Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[N:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(Br)nc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.34 ml (1.34 mmol) of a 1 M solution of lithium aluminum hydride in THF are initially introduced into 5 ml dry THF under argon, and a solution of 500 mg (2.69 mmol) 6-bromo-3-pyridinecarbaldehyde in 3 ml dry THF is added dropwise at 0° C. The mixture is subsequently stirred at RT for 1 h, 25 ml ethyl acetate are then added, while cooling in an ice bath, and hydrolysis is carried out slowly with 50 ml saturated sodium bicarbonate solution. The aqueous phase is extracted with ethyl acetate (three times with 20 ml each time). The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After removal of solvent residues in vacuo, 375 mg (74% of th.) of the title compound are obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1.[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[CH2:14][CH2:13]1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCN(c2ccccc2F)CC1
Agent: Cl
Product: O=C(CN1CCN(c2ccccc2F)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 27.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(2-fluorophenyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 127, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(2-fluorophenyl)piperazin-1-yl)acetamido)propanamide (13.1 mg, 27.3%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): 10.23 (s, 1H), 8.02 (d, 1H), 7.60 (d, 2H), 7.25-7.30 (m, 5H), 7.19-7.23 (m, 2H), 7.10-7.19 (m, 2H), 6.98-7.04 (m, 6H), 4.71 (m, 1H), 4.53 (s, 2H), 3.72-3.80 (m, 2H), 3.07 (d, 2H), 3.00 (m, 4H), 2.63 (m, 4H). MS (EI) for C34H34F2N4O4. found 601.6 (MH+).
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]5[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=5)=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Reactant: FC(F)(F)c1csc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c2cc(-n3ccc(OCc4cc(C(F)(F)F)cs4)cc3=O)ccc2nn1C1CC1
Reaction time: 8 h
Yield: 48 %

Procedure:
To a mixture of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (200 mg) and 2-(chloromethyl)-4-(trifluoromethyl)thiophene (171 mg) in DMF (4 ml) was added potassium carbonate (118 mg) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was fractionated by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% NH4HCO3)), and saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol-water to give the title compound (152 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:35])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccn2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccn2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(pyridin-2-ylcarbonyl)piperazin-1-yl}quinolin-7-yl}ethanone (0.015 g, 0.038 mmol) and ammonium acetate (0.0293 g, 0.380 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.095 mL, 0.095 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H23ClN5O (M+H)+: m/z=396.2; Found: 396.2.
Reaction SMILES: O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH:13]1([CH2:19][C@H:20]([NH:32][CH2:33]C(=O)NC(C)(C)C)[CH2:21][NH:22][C:23](=[O:31])[O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C.CCOCC>[CH:13]1([CH2:19][C@H:20]([NH:32][CH3:33])[CH2:21][NH:22][C:23](=[O:31])[O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)NC(=O)CN[C@H](CNC(=O)OCC[Si](C)(C)C)CC1CCCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CN[C@H](CNC(=O)OCC[Si](C)(C)C)CC1CCCCC1
Reaction time: 2 h
Yield: 9.4 %

Procedure:
A solution of toluenesulfonic acid monohydrate (10 mg, 0.053 mmol) in absolute ethanol (1 mL) was added to a solution of 2-(trimethylsilyl)ethyl (S)-3-cyclohexyl-2-((tert-butyl-carbamoyl)methylamino)propylcarbamate (21.3 mg, 0.51 mmol) in Et2O (10 mL). This solution was placed in a flask on a rotary evaporator and the Et2O was removed at ambient temp. The flask was then lowered into a water bath (60° C.) and selective removal of the Boc group proceeded concurrently with removal of the solvent. The reaction was complete within 2 h. This material was taken up in CH2Cl2 (20 mL) and 1N aq NaOH (10 mL) and extracted with CH2Cl2 (2×10 mL). The combined organic layers were washed with brine (2×5 mL), dried over Na2SO4, decanted, and stripped to afford 2-(trimethylsilyl)ethyl (S)-3-cyclohexyl-2-(methylamino)propylcarbamate (15.0 mg, 94%) as a clear film. MS ESI+ve m/z 315 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]>ClCCl.C(OCC)(=O)C>[F:2][C:3]1([F:9])[CH2:8][CH2:7][N:6]([C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:19])[CH2:5][CH2:4]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: FC1(F)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(F)(F)CC1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 4,4-difluoropiperidin hydrochloride (2.15 g, 14 mmol) in 30 mL of dichloromethane was added triethylamine (5.7 ml, 41 mmol), followed by 4-nitrophenyl chloroformate 40 (3.0 g, 15 mmol). After 1 h, the reaction was diluted with ethyl acetate and was washed with 3×30 mL of sat. NaHCO3, and 1×30 mL brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 4-nitrophenyl 4,4-difluoropiperidin-1-carboxylate 41 (3.9 g, 100% yield). 1H-NMR (400 MHz, CDCl3): δ 8.26 (m, 2H), 7.30 (m, 2H), 3.76 (m, 4H), 2.09 (m, 4H). MS 286.1 (calc'd) 287.1 (M+H, found).
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl)=[CH:4][N:3]=[N:2]1.[C:15]1([C:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:15]1([C:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:7]([NH:6][C:5]4[S:1][N:2]=[N:3][CH:4]=4)=[O:14])[CH2:28][CH2:27]3)[S:24][CH:25]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Nc1cnns1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cnns1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 68.4 %

Procedure:
A mixture of 2,2,2-trichloroethyl 1,2,3-thiadiazol-5-ylcarbamate (190 mg, 0.686 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (153 mg, 0.624 mmol) and diisopropylethylamine (0.217 ml, 1.25 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 159 mg (68.4%) of the desired product as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[CH2:5]([C:7]([C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[N:12]=1)([OH:10])[CH2:8][CH3:9])[CH3:6]>>[CH2:5]([C:7]([C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[N:12]=1)([O:10][CH3:3])[CH2:8][CH3:9])[CH3:6]
Reactant: CCC(O)(CC)c1ccc2ccc3cccnc3c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCC(CC)(OC)c1ccc2ccc3cccnc3c2n1
Yield: 64 %

Procedure:
By using General Procedure II, NaH (0.035 g, 1.5 mmol), methyl iodide (0.092 mL, 1.5 mmol), and 2-[(1-ethyl-1-hydroxypropyl)]-1,10-phenanthroline (0.098 g, 0.368 mmol), prepared as described by Example 2, were reacted to yield 0.066 g (65% yield) of the title methyl ether as a colorless oil: 1H NMR (300 MHz, CDCl3) δ9.24 (dd, J=4.50, 1.80 Hz, Hp9), 8.23 (dd, J=8.40, 1.80 Hz, Hp7), 8.20 (d, J=8.40 Hz, Hp4), 7.97 (d, J=8.40 Hz, Hp3), 7.78 and 7.72 (two d, J=8.80 Hz, Hp5 and Hp6), 7.60 (dd, J=7.80, 4.50 Hz, Hp8), 3.24 (s, OCH3), 2.34 and 2.24 (two dq, J=7.5 Hz, (CH2CH3)2), 0.73 (t, J=7.50 Hz, (CH2CH3)2); 13C NMR (75 MHz) δ164.85, 150.31, 146.45. 145.28, 136.10, 135.54, 128.89. 127.24, 126.55, 125.88, 122.48, 121.52, 84.26, 49.80, 28.17, 7.54; IR (CHCl3) 2969 (C—H Ar), 2935 (CH), 910 (C—H Ar) cm−1; HRMS m/e Calcd for C18H21N2O (MH+): 281.164, found, 281.1646.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3]O.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[OH-].[Na+]>>[C:8]1([S:14][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Sc1ccccc1
Reactant: N[C@@H](CO)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H](CSc1ccccc1)C(=O)O
Temperature: 35 °C
Reaction time: 20 h

Procedure:
To 500 g of an aqueous solution containing 10% of L-serine, 10% of thiophenol and 25 ppm of pyridoxal phosphate and having a pH of 10.0 (adjusted with NaOH), the cells were added to a concentration of 0.9% as calculated based on dry cells. The resultant mixture was stirred at 35° C. for 20 hours under a nitrogen gas atmosphere. During this stirring, the stirring power was controlled at 10 W per liter of the reaction mixture. The molar yield of S-phenyl-L-cysteine so formed was 85% based on the charged L-serine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][C:15]23[CH2:30][CH2:29][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=42)[C:21]2[C:16]3=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1)C1C=CC=CC=1.[ClH:31]>C(O)(=O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][C:15]23[CH2:30][CH2:29][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=42)[C:21]2[C:16]3=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1.[ClH:31]
Reactant: c1ccc(CN2CCOC(CC34CCC(c5ccccc53)c3ccccc34)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc2c(c1)C1CCC2(CC2CNCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 9-(4-benzyl-2-morpholinylmethyl)-9,10-dihydro-9,10-ethanoanthracene (150 mg) in acetic acid was added to 10% palladium on charcoal (60 mg) pretreated under hydrogen in hydrochloric acid, and the resulting mixture was stirred under hydrogen at room temperature for 14 hours. After elimination of the catalyst by filtration, the filtrate was evaporated. The residue was neutralized with 10% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified over silica gel chromatography to give 9-(2-morpholinylmethyl)-9,10-dihydro-9,10-ethanoanthracene, M.P. 242° - 244° C. (hydrochloride).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[Cl:8][C:9]1[C:10]([N:15]2[C:19]3=[N:20][CH:21]=[N:22][C:23]([O:24][C@@H:25](CCO)[C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=4)=[O:27])=[C:18]3[CH:17]=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:8][C:9]1[C:10]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([O:24][C@H:25]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=4)=[O:27])[CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:18]=3[CH:17]=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(NC(=O)[C@H](CCO)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 45.8 %

Procedure:
Acetic anhydride (0.035 mL, 0.38 mmol) was added to (2S)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-4-hydroxy-N-(5-methylpyridin-2-yl)butanamide (Example 143) (150 mg, 0.34 mmol), N,N-Diisopropylethylamine (0.089 mL, 0.51 mmol) and 4-dimethylaminopyridine (4.17 mg, 0.03 mmol) in DCM (2 mL) at 0° C. over a period of 5 minutes under nitrogen. The resulting solution was stirred at 0° C. for 25 minutes. The volatiles were removed under reduced pressure and the crude product was purified by flash silica chromatography, eluting with 0 to 100% ethyl acetate in isohexane to afford the product (75 mg, 45.6%). 1H NMR (400 MHz, CDCl3) δ 1.95 (3H, s), 2.29 (3H, s), 2.54 (2H, q), 4.31-4.39 (2H, m), 6.00 (1H, t), 7.45-7.49 (1H, m), 7.53 (1H, d), 8.00-8.02 (1H, m), 8.10-8.14 (2H, m), 8.43 (1H, s), 8.61 (1H, q), 8.64 (1H, s), 8.80 (1H, s); m/z (ES+) (M+H)+=482; HPLC tR=2.04 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>ClCCl>[F:27][C:28]1[CH:29]=[C:30]([S:34]([NH:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:4]3[CH2:3][C:2]([CH3:20])([CH3:1])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=4)[NH:5]3)[CH:14]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(=O)(=O)c3cccc(F)c3)c1)N2
Yield: 37.7 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (135 mg, 0.5 mmol) in dichloromethane (3 mL) was added pyridine (60 mg, 0.75 mmol) in dichloromethane (2 mL) and 3-fluoro-benzenesulfonyl chloride (108 mg, 0.56 mmol) under nitrogen. The resultant mixture was stirred for 4 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether: Ethyl acetate=12:1) to afford 80 mg of 3-fluoro-N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide as yellow solid (Yield: 38%). MS (ESI+APCI) M+1=425.2.
Reaction SMILES: Cl[C:2]1C=C(C=C(OC(C)C)C=1OC)C(O)=O.[CH2:17]([O:24][C:25]1[C:43]([O:44][CH:45]2[CH2:50]CCC[CH2:46]2)=[CH:42][C:28]([C:29]([NH:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)=[O:30])=[CH:27][C:26]=1[Cl:51])C1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O.C(Cl)Cl>[Cl:51][C:26]1[CH:27]=[C:28]([CH:42]=[C:43]([O:44][CH:45]([CH3:46])[CH3:50])[C:25]=1[O:24][CH3:17])[C:29]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:40]([CH3:2])[CH:41]=1)=[O:30]
Reactant: COc1c(Cl)cc(C(=O)O)cc1OC(C)C
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OCc3ccccc3)c(OC3CCCCC3)c2)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OC)c(OC(C)C)c2)cc1C
Temperature: 60 °C
Yield: 41.8 %

Procedure:
A mixture of 3-chloro-5-isopropoxy-4-methoxybenzoic acid (5) (250 mg, 1.02 mmol), methyl 4-amino-2-methylbenzoate (6) (177 mg, 1.07 mmol) and TEA (150 μL, 1.07 mmol) in EtOAc (2.5 mL) was treated with T3P (50% in EtOAc) (1.63 mL, 2.55 mmol) and the mixture was heated at 60° C. for 5 h. The mixture was diluted with DCM (5 mL) and washed with 1M HCl (5 mL) followed by satd. NaHCO3 solution (5 mL). The organic solvents were removed in vacuo and the residue purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane to yield methyl 4-(3-chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoate (7) (167 mg, 40%): m/z 392 [M+H]+ (ES+), 390 [M−H]− (ES−). 1H NMR (400 MHz, CDCl3) δ:7.98 (1H, d), 7.78 (1H, s), 7.59-7.50 (2H, m), 7.40 (2H, dd), 4.67 (1H, sep), 3.94 (3H, s), 3.89 (3H, s), 2.62 (3H, s), 1.40 (6H, d).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[CH2:4][C:5]([CH3:8])([CH3:7])[CH:6]=1.[N+:10]([CH3:13])([O-:12])=[O:11]>>[CH3:1][CH:2]1[CH:6]([CH2:13][N+:10]([O-:12])=[O:11])[C:5]([CH3:8])([CH3:7])[CH2:4][C:3]1=[O:9]
Reactant: CC1=CC(C)(C)CC1=O
Reactant: C[N+](=O)[O-]
Product: CC1C(=O)CC(C)(C)C1C[N+](=O)[O-]

Procedure:
2,4,4-trimethyl-cyclopent-2-en-1-one is reacted with nitromethane to give 2,4,4-trimethyl-3-nitromethyl-cyclopentanone which, after treatment with a base, is converted into 1-formyl-3-oxo-2,5,5-trimethyl-cyclopentane either with the aid of an oxidizing agent, such as potassium permanganate, ozone, or with a hydrohalic acid, a mineral acid or titanium trichloride.
Reaction SMILES: Cl.N[C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1>C(O)C>[CH2:15]([C:8]1([O:7][C:6]2[CH:22]=[CH:23][CH:3]=[CH:4][CH:5]=2)[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN1CCC(Cc2ccccc2)(Oc2ccc(N)cc2)CC1
Agent: Cl
Solvent: CCO
Product: CN1CCC(Cc2ccccc2)(Oc2ccccc2)CC1

Procedure:
[as the hydrochloride of m.p. 197° to 198° C. (from ethanol)] from 4-(4-aminophenoxy)-4-benzyl-1-methylpiperidine.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[CH2:18]([O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B1OC(C)(C)C(C)(C)O1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:14]1[CH:15]=[N:16][C:2]([NH2:1])=[C:3]([C:4](=[O:5])[NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:13]=1)[CH3:19]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Product: CCOC(=O)c1ccccc1-c1cnc(N)c(C(=O)Nc2ccncc2)c1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate gives “A70”; method 1: HPLC/MS: 1.37 min, [M+H]=363;
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[N:24]=[C:25]=[S:26])(=[O:3])[CH3:2].[CH3:27][C:28]1[N:33]([CH3:34])[N:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:30](=[O:31])[C:29]=1[NH2:41]>C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH:24][C:25]([NH:41][C:29]1[C:30](=[O:31])[N:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:33]([CH3:34])[C:28]=1[CH3:27])=[S:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(N=C=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Solvent: c1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](NC(=S)Nc2c(C)n(C)n(-c3ccccc3)c2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
To 5 ml of anhydrous benzene were added 390 mg (1 mmol) of 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl isothiocyanate and 200 mg (1 mmol) of 4-aminoantipyrine and the mixture was heated at 60°-70° C. for 4 hours and allowed to cool to room temperature. Crystals formed were filtered off and recrystallized from petroleum ether to give pure crystals melting between 148° and 150° C. (uncorrected). Yield: 300 mg (61%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N:37]=[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH:35]=[CH:34]2>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:42]2[CH2:43][CH2:44][N:39]([C:36]3[CH:35]=[CH:34][C:33]4[C:38](=[C:29]([Cl:28])[CH:30]=[CH:31][CH:32]=4)[N:37]=3)[CH2:40][CH2:41]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: Clc1cccc2ccc(N3CCNCC3)nc12
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cccc(Cl)c4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 8-chloro-2-piperazin-1-yl-quinoline. Melting point: 68° C. C33H32ClF3N4O2 (M=609.09) Calc.: molecular peak (M+H)+: 609/611. Found: molecular peak (M+H)+: 609/611.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH:13]=[N:12][C:11]([NH:15][C:16]1[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1)=[CH:10]2>CN(C=O)C.[Cu](I)I>[CH3:1][O:2][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH:13]=[N:12][C:11]([NH:15][C:16]1[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1)=[CH:10]2
Reactant: N#Cc1cnc(Nc2cc3cccc(Br)c3cn2)cn1
Reactant: C[O-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2cc(Nc3cnc(C#N)cn3)ncc12
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 6 %

Procedure:
Sodium methoxide (55 mg, 0.10 mmol) was added to a pre-stirred mixture of 5-(8-bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (33 mg, 0.10 mmol) and copper iodide (19 mg, 0.10 mmol) in DMF in triplicate. The three reaction mixtures were heated at 140° C. for 30 minutes, 110° C. for 18 hours, and 120° C. for 10 minutes, respectively. The combined reaction mixtures were partitioned between ethyl acetate and water and the aqueous layer re-extracted with more ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by preparative HPLC gave the title compound (1.7 mg, 0.006 mmol, 2%). 1H NMR (DMSO, 400 MHz) δ 9.33 (s, 1H), 8.81 (d, 1H, J=1.3 Hz), 8.71 (d, 1H, J=1.3 Hz), 8.43 (s, 1H), 7.64 (t, 1H, J=8.1 Hz), 7.43 (d, 1H, J=8.3 Hz), 6.97 (d, 1H, J=7.6 Hz), 4.01 (s, 3H). LCMS (2) Rt=2.87 min, m/z (ESI+) 278 (MH+).