Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>CC(C)=O>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2
Reactant: Fc1cccc(CBr)c1
Reactant: O=C1NCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1NCc2cc(OCc3cccc(F)c3)ccc21
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of 5-hydroxy-2,3-dihydro-isoindol-1-one (2.4 g, 16 mmol), potassium carbonate (2.4 g, 18 mmol) and 3-fluorobenzyl bromide (3.3 g, 18 mmol) in acetone (40 mL) was heated under reflux for 22 h. After cooling to RT the mixture was filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2:2N NH3-MeOH 90:10) to afford the title product (2.8 g, 67%) as a white solid. MS m/e=257.2 (M+).
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[CH2:9][CH:8]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[C:12]([CH2:18][C:19]#[N:20])[C:11]=2[CH3:21])[CH2:7][C:6](=[O:22])[C:5]=1[C:23](=[O:26])[CH2:24][CH3:25]>C1(C)C=CC=CC=1>[OH:3][C:4]1[CH2:9][CH:8]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[C:12]([CH2:18][C:19](=[O:1])[NH2:20])[C:11]=2[CH3:21])[CH2:7][C:6](=[O:22])[C:5]=1[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: [OH-]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CC#N)c2C)CC1=O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CC(N)=O)c2C)CC1=O
Yield: 40 %

Procedure:
Sodium hydroxide solution (10%, 4 ml) was added to a solution of 3-hydroxy-2-propionyl-5-(3-cyanomethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.5 g, 4.6 mmol) in toluene (10 ml) and the mixture was refluxed for 2 h. After cooling the toluene was separated and the aqueous layer acidified and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. Chromatography on silica gel (elution with an increasing gradient of ethylacetate in methylene chloride) gave 3-hydroxy-2-propionyl-5-(3-carbamoylmethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a pale solid (0.6 g, 40%). Proton magnetic resonance spectrum (CDCl3 ; 67 in ppm): 1.25 (3H,t,J6.5 Hz); 2.24 (3H,s); 2.28 (3H,s); 2.32 (3H,s); 2.2-4.2 (7H,m); 3.60 (2H,s); 5.3 (1H,brs); 6.0 (1H,brs); 6.85 (1H,s); 18.10 (1H,s). Infrared spectrum (CHCl3): ν max 1670 b cm-1. Also recovered from the chromatography was a sodium bicarbonate soluble fraction identified as 2-[3-(4-propionyl-5-hydroxycyclohex-3-one-4-enyl)-2,4,6-trimethylpheny]acetic acid (0.25 g, 17%) a colourless solid. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.2 (3H, t,J6.5 Hz); 2.13 (3H,s); 2.2 (3H,s); 2.26 (3H, s); 2.3-4.1 (7H,m); 3.50; (2H,s); 6.75 (1H,s). Infrared spectrum: ν max (NUjol) 3300-2500 b, 1680-1630 b cm-1.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:8][OH:9]>CO>[C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:8][OH:9]
Reactant: OC1CCCCC1
Agent: OO
Solvent: CO
Product: O=C1CCCCC1
Reaction time: 4 h

Procedure:
50 cc of methanol (40 g), 20 g of cyclohexanol, 6 cc of 36% w/v aqueous hydrogen peroxide and 3 g of catalyst are fed into a glass autoclave. After 4 hours at 88° C., 95.6% of the fed hydrogen peroxide has reacted. 5.6 g of cyclohexanone are obtained with an H2O2 yield of 90%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[N:11]([CH3:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:17][C:6]1[C:7]2[N:11]([CH3:12])[C:10]([C:13]([F:16])([F:14])[F:15])=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2c1nc(C(F)(F)F)n2C
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)c2c1nc(C(F)(F)F)n2C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a solution of 7-methoxy-3-methyl-2-trifluoromethylbenzimidazole (1.4 g) in chloroform (50 ml) under nitrogen was added N-bromosuccinimide (1.2 g). The mixture was stirred for 20 minutes before the reaction was quenched by the addition of 5% sodium metabisulphite solution (50 ml) and the organic layer was separated. Washing with water (50 ml), drying over anhydrous magnesium sulphate and removal of the solvent in vacuo gave an orange oil. Purification by flash chromatography eluting with 50% ethyl acetate in hexane gave the title compound as an orange solid (1.73 g).
Reaction SMILES: [AlH4-].[Li+].[NH2:3][C:4]1([C:14](O)=[O:15])[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1>O1CCCC1>[NH2:3][C:4]1([CH2:14][OH:15])[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6][CH2:5]1
Reactant: NC1(C(=O)O)CCC2(CC1)OCCO2
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1(CO)CCC2(CC1)OCCO2
Temperature: 0 °C
Yield: 87.6 %

Procedure:
Lithium tetrahydroaluminate (189 mg, 4.97 mmol) was added in portions to a solution of 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (from Aldrich, 0.50 g, 2.5 mmol) in tetrahydrofuran (20 mL) with stirring at about 0° C. The resulting mixture was slowly warmed to room temperature and stirred overnight. Fieser workup (0.2 mL H2O, 0.2 mL 10% NaOH, 0.6 mL H2O) was performed followed by filtration through Celite and concentrated to give 0.41 g of the desired product to be used without further purifications. LCMS calculated for C9H18NO3 (M+H)+: m/z=188.1. Found: 188.0.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[F:16][C:17]([F:50])([F:49])[C:18]1[CH:19]=[C:20]([CH2:28][O:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32](CC3C=[NH+]C=CC=3)[C@@H:31]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>CN(C)C=O.O>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:21]=[C:20]([CH2:28][O:29][C@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([CH2:2][C:3]3[CH:8]=[N:7][CH:6]=[CH:5][N:4]=3)[C@H:31]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:19]=[C:18]([C:17]([F:50])([F:16])[F:49])[CH:23]=1
Reactant: ClCc1cnccn1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CCCN(Cc3ccc[nH+]c3)[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CO[C@H]2CCCN(Cc3cnccn3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
2-(Chloromethyl)pyrazine (0.17 g), potassium carbonate (0.6 g) and the compound of Description 3 (0.35 g) were suspended in dimethylformamide (3 ml); the reaction mixture was heated at 60° C. for 12 h. The mixture was cooled, diluted with water (30 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford a brown oil. The product was purified by column chromatography on silica gel using a gradient elution of 15-35% ethyl acetate in hexane. This afforded the product as a white solid, which was recrystallised from pentane to give colourless crystals: mp 108°-110° C. 1H NMR (360 MHz, DMSO-d6) d 1.42-1.60 (2H, m NCH2CH2CH2), 1.77-1.92 (1H, m, NCH2CHH), 2.13-2.25 (2H, m, NCHH+NCH2CHH), 2.84-2.92 (1H, m, NCHH), 3.12 (1H, d, J=14.0 Hz, NCHH-pyrazine), 3.55 (1H, m, CHO), 3.63 (1H, m, CHPh), 3.78 (1H, d, 14.0 Hz, NCHH-pyrazine), 4.11 (1H, d, J=13.0 Hz, OCHHAr), 4.64 (1H, d, J=13.0 Hz, OCHHAr), 7.20-7.33 (3H, m, ArH), 7.49-7.56 (2H, m, ArH), 7.71 (2H, s, ArH), 7.93 (1H, s, ArH), 8.48-8.63 (3H, m, ArH); MS (CI+) 496 (M+ +1, 60%). Found: C, 60.90; H, 4.86; N, 8.48. Calcd. for C25H23F6N3O: C, 60.60; H, 4.68; N, 8.48%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[S:23]1[C:27](B(O)O)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2.C([O-])([O-])=O.[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:23]1[C:27]([C:2]2[CH:3]=[C:4]([N:8]3[C:16]4[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=4[C:10]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cc4ccccc4s3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), benzo[b]thien-2-ylboronic acid (100 mg, 0.557 mmol) and K2CO3 (116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(benzo[b]thiophen-2-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 7.8-7.91 (m, 3H), 7.78 (s, 2H), 7.61-7.7 (t, 1H), 7.3-7.4 (m, 4H), 7.18 (d, 1H), 7.02 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.81 (m, 1H), 3.5 (m, 1H), 3.2 (m, 1H), 3.18 (s, 3H), 3.01 (m, 1H), 2.41 (s, 3H).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([NH2:26])=[N:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2.[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46](Cl)=[O:47])=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[S:1]1[C:5]([C:6]2[C:7]([NH:26][C:46](=[O:47])[CH2:45][C:42]3[CH:41]=[CH:40][C:39]([O:38][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])=[CH:44][CH:43]=3)=[N:8][CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[N:11]=2)=[CH:4][C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cc4ccccc4s3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cc3ccccc3s2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
Under an argon atmosphere, to a mixture of 3-(benzo[b]thiophen-2-yl)-5-[4-(tert-butyldimethylsilyloxy)phenyl]pyrazin-2-amine (7h) (505 mg, 1.16 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyl dimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1). The resulting solid was recrystallized (n-hexane/ethanol) to give Compound 11h (294 mg, 431 μmol, 37.0%) as a colorless solid. Rf=0.19 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.19 (s, 6H), 0.25 (s, 6H), 0.96 (s, 9H), 0.97 (s, 9H), 3.71 (s, 2H), 6.82-6.89 (AA′BB′, 2H), 7.01-7.08 (AA′BB′, 2H), 7.26-7.42 (m, 4H, includes AA′BB′), 7.60-7.65 (m, 2H), 7.96 (d, 1H, J=7.9 Hz), 8.10-8.18 (AA′BB′, 2H), 9.02 (s, 1H), 10.82 (s, 1H), IR (KBr, cm−1) 525, 677, 692, 710, 727, 743, 779, 797, 808, 835, 922, 972, 1011, 1074, 1171, 1256, 1327, 1362, 1391, 1416, 1445, 1503, 1603, 1657, 859, 2886, 2930, 2957, 3059, 3161, 3211; HRMS (ESI+) m/z 704.2758 ([M+Na]+, C38H47N3NaO3SSi2+ requires 704.2769).
Reaction SMILES: [CH2:1]([N:8]1[CH:15](O)[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[O:26][C:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1.B(F)(F)F.CCOCC>ClCCl.CCOCC>[CH2:1]([N:8]1[C@@H:15]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][C:27]2=[O:26])[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)OC1=CCCCC1
Reactant: O=C1N(Cc2ccccc2)C(O)[C@@H]2CS[C@@H](c3ccccc3)N12
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCCCC1[C@H]1[C@@H]2CS[C@@H](c3ccccc3)N2C(=O)N1Cc1ccccc1
Temperature: 20 °C

Procedure:
To a solution of compound 6-benzyl-7-hydroxy-3-phenyl-(3S, 7aR)-perhydroimidazo[1,5-C][1,3]thiazol-5-one of formula (6) (0.326 parts, 1 mmol) in dichloromethane (10 parts) was added 1-trimethylsilyloxy-1-cyclohexene (0.340 parts. 2 mmol). Then the solution was cooled to 20° C., and Lewis acid for example BF3.Et2O (0.142 parts, 1 mmol) was added drop wise. The reaction mixture was stirred at 20° C. for 10 mints. and the reaction mixture was quenched with saturated ammonium chloride (10 parts). Then the organic layer was separated, concentrated and column purification with ethylacetate:pet.ether (15:85) as eluent provided compound 6-benzyl-7-(2-oxocyclohexyl)-3-phenyl-(3S, 7S, 7aR)-perhydroimidazo[1,5-C][1,3]-thiazol-5-one of formula (7d) (viscous liquid, 0.398 parts, 0.98 mmol) in98% yield.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[O:19]1[CH:7]2[CH2:6][C:5]3[C:10]([CH2:9][CH:8]12)=[CH:1][CH:2]=[CH:3][CH:4]=3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=CCc2ccccc2C1
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)CC1OC1C2

Procedure:
A solution of 1,4-dihydronaphthalene (32.5 g, 0.25 M) in 300 ml chloroform is cooled in an ice bath and, while stirring, is treated portionwise with 61 g (~20% excess) of 85% m-chloroperbenzoic acid. The mixture is stirred overnight at room temperature. After cooling in an ice bath, the solids are removed by filtration. The filtrate is washed twice with 5% K2CO3 solution, dried over MgSO4, filtered and the solvent is removed in vacuo leaving 37.7 g of yellow partially crystalline material. This is distilled from a small amount of solid K2CO3. After removal of some low boiling material, 16.0 g (44%) of the desired epoxide is collected, boiling point 95°-110° at 0.1 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:14]#[N:15])[C:10]([O:12][CH3:13])=[O:11].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:14]#[N:15])([C:10]([O:12][CH3:13])=[O:11])[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(C#N)Cc1ccccc1Cl
Reactant: COC(=O)CBr
Product: COC(=O)CC(C#N)(Cc1ccccc1Cl)C(=O)OC

Procedure:
In the same manner as Example 1-(b), 100 g of methyl 3-(2-chlorophenyl)-2-cyanopropionate was reacted with methyl bromoacetate to obtain methyl 4-(2-chlorophenyl)-3-cyano-3-methoxycarbonylbutyrate.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([O:18]C)=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[Li+].[OH-].Cl>C(OCC)(=O)C>[C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc2c(NC(C)(C)C)nccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nccc2c(C(=O)O)cccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 39.6 %

Procedure:
Methyl 1-(t-butylamino)isoquinoline-5-carboxylate (1.6 g, 6.20 mmol) obtained in Step (5) above was stirred in a solution of tetrahydrofuran (16 mL) and distilled water (16 mL). The reaction solution was added with LiOH (0.57 g, 13.6 mmol) and stirred for about 12 hours at 80° C. The reaction mixture was cooled to room temperature and adjusted to have a pH value in a range of 1˜2 by adding 1N aqueous HCl. The reaction mixture was diluted with ethyl acetate, and washed with distilled water. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.6 g, 40%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[CH3:37][O:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46]>>[C@@H:24]1([N:6]([CH2:5][C:4]2[CH:34]=[C:35]([C:41]3[CH:40]=[C:39]([O:38][CH3:37])[C:44]([O:45][CH3:46])=[C:43]([O:47][CH3:48])[CH:42]=3)[CH:36]=[CH:2][CH:3]=2)[C:7]([C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[C:21]([OH:23])=[O:22])=[O:8])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN(C(=O)c3cc(C(=O)O)c(C(=O)O)cc3C(=O)O)[C@H]3CCCc4ccccc43)c2)cc(OC)c1OC

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 3,4,5-trimethoxyphenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: ClC[CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2C(C3C=CC(O)=CC=3)=C(C(F)(F)F)C3C=CC(O)=CC=3[O:12]2)=[CH:7][CH:6]=1.[I-].[K+].O.C(OCC)(=[O:38])C>N1CCCCC1>[CH3:3][S:4]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1)=[O:38]
Reactant: Oc1ccc(C2=C(C(F)(F)F)c3ccc(O)cc3OC2c2ccc(SCCCl)cc2)cc1
Reactant: CCOC(C)=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCNCC1
Product: CS(=O)c1ccc(C=O)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
220 mg of 2-[4-(3-chloro-1-thiapropyl)-phenyl]-7-hydroxy-3-(4-hydroxyphenyl)-4-(trifluoromethyl)-2H-1-benzopyran in 2 ml of piperidine is mixed with 42.7 mg of potassium iodide and stirred for 6 hours at 100° C. After cooling, it is poured into water and shaken out three times with ethyl acetate. The combined organic phases are washed twice with water, dried on magnesium sulfate and concentrated by evaporation in a rotary evaporator. The purification of the product is carried out on silica gel with dichloromethane/methanol-9:1. 274 mg of product accumulates.
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:4]2=[CH:3][C:2]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([C:27]([N:9]2[CH2:8][CH2:7][CH2:6][N:5]3[N:1]=[C:2]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:4]3[CH2:10]2)=[O:28])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc2n(n1)CCCNC2
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)c1cc2n(n1)CCCN(C(=O)c1ccc(-c3ccccn3)s1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (0.033 g, 0.16 mmol) and 5-(2-pyridyl)thiophene-2-carboxylic acid (0.036 g, 0.18 mmol) in methylene chloride (1 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.07 g, 0.184 mmol) and N-methylmorpholine (0.053 mL, 0.48 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with methylene chloride (3 mL) and washed with saturated aqueous NaHCO3 (2 mL). The aqueous layer was extracted with additional methylene chloride (3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford Intermediate 31.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[O:14][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C:13]1[O:14][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][N:17]=1)=[O:11]
Reactant: CC(C)(C)c1cnc(CO)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)c1cnc(C=O)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a stirred solution of oxalyl chloride (45 mL, 90 mmole) at −78 deg C. under argon was added dropwise dimethyl sulfoxide (8.80 mL, 124 mmole). The reaction mixture was stirred at −78 deg C. for 10 min., and was treated with a solution of 2-hydroxymethyl-5-t-butyloxazole (11.7 g, 75.1 mmole) in anhydrous methylene chloride (30 mL) over 20 min. The mixture was stirred at this temperature for 1 hour, then triethylamine was added slowly (31.0 mL, 222 mmole), during which the reaction mixture became a yellowish slurry. After stirring at −78 deg C. for 20 min, the reaction mixture was warmed to room temperature, added with methylene chloride (100 mL) and stirred for 1 hour. The solid was filtered off and washed with EtOAc. The filtrate was washed with 5% aqueous citric acid (100 mL) and brine (50 mL), dried over MgSO4. Concentration and column chromatography (silica gel, EtOAc/hexane 1:4) afforded 2-formyl-5-t-butyloxazole as a light yellow oil (10.1 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[OH:32][CH:33]([CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])[C:34]([NH:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][C:44](O)=[O:45])=[O:35].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(#N)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:44]([CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][NH:36][C:34](=[O:35])[CH:33]([OH:32])[CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])=[O:45])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
22 is prepared similarly to 18 starting from 100 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one, 122 mg of {2-[2-(2,3,4,5,6-pentahydroxyhexanoylamino)ethoxy]ethoxy}acetic acid 20, 93 μl of diisopropylcarbodiimide and 65 mg of hydroxybenzotriazole in 2 ml of dimethylformamide and 1 ml of acetonitrile. This gives 22:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1F)=O.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][O:10][C:7]1[CH:6]=[C:5]2[C:4]([C:2]([CH3:1])=[N:14][NH:15]2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: COc1ccc(C(C)=O)c(F)c1
Solvent: CCO
Solvent: O
Product: COc1ccc2c(C)n[nH]c2c1
Temperature: 150 °C
Yield: 60 %

Procedure:
To a solution of 2-fluoro-4-methoxyacetophenone (1.90 g, 11.3 mmol) in ethanol (20 ml) was added hydrazine hydrate (1.4 ml, 45.0 mmol) and heated at reflux temperature for 6 h. This mixture was evaporated to a residue and ethylene glycol (10 ml) was added. The mixture was heated at 150° C. for 18 h, cooled to room temperature, diluted with water (50 ml), and extracted with dichloromethane (3×60 ml). The combined extracts were washed with brine (10 ml), dried (MgSO4) and evaporated to a residue, which was crystallized from ethyl acetate to give a solid (1.1 g, 59%): MS(ES) m/z 163 (M+).