Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC(C2C3C=C(N(C)C)C=CC=3S(=O)(=O)CCC2)=CC=1.C([O-])([O-])=O.[K+].[K+].[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([O:40][CH2:41][CH2:42][CH2:43]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:39])=[O:38])=[CH:33][CH:32]=1>CC(C)=O>[S:37]([C:34]1[CH:33]=[CH:32][C:31]([CH3:30])=[CH:36][CH:35]=1)([O:40][CH2:41][CH2:42][CH3:43])(=[O:38])=[O:39]
Reactant: Cc1ccc(S(=O)(=O)OCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: CN(C)c1ccc2c(c1)C(c1ccc(O)cc1)CCCS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 65 °C
Reaction time: 21 h
Yield: 85.9 %

Procedure:
A solution of 5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone (100 mL) at 25° C. under N2 was treated with powdered K2CO3 (3.8 g, 27.2 mmol, 2.5 eq.) and 1,3-propanediol di-p-tosylate (13.0 g, 32.6 mmol, 3.0 eq.), and the resulting mixture was stirred at 65° C. for 21 hours. The cream-colored slurry was cooled to 25° C. and was filtered through a sintered glass funnel. The filtrate was concentrated and the residue was dissolved in EtOAc (150 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×150 mL) and saturated aqueous NaCl (2×150 mL), and was dried (MgSO4) and concentrated in vacuo to provide a pale orange oil. Purification by flash chromatography (4.4×35 cm silica, 20-30% EtOAc/hexane) afforded the propyl tosylate intermediate (6.0 g, 80%) as a white foam: 1H NMR (CDCl3) δ 0.91 (m, 6H), 1.11-1.47 (br m, 10H), 1.63 (m, 1H), 2.14 (m, 2H), 2.21 (m, 1H), 2.41 (s, 3H), 2.81 (s, 6H), 3.06 (ABq, J=15.1 Hz, J=49.0 Hz, 2H), 4.01 (t, J=5.3 Hz, 2H), 4.10 (m, 1H), 4.26 (t, J=5.9 Hz, 2H), 5.29 (s, 1H), 5.48 (s, 1H), 5.98 (s, 1H), 6.51 (dd, J=8.9, 1.8 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.9 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[O:8]=[C:4]1[CH:3]=[C:2]([O:1][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:7]=[CH:6][NH:5]1
Reactant: O=c1cc(O)cc[nH]1
Reactant: CC(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Temperature: 140 °C
Yield: 44 %

Procedure:
A stirring mixture of 4-hydroxypyridin-2(1H)-one (1.5 g, 13 5 mmol), isopropyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (5.0 g, 18.9 mmol, prepared according to the procedure described in Step C of Example 1) and potassium carbonate (3.7 g, 27 0 mmol, EMD) in DMF (80 mL) was heated at 140° C. for 2 h and then cooled to room temperature. The resulting mixture was diluted with EtOAc and H2O and the aqueous layer was extracted further with EtOAc (7×). The combined extracts were washed with saturated NH4Cl aqueous solution (2×), dried (Na2SO4) and evaporated. The residual was purified by flash chromatography (0 to 100% EtOAc/Hexanes and then 5% MeOH/CH2Cl2) to yield 1.67 g (44%) of the product as an off-white solid. MS (ESI) 281 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:10]=3[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[C:33]([NH:40][CH2:41][C:42](O)=[O:43])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:32][C:30]1[CH:29]=[CH:28][C:10]2[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=[C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:42](=[O:43])[CH2:41][NH:40][C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:7][CH2:6]3)[C:9]=2[CH:31]=1
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(N)CC2)c2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(NC(=O)CNC(=O)OC(C)(C)C)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.6 %

Procedure:
5-(4-Aminopiperidin-1-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (15 mg, 0.034 mmol) was dissolved in anhydrous N,N-dimethylformamide (0.3 mL), and Boc-glycine (7 mg, 0.037 mmol), and then 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (8 mg, 0.04 mmol), 1-hydroxybenztriazole (5 mg, 0.04 mmol), and triethylamine (6 μL, 0.04 mmol) were added. The reaction was stirred at ambient temperature for 24 hours. The solution was diluted with ethyl acetate (5 mL), washed with saturated sodium bicarbonate (3×1 mL), dried with sodium sulfate, decanted and concentrated in vacuo. Column chromatography eluting with a gradient of 70-100% ethyl acetate in hexanes provided tert-butyl 2-(1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-ylamino)-2-oxoethylcarbamate (3 mg, 15%). This material was dissolved in dichloromethane (0.2 mL) and trifluoroacetic acid (0.1 mL) and stirred at ambient temperature for 1 hour then concentrate in vacuo. Azeotroping four times with dichloromethane provided 2-amino-N-(1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-yl)acetamide as the trifluoroacetate salt (3 mg, quant. yield). ESI m/z measured 504.2173 [M+H]+. calculated 504.2166.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26]([OH:28])=O.O[NH:37][C:38]([C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([CH2:49][OH:50])=[CH:43]2)=[NH:39]>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[O:28][N:39]=[C:38]([C:40]3[CH:41]=[C:42]4[C:46](=[CH:47][CH:48]=3)[NH:45][C:44]([CH2:49][OH:50])=[CH:43]4)[N:37]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: N=C(NO)c1ccc2[nH]c(CO)cc2c1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]c(CO)cc4c3)no2)cc1Cl
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
EDCI (144 mg) and HOBT (104 mg) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (150 mg) in DMF (5 mL) at RT. The resulting solution was stirred for 10 min. N-Hydroxy-2-(hydroxymethyl)-1H-indole-5-carboximidamide (D25) (144 mg) was added and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was heated to 80° C. and stirred at that temperature for 7 hours. EtOAc (50 mL) was added and the organic solution was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was recrystallized from EtOAc/ether to afford [5-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]methanol (E11) (95 mg) as a light brown solid. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 4.65 (2H, d), 4.89 (1H, m), 5.36 (1H, t), 6.46 (1H, s), 7.47 (2H, m), 7.78 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d), 8.27 (1H, s), 11.43 (1H, s). MS (ES): C20H18ClN3O3 requires 383; found 384.0 (M+H+).
Reaction SMILES: [CH2:1]([O:4][CH3:5])[CH:2]=[CH2:3].B1C2CCCC1CCC2.Br[C:16]1[CH:17]=[C:18]([CH:22]2[C:31]3[CH:32]=[C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:34]=[CH:35][C:30]=3[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[O:41][CH:42]([F:44])[F:43])[O:23]2)[CH:19]=[CH:20][CH:21]=1.ClCCl.C[O-].[Na+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:44][CH:42]([F:43])[O:41][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][C:31]=1[CH:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:3][CH2:2][CH2:1][O:4][CH3:5])[CH:17]=1)[O:23]2
Reactant: C=CCOC
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(c1cccc(Br)c1)Oc1cccc(OC(F)F)c1-2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COCCCc1cccc(C2Oc3cccc(OC(F)F)c3-c3ccc(NS(C)(=O)=O)cc32)c1
Temperature: 23 °C
Reaction time: 15 h

Procedure:
A solution of allylmethylether (0.015 g, 0.2 mmol) and 9-BBN (0.4 mL of 0.5M solution in THF, 0.2 mmol) was shaken for 3 hours at 65° C, cooled down to 23° C., treated with solution of Example 103 (0.05 g, 0.10 mmol), [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (0.004 g, 0.005 mmol), and sodium methoxide (0.016 g, 0.3 mmol) in THF (1 mL), shaken at 65° C. for 15 hours, cooled down to 23° C., treated with water (50 mL), and extracted with ethyl acetate(3×50 mL). The combined extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The concentrate was purified by HPLC with aqueous 0.1% TFA and CH3CN to provide the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.15 (d, J=9 Hz, 1H), 7.07-7.56 (m, 7H), 6.87-6.92 (m, 3H), 6.25 (s, 1H), 3.24 (t, J=6 Hz, 2H), 3.14 (s, 3H), 3.01 (s, 3H), 2.56 (t, J=7 Hz, 2H), 1.72 (m, J=7 Hz, 2H); MS (ESI(−)Q1MS m/z 488 (M−H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][CH2:20][OH:21].[I-].[K+].[OH-].[Na+].CC(O)(CC)C>>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH2:19][CH2:20][OH:21])=[CH:7][CH:8]=1
Reactant: OCCc1ncc[nH]1
Reactant: COc1ccc(CCCCBr)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: COc1ccc(CCCCn2ccnc2CCO)cc1

Procedure:
A mixture of 3.65 g (15.0 mmol) 1-(4-bromo-butyl)-4-methoxy-benzene, 2.52 g (22.5 mmol) 2-(1H-imidazol-2-yl)-ethanol, 2.74 g (16.5 mmol) potassium iodide, 0.90 g (22.5 mmol) sodium hydroxide and 15 ml 2-methyl-2-butanol was heated to reflux for 12 h. Solvents were distilled off, the residue dissolved in toluene and washed with water. After drying over Na2SO4 and removal of solvents in vacuo the residue was stirred with 7 ml ethyl acetate, isolated by filtration, washed with ethyl acetate and dried. Yield 2.41 g (59%).
Reaction SMILES: C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH:14]([N:17]([CH:26]([CH3:28])[CH3:27])[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)([CH3:16])[CH3:15].[CH3:29][O:30][C:31]1[CH:46]=[CH:45][C:34]([C:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[O:36])=[CH:33][CH:32]=1>O1CCCC1.C(NC(C)C)(C)C.O>[OH:36][C:35]([C:24]1[CH:23]=[N:22][CH:21]=[CH:20][C:19]=1[C:18]([N:17]([CH:14]([CH3:16])[CH3:15])[CH:26]([CH3:28])[CH3:27])=[O:25])([C:34]1[CH:45]=[CH:46][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)[C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: CC(C)N(C(=O)c1ccncc1)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2ccc(OC)cc2)c2cnccc2C(=O)N(C(C)C)C(C)C)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
In 480 ml of dry tetrahydrofuran was dissolved 81.5 ml of diisopropylamine under nitrogen atmosphere, and the solution was cooled to -70° C. Then, 375 ml of 1.6N n-butyllithium was dropwise added to the extent that the temperature of the mixture was not higher than -65° C., to thereby produce lithium diisopropylamide. The reaction mixture was kept at -70° C. for one hour, and to the reaction mixture was added a solution of 43.97 g of N,N-diisopropylisonicotinamide in 150 ml of dry tetrahydrofuran, to the extent that the temperature of the mixture was not higher than -65° C. The mixture was stirred for one hour and 15 minutes, and to the reaction mixture was dropwise added a solution of 46.94 g of 4,4'-dimethoxybenzophenone in 945 ml of dry tetrahydrofuran to the extent that the temperature of the mixture was not higher than -65° C., followed by stirring for 15 minutes. Thereafter, the temperature was allowed to be brought back to room temperature, and water was added thereto. After extraction with ethyl acetate, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 63.69 g of the desired compound as a solid.
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:6]([O:7][CH2:8][C:9]#[N:10])=[CH:5][C:4]=1[CH3:14])=[O:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[CH3:14][C:4]1[CH:5]=[C:6]([O:7][CH2:8][C:9]2[NH:17][N:16]=[N:15][N:10]=2)[CH:11]=[C:12]([CH3:13])[C:3]=1[CH:1]=[O:2]
Reactant: Cc1cc(OCC#N)cc(C)c1C=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2nnn[nH]2)cc(C)c1C=O
Temperature: 100 °C

Procedure:
To a solution of (4-formyl-3,5-dimethyl-phenoxy)-acetonitrile (120 mg) in DMF (3 mL) were added sodium azide (62 mg) and ammonium chloride (51 mg). The reaction mixture was heated at 100° C. for 1 h. The mixture was then diluted by water and the whole was loaded onto a cartridge that contained C18 silica gel (reverse phase). Wash-to-waste (10 mL water) was followed by elute-to-collect (10 mL, acetonitrile) and, after evaporation of volatiles, 2,6-dimethyl-4-(1H-tetrazol-5-yl-methoxy)-benzaldehyde was obtained.
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[C:6]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:5]=1)=[C:2]=[O:3].[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1>C(Cl)Cl>[F:15][C:12]([F:13])([F:14])[CH2:11][O:10][C:8]1[CH:7]=[C:6]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:5]=[C:4]([NH:1][C:2](=[O:3])[N:23]([CH3:22])[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=2)[N:9]=1
Reactant: O=C=Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reactant: CNc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(OC(F)(F)F)cc1
Reaction time: 18 h
Yield: 38.6 %

Procedure:
To a solution of 2-isocyanato-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (400 mg, 1.26 mmol) in CH2Cl2 (1 mL) was added a solution of N-methyl-4-(trifluoromethoxy)aniline (285 mg, 1.50 mmol) in CH2Cl2 (2 mL). The resulting solution was stirred 18 h and then concentrated. The resulting residue was purified by column chromatography (silica, hexanes/EtOAc) to afford 7 as a white solid (247 mg, 38% yield): m.p. 100-102° C.; 1H NMR (CDCl3) δ 7.39 (app s, 4H), 5.96 (s, 1H), 6.82 (bs, 1H), 4.77-4.69 (q, 4H, J=8.5 Hz); ESI/MS 509 (M+H), 507 (M−H).
Reaction SMILES: [C:1]([C:6]1[N:10]([CH3:11])[C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[N:8][C:7]=1[CH3:22])(OCC)=[O:2].[H-].[Al+3].[H-].[H-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>CCOCC.O>[CH3:11][N:10]1[C:6]([CH2:1][OH:2])=[C:7]([CH3:22])[N:8]=[C:9]1[S:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1c(C)nc(SCc2ccc(OC)cc2)n1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(CSc2nc(C)c(CO)n2C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Carbethoxy-1,4-dimethyl-2-(4-methoxybenzylthio)imidazole (31 g, 0.1 mole) dissolved in ether (250 ml) was added dropwise to a solution of aluminum hydride in ether stirred at 0° C. [the aluminum hydride in ether was prepared by adding lithium aluminum hydride (7.4 g, 0.19 mole) in portions to a solution of aluminum chloride (8.6 g, 0.065 mole) stirred in ether (200 ml) at 0° C⟧ The mixture was stirred at 0° C. for 1 hour, treated with water and 10% aqueous sodium hydroxide, filtered and concentrated in vacuo. The resulting oil was dissolved in methylene chloride, dried with magnesium sulfate, filtered and concentrated in vacuo to give 1,4-dimethyl-5-hydroxymethyl-2-(4-methoxybenzylthio)imidazole.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([NH:20][NH2:21])=[O:19])=[N:12][CH:11]=2)=[CH:6][CH:5]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:47][O:48][C:49](=[O:60])[C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57](O)=[O:58])=[CH:52][CH:51]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH3:47][O:48][C:49](=[O:60])[C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([NH:21][NH:20][C:18](=[O:19])[C:17]2[CH:22]=[CH:23][CH:24]=[C:15]([C:13]3[O:14][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=4)=[CH:11][N:12]=3)[CH:16]=2)=[O:58])=[CH:52][CH:51]=1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Reactant: COc1ccc(-c2cnc(-c3cccc(C(=O)NN)c3)o2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC(=O)NNC(=O)c2cccc(-c3ncc(-c4ccc(OC)cc4)o3)c2)cc1
Reaction time: 14 h
Yield: 49.4 %

Procedure:
0.7 g (2.0 mmol) of 3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoic acid hydrazide hydrochloride from Preparation 6, 0.49 g (2.6 mmol) EDAC.HCl, 0.35 g (2.6 mmol) HOBT, and 0.50 g (2.6 mmol) 4-carboxymethyl-benzoic acid methyl ester from Preparation 7 was dissolved in 20 mL of dimethylformamide. 0.33 g (2.6 mmol) Di-isopropylethylamine was then added. Stirring was continued 14 hours at room temperature. Water (60 ml) was added and the product was extracted with 1:1 Et2O/EtOAc (2×). Combined the organic extracts and washed with saturated aqueous NaCl solution (4×), dried (MgSO4). The resulting solid was triturated in EtOAc and filtered. Dried in a vacuum oven overnight at 70° C. to provide 0.48 g (49%) desired product. MS: m/z (APCI, AP+) 486 [M−]+
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][N:53]2[CH:57]=[C:56]([C:58]3[C:66]4[C:61](=[N:62][CH:63]=[C:64]([C:67]5[CH:72]=[CH:71][C:70]([N:73]6[CH2:78][CH2:77][N:76]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:75][CH2:74]6)=[CH:69][CH:68]=5)[CH:65]=4)[N:60](S(C4C=CC(C)=CC=4)(=O)=O)[CH:59]=3)[CH:55]=[N:54]2)[CH:47]=1.[OH-].[Li+]>C1COCC1.CO.O>[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][N:53]2[CH:57]=[C:56]([C:58]3[C:66]4[C:61](=[N:62][CH:63]=[C:64]([C:67]5[CH:68]=[CH:69][C:70]([N:73]6[CH2:74][CH2:75][N:76]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:77][CH2:78]6)=[CH:71][CH:72]=5)[CH:65]=4)[NH:60][CH:59]=3)[CH:55]=[N:54]2)[CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccnc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccnc6)c5)c4c3)cc2)CC1

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (130 mg, 0.188 mmol) was hydrolyzed with lithium hydroxide (24 mg, 0.565 mmol) in THF/methanol/water (2/2/2 mL) to yield 100 mg (crude) of the titled compound. MS: m/z=536.7 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:33]=2)C=CC=CC=1.C(OCC)(=O)C.O>CS(C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:30]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:33]=2)=[O:29])=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(S(C)(=O)=O)c4)cc3)c2cc1OC
Yield: 87.1 %

Procedure:
The 4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine (296 mg, 1.00 mmol) obtained by the method described in WO97/17329 and (3-methanesulfonylphenyl)carbamic acid phenyl ester (291 mg, 1.00 mmol) were heated and stirred in dimethylsulfoxide (3 ml) at 85° C. for 2 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated saline and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:methanol=30:1), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (430 mg, 0.871 mmol, 87%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=3)[CH:11]=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 33.6 %

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added 4-(methanesulfonyl)phenylboronic acid 86 mg, sodium carbonate 69 mg and polymer-carried bis(acetato)triphenylphosphine palladium(II) 31 mg at room temperature, and it was stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. 2.0 mol/L Sodium hydroxide aqueous solution 1.0 mL and ethanol 6.0 mL were added to the obtained residue, and it was stirred at room temperature for 1 hour. 0.5 mol/L Hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated and collected, and the solvent was removed under reduced pressure. The obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 40-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-(4-(methanesulfonyl)phenyl)benzoic acid 28 mg of pale yellow solid.