Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14](OCC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:61]([NH2:65])([CH3:64])([CH3:63])[CH3:62]>CN(C=O)C.CCOCC>[CH3:4][C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:25]([NH:65][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:27])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 153.7 %

Procedure:
A solution of N-(tert-Butyloxycarbonyl)-O-benzyl-L-tyrosine (Bachem, 2.00 g, 5.38 mmol) in 20 mL of DMF was cooled to 0° C. and treated with i-Pr2NEt (1.5 mL, Aldrich, Milwaukee, Wis.) followed by O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (2.04 g, 538 mmol, Novabiochem, La Jolla, Calif.). The resulting suspension was stirred for 30 minutes at 0° C. and then treated with tert-butylamine (0.48 g, 6.56 mmol, Aldrich, Milwaukee, Wis.). The reaction mixture was stirred for 1 hour at 0° C. and warmed to room temperature. The reaction mixture was then poured into Et2O, and washed sequentially with saturated aqueous NaUCO3 solution and saturated aqueous NaCl solution. The organic phase was dried over MgSO4, filtered, and concentrated. The crude residue was purified by chromatography (silica gel, 3:1 heptane/ethyl acetate) to give (S)-[2-[(1,1-dimethylethyl)amino]-2-oxo-1-(phenylmethyl)ethyl]-carbamic acid 1,1-dimethylethyl ester (2.65 g). MS (CI) 427 (MH)+.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CCO>[F:9][CH:8]([F:10])[CH2:7][N:6]1[C:2]([N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:27])[C:23]([F:25])([F:24])[F:26])[CH2:16][CH2:15]2)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]1
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Reactant: O=[N+]([O-])c1cnn(CC(F)F)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC1)C(F)(F)F
Yield: 64.9 %

Procedure:
A solution of 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (438 mg, 2.07 mmol), (R)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide (438 mg, 2.07 mmol) and DIPEA (1 mL) in EtOH (4 mL) was heated at 155° C. in the microwave for 5 hr. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale orange gum (518 mg). A portion of this gum (39 mg, 0.10 mmol) in dry THF (2 mL) was treated with sodium hydride (60% in mineral oil, 5 mg, 0.12 mmol). After stirring at room temperature for 10 min, iodomethane (0.01 mL, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 2 hr. The reaction was repeated on the remaining (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide. Water (50 mL) was added carefully and the mixture was extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and the solvent was removed under reduced pressure to give (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide as a pale yellow gum (518 mg). This gum (514 mg, 1.29 mmol) was dissolved in MeOH (20 mL) and treated with ammonium formate (325 mg, 6.15 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 85° C. for 2 hr. After cooling to room temperature the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between DCM (50 mL) and water (30 mL) and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure to afford (R)—N-(1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide as a pale yellow gum (348 mg, 46% over three steps). 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 6.19 (tq, J=55.4, 4.4 Hz, 1H), 4.65-4.15 (m, 3H), 3.40-3.10 (m, 4H), 3.10 and 2.97 (2s, 3H), 2.80 (br s, 2H), 2.10-1.70 (m, 6H).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:6]=[N:7][N:8]([CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=1)C.Cl.CCOCC>C1COCC1.O>[CH3:14][Si:11]([CH2:10][N:8]1[CH:9]=[C:5]([CH:4]=[O:3])[N:6]=[N:7]1)([CH3:12])[CH3:13]
Reactant: CCOC(OCC)c1cn(C[Si](C)(C)C)nn1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)Cn1cc(C=O)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a solution of 4-(diethoxymethyl)-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazole (1.620 mg, 6.290 mmol) in 10.0 ml of THF was added 2.0N HCl in Et2O (9.44 ml, 18.88 mmol), and the mixture was stirred at RT for 15 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the crude title compound as a light yellow liquid (1.050 g, 91% crude). ES-MS [M+1]+: 184.1. This intermediate was carried over to the next step without further purifications and characterizations.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[C:14]([C:18]1[CH:30]=[CH:29][C:21]([O:22][C:23]2[C:27](Cl)=[N:26][S:25][N:24]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:13][C:27]2[C:23]([O:22][C:21]3[CH:29]=[CH:30][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=3)=[N:24][S:25][N:26]=2)=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(Oc2nsnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(Oc2nsnc2Oc2ccc(C(C)(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a suspension formed by suspending 0.16 g of sodium hydride (60%) in N,N-dimethylformamide was added 0.6 g of 4-t-butylphenol and after stirring the mixture for one hour at 60° C., 0.81 g of 3-(4-t-butylphenoxy)-4-chloro-1,2,5-thiadiazole was added to the mixture followed by stirring for 12 hours at 100° C. After allowing to cool, the reaction mixture was poured in water and extracted with ether. The ether layer collected was washed twice each time with a diluted aqueous sodium hydroxide solution, water, and then a saturated aqueous sodium chloride solution. The ether layer thus washed was dried with anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography to provide 0.84 g of 3,4-bis(4-t-butylphenoxy)-1,2,5-thiadiazole.
Reaction SMILES: N[C@H](C1C=CC=CC=1)[C@H](NS(C1C(C)=CC(C)=CC=1C)(=O)=O)C1C=CC=CC=1.C(N(CC)CC)C.[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][NH:37]1.C(O)=O>C(#N)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][NH:37]1
Reactant: C1=Cc2ccccc2CN1
Agent: Cl[Ru]Cl
Agent: Cc1cc(C)c(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)c(C)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=CO
Product: c1ccc2c(c1)CCNC2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In a second flask dichloro(p-cymene)ruthenium (II) dimer (0.15 mmol) is added to a solution of N-((1R,2R)-2-amino-1,2-diphenyl-ethyl)-2,4,6-trimethyl-benzene-sulfonamide (0.30 mmol) and triethylamine (0.60 mmol) in acetonitrile (3.3 mL). The mixture is stirred for 1 h at 80° C. A portion of this solution (0.10 mL) is added to the solution of the respective dihydroisoquinoline (described above). An azeotropic mixture of formic acid and triethylamine (5:2, 0.3 mL) is added (gas evolution). After 2 d the mixture is concentrated in vacuo and purified by prep. HPLC to give the respective 1,2,3,4-tetra-hydroisoquinoline.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH:32](=O)[CH2:33][CH3:34].CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:32]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[CH2:33][CH3:34]
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: CCC=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCCN1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 113 mg (0.27 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 2.5 mL chloroform was treated with 0.20 mL (2.7 mmol) propionaldehyde and 180 mg (0.82 mmol) NaBH3(CN), followed by addition of 2.5 mL methanol. The mixture was stirred at ambient temperature for 1 h when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by HPLC, the title compound was obtained. MS (ES+): 454 (M+H)+.
Reaction SMILES: ClC(OCC(C)C)=O.[O:9]=[C:10]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([OH:25])=O)[C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14].[NH3:26].C(O)C>C(Cl)Cl.O>[O:9]=[C:10]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([NH2:26])=[O:25])[C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14]
Reactant: N
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.8 %

Procedure:
Isobutyl chloroformate (20 mmol, 2.7 mL) was added to a solution containing (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (4.89 g, 20 mmol) (from Example 1) in 50 mL methylene chloride at −10° C. with stirring. After 5 minutes, ammonia was added dropwise (20 mmol, 10 mL of 2 M ethyl alcohol solution). The reaction was warmed up to room temperature after stirring at −10° C. for 30 minutes. The mixture was diluted with water, and extracted into 200 mL methylene chloride. The organic extract was concentrated and further purified by silica gel to give 4.0 g of product as a white solid (81.8% yield). 1H NMR (CDCl3): δ0.91 (t, 3H, J=7.5); 1.28 (s, 6H, each); 1.63–1.84 (m, 2H); 1.95–2.22 (m, 3H); 2.46 (m, 1H); 3.55–3.67 (m, 2H); 4.67 (t, 1H, J=7.8); 5.51–5.53 (br, 1H, NH); 6.80 (br, 1H, NH).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2)([OH:3])=O.[Cl:14][C:15]1[CH:16]=[C:17]([NH2:23])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([NH:23][C:1]([C:4]2[C:5]3[CH2:6][C:7](=[O:13])[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)=[O:3])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: O=C1Cc2c(cccc2C(=O)O)N1
Reactant: COc1ccc(N)cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2cccc3c2CC(=O)N3)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-carboxy-2-oxindole (200 mg, 1.13 mmol) and 3-chloro-4-methoxyphenylamine (178 mg, 1.13 mmol) in dimethylformamide (15 mL) at room temperature was added benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 997 mg, 2.26 mmol) followed by 4-dimethylaminopyridine (206 mg, 1.69 mmol). The mixture was stirred at room temperature for 72 hours. The reaction was then diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate (100 mL), water, 2N hydrochloric acid (100 mL), water (3×200 mL) and brine. It was then dried over magnesium sulfate and concentrated. The residue was triturated with ethyl acetate to give 2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid (3-chloro-4-methoxyphenyl)-amide as a pink solid.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[C:7]([CH:9](Br)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=O)[CH:6]=[CH:5][N:4]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33](=[S:35])[NH2:34])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[S:35][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH2:2])[CH:8]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[N:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Nc1cc(C(Br)C(=O)c2cccc(Cl)c2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(Cl)c3)c(-c3ccnc(N)c3)s2)CC1
Yield: 50 %

Procedure:
A solution of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-chlorophenyl)ethanone hydrobromide (2.74 g, 8.36 mmol) and 1-tert-butoxycarbonylpiperidine-4-carbothioamide in N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 hours. Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) and then purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), ethyl acetate). The obtained crude crystalline was recrystallized from ethyl acetate-hexane to give a title compound (1.94 g, yield 50%).
Reaction SMILES: [Li]CCCC.CCCCCC.C(=O)=O.Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[C@@H:36]1[N:40]2[CH:41]=[N:42][CH:43]=[C:39]2[C:38](=[O:44])[CH2:37]1)[C:31]#[N:32]>C1COCC1.CC(C)=O>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[C@@H:36]1[N:40]2[CH:41]=[N:42][CH:43]=[C:39]2[C@@:38]([OH:44])([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[CH2:37]1)[C:31]#[N:32]
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1ccc([C@H]2C[C@](O)(c3ccc(OC(F)(F)F)cc3)c3cncn32)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
To a solution of a 1.6 M n-BuLi solution in hexane (0.428 ml, 0.684 mmol) cooled in a dry ice and acetone bath was added a solution of 1-bromo-4-(trifluoromethoxy)benzene (0.046 ml, 0.311 mmol) in 1 mL THF. The yellow crude was stirred at −78° C. for 1 hr. This crude was cannulated to a solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (75 mg, 0.311 mmol) in THF (1 mL) cooled to −78° C. The crude was slowly warmed to room temperature over 5 hrs. The crude was quenched with NH4Cl and diluted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was first purified via preparation plate using 5% (2M NH3 in MeOH)/CH2Cl2. The product was further purified using HPLC to give 19.8 mg of the entitled product as the major diastereomer. MS 404.2 (M+H); LCMS condition A, retention time 1.38 min. 1H NMR (400 MHz, CDCl3) δ ppm 2.94 (d, 1H), 3.26 (dd, 1H), 5.71 (d, 1H), 6.72 (br. s., 1H), 7.03-7.17 (m, 3H), 7.27-7.39 (m, 3H), 7.40-7.52 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:9]([O:11][CH3:12])=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1)=[CH2:2]>[Pd].C(O)C>[CH2:1]([C:3]1[C:4]([C:9]([O:11][CH3:12])=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1cccnc1C(=O)OC
Agent: [Pd]
Solvent: CCO
Product: CCc1cccnc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Palladium on carbon (10%, 25 mg) was added to a solution of methyl 3-vinylpicolinate (120 mg, 0.74 mmol) in ethanol (10 mL). The suspension was stirred at room temperature under an atmosphere of hydrogen for 1 h before it was filtered through Celite and the pad of Celite was washed with methanol. The filtrate was concentrated down to dryness to yield methyl 3-ethylpicolinate (i.e. Cap-175, step b) which was taken directly into the next reaction. Rt=1.15 min (Cond.-MD1); LC/MS: Anal. Calcd. for [M+H]+ C9H12NO2: 166.09. found: 166.09.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([NH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(NCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 113.8 %

Procedure:
To a solution of 5-aminosalicylic acid (2.0 g, 13 mmole, purchased from Aldrich Chemical Company, USA) and triethylamine in dried DMF (25 ml) was added benzyl bromide (2.68 g, 1.90 ml, 15.6 mmole) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 4 hr at room temperature. Ice chips were added to the reaction mixture and then solvent was removed in vacuo. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and brine, and then dricd over anhydrous MgSO4. After evaporation of the solvent, the residue was purified by column chromatography and recrystallized from methanol/ethyl acetate/hexane (1:3:1), to give 3.6 g (73% yield) of 5-benzylaminosalylic acid as a white solid.: mp 173.5-174.5° C. (decompose).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)#[N:2].Cl.[OH-].[Na+].CCOCC>C1COCC1.C(Cl)Cl>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1
Reactant: COc1cc2c(cc1OC)CN(CCC#N)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2c(cc1OC)CN(CCCN)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2-(2-cyanoethyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (5.70 g, 23.1 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0M, 81 mL, 81 mmol, 3.5 equiv) at room temperature. The mixture was stirred at reflux for 4.5 hours and then cooled to room temperature. Aqueous HCl (6N, 130 mL) was added cautiously at room temperature and stirring was continued for 2.5 hours at 55-60° C. The mixture was cooled to 0° C., basified to pH 10-11 by addition of 6N aq. NaOH, and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. To a solution of the residue in CH2Cl2 (20 mL) was added HCl in ether (1.0M, 40 mL, 1.7 equiv). The resulting solution was added dropwise into ether (250 mL) with swirling. The precipitate was filtered and washed with ether (3×100 mL). This solid was taken up in water (50 mL), which was basified to pH 10 by addition of 1M aqueous NaOH, and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 5.10 g (88%) of white solid, which was characterized spectroscopically.
Reaction SMILES: CO[CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.C1(C)C=C[C:20]([S:23](O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:6]([O:5][CH2:4][CH:3]1[S:23][CH2:20][CH2:15][O:14]1)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(COC(=O)c1ccccc1)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCC1OCCS1)c1ccccc1
Temperature: 25 °C
Yield: 5173.6 %

Procedure:
Aliquots of 2-benzoyloxyacetaldehyde dimethyl acetal (50.0 g) prepared according to Example 1,2-mercaptoethanol (20.4 g), p-toluenesulfonic acid monohydrate (0.90 g) and toluene (250 mL) were placed in a three-neck flask, followed by heating. By-produced methanol was distilled off with the solvent. After distilling off about 150 mL, the reaction mixture was cooled to room temperature, was washed with a saturated aqueous sodium hydrogen carbonate solution and water and was dried over anhydrous sodium carbonate. After filtration and vacuum distillation at 144-147° C. and at 0.60 mmHg, the target compound (54.9 g) was obtained in a yield of 100%.
Reaction SMILES: C[C:2]1[C:7](Br)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)[CH3:11]>>[Br:9][C:5]1[CH:4]=[N:3][CH:2]=[C:7]([C:15]2[CH:16]=[CH:17][C:12]([CH2:10][CH3:11])=[CH:13][CH:14]=2)[CH:6]=1
Reactant: Cc1ncc(Br)cc1Br
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2cncc(Br)c2)cc1

Procedure:
23 g (97 mmol) of methyl 3,5-dibromopyridine and 18 g (117 mmol, 1.2 eq.) of 4-ethylphenylboronic acid were reacted according to General Method 1A. Yield: 17 g (66% of theory)
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3(O)[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][CH:17]34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[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]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=Cc1ccc2c(c1)CCC1C2=NOC1(O)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
The 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol (5 g, 11.73 mmol) was mixed with thionyl chloride (1.712 mL, 23.45 mmol) and anhydrous toluene (80 mL). Pyridine (0.190 mL, 2.345 mmol) was then added dropwise. The mixture was stirred under nitrogen at room temperature for 30 min and 90° C. for 15 min. The mixture was concentrated under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and dichloromethane (100 mL, 2×50 mL). The combined dichloromethane extracts were dried over sodium sulfate, filtered through a pad of silica gel and concentrated under reduced pressure. Flash chromatography purification (220 g silica gel column, 25→60% dichloromethane in hexanes) and trituration with methanol gave 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (1.96 g, 4.80 mmol, 40.9% yield) as a white solid. The compound had an HPLC retention time=4.28 min (condition C); LC/MS M+1=408.9.