Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[Br:1][C:12]1[CH:13]=[CH:14][C:9]([CH:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:10][CH:11]=1
Reactant: c1ccc(C2CCCNC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Brc1ccc(C2CCCNC2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
N-Bromosuccinimide (912 mg, 5.12 mmol) was added to a solution of 1.18 g (7.32 mmol) of 3-phenylpiperidine in 50% sulfuric acid (12 ml), and the mixture was stirred at 70° C. for 30 min. A saturated aqueous potassium carbonate solution was added to the reaction solution under ice cooling, and the mixture was extracted twice with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, was filtered, and was then concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol:concentrated aqueous ammonia=9:0.6:0.06) to give 352 mg (yield 20%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](OC)=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:6][C:7]#[C:8][CH3:9])[CH3:2].[CH3:27]C1C=CC=CC=1CBr.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:27])=[CH:12][CH:11]=1)[CH2:6][C:7]#[C:8][CH3:9])[CH3:2]
Reactant: CC#CCC(C(=O)OCC)c1ccc(OCc2ccc(OC)cc2)cc1
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC#CCC(C(=O)OCC)c1ccc(OCc2ccccc2C)cc1
Temperature: 80 °C

Procedure:
Ester 15.1 (3.19 g, 9 mmol) was taken up in glacial acetic acid (100 mL) in a 250 mL RB Flask, and the suspension was heated to reflux for 16 h. The solvent was removed under reduced pressure, and the residue was re-dissolved in ethyl acetate (200 mL). The solution was washed with 1 N HCl(aq) (200 mL) and saturated brine (200 mL), dried over MgSO4 and concentrated to a thick yellow oil, to which was added 2-methylbenyl bromide (2.57 g, 13.9 mmol), cesium carbonate (6.03 g, 18.5 mmol) and DMF (20 mL). The suspension was heated to 80° C. for overnight. After cooling, the reaction was quenched with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with NaHCO3 (sat. 2×100 mL), and NaCl (sat. 3×100 mL), dried over MgSO4, and concentrated to a white powder (2.41 g, 79%).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C([Li])CCC.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3[CH:27]=[C:28]4[C@:33]([C:35](OC)=[O:36])([CH2:34][C:25]=3[CH:24]=[N:23]2)[CH2:32][N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][CH2:29]4)=[CH:18][CH:17]=1.O>CCOCC>[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3[CH:27]=[C:28]4[C@:33]([C:35]([C:5]5[S:4][C:3]([Si:2]([CH3:9])([CH3:8])[CH3:1])=[N:7][CH:6]=5)=[O:36])([CH2:34][C:25]=3[CH:24]=[N:23]2)[CH2:32][N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][CH2:29]4)=[CH:18][CH:17]=1
Reactant: C[Si](C)(C)c1nccs1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2cnc([Si](C)(C)C)s2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
2-(Trimethylsilyl)thiazole (285 μl, 1.784 mmol) in dry ether (2 mL) was added to butyllithium (2.5 M in Hexanes) (731 μl, 1.828 mmol) in dry ether (1 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (250 mg, 0.585 mmol) in dry ether (6 mL) was added dropwise and the reaction mixture was stirred for 0.5 hour at −78° C. Water (10 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange solid. The crude product was purified by chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-5-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (88 mg) as a yellow solid. LCMS (Method F, ES-API): RT 2.38 min, m+H=481.2.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[CH3:7][C:8]([CH3:15])([CH3:14])[C:9](=O)[C:10](O)=[O:11]>O>[C:8]([C:9]1[C:10](=[O:11])[N:2]([NH2:1])[C:3]([SH:4])=[N:5][N:6]=1)([CH3:15])([CH3:14])[CH3:7]
Reactant: NNC(=S)NN
Reactant: CC(C)(C)C(=O)C(=O)O
Solvent: O
Product: CC(C)(C)c1nnc(S)n(N)c1=O

Procedure:
Analogously to instructions given by A. Dornow and others (Chem. Berichte 97 (1964), page 2173-2178), 53 g (0.5 mole) of thiocarbohydrazide are dissolved in 500 ml of boiling water and 65 g (0.5 mole) of trimethylpyruvic acid are added slowly. A colorless precipitate is deposited, which is filtered off, washed with water and dried in vacuo at 50° C. 6-tert.-butyl-3-mercapto-4-amino-1,2,4-triazin-5(4H)-one is obtained from this reaction in almost quantitative yield.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2cnccn2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.02 mmol), 2-(tributylstannyl)-pyrazine (0.818 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.233 g, 0.20 mmol) in toluene (4 mL) to give 4-chloro-5,7-difluoro-3-methyl-2-(pyrazin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=292.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:52]=[CH:51][C:39]([CH2:40][CH2:41]B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([CH2:41][CH2:40][C:39]3[CH:51]=[CH:52][C:36]([Cl:35])=[CH:37][CH:38]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CC1(C)OB(CCc2ccc(Cl)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(CCc2ccc(Cl)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), 2-(4-chlorophenethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (88 mg, 0.329 mmol) and PdCl2(PPh3)2 (63.1 mg, 0.090 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(4-chlorophenethyl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in dichloromethane (3 mL) and treated with TFA (3 mL) at room temperature for 1 hour to remove the protecting groups. The volatiles were subsequently evaporated from the reaction mixture and the residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 20-65% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (43 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (d, J=9.60 Hz, 1H), 1.90-2.15 (m, 1H), 2.86-3.02 (m, 2H), 3.19-3.38 (m, 2H), 3.47-3.61 (m, 1H), 3.61-3.75 (m, 2H), 3.81-4.03 (m, 2H), 4.13-4.41 (m, 3H), 6.99 (d, J=5.31 Hz, 1H), 7.22 (m, J=8.34 Hz, 2H), 7.32 (m, J=8.34 Hz, 2H), 7.91 (br s, 3H), 8.33 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H22ClFN4O2, 405. found, 405.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:14][OH:15])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:16][C:17]([CH3:19])=O.COC(OC)(C)C.S(=O)(=O)(O)O>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:16][C:17]1([CH3:19])[O:1][CH2:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:14][O:15]1
Reactant: CC(C)=O
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COC(C)(C)OC
Product: CCOC(=O)C1(C(=O)OCC)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 94 %

Procedure:
To a clear solution of diethyl bis(hydroxymethyl)malonate in 478 mL (6.52 mol) of acetone and 478 mL (8.45 mol) of acetone dimethylacetal was added 1.1 mL (42 mmol) of concentrated sulfuric acid and the reaction was stirred at room temperature overnight (19 hours). After 120 mL of saturated sodium carbonate was added, the mixture was stirred at room temperature for 15 minutes. The layers were separated and the semi-crystalline residue was washed with acetone (2×250 mL). The organics were evaporated. The residue was dispersed in 500 mL of ether and 250 mL of saturated Na2CO3, and stirred for 20 minutes. After the layers were separated, the organic layer was stirred with 250 mL of brine for 5 minutes and the layers separated. The organic layer was dried, evaporated, and placed under vacuum for 3 hours to produce a colorless oil, 527.5 g, in 94% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[NH2:13][C:14]1[C:19](Br)=[N:18][C:17]([Br:21])=[CH:16][N:15]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>O1CCCC1>[Br:21][C:17]1[N:18]=[C:19]([O:10][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])[CH3:9])[C:14]([NH2:13])=[N:15][CH:16]=1
Reactant: COc1ccc(F)cc1C(C)O
Reactant: Nc1ncc(Br)nc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)Oc1nc(Br)cnc1N
Temperature: 66 °C
Yield: 52.5 %

Procedure:
To a solution of 1-(5-fluoro-2-methoxy-phenyl)-ethanol (33.6 g, 197 mmol, 1.5 eq.) in tetrahydrofuran (140 mL) was added 2-amino-3,5-dibromo-pyrazine (39.9 g, 158 mmol) followed by a solution of sodium hexamethyldisilazide (1M in tetrahydrofuran, 200 mL, 1.5 eq.). This mixture was then heated to 66° C. for 4 hr before cooling and evaporating under reduced pressure. The residue was purified by chromatography on silica gel (100 g) eluting with tert-butyl methyl ether to give an orange solid after evaporating under reduced pressure. This solid was slurried in ice cold methanol and filtered to give the title compound as a beige solid (28.4 g, 42%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:45]=1[S:51](Cl)(=[O:53])=[O:52]>C(#N)C>[CH3:42][O:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:45]=1[S:51]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:53]
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(C)ccc1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 50.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0324 g, 0.0702 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0590 mL, 0.421 mmol) and 2-methoxy-4-methylbenzenesulfonyl chloride (0.0460 g, 0.211 mmol) to obtain 4-(2-methoxy-4-methylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0227 g, yield 50%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:14](=[O:13])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:5][CH:6]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
To a solution of 1.00 g (5.75 mmol) of 4-(2-aminoethyl)phenol in 5 mL of dioxane at 22° C. was added 2 mL of 1 N NaOH followed by 1.88 g (8.62 mmol) of BOC2O dissolved in 2 mL of dioxane. The mixture was stirred at 22° C. for 2 h and then neutralized by adding 25 mL of saturated NaHCO3 which resulted in a pH of about 7.5-8. The aqueous layer was separated and extracted with DCM (3×50 mL). The organics were combined, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography on silica gel eluting with a mixture of hexane and ethyl acetate to give tert-butyl 4-hydroxyphenethylcarbamate as a colorless oil.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1CCC(N=C=NC2CCCCC2)CC1.[C:36](O)(=[O:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C1C=CN=CC=1)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]([O:20][C:36](=[O:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC(=O)O
Reactant: CCCCCc1ccc(-c2ccc(C(C)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCCCCC(=O)OC(C)c1ccc(-c2ccc(CCCCC)cc2)cc1

Procedure:
Racemic (±)-4-pentyl-4'-(1-hydroxyethyl)biphenyl (m.p. 90.0° C.) was optically resolved by biochemical transesterification. Using the obtained 5.0 g of (-)-4- pentyl-4'-(1-hydroxyethyl)biphenyl (m.p. 83.8° C., [α]D 24.5 -25.0° (c 1.0, CH3OH)), 7.0 g of DCC, 1.0 g of DMAP and 3.0 g of caproic acid, optically active 4-pentyl-4'-(1-hexanoyloxyethyl)biphenyl 3.2 g was obtained by the same method as described in Example 1. The melting point of the obtained biphenyl was 10° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[N:11]=[C:10]([Cl:12])[NH:9][N:8]=1)=[O:6].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[N:11]=[C:10]([Cl:12])[N:9]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[N:8]=1)=[O:6]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1n[nH]c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)n(COCC[Si](C)(C)C)n1
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a suspension of NaH (60% dispersion, 53.9 mg, 1.34 mmol) in DMF (5 mL) at 0° C., a solution of 5-chloro-1H-[1,2,4]-triazole-3-carboxylic acid methyl ester (Bull. Pharm. Sci., 20(1): 47-61, (1997), 218 mg, 1.35 mmol) in DMF (10 mL) was added dropwise. The resulting suspension was stirred at the same temperature for 30 min and then treated with SEMCl (0.24 mL, 1.4 mmol). The resulting solution was stirred at RT for 30 min and poured onto ice. The mixture was extracted with ether (3×20 mL) and the ether layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue obtained was chromatographed on silica (10% EtOAc/hexane) to obtain the title compound (227 mg, 58%). Mass spectrum (ESI, m/z): Calcd. for C10H18C1N3O3Si, 292.0 and 294.0 (M+H). found 291.5 and 293.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.CS(O[CH:41]1[CH2:45][CH2:44][O:43][CH2:42]1)(=O)=O>>[O:43]1[CH2:44][CH2:45][CH:1]([O:2][C:3]2[C:8]3[C:9]([C:31]4[CH:35]=[N:34][N:33]([CH:45]5[CH2:41][CH2:42][O:43][CH2:44]5)[CH:32]=4)=[N:10][NH:11][C:7]=3[CH:6]=[CH:5][N:4]=2)[CH2:41][CH2:42]1
Reactant: CS(=O)(=O)OC1CCOC1
Reactant: COc1nccc2c1c(-c1cn[nH]c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: c1cc2[nH]nc(-c3cnn(C4CCOC4)c3)c2c(OC2CCOCC2)n1
Yield: 24 %

Procedure:
Prepared according to the general procedure described in Example 92, by reacting 4-methoxy-3-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine with tetrahydrofuran-3-yl methanesulfonate to give the title compound as a mixture of enantiomers. The enantiomers were separated via supercritical fluid chromatography to give the separated enantiomers. (7.9 mg, 7.7 mg, total yield 24% over two steps). LC-MS (Method G): m/z=286.1 [M+H]+; 2.97 min. 1H-NMR (400 MHz, DMSO): δ 13.27 (s, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.85 (d, J=6.0, 1H), 7.09 (d, J=6.0 1H), 5.17-5.09 (m, 1H), 4.06 (s, 3H), 4.05-3.98 (m, 2H), 3.95 (dd, J=9.4, J=3.7, 1H), 3.91-3.83 (m, 1H), 2.47-2.36 (m, 1H), 2.36-2.25 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.O1CCOCC1.O.[Cl-].[Na+].O>[C:12]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCCNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(Method J10) To the solution of 6-aminocaproic acid (2h) (0.982 g, 7.5 mmol) in water/dioxane (1:1) mixture (30 ml) NaOH (0.8 g, 20 mmol) in H2O (2 ml) and benzoyl chloride (1/67) (1.16 ml, 10 mmol) were added. The mixture was stirred for 6 h at room temperature and diluted with brine (150 ml). The mixture was washed with diethyl ether (2×25 ml), acidified with conc. HCl to pH 4, and extracted with ethyl acetate (4×25 ml). The organic solution was washed with brine (3×25 ml), dried (Na2SO4) and evaporated. The crude title compound (1.589 g, 90%) was purified by column chromatography on silica gel with chloroform-ethyl acetate (1:2) as eluent. 1H NMR (CDCl3, HMDS) δ: 1.18-1.85 (m, 6H); 2.34 (t, J=7.0 Hz, 2H); 3.45 (q, J=6.0 Hz, 2H); 6.27 (bs, 1H); 7.29-7.52 (m, 3H); 7.61-7.85 (m, 2H); 10.41 (bs, 1H).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH2:38])[C:19]3=[O:39])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]1([C:46]([NH:59][C:60]2[S:61][CH:62]=[C:63](/[C:65](=[N:69]/[O:70][C:71]([O:74][CH3:75])([CH3:73])[CH3:72])/[C:66](O)=[O:67])[N:64]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O1CCCC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:66](=[O:67])/[C:65](/[C:63]2[N:64]=[C:60]([NH:59][C:46]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:61][CH:62]=2)=[N:69]\[O:70][C:71]([O:74][CH3:75])([CH3:73])[CH3:72])[C:19]3=[O:39])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(C)(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](N)[C@H]4SC3)sc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nn4c(=O)cc(C)nc4s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
The product obtained in Step 2 (3.25 g) and 2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(1-methoxy-1-methylethyl)oxyimino]acetic acid (5.64 g) were dissolved in dichloromethane (93 ml) and tetrahydrofuran (93 ml) under a nitrogen stream, and the solution was cooled to 0° C. Dicyclohexylcarbodiimide (2.32 g) was added to this solution by small portions, and the mixture was stirred overnight at room temperature. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure. The residue was redissolved in ethyl acetate and the insoluble matters were filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 2.5 g of the objective compound as yellow crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[S:29].N12CCN(CC1)CC2.Cl>CN(C=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[O:18][C:28](=[S:29])[N:27]([CH3:31])[CH3:26])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C(=S)Cl
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.5 g of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester, Example D-7f, in 6.3 ml of anhydrous DMF was added 578 mg of dimethylthiocarbamoylchloride and 1.5 g of 1,4-diazabicyclo[2.2.2]octane. The mixture was stirred overnight at room temperature. The mixture was poured into 30 ml of 1 N HCl and extracted three times with 30 ml portions of ethyl acetate. The organic fractions were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to 1.9 g of product; MS (+) m/z 425.27 (M+1)