Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)=[O:12])=[C:6]([O:24][CH3:25])[CH:5]=1.CO.O.[OH-].[Li+]>O>[CH3:25][O:24][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][N:15]=1)=[O:12])[C:3]([OH:26])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)Nc2cnc(C(F)(F)F)cn2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1NC(=O)Nc1cnc(C(F)(F)F)cn1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-methoxy-4-[3-(5-trifluoromethyl-pyrazin-2-yl)-ureido]-benzoic acid methyl ester (213 mg, 0.575 mmol) in 5.75 mL 3:1 MeOH:H2O at room temperature under nitrogen was added lithium hydroxide monohydrate (240 mg, 5.8 mmol) and the reaction warmed to 65° C. After reaching temperature, the suspension gradually became a bright yellow solution. After about 4 hours a precipitate formed but the reaction was continued overnight. After cooling to RT, MeOH was removed by rotovap and the aqueous suspension neutralized to pH=5 with concentrated HCl; As pH=5 was approached, the suspension turned from yellow to white. The suspension was then filtered through paper on a ceramic funnel. When most of the H2O was removed the residue was dryed under high vacuum in a dessicator overnight (133 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C@@H:25](Cl)[CH3:26]>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C@@H:25]([C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])[CH3:26])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: C[C@H](Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(Br)cc21
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of 6-bromoindazole (3.4 g, 17.0 mmol) and Cs2CO3 (15.8 g, 48.5 mmol) in 1-methyl-2-pyrrolidinone (NMP, 11 mL) at 85° C. was added crude (S)-2,4-dichloro-1-(1-chloroethyl)benzene (3.2 g, 15.4 mmol) dropwise. The reaction mixture was heated for 10 min, and cooled to room temperature. The mixture was diluted with ethyl acetate (20 mL), washed with deionized water and brine, dried (Na2SO4), and concentrated in vacuo. The resulting crude material was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to afford (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-indazole (2.2 g, 6.0 mmol, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.O=S(Cl)Cl.N1C=CC=CC=1.Cl>C1COCC1>[C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: COc1cccc(C2(O)CCCCC2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1cccc(C2=CCCCC2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 1L 3-neck RBF under argon was charged with crude 1-(m-methoxyphenyl)cyclohexanol (59.2 g, 287 mmol). To the flask was added 592 mL of dry THF. The reaction was cooled to 0° C., and to it was slowly added SOCl2 (58.6 mL, 803.6 mmol). After stirring for 10 minutes, pyridine (104 mL, 1.29 mol) was added slowly. The reaction mixture stirred slowly at 22° C. for 2 hours, and then it was cooled back to 0° C. 1N HCl (500 mL) was slowly added to the reaction. The layers were separated. The THF layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude product was chromatographed using 100% hexane as eluent to provide 39.5 g (82%, 2 steps) of product. 1H NMR (CDCl3) δ1.72 (m, 2H), 1.83 (m, 2H), 2.24 (m, 2H), 2.45 (m, 2H), 3.86 (s, 3H), 6.18 (m, 1H), 6.83 (dd, J=8.1, 1.7 Hz, 1H), 6.98 (m, 1H), 7.03 (d, J=6.1 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([C:23]([O:25]CC)=[O:24])=[C:21]([C:28]([OH:31])([CH3:30])[CH3:29])[N:20]=[C:19]2[CH2:32][CH2:33][CH3:34])=[CH:13][CH:12]=1)([OH:4])=[O:3].O.[OH-].[Li+].Cl>O>[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[C:22]([C:23]([OH:25])=[O:24])=[C:21]([C:28]([OH:31])([CH3:29])[CH3:30])[N:20]=[C:19]2[CH2:32][CH2:33][CH3:34])=[CH:15][CH:16]=1)([OH:4])=[O:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 98 %

Procedure:
A solution of 0.20 g of ethyl 1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate hydrochloride (prepared as described in Example 16) in an aqueous solution of 84 mg of lithium hydroxide monohydrate in 5 ml of water was stirred at room temperature for 6 hours. At the end of this time, 2 ml of 1N aqueous hydrochloric acid were added dropwise to the reaction mixture, and the resulting precipitate was collected by filtration, to give 0.17 g of the title compound, melting at 176°-179° C. (with decomposition).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:39])/[CH:15]=[CH:16]/[C@@H:17]([O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[C@@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1>[C:1]([O:5][C:6](=[O:40])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]([OH:39])/[CH:15]=[CH:16]/[C@@H:17]([O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[C@@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCC[C@H](OC(C)=O)[C@@H](/C=C/C(=O)CCCCCCCC(=O)OC(C)(C)C)O[Si](C(C)C)(C(C)C)C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC[C@H](OC(C)=O)[C@@H](/C=C/[C@H](O)CCCCCCCC(=O)OC(C)(C)C)O[Si](C(C)C)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
(R)-binal-H (0.5 M tetrahydrofuran solution, 232 μL, 0.116 mmol) was added dropwise to a tetrahydrofuran solution (0.35 mL) of (12R,13S)-(E)-13-acetoxy-9-oxo-12-triisopropylsiloxy-10-octadecaenoic acid t-butyl ester (18) (20.5 mg, 0.0352 mmol) synthesized in Example 4-4) at −78° C. over 5 minutes under the argon atmosphere, and the mixture was stirred at −78° C. for 1 hour. Hydrochloric acid (1.0 N, 1 mL) was added to the reaction solution, and the mixture was extracted with chloroform (5 mL) three times. The organic layers were combined, washed successively with 1.0 N sodium hydroxide (5 mL×3) and saturated brine (5 mL), dried over sodium sulfate, and concentrated. The resulting colorless oily crude product (21 mg) was separated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain (9R,12R,13S)-(E)-13-acetoxy-9-hydroxy-12-triisopropylsiloxy-10-octadecaenoic acid t-butyl ester (21) (20.3 mg, 99%)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[N:7]([N:11]2C(=O)C3=CC=CC=C3C2=O)[CH:8]=[CH:9][CH:10]=1)=[O:5].CN>C(O)C.O>[NH2:11][N:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4](=[O:5])[C:3]1[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=1[Cl:1]
Reactant: O=C(c1ccccc1Cl)c1cccn1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CCO
Solvent: O
Product: Nn1cccc1C(=O)c1ccccc1Cl
Reaction time: 2.5 h
Yield: 93.8 %

Procedure:
2-(2-chlorobenzoyl)-1-phthalimidopyrrole (40 g, 0.114 mol) was suspended in 350 ml of 95% ethanol. To this rapidly stirred slurry was added 50 ml of a 40% aqueous solution of methylamine over 10 minutes. After 2.5 hours of rapid stirring the mixture was diluted with 400 ml of water and extracted with four 200 ml portions of ether. The combined extracts were washed with water, dried over anhydrous MgSO4, filtered and evaporated to an oil which solidified upon standing. Trituration of this solid with hexane and collection upon a filter yielded 23.6 g (94%) of solid, m.p. 76°-78°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.C1(C)C=CC(S(O[CH:21]2[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22]2)(=O)=O)=CC=1.[I-].[K+].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[F:10][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([O:8][CH:21]2[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22]2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(C)C2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCC(Oc2cc(N)c(F)cc2Cl)C1
Temperature: 100 °C
Yield: 42.8 %

Procedure:
A round-bottomed flask (200 cc) equipped with a mechanical stirrer was charged with 5-amino-2-chloro-4-fluorophenol (3.00 g, 18.6 mmol), 3-methylcyclopentyl p-toluenesulfonate (4.60 g, 18.6 mmol), tetrabutylammonium bromide (300 mg, 0.93 mmol) and potassium iodide (300 mg, 1.81 mmol) to prepare a solution in toluene (30 mL). Subsequently, 48% sodium hydroxide in aqueous solution (30 mL) was added slowly and the mixture was stirred under heating at 100° C. for 48 h. After completion of the reaction, the reaction mixture was cooled to room temperature and water (50 mL) was added, followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with water (10 mL) and saturated brine (10 mL) and dried with anhydrous magnesium sulfate. After the desiccant was removed, the solvent was distilled off under vacuum to give 2-fluoro-4-chloro-5-(3-methylcyclopentyloxy)aniline (1.94 g, 7.96 mmol; yield=42.9%) as a brown oil. 1H-NMR(CDCl3,TMS,ppm): δ1.02 and 1.10(total 3H, each d,J=6.0Hz), 1.22-2.58(7H,m), 3.75(2H,brs), 4.65(1H,m), 6.33(1H,d,JHF =8.0Hz), 6.98(1H,d,JHF =10.0Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1.[CH3:43][O:44][CH2:45][CH2:46][CH2:47][C:48](Cl)=[O:49]>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:7][CH:6]2[O:5][CH2:4][C:3]2[CH:39]=[CH:40][CH:41]=[CH:42][C:2]=2[NH:1][C:48](=[O:49])[CH2:47][CH2:46][CH2:45][O:44][CH3:43])=[CH:17][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccccc2N)cc1
Reactant: COCCCC(=O)Cl
Product: COCCCC(=O)Nc1ccccc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Example 116b, 0.135 g of tert-butyl 3-(2-aminobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0034 g of 4-methoxybutyryl chloride are reacted. The title compound is obtained as a beige oil. Rf=0.10 (1:1 EtOAc-heptane); Rt=5.86.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH2:16][OH:17])[C:12]1[N:8]([CH:9]=[C:10]([C:18]3[N:22]([CH:23]([CH3:25])[CH3:24])[N:21]=[CH:20][N:19]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.IC1C=CC=CC=1C(O)=O>CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH:16]=[O:17])[C:12]1[N:8]([CH:9]=[C:10]([C:18]3[N:22]([CH:23]([CH3:25])[CH3:24])[N:21]=[CH:20][N:19]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: Cc1cc2c(cc1CO)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Agent: O=C(O)c1ccccc1I
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C=O)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 80 °C
Yield: 71.1 %

Procedure:
To a solution of {12-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-13-yl}methanol (92 mg, 0.271 mmol) in EtOAc (10 mL) was added 2-iodobenzoic acid (304 mg, 1.086 mmol). The mixture was heated at 80° C. overnight. The solid was filtered, the filtrate was concentrated and purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:1) to give 12-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-13-carbaldehyde (65 mg, 71% yield) as a yellow solid. LCMS (ESI) m/z: 338.1 [M+H+].
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18](Br)[CH:19]=3)[CH:12]=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[C:23]([O:26][CH2:27][C:28]1[C:29]([N:37]2[C:49](=[O:50])[C:48]3[S:47][C:46]4[CH2:45][CH2:44][CH2:43][CH2:42][C:41]=4[C:40]=3[CH:39]=[N:38]2)=[N:30][CH:31]=[CH:32][C:33]=1B(O)O)(=[O:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].C(#N)C.O>[C:23]([O:26][CH2:27][C:28]1[C:29]([N:37]2[C:49](=[O:50])[C:48]3[S:47][C:46]4[CH2:45][CH2:44][CH2:43][CH2:42][C:41]=4[C:40]=3[CH:39]=[N:38]2)=[N:30][CH:31]=[CH:32][C:33]=1[C:18]1[CH:19]=[C:14]([NH:13][C:11]2[CH:12]=[C:6]3[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8][N:7]3[N:10]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C(C)=O)C4)c(=O)n(C)c2)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Temperature: 90 °C
Yield: 31.2 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 3-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 209c (183 mg, 0.50 mmol), {3-[(acetoxy)methyl]-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridin-4-yl}boronic acid 230i (200 mg, 0.50 mmol), Pd(dppf)Cl2 (37 mg, 0.05 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), water (0.5 mL), and acetonitrile (5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 20:1) to afford 247a as yellow solid (100 mg, 31%). MS-ESI: [M+H]+ 641.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C@@H:9]1[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.[I:32][Si](C)(C)C.II.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][CH:12]([I:32])[C:11](=[O:14])[NH:10][C@@H:9]1[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(=O)N[C@@H]1c1cc(F)ccc1F
Reactant: C[Si](C)(C)I
Agent: CN(C)CCN(C)C
Agent: II
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC(I)C(=O)N[C@@H]1c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Step B (2 g, 6.13 mmol) in dichloromethane (50 mL) at 0° C. was added N,N,N′,N′-tetramethylethylenediamine (4.62 mL, 30.6 mmol) followed by slow addition of iodotrimethylsilane (2.59 mL, 19.0 mmol). The yellow mixture was stirred for 2 h at 0° C. and iodine (3.11 g, 12.26 mmol) was added in one portion. The mixture was stirred for 3 h at ° C. and saturated aqueous sodium thiosulfate (50 mL) added. The mixture was stirred for 10 min, the layers were separated and the aqueous phase extracted with dichloromethane (3×25 mL) and the combined organic phases dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The crude yellow solid was purified by column chromatography (silica gel Biotage 40S) eluting with ethyl acetate/hexane (gradient from 0% to 100%) to give the title compound as a colorless solid. LC/MS 453.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C@H](NC(=O)OC(C)(C)C)C)=[CH:15][CH:14]=2)[N:3]=1.NC1C=CC([CH2:34][OH:35])=CC=1>>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:34][OH:35])=[CH:15][CH:14]=2)[N:3]=1
Reactant: Nc1ccc(CO)cc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Product: OCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1

Procedure:
C7 was prepared in a manner similar to that described in for making C3 in Step 3 of Example 1 except that 4-aminobenzyl alcohol (2.4 g, 19 mmol) was used instead of C2. When the reaction was complete the reaction mixture was concentrated and dissolved in EtOA. The resultant solution was washed with water, brine, dried over MgSO4, and concentrated. The resultant tan solid was triterated with ether and a small amount of EtOAc, filtered and concentrated to provide C7 as a tan solid. Yield: 2.98 g, 50%. MS+ 304.1. 1H NMR (500 MHz, d6-DMSO) δ: 10.61 (s, 1H), 8.76 (s, 1H), 7.59 (d, 2H), 7.26 (d, 2H), 5.10 (bs, 1H), 4.43 (s, 2H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:14]2=[N:15][CH:16]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:1]1([C:11]2[CH:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:21])=[O:22])[C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)cnc32)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(-c4ccccc4)cnc32)cc1

Procedure:
A mixture of phenyl boronic acid (1.74 g), 5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [5 g, Reference Example 9(d)], (tetrakis)triphenylphosphine palladium[0] (0.49 g) and saturated aqueous sodium bicarbonate solution (133 mL) and dimethylformamide (266 mL), under nitrogen, was heated at reflux temperature overnight. The reaction mixture was filtered through Hyflo and then evaporated. The residue was partitioned between ethyl acetate (50 mL) and water (25 mL) and the aqueous layer was extracted with ethyl acetate (25 mL). The combined organic phases were washed with water (25 mL), then with brine (20 mL), then dried over magnesium sulfate and then evaporated. The residue subjected to chromatography on silica eluting with a mixture of pentane and ether (1:1, v/v) to give the title compound as a white solid, mp. 151-152° C. MS: 335 (MH+).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.O[CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1>[NH:17]1[CH:18]=[C:14]([CH2:13][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[N:15]=[CH:16]1
Reactant: OCc1c[nH]cn1
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCCN2Cc1c[nH]cn1
Temperature: 25 °C

Procedure:
A mixture of 1,2,3,4-tetrahydro-quinoline (Intermediate F1) (Commercially available from Aldrich) (1.62 mL, 12.6 mmol) and 4-hydroxymethyl-imidazole hydrochloride salt (commercially available from Aldrich) (Intermediate F2) (0.70 g, 5.1 mmol) and sodium carbonate (1.6 g, 15.1 mmol) in water (20 mL) and dioxane (10 mL) were heated at reflux for 24 h. The mixture was cooled to rt and extracted with ethyl acetate. The organic solution was dried over MgSO4, filtered and freed of solvent. The resultant oil was purified by chromatography on silica gel with 5% NH3-MeOH: dichloromethane to give 1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline (Intermediate F3) as a solid, 0.54 g (50%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([O:24][CH2:25][CH3:26])=[CH:14][CH:13]=2)(C)(C)C.[ClH:34]>C(OCC)(=O)C>[ClH:34].[NH2:7][CH2:8][C:9]1[N:10]([CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([O:24][CH2:25][CH3:26])=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(OCC)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)(C)C)c(=O)c2ccc(OCC)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of tert-butyl(4-butoxy-6-ethoxy-2neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.28 g, 0.6 mmol) in ethyl acetate (5 ml) was added a solution of 4N hydrogen chloride in ethyl acetate (5 ml), and the obtained solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diisopropyl ether to give 3-(aminomethyl)-4-butoxy-6-ethoxy-2-neopentyl-1(2H)-isoquinolinone hydrochloride (0.23 g, 95.8%) as crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[N:11]=[CH:12][N:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[OH:21])[CH:14]=1)([O-:9])=[O:8].C(N(CC)CC)C.C(=O)=O.CO.C(=O)([O-])O.[Na+]>ClCCl.CS(C)=O>[N+:7]([C:10]1[N:11]=[CH:12][N:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=[O:21])[CH:14]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cn(C2CCCCC2O)cn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: O=C=O
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCCC1n1cnc([N+](=O)[O-])c1
Reaction time: 0.07 h
Yield: 84 %

Procedure:
A solution of 19.0 ml (218 mmol) of oxalyl chloride in 250 ml of dichloromethane was cooled in a dry ice-methanol bath. A solution of 27.0 ml (380 mmol) of dimethyl sulfoxide in 90 ml of dichloromethane was dropped into the above solution in 10 minutes at such a rate that the bulk temperature was kept within the range of -60° to -50° C. The obtained mixture was further stirred for 4 minutes to give a colorless solution. A solution of 31.92 g (151 mmol) of the 2-(4-nitroimidazol-1-yl)cyclohexanol prepared in the Preparative Example 11 in a mixture comprising 240 ml of dichloromethane and 30 ml of dimethyl sulfoxide was dropped into the colorless solution in 7 minutes at such a rate that the bulk temperature did not exceed -50° C. The obtained mixture was further stirred for 15 minutes. 80.0 ml (570 mmol) of triethylamine was dropped into the resulting mixture in 7 minutes at such a rate that the bulk temperature did not exceed -50° C. The obtained mixture was further stirred for 7 minutes and thereafter the dry ice-methanol bath was taken off. After 30 minutes, the bulk temperature reached +10° C. A saturated aqueous solution of sodium hydrogencarbonate was added to the resulting mixture and the obtained mixture was left standing to cause liquid-liquid separation. The organic phase was concentrated in a vacuum and the obtained residue was dissolved in ethyl acetate. Further, the aqueous phase was extracted with ethyl acetate and the ethyl acetate phase was combined with the ethyl acetate solution prepared above. The obtained mixture was washed with a saturated aqueous solution of common salt. The organic phase was dried over anhydrous magnesium sulfate and concentrated in a vacuum to give 33.9 g of a crude crystal. This crude crystal was recrystallized from dichloromethane/ethyl acetate to give 26.53 g of the title compound as a colorless crystal. Further, the mother liquor was recrystallized from dichloromethane/diisopropyl ether to give 2.52 g of the title compound as a lightly yellowish-brown crystal. Thus, 29.05 g of the title compound was obtained in total (yield: 92%).