Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]I)[CH2:20][CH3:21].ICCC.[Mg].[Cl-].[NH4+]>C(OCC)C.O>[CH:1]([N:14]1[CH2:17][C:16]([OH:18])([CH2:19][CH2:20][CH3:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCC[Mg]I
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCCI
Solvent: CCOCC
Product: CCCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 7.5 g of 1-benzhydryl-3-oxoazetidine dissolved in 50 cm3 of ethyl ether is added in the course of 20 minutes at between 0 and 5° C. to a solution of propylmagnesium iodide in ethyl ether, prepared under the usual conditions from 10.75 g of iodopropane and 1.55 g of magnesium in 75 cm3 of ethyl ether. The temperature is allowed to rise to approximately 20° C. and the mixture is stirred at the same temperature for 2 hours. After cooling to approximately 0° C., 50 cm3 of water and 50 cm3 of 10% aqueous ammonium chloride solution are added successively while the latter temperature is maintained. The aqueous phase is extracted with 3 times 50 cm3 of ethyl ether. The combined organic extracts are dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 kPa) at approximately 30° C. The dry extract is chromatographed on 100 g of silica gel (0.04-0.063 mm) suspended in a cyclohexane mixture containing 20% of ethyl acetate. The desired product is eluted with 130 cm3 of the same solvent mixture. 8 g of 1-benzhydryl-3-hydroxy-3-propyl-azetidine are obtained in the form of a pale yellow oil, which is used without further purification for the subsequent steps.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl.C(OCC)(=O)C>[N:13]1([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[N:3]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Clc1cncc(-c2ccsc2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: c1cc(-c2cncc(N3CCNCC3)n2)cs1
Temperature: 85 °C

Procedure:
A mixture of the product from step 1 above (1.04 g, 5.29 mmol), piperazine (1.32 g, 15.3 mmol), and K2CO3 (0.81 g, 5.82 mmol) in acetonitrile (6 mL) was heated in a sealed pyrex flask at 85° C. for 8.5 h. The reaction mixture was diluted with dichloromethane, filtered, and concentrated in vacuo. The semi-solid residue was purified by column chromatography on silica gel (18×5 cm) using CHCl3/MeOH (9:1) as eluent to furnish an oil. This material was redissolved in ethyl acetate, filtered, and concentrated in vacuo. This gave 0.98 g (75%) of the title compound as a yellow sticky oil. HRMS m/z calcd for C12H14N4S (M)+ 246.0939, found 246.0943. Anal. (C12H14N4S) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:17]([C:14]1[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=1)[OH:18]
Reactant: O=Cc1ccncc1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1ccncc1)c1c[nH]c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a stirred solution of 5-fluoroindole (3.10 g, 23.0 mmol) in methanol (10.0 mL) was added 4-pyridinecarboxaldehyde (2.20 mL, 23.0 mmol), followed by addition of NaOH (2.5 mL, 50%) at 0° C. After stirring for 1 h at 0° C., the reaction Mixture was warmed to room temperature and stirred for 3 h, followed by the addition of water (10.0 mL). The precipitate was collected by filtration and dried under vacuum to afford 5.2 g (93%) of a light yellow solid: mp 171-173° C.; 1H NMR (DMSO, 400 MHz), 5.85 (d, 1H), 5.93 (d, 1H), 6.86-7.34 (m, 4H), 7.43 (dd, 2H), 8.48 (dd, 2H), 11.09 (br s, 1H); MS (EI) m/z 242 (M+); HRMS calcd for C14H12FN2O [M+H] 243.09337, found 243.09576.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:18][CH:19]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:20]([C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:19]=[CH:18][CH:17]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCC=Cc1cccc(CCCCCOCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCc1cccc(CCCCCO)c1

Procedure:
A solution of 840 mgs of 3-(5-benzyloxypentyl)-1-(1-hexenyl)benzene in 25 mls of methanol is hydrogenated over 5% palladium on carbon and then filtered through celite, concentrated, and chromatographed over silica gel (3:2 ether:hexane) to yield pure 5-(3-hexylphenyl)-pentanol.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:9][CH3:10])S(O)(=O)=O)#[N:2].[CH3:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>C(O)C>[C:1]([N:3]=[C:4]([NH:21][CH2:20][CH2:19][S:18][CH2:17][C:13]1[N:14]=[CH:15][NH:16][C:12]=1[CH3:11])[NH:9][CH3:10])#[N:2]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CNC(=NC#N)S(=O)(=O)O
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Yield: 21.4 %

Procedure:
A solution of cyanoimino-methylaminomethanesulfonic acid (DBU salt) (0.70 g) and 2-(5-methylimidazol-4-ylmethylthio)ethylamine (0.57 g) in ethanol (14 ml) was heated under reflux for 7 hrs. After removal of the solvent under a reduced pressure, the residue was purified by column chromatography on SiO2 [eluant: CH3CN-CH3OH (4:1)]. After concentration of the eluate under a reduced pressure, the residue was subjected to preparative thin layer chromatography [SiO2, CH3COOCH3 -CH3OH- 28% NH3 (aq) (10:1:1)] and then recrystallized from CH3OH-CH3CN to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (0.18 g). Yield 32.4%, m.p. 140°-141° C.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:37]
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[N:4]=[C:5]([CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[CH:17][CH:16]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[S:6][CH:7]=1.B(F)(F)F.CCOCC>CCS>[F:30][C:2]([F:1])([F:29])[C:3]1[N:4]=[C:5]([CH:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[S:6][CH:7]=1
Reactant: COC(=O)CC(Cc1ccc(OCc2ccccc2)cc1)c1nc(C(F)(F)F)cs1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCS
Product: COC(=O)CC(Cc1ccc(O)cc1)c1nc(C(F)(F)F)cs1
Temperature: 0 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
To a solution of methyl (±)-3[4-(trifluoromethyl)thiazol-2-yl]-4-(4-benzyloxyphenyl)butanoate (0.44 mmole, crude) in EtSH (5 mL) at RT was added BF3.OEt2 (0.3 mL). After 18 hr. additional BF3.OEt2 (0.3 mL) was added. After another 18 hr, the mixture was cooled to 0° C. and carefully quenched with saturated NaHCO3. The resulting mixture was extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel (30% EtOAc/hexanes) to give the title compound (123 mg, 81% over 3 steps) as a yellow oil: MS (ES) m/e 346 (M+H)+.
Reaction SMILES: C[Al](C)C.[C:5](=[N:18][NH2:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]2[CH2:32][O:31][C:30](=[O:33])[CH2:29]2)[CH:25]=[CH:26][CH:27]=1.[OH-].[Na+]>ClCCl>[C:5](=[N:18][NH:19][C:30](=[O:33])[CH2:29][CH:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=1)[CH2:32][OH:31])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(C2COC(=O)C2)c1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cccc(C(CO)CC(=O)NN=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trimethylaluminum (12 mL, 2 M in hexane, 24 mmol) is added dropwise to a solution of benzophenone hydrazone (1.57 g, 8 mmol) in dichloromethane (20 mL) at room temperature and under nitrogen. After the mixture is stirred for 30 min, 4-(3-methoxy-phenyl)-dihydro-furan-2-one, (1.54 g, 8 mmol) in dichloromethane (5 mL) is added. The mixture is refluxed for 5 h cooled to room temperature and diluted with dichloromethane (30 mL). The mixture is treated with 4 N sodium hydroxide (30 mL) and stirred one hour. The organic layer is separated, washed with brine and, dried over magnesium sulfate. The mixture is filtered, concentrated in vacuo and chromatographed on SiO2 (2% methanol/dichloromethane) to yield the title compound, 2.25 g (73%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][CH:20]=1)(=[NH:14])=[O:13].Cl.CN(C)CCCN=C=NCC.CCOC(C)=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:14]=[S:12]([C:15]2[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][CH:20]=2)([CH3:11])=[O:13])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: COC(=O)Cc1cccc(S(C)(=N)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 5-bromonicotinic acid (648 mg, 3.21 mmol), methyl [3-(S-methylsulfonimidoyl)phenyl]acetate (802 mg, 3.53 mmol), and catalytic DMAP in 15.0 ml DMF at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (738 mg, 3.85 mmol). The reaction was stirred 1 hour at room temperature then added to EtOAc. The EtOAc solution was washed with dilute brine, NaHCO3 solution, brine, dilute HCl/brine mixture, brine/NaHCO3 solution, dried with anhydrous Na2SO4 and rotary evaporated. The oil was chromatographed eluting with CHCl3/EtOAc to give viscous clear oil (994 mg, 75%).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[N:11]=[C:12]([N:28]2[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29]2)[C:13]2[N:18]=[N:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:14]=2[N:15]=1.Cl>C1COCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:16]2[C:14]3[N:15]=[C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[N:11]=[C:12]([N:28]4[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29]4)[C:13]=3[N:18]=[N:17]2)=[CH:25][CH:24]=1
Reactant: OCC(F)(F)F
Reactant: COc1ccc(Cn2nnc3c(N4CC[C@H](O)C4)nc(Cl)nc32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc3c(N4CC[C@H](O)C4)nc(OCC(F)(F)F)nc32)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2,2,2-trifluoroethanol (936 mg, 9.35 mmol) in THF was treated with NaH for 1 h at room temperature. (S)-1-[5-Chloro-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 109, c) was added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was poured into 1 M HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield the crude title compound which was used in the consecutive step without further purification. MS (m/e): 425.4 (MH+).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.[CH2:12]([Li])[CH3:13].[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>C(OCC)C>[C:15]([O:11][C:2]1([CH2:12][CH3:13])[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)Cl
Reactant: [Li]CC
Reactant: O=C1C2CC3CC(C2)CC1C3
Solvent: CCOCC
Product: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Yield: 60 %

Procedure:
50 g of diethyl ether was added to 31.1 g of 2-adamantanone to prepare a solution. Then, 200 ml of a diethyl ether solution containing ethyl lithium in a concentration of 1.14 mole/L was added dropwise thereto at such a rate as to keep the temperature of the solution not exceeding 10° C. After stirring the solution thus obtained at 0° C. for 2 hours, 26.2 g of methacrylic acid chloride (1.2 mole times with respect to 2-adamantanone) was added dropwise thereto at such a rate as to keep the temperature not exceeding 10° C. After the completion of dropwise addition, the resulting solution was stirred at room temperature for 12 hours. Thereafter, the deposited inorganic salts were separated by filtration, and the organic layer was washed with a 5% by weight aqueous solution of sodium bicarbonate, followed by washing with water for 2 times. The organic layer was concentrated, and then subjected to distillation under reduced pressure to obtain 2-ethyl-2-adamantyl methacrylate represented by the following formula in a 60% yield.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: CS(=O)(=O)Nc1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 7 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and N-(cis-2,3,4,4a,9,9a-Hexahydro-1H-indeno[2,1-b]pyridin-7-yl)-methanesulfonamide following a procedure analogous to that described in Example 1. Yield: 7% of theory; LC (method 1): tR=2.07 min; Mass spectrum (ESI+): m/z=411 [M+H]+.
Reaction SMILES: FC1C(O[C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[Cl:26])=C(F)C(F)=C(F)C=1F.[NH2:32][O:33][CH2:34][CH2:35][OH:36].C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:26][C:20]1[CH:21]=[C:22]([I:25])[CH:23]=[CH:24][C:19]=1[NH:18][C:11]1[C:12]([F:17])=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:9]([NH:32][O:33][CH2:34][CH2:35][OH:36])=[O:27]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Reactant: NOCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Yield: 89.6 %

Procedure:
To a solution of 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid pentafluorophenyl ester (10.0 g, 17.4 mmol) in anhydrous dimethylformamide (36 mL) was added 2-(aminooxy)-ethanol (1.6 g, 20.8 mmol) and N,N-diisopropylethylamine (6.0 mL, 34.8 mmol). The resultant solution was stirred at ambient temperature for 16 h. The reaction mixture was concentrated to 20% volume then diluted with ethyl acetate (360 mL). The resultant solution was washed with water (6×60 mL) and brine (2×60 mL). The organics were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a white solid that was purified on silica gel. Elution with ethyl acetate-methanol (9:1) afforded 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (7.31 g, 90%) as a white solid. Recrystallization from methanol afforded analytically pure material, identical in all respects to the material prepared by method A.
Reaction SMILES: [C:1]([C@@:3]1([OH:25])[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1)#[CH:2].[Br:26]Br>CO.Br.C(Cl)Cl>[Br:26][CH2:14][C:13](=[O:15])[C@@H:12]1[C@:16]2([CH3:24])[C@H:9]([C@H:8]3[C@H:19]([CH2:18][CH2:17]2)[C@:20]2([CH3:23])[C@H:5]([CH2:4][C@:3]([C:1]#[CH:2])([OH:25])[CH2:22][CH2:21]2)[CH2:6][CH2:7]3)[CH2:10][CH2:11]1
Reactant: C#C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reactant: BrBr
Agent: Br
Solvent: CO
Solvent: ClCCl
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of 3β-ethynyl-3α-hydroxy-5α-pregnan-20-one (2.3 g, 6.72 mmol) in MeOH (80 mL) was treated with two drops of HBr (48%), followed by bromine (0.4 mL, 7.73 mmol). The mixture was stirred at room temperature for 1 hr and was poured into ice-water. The separated solid was collected by filtration, washed with water, and dried (2.5 g). This semi-dried solid was then dissolved in EtOAc and dried over anhyd. MgSO4. Filtration and removal of the solvent gave the crude bromo derivative. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with hexane:EtOAc mixture (85:15) gave 21-bromo-3β-ethynyl-3α-hydroxy-5α-pregnan-20-one (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15])[CH3:11].C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:14]([CH3:16])([C:13]([O:12][CH2:10][CH3:11])=[O:18])[CH3:15])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Nc1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 61.9 %

Procedure:
A 15-mL sealed tube equipped with a magnetic stirring bar was charged with 3,4-dichloroaniline (1.63 g, 10.0 mmol) and treated with ethyl-2-bromoisobutyrate (1.6 mL, 11 mmol), diisopropylethylamine (1.9 mL, 11.0 mmol), and NaT (824 mg, 0.600 mmol). The vessel was sealed tightly, heated to 110° C. and maintained at that temperature for 48 h. After allowing the reaction mixture to cool to room temperature, the reaction was diluted with THF and the solids were filtered off. The filtrate was collected and concentrated under vacuum. The crude oil was purified by silica gel chromatography (35 g Redisep column, silica 40 um, 35 mL/min, A: CH2Cl2, B: MeOH, B: 0% for 20 min, 5% for 5 min, 10% for 5 min; detection at 214 nm) to give 1.71 g (55%) of ethyl N-(3,4-dichlorophenyl)-2-methylalaninate as a brown oil. MS (ES) m/z 276 [M+H]+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:25]=[CH:24][C:11]2[N:12]([N:22]=O)[CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][O:15][C:10]=2[CH:9]=1>C(OCC)C.C1COCC1.CCCCCC>[CH3:7][C:8]1[CH:25]=[CH:24][C:11]2[N:12]([NH2:22])[CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][O:15][C:10]=2[CH:9]=1
Reactant: Cc1ccc2c(c1)OCC(c1ccccc1)N2N=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc2c(c1)OCC(c1ccccc1)N2N
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A slurry of lithium aluminum hydride (6.9 g, 183 mmol) in ethyl ether (300 mL) is stirred in an ice bath under an argon atmosphere. A solution of 7-methyl-4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine (23.22 g, 91.3 mmol) in ethyl ether (250 mL) and dry THF (40 mL) is added dropwise over 1.5 h. The mixture is removed from the ice bath and allowed to stir for 18 h. Water (50 mL) is slowly added, forming solids. The solids are collected by filtration and washed with ethyl ether. The resulting filtrates are combined and washed three times with water (400 mL), dried over magnesium sulfate, and concentrated to dryness to give a solid. The solids are slurried in hexane, collected, and dried to give 16.5 g (69%) of 7-methyl-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-amine.
Reaction SMILES: [Cl:1]C1C=CC(S[C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3([C:24]([NH:26][OH:27])=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=CC=1.[N:28]1([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH:32]=[N:31][CH:30]=[N:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[ClH:1].[OH:27][NH:26][C:24]([C:18]1([S:15]([C:12]2[CH:13]=[CH:14][C:9]([O:39][C:36]3[CH:35]=[CH:34][C:33]([N:28]4[CH:32]=[N:31][CH:30]=[N:29]4)=[CH:38][CH:37]=3)=[CH:10][CH:11]=2)(=[O:16])=[O:17])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)=[O:25]
Reactant: Oc1ccc(-n2cncn2)cc1
Reactant: O=C(NO)C1(S(=O)(=O)c2ccc(Sc3ccc(Cl)cc3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cl
Product: O=C(NO)C1(S(=O)(=O)c2ccc(Oc3ccc(-n4cncn4)cc3)cc2)CCOCC1
Yield: 80 %

Procedure:
Part A: To a solution of the protected hydroxamate of Example 25, part B (2.9 g, 7.5 mmol) in DMF (10 mL) was added 4-(1,2,4-triazol-1-yl)phenol (2.47 g, 15 mmol) in DMF (5 mL) followed by Cs2CO3 (7.33 g, 22.5 mmol), and the solution was heated at 95 degrees Celsius for 5 hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated NaCl and dried over Na2SO4. Chromatography (on silica, ethyl acetate/hexane/methanol) provided the phenol as a white solid (3.16 g, 80%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31].N1C=CC=CC=1>ClCCl>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[S:30]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNS(=O)(=O)c1ccc(Cl)cc1Cl
Reaction time: 4 h
Yield: 4.1 %

Procedure:
To a solution of 33 mg of ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 25 mg of 2,4-dichlorobenzenesulfonyl chloride in 0.8 ml of dichloromethane was added 40 μl of pyridine under ice-cooling, and stirring was continued at room temperature for 4 hours. After removing the solvent, to the residue were added 1.0 ml of ethanol and 0.3 ml of 2N aqueous sodium hydroxide, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water, and neutralized with 2N hydrochloric acid. The mixture was extracted with ethyl acetate and concentrated. Then, the residue was purified by HPLC using a reverse-phase column by using an elution solvent of water-acetonitrile-trifluoroacetic acid system, to give 2.0 mg of the title compound.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[OH-].[Na+].[NH2:10][C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[CH3:1][O:20][C:19](=[O:21])[C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:10]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
A 0.2 molar solution phenylalanine methyl ester in 10 milliliters of water was prepared. Toluene was added and the pH of the system adjusted to 7.0 with sodium hydroxide. Chymotrypsin in the amount of 1 milligram was added. The concentration of phenylalanine in the aqueous phase was monitored. The initial concentration was 0.05 molar and the final concentration at the end of the hydrolysis was 0.15 molar, consistent with only one isomer being extracted.