.8 g 28.9 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated tetrahydrofuran (200 mL) and dry dimethyl sulfoxide (5 mL) are added and the suspension is cooled on an ice-bath. Sodium hydride 95% (0.69 g, 28.9 mmol) is then slowly added and the solution is stirred at room temperature for 30 minutes. (1S,4R)-cis 4-Acetoxy-2-cyclopenten-1-ol (3.9 g, 27.5 mmol), triphenylphosphine (1.08 g, 4.13 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (1.27 g, 1.38 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated tetrahydrofuran (20 mL) is added and stirred at room temperature for 30 minutes. This solution is added to the anion solution via syringe and is then stirred at 50° C. for 6 hours. The reaction mixture is allowed to cool and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, 0% to 10% MeOH in DCM). 1H NMR (MeOD, 400 MHz); 8.15 (s, 1H), 7.40-7.15 (m, 10H), 6.30 (m, 1H), 5.95 (m, 1H), 5.60 (m, 1H), 5.50 (m, 1H), 4.85 (m, 1H), 4.55 (m, 1H), 4.30 (m 2H), 4.00 (s, 2H), 2.65 (s, 3H).
Reaction SMILES: [Na].[N+]([C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[CH:6]=1)([O-])=O.[C:13](O)(=[O:15])C.C([O-])(O)=O.[Na+]>CO.O>[CH3:13][O:15][C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[CH:6]=1
Reactant: CC(=O)O
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1
Temperature: 25 °C

Procedure:
With stirring, sodium pellets (3.95 g, 0.172 mol), maintained dry under hexane, were added to 540 ml dry methanol, under N2. Following dissolution, the mixture was diluted with 900 ml methanol, 4-nitro-2-methylpyridine N-oxide (26.0 g, 0.169 mol) was added, and the mixture heated at reflux for 1 hour, cooled to room temperature and acidified with 18 ml glacial acetic acid. After stirring 15 minutes, the reaction mixture was stripped of solvent, the orange residue taken up in 300 ml of H2O, neutralized with saturated NaHCO3, reconcentrated to dryness, and the residue triturated 5×50 ml of ethanol. The ethanol triturates were combined, stripped to dryness, and the residue restripped 3×50 ml toluene to yield solids (36.1 g) which were chromatographed on silica gel using 6:1 CH2Cl2 :CH3OH as eluant to yield purified title product, 21.14 g; MS 139 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>C(#N)C.N1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(O)nc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Cl)c1ccc(O)nc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
13.92 g (0.1 mol) of 6-hydroxynicotinic acid and 0.04 g (0.5 mmol) of pyridine were heated in 60 ml of acetonitrile to 80° C. 12.49 g (0.105 mol) of thionyl chloride was instilled and the reaction again stirred for 30 minutes at 80° C. After cooling, the precipitate was filtered off, washed twice each with 10 ml of cold acetonitrile and concentrated by evaporation in a vacuum. 13.38 g (0.085 mol) of 6-hydroxynicotinoyl chloride was obtained as a light yellowish powder, corresponding to a yield of 85 percent relative to the 6-hydroxynicotinic acid. Further data concerning the product was:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:10][CH2:9][CH2:8][O:7][C:6]1[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=1[O:4][CH2:3][C:2]([F:15])([F:16])[F:1])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccccc1OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccccc1OCC(F)(F)F

Procedure:
To a solution of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (210 mg) in methylene chloride (1 ml) were added triethylamine (186 μl) and methanesulfonyl chloride (83 μl) with stirring under ice cooling, and the mixture was reacted at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and ethyl acetate (2/1) as eluent to give 273 mg of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methansulfonate melting at 40.5°-42.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:41][CH2:40][O:39][CH2:38]C1>C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:14]1[CH:15]=[C:6]([CH:4]=[O:3])[CH:7]=[CH:41][C:40]=1[O:39][CH3:38])=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C=O)ccc1OC

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 5-formal-2-methoxylphenylboronic acid (100 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(5-formyl-2-methoxy-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH2:9]1.[Br:25][C:26]1[N:31]=[C:30]([C:32](O)=[O:33])[CH:29]=[CH:28][C:27]=1[F:35]>CCOC(C)=O>[Br:25][C:26]1[N:31]=[C:30]([C:32]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]3[C:15](=[O:24])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22]3=[O:23])[CH2:9]2)=[O:33])[CH:29]=[CH:28][C:27]=1[F:35]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: Nc1cnccc1C1CCCC(N2C(=O)c3ccccc3C2=O)C1
Solvent: CCOC(C)=O
Product: O=C(Nc1cnccc1[C@@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1)c1ccc(F)c(Br)n1

Procedure:
Following Method 9, 2-(3-(3-aminopyridin-4-yl)cyclohexyl)isoindoline-1,3-dione and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, 6-bromo-N-(4-((1R,3S)-3-(1,3-dioxoisoindolin-2-yl)cyclohexyl)pyridin-3-yl)-5-fluoropicolinamide was obtained. LCMS (m/z): 523.2/525.2 (MH+); LC Rt=3.31 min.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][Si](C)(C)C)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:30]([F:33])([F:32])[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:30]([F:33])([F:32])[F:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Yield: 140.4 %

Procedure:
A solution of the above oil, 3-benzyl-8-trifluoromethyl-4-(3-trimethylsilanylethynylphenyl)-quinoline (730 mg, 1.6 mmol) and potassium carbonate (220 mg, 1.6 mmol) in methanol (30 mL) is stirred at ambient temperature for 3 h. The reaction mixture is stripped to dryness and the residue taken up in ethyl acetate and washed with 30 mL (1N HCl). The organic layer is dried and concentrated in vacuo to provide after chromatography 870 mg (80%) of the title compound: MS (ESI) m/z 388.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Br:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[Br:13][CH2:14][CH2:15][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(F)cc1C(F)(F)F
Reactant: OCCBr
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(OCCBr)c(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)phenol (1.05 g, 5.83 mmol), 2-bromoethanol (0.62 mL, 8.7 mmol) and triphenylphosphine (2.29 g, 8.73 mmol) in tetrahydrofuran (20 mL) was stirred for 5 minutes. Diisopropyl azodicarboxylate (94%, 1.84 mL, 8.71 mmol) was then added drop-wise over 20 minutes, and the reaction was stirred at room temperature for 16 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (2×75 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) afforded the title compound as a white solid. Yield: 600 mg, 2.09 mmol, 36%. GCMS m/z 286. 1H NMR (400 MHz, CDCl3) δ 3.66 (dd, J=6.6, 6.4 Hz, 2H), 4.35 (dd, J=6.5, 6.4 Hz, 2H), 6.97 (br dd, J=9.0, 4.1 Hz, 1H), 7.18-7.24 (m, 1H), 7.32 (br dd, J=8.3, 3.2 Hz, 1H).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]#[N:34])[CH2:29][CH2:28]3)[C:20]=2[S:19][CH:18]=1.[NH4+].[Cl-].[N-:37]=[N+:38]=[N-:39].[Na+]>O>[N:34]1[NH:37][N:38]=[N:39][C:33]=1[N:30]1[CH2:31][CH2:32][CH:27]([O:26][C:25]2[C:20]3[S:19][CH:18]=[C:17]([C:8]4[CH:9]=[CH:10][C:11]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:12][C:7]=4[F:6])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:28][CH2:29]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCN(C#N)CC4)ncnc23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCN(c5nn[nH]n5)CC4)ncnc23)c(F)c1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
2.5 ml of dimethylformamide was added to 200 mg 4-(7-(2-fluoro-4-methanesulfonyl-phenyl)thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-carbonitrile of Example 75, and 33 mg of NH4Cl and 45 mg of NaN3 45 mg were added thereto with stirring. The mixture was stirred at 100° C. for 12 hr. The resulting mixture was cooled to room temperature, added with water and stirred. The solid thus obtained was filtered to obtain 120 mg of the title compound.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:40])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(OCC)(=O)C>[N:18]1([C:21](=[S:40])[O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32](=[O:39])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:28][CH:29]=2)[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)OCc2ccc(OCC(=O)c3ccccc3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(COc1ccc(COC(=S)N2CCNCC2)cc1)c1ccccc1
Yield: 78.8 %

Procedure:
a solution of HCl in dioxane (4 M; 380 uL, 10 eq) was added to a solution of 4-(2-oxo-2-phenylethoxy)benzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (72.1 mg) in ethyl acetate (2 mL) and the resultant mixture was shaken at ambient temperature for 16 h. The solvent was removed in vacuo and the resultant crude material was suspended in dichloromethane (4 mL) and shaken with MP—CO3 (1 g, 17 eq) at ambient temperature for 1 h. Purification by ion-exchange chromatography [SCX-2 (500 mg); DCM, MeOH, NH3—MeOH] afforded the desired product (44.7 mg, 79%) as a colourless oil: NMR δH(400 MHz; CDCl3) 2.82–2.86 (4H, m), 3.41–3.63 (4H, br s), 4.12 (2H, s), 5.23 (2H, s), 6.84–6.90 (2H, m), 7.24–7.29 (2H, m), 7.46–7.52 (2H, m) and 7.58–7.64 (1H, m); HPLC (XTERRA, 50/80, 235 nm) 97.7% (2.05 min).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][S:13][CH:14]=1>C(O)(=O)C>[Cl:1][C:12]1[S:13][CH:14]=[C:10]([Cl:9])[C:11]=1[NH:15][C:16](=[O:21])[C:17]([F:18])([F:20])[F:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(Nc1cscc1Cl)C(F)(F)F
Solvent: CC(=O)O
Product: O=C(Nc1c(Cl)csc1Cl)C(F)(F)F
Reaction time: 0.58 h

Procedure:
A solution of 1.4 g of N-chlorosuccinimide in 25 ml of glacial acetic acid was added dropwise with stirring to a solution of 2.3 g of 4-chloro-3-trifluoroacetylaminothiophene in 60 ml of glacial acetic acid, the mixture was stirred at 40–45° C. for a further 35 minutes and the solvent was distilled off. The residue was admixed with water and extracted with ethyl acetate, the organic phase was washed with water and dried over sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography on silica gel using a mixture of 10 parts by volume of toluene and 2 parts by volume of n-heptane, and removed from the still unconverted monochloro compound.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=O.[NH3:31]>>[NH2:31][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:28])[F:29])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)=[O:3]
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Reactant: N
Product: CC(Cc1ccc(OCC(N)=O)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1

Procedure:
Prepared by analogy to Example 24 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine with ammonia followed by purification on a silica gel column using ethyl acetate/toluene=8:2 as eluant.