Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)=[O:22])[C:3]1=[O:29].[CH3:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38]=[O:39])[CH:34]=[CH:35][CH:36]=1>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([N:23]2[CH2:24][CH2:25][S:26][CH2:27][CH2:28]2)=[O:22])[C:3](=[O:29])[CH:2]([NH:1][C:38]([NH:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH3:30])[CH:32]=2)=[O:39])[N:8]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CCSCC2)C1=O
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(CC(=O)N3CCSCC3)C2=O)c1
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of (3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-(thiomorpholin-4-yl)carbonylmethyl-1H-1,4-benzodiazepin-2-one (0.11 g) in dry methylene chloride (10 ml) was added dropwise a solution of 3-methylphenyl isocyanate (0.043 g) in dry methylene chloride (5 ml) at ambient temperature. After completion of addition, the mixture was stirred at the same condition overnight. The reaction mixture was concentrated in vacuo to afford a crude product. The product was purified by column chromatography on silica gel with an eluent of a mixture of chloroform and methanol (100:1) to afford N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1-(thiomorpholin-4-yl) carbonylmethyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea as a colorless crystalline solid (0.10 g).
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:22]1[NH:26][N:25]=[N:24][N:23]=1)[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:12]([C:22]1[NH:26][N:25]=[N:24][N:23]=1)[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCc1ccccc1)c1nnn[nH]1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CC[C@@H](N)c1nnn[nH]1
Yield: 91.1 %

Procedure:
A solution of tert-butyl (4R)-4-(benzyloxycarbonylamino)-4-(tetrazol-5-yl)-butyrate (1.2 g, 3.32 mmol) in ethanol (77 ml) was stirred with 10% Pd-C (0.166 g) under a hydrogen atmosphere at ambient temperature for 16 hours. The catalyst was removed by filtration and the filtrate evaporated. Dichloromethane was added to the residue and evaporated and the resulting solid was triturated with hexane and dried to give tert-butyl (4R)-4-amino-4-(tetrazol-5-yl)butyrate (0.687 g, 91%), m.p. 175° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: Cc1ccc(S(=O)(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)cc1
Yield: 30 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 12.8 mg (0.067 mMol) 4-methylbenzenesulfonyl chloride, 5.3 mg (31%) of the title compound were recovered as a light beige solid.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:8]=[CH:7][C:6]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:5]=2[CH:4]=1.[F:18][C:19]([F:27])([C:23]([F:26])([F:25])[F:24])[CH:20](O)[CH3:21].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][O:13][C:10]1[CH:9]=[C:6]2[C:5](=[CH:12][CH:11]=1)[CH:4]=[C:3]([CH:2]([CH3:1])[C:15]([O:17][C@H:20]([C:19]([F:27])([F:18])[C:23]([F:26])([F:25])[F:24])[CH3:21])=[O:16])[CH:8]=[CH:7]2
Reactant: CC(O)C(F)(F)C(F)(F)F
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2cc(C(C)C(=O)O[C@@H](C)C(F)(F)C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-naproxen (9.23 g, 40.1 mmol), racemic 3,3,4,4,4-pentafluoro-2-butanol (6.58 g, 40.1 mmol), EDC (9.20 g, 48.0 mmol) and DMAP (4.89 g, 40.0 mmol) was dissolved in CH2Cl2 (40 mL) at room temperature. After stirring for 8 h at room temperature, the mixture was diluted with CH2Cl2, then washed successively with 1 N HCl, sat. NaHCO3, and brine. After drying over Na2SO4 and concentrating, a mixture of diastereomeric naproxen esters was obtained as a white solid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1([C:28](Cl)=[O:29])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>>[CH2:1]([NH:9][C:28]([C:15]1([CH2:14][CH2:13][CH2:12][CH2:11][Br:10])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:29])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCCc1ccccc1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from phenethylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: C([O:8][P:9]1[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][O:10]1)C1C=CC=CC=1.[CH2:17](I)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[CH2:17]([P:9]1(=[O:8])[O:10][CH2:11][C:12]([CH3:15])([CH3:16])[CH2:13][O:14]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ICc1ccccc1
Reactant: CC1(C)COP(OCc2ccccc2)OC1
Solvent: Cc1ccccc1C
Product: CC1(C)COP(=O)(Cc2ccccc2)OC1
Reaction time: 1.5 h
Yield: 8386.1 %

Procedure:
A mixture of 2-benzyloxy-5,5-dimethyl-1,3,2-dioxaphosphorinane (100 g, 0.416 M) from Example II, benzyl iodide (1.0 g), and xylene (50 ml) was heated until the temperature reached 165° C., and then slowly dropped to 155° C. After 1.5 hrs, the mixture was allowed to cool to yield 92.4 g (92.4% yield) of pure crystalline 2-benzyl-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-one, melting point 109.5°-110.5° C. Analysis by gas-liquid chromatography showed no impurities present.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10].Cl>C1COCC1>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:9]1=[O:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1S
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2s1
Reaction time: 12 h

Procedure:
To 2-amino-benzenethiol (10 g, 79.9 mmol) in THF (200 mL) at room temperature was added carbonyldiimidazole (14.3 g, 87.9 mmol) and the reaction solution stirred for 12 hours. Upon disappearance of starting material, the reaction solution was poured into 1N HCl (125 mL) and extracted with ethyl acetate (125 mL). The organic layer was dried over sodium sulfate and concentrated to give 1,3-benzothiazol-2(3H)-one as a white solid. MS (ES) m/z 152.1.
Reaction SMILES: [NH3:1].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13](Cl)(=[O:15])=[O:14])(=[O:5])=[O:4]>O1CCCC1>[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:1])(=[O:15])=[O:14])(=[O:5])=[O:4]
Reactant: CS(=O)(=O)Oc1ccccc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccccc1S(N)(=O)=O

Procedure:
Ammonia was passed at -30° C. into a solution of 130.3 g of 2-chlorosulfonylphenyl methanesulfonate in 1 l of tetrahydrofuran, and the conversion was checked by thin-layer chromatography. After the reaction was complete, the tetrahydrofuran was distilled off under reduced pressure from a water pump and the residue was triturated with water and diethyl ether. This gave 110.2 g (91%) of the title compound of melting point 131°-132° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:9][CH:8]=1)[CH3:2].O.[OH-].[Li+]>C1COCC1>[CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][S:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1F)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(CCSc2ccccc2C(=O)O)cc1
Yield: 96.9 %

Procedure:
Methyl 2-{[2-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}-benzoate was dissolved in a mixture of THF (freshly distilled)/water (2/1, 3 ml), Lithium hydroxide (0.015 g, 0.629 mmol) was added. The reaction was performed in a single node microwave oven (5 min, 150 deg). THF was removed by evaporation. Water was added (10 ml) and the basic water phase was washed with diethyl ether (2×10 ml). Addition of HCl (2 ml, 1 M, pH 1). The water phase was extracted with two portions of DCM (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.095 g of 2-{[2-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethyl]-thio}benzoic acid (yield 96.9%)
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C=Cc2ccccc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C=Cc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
A mixture of methyl 4-(2-chlorostyryl)benzoate (trans form) (1.42 g), 5N sodium hydroxide (1.6 ml) and methanol (20 ml) is stirred at room temperature for three hours, and refluxed for two hours. The mixture is evaporated to remove the methanol, and to the residue is added water. The mixture is acidified with conc. hydrochloric acid, and stirred at room temperature for 16 hours. The precipitated crystals are collected by filtration to give 4-(2-chlorostyryl)benzoic acid (1.36 g) as white powder.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([C:7]2([C:10]3[N:14]4[CH2:15][CH2:16][S:17][C:18]([CH2:21][O:22][Si](C(C)(C)C)(C)C)([CH3:20])[CH2:19][C:13]4=[N:12][N:11]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl>CO>[C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:2]=[CH:3][C:4]([C:7]2([C:10]3[N:14]4[CH2:15][CH2:16][S:17][C:18]([CH2:21][OH:22])([CH3:20])[CH2:19][C:13]4=[N:12][N:11]=3)[CH2:8][CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccccc5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccccc5)cc4)CC3)n2CCS1
Yield: 90.4 %

Procedure:
A solution of the compound (197 mg, 0.39 mmol) obtained in Example 1-3) and 4 M hydrochloric acid (1,4-dioxane solution, 0.5 mL) in methanol (2 mL) was stirred at room temperature for 21 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 30:70, gradient) to obtain the title compound (138 mg, 91%) as a colorless solid.
Reaction SMILES: [C:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH2:6]3)[CH2:4]1)[CH2:10]2)#[CH:2].Cl[C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1>C(#N)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:23]1[CH:24]=[CH:25][N:26]=[CH:27][C:22]=1[C:2]#[C:1][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: C#CC12CC3CC(C1)CC(NC(=O)OC(C)(C)C)(C3)C2
Reactant: Clc1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC12CC3CC(CC(C#Cc4cnccn4)(C3)C1)C2
Temperature: 70 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a stirred solution of tert-butyl 3-ethynyl-1-adamantylcarbamate (120 mg, 0.44 mmol) and 2-chloropyrazine (120 mg, 1.05 mmol) in TEA (3 mL) and acetonitrile (15 mL) was added Pd(PPh3)4 (5 mg, 0.04 mmol), followed by an addition of Cut (5 mg, 0.026 mmol) under N2 atmosphere. After stirring at 70° C. for three hours, the reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1) to give 108 mg (70%) of the title compound, tert-butyl 3-(pyrazin-2-ylethynyl)-1-adamantylcarbamate as a white solid. ESI-MS m/z: 298 (M-55)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:17][C:16]2[NH:15][N:14]=[C:13]([CH3:18])[C:12]=2[C:11](=O)[CH2:10]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:11]1[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:17][C:16]2[NH:15][N:14]=[C:13]([CH3:18])[C:12]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: N=C(N)NN
Reactant: COc1ccccc1C1CC(=O)c2c(C)n[nH]c2C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccccc1C1CC(=NNC(=N)N)c2c(C)n[nH]c2C1
Yield: 110.2 %

Procedure:
A mixture of 6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.2 g), aminoguanidine hydrochloride (0.095 g), concentrated hydrochloric acid (0.12 ml), water (0.12 ml) and ethanol (30 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was washed with ethyl acetate and concentrated under reduced pressure, and the resulting crystals were recrystallized from water-ethanol to give 4-guanidinoimino-6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 25) (0.3 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[C:29]([NH2:34])([CH2:32][CH3:33])([CH3:31])[CH3:30]>C(Cl)(Cl)Cl>[C:29]([NH:34][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])([CH2:32][CH3:33])([CH3:31])[CH3:30]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCC(C)(C)N
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(C)(C)NC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 54 %

Procedure:
A mixture containing 8.16 g (0.04 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 6.2 ml (0.044 mol) of triethylamine in 240 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 4 ml (0.042 mol) of ethyl chloroformate in 20 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -17° C. during 15 minutes. After stirring for 5 minutes, 3.84 g (0.044 mol) of tert.-pentylamine dissolved in 40 ml of chloroform are dropped to the above solution at the same temperature during 15 minutes. The reaction mixture is stirred for 1 hour at about -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 50 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 50 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. The residue slowly becomes crystalline to give 5.9 g (54%) of the named compound, m.p.: 87°-89° C. after recrystallization from ethanol.
Reaction SMILES: Cl[C:2]([CH3:7])([OH:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl>[OH-].[Na+]>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:7][CH:2]([OH:6])[C:3]([OH:5])=[O:4])=[CH:11][CH:10]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(O)(Cl)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(O)COc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.8 g (14.7 mmoles) 3=chlorolactic acid and 3.4 g p-chlorophenol in 15 ml 3.3 N sodium hydroxide was stirred under reflux for two hours. The mixture was cooled to room temperature and acidified to pH=3, with concentrated hydrochloric acid. The resulting white crystals were filtered and dissolved in hot water and the hot solution was adjusted to pH=1 with concentrated sulfuric acid. Upon cooling the product, 3-(p-chlorophenoxy)-lactic acid was collected as clear crystals, 0.7 g, m.p. 135° to 136° C.; Edelson, et al., Biochem Pharmacol 18, 2331 (1969) reported m.p. 137° to 138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23]OS(C)(=O)=O)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[I-:29].[Na+]>CC(=O)CC>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][I:29])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCI)CC1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.50 g (1.11 mmol) of crude methanesulfonic acid 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl ester in 20 ml of 2-butanone was treated with 0.33 g (2.23 mmol) of sodium iodide and stirred at 95° C. for 30 min. The reaction was cooled, evaporated, suspended in 60 ml dichloromethane/Et2O (1:3), filtered and the organic solvent discarded. The residue was then washed again with dichloromethane to give after evaporation 0.27 g (51%) of the title compound as white solid. MS: 481.0 (MH+, 2Cl).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)([CH3:11])[C:9](=[O:20])[N:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:7]1=[O:27])C.[OH-].[Na+]>C1COCC1.CS(C)=O>[F:18][C:16]1[CH:17]=[C:12]([C:10]2([CH3:11])[N:6]([CH2:5][C:4]([OH:28])=[O:3])[C:7](=[O:27])[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:9]2=[O:20])[CH:13]=[C:14]([F:19])[CH:15]=1
Reactant: CCOC(=O)CN1C(=O)N(c2ccccn2)C(=O)C1(C)c1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2cc(F)cc(F)c2)C(=O)N(c2ccccn2)C(=O)N1CC(=O)O
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl[5-(3,5-difluorophenyl)-5-methyl-2,4-dioxo-3-pyridin-2-ylimidazolidin-1-yl]acetate, isomer A from Step A (67.0 mg, 0.172 mmol) in THF (2 mL) was added a solution of 1 N NaOH (0.516 mL, 0.516 mmol) and stirring continued for 16 h. The reaction mixture was diluted with DMSO (1 mL) and purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the racemic title compound. MS: m/z=362 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:57]1[CH2:61][CH2:60][CH2:59][CH:58]1[C:62]([O:64][CH3:65])=[O:63]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29]([N:57]2[CH2:61][CH2:60][CH2:59][CH:58]2[C:62]([O:64][CH3:65])=[O:63])=[O:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCCN1
Reactant: O=C(O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C1CCCN1C(=O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
To a stirred solution of 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinic acid (80.0 mg, 0.190 mmol) (prepared as in Example 12) in DMF (2 mL), were added DMAP (35.0 mg, 0.285 mmol) and HATU (108 mg, 0.285 mmol) and the reaction mixture was stirred for 10 minutes. Methyl pyrrolidine-2-carboxylate (12.0 g, 0.0950 mmol) was added and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture concentrated under reduced pressure to remove DMF and to the resulting residue water (10 mL) was added. The aqueous mixture was extracted with CH2Cl2 (15×2 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-68 as described in general methods) to obtain methyl 1-(5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinoyl)pyrrolidine-2-carboxylate (30.0 mg, 59.3%). LCMS Condition B-14: retention time 2.31 min, [M−1]=531.2. HPLC Condition B-63: retention time 16.30 min, Purity 99.70%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.87-1.98/2.30-2.35 (m, 4H), 3.44/3.70 (s, 3H), 3.55/3.67 (dd, J=6.0 Hz, J=6.8 Hz, 2H), 4.47-4.49/4.56-4.58 (m, 1H), 4.54/4.82 (d, J=5.6 Hz, 2H), 6.71/6.76 (t, J=5.6 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 7.23-7.56 (m, 10H), 7.91/7.94 (d, J=2.8 Hz, 1H), 8.44/8.58 (t, J=2.0 Hz, 1H), 8.65/8.81 (d, J=2.0 Hz, 1H), 9.39/9.44 (d, J=2.0 Hz, 1H). Molecule exists as two rotomers with ratio 70/30.
Reaction SMILES: [CH3:1][C:2]([CH3:77])=[CH:3][CH2:4][CH2:5][C@:6]([O:54][C@@H:55]1[O:60][C@H:59]([CH2:61][O:62][C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H:58]([OH:74])[C@H:57]([OH:75])[C@H:56]1[OH:76])([C@@H:8]1[C@H:12]2[C@H:13]([OH:52])[CH2:14][C@@H:15]3[C@@:20]4([CH3:50])[CH2:21][CH2:22][C@H:23]([O:27][C@@H:28]5[O:33][C@H:32]([CH2:34][OH:35])[C@@H:31]([OH:36])[C@H:30]([OH:37])[C@H:29]5[O:38][C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)[C:24]([CH3:26])([CH3:25])[C@@H:19]4[CH2:18][CH2:17][C@@:16]3([CH3:51])[C@:11]2([CH3:53])[CH2:10][CH2:9]1)[CH3:7]>O>[CH3:1][C:2]([CH3:77])=[CH:3][CH2:4][CH2:5][C@:6]([O:54][C@@H:55]1[O:60][C@H:59]([CH2:61][OH:62])[C@@H:58]([OH:74])[C@H:57]([OH:75])[C@H:56]1[OH:76])([C@@H:8]1[C@H:12]2[C@H:13]([OH:52])[CH2:14][C@@H:15]3[C@@:20]4([CH3:50])[CH2:21][CH2:22][C@H:23]([O:27][C@@H:28]5[O:33][C@H:32]([CH2:34][OH:35])[C@@H:31]([OH:36])[C@H:30]([OH:37])[C@H:29]5[OH:38])[C:24]([CH3:25])([CH3:26])[C@@H:19]4[CH2:18][CH2:17][C@@:16]3([CH3:51])[C@:11]2([CH3:53])[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(C)=CCC[C@](C)(O[C@@H]1O[C@H](CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@H](O)[C@H]1O)[C@H]1CC[C@]2(C)[C@@H]1[C@H](O)C[C@@H]1[C@@]3(C)CC[C@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)C(C)(C)[C@@H]3CC[C@]12C
Solvent: O
Product: CC(C)=CCC[C@](C)(O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H]1CC[C@]2(C)[C@@H]1[C@H](O)C[C@@H]1[C@@]3(C)CC[C@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)C(C)(C)[C@@H]3CC[C@]12C
Yield: 96.1 %

Procedure:
200 g ginsenoside Rb1 with high purity is taken into reaction vessel, 500 ml of purified water is added, and alpha-galactosidase is added, it is decomposed by enzymolysis at 30° C. for 4˜44 hours (more preferably 8˜12 hours, extracted with 200 ml n-butanol for three times, and the n-butanol is combined, concentrated under reduced pressure and dried to obtain 136 g ginsenoside F2.