Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[BH4-].[Na+].CO.C(O)(=O)C>COC(C)(C)C.O1CCCC1.O>[CH2:9]([O:8][C:6]([NH:5][CH:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=1)[CH2:3][OH:2])=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCCOc1ccc(CC(CO)NC(=O)OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
4.15 g (11.2 mmol) of N-benzyloxycarbonyl-3-[4-propoxyphenyl]-alanine-methyl ester is dissolved in 20 ml of tert-butyl methyl ether and mixed with 0.17 g (4.5 mmol) of sodium borohydride. At 0° C., 6 ml of methanol is added and it is stirred for three hours under argon at a temperature below 5° C. Then, 0.8 ml of acetic acid, dissolved in 3 ml of tetrahydrofuran, is added, mixed with 3 ml of water and stirred for ten minutes at room temperature. The organic phase is separated, washed with water and dried on sodium sulfate. The drying agent is suctioned off, the filtrate is concentrated by evaporation and the residue is chromatographed for purification on silica gel (eluent: ethyl acetate/hexane).
Reaction SMILES: C(=O)([O:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:19]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:20][NH:21][C:22]([CH3:33])([CH3:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=[O:31])[CH:25]=2)=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]=[CH:13]2)OC(C)(C)C.N>CO>[Si:35]([O:34][C@H:19]([C:11]1[CH:10]=[CH:9][C:8]([OH:7])=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15](=[O:18])[NH:16]2)[CH2:20][NH:21][C:22]([CH3:33])([CH3:32])[CH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH:30]=[O:31])([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36]
Reactant: CC(C)(Cc1cccc(C=O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OC(=O)OC(C)(C)C)c2[nH]c(=O)ccc12
Agent: N
Solvent: CO
Product: CC(C)(Cc1cccc(C=O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 3 h

Procedure:
A solution of (R)-tert-butyl 5-(1-(tert-butyldimethylsilyloxy)-2-(1-(3-formylphenyl)-2-methylpropan-2-ylamino)ethyl)-2-oxo-1,2-dihydroquinolin-8-yl carbonate (Example 275, step g) (0.42 g) in methanol (15 mL) was treated with ammonia (35% aqueous) (2 mL). The reaction mixture was allowed to stand for 3 hours at 20° C. The solvent was removed under a stream of nitrogen and the residue was partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate and the combined organics dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.34 g.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Li][CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:16])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 6-[4-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (2.50 g, 9.95 mmol) in dry THF (100 mL) was cooled to 0° C. (ice/water bath) and treated with nBuLi (6.8 mL of a 1.6M solution in hexanes, 10.88 mmol) under nitrogen drop-wise over 20 minutes. The resulting deep red coloured solution was stirred at 0° C. for 1.5 hours and then quenched by the addition of aqueous HCl (2M, 10 mL) and allowed to warm to rt over about 20 minutes. The solvents were then removed under vacuum and the residue partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (150 mL) and the layers separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with water (200 mL), brine (200 mL), dried (MgSO4), filtered and reduced to give a pale yellow foam. Purification by Biotage™ chromatography (silica) eluting with cyclohexane:EtOAc (gradient 100:1 to 0:1) afforded the title compound as a pale yellow oil (1.99 g).
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10]C>C(OCC)C>[CH:1]1([Li:5])[C:10]2[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:3]=[CH:2]1
Reactant: [Li]CCCC
Reactant: CCCCCC
Solvent: CCOCC
Product: [Li]C1C=Cc2ccccc21
Reaction time: 2 h

Procedure:
18.8 ml (30.0 mmol) of a 1.60 molar solution of n-butyllithium in n-hexane are added dropwise at room temperature to a solution of 30.0 mmol of the appropriately substituted indene in 150 ml of diethyl ether. The mixture is stirred at this temperature for two hours. The solvent is removed in an oil pump vacuum and the residue is suspended overnight in 100 ml of pentane. The suspension is filtered through a frit and the residue is washed with a little pentane. The product is dried in an oil pump vacuum.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][C:11]1[CH:12]=[C:13]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[CH:28][CH:29]=[C:30]4[C:34]=3[N:33]([CH3:35])[CH:32]=[C:31]4[CH:36]=O)[N:22]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH3:20])[CH3:19].[OH-].[Na+]>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[CH:28][CH:29]=[C:30]4[C:34]=3[N:33]([CH3:35])[CH:32]=[C:31]4[CH2:36][NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:22]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH3:19])[CH3:20]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCNCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
ethyl β-alaninate hydrochloride (768 mg) and 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (396 mg) was added to a solution of NaOH (200 mg) in ethanol (10 mL). After stirring for 0.5 hour, ethanol was evaporated off and then dichloromethane (40 mL) containing AcOH (0.5 mL) was added to the residue. NaBH(OAc)3 (1.06 g) was added to the above mixture. The reaction mixture was stirred at room temperature overnight and then terminated by saturated NaHCO3 solution. The organic layer was separated and washed with water and brine. After the solvent was evaporated off the residue was purified by Mass Directed AutoPrep to afford ethyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-6-alaninate (D78) (288 mg) as a yellow solid. δH (CDCl3, 400 MHz): 1.24 (3H, t), 1.46 (6H, d), 1.74 (1H, br s), 2.78 (2H, t), 3.25 (2H, t), 3.74 (3H, s), 4.31 (2H, s), 4.69-4.76 (1H, m), 7.07 (1H, d), 7.70 (1H, t), 7.60 (1H, d), 7.80 (1H, dd), 8.02 (1H, dd), 8.22 (1H, d). MS (ES): C26H29ClN4O4 requires 496; found 380.2 (M—NHCH2CH2COOEt+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:35](O)=[O:36])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[K]>C(OCC)C.C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([CH:35]=[O:36])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:26]=1)=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [K]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-valyl-O-benzyl-L-tyrosine, N,O-dimethylhydroxamate (8.90 g, 16.2 mmol) in anhydrous diethyl ether (150 ml) and anhydrous THF (20 ml) at 0° C. is added lithium aluminum hydride (0.67 g, 17.7 mmol). The mixture is stirred at 0° C. for 1 hour. A solution of 1M potassium hydrogenosulphate (25 ml) is then added with precaution. The organic layer is separated and the aqueous phase is extracted twice with ethyl acetate (2×100 ml). The combined organic layers are then washed with a 3N solution of hydrochloric acid (30 ml), water (30 ml) and brine (30 ml), and dried over anhydrous magnesium sulphate. Filtration and evaporation of the solvent in vacuo affords a white solid which is recrystallized in ethylacetate/pentane to give the title compound (5.40 g, 68% yield).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]1([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([N:27]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([C:36]([N:38]6[CH2:42][CH2:41][CH2:40][CH2:39]6)=[O:37])[CH:34]=5)[C:29]([S:43][CH3:44])=[CH:28]4)=[N:25][CH:26]=3)[CH:16]=2)[CH2:14][CH2:13]1>ClCCl>[CH:12]1([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH:26]=[N:25][C:24]([N:27]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([C:36]([N:38]6[CH2:42][CH2:41][CH2:40][CH2:39]6)=[O:37])[CH:34]=5)[C:29]([S:43]([CH3:44])=[O:6])=[CH:28]4)=[N:23][CH:22]=3)[CH:16]=2)[CH2:13][CH2:14]1
Reactant: CSc1cn(-c2ncc(-c3cc(C4CC4)ccn3)cn2)c2cc(C(=O)N3CCCC3)ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(-c3cc(C4CC4)ccn3)cn2)c2cc(C(=O)N3CCCC3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
m-Chloroperoxybenzoic acid (77%, 79 mg, 0.35 mmol) was added to an ice cooled solution of 341b) (0.2 g, 0.43 mmol) in dichloromethane (30 mL). The mixture was stirred at room temperature for 1 h and then diluted with dichloromethane (25 mL). The organic phase was washed successively with saturated sodium hydrogen solution (2×15 mL) and brine (1×15 mL), dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography [silica; dichloromethane with 0-2% methanol]. White solid. Yield: 0.08 g (39% of theory)
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.C(Cl)C1C=CC2OC[O:14][C:13]=2C=1.C1N2CN3CN(C2)CN1C3>>[CH:6]1[C:7]([CH:13]=[O:14])=[CH:8][C:3]2[O:2][CH2:1][O:9][C:4]=2[CH:5]=1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: c1ccc2c(c1)OCO2
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1ccc2c(c1)OCO2
Yield: 70 %

Procedure:
A typical process for preparing piperonal from 1,2-methylenedioxybenzene has been reported by P. P. Shorygin et al. [J. Gen. Chem. (U.S.S.R.), 8,975 (1938)]. This is a two-step process. In the first step, 1,2-methylenedioxybenzene is reacted with formalin in petroleum benzine under the influence of hydrogen chloride gas and zinc chloride to form piperonyl chloride (with a 70-78% yield based on the amount of 1,2-methylenedioxybenzene having reacted). This is followed by the second step in which the piperonyl chloride is reacted with an equimolar amount of hexamine in 60% alcohol to give a 70-80% yield of piperonal. By E. D. Laskina et al. [Chemical Abstracts, 57,9714 (1962)], another process has been described in which 1,2-methelenedioxybenzene is reacted with formalin in the presence of a large excess of the sodium salt of m-nitrobenzenesulfonic acid, hydrogen chloride, and an aluminum catalyst to give a 42.4% yield of piperonal.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(O)(=O)C.[N:14]([O-])=[O:15].[Na+]>O>[N:14]([C:7]1[N:6]=[C:5]([NH2:8])[N:4]=[C:3]([NH2:9])[C:2]=1[NH2:1])=[O:15]
Reactant: O=N[O-]
Reactant: Nc1ncc(N)c(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N)c(N=O)n1
Temperature: 8 °C

Procedure:
In a 500-gallon glasslined reactor, crude damp triaminopyrimidine was dissolved in 150 gallons of deionized water with the aid of 117 pounds of acetic acid. HPLC assay showed 137 pounds of triaminopyrimidine in solution. The solution was cooled to 8° C. and treated with 80 pounds of sodium nitrite in 45 gallons of deionized water over a period of 13 minutes, with full refrigeration on the reactor jacket. A dense granular slurry of nitrosotriaminopyrimidine formed during the next 15 minutes as the temperature rose to 13° C. Analysis showed less than 0.1% of the triaminopyrimidine remaining unreacted in the filtrate, and a sample of the slurry was taken for small scale experiments. It remained a stable slurry under refrigeration for several days. The remainder of the slurry was reduced in situ to tetraaminopyrimidine sulfite by reaction with 382 pounds of sodium dithionite, filtered hot and chilled to 0°-5° C. to precipitate 609 pounds of damp cake, containing 186 pounds of tetraaminopyrimidine sulfite.
Reaction SMILES: Cl[CH:2]([CH3:4])[CH3:3].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.ClC(C)C>>[CH:2]([C:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])[CH3:3]
Reactant: c1ccc2ccccc2c1
Reactant: CC(C)Cl
Product: CC(C)c1cccc2ccccc12

Procedure:
Reaction was carried out as in Example 4, but using 2-chloropropane as the alkylating agent with a molar ratio of naphthalene/2-chloropropane of 1:0.8. Yield of isopropylnaphthalene obtained was 54%, with an isomer distribution of 98% β- and 2% α-isopropylnaphthalene.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]2[C:13]3[N:18]([CH2:19][C:4]=12)[C:17](=[O:20])[C:16]([CH3:21])=[C:15]([CH:22]([O:25][C:26](=[O:36])[CH2:27][NH:28]C(OC(C)(C)C)=O)[CH2:23][CH3:24])[CH:14]=3)#[N:2].C(C(O)=O)(F)(F)F>O>[NH2:28][CH2:27][C:26]([O:25][CH:22]([C:15]1[CH:14]=[C:13]2[N:18]([CH2:19][C:4]3[C:5]2=[N:6][C:7]2[C:12]([C:3]=3[C:1]#[N:2])=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:17](=[O:20])[C:16]=1[CH3:21])[CH2:23][CH3:24])=[O:36]
Reactant: CCC(OC(=O)CNC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1c-2nc2ccccc2c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCC(OC(=O)CN)c1cc2n(c(=O)c1C)Cc1c-2nc2ccccc2c1C#N

Procedure:
The title compound was prepared according to the procedure in Example 3B except using (±)-12-cyano-8-methyl-7-[1-[[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one. 1H NMR (CDCl3 /MeOH-d4) d 8.28 (d, J=8.5 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.95 (m, 1H), 7.82 (m, 1H), 7.36 (s, 1H), 6.00 (apparent t, J=6.6 Hz, 1H), 5.41 (s, 2H), 3.92 (br s, 2H), 2.33 (s, 3H), 2.08-1.82 (m, 2H), 1.00 (t, J=7.2 Hz, 3H). Anal. Calcd for C22H20N4O3.3/2 CF3CO2H.5/2 H2O: C, 49.67; H, 4.42; N, 9.27. Found: C, 49.41; H, 4.23; N, 9.29.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[F:16][C:17]1[CH:18]=[C:19]([N:33]2[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([N:33]2[CH2:37][C@@H:36]([CH2:38][NH+:39]([O-:6])[C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(S(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Solvent: ClCCl
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCN(S(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pertrifluoroacetic acid is prepared in situ by the addition of 30% H2O2 solution (0.15 mL) to trifluoroacetic anhydride (0.45 mL) in 5 mL of methylene chloride at 0° C. This solution is stirred at 0° C. for ten minutes, at 25° C. for 30 minutes and then cooled back to 0° C. (S)-N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide (VIII-G, R1=COCH3, R9=CH3, X1=F, X2=H) (0.207 g) is added and the reaction is stirred at 25° C. for 30 minutes and then concentrated. The residue is chromatographed on silica gel using 10% methanol (saturated with ammonia) in chloroform as the eluent to afford 0.14 g the N-oxide as a hydrate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:23][OH:24])[NH:5][C:6]([O:8][CH2:9][CH:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[C:35]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2>C(#N)C>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:23][O:24][C:35]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:5][C:6]([O:8][CH2:9][CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7]
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: BrC1(c2ccccc2)c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H](COC1(c2ccccc2)c2ccccc2-c2ccccc21)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a mixture of 0.17 g (0.5 mmol) Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester, 0.043 g (0.6 mmol) potassium carbonate and 0.083 g (0.5 mmol) potassium iodide in acetonitrile (2 mL) was added 0.16 g (0.5 mmol) of 9-bromo-9-phenyl-9H-fluorene (Aldrich), and the mixture stirred at 40° C. for 2 h. Filtration and removal of the solvent under vacuo gave the crude Nα -(9-fluorenylmethoxycarbonyl)-O-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester which was subjected to the Fmoc deprotection in Step 2 without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@H](C2C=CC=CC=2)CO)C1.[NH2:37][C:38]1[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=1>>[CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]([NH:37][C:38]2[CH:39]=[CH:40][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:46][CH:47]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1
Reactant: COCO[C@H]1CCN(C[C@@H](O)c2ccccc2)C1
Reactant: COC(=O)c1ccc(N)cc1
Agent: COCO[C@H]1CCN([C@@H](CO)c2ccccc2)C1
Product: COCO[C@H]1CCN(C[C@@H](Nc2ccc(C(=O)OC)cc2)c2ccccc2)C1
Yield: 69 %

Procedure:
This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 4-aminobenzoate in 69% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([OH:27])=[CH:22][CH:23]=3)[CH:18]2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[ClH:50].[N:51]1([CH2:57][C:58](O)=[O:59])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.C(N(CC)CC)C>>[ClH:50].[ClH:50].[CH3:1][C:2]1[C:3]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:27][C:58](=[O:59])[CH2:57][N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[CH:22][CH:23]=3)[CH:18]2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][C:7]=1[CH3:8]
Reactant: O=C(O)CN1CCOCC1
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccc(O)cc3C2C)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccc(OC(=O)CN4CCOCC4)cc3C2C)c1C

Procedure:
The same procudures as in Example 167 were repeated using 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol), 4-morpholineacetic acid hydrochloride(28.8 mg, 0.158 mmol), and triethylamine(46 μl, 0.330 mmol) to afford the titled compound.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:25]=1[CH2:26][N:27]1[C@@H:32]([CH3:33])[CH2:31][NH:30][C:29](=O)[C:28]1=[O:35]>C1COCC1>[Cl:23][C:24]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:25]=1[CH2:26][N:27]1[C@@H:32]([CH3:33])[CH2:31][NH:30][C:29](=[S:10])[C:28]1=[O:35]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@H]1CNC(=O)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Solvent: C1CCOC1
Product: C[C@H]1CNC(=S)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 55 °C
Yield: 176.3 %

Procedure:
To a heterogeneous mixture of Lawesson's reagent (650 mg, 1.6 mmol) in THF (30 mL) was added Intermediate 4 (1.0 g, 3.1 mmol) in one portion. The mixture was heated at 55° C. for 20 minutes and then concentrated to remove solvent. Purification by chromatography (SiO2; hexanes—100% EtOAc) afforded the desired product as a yellow solid (950 mg, 90%). MS (ESI): mass calcd. for C13H12ClF3N2OS, 336.0; m/z found, 337.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.78 (d, J=4.2 Hz, 1H), 7.65 (d, J=7.9 Hz, 2H), 7.38 (t, J=7.8 Hz, 1H), 5.17 (d, J=15.6 Hz, 1H), 4.53 (d, J=15.6 Hz, 1H), 3.84-3.66 (m, 2H), 3.40 (dd, J=11.7, 5.6 Hz, 1H), 1.38 (d, J=6.7 Hz, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@H:5]([NH:7][S:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[N:16][CH:15]=[CH:14]2)(=[O:10])=[O:9])[CH3:6].[C:21]1([CH2:27][C:28]([Cl:30])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[ClH:30].[CH:17]1[C:18]2[C:13](=[CH:12][C:11]([S:8]([NH:7][C@H:5]([CH3:6])[CH2:4][NH:3][C:28](=[O:29])[CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:10])=[O:9])=[CH:20][CH:19]=2)[CH:14]=[CH:15][N:16]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C[C@H](CN)NS(=O)(=O)c1ccc2cnccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](CNC(=O)Cc1ccccc1)NS(=O)(=O)c1ccc2cnccc2c1
Yield: 42.5 %

Procedure:
The compound of Example 102 (100 mg) and phenylacetyl chloride (45 mg) were condensed (72 mg, 63%) in the presence of triethylamine (0.123 mL) in dichloromethane. Subsequently, 52 mg of the title compound was obtained as a pale yellow solid (66%) with reference to the method of Step 3 of Example 1.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:2].[BH4-].[Na+].O>C(O)C.O1CCCC1>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccc(C=O)cc1CNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1ccc(CO)cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
1.8 g of t-butyl N-(5-formyl-2-methoxybenzyl)carbamate was dissolved in 12 ml of ethanol and 6 ml of tetrahydrofuran, and 0.15 g of sodium borohydride was added. After stirring at room temperature overnight, water was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography, to give 1.65 g of the title compound from the 1:1 hexane-ethyl acetate fraction.