Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.[OH:10][C:11]1[C:20]([CH3:21])=[C:19]2[C:14]([CH:15]=[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17](=[O:22])[O:18]2)=[CH:13][C:12]=1[O:34][CH:35]([CH3:37])[CH3:36].ClC(Cl)(Cl)C(=N)O[C@H:42]1[C@@H:47]2[O:48][C:49](=[O:51])[O:50][C@@H:46]2[C@@H:45]([O:52][CH3:53])[C:44]([CH3:55])([CH3:54])[O:43]1.C(N(CC)CC)C>C(Cl)Cl>[CH:35]([O:34][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([CH3:21])[C:11]=1[O:10][C@H:42]1[C@@H:47]3[O:48][C:49](=[O:51])[O:50][C@@H:46]3[C@@H:45]([O:52][CH3:53])[C:44]([CH3:55])([CH3:54])[O:43]1)[O:18][C:17](=[O:22])[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:15]2)([CH3:37])[CH3:36]
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Reactant: Cc1c(O)c(OC(C)C)cc2cc(NC(=O)OCc3ccccc3)c(=O)oc12
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](Oc2c(OC(C)C)cc3cc(NC(=O)OCc4ccccc4)c(=O)oc3c2C)OC1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
Boron trifluoride etherate (1.30 μL, 0.010 mmol) was added to 23c (13.0 mg, 0.034 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (83.0 mg, 0.23 mmol) in anhydrous CH2Cl2 (1.30 mL). After stirring at room temperature for 1.5 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to give 25c as a colorless foam (19.0 mg, 95%): 1H NMR (CDCl3, 500 MHz) 8.17 (s, 1H), 7.51 (s, 1H), 7.35 (s, 1H), 7.34-7.33 (m, 4H), 6.74 (s, 1H), 5.54 (dd, J=9.2, 1.2 Hz, 1H), 5.16 (s, 2H), 4.87-4.84 (m, 1H), 4.73 (dd, J=7.9, 1.9 Hz, 1H), 4.51 (quintet, J=6.0 Hz, 1H), 3.52 (s, 3H), 3.28 (d, J=4.8 Hz, 1H), 2.33 (s, 3H), 1.80-1.77 (m, 6H), 1.30 (s, 3H), 1.27 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 161.6, 158.6, 153.2 153.1, 147.1, 146.8, 142.5, 135.5, 128.7, 128.6, 128.3, 123.3, 121.4, 121.1, 116.2, 108.6, 99.4, 83.1, 79.9, 76.1, 74.7, 72.2, 68.0, 60.5, 27.1, 25.6, 21.9, 21.6, 21.0, 10.1; IR (film) νmax 2955, 2922, 2853, 2359, 2339, 1819, 1711, 1520, 1464, 1375, 1171, 1111, 1034, 962, 822, 766 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C30H33NO11, 584.2132; found, 584.2111.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][O:4][C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:19]([O-])=O)[CH:18]=[C:13]3[C:12]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[N:11]2)=[CH:7][CH:6]=1>CCO.O.CCOC(C)=O.O.[Fe]>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:19])[CH:18]=[C:13]3[C:12]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[N:11]2)=[CH:27][CH:28]=1
Reactant: COCCOc1nn(Cc2ccc(OC)cc2)c2ncc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COCCOc1nn(Cc2ccc(OC)cc2)c2ncc(N)cc12
Temperature: 85 °C
Reaction time: 5 h
Yield: 91.9 %

Procedure:
Fe (0) (0.251 g, 4.49 mmol) and ammonium chloride (0.600 g, 11.2 mmol) were added to 1-(4-methoxybenzyl)-3-(2-methoxyethoxy)-5-nitro-1H-pyrazolo[3,4-b]pyridine (402 mg, 1.12 mmol) in EtOH (8 mL) and water (3.7 mL). The mixture was stirred at 85° C. for 5 hours. The mixture was diluted with EtOAc-water and filtered through GF/F paper. The filtrate was diluted with aqueous bicarbonate and extracted with EtOAc (3×12 mL), dried over sodium sulfate, decanted and concentrated to provide 1-(4-methoxybenzyl)-3-(2-methoxyethoxy)-1H-pyrazolo[3,4-b]pyridin-5-amine (338 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](Cl)[C:9]3=[CH:13][C:14]([CH3:16])=[CH:15][N:8]3[CH2:7][C:6]=2[CH:17]=1.Cl.Cl.[CH3:20][C:21]([CH3:33])([CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:22]([O:24][CH3:25])=[O:23].C(NC(C)C)(C)C.C(#N)C>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([N:30]3[CH2:29][CH2:28][N:27]([CH2:26][C:21]([CH3:33])([CH3:20])[C:22]([O:24][CH3:25])=[O:23])[CH2:32][CH2:31]3)[C:9]3=[CH:13][C:14]([CH3:16])=[CH:15][N:8]3[CH2:7][C:6]=2[CH:17]=1
Reactant: Cc1cc2n(c1)Cc1cc(Cl)ccc1N=C2Cl
Reactant: COC(=O)C(C)(C)CN1CCNCC1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(Cl)cc3Cn3cc(C)cc32)CC1
Reaction time: 26 h
Yield: 98.9 %

Procedure:
Heat a mixture of 7,11-dichloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (10.0 g, 37.7 mmol), methyl 2,2-dimethyl-3-(piperazin-1-yl)-propionate dihydrochloride (19.4 g, 71.0 mmol), diisopropylamine (22.9 g, 226 mmol), and acetonitrile (80 g) at 80° C. to 85° C. for 22 hr. to 26 hr. Cool to 30° C. to 40° C. and add ethyl acetate (80 g). Add water (80 g) dropwise. Stir 40 min. to 60 min. and separate the layers. Extract the aqueous layer with ethyl acetate (60 g to 80 g). Wash the combined organic layers with 25% aqueous sodium chloride (2×40 g). Concentrate the organic layer to a total of 1.5 volumes and 3.5 volumes while maintaining the temperature below 50° C. Add heptane (41 g to 55 g) at 40° C. to 50° C.)\ and stir for 2 hr. to 3 hr. Concentrate to a total of 1.5 volumes to 3.0 volumes while maintaining the temperature below 50° C. Cool to 0° C. to 10° C. and stir for 2 hr. to 3 hr. Filter, wash the filtercake with heptane (3.0 g to 10.0 g), and dry under vacuum, at below 60° C., to afford the title compound (16.0 g, 94.7% w/w % assay, 94% yield) as a light, yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.[CH2:17]([Sn](CCCC)(CCCC)CCCC)[CH:18]=[CH2:19].[F-].[Cs+].O1CCOCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN(C=O)C>[CH2:19]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[CH:18]=[CH2:17]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1cccc2c1CCOC2C1=NCCN1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C=CCc1cccc2c1CCOC2C1=NCCN1
Temperature: 160 °C

Procedure:
To a mixture of 2-(5-chloroisochroman-1-yl)-4,5-dihydro-1H-imidazole (50 mg), allyltributyltin (69.9 mg), CsF (70.6 mg) and bis(tri-t-butylphosphine)palladium (3.24 mg) were added dioxane (2 ml) and DMF (0.5 ml). The reaction mixture was degassed with N2 and heated in a microwave oven for 30 min at 160° C. The title compound was purified by applying methods F and G. (Yield 5.8 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[N:18][CH:19]=1)[CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12])[CH3:2].B1C2CCCC1CCC2.Cl[C:32]1[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[N:18][CH:19]=1)[CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH2:12][C:32]1[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=1)[CH3:2]
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: C=CCCC(=O)CC(CC(=O)OCC)c1cnc(C)nc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Product: CCOC(=O)CC(CC(=O)CCCCc1cc(N)nc(N)n1)c1cnc(C)nc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The ester 15-5 (400 mg, 1.38 mmol) was treated with 9-BBN (8.28 mL, 4.14 mmol; 0.5M in TBF) at room temperature for 16 hours. To this solution was added Pd(OAc)2 (31 mg, 0.14 mmol), 6-chloro-2,4-diaminopyrimidine (219 mg, 1.52 mmol), K2CO3 (381 mg, 2.75 mmol), 1,1′-bis(diphenylphosphino)-ferrocene (76 mg, 0.14 mmol) and DMF (15 mL). The mixture was degassed with argon for 10 minutes then heated to 80° C. for 24 hours. The reaction mixture was cooled and stirred with ethanolarnine (5 mL) for 2 hours. The mixture was partitioned between 1N HCl and EtOAc. The aqueous layer was made basic with K2CO3 and extracted with EtOAc (5×). The organic layers were washed with brine, dried (MgSO4) and concentrated. Purification by silica gel chromatography (20% MeOH in CHCl3) afforded the title compound 15-6 as an oil.
Reaction SMILES: [CH:1]([C:3]1[N:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13])=O.[CH3:16][C:17]([S:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].OS([O-])(=O)=O.[K+]>ClCCl>[C:17]([S:20](/[N:22]=[CH:1]/[C:3]1[N:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13])=[O:21])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)S(N)=O
Reactant: COC(=O)c1cc2n(c1C=O)CCCC2
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1cc2n(c1/C=N/S(=O)C(C)(C)C)CCCC2
Temperature: 25 °C
Reaction time: 10 h
Yield: 82.7 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with methyl 3-formyl-5,6,7,8-tetrahydroindolizine-2-carboxylate (10.0 g, 48.3 mmol, 1.0 eq.), 2-methylpropane-2-sulfinamide (11.7 g, 96.6 mmol, 2.0 eq.), KHSO4 (32.8 g, 241.5 mmol, 5 eq.), and dichloromethane (250 mL). The mixture was stirred at room temperature for 10 h. It was then filtered and filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 1:3 ethyl acetate/petroleum ether to afford 238a (12.4 g, 83%) as a yellow solid. MS: [M+H]+ 311.3.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].Br[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=CCCCCCCc1ccccc1
Product: O=[N+]([O-])c1ccc(CCCCCCCCc2ccccc2)cc1
Yield: 64.4 %

Procedure:
General procedure M was used to convert 5.31 mmol of 15a and 5.84 mmol of 1-bromo-4-nitrobenzene to 3.42 mmol (71%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][CH2:21]O)[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[CH2:21][CH2:20][N:7]3[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CCO)c12
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
To a solution of 2-{4-chloro-2-[(2,4-dichlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}ethanol (Reference Example 19; 66 mg, 0.155 mmol) in tetrahydrofuran (0.8 mL) were added diisopropylethylamine (0.053 ml, 0.310 mmol) and methanesulfonyl chloride (0.013 ml, 0.170 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. Additional diisopropylethylamine (0.053 ml, 0.310 mmol) and methanesulfonyl chloride (0.013 mL, 0.170 mmol) were added at 0° C., followed by stirring at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-25% ethyl acetate/n-hexane gradient mixture. The desired fractions were concentrated in vacuo, and the resulting solid was washed with n-hexane to give the title compound (15 mg, 0.0360 mmol, 23%) as a colorless solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]([NH:30][C:31]([C:33]1[CH:42]=[CH:41][C:36]([CH2:37][N:38]=[N+]=[N-])=[CH:35][CH:34]=1)=[NH:32])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C(Br)C1C=CC=CC=1)#N>C1COCC1>[NH2:38][CH2:37][C:36]1[CH:41]=[CH:42][C:33]([C:31](=[NH:32])[NH:30][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[CH:34][CH:35]=1
Reactant: [N-]=[N+]=NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1
Agent: N#CC(Br)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1

Procedure:
26.3 g (100 mmol) triphenylphosphine was added at room temperature to the 4-(benzyloxycarbonylamidino) benzyl azide from (iii) above dissolved in 160 ml THF. After 16 h an additional 6.6 g (25 mmol) triphenylphosphine was added and the solution was allowed to stand for 4 h before removal of the solvent in vacuo. The residue was dissolved in methylene chloride and extracted with 2M HCl. The aqueous phase was washed with methylene chloride and ether and was subsequently made alcaline with 3.75M sodium hydroxide solution. Extraction with methylene chloride followed by drying (K2CO3) and removal of the solvent in vacuo gave 20 g (The total yield starting from cyanobenzyl bromide is 28%) of a yellow oil which solidified on standing.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([C@@H:23]([CH3:35])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH2:20][CH2:21][CH3:22])[C:10](=[O:36])[CH2:9]1)=O)(C)(C)C.[ClH:37].C(=O)([O-])[O-].[Na+].[Na+]>>[ClH:37].[ClH:37].[CH3:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C@@H:23]([N:19]([CH2:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15][N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][C:10]2=[O:36])[CH3:35])=[CH:26][CH:27]=1)(=[O:32])=[O:33]
Reactant: CCCN(CCCCN1CCCN(C(=O)OC(C)(C)C)CC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN(CCCCN1CCCNCC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(4-{[(S)-2-(4-methanesulfonylphenyl)-1-methylethyl]-propylamino}butyl)-3-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.9 g, 1.75 mmole) and 3N hydrochloric acid (4 mL) was warmed to 50° C. The reaction mixture was stirred at room temperature for 30 minutes, and the pH was adjusted to 10 with saturated sodium carbonate. The mixture was extracted with ethyl acetate (30 mL), and the organic phase was dried (magnesium sulfate), and concentrated. The residue was dissolved in diethyl ether (10 mL) and 1M hydrogen chloride in diethyl ether (2 mL) was added. The precipitate was collected, washed with diethyl ether and hexane, and dried in vacuo to give 1-(4-{[(S)-2-(-4-methanesulfonyl-phenyl)-1-methylethyl]propylamino}butyl)-[1,4]diazepan-2-one, dihydrochloride salt (0.49 g), 149, M+H=424.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])(C(C)(C)C)(C)C.C(O)(=O)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N:11]([CH2:10][CH2:9][OH:8])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1cc2c(s1)-c1ccccc1OCC2)N(CCO)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of N-(2-(tert-butyldimethylsilyloxy)ethyl)-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (0.030 g, 0.058 mmol) in acetic acid (0.0033 mL, 0.058 mmol) and tetrahydrofuran (0.3 mL, 4 mmol) was added 1 M of tetrabutylammonium fluoride hydrate in tetrahydrofuran (0.058 mL). The reaction was stirred at room temperature w/TLC and LC/MS monitor. Deprotection was complete after overnight stirring. The reaction mixture was concentrated in vacuo, taken into ethylacetate and washed with water/saline and concentrated to a glassy residue, which was purified by MPLC, eluting with ethylacetate/hexanes, gradient 0-50% B to give 22.4 mg of 106 (yield 40%). MS: (ESI+) 401
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].ClC1C(CC)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:20][CH2:21][C:22](=[O:23])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NCC(=O)c1ccccc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: Cl
Product: Cc1c(N[C@@H](C(=O)NCC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Yield: 91.7 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (6.0 g, 22.33 mmol) and 2-amino-1-phenylethanone hydrochloride (3.83 g, 22.33 mmol) were reacted using the techniques described in for the preparation of intermediate 11c to furnish the title compound (7.9 g, 92%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.03 (d, J=8 Hz, 2H), 7.92 (br s, 1H), 7.68 (t, J=8 Hz, 1H), 7.54-7.58 (m, 3H), 6.70 (d, J=8 Hz, 1H), 5.63 (d, J=6 Hz, 1H), 4.79-4.81 (m, 2H), 4.70 (d, J=4 Hz, 1H), 4.38-4.42 (m, 1H), 4.08-4.12 (m, 1H), 2.38 (s, 3H), 1.33 (d, J=6 Hz, 3H).
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[F:11][C:12]([F:30])([F:29])[CH:13]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=O.S(=O)(=O)(O)O>C(OCC)C>[F:11][C:12]([F:29])([F:30])[CH:13]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:14][CH2:15][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: CCCCC(CC(=O)c1ccc(OC)cc1)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCC(CCc1ccc(OC)cc1)C(F)(F)F
Yield: 100.7 %

Procedure:
To a mixture of 0.1 g of aluminum lithium hydride and 2.5 ml of dry diethyl ether, 0.275 g of aluminum chloride and 2.5 ml of dry diethyl ether were added under stirring. To the resultant mixture, a solution of 0.48 g of the above-prepared 4-(3-trifluoromethylheptanoyl)anisole in 2.5 ml of diethyl ether, followed by heat-refluxing for 30 minutes. After the reaction, 5 ml of 6N-sulfuric acid was added to the reaction mixture, followed by extraction with diethyl ether. The ether layer was dried with anhydrous sodium sulfate, followed by distilling-off of the solvent to obtain 0.46 g of crude 4-(3-trifluoromethylheptyl)anisole
Reaction SMILES: C([Li])CCC.I[C:7]1[C:8]2[CH:15]=[CH:14][N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:9]=2[N:10]=[CH:11][N:12]=1.[CH:26]1([CH:32]=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH:26]1([CH:32]([C:7]2[C:8]3[CH:15]=[CH:14][N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:9]=3[N:10]=[CH:11][N:12]=2)[OH:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=CC1CCCCC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)ncnc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CCCCC3)ncnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
n-Butyllithium (1.6 M solution in hexane, 0.23 mL, 0.380 mmol) was gradually added dropwise to 4-iodo-7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidine (126 mg, 0.310 mmol) in tetrahydrofuran (1.5 mL) cooled to −78° C., and the reaction mixture was stirred at −78° C. for 30 minutes. After addition of cyclohexanecarbaldehyde (42 μL, 0.35 mmol) in tetrahydrofuran (1.5 mL), the reaction mixture was gradually warmed from −78° C. to room temperature and stirred for one day. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hi Flash column amino type manufactured by Yamazen Corporation: hexane/ethyl acetate=10/1→7/1→4/1 (v/v)) to give the title compound as a colorless oil (65.5 mg, yield 55%).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][N:27]1[C:31](=[O:32])[C:30]2[C:33]([CH:39]([CH3:41])[CH3:40])=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:29]=2[S:28]1(=[O:43])=[O:42].O>CO.CN(C=O)C>[CH:39]([C:33]1[C:30]2[C:31](=[O:32])[N:27]([CH2:26][O:12][C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:10]=3)[S:28](=[O:43])(=[O:42])[C:29]=2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=1)([CH3:41])[CH3:40]
Reactant: O=C1CC(c2ccccc2)=NN1c1ccccc1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(-c3ccccc3)nn1-c1ccccc1)C2=O
Temperature: 20 °C
Reaction time: 21 h
Yield: 52.6 %

Procedure:
A mixture 2,4-dihydro-2,5-diphenyl-3H-pyrazol-3-one (Formula III: R1 =R2 =Ph; R3 =H) (651 mg; 2.76 mmol) and Cs2CO3 (450 mg; 1.38 mmol) in methanol (12 ml) was stirred at 20° C. for 5 hours. The solvent was concentrated in vacuo, and the residue was dried in vacuo overnight. To a solution of the above residue in 12 ml of DMF was added 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (800 mg, 2.3 mmol) and the resulting mixture was stirred at room temperature (20° C.) for 21 hours and then poured into water. The above mixture was extracted with ether (3×) and the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue (yellow foam, 854 mg, 74%) was purified by flash column chromatography (silica gel; 18-50% ethyl acetate in hexane) and by recrystallization from ethyl acetate/hexane to afford 609 mg of 4-isopropyl-6-methoxy-2-(1,3-diphenylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =R2 =Ph; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white foam, m.p. 62°-76° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Yield: 21.9 %

Procedure:
A solution of 4-hydroxybenzoic acid (5.52 g; 0.40 mole), benzyl bromide (11.89 mL; 0.1 mol) and tricaprylylmethylammonium chloride (100 mg, Aliquat 336® Henkel Corporation) in methanol (50 mL) was refluxed in presence of potassium carbonate (16.52 g) for 12 hours. The reaction mixture was then poured slowly into a solution of 2N hydrochloric acid solution. The precipitated acid was filtered, dried and recrystallized from hexane/ethyl acetate to give 5 g of 4-benzyloxybenzoic acid (yield=55%).