Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>C(O)C>[CH3:2][CH:3]1[CH2:8][C:7]2[C:16]3[C:15](=[CH:14][CH:13]=[C:12]([CH3:11])[CH:17]=3)[NH:9][C:6]=2[CH2:5][CH2:4]1
Reactant: Cc1ccc(NN)cc1
Reactant: CC1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: Cc1ccc2[nH]c3c(c2c1)CC(C)CC3
Temperature: 0 °C
Yield: 66.2 %

Procedure:
Bis-1,3(N-3',6'-dimethylcarbazolyl)propane. A mixture of 25.0 g (157 mmol) of p-methylphenylhydrazine hydrochloride and 17.6 g (157 mmol) of 4-methylcyclohexanone was stirred overnight in 75 ml of 95% ethanol. The mixture was cooled to 0° C, filtered, and the product recrystallized from ethanol/water to give 20.7 g (66%) of 3,6-dimethyl-1,2,3,4-tetrahydrocarbazole, mp 118.5°-20° C (lit. mp 112° C).
Reaction SMILES: [Na].[S:2]1C=CC=C1CC(O)=O.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].[OH-].[Na+].Cl>CO>[SH:2][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]
Reactant: OCCCCCCCCCCCCCCCCBr
Reactant: O=C(O)Cc1cccs1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: OCCCCCCCCCCCCCCCCS
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
Under inert atmosphere 365 mg of sodium metal suspension (40% in mineral oil) were added dropwise to 20 ml of dry methanol at 0° C. After completion of addition the reaction mixture was stirred for 10 min at RT followed by addition of 0.45 ml (6.30 mmole) of thiolacetic acid. After additional 10 min of stirring 3 ml degassed methanolic solution of 1.0 gr (3.11 mmole) of 16-bromohexadecan-1-ol were added. The resulted mixture was refluxed for 15 hrs, allowed to cool to RT and 20 ml of degassed 1.0 M NaOH aqueous solution were injected. The reaction completion required additional 3 hr of reflux. Resulted reaction mixture was cooled with ice bath and poured, with stirring, into a vessel containing 200 ml of ice water. This mixture was titrated to pH=7 by 1.0 M HCl and extracted with 300 ml of ether. The organic layer was separated, washed with 3×50 ml of water, 150 ml of saturated NaCl aqueous solution and dried over sodium sulfate. After ether removal material was dissolved in minimum amount of dicloromethane and purified by silica gel chromatography (100% dicloromethane as eluent). 600 mg (70% yield) of the desired product were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].ClCl.[N+]([O-])(O)=[O:14]>C(O)(=O)C>[CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])=[CH:5][C:6](=[O:14])[C:7]=1[CH3:8]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: O=[N+]([O-])O
Agent: ClCl
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Reaction time: 0.5 h
Yield: 90 %

Procedure:
13.6 g (0.1 mole) of 2,3,6-trimethylphenol was dissolved in 100 g of acetic acid, and 7.4 g (0.104 mole) of chlorine gas bubbled thereinto at 20° - 30°C under stirring. Gas chromatography at this stage showed that p-chloro derivative was produced fairly quantitatively. 10 g of commercially available concentrated nitric acid (63 percent) was added dropwise thereto in 30 minutes without removing acetic acid. The temperature rose to 30°C. After dropwise addition, the stirring was continued for another 30 minutes, and then the reaction solution was subjected to steam distillation. The steam distillation was discontinued at the time when the yellow color of the distillate disappeared, and the distillate was extracted with ether. The ether layer was washed with an aqueous solution of sodium bicarbonate and dried over sodium sulfate (anhydrous), followed by distillating off ether. Thus, there was obtained 13.5 g (90 percent in yield) of 2,3,6-trimethyl-p-benzoquinone.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH3:20])=[CH:10][C:9]1=[O:21].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O>Cl>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12]([C:11]([CH3:20])=[CH:10][C:9](=[O:21])[N:8]2[CH2:7][CH2:6][CH:2]=[O:1])=[CH:13][CH:14]=1
Reactant: COc1ccc2c(C)cc(=O)n(CCC3OCCO3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Product: COc1ccc2c(C)cc(=O)n(CCC=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 1-[2-(1,3-dioxolan-2-yl)ethyl]-7-methoxy-4-methylquinolin-2(1H)one (30 ml) was added 4N hydrochloric acid (30 ml) and the mixture was stirred at room temperature for 2 hours. An aqueous solution of sodium carbonate/hydrogen carbonate was added to the reaction solution and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the obtained crude product was purified by thin layer chromatography (hexane/ethyl acetate) to yield 630 mg (74%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[NH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][CH:43]=2)=[CH:40][N:41]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>COCCOC.O>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[NH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:21]3[CH:22]=[CH:23][C:18]([C:15]4[NH:14][C:13]([CH:10]5[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]5)=[N:17][CH:16]=4)=[CH:19][CH:20]=3)=[CH:44][CH:43]=2)=[CH:40][N:41]=1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)C1
Temperature: 80 °C
Yield: 63.7 %

Procedure:
Pd(Ph3)4 (54 mg, 0.046 mmol) was added to a mixture 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (378 mg, 0.97 mmol), 2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (408 mg, 0.93 mmol), NaHCO3 (273 mg, 3.26 mmol) in 1,2-dimethoxyethane (8 mL) and water (2 mL). The reaction mixture was flushed with nitrogen, heated at 80° C. for 6 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (370 mg, 64%). m/z 625.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][S:9]1(=[O:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39][CH:40](O)[CH3:41].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:39][CH2:40][CH2:41][N:10]1[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:19])=[O:18]
Reactant: O=S1(=O)NCc2ccccc2N1c1ccccc1F
Reactant: CC(O)Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S1(=O)N(CCBr)Cc2ccccc2N1c1ccccc1F
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of 1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.46 g, 1.7 mmol) in tetrahydrofuran (20 mL) was cool to 0° C. and treated with triphenylphosphine (0.65 g, 2.5 mmol), bromoethanol (0.25 mL, 3.5 mmol) and diisopropyl azodicarboxylate (0.5 mL, 2.6 mmol). After the final addition, the reaction mixture was warmed to room temperature for 2 h, evaporated to a brown oil. The crude product residue was purified by flash chromatography (SiO2, 3-50% ethyl acetate/heptane) to afford 3-(2-bromoethyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.44 g, 63%) as a white solid:
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=O)=CC=1.OC1C=CC(C2C=CC(O)=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+].[N+]([C:40]1[CH:41]=[C:42]([C:48]#[N:49])[C:43](=[CH:46][CH:47]=1)[C:44]#[N:45])([O-])=O>C(O)C.O.C1(C)C=CC=CC=1.CC(N(C)C)=O>[C:48](#[N:49])[C:42]1[C:43](=[CH:46][CH:47]=[CH:40][CH:41]=1)[C:44]#[N:45]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: CCO
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1C#N
Temperature: 100 °C
Yield: 282.9 %

Procedure:
To a 100 ml, 3-necked flask equipped with a thermometer and a Dean-Stark trap was added 12.01 gm (55.1 mmol) of 4,4'-difluorobenzophenone, 20.11 gm (108.1 mmol) of 4,4'-dihydroxybiphenyl, and 70 ml of dimethylacetamide (DMAC). After flushing the mixture for 20 minutes with dry nitrogen, 21.2 gm (153.4 mmol) of pulverized anhydrous potassium carbonate was added with stirring. The Dean-Stark trap was filled with toluene. Five milliliter of toluene was also added to the reaction mixture. The mixture was then heated at 100° C. for 1 hour and at reflux (140° C) for 12 hours total. During this time, the water formed as a by-product was removed by azeotropic distillation. After refluxing, the toluene was removed by distillation. When the temperature of the reaction mixture had reached 165° C., it was assumed that the toluene had been removed. The reaction temperature was then reduced to 90° C. whereupon 19.0 gm (109.8 mmol) of 4-nitrophthalonitrile was added. The reaction mixture turned purple. The reaction content was then stirred at 95°-100° C. for 16 hours (overnight). The reaction was monitored by FTIR spectroscopy and showed the complete disappearance of the absorptions attributed to the nitro group. The room temperature mixture was poured into 50% aqueous ethanol with stirring. The solid precipitate was collected by suction filtration, washed exhaustively with water, washed with ethanol, and dried to afford 39.8 gm of oligomeric phthalonitrile monomer. A DSC thermogram showed an endothermic transition between 260°-280° C.
Reaction SMILES: CC(=O)CCC(=O)C.[CH:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1.N1CCCC1.CC(OC[C:24]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](COC(C)=O)=[C:30]2C=1C=C[CH:28]=[CH:29]2)=O>CO>[C:10]1(=[C:34]([CH2:35][CH2:36][C:37](=[C:32]2[CH:28]=[CH:29][CH:30]=[CH:31]2)[CH3:24])[CH3:33])[CH:9]=[CH:13][CH:12]=[CH:11]1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: C1=CCC=C1
Agent: CC(=O)CCC(C)=O
Solvent: C1CCNC1
Solvent: CO
Product: CC(CCC(C)=C1C=CC=C1)=C1C=CC=C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a modified reaction procedure [a], 11.0 g (96.3 mmol) of 2,5-hexanedione and 12.7 g (193 mol) of freshly cracked cyclopentadiene are dissolved in 60 ml of methanol, the solution is cooled to 0° C., and 8.60 g (121 mmol) of pyrrolidine are added. The reaction solution is stirred at 0° C. for 90 minutes, hydrolyzed using 5 ml of glacial acetic aaid and 50 ml of water, and extracted twice with 70 ml of diethyl ether in each case, and the combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate, giving, after removal of the solvent in vacuo, 18.0 g (89%) of the difulvene as an orange-red, oily residue.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1>>[NH2:13][C:10]1[C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:8][C:7]([Br:6])=[CH:12][N:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: Nc1ccc(Br)cn1
Product: Nc1ncc(Br)cc1S(=O)(=O)Cl
Temperature: 25 °C
Yield: 77 %

Procedure:
To a cooled (0° C.) solution of chlorosulfonic acid (58 mL) under vigorous stirring was added 5-bromo-2-pyridinamine (15 g, 86.7 mmol) portionwise. The reaction mixture was then heated at reflux for 3 hrs. Upon cooling to room temperature, the reaction mixture was poured over ice (p100 g) with vigorous stirring. The resulting yellow precipitate was collected by suction filtration, washing with cold water and petroleum ether to provide the title compound as an orange-yellow solid (18.1 g, 77% yield). MS(ES)+ m/e 272.8 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Cl-].[NH:9]([C:16]1[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][O:31]CCO)=[CH:26][CH:25]=2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(NCC)C>C(Cl)Cl>[NH:9]([C:16]1[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][O:31][CH2:2][CH2:1][N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])=[CH:28][CH:29]=2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)CC
Reactant: OCCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)CCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Triethylamine (33 ml, 0.241 mmol) and mthanesulphonyl chloride (19 ml, 0.241 mmol) were added to a solution of 4-anilino-5-bromo-2-[4-(2-hydroxyethoxy)methylanilino]pyrimidine (Example 31; 100 mg, 0.241 mmol) in DCM (5 ml) at 0° C. The solution was warmed to ambient temperature and left to stand for 1 hour. Diethylamine (2 ml) was added, and the mixture was heated at 50° C. for 3 hours. The solvent was removed by evaporation, and the residue was purified by column chromatography, eluting with 0–2% methanol solution in DCM containing 0.5% aqueous ammonia solution, to give the product as a cream solid (38 mg, 34%). NMR (CDCl3): 1.03 (t, 6H), 2.58 (q, 4H), 2.69 (t, 2H), 3.54 (t, 2H), 4.48 (s, 2H), 7.06 (d, 2H), 7.17 (t, 1H), 7.22 (s, 1H), 7.26 (s, 1H), 7.38 (dd, 2H), 7.49 (d, 2H), 7.58 (d, 2H), 8.15 (s, 1H); MS (MH+): 470.4, 472.4.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Product: CN1CCN(c2ccc(C#N)cc2)CC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 4-fluorobenzonitrile and 1-methylpiperazine.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[CH:24][C:23]3[CH:26]=[C:27]([C:33]4[CH:34]=[N:35][NH:36][CH:37]=4)[N:28](S(C)(=O)=O)[C:22]=3[CH:21]=2)=[CH:15][CH:14]=1>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[N:25]=[CH:24][C:23]3[CH:26]=[C:27]([C:33]4[CH:37]=[N:36][NH:35][CH:34]=4)[NH:28][C:22]=3[CH:21]=2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)n1c(-c2cn[nH]c2)cc2cnc(Nc3ccc(F)cc3)cc21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Fc1ccc(Nc2cc3[nH]c(-c4cn[nH]c4)cc3cn2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
DBU (2 μL, 0.016 mmol) was added to a solution of N-(4-fluorophenyl)-1-(methylsulfonyl)-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine (Example 187, 3 mg, 8.08 μmol) in DMF (54 μL). The reaction mixture was stirred for 1 hour at 50° C. and for 1 hour at 100° C. The reaction mixture was diluted with water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then purified using preparative TLC eluting with DCM/MeOH, 90/10 to afford the title compound as a brown solid (2 mg, 84%). 1H NMR (500 MHz, CD3OD): δ 6.60 (d, J=0.9 Hz), 6.85 (s, 1H), 6.99-7.06 (m, 2H), 7.26-7.32 (m, 2H), 8.00 (br s, 2H), 8.34 (s, 1H). ESI-HRMS Found 294.1158, calculated for C16H13FN5 [M+H]+: 294.1150. MPS1 IC50 (uM): 0.140
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22](O)=[O:23])=[N:16]1)=[O:8].C(Cl)(Cl)Cl.C(Cl)(=O)OCC.[NH3:35]>C(N(CC)CC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22]([NH2:35])=[O:23])=[N:16]1)=[O:8]
Reactant: O=C(O)c1nc(CCl)n(-c2ccccc2C(=O)c2ccccn2)n1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: NC(=O)c1nc(CCl)n(-c2ccccc2C(=O)c2ccccn2)n1
Reaction time: 0.17 h

Procedure:
To a solution of 0.258 g. of 1-[2-(2-pyridinecarbonyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid in 7.5 ml. of chloroform are added 0.14 ml. of triethylamine and then 0.1 ml. of ethyl chlorocarbonate with ice-cooling. After stirring for 10 minutes, to the resulting mixture is added 0.5 ml. of concentrated aqueous ammonia, and the whole mixture is further stirred for 30 minutes. The precipitated crystals are collected by filtration, washed successively with water, ethanol and ether, and then dried to give 1-[2-(2-pyridinecarbonyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxamide as crystals. The filtrate is extracted with chloroform and the chloroform layer is washed with water, dried over sodium sulfate, followed by evaporation of the solvent to give additional crystals identical with the abovementioned crystals. Recrystallization of the combined crystals from chloroform-ethanol gives colorless needles, melting at 228° to 229° C. (decomposition).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[I-:11].[Na+]>CC(=O)CC.C(OCC)(=O)C>[I:11][CH2:2][C:3](=[O:10])[N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=C(CI)N1CCOCC1
Yield: 86.1 %

Procedure:
Dissolve 1-chloro-2-oxo-2-(morpholin-4-yl)ethane (7.0 g, 42.8 mmol) and sodium iodide (8.0 g, 53.4 mmol) in 2-butanone (150 mL) and reflux for 3 hours under nitrogen. Dilute with ethyl acetate (200 mL), filter, concentrate under reduced pressure and chromatograph on flash silica using neat ethyl acetate to obtain 9.4 g (86%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)=[O:5])[CH3:2].CN([CH:18]=[CH:19][N+:20]([O-:22])=[O:21])C>C(OCC(F)(F)F)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH:18]=[CH:19][N+:20]([O-:22])=[O:21])=[CH:9][NH:10]2)=[O:5])[CH3:2]
Reactant: CN(C)C=C[N+](=O)[O-]
Reactant: CCOC(=O)c1cccc2[nH]ccc12
Agent: CC(=O)OCC(F)(F)F
Product: CCOC(=O)c1cccc2[nH]cc(C=C[N+](=O)[O-])c12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5 g of 4-ethoxycarbonyl indole are added to a solution of 3.1 g of dimethylamino-2-nitroethylene in 20 ml of trifluoroethyl acetate refrigerated under argon. The reaction mixture is introduced into ice water after it had been standing overnight at room temperature. The aqueous phase is repeatedly extracted with ethyl acetate. The combined ethyl acetate extracts are extracted first with sodium bicarbonate solution, then a saturated sodium chloride solution, dried and evaporated. The residue is recrystallized from ethanol. Yield: 4.5 g of 4-ethoxycarbonyl-3-(2-nitrovinyl)-indole. Yellow crystals with a 197°-199° C. melting point.
Reaction SMILES: ClC1C=CC(OCC(O)=O)=C([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[C:10]([F:21])[CH:9]=2)C=1.B([C:30]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:31]=1[O:32][C@@H:33]([CH3:37])[C:34]([OH:36])=[O:35])(O)O>>[F:21][C:10]1[CH:9]=[C:8]([C:30]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:31]=2[O:32][C@@H:33]([CH3:37])[C:34]([OH:36])=[O:35])[CH:13]=[CH:12][C:11]=1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15]
Reactant: O=C(O)COc1ccc(Cl)cc1-c1ccc(C(=O)N2CCCC2)c(F)c1
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Product: C[C@H](Oc1ccc(C(F)(F)F)cc1-c1ccc(C(=O)N2CCCC2)c(F)c1)C(=O)O

Procedure:
The title compound was prepared using the product of example 24 part a) and (2S)-2-[2-borono-4-(trifluoromethyl)phenoxy]-propanoic acid [WO2004089885] by the method of example 32 step b).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccc(F)cc3-c3ccccc3C2C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2ccccc2-c2cc(F)ccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
The title compound was prepared from 2-fluoro-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (220 mg, 0.57 mmol), cyclohexene (1.2 mL, 11.5 mmol), and 1.0 M solution of boron tribromide in dichloromethane (3.4 mL) according to the procedure and in the same manner as described in Example 105, step e. The volatile components were removed in vacuo, and the crude residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-30% methyl tert-butyl ether in hexane, to afford the product (164 mg, 77%) as a solid, m.p. 216-218° C.;
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(N)c(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: COc1ccc(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)c(NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-Amino-5-methoxy-phenyl)-carbamic acid tert-butyl ester (Example J12) (179 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown foam (256 mg).
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[C@H:11]([CH3:24])[CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].C(O)CO>O>[CH3:24][C@H:11]1[C@@H:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:13][CH2:14][NH:9][CH2:10]1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CC[C@@H]1c1c[nH]c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: C[C@@H]1CNCC[C@@H]1c1c[nH]c2ccccc12
Temperature: 130 °C
Yield: 80 %

Procedure:
A mixture of 21 parts of cis-1-benzoyl-4-(1H-indol-3-yl)-3-methylpiperidine, 60 parts of potassium hydroxide 385 parts of 1,2-ethanediol and 80 parts of water was stirred and refluxed (about 130° C.) overnight. After cooling for a while, about 200 parts of water were added whereupon the product was crystallized. The whole was further cooled and the solid product was filtered off, washed with a lot of water and with 2,2'-oxybispropane and dried, yielding 11.2 parts (80%) of cis-3-(3-methyl-4-piperidinyl)-1H-indole (intermediate 23).