Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:31])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([C:19](=[O:29])[C:20]2[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=2[Cl:28])[C:9]=1[CH3:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-].Cl>C1COCC1>[Cl:28][C:21]1[CH:22]=[C:23]([Cl:27])[CH:24]=[C:25]([Cl:26])[C:20]=1[C:19]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([CH2:7][C:6]([OH:31])=[O:5])=[C:9]1[CH3:30])=[O:29]
Reactant: COc1ccc2c(c1)c(CC(=O)OCC[Si](C)(C)C)c(C)n2C(=O)c1c(Cl)cc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1c(Cl)cc(Cl)cc1Cl
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To 1-(2,4,6-trichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid 2-(trimethylsilyl)ethyl ester (2.80 g) in THF (25.0 mL) at 0° C. was added TBAF (14.7 mL). After a period of 5 h at room temperature, the reaction mixture was acidified by the addition of NH4Cl and HCl, extracted with EtOAc, dried over Na2SO4 and evaporated. The resulting solid was washed with 10% EtOAc in hexane and recrystallized (EtOAc-hexane) to afford 1.73 g of the title compound, m.p. 193°-196° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH2:14]Br.C[N+]([O-:20])(C)C>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH:14]=[O:20]
Reactant: BrCc1cc(-c2ncccn2)ccc1Br
Reactant: C[N+](C)(C)[O-]
Solvent: CS(C)=O
Product: O=Cc1cc(-c2ncccn2)ccc1Br
Temperature: 55 °C
Reaction time: 12 h

Procedure:
To a solution of 1.75 g of the crude title compound of Step D in 6 mL of anhydrous dimethylsulfoxide ("DMSO") under argon, 3.0 g of anhydrous trimethylamine N-oxide (prepared as described in Soderquist et al., Tet. Letters., 27, 3961 (1986); this compound is also commercially available) were added and the mixture stirred at 55° C. for 12 hrs. The mixture was then cooled and added to 100 mL of ice/water and extracted with 3×50 mL of EtOAc. The combined organic extracts were washed once with 100 mL of brine and dried and evaporated. The residue was chromatographed on 100 mL of silica gel using Hexanes/EtOAc 6:1 to afford 0.86 g (81.5% for two steps) of the title compound of this step as a white solid.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6](N)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:18]>>[F:18][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: Nc1cccc2ncccc12
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: Fc1cccc2ncccc12
Reaction time: 1 h

Procedure:
To a solution of quinolin-5-amine (2 g, 13.9 mmol) in 10 mL of 48% HBF4 at 0° C. was added sodium nitrite (933 mg, 13.5 mmol) portionwise. This was stirred for 1 hour and then poured into 1:1 ethyl acetate diethyl ether mixture (50 mL). The resulting suspension was filtered and the solid was dried. This solid was added portionwise to refluxing xylene (30 mL) and stirred for 3 hours, then allowed to cool. The xylene was decanted off and the residue was dissolved in 1N HCl (50 mL). After neutralization with NaHCO3, the mixture was extracted with ethyl acetate (3×50 mL). The extracts were dried over sodium sulfate, filtered and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (3% EtOAc/PE) to afford 800 mg of title compound as colorless oil. LC-MS: m/z 148.2 (M+H)+
Reaction SMILES: ClCCl.[NH:4]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5]1.C(N(CC)CC)C.[C:17]([N:21]=[C:22]=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(OCC)C>[C:17]([NH:21][C:22]([N:4]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: O[C@H]1CCNC1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CC[C@H](O)C1
Reaction time: 0.5 h

Procedure:
To a dichloromethane (100 mL)/diethyl ether (200 mL) solution of (S)-pyrrolidin-3-ol (9.80 mL, 121 mmol) and triethylamine (21.9 mL, 157 mmol) at 0° C. was added tert-butyl isocyanate (13.8 mL, 121 mmol). The reaction mixture was stirred for 30 minutes and concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 4.54-4.38 (m, 1H), 4.10 (br s, 1H), 3.48-3.32 (m, 5H), 2.06-1.95 (m, 2H), 1.35 (s, 9H); LC-MS: m/z 187.3 (M+H).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([NH:8][C@@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][O:11][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](CO)NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To methyl N-benzyl-D-serinate (1 eq.) in CH2Cl2 (0.3 M) at rt were added triethylamine (1 eq) and DMAP (0.05 eq). The reaction mixture was cooled to 0° C. and TBS-Cl (1.1 eq) was added. The reaction mixture was stirred at rt for 16 hrs, water was added and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered and concentrated. The crude product was used as such for the next step.
Reaction SMILES: [CH2:1]([C:4]1[O:5][CH2:6][C:7]([CH3:11])([CH2:9][OH:10])[N:8]=1)[CH2:2][CH3:3].[C:12](O)(=[O:15])[CH2:13][CH3:14]>>[CH2:1]([C:4]1[O:5][CH2:6][C:7]([CH3:11])([CH2:9][O:10][C:12](=[O:15])[CH2:13][CH3:14])[N:8]=1)[CH2:2][CH3:3]
Reactant: CCC(=O)O
Reactant: CCCC1=NC(C)(CO)CO1
Product: CCCC1=NC(C)(COC(=O)CC)CO1

Procedure:
The 2-propyl-4-methyl-4-hydroxymethyl-2-oxazoline is reacted with propionic acid in a 1:1 molar ratio following the method of Purcell to form 2-propyl-4-methyl-4-propionyloxymethyl-2-oxazoline.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[NH:10][C:9]=2[C:21]=1[C:22](O)=[O:23])(O)=[O:2].[NH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.CCN(CC)CC>C(O)CO.CCOC(C)=O.C(Cl)Cl>[CH3:48][O:47][C:41]1[CH:40]=[C:39]([CH2:38][CH2:37][N:29]([CH2:28][CH2:27][CH2:26][N:25]2[C:1](=[O:2])[CH2:4][C:5]3[CH:6]=[CH:7][C:8]4[N:12]=[C:11]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[O:19][CH3:20])[NH:10][C:9]=4[C:21]=3[C:22]2=[O:23])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH:44]=[CH:43][C:42]=1[O:45][CH3:46]
Reactant: COc1ccc(CCN(CCCN)C(=O)OC(C)(C)C)cc1OC
Reactant: COc1ccccc1-c1nc2ccc(CC(=O)O)c(C(=O)O)c2[nH]1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCN(CCCN2C(=O)Cc3ccc4nc(-c5ccccc5OC)[nH]c4c3C2=O)C(=O)OC(C)(C)C)cc1OC
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 54.5 %

Procedure:
A solution of 6-(carboxymethyl)-2-(2-methoxyphenyl)-1H-benzimidazole-7-carboxylic acid (800 mg, 2.45 mmol) and tert-butyl (3-aminopropyl)[2-(3,4-dimethoxyphenyl)ethyl]carbamate (1.00 g, 2.94 mmol) in ethyleneglycol (6.1 mL) was heated at 180° C. for 1 h. The cooled mixture was dissolved in EtOAc (500 mL) and the resulting solution was washed with water (2×100 mL) and brine (200 mL), dried (MgSO4) and concentrated under reduced pressure. A solution of the resulting yellow solid (1.04 g) and aqueous 1 N HCl solution (33 mL) in MeOH (100 mL) was heated at 70° C. for 16 h. The mixture was concentrated under reduced pressure. (BOC)2O (1.34 g, 6.12 mmol) and Et3N (2.06 g, 20.4 mmol) were successively added to a solution of the residue in CH2Cl2 (30 mL). The mixture was stirred at room temperature for 15 min then was diluted with CH2Cl2 (300 mL). The resulting solution was washed with water (2×100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10-40μ silica gel; hexane:EtOAc 1:2 to 1:3) to give the title compound (839 mg, 54% yield) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=C)=[CH:23][CH:22]=5)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1.I([O-])(=O)(=O)=O.[Na+].[NH:45]1[CH2:48][CH:47]([C:49]([OH:51])=[O:50])[CH2:46]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O.ClCCCl.CO>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH2:29][N:45]3[CH2:48][CH:47]([C:49]([OH:51])=[O:50])[CH2:46]3)=[CH:23][CH:22]=5)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1snc(-c2ccccc2)c1C(F)(F)F
Reactant: O=C(O)C1CNC1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C(O)C1CN(Cc2ccc3c(c2)CCc2c-3noc2-c2snc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
To a clear solution of 3-(3-phenyl-4-(trifluoromethyl)isothiazol-5-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 103F, 40 mg, 0.094 mmol) in THF (3 mL) were sequentially added NMO (50% in water, 0.029 mL, 0.141 mmol) and osmium tetroxide (4% in water, 0.023 mL, 3.77 μmol) at room temperature. The solution was vigorously stirred at room temperature for 3 hr before additional NMO (0.05 mL) and osmium tetroxide (0.05 mL) was added. The mixture was stirred at room temperature overnight. Sodium periodate (28.2 mg, 0.132 mmol) in water (0.5 mL) was added. The mixture was stirred at room temperature under nitrogen for 0.5 h. The mixture was mixed with water (2 mL) and concentrated. The solid was filtered, washed with water (3×1 mL) and dried. The solid was mixed with MeOH (1 mL), 1,2-dichloroethane (1 mL), azetidine-3-carboxylic acid (19.06 mg, 0.188 mmol) and acetic acid (0.032 mL, 0.565 mmol). The reaction mixture was heated at 60° C. (oil bath temp.) for 1.5 h under nitrogen and then cooled to room temperature. Sodium cyanoborohydride (11.84 mg, 0.188 mmol) was added in one lot. The mixture was stirred at room temperature till the reaction was complete. The mixture was concentrated. The residue was dissolved in MeOH with some dichloromethane and TFA. Purification using reverse phase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration, neutralization with aqueous NaOAc, filtration gave a white solid. The solid was triturated with a mixture of methanol and ethyl acetate to give 1-((3-(3-phenyl-4-(trifluoromethyl)isothiazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid (14 mg, 0.026 mmol, 27.9% yield) as a white solid. The compound had an HPLC retention time=3.19 min. (condition C); LC/MS M+1=512.0. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.84 (1H, d, J=7.8 Hz), 7.60-7.65 (2H, m), 7.53-7.58 (3H, m), 7.35 (1H, s), 7.32 (1H, d, J=7.8 Hz), 3.59 (2H, s), 3.42 (2H, s), 3.16-3.25 (3H, m), 3.02 (2H, t, J=6.9 Hz), 2.93 (2H, t, J=6.9 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:13]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[Cl:38])[CH:12]2[C:39]([NH:41][O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)=[O:40])C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>FC(F)(F)C(O)=O>[Cl:38][C:32]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=1[CH:13]1[CH:12]([C:39]([NH:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)=[O:40])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[C:15](=[O:19])[N:14]1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccc(OCc3ccccc3)cc2C(C(=O)NOCc2ccccn2)C1c1ccc(Cl)cc1Cl
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccc(O)cc2C(C(=O)NOCc2ccccn2)C1c1ccc(Cl)cc1Cl
Yield: 99.9 %

Procedure:
A solution of 400 mg of (3RS,4RS)-6-(benzyloxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 245 mg of pentamethylbenzene in 15 ml of trifluoroacetic acid was stirred at room temperature overnight. The trifluoroacetic acid was evaporated under reduced pressure, and ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was solidified with ethyl acetate-isopropyl alcohol and collected by filtration to obtain 350 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-6-hydroxy-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:15]=[C:14]([CH2:16][C:17](=O)[CH3:18])[CH:13]=[CH:12][CH:11]=3)=[CH:6][C:5]=12.Cl.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[BH3-]C#N.[Na+].C1COCC1>CO>[N:21]1([CH:17]([CH3:18])[CH2:16][C:14]2[N:15]=[C:10]([C:7]3[CH:8]=[CH:9][N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC(=O)Cc1cccc(-c2ccn3ccnc3c2)n1
Reactant: C1COCCN1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Cc1cccc(-c2ccn3ccnc3c2)n1)N1CCOCC1
Reaction time: 24 h
Yield: 71.9 %

Procedure:
In a well mixed round bottomed flask under N2 charge 1-(6-Imidazo[1,2-a]pyridin-7-yl-pyridin-2-yl)-propan-2-one (1.8 g, 7.2 mmol), morpholine mono HCl salt (16 g, 129 mmol), 3 Å molecular sieves (powdered, vacuum oven dried 110° C. for 24 hours., 3.6 g), methanol (200 mL), and 1 M NaCNBH3 solution in THF (12.9 mL, 12.9 mmol). Stir for 24 hours. at room temp. Filter through Celite® strip off solvents under reduced pressure. Take up into DCM and adjust pH to 10 with 5N NaOH and extract with DCM (5×). Concentrate DCM under reduced pressure and chromatograph on (120 g ISCO®) SiO2 eluting with a slow gradient of 0% to 10% 2 M NH3 in MeOH with the balance DCM. Strip off solvents under reduced pressure to give clear oil 1.67 g (72%) MS(ES), m/z 323 (M+1).
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19]1([C:25]2[C:26]3[CH:27]=[CH:28][C:29]([C:47]([O:49][CH3:50])=[O:48])=[CH:30][C:31]=3[N:32]3[CH2:38][C:37]([C:39]([O:41]C)=[O:40])=[CH:36][C:35]4[CH:43]=[CH:44][CH:45]=[CH:46][C:34]=4[C:33]=23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH:19]1([C:25]2[C:26]3[CH:27]=[CH:28][C:29]([C:47]([O:49][CH3:50])=[O:48])=[CH:30][C:31]=3[N:32]3[CH2:38][C:37]([C:39]([OH:41])=[O:40])=[CH:36][C:35]4[CH:43]=[CH:44][CH:45]=[CH:46][C:34]=4[C:33]=23)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)C1=Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)=Cc1ccccc1-3

Procedure:
Tetrabutylammoniumhydroxide (9.1 mL, 40% solution in water) was added dropwise to a cooled solution (0° C., ice bath) containing dimethyl 13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate and THF (463 mL). The solution was maintained with continued cooling for 50 min. and then concentrated to a volume of about 50 mL. The resultant solution was diluted with ethyl acetate (250 mL), washed with aq. HCl (0.5 N, 3×150 mL), washed with brine (150 mL), dried (magnesium sulfate), filtered, and concentrated to afford a yellow solid. LCMS: retention time: 1.698 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode: m/z 416 (MH+). 1H NMR (300 MHz, DMSO-D6) δ ppm: 12.97 (s, 1H), 8.17 (m, 1H), 7.91 (m, 2H), 7.63 (m, 5H), 5.56 (s, 1H), 4.51 (m, 1H), 3.89 (m, 3H), 2.80 (m, 1H), 1.99 (m, 6H), 1.30 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH:9]=[C:8]([O:12]C)[CH2:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.C(OCC)(=O)C>O1CCCC1>[C:2]1(=[O:1])[C:11]2[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: COC1=CCC2=C(CCCC2=O)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCC2=C(CCCC2=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
6.8 g (38.2 mmol) of 1,2,3,4,5,8-hexahydro-1-oxo-6-methoxynaphthalene was dissolved in 50 ml of tetrahydrofuran and 5 ml of 1 N hydrochloric acid was added thereto. After stirring at room temperature for 1 hour, ethyl acetate was added thereto. Then the reaction mixture was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After concentrating, a small amount of a mixture of n-hexane with ethyl acetate (1:1) was added thereto and the obtained mixture was cooled in a dry ice-ether bath. The precipitate thus formed was recovered by filtration and washed with a small amount of n-hexane to thereby give 4.8 g of the title compound.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([O:16][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.Cl>C1COCC1>[O:16]=[C:13]1[N:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[CH:5][CH:6]=2)=[CH:15][NH:14]1
Reactant: COC(OC)c1ccc(-c2cnc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cnc(=O)[nH]c2)cc1
Reaction time: 1 h
Yield: 116.9 %

Procedure:
To a solution of 4-(2-[t-butyldiphenylsilyloxy]-pyrimidin-5-yl)-benzaldehyde dimethyl ketal (2.28 g, 4.7 mmol reference example 97a) in THF (10 mL) is added hydrochloric acid (10 mL, 2M). The resulting mixture is stirred for 1 h. This mixture is concentrated to about half its original volume under reduced pressure. The solid is filtered then washed with water and ether to give the title compound (1.1 g) as a white solid. 1H NMR (DMSO) δ 7.88 (d, J=8 Hz, 2H), 7.95 (d, J=8 Hz, 2H), 8.79 (s, 2H), 9.99 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Br:16])[C:10]=1[CH2:17][Br:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([Br:19])[Br:16])[C:10]=1[CH2:17][Br:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1CBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1cccc(C(Br)Br)c1CBr
Yield: 91.5 %

Procedure:
1-Benzoyl-2,3-bis(bromomethyl)benzene (8.0 g, 22 mmol) (crude, Description 7) was dissolved in carbon tetrachloride (50 ml) and recrystallized N-bromosuccinimide (3.9 g 22 mmol) and dibenzoyl peroxide (100 mg) were added. The mixture was heated to reflux for sixteen hours, cooled and filtered. The solid was washed with carbon tetrachloride (2×10 ml) and the combined organic layers were evaporated under reduced pressure to give crude 1-benzoyl-2-bromomethyl-3-(dibromomethyl)benzene (9.0 g, 93% recovery).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Sn](C)(C)[C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[N:34][CH:33]=1>CN1C(=O)CCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[N:34][CH:33]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)[nH]1
Reactant: C[Sn](C)(C)c1cncc2ccccc12
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-c2cncc3ccccc23)[nH]1
Yield: 55 %

Procedure:
5-Bromo-1H-pyrrole-2-carboxylic acid methyl ester (1.49 mmol, 0.30 g, prepared according to the procedure described in Method 4 of Example 2) in NMP (10 ml) was treated with triphenylarsine (0.30 mmol, 91 mg), tris(dibenzylideneacetone) dipalladium(0) (0.07 mmol, 68 mg), and 4-(trimethylstannyl)-isoquinoline (2.22 mmol, 0.65 g), then heated to reflux under an argon atmosphere overnight. The resulting mixture was concentrated under reduced pressure, then purified by silica gel chromatography to provide 0.21 g (55%) of 5-isoquinolin-4-yl-1H-pyrrole-2-carboxylic acid methyl ester. 1H NMR (CDCl3) δ 9.81 (1H, br s), 9.35 (1H, s), 8.66 (1H, s), 8.31 (1H, d, J=8.5), 8.10 (1H, d, J=8.1), 7.91 (1H, t, J=15.2), 7.79 (1H, t, J=15.2), 7.11 (1H, dd, J=3.8, 2.5), 6.64 (1H, dd, J=3.7, 2.7), 3.90 (3H, s).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:30]([F:33])([F:32])[F:31])=[N:19][C:20]([C:21](=[O:29])[NH:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:45]>C(OCC)(=O)C>[ClH:45].[CH3:28][S:25]([CH2:24][CH2:23][NH:22][C:21]([C:20]1[N:19]=[C:18]([C:30]([F:32])([F:31])[F:33])[N:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:34][C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[CH2:13][C:14]=12)=[O:29])(=[O:26])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NCCS(C)(=O)=O)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2

Procedure:
(R)-[3-[1-(2-Methanesulfonyl-ethylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 2b (0.06 g, 0.091 mmol) was dissolved in a little ethyl acetate. A solution of 3.1 N hydrochloric acid in 4 mL of ethyl acetate was then added to the solution. The reaction mixture was reacted at room temperature for 4 hours until thin lay chromatography showed the starting material disappeared, and was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (2-methanesulfonyl-ethyl)-amide hydrochloride 2 (60 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.CN(C)[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1>[F:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C=O)c(F)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-2-fluoro-4-methoxybenzene (3.02 g) in tetra hydrofuran (75 mL) was added n-butyl lithium (2.71 mol/L n-hexane solution, 6.0 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To this mixture was added N,N-dimethylformamide (1.7 mL) at the same temperature, and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=8/1-4/1) to give 2-fluoro-4-methoxybenzaldehyde (1.54 g). The title compound was prepared in a similar manner to that described in Reference Example 45 using this material instead of 4-isobutylbenzaldehyde.