Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[NH:8][C:7]=1[CH3:26])=[O:5])C.[OH-].[Na+].C(Cl)(Cl)Cl.CO>C(O)C>[C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[NH:8][C:7]=1[CH3:26])([OH:5])=[O:3]
Reactant: C#Cc1cccc(C2C(C(=O)OCC)=C(C)NC(C)=C2C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C#Cc1cccc(C2C(C(=O)O)=C(C)NC(C)=C2C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.1 %

Procedure:
In 80 ml of ethyl alcohol was dissolved 7.5 g (0.02 mol) of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-(3-ethynylphenyl)pyridine obtained in Example 2. Thereto was added 20 ml of 5N sodium hydroxide. After stirring for 24 hours at room temperature, the mixture was reacted further for 30 hours at 40°-45° C. After completing the reaction, the reaction solution was distilled away under reduced pressure. Water and chloroform were added to the residue, and a water layer was collected. The water layer was acidified with concentrated hydrochloric acid to give precipitate. The precipitate was purified by subjecting to silica gel column chromatography [eluent: chloroform-methyl alcohol (100 : 5)]to give 1.5 g of the desired compound (yield: 23.1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[C:5](\[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)/[CH3:6].[C:18](#[N:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:4]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:25][N:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[C:5]=1[CH3:6])=[O:17]
Reactant: N#Cc1ccccc1
Reactant: COC(=O)/C=C(/C)Nc1ccc([N+](=O)[O-])cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: COC(=O)c1c(-c2ccccc2)nn(-c2ccc([N+](=O)[O-])cc2)c1C
Yield: 75 %

Procedure:
According to AVV A, (Z-3-(4-nitrophenylamino)-but-2-enoic acid methylester (236.2 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into benzonitrile (3.0 ml, 29.4 mmol, 29.4 equiv.) for 14 hours at 120° C. The brown solid obtained as raw product (533.2 mg) was purified by means of column chromatography (silica gel (50 g), CH2Cl2/EtOAc 100:0→90:10→0:100), whereby the pure product was obtained in the form of a slightly yellowish solid (253.5 mg, 0.75 mmol, 75%).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[S:22][C:23]4[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=4[N:25]=3)[CH2:17][CH2:16]2)[CH:6]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[Cl:30][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([N:18]3[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][NH:12][CH2:11][C:7]4[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:10]=[CH:9][CH:8]=4)[CH2:16][CH2:17]3)[S:22][C:23]=2[CH:29]=1
Reactant: COC(=O)Cc1cccc(CNCCC2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1cccc(CNCCC2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
A mixture of [3-[[[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethylamino]methyl]phenyl]acetic acid methyl ester (65 mg), 2N sodium hydroxide (0.36 mL), tetrahydrofuran (1 mL) and methanol (1 mL) was stirred at room temperature for 1 hour. The solution was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the obtained residue was washed with the mixed solvent of ethyl acetate and n-hexane to give the title compound (19 mg). Yield: 30%.
Reaction SMILES: [F:1][C:2]1[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:29][CH:28]=[C:27]([F:38])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([O:16][CH3:17])=[N:14][N:13](CC3C=CC(OC)=CC=3)[C:10]2=[N:11][CH:12]=1)=[O:5]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:29][CH:28]=[C:27]([F:38])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([O:16][CH3:17])=[N:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(OC)nn3Cc2ccc(OC)cc2)c1F
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(OC)c3c2)c1F
Yield: 89.8 %

Procedure:
2,6-Difluoro-N-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.0030 g, 0.0055 mmol) was taken up in TFA (2 mL) and heated to reflux for 8 hours. The reaction mixture was concentrated and purified by column chromatography (1:1 hexane/EtOAc) to provide 2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.0021 g, 90%) as a solid. 1H NMR (400 MHz, (CD3)2CO) δ 8.65-8.66 (m, 2H), 7.65-7.71 (m, 1H), 7.15-7.20 (m, 1H), 4.07 (s, 3H), 3.16-3.19 (m, 2H), 1.84-1.90 (m, 2H), 1.03-1.07 (m, 3H); m/z (APCI-pos) M+1=426.1.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][CH2:16]Br.C(Cl)Cl>CC#N>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[Br:12])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1[nH]c2ncccc2c1C
Reactant: BrCCc1ccccc1Br
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nc2n(CCc3ccccc3Br)cccc-2c1C

Procedure:
A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (554 mg, 3.8 mmol) and o-bromophenethyl bromide (1000 mg, 3.8 mmol) in 11 ml CH3CN was refluxed for 16 h. The solvent was evaporated and the residue chromatographed (silica, CH2Cl2 /MeOH; 9/1) to give 546 mg enriched product. Pure 2,3-dimethyl-7-(o-bromophenethyl) pyrrolo[2,3-b]pyridine was obtained by a second chromatography (silica, CH2Cl2 saturated with NH3/petroleum ether; 7/3). A deaerated solution of 2,3-dimethyl-7- (o-bromophenethyl) pyrrolo[2,3-b]pyridine (249 mg, 0.76 mmol) in 25 ml dry THF was cooled to -78° C. and treated with 1.6M n-BuLi in hexane (576 μl, 0.91 mmol). After 3 min a vigurous stream of CO2 (g) was bubbled through the solution. The solution was allowed to warm to room temperature and 1.5 ml H2O was added. The solvent was evaporated and the residue chromatographed (reversed phase silica, MeOH/H2O; 6/4) yielding 51 mg (23%) pure amino acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(OC(O)C)C>N1C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cccc(Cl)c1
Agent: CCOC(C)O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(Cl)c3)c2cc1OC
Yield: 54.2 %

Procedure:
A mixture of 0.5 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.51 g of 3-chloroaniline, 0.16 ml of pyridine, and 6 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 6 h. The mixture was cooled and partitioned with dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexanes to give 0.37 g of 4-[(3-chlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile as a solid, mp 214-217° C.
Reaction SMILES: [H-].[Na+].[CH2:3]=[CH:4][CH2:5][CH2:6][CH:7]([OH:12])[CH2:8][CH2:9][CH:10]=[CH2:11].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:12][CH:7]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:6][CH2:5][CH:4]=[CH2:3]
Reactant: C=CCCC(O)CCC=C
Reactant: BrCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC(CCC=C)OCCCCCCCCCCBr
Reaction time: 21 h
Yield: 31.3 %

Procedure:
2.1 g of 60% sodium hydride was suspended in 50 ml of THF, and 6.6 g of 1,8-nonadien-5-ol was dropped therein in an atmosphere of argon. 28 g of 1,10-dibromodecane was further dropped therein, and reflux was then carried out for 21 hours in an atmosphere of argon. After the generated precipitate was filtered off, the solvent was evaporated, and the residue was purified by silica gel column chromatography, to obtain 5.3 g of the compound (7). (Yield: 31%)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[N:3]=1.[CH2:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:23].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[ClH:1].[ClH:1].[CH2:22]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:3]=2)[CH2:26][CH2:25]1)[CH3:23]
Reactant: COc1ccc2cc(-c3ccccc3OC)nc(Cl)c2c1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccccc3OC)cc3ccc(OC)cc23)CC1
Product: Cl

Procedure:
1-Chloro-7-methoxy-3-(2-methoxyphenyl)isoquinoline (0.56 g) was reacted with N-ethylpiperazine (5 ml) and potassium carbonate (0.5 g) at 120° C. for 5 hr. To the resulting reaction solution were added ethyl acetate and water, and then it was extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 0.43 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH2:11])[O:3]1.[CH2:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]([CH3:20])[CH3:19]>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][S:21]([CH2:17][CH:18]([CH3:20])[CH3:19])(=[O:23])=[O:22])[O:5]1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: CC(C)CS(=O)(=O)Cl
Product: CC(C)CS(=O)(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1

Procedure:
The title compound was prepared using methods analogous to those described in Step B of Example 490 using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and isobutylsulfonyl chloride. 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.81-7.75 (m, 1H), 7.63-7.58 (m, 1H), 7.49-7.41 (m, 1H), 7.14-7.06 (m, 1H), 2.96 (d, J=10.1, 2H), 2.39-2.19 (m, 1H), 1.37 (s, 12H), 1.11-0.99 (m, 6H).
Reaction SMILES: CN(CC)C.O=[C:7]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[N:17][C:11]=2[N:10]2[CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:9]2[CH2:8]1.CO.[OH-].[Na+]>O1CCCC1.O>[N:17]1[C:11]2[N:10]3[CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:9]3[CH2:8][CH2:7][NH:13][C:12]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncccc3NC(=O)CC2C1
Agent: CCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2c3ncccc3NCCC2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of alane-N,N-dimethylethylamine complex (0.5 M in toluene, 5.0 mL, 2.50 mmol) was added dropwise over 2 minutes to a solution of the product of Example 64A (506 mg, 1.59 mmol) in dry tetrahydrofuran (22 mL). The reaction was stirred at room temperature for 5 hours. Additional portions of alane-N,N-dimethylethylamine complex (0.5 M in toluene, 5.0 mL, 2.50 mmol) were added after 1 hour, and again after 4 hours. Methanol (10 mL) was added, followed after 10 minutes by water (20 mL) and 25% NaOH (3 mL). The mixture was stirred for 10 minutes, and the aqueous layer was separated and extracted with ethyl acetate (30 mL). The combined organic phases were washed with brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography (SiO2, eluted with ethyl acetate-ethanol, 90:10) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 1.73-1.88 (m, 1H), 1.90-2.07 (m, 1H), 3.17-3.40 (m, 2H), 3.40-3.83 (m, 7H), 6.67 (dd, J=7.8, 4.8 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 7.75 (dd, J=4.7, 1.7 Hz, 1H); MS (DCI) m/z 305 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1.I[CH3:12]>CN(C=O)C>[Br:3][C:4]1[N:9]=[C:8]([NH:10][CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: Nc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
NaH (150 mg, 3.80 mmol, 60%) was added to a solution of 6-bromo-pyridin-2-ylamine (300 mg, 1.73 mmol) in DMF at 0° C. followed by iodomethane (3.47 mL, 6.94 mmol). The reaction mixture was stirred for 1 hour at room temperature and was quenched with water. The aqueous phase was extracted with Et2O. The organic phase was washed with water, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 90 mg (0.48 mmol, 28%) of (6-bromo-pyridin-2-yl)-methyl-amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:17][C:11]=2[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:35]Br.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:35][C:34]1[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:32]([Cl:31])[CH:33]=1)[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)(=[O:20])=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(F)cc3)ccc2[nH]1
Reactant: COc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3[nH]2)cc1Cl
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
A stirred solution of 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-3H-benzoimidazol-5-yl ester (Example 55 (step 3), 200 mg) in dry dimethylformamide (3 ml) was treated with sodium hydride (12 mg, 60% dispersion in mineral oil). After stirring for 30 minutes the mixture was treated with a solution of 3-chloro-4-methoxy-benzyl bromide (94 mg) in dimethylformamide (1 ml) and stirring was continued for a further 3 hours. The reaction mixture was poured into water (10 ml) and then extracted three times with ethyl acetate (10 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:2, v/v) to give 4-fluoro-benzenesulfonic acid 2-[tert-butoxycarbonyl-(3-chloro-4-methoxy-benzyl)-amino]-3H-benzoimidazol-5-yl ester (70 mg) as a beige solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21](=[O:33])[C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([Br:32])[CH:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.CCOC(C)=O>ClCCl>[Br:32][C:24]1[CH:23]=[C:22]([C:21]([CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[O:33])[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Br)cc(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Br)cc(C(F)(F)F)c1)C1CCNCC1
Yield: 135.2 %

Procedure:
Add trifluoroacetic acid in dichloromethane (20%, 5 mL) to the solution of tert-butyl-4-(3-bromo-5-(trifluoromethyl)benzoyl)piperidine-1-carboxylate (387 mg, 0.88 mmol) in dichloromethane (5 mL) at 0° C., stir the mixture. TLC (PE:EtOAc=5:1) shows the reaction is complete. Concentrate under reduced pressure to dryness to afford the crude product (400 mg, 100%) which is used directly in next step. MS: (M+1): 336.0.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9](Cl)(=[O:11])[CH3:10].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[C:25]1([Mg]Cl)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:9]([N:6]1[CH:7]=[CH:8][C:3](=[O:2])[CH2:4][CH:5]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: Cl[Mg]c1ccccc1
Reactant: COc1ccncc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)N1C=CC(=O)CC1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 4-methoxypyridine (45.871 mmol, 1.0 eq.) in dry tetrahydro-furan (200 ml) was added acetyl chloride (45.871 mmol, 1.0 eq.), followed by TMSOTf (45.871 mmol, 1.0 eq.) at room temperature. The reaction mixture was cooled to −78° C. and stirred for 1 h. PhMgCl (3.0 eq., 2M solution in THF) was added dropwise to the reaction mixture at −78° C. and mixture was stirred at same temperature for additional 1 h. The reaction mixture was quenched with 2M HCl and warmed to room temperature. The mixture was extracted with ethyl acetate, dried over sodium sulfate and solvent was evaporated under reduced pressure to get crude product which was purified by column chromatography. Yield: 65%
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:10][C@H:9]2[OH:22])=[C:6]([O:23][CH3:24])[CH:5]=[C:4]([O:25][CH3:26])[C:3]=1[C:27](=[O:29])[CH3:28].[Cl:30][C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[C:33](OC)=O.[H-].[Na+]>CN(C=O)C>[Cl:30][C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[C:33]1[O:1][C:2]2[C:3]([C:27](=[O:29])[CH:28]=1)=[C:4]([O:25][CH3:26])[CH:5]=[C:6]([O:23][CH3:24])[C:7]=2[C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:10][C@H:9]1[OH:22]
Reactant: COc1ccc(N2CC[C@@H](c3c(OC)cc(OC)c(C(C)=O)c3O)[C@H](O)C2)cc1
Reactant: COC(=O)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CC[C@@H](c3c(OC)cc(OC)c4c(=O)cc(-c5ccccc5Cl)oc34)[C@H](O)C2)cc1

Procedure:
Compound of example 121 (2.0 g, 5.0 mmol) in dry DMF (25 mL) was reacted with methyl 2-chlorobenzoate (2.55 g, 15 mmol) in the presence of NaH (50%, 1.19 g, 25 mmol) as described in example 16 to obtain the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:16]([C:25]([O:27]C1C=CC=CC=1)=O)[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:16]([C:25]([NH:41][C:38]1[CH:37]=[CH:36][C:35]([F:34])=[CH:40][N:39]=1)=[O:27])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)cn1
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Product: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1ccc(F)cn1

Procedure:
From intermediate 38 and 5-fluoropyridin-2-amine, reacted in an analogous manner to the preparation of intermediate 37. (UPLC-MS 3) tR 1.64 min; ESI-MS 491.3 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:26]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])=[N:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=4)[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:26]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])=[N:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=4)[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c(N3CCC[C@@H]3C)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-[1-[(tert-butoxy)carbonyl]-1H-indazol-5-yl]-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (105 mg, crude) in dichloromethane (20 mL) was added 2,2,2-trifluoroacetic acid (4 mL), The solution was stirred for 3 h at room temperature and concentrated under vacuum. The residue was quenched by the addition of water (50 mL) and adjusted pH to 9 with NaHCO3 (aq.), extracted with dichloromethane (3×30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford methyl 2-(1H-indazol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate as a light yellow solid (69 mg, crude).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34](SC)[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[O:41][S:42]([O-:44])=O.[K+].[CH3:46]O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([S:42]([CH3:46])(=[O:44])=[O:41])[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[N:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSc1nccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2cccc(C(F)(F)F)c2)n1
Agent: [K+]
Product: CS(=O)(=O)c1nccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2cccc(C(F)(F)F)c2)n1
Reaction time: 4 h

Procedure:
To a stirring solution of 4-[5-(2-methylthiopyrimidin-4-yl)-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]piperidine-1-carboxylic acid benzyl ester (2.5 g, 0.0045 mole) in methanol (75 mL) at 20° C. was slowly added an aqueous solution (75 mL) of Oxone® (8.32 g, 0.0135 mole). The reaction was allowed to stir for 4 hours, concentrated in vacuo to remove methanol, diluted with 10% aqueous sodium bicarbonate (100 mL), and extracted with ethyl acetate (2×150 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (2.75 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br.Br[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:20]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: BrCc1cccnc1
Agent: Br
Product: Cc1cc(C#Cc2cn(Cc3cccnc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=288.9 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: [CH:1]1([CH:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][C:8]=2[CH3:18])O)[CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)cc1C(O)C1CCC1
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)cc1C(Cl)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of cyclobutyl(2-methyl-5-phenylfuran-3-yl)methanol (1.3 g) in toluene (10 mL) was added thionyl chloride (1.2 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (1.4 g, 100%) as an oil.