Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:21]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3N=N[N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:21]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1Cc1cc(-c2cccnc2)no1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1Cc1cc(-c2cccnc2)no1

Procedure:
A mixture of 8-(ethoxymethyl)-5,6-dimethyl-7-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridine (0.1712 g, 0.423 mmol) and triphenylphosphine (0.120 g, 0.466 mmol) in toluene (2 mL) was heated at reflux for five days. The solvent was removed and the resulting brown solvent was dissolved in 1 M hydrogen chloride in methanol (5 mL). The solution was heated at reflux for four hours and then concentrated to an oil. The oil was dissolved in hot water. A precipitate formed and was isolated by filtration. The filtrate was washed five times with dichloromethane and then adjusted to pH 14 with 50% (w/w) aqueous sodium hydroxide, resulting in a brown precipitate. The mixture was extracted with several portions of dichloromethane that were combined, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The resulting white solid was triturated with diethyl ether and dried to yield 2-(ethoxymethyl)-6,7-dimethyl-1-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]pyridin-4-amine as a white powder, mp 189.0-191.0° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH:12]=[CH:13][CH:14]=2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28][OH:29])=[CH:24][CH:23]=1.Cl.C(Cl)(Cl)Cl.CO>C(O)CCC>[F:20][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][OH:29])=[CH:30][CH:31]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(OCCO)cc1
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Cl)ncc2F)c1
Agent: Cl
Solvent: CO
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCO)cc3)ncc2F)c1
Temperature: 25 °C
Yield: 18.6 %

Procedure:
To a solution of N-{3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}prop-2-enamide (0.05 g) and 2-(4-aminophenoxy)ethanol (0.031 g) in 1-butanol (2 mL), was added HCl (0.3 mg). The reaction mixture was heated to reflux for 5 hr. Completion of reaction was monitored by TLC using chloroform:methanol (9:1) as mobile phase. After completion, the reaction mixture was allowed to cool at room temperature. The reaction mixture was quenched in water and neutralized with sodium bicarbonate. The mixture was extracted in ethyl acetate, organic layer washed with brine, dried over sodium sulfate and concentrated completely under reduce pressure at 50° C. The obtained semisolid was purified by preparative HPLC to give 13 mg of N-{3-[(5-fluoro-2-{[4-(2-hydroxyethoxy)phenyl]amino}pyrimidin-4-yl)amino]phenyl}prop-2-enamide. M+1=410.1 1H NMR (DMSO-d6, 400 MHz) 3.671-3.694 (t, 2H, J=4.4), 3.880-3.906 (t, 2H, J=5.2), 4.83 (br, 1H), 5.741-5.771 (dd, 1H, J=2.8, 8.4), 6.237-6.284 (dd, 1H, J=2, 15.2), 6.460-6.527 (dd, 1H, J=10, 6.8), 6.749-6.771 (d, 2H, J=8.8), 7.253-7.293 (t, 1H, J=8), 7.426-7.447 (d, 1H, J=8.4), 7.473-7.492 (d, 1H, J=7.6), 7.527-7.550 (d, 2H, J=9.2), 7.998 (s, 1H), 8.062-8.071 (d, 1H, J=3.6), 9.071 (s, 1H), 9.381 (s, 1H), 10.206 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][NH:4][N:3]=1.O1CCCC1.C(=O)(O)[O-].[Na+].[F:20][C:21]([F:31])([F:30])[CH2:22][CH2:23][S:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>O>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][CH3:9])[C:27](=[O:28])[CH2:26][CH2:25][S:24][CH2:23][CH2:22][C:21]([F:31])([F:30])[F:20])=[CH:5][NH:4][N:3]=1
Reactant: O=C(Cl)CCSCCC(F)(F)F
Reactant: CCNc1c[nH]nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(C(=O)CCSCCC(F)(F)F)c1c[nH]nc1Cl
Temperature: 5 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
A 500-mL 3-neck flask was charged with 3-chloro-N-ethyl-1H-pyrazol-4-amine (3.25 g, 22.3 mmol), tetrahydrofuran (80 mL) and water (80 mL). The resulting suspension was cooled to 5° C. and sodium bicarbonate (3.75 g, 44.6 mmol) was added, followed by dropwise addition of 3-((3,3,3-trifluoropropyl)thio)propanoyl chloride (5.42 g, 24.56 mmol) at <5° C. The reaction mixture was stirred at <10° C. for 3 hours. The reaction mixture was poured into water (100 mL) and the mixture was extracted with dichloromethane (150 mL×3). The combined organics were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to afford crude product as a light brown oil, which was purified by flash column chromatography using 0-5% methanol/dichloromethane as eluent. The fractions containing pure product were concentrated to give the desired product as a white solid (3.60 g, 48%): mp 67-68° C.; 1H NMR (400 MHz, CDCl3) δ 11.55 (bs, 1H), 7.65 (s, 1H), 3.73-3.68 (dd, J1=7.2, J2=14.0, 2H), 2.86-2.82 (t, J=7.2, 2H), 2.67-2.63 (t, J=8.0, 2H), 2.45-2.30 (m, 4H), 1.16-1.12 (t, J=7.2, 3H); 13C NMR (101 MHz, CDCl3) δ 171.87, 137.89, 128.40, 125.97 (q, J=277.4 Hz), 120.81, 44.01, 34.31 (q, J=27.3 Hz), 33.97, 27.30, 24.08 (q, J=3.4 Hz), 12.77; ESIMS m/z 330 ([M+H]+).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][CH:6]1CCCCC1)=C.C([O:14][CH:15]=[CH2:16])=C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=[O:19].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:6][CH:5]([O:14][C:15]([CH3:16])=[O:19])[CH2:4][O:3][CH3:1]
Reactant: C=COC=C
Reactant: C=COCCC1CCCCC1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCC(C)OC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Subsequently, 5.78 g of 2-cyclohexylethyl vinyl ether as the vinyl ether compound and 1.45 g of 2% camphorsulfonic acid (PGMEA solution) were added to Solution p-1, and the mixture was stirred at room temperature for 4 hours. After 1.05 g of 6% triethylamine (PGMEA solution) was added and the mixture was stirred for a while, the reaction solution was transferred to a separating funnel containing 165 mL of ethyl acetate, and the organic layer was washed with 200 mL of distilled water three times. The organic layer was concentrated by an evaporator to remove ethyl acetate, and this reaction solution was added dropwise in 2 L of hexane. A part of the obtained precipitate was sampled for NMR measurement, and the remaining was dissolved in 70 g of PGMEA. From the obtained solution, the low boiling point solvent was removed by an evaporator to obtain 105.6 g of a PGMEA solution (32.7 mass %) of Resin (P-1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([OH:12])[CH:5]=1.[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH2:16][CH:15]=[CH2:14])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(OC)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cc(OC)cc(C(=O)OC)c1

Procedure:
3-Hydroxy-5-methoxybenzoic acid methyl ester is reacted with allyl bromide in the presence of potassium carbonate to give 3-allyloxy-5-methoxybenzoic acid methyl ester. B.p. 128°-30°C/0.4 mmHg. The ester is hydrolized to the corresponding acid with 20% potassium hydroxide in aqueous ethanol. The acid (m.p. 85°-7°C) when heated for 2 hours at 230°C undergoes Claisen rearrangement and cyclization to the title compound which melts at 195°-7°C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[OH:38][C:34]1[CH:33]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:37]=[CH:36][CH:35]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3cccc(O)c3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 120 mg, 0.298 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (40 mg, 0.3665 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 70% yield (0.103 g, 0.2087 mmol).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[N+:14]([O-:16])=[O:15])[CH2:9]1)C1C=CC=CC=1.[Cl:17]CCOC(Cl)=O>ClCCCl>[ClH:17].[N+:14]([CH:11]1[CH:12]2[CH:10]1[CH2:9][NH:8][CH2:13]2)([O-:16])=[O:15]
Reactant: O=[N+]([O-])C1C2CN(Cc3ccccc3)CC21
Reactant: O=C(Cl)OCCCl
Solvent: ClCCCl
Product: Cl
Product: O=[N+]([O-])C1C2CNCC21
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane (2.47 g, 11.3 mmol) in 1,2-dichloroethane (5 ml) was added chloroethylchloroformate (1.83 ml, 16.9 mmol) at 0° C. The reaction mixture was heated to 55° C. for 4 h. Further chloroethylchloroformate (0.5 ml) was added and heating continued for 2 h. The reaction mixture was evaporated to dryness. MeOH (15 ml) was added and the reaction mixture was heated at 65° C. for 3 h. Conc. HCl (1 ml) was added and the reaction stirred at r.t. for 2 h. A grey precipitate had formed, this was isolated by filtration and washed with Et2O. The title compound was obtained as a grey powder (464 mg, 25%). 1H NMR (300 MHz, d6-DMSO) δ: 2.90 (2H, s), 3.3-3.6 (4H, m), 4.75 (1H, s), 9.50 (2H, br s).
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:16]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:11][CH:10]=1)[Si](C(C)(C)C)(C)C.[OH-].[Na+]>CCO>[OH:1][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:16]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1C(c2ccc(OC)cc2)c2ccccc2C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1C(c2ccc(O)cc2)c2ccccc2C1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of ethyl(1RS,2SR,3SR)-1-(4-t-butyldimethylsiloxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylate (723 mg, 1.4 mmol) in EtOH (20 ml) was added 1M NaOH (1.6 ml, 1.6 mmol), and the resulting mixture was stirred at room temperature for 30 min. The mixture was then partitioned between 3M HCl and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to afford the title compound (554 mg, 100%).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH3:7][O:8][C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13]>O.CC(C)=O>[CH3:7][O:8][C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]([OH:2])=[O:13]
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(=O)O)c([N+](=O)[O-])c1OC

Procedure:
A solution of 823 g. potassium permanganate in about 8.5 liters of H2O was gradually added to a refluxing solution of 3,4-dimethoxy-2-nitrobenzaldehyde (550 g., 2.60 moles) in 5.6 liters of acetone. The reaction mixture was refluxed for four more hours, then filtered through diatomaceous earth while hot and the filter cake washed with hot water. The acetone was removed in vacuo and a small amount of unreacted solid was filtered off. The aqueous solution was acidified with 2 N hydrochloric acid (1.8 liters) to yield 505 g. (85%) of the essentially pure title compound. Recrystallization from water afforded colorless crystals, M.P. 200°-202° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.C[Si](C)(C)O[CH2:43][C:44]([O:46][Si](C)(C)C)=[O:45].FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.C(Cl)Cl>C(OCC)(=O)C>[O:33]=[C:31]1[O:30][N:29]=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:15][C:12]3[C:13](=[O:14])[N:8]([CH:5]4[CH2:6][CH2:7][C:2]5([O:46][C:44](=[O:45])[CH2:43][O:1]5)[CH2:3][CH2:4]4)[C:9]4[N:10]([N:37]=[CH:38][N:39]=4)[C:11]=3[CH2:34][CH2:35][CH3:36])=[CH:21][CH:20]=2)[NH:32]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: C[Si](C)(C)OCC(=O)O[Si](C)(C)C
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCC(=O)O3)c2ncnn12
Temperature: -78 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), trimethylsilyl [(trimethylsilyl)oxy]acetate (0.16 mL), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.18 mL) and methylene chloride (5 mL) was stirred at −78° C. for 1 hr, and then at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.066 g, 26%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:40])[CH:13]([C:23]3[CH:28]=[CH:27][C:26]([O:29][Si](C(C)C)(C(C)C)C(C)C)=[CH:25][CH:24]=3)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[OH:29][C:26]1[CH:27]=[CH:28][C:23]([CH:13]([C:12]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)=[O:40])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:24][CH:25]=1
Reactant: CC(C)[Si](Oc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-(triisopropyl silyloxy)phenyl)propylcarbamate (E7) in THF at 0° C. was added TBAF, and the solution was stirred for 45 min at 0° C. The compound was poured into EtOAc and washed with NH4Cl(sat), dried (Na2SO4), filtered, and evaporated. Column chromatography 6% MeOH/CH2Cl2 gave pure tert-butyl 2-(4-hydroxyphenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E8).
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH2:9][F:10])[CH:8]=1.[OH-].[Na+].[F:14][C:15]([F:22])([F:21])[C:16]([F:20])=[C:17]([F:19])[F:18]>CC(C)=O.O>[F:18][C:17]([O:11][C:5]1[CH:4]=[C:3]([CH2:2][F:1])[CH:8]=[C:7]([CH2:9][F:10])[CH:6]=1)([F:19])[CH:16]([F:20])[C:15]([F:22])([F:21])[F:14]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: Oc1cc(CF)cc(CF)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: FCc1cc(CF)cc(OC(F)(F)C(F)C(F)(F)F)c1

Procedure:
490 g of 3,5-bis-fluoromethyl-phenol were placed in 1000 ml of acetone together with 50 g of 50% by weight aqueous sodium hydroxide solution, and hexafluoropropene was introduced at 25° C. up to the saturation point. The batch was then diluted with 11 of water and the organic phase was separated off, dried and distilled to give 673 g of 3,5-bis-fluoromethyl-phenyl 1,1,2,3,3,3-hexafluoropropyl ether with a boiling point of 65° to 70° C. at 22 mbar and a refractive index nD2 of 1.3560.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:5]1=[O:31])[CH:2]=[CH2:3].C([N-]C(C)C)(C)C.[Li+].[F:41][CH:42]([F:45])[CH2:43]I>C1COCC1>[CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:43][CH:42]([F:45])[F:41])[C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: FC(F)CI
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(Cc2ccccn2)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC(F)F)c2ccccn2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyridin-2-ylmethyl)piperidin-2-one (705 mg, 1.515 mmol; Example 71, Step D) in inhibitor free THF (7 mL) under N2 at −78° C. was added lithium diisopropylamide (1.515 mL, 3.03 mmol) and the mixture was stirred for 30 min. 1,1-Difluoro-2-iodoethane (727 mg, 3.79 mmol; Oakwood) was added and the orange reaction mixture was stirred at −78° C. for 1 h. The reaction was warmed to rt overnight and quenched with 0.2 mL of MeOH, filtered and concentrated. The residue was purified by HPLC (C18 column, eluted with 10-95% CH3CN in water, with 0.1% TFA) to give (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-3,3-difluoro-1-(pyridin-2-yl)propyl)-3-methylpiperidin-2-one (HPLC retention time 7.38 min, Agilent Eclipse Plus C18 column, 0.1% TFA in CH3CN/H2O, gradient 70%-90% over 25 minutes) and (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-difluoro-1-(pyridin-2-yl)propyl)-3-methylpiperidin-2-one (HPLC retention time 7.94 min, Agilent Eclipse Plus C18 column (Agilent Technologies, Santa Clara, Calif.), 0.1% TFA in CH3CN/H2O, gradient 70%-90% over 25 minutes). Mass Spectrum (ESI) m/z=529 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]([CH3:31])[CH3:30]>O1CCOCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:32]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CNCC(C)C
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN(CC(C)C)CC(C)C)cc2c1C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (360 mg, 0.93 mmol, Example 56, Step D) in dioxane (10 mL) was added diisobutylamine (1.62 mL, 9.3 mmol). The mixture was stirred at 100° C. overnight and then partitioned between methylene chloride and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a solid residue, which was purified by chromatography (20% ethyl acetate in hexanes) to give 303 mg (77%) of the desired product as a white solid: mp 134-135° C.; MS(APCI+): m/z 421.3 (MH+); Anal. Calcd for C27H36N2O2: C, 77.10; H, 8.63; N, 6.66. Found: C, 76.94; H, 8.75; N, 6.55.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:16]([CH3:18])[CH3:17])([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[O:5][C:4](=[O:19])[CH:3]=1.[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33][C:3]1[C:4](=[O:19])[O:5][C:6]([CH:16]([CH3:17])[CH3:18])([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:7][C:2]=1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)C1(CCc2ccccn2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccccn3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 4-hydroxy-6-isopropyl-6-(2-pyridin-2-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-14; 0.8 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.9 mmol), potassium carbonate (3.1 mmol) in DMF (5 mL). The product was triturated from Et2O. mp 100-110° C. MS (APCI): 470 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.C(N(CC)CC)C.[CH2:21]([O:28][CH2:29][C:30](Cl)=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[NH2:34][CH:35]1[CH2:40][CH2:39][C:38](=[O:41])[NH:37][C:36]1=[O:42].C(O)(=O)C>O>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])[CH2:29][O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:13][C:6]=1[C:7]([NH:34][CH:35]1[CH2:40][CH2:39][C:38](=[O:41])[NH:37][C:36]1=[O:42])=[O:9]
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Nc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(NC(=O)COCc2ccccc2)cc1C(=O)NC1CCC(=O)NC1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
To a stirred mixture of 5-amino-isatoic anhydride (1.0 g, 5.6 mmol) and triethyl amine (0.8 mL, 9.0 mmol) in acetronitrile (15 mL), was added benzyloxyacetyl chloride (0.87 mL, 5.6 mmol) dropwise at room temperature. The mixture was kept at room temperature overnight. To the mixture, was added triethylamine (3.1 mL, 22 mmol), 3-amino-piperidine-2,6-dione hydrogen chloride (0.92 g, 5.6 mmol), and acetic acid (3.2 mL, 56 mmol). The mixture was heated at 80° C. for 8 hours. To the mixture, was added water (75 mL). The suspension was filtered and washed with water (75 mL) and ethyl acetate (75 mL) to give a dark solid, which was purified with column chromatography (Silica Gel, methanol/methylene chloride 0% to 10% in 15 min) to give 2-amino-5-(2-benzyloxy-acetylamino)-N-(2,6-dioxo-piperidin-3-yl)-benzamide as a white solid (0.28 g, 12% yield): 1H NMR (DMSO-d6) δ 1.92-2.18 (m, 2H, 2CHH), 2.50-2.55 (m, 1H, CHH), 2.72-2.84 (m, 1H, C H), 4.03 (s, 2H, CH2), 4.61 (s, 2H, CH2), 4.68-4.77 (m, 1H, NCH), 6.19 (br, 2H, NH2), 6.68 (d, J=9 Hz, 1H, Ar), 7.30-7.42 (m, 6H, Ar), 7.62 (d, J=2 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H, NH), 9.44 (s, 1H, NH), 10.84 (s, 1H, NH); 13C NMR (DMSO-d6) δ 24.09, 30.96, 49.12, 69.37, 72.35, 114.27, 116.23, 121.11, 125.99, 126.13, 127.64, 127.77, 128.27, 137.68, 146.19, 167.28, 168.36, 172.35, 173.01.