Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[F:14][C:15]([F:32])([F:31])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH2:26][CH2:25]3)=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[F:32][C:15]([F:14])([F:31])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:26][CH2:25]3)=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)CCN3)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Temperature: 25 °C

Procedure:
1.25 g of commercially available 4-cyano-benzenesulfonyl chloride were dissolved in 35 ml dichloromethane. Then 760 mg 5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole hydrochloride were added followed by 2.14 ml triethylamine. The mixture was stirred at room temperature for fifteen minutes. Then 100 ml of dichloromethane were added, the mixture washed with 40 ml water and brine and then dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by reversed phase HPLC to obtain 517 mg of 4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile as amorphous lyophilisate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([Br:23])=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([Br:23])=[CH:17][N:18]3[S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]cc(Br)c23)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of 0.35 g (0.92 mmole) 4-(3-bromo-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 mL benzene was added 0.106 g (1.1 mmole) sodium t-butoxide and 0.19 g (1.1 mmole) benzenesulfonyl chloride. The reaction mixture was stirred at room temperature for 16 hrs. The mixture was washed with 2 mL water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to provide 0.42 g of 4-(1-benzenesulfonyl-3-bromo-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester, m.p. 188-189°.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:10]1[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+]>CO>[CH2:3]([C:10]1[C:11]([O:16][CH3:17])=[N:12][CH:13]=[C:14]([Br:1])[CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: COc1ncccc1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ncc(Br)cc1Cc1ccccc1

Procedure:
0.12 ml of bromine was added to a mixture of 430 mg of 3-benzyl-2-methoxypyridine, 460 mg of sodium bicarbonate and 10 ml of methanol under stirring in an ice bath, followed by stirring at room temperature for 8 hours. The mixture was partitioned by adding an aqueous sodium thiosulfate solution and ethyl acetate thereto. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography and eluted with 5% ethyl acetate/hexane, to give 140 mg of the target compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[N:22][CH:23]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[N:22][CH:23]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Fc1ccc(CBr)cn1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccc(F)nc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl) amino]pyrimidine and 5-(bromomethyl)-2-fluoropyridine
Reaction SMILES: C(O)C.[OH-].[Na+].[CH2:6]([O:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])=[C:16]([Cl:30])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[CH2:6]([O:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([OH:20])=[O:19])=[C:16]([Cl:30])[CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1ccc(OCc2ccccc2)cc1Cl
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
Ethanol (8.8 ml), 1,4-dioxane (2.2 ml) and a 1N aqueous sodium hydroxide solution (4.7 ml) were added to benzyl 4-benzyloxy-2-chlorobenzoate (1.12 g). The mixture was stirred at 70° C. for 1.5 hr. The solvent was evaporated and water was added to the residue to dissolve the same. After washing with ether, the aqueous layer was acidified with 1N hydrochloric acid, and the resulting precipitate was collected by filtration to give the objective compound (810 mg) as a pale-yellow powder.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)(=O)C.[OH-].[Na+]>CO>[O:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][OH:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)OCc1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1cccc(Oc2ccccc2)c1
Yield: 95 %

Procedure:
2.42 g. (0.01 mole) of 3-phenoxybenzyl acetate, 5 cm3. of methanol and 5 cm3. of 2N sodium hydroxide solution are refluxed for three hours. Then the methanol is distilled off and the organic phase is dissolved in 30 cm3. of methylene chloride, washed with 10 cm3. of 1N hydrochloric acid solution and 10 cm3. of water. 1.90 g. of 3-phenoxybenzyl alcohol are obtained. nD20 : 1.593, yield 95%.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:25].[Na+]>CO>[NH2:25][CH:16]1[CH2:17][CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][C:15]1([CH2:22][CH3:23])[CH2:20][CH3:21]
Reactant: [BH3-]C#N
Reactant: CCC1(CC)CN(Cc2ccccc2)CCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC1(CC)CN(Cc2ccccc2)CCC1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (7.85 g, 102 mmol) was added to the stirred solution of 1-benzyl-3,3-diethyl piperidin-4-one (5.0 g, 20.40 mmol) in methanol (100 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (1.3 g, 20.40 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,3-diethyl piperidine. Yield 8.2 (82%), C16H26N2, m/z 247 (M+1), PMR (CDCl3): 0.84 (s, 3H), 0.98 (s, 3H), 1.48 (bs, 2H, D2O exchangeable), 1.66 (m, 2H), 2.04 (m, 2H), 2.42 (m, 2H), 2.86 (m, 1H), 3.46 (dd, 2H), 7.32 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1.[H-].[Na+].[CH3:23]I.Cl>C1COCC1.O1CCOCC1>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:2][O:1][CH3:23])[CH:8]=[CH:7][C:6]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(-c2ccc(CO)cc2OC)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COCc1ccc(-c2ccc(C(=O)OC)cc2)c(OC)c1
Reaction time: 0.5 h

Procedure:
A solution of Example 417A (142 mg, 0.5 mmol) in THF (3 mL) at room temperature was treated with 60% sodium hydride in oil (40 mg, 1.0 mmol) and methyl iodide (0.30 mmol), stirred for 30 minutes, adjusted to pH<7 with 4M HCl in dioxane (0.5 mL), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [C:1]([O:4][CH:5](I)[CH3:6])(=[O:3])[CH3:2].[Cl:8][C:9]1[C:10]([F:49])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][C:39]=2[O:47][CH3:48])=[O:36])[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:9]1[C:10]([F:49])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([O:44][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])=[O:43])=[CH:40][C:39]=2[O:47][CH3:48])=[O:36])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)I
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OC(C)OC(C)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a mixture of the above 1-iodoethyl acetate (311 mg, 1.457 mmol) and chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (US20100152190A1, 201.7 mg, 0.327 mmol) in dimethylformamide (6 mL) was added cesium carbonate (659 mg, 2.00 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was taken up in ethyl acetate, washed with water and then brine. The organic layer was dried over sodium sulfate and concentrated to dryness. The crude material was purified by flash chromatography (hexane/ethyl acetate, 80/20 to 20/80) to give 1-acetoxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (149.4 mg, 65% yield). MS (ES+) m/z calcd. for C35H36Cl2F2N3O6: [(M+H)+]: 702.19, found: 702.4
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1([CH3:22])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]3=[C:11]([OH:16])[CH:12]=2)[O:7]1.[OH-].[Na+].O1CCO[CH2:28][CH2:27]1>O>[OH:16][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]3[CH:20]4[CH2:27][CH2:28][CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]=13)[O:7][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:23])([CH3:22])[CH2:15][CH2:14]2
Reactant: C1COCCO1
Reactant: COC(=O)CCC1(C)CCc2cc(O)c3c(c2O1)C1CCC3C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(CCC(=O)O)CCc2cc(O)c3c(c2O1)C1CCCC3CC1
Reaction time: 15 h

Procedure:
To a solution of 3-(6-Hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid methyl ester (235 mg, 0.68 mmol) in 5 mL of dioxane was added a solution of NaOH (41 mg, 1.02 mmol) in 400 mL water. The resulting suspension was vigorously stirred for 15 h and quenched by adding 50 mL of saturated NaH2PO4 solution. The mixture was extracted with EtOAc (3×50 mL) and the organic layers were dried over Na2SO4 and concentrated. The crude product was purified by chromatography on silica gel to afford 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-propano-2H-benzo[h]chromen-2-yl)-propionic acid as a white sticky solid (184 mg). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 7.71 (ws, 1 H), 6.41 (s, 1 H), 3.54 (m, 1 H), 3.38 (m, 1 H), 2.73 (m, 2 H), 2.56 (m, 2 H), 2.10-1.62 (m, 12 H), 0.95 (m, 5 H); 13C-NMR δ (ppm): 180.1, 144.0, 142.9, 132.8, 128.9, 118.5, 112.7, 74.0, 34.48, 34.0, 32.0, 31.9, 31.8, 29.5, 28.7, 28.6, 26.4, 26.3, 26.0, 23.9, 23.3, 22.7, 22.3; MS (ESI) m/z: 331 (M+H+, 100%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[C:48]([O:51][C:52]1[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=1[C:54](O)=[O:55])(=[O:50])[CH3:49].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:54](=[O:55])[C:53]3[CH:57]=[CH:58][CH:59]=[CH:60][C:52]=3[O:51][C:48](=[O:50])[CH3:49])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-acetyloxybenzoic acid (6.0 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([Cl:3])=[O:14])=[N:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)cn1
Temperature: 25 °C

Procedure:
N,N-Dimethylformamide (one drop) and thionyl chloride (1 mL) were added to a suspension of 5-chloropyridinecarboxylic acid (55.2 mg) in toluene (5 mL). The mixture was heated under reflux for one hour. The reaction solution was cooled to room temperature and then the solvent was evaporated under reduced pressure to obtain 5-chloropyridinecarboxylic acid chloride. A solution of 5-chloropyridinecarboxylic acid chloride in THF (5 mL) and pyridine (115 μL) were sequentially added to a solution of the compound of Preparation Example 2-(2) (111 mg) in THF (10 mL) under ice-cooling. The mixture was warmed to room temperature and stirred for 30 minutes. After confirming completion of the reaction, a saturated sodium bicarbonate solution was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain an amide compound of a synthetic intermediate. The resulting amide was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added and the mixture was stirred at room temperature for three hours. The reaction solution was diluted with diethyl ether. Then, the reaction mixture was neutralized with a sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by NH-silica gel column chromatography to obtain the title compound (115 mg; >99% ee).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[F:13].[H-].[Na+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CC(N(C)C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:22][C:21]3[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[F:13]
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]ccc2cc(F)c(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(F)c(Br)cc3c2=O)cc1
Temperature: 25 °C
Yield: 116.3 %

Procedure:
9.66 g (39.9 mmol) of 7-bromo-6-fluoro-2H-isoquinolin-1-one (312) were dissolved in 180 mL of dimethyl acetamide and 1.92 g (48.0 mmol) of sodium hydride (60%) were added. After 1 h at room temperature a solution of 7.50 g (48.0 mmol) of 4-methoxy benzylchloride in 25 mL of dimethyl acetamide was added. The mixture was stirred at room temperature until complete conversion is achieved. For the isolation procedure, the solvent is removed i. vac., the residue was taken up in saturated sodium bicarbonate solution and extracted three times with dichloromethane. The organic layers are dried with MgSO4 and evaporated to yield 16.8 g of a dark oil as crude product, which was stirred in methanol. Filtration of the precipitate gave 6.56 g of the title compound as a yellow solid. The mother liquor was evaporated and the residue purified by preparative HPLC, which gave additional 2.62 g of the desired product. Rt=1.71 min (Method C). Detected mass: 362.3/364.3 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C.O>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 110.5 %

Procedure:
Indole-5-carboxylic acid (1.00 g, 6.21 mmol) was dissolved in DMF (10 mL) and the solution was added with EDCI (2.38 g, 12.4 mmol), HOBT monohydrate (839 mg, 6.21 mmol) and 1-(tert-butoxycarbonyl)piperazine (1.73 g, 9.29 mmol), followed by stirring at room temperature for 3.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, 1 mol/L hydrochloric acid, and saturated brine, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 5-[4-(tert-butoxycarbonyl)piperazin-1-ylcarbonyl]indole (2.26 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[O:32]([CH3:34])[Na]>CO.CCOC(C)=O>[C:26]([C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[C:17]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([O:32][CH3:34])=[N:3][C:4]([C:28]([F:31])([F:30])[F:29])=[CH:5][CH:6]=1)#[CH:27]
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Reactant: CO[Na]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OC)cc(F)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (50 mg, 0.105 mmol) in CH3OH (1 mL) was added dropwise 30% NaOCH3 in CH3OH (3 eq) at 0° C. The mixture was stirred for 12 hours at room temperature. The reaction was diluted with EtOAc and washed two times with 1N HCl and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (10 mg, 20%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[N:12]=[CH:13][N:14]([CH3:17])[C:15]=2Br)[CH:6]=1)=[O:4].[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=2B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=2[C:15]2[N:14]([CH3:17])[CH:13]=[N:12][C:11]=2[C:7]2[CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][N:8]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)c1ccnc(-c2ncn(C)c2Br)c1
Reactant: CC1(C)OB(c2cc(F)c(F)cc2OCC2CC2)OC1(C)C
Product: Cn1cnc(-c2cc(C(=O)O)ccn2)c1-c1cc(F)c(F)cc1OCC1CC1
Yield: 5 %

Procedure:
The title compound was prepared in 5% yield from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carboxylic acid methyl ester and 2-(cyclopropylmethoxy)-4,5-difluorophenylboronic acid pinacol ester according to the procedure for the preparation of Example 3, part A followed by hydrolysis. 1H NMR (400 MHz, DMSO-d6): δ 0.29-0.32 (2H, m), 0.53-0.58 (2H, m), 1.22 (1H, m), 3.43 (3H, s), 3.82 (2H, d, J=7.0 Hz), 6.82 (1H, br s), 7.09-7.14 (1H, m), 7.27 (1H, t, J=7.7 Hz), 7.42 (1H, d, J=3.6 Hz), 7.90 (1H, s), 8.20 (1H, d, J=4.3 Hz), 8.30 (1H, s). [M+H] Calc'd for C20H12F2N3O3, 386. Found, 386.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].F[C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=3[N+:26]([O-:28])=[O:27])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2cccc3cnccc23)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
5-Isoquinolinethiol 1.00 g (6.2 mmol) was dissolved in DMF 14 ml, potassium carbonate 1.01 g (7.3 mmol) and 4-fluoro-3-nitroaniline 0.96 g (6.1 mmol) were added and the mixture was heated with stirring for 2 hours at 100° C. The reaction solution was concentrated under reduced pressure, the resulting residue was washed with water to obtain 4-(5-isoquinolylsulfanyl)-3-nitroaniline 1.75 g (96.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14]O)[CH2:10][C@@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14][Br:39])[CH2:10][C@@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](CCO)CN1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](CCBr)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 0.58 g of cis methyl N-t-butoxycarbonyl-4-(2-hydroxyethyl)pyrrolidine-2-carboxylate in 6 ml methylene chloride is added at 0° 0.577 g triphenylphosphine followed by 0.388 g N-bromosuccinimide. After stirring 0.5 hour, the solvent is evaporated and the residue flash chromatographed using ethyl acetate/hexane (35:65) to afford cis methyl N-t-butoxycarbonyl-4-(2-bromoethyl)-pyrrolidine-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16](Br)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([S:22]SCC)[CH3:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:22][CH2:20][CH3:21])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCSSCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Product: CCSc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Yield: 86 %

Procedure:
Prepared in analogy to example 4 (b) from 4-(5-bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 4(a)) and diethyl disulphide. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a white crystalline solid (yield 86%). MS (m/e): 330.3 (M+H+, 100%).