Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[CH:17]3)[CH:10]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[O:27]1[CH2:28][CH2:29][CH:24]([CH2:23][CH:10]2[CH2:9][NH:8][CH2:13][CH2:12][N:11]2[C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[CH:17]3)[CH2:25][CH2:26]1
Reactant: c1ccc(CN2CCN(c3ccc4[nH]ncc4c3)C(CC3CCOCC3)C2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1cc2[nH]ncc2cc1N1CCNCC1CC1CCOCC1
Yield: 61.8 %

Procedure:
To a mixture of 5-[4-benzyl-2-(tetrahydro-pyran-4-ylmethyl)-piperazin-1-yl]-1H-indazole (0.27 g, 0.7 mmol), Pd(OH)2 (0.050 g), in 75 mL MeOH was added ammonium formate (0.43 g, 6.9 mmol). The mixture was heated to reflux. After 1 hr the mixture was cooled, filtered through celite and concentrated in vacuo to give a crude solid. Purification via flash chromatography afforded 5-[2-(tetrahydro-pyran-4-ylmethyl)-piperazin-1-yl]-1H-indazole (0.13 g, 62%) as a white foam: 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J=0.9 Hz, 1H), 7.40 (dd, J=9.6, 0.9 Hz, 1H), 7.23-7.11 (m, 2H), 3.94-3.80 (m, 2H), 3.63-3.52 (m, 2H), 3.37-2.89 (m, 8H), 1.68-0.97 (m, 7H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([N+:19]([O-])=O)[CH3:18])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.O.[C].[Pd]>[CH3:13][O:12][C:10](=[O:11])[C@H:9]([CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([CH3:18])[NH2:19])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CCCC(C)(C)[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](CCCC(C)(C)N)NC(=O)OC(C)(C)C
Yield: 77.3 %

Procedure:
Methyl (S)-2-t-butoxycarbonylamino-6-methyl-6-nitroheptanoate (500 mg, 1.57 mmol) was dissolved in methanol (8 ml) and water (0.5 ml), and 5% palladium-carbon (219 mg, 50% wet) and ferrous sulfate 7 hydrate (1.32 g, 4.75 mmol) were added. The mixture was stirred at a hydrogen pressure of 3 atm and room temperature for 3 h. Palladium-carbon was removed by filtration and methanol was evaporated by concentration under reduced pressure. Ethyl acetate (50 ml), water (50 ml) and sodium carbonate were added for pH adjustment to 10 and extraction. After layer partitioning, the aqueous layer was extracted again with toluene-isopropyl alcohol (1:1, 100 ml). The organic layers were combined and the solvent was evaporated by concentration under reduced pressure to give the objective compound (350 mg, yield 77.3%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O[C:21]1C=CC(C(OC)=O)=C[CH:22]=1.C1(CCO)CCCC1>>[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)[CH2:3][CH2:2][CH2:22][CH2:21]1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: OCCC1CCCC1
Product: O=C(O)CNC(=O)c1ccc(OCCC2CCCC2)cc1
Yield: 79 %

Procedure:
Reactions similar to those described in Example 1 (1a) and (1b) were conducted using methyl 4-hydroxybenzoate (6.09 g, 40.0 mmol) and 2-cyclopentylethanol (4.57 g, 40.0 mmol) to give 9.20 g of the title compound (white solid, yield: 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:13]1[CH2:14][CH2:15][C:16]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[O:9][C:10](=[O:17])[C:11]=2[CH2:12]1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: O=Cc1cccc(Cl)c1
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1cccc(Cl)c1)CC3
Yield: 65 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 3-chlorobenzaldehyde. Yield 65%; mp 112°-115° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14]([CH2:16][C:17]([O:19]CC)=[O:18])#[N:15].N1CCCCC1>C(O)C>[C:14]([C:16](=[CH:1][C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1)[C:17]([OH:19])=[O:18])#[N:15]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C=C(C#N)C(=O)O)cc(OC)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a solution of 2 g (11.0 mmol) of syringaldehyde and 1.2 ml (11.3 mmol) of ethyl cyanoacetate in 30 ml of ethanol was added 2 ml of piperidine, and the mixture was stirred at room temperature for 16 hours. The solution was evaporated under reduced pressure, subsequently the residue was acidified by adding 1N hydrochloric acid and extracted with 200 ml of ethyl acetate. The organic layer was washed with water, and concentrated under reduced pressure. A formed precipitate was washed with ethanol, and then dissolved in a mixed solvent of tetrahydrofuran and methanol (30 ml, 20 ml). To the solution was added potassium hydroxide solution (3.0 g/30 ml), and the mixture was stirred at room temperature for 1.5 hours. A 100 ml of water and 50 ml of ethyl acetate was added to the solution for separation of each layer. An aqueous layer was acidified with conc. hydrochloric acid, and a formed precipitate was filtrated to give 1.4 g (yield 51.1%) of objective α-cyano-3,5-dimethoxy-4-hydroxycinnamic acid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][N:24]=1)=[O:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.O>ClCCl>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:30][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][N:24]=1)=[O:22])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(COS(C)(=O)=O)cn1
Reaction time: 1 h
Yield: 94 %

Procedure:
Under ice cooling, methanesulfonyl chloride (4.2 mL, 54 mmol) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-5-hydroxymethylpyridine-2-carboxylic acid amide (Reference Compound No. 3-1, 16 g, 45 mmol) and triethylamine (16 mL, 110 mmol) in dichloromethane (150 mL), and then the reaction mixture was stirred for 1 hour. Water (400 mL) was added thereto, and then the whole was extracted with ethyl acetate (500 mL) five times. The organic layer was washed with water (500 mL), dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration with hexane (80 mL) and ethyl acetate (20 mL) to give 18 g of the title reference compound as a white solid. (Yield 94%)
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].COC(C1NN=C(OC[C:38]2[C:39]([C:44]3[CH:49]=CC=CC=3)=[N:40][O:41][C:42]=2C)C=1)=O.NC1CCOCC1>>[O:41]1[CH2:49][CH2:44][CH:39]([NH:40][C:3]([C:5]2[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[N:14][O:15][C:16]=3[CH2:17][OH:18])[CH:9]=2)=[O:4])[CH2:38][CH2:42]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Agent: NC1CCOCC1
Product: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)NC1CCOCC1
Yield: 67 %

Procedure:
As described for example 1b, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (150 mg, 0.42 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using 4-aminotetrahydropyran instead of morpholine, to the title compound (120 mg, 67%) which was obtained as a white solid. MS: m/e=429.1 [M−H]−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>C1(C)C(C)=CC=CC=1>[CH:19]([NH:22][C:2]1[N:7]=[C:6]([NH:9][CH:10]([CH3:17])[CH3:11])[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1)([CH3:21])[CH3:20]
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)nc(Cl)n1
Reactant: CC(C)N
Solvent: Cc1ccccc1C
Product: CC(C)Nc1nc(NC(C)C)nc(N2C(C)(C)CCCC2(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
43.4 g of 2,4-dichloro-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine are heated in an autoclave to 160° for 8 hours with 39.0 g of isopropylamine in 200 ml of xylene. After cooling to room temperature, the autoclave contents are washed three times, each with 100 ml of water, and the yellowish xylene solution is dried over sodium sulfate, stirred for 10 minutes with 5 g of Tonsil Optimum (bleaching earth), filtered and evaporated. The 2,4-bis-isopropylamino-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine obtained is a slightly yellowish resin which could not be crystallized.
Reaction SMILES: [SH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:46][O:47][C:48](=[O:55])/[CH:49]=[C:50](\[CH3:54])/[CH2:51][CH2:52]O>C(OCC)(=O)C.C1COCC1>[CH3:46][O:47][C:48](=[O:55])/[CH:49]=[C:50](\[CH3:54])/[CH2:51][CH2:52][S:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1
Reactant: COC(=O)/C=C(\C)CCO
Reactant: Sc1nnnn1-c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C(\C)CCSc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
5-Mercapto-1-phenyltetrazole (2.62 g, 14.60 mmol), triphenylphosphine (3.83 g, 14.60 mmol) and diisopropyl azodicarboxylate (95%, 2.96 g, 14.60 mmol) were added to a THF (36.8 ml) solution of methyl-(2E)-5-hydroxy-3-methylpent-2-enoate (1.16 g, 7.31 mmol) while ice cooling. The reaction solution was warmed to room temperature and stirred for two hours. After the reaction solution was diluted with ethyl acetate, it was washed with distilled water and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:ethyl acetate=5:1) to obtain the title compound (2.33 g) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].[Cl:14][CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH2:6][NH:7][S:18]([CH2:17][CH2:16][CH2:15][Cl:14])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COc1ccc(CN)c(OC)c1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)CCCCl)c(OC)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a solution of 2,4-dimethoxy-benzylamine hydrochloride (1 eq.) and TEA (2 eq.) in DCM was added dropwise at 0° C. a solution of 3-chloro-propane-1-sulfonyl chloride (1 eq.) in DCM. The reaction was stirred at 20° C. for 20 h. The crude was diluted with DCM, washed twice with water, twice with aqueous HCl (0.1N) and twice with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 100/0 to 20/80) to afford 3-chloro-propane-1-sulfonic acid 2,4-dimethoxy-benzylamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:14])[C:5]2[O:10][CH2:9][CH:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1.[CH3:15][S:16]([O-:18])=[O:17].[Na+].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[F:14][C:4]1[C:5]2[O:10][CH2:9][CH:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=[C:2]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:3]=1
Reactant: CS(=O)[O-]
Reactant: OCC1COc2c(F)cc(Br)cc2O1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CO)CO2
Temperature: 140 °C
Yield: 33.2 %

Procedure:
A mixture of (7-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol (0.6 g, 2.3 mmol), sodium methanesulfinate (85%) (0.4 g, 3.5 mmol), CuI (0.04 g, 0.2 mmol), L-proline (0.05 g, 0.5 mmol) and K2CO3 (0.06 g, 0.5 mmol) in DMSO (6 ml) was heated in two batches under microwave radiation at 140° C. for 2 h in nitrogen-flushed vials. After cooling to ambient temperature, the batches were mixed, water and EtOAc were added and the water phase was extracted with EtOAc. The combined organic phases were washed with LiCl (5%), HCl (1 N), brine, dried (Na2SO4) and evaporated to dryness. The product was mixed with another batch of the same compound. Purification on flash column chromatography (isooctane/EtOAc/MeOH) gave the title compound (0.2 g). MS m/z (rel. intensity, 70 eV) 262 (M+, bp), 231 (32), 206 (12), 183 (17), 152 (14).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:24][CH2:25][N:26]3[C@H:31]4[CH2:32][CH2:33][C@@H:27]3[CH2:28][CH:29]([N:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[N:36]=[C:35]3[CH3:43])[CH2:30]4)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]([CH3:22])([CH3:21])[C:16]([O:18]CC)=[O:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:24][CH2:25][N:26]3[C@H:27]4[CH2:33][CH2:32][C@@H:31]3[CH2:30][CH:29]([N:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[N:36]=[C:35]3[CH3:43])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]([CH3:21])([CH3:22])[C:16]([OH:18])=[O:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)C(=O)N1CCC(CCN2[C@@H]3CC[C@H]2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(C)C(=O)O)CC1
Yield: 85 %

Procedure:
3-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,2-dimethyl-3-oxopropanoic acid was obtained from 3-Ethoxy-2,2-dimethyl-3-oxopropanoic acid, Example 628, (0.029 g, 0.18 mmol), 1-(8-(2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl)-8-aza-bicyclo[3.2.1]oct-3-yl)-2-methyl-1H-enzoimidazole dihydrochloride (0.075 g, 0.18 mmol), and HATU (0.067 g, 0.18 mmol) following the procedure outlined in example 5 to produce ethyl 3-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,2-dimethyl-3-oxopropanoate. Ethyl 3-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,2-dimethyl-3-oxopropanoate (0.100 g, 0.170 mmol), 5 N NaOH (10 ml) and ethanol (4 ml) was stirred at 90° C. for 3 hrs. The reaction was evaporated to dryness and residue was suspend in water (10 ml) and neutralized with 1N HCl. The aqueous layer was extracted with ethyl acetate (3×10 ml). The organic layer was dried using magnesium sulfate and concentrated down to form the title compound as a white solid (0.081 g, 85%). ES-LCMS m/z 561 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([CH2:32][CH3:33])[CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:34])C.[OH-].[Na+]>C1COCC1.CCO>[CH2:32]([N:14]([CH2:15][C:16]1[S:20][C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=2)=[N:18][C:17]=1[CH3:31])[C:10]1[CH:11]=[C:12]([CH3:13])[C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([CH3:34])[CH:9]=1)[CH3:33]
Reactant: CCOC(=O)COc1c(C)cc(N(CC)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C)c1cc(C)c(OCC(=O)O)c(C)c1
Reaction time: 1 h

Procedure:
0.66 g (0.13 mmol) of the above prepared (4-{ethyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2,6-dimethyl-phenoxy)-acetic acid ethyl ester was dissolved in 0.80 ml of THF/EtOH=1/1, treated with 0.40 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 1 h. The reaction mixture was then poured onto crashed ice/EtOAc/HCl dil., the organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Crystallization from hexane/EtOAc generated finally 0.056 g of the title compound as off-white crystals of mp. 161-162° C., MS: 477.0 (M-H)−.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C@@H:12]1[CH2:16][O:15][CH2:14][C@H:13]1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([O:20][CH2:21]C)=[CH2:19].C(N(CC)CC)C>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C@H:12]1[C@H:13]([O:17][CH2:21][O:20][CH2:18][CH3:19])[CH2:14][O:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COCC
Reactant: O[C@@H]1COC[C@H]1OCCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCO[C@@H]1COC[C@H]1OCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
Trans-4-[2-(benzyloxy)ethoxy]tetrahydrofuran-3-ol (2.20 g, 9.23 mmol) synthesized in (18a), ethyl vinyl ether (3.33 g, 46.2 mmol), and pyridinium paratoluene sulfonate (231 mg, 0.92 mmol) were dissolved in dichloromethane (22 ml), followed by stirring at room temperature for one hour. Triethylamine (187 mg, 1.84 mmol) was then added, and the resulting mixture was directly purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, V/V) to give trans-3-[2-(benzyloxy)ethoxy]-4-(ethoxymethoxy)tetrahydrofuran (2.88 g, yield 100%). This compound (1.55 g, 5.00 mmol) was dissolved in methanol (30 ml), to which 20% palladium hydroxide-carbon (155 mg) was added, followed by stirring at room temperature for one hour under a hydrogen atmosphere. The resulting solution was concentrated under reduced pressure to give the desired title compound (725 mg, yield 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[N:5]([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH:15]2[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]2[CH2:17]4)[CH2:21]3)[C:3]1=[O:25]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][C:2]1([CH3:26])[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH:15]2[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]2[CH2:17]4)[CH2:21]3)[C:3]1=[O:25]
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C/C=C/c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1CCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A solution of 4,4-dimethyl-1-[(2E)-3-phenylprop-2-en-1-yl]-2-(adamantan-2-yl)-1,2-diazetidin-3-one (30.0 mg, 0.0860 mmol) prepared in Example 260 in ethyl acetate (2 mL) was added with 10% palladium carbon (catalyst amount), and under a hydrogen atmosphere the resultant was stirred at room temperature for 1 hour. The reaction solution was filtered using celite, concentrated in vacuo, and the title compound (24.3 mg, 80.2%) was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=1)([O-])=O>C(O)(=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=2[C:18]([F:21])([F:19])[F:20])[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(SCc2cccnc2)c(C(F)(F)F)c1
Solvent: CC(=O)O
Product: Nc1ccc(SCc2cccnc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 41.7 %

Procedure:
To 3-[[[4-nitro-2-(trifluoromethyl)phenyl]sulfanyl]methyl]pyridine (2.2 g) was added acetic acid (22 ml), and reduced iron (6.6 g) was added to the mixture, and the mixture was stirred for 240 hours at room temperature. The mixture was filtered with Celite, and the mixture was washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[(3-pyridinylmethyl)sulfanyl]-3-(trifluoromethyl)aniline (0.83 g).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:31]([CH3:43])[CH:30]=3)[C:12]3[C:13]([F:28])=[CH:14][C:15]([O:20][CH2:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:44])=[N:6]1)([CH3:4])[CH3:3].Cl[CH:46](Cl)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:31]([CH3:43])[CH:30]=3)[C:12]3[C:13]([F:28])=[CH:14][C:15]([O:20][CH2:21][CH:22]4[CH2:23][CH2:24][N:25]([CH3:46])[CH2:26][CH2:27]4)=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:44])=[N:6]1)([CH3:1])[CH3:3]
Reactant: CC(Cl)Cl
Reactant: COc1c(OCC2CCNCC2)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1c(OCC2CCN(C)CC2)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To 3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-8-[(piperidin-4-ylmethyl)oxy]-3H-pyrazolo[3,4-c]iso-quinoline (159 mg, 0.26 mmol) was added dichloroethane (2 mL), 37% aqueous formaldehyde (40 μL, 0.52 mmol), and sodium triacetoxyborohydride (110 mg, 0.52 mmol). The mixture was stirred for 1 h at rt. Water and CH2Cl2 were added, and the layers were partitioned. The aqueous phase was extracted with CH2Cl2. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (90% CH2Cl2, 10% methanol) to provide 83.1 mg of To 3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-8-{[(1-methylpiperidin-4-yl)methyl]oxy}-3H-pyrazolo[3,4-c]isoquinoline (0.136 mmol, 52% yield) as a yellow film. 1H NMR (400 MHz, CDCl3): δ 7.49-7.32 (m, 7H), 6.96 (d, 1H), 6.81 (d, 1H), 5.15 (s, 2H), 3.98 (d, 2H), 3.89 (s, 3H), 3.10 (d, 2H), 2.87 (s, 3H), 2.40 (s, 3H), 2.36 (s, 3H), 2.17 (br t, 2H), 2.03-1.96 (m, 3H), 1.84 (s, 9H), 1.62 (m, 2H); MS (EI) for C37H43FN4O3: 611 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:13][NH:14][CH2:15][C:16]#[N:17].N1C(C)=CC=CC=1C>C(Cl)Cl>[C:16]([CH2:15][N:14]([CH3:13])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[OH:1])#[N:17]
Reactant: CNCC#N
Reactant: COc1ccc(C(=O)Cl)c(O)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(C(=O)N(C)CC#N)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-4-methoxybenzoyl chloride (22.19 g, 118.9 mmol) in 500 CH2Cl2 were added (methylamino)acetonitrile (10 g, 142.7 mmol) and 2,6-lutidine (19.1 g, 178.4 mmol). The reaction was stirred at rt overnight. The reaction mixture was then partitioned between EtOAc and 1(N) aq HCl. Organic layer washed with 1(N) aq HCl (2×), dried over Na2SO4 and concentrated to light yellow viscous material (24.63 g, 94%). This material was used in the next step without further purification.