Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH:3]([C:11]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:22])[NH:16]2)[CH:4]([NH:7][CH:8]([CH3:10])[CH3:9])[CH2:5][CH3:6].[CH3:23][O-:24].[Na+].N1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=CC1=O>CO>[OH:2][CH:3]([C:11]1[CH:20]=[CH:19][C:18]([O:21][C:23](=[O:24])[C:34]2[CH:33]=[CH:32][C:31]([CH3:30])=[CH:36][CH:35]=2)=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:22])[NH:16]2)[CH:4]([NH:7][CH:8]([CH3:10])[CH3:9])[CH2:5][CH3:6]
Reactant: C[O-]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: CCC(NC(C)C)C(O)c1ccc(O)c2c1CCC(=O)N2
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCC(NC(C)C)C(O)c1ccc(OC(=O)c2ccc(C)cc2)c2c1CCC(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.28 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxy-3,4-dihydrocarbostyril hydrochloride was dissolved in 50 ml of methanol, and a 20% methanolic solution of sodium methylate was added to the solution in an amount of 2 moles per mole of the starting carbostyril compound. The mixture was then concentrated to dryness, and the residue was dissolved in dimethylformamide. 1.7 g of p-toluylic acid chloride was added to the solution while cooling with ice-water and the mixture was stirred for 4 hours at room temperature. The reaction mixture was poured into ice-water and extracted with chloroform. A mixture of diethyl ether and petroleum benzene was added to the chloroform extract to obtain 1.94 g of crystalline 5-(1-hydroxy-2-isopropylaminobutyl)-8-p-methylbenzoyloxy-3,4-dihydrocarbostyril having a melting point of 151.5°-152.5° C. (after recrystallization from chloroform-n-hexane).
Reaction SMILES: C(OC([N:8]1[CH:16]=[C:15]2[C:10]([NH:11][C:12]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:13]([C:24]#[N:25])[CH:14]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[ClH:23].[ClH:23].[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:14]1[C:13]([C:24]#[N:25])=[C:12]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[NH:11][C:10]2=[N:9][NH:8][CH:16]=[C:15]12
Reactant: CC(C)(C)OC(=O)n1cc2c(n1)NC(CN1CCOCC1)=C(C#N)C2c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N#CC1=C(CN2CCOCC2)Nc2n[nH]cc2C1c1ccccc1Cl
Yield: 181.3 %

Procedure:
A solution of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (22.9 g), di-t-butyl dicarbonate (19.4 g) and dimethylaminopyridine (0.5 g) in tetrahydrofuran (200 ml) was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled and the precipitated crystals were collected by filtration to give 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (21.8 g) as white crystals. 2-(t-Butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (5.0 g), N-bromosuccinimide (2.5 g) and azobisisobutyronitrile (66 mg) were suspended in benzene (50 ml) and the suspension was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (2:1)) and crystallized from ethyl acetate to give 6-bromomethyl-2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine as white crystals. To a suspension of sodium hydride (32 mg) in DMF (10 ml) was added morpholine (70 μl) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 6-bromomethyl-2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.36 g) and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water, and the precipitated crystals were collected by filtration and washed with hexane to give 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine (450 mg) as white crystals. A solution of 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine (440 mg) in trifluoroacetic acid (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and 4M hydrochloric acid-dioxane solution was added. The precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound (250 mg) as pale-yellow crystals.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:19]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH:29][C:7](=[O:9])[CH:6]([CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)[CH2:5][S:4][C:1](=[O:3])[CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)SCC(C(=O)O)C1CCc2ccccc21
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Product: CC(=O)SCC(C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C1CCc2ccccc21
Yield: 72 %

Procedure:
Using the procedure described in Example 60, but starting with 3-acetylthio-2-(1-indanyl)propanoic acid and alanine benzyl ester, N-[3-acetylthio-2-(1-indanyl)-1-oxopropyl)alanine benzyl ester is obtained in a 72% yield in the form of a white solid, having the following characteristics: m.p.: 95° C.; Rf =0.17 [cyclohexane/ethyl acetate (4:1 by volume)].
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:29]3[CH:30]=[CH:31][C:32]4[C:36]([CH:37]=3)=[N:35][N:34]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]=4)[CH:9]=[C:10]([C:11]3[N:12]=[C:13]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[S:14][CH:15]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[ClH:45]>CO.O1CCOCC1>[ClH:45].[CH2:38]([N:34]1[CH:33]=[C:32]2[C:36]([CH:37]=[C:29]([C:8]3[CH:9]=[C:10]([C:11]4[N:12]=[C:13]([CH:16]5[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[S:14][CH:15]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:30]=[CH:31]2)=[N:35]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cs2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncnn2c(-c3csc(C4CCNCC4)n3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-{4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (586 mg, 0.97 mmol) in MeOH (4 mL) was added 4M HCl in dioxane (2 mL). The mixture was stirred at rt for 16 h. The mixture was concentrated to afford 577 mg (100%) of, the desired product, which was used without further characterization.
Reaction SMILES: C[CH:2]1[C:8]2[CH2:9][CH2:10][C:11]3[CH2:12][CH:13](C(OC(C)(C)C)=O)[NH:14][C:15]=3[C:7]=2[CH:6]=[N:5][C:4]([N:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]=[N:31]C(C(F)(F)F)=[CH:33][CH:34]=3)=[N:25][C:24]2=[O:39])=[CH:3]1.[C:40](O)([C:42]([F:45])([F:44])[F:43])=O.[CH2:47](Cl)[Cl:48]>>[ClH:48].[CH3:47][N:5]1[C:2]2[CH:3]=[C:4]([N:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][C:40]([C:42]([F:45])([F:44])[F:43])=[CH:33][CH:34]=4)=[N:25][C:24]3=[O:39])[CH:10]=[CH:9][C:8]=2[C:7]2[CH2:15][NH:14][CH2:13][CH2:12][CH2:11][C:6]1=2
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Reactant: CC1C=C(n2ccc(-c3ccc(C(F)(F)F)nc3)nc2=O)N=CC2=C1CCC1=C2NC(C(=O)OC(C)(C)C)C1
Product: Cl
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)nc4=O)cc31)CNCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a solution of tert-butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-]indole-2(1H) carboxylate (55 mg, 0.13 mmol) in DCM (10 mL) was added TFA (0.50 mL). The reaction solution was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting residue was purified by semi-preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.20 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA). The resulting free base was converted to the HCl salt using HCl in methanol to afford the title compound (23.0 mg, 37%) as a brown-reddish solid: 1H NMR (500 MHz, CD3OD) δ 9.47 (d, J=1.5 Hz, 1H), 8.80 (dd, J=6.0, 2.0 Hz, 1H), 8.41 (d, J=6.5 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 6.64 (d, J=1.5 Hz, 1H), 7.37 (d, J=7.0 Hz, 1H), 7.23 (dd, J=8.5, 2.0 Hz, 1H), 4.58 (s, 2H), 3.72 (s, 3H), 3.61-3.58 (m, 2H), 3.24-3.21 (m, 2H), 2.27-2.20 (m, 2H); ESI MS m/z 440 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A152) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:43]=[CH:44][CH:45]=1)[O:24][C:25]1[CH:32]=[C:31]([B:33]2[O:37]C(C)(C)[C:35](C)(C)[O:34]2)[C:28](C=O)=[C:27]([CH3:42])[CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:35]1[O:34][B:33]([OH:37])[C:31]2[CH:32]=[C:25]([O:24][C:23]3[CH:43]=[CH:44][CH:45]=[C:21]([O:20][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:22]=3)[CH:26]=[C:27]([CH3:42])[C:28]1=2)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(Oc2cccc(OCc3ccccc3)c2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(OCc4ccccc4)c3)cc(C)c21
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
To a suspension of zinc dust (1.03 g, 15.75 mmol) in THF (15 mL) was added trimethylsilyl chloride (1.2 mL, 9.45 mmol) at 40° C. The mixture was heated to 55° C. and stirred for 15 minutes. After cooling down to 37° C., ethyl bromoacetate (1.74 mL, 15.75 mmol) was slowly added to the reaction mixture at 37-40° C. After addition, the resulting mixture was cooled to room temperature over 30 minutes. This solution was added to a solution of 4-(3-benzyloxy-phenoxy)-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (1.4 g, 3.75 mmol) in THF (50 mL) at −78° C. The mixture was allowed to warm to room temperature over 3 hours, quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2×25 mL). The organic extracts were washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (hexane:EtOAc 50:50) to give [6-(3-benzyloxy-phenoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.93 g, 68%). 1H NMR (400 MHz, DMSO): δ 9.22 (s, 1H), 7.41-7.24 (m, 6H), 7.07 (s, 1H), 6.95 (s, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.61 (s, 1H), 6.51 (d, J=6.8 Hz, 1H), 5.48 (d, J=7.2 Hz, 1H), 5.05 (s, 2H), 4.02 (q, J=7.2 Hz, 2H), 3.10 (dd, J=2.4, 15.6 Hz, 1H), 2.30-2.27 (m, 1H), 2.26 (s, 3H), 1.11 (t, J=6.8 Hz, 3H). MS (ESI) m/z=433 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:27])=[O:26])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)=[C:11]([O:40][CH3:41])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:42][C:43]1[N:48]=[C:47]([NH2:49])[CH:46]=[CH:45][N:44]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25]([NH:49][C:47]5[CH:46]=[CH:45][N:44]=[C:43]([CH3:42])[N:48]=5)(=[O:27])=[O:26])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)=[C:11]([O:40][CH3:41])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1nccc(N)n1
Reactant: COc1cc(-c2cc(F)cc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cc(F)cc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccnc(C)n3)ccc12
Reaction time: 0.67 h
Yield: 50.5 %

Procedure:
A vial was charged with perfluorophenyl 1-(3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE KKKKK; 64.75 mg, 0.109 mmol), 2-methylpyrimidin-4-amine (12.50 mg, 0.115 mmol), and THF (546 μl) (not all the amine dissolved). The vial was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (229 μl, 0.229 mmol) was added. After 40 min, the mixture was loaded directly onto a silica gel loading column. The column was eluted onto a pre-equilibrated 12-g Redi-Sep Gold column with 0-5% MeOH/DCM to give 1-(3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(2-methylpyrimidin-4-yl)isoquinoline-6-sulfonamide (28.4 mg, 0.055 mmol, 50.2% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=13.32 (br. s., 1H), 8.68 (d, J=5.7 Hz, 1H), 8.62 (s, 1H), 8.17-8.03 (m, 2H), 7.95 (dd, J=1.7, 8.9 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.68-7.59 (m, 2H), 7.56-7.48 (m, 2H), 7.46-7.39 (m, 1H), 7.29 (tt, J=2.2, 9.3 Hz, 1H), 6.90 (br. s., 1H), 3.77 (s, 3H), 2.35 (s, 3H). m/z (ESI) 519.0 (M+H)+.
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1)=O)(C)(C)C>O1CCOCC1.CCOC(C)=O>[CH3:23][CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH2:9])=[CH:16][CH:15]=1)[CH2:18][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(CC(C)(C)C)c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(CC(C)(C)C)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Add 4N hydrogen chloride in dioxane (10 mL) to a stirred solution of N-(tert-butoxycarbonyl)-4-(1,3,3-trimethyl-butyl)-benzylamine (225 mg, 0.74 mmol) in EtOAc (15 mL) and stir the mixture at ambient temperature overnight. Concentrate in vacuo and wash the solid with diethyl ether. Suspend the solid in dichloromethane and saturated aqueous NaHCO3 and stir until both phases are clear (15 min). Extract the aqueous phase twice with dichloromethane. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to give the title compound as an oil (0.136 g, 90%) that was used without any further purification. MS (ES+) m/z: 206 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([CH:12]([F:14])[F:13])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)=[O:4].[BH4-].[Na+]>CO.O>[F:1][C:2]([F:15])([CH:12]([F:13])[F:14])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)[OH:4]
Reactant: Cc1cccc(C(=O)C(F)(F)C(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc(C(O)C(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2,3,3-tetrafluoro-1-(3-methylphenyl)propane-1-one (9.11 g, 41.4 mmol) in methanol (50 ml) was added sodium borohydride (0.76 g, 20 mmol) by small portions under ice-cooling and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-3/1) to give the objective substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[O:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16].CCOCC>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]([OH:14])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1
Reactant: CC1(C)COc2c(C=O)cc(Br)cc21
Reactant: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(C)COc2c(C(O)C(C)(C)C)cc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A stirred, cooled (ice-bath) solution of 5-bromo-3,3-dimethyl-2,3-dihydrobenzofuran-7-carbaldehyde (Intermediate 30, 1.72 g, 6.74 mmol) in 15 mL of anhydrous tetrahydrofuran was treated with a 1M solution of tert-butyl magnesium chloride solution in ether (6.74 mL, 6.74 mmol). The reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to an oil that on flash column chromatography using 5% ethyl acetate in hexane as the eluent afforded the title compound (0.95 g, 45%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].C(O)(=O)C.[Br:16][C:17]1[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][N:18]=1.C([BH3-])#N.[Na+]>CO.O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH2:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([Br:16])[CH:22]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=Cc1ccnc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
6.04 g (40 mmol) of anthranilic acid methyl ester in 600 ml of methanol is mixed with 3.2 ml of acetic acid and 7.4 g (40 mmol) of 2-bromopyridine-4-carbaldehyde and stirred overnight at 40° C. 3.8 g (60 mmol) of sodium cyanoborohydride is added thereto and stirred overnight at 40° C. 3.8 g (60 mmol) of sodium cyanoborohydride is added again and stirred over the weekend at 40° C. It is mixed with water and largely concentrated by evaporation. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are dried, filtered and concentrated by evaporation. The crude product is chromatographed on silica gel with a gradient that consists of hexane and hexane/ethyl acetate 1:3 and hexane/ethyl acetate 1:1 as an eluant. 10.0 g (78% of theory) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester is obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:42])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([OH:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH3:22])=[C:17]([CH2:34][O:35]CC[Si](C)(C)C)[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:42])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([OH:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH3:22])=[C:17]([CH2:34][OH:35])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2COCC[Si](C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2CO)c1
Yield: 105.2 %

Procedure:
A solution of 157 mg of N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(3-methoxyphenyl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 3 mL of 75% TFA in CH2Cl2 is stirred at room temperature for 4 h, then diluted with CHCl3 and added to stirred aq. NaHCO3. The aqueous phase is extracted with 4 portions of CH2Cl2, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 3-6% MeOH in CH2Cl2 provides 140 mg of the title compound as a white solid. Recrystallization from acetonitrile affords white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][OH:28]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:25][CH2:26][CH2:27][OH:28])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCCCOc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.4 %

Procedure:
1.45 g (corresponding to 5.0 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 50 mL of N,N-dimethylformamide, and 2.07 g (corresponding to 15.0 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 680 μL (corresponding to 7.5 mmol) of 3-bromo-1-propanol, and then the solution was stirred at room temperature for 17 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was recrystallized from methanol to obtain 1.28 g (corresponding to 3.67 mmol) of 6-bromo-2-[4′-(3″-hydroxypropoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 2-11, Step 3).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:13])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>C(OCC)(=O)C>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:13])[N:9]2[CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=c1cnc2ccc(F)c(F)c2[nH]1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)c(F)c32)CC1
Yield: 14.2 %

Procedure:
7,8-Difluoroquinoxalin-2(1H)-one (Intermediate 155—a mixture of regioisomers containing 30% 5,6-difluoroquinoxalin-2(1H)-one, 1.0 g, 5.50 mmol) was deprotonated with sodium hydride (60% in oil, 0.26 g, 6.60 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (6.6 mmol) as described for Intermediate 2. Chromatography on silica gel with 70-100% ethyl acetate in hexanes gave 320 mg of the product as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]([S:14](N2C=CC=C2)(=[O:16])=[O:15])=[CH:11][CH:10]=1.[Na].S(Cl)([Cl:26])(=O)=O>>[Cl:26][S:14]([C:12]1[S:13][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: COc1ccccc1-c1ccc(S(=O)(=O)n2cccc2)s1
Reactant: O=S(=O)(Cl)Cl
Agent: [Na]
Product: COc1ccccc1-c1ccc(S(=O)(=O)Cl)s1
Yield: 24 %

Procedure:
5-chlorosulfonyl-2-(2-methoxyphenyl)thiophene was prepared in the same manner as described in Example 65E from N-[5-(2-methoxyphenyl)thiophene-2-sulfonyl]pyrrole by hydrolysis of the sulfonamide to the sodium salt of sulfonic acid (83%) followed by conversion of the salt to the corresponding sulfonyl chloride, resulting in a 24% yield.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:2]([CH3:5])([CH3:4])[CH3:3])[CH:8]=1
Reactant: Brc1cccc(I)c1
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)c1cccc(Br)c1

Procedure:
1-Bromo-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1-bromo-3-iodobenzene as the dihalo compound of formula (II).