Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([NH:21][C@H:22]([C:26]([NH:28][CH:29]([CH:37]([OH:64])[CH:38]([NH:46][C:47](=[O:63])[C@H:48]([CH:60]([CH3:62])[CH3:61])[NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O.C(Cl)Cl>[C:50]([NH:49][C@H:48]([C:47]([NH:46][CH:38]([C:37](=[O:64])[CH:29]([NH:28][C:26](=[O:27])[C@H:22]([CH:23]([CH3:25])[CH3:24])[NH:21][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:63])[CH:60]([CH3:61])[CH3:62])([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(=O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.9 %

Procedure:
To a cold (-78° C.) solution of oxalyl chloride (93 mg, 0.73 mmol) in 11 mL of freshly distilled methylene chloride was added, with stirring, 103 μL (1.46 mmol) of DMSO. To this soltuion at -78° C. after stirring for 5 minutes was added a solution of the resultant compound of Example 70 (450 mg, 0.61 mmol) in 5.5 mL of methylene chloride/DMSO (10:1). The reaction mixture was stirred at -78° C. for ~50 min, triethylamine (426 μL, 3.0 mmol) was added and stirring was continued for 5 min at -78° C. The cold bath was removed and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with 150 mL of chloroform. The chloroform solution was washed with 100 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in -3 mL of chloroform and applied to a 1.0×45 cm column of silica gel. The column was eluted with 100 mL of chloroform and 100 mL of 0.5% methanol in chloroform to give 376 mg (84% yield) of the title compound; DCI/NH3 MS M/Z: 501 (M+ NH4)+. The 300 MHz 1H NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: Fc1ccccc1I
Product: Fc1ccccc1-n1ccc2ccc(Cl)cc21

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-fluoro-2-iodobenzene: ESMS m/e: 245.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]2([CH2:27][CH:28]([CH3:30])[CH3:29])[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19](=[O:26])[O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:1]([NH:8][C:9]([N:23]1[CH2:24][CH2:25][C:20]2[C:19](=[O:26])[O:18][C:17]([CH2:27][CH:28]([CH3:29])[CH3:30])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:21]=2[CH2:22]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Benzyl isocyanate (0.02 9 g, 0.22 mmol) was added to a solution of 3-phenyl-3-isobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (0.05 g, 0.184 mmol prepared in a manner analogous to compound 2) in dichloromethane (5 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.051 g, 68%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.85 (d, J=6.40 Hz, 3H), 0.89-0.98 (m, 3H), 1.65 (ddd, J=13.56, 6.78, 4.90 Hz, 1H), 1.73-1.87 (m, 1H), 2.24-2.40 (m, 3H), 3.27 (ddd, J=13.56, 7.35, 5.09 Hz, 1H), 3.54 (dt, J=13.66, 5.23 Hz, 1H), 3.92 (dt, J=18.84, 2.64 Hz, 1H), 4.40 (d, J=5.65 Hz, 2H), 4.49 (dt, J=19.12, 2.12 Hz, 1H), 5.00 (t, J=5.46 Hz, 1H), 7.21-7.42 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1.[CH3:35][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])([CH3:35])[CH3:9])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(C)=O)c12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(C)(C)O)c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In an oven dried flask and under a nitrogen gas atomosphere, 1-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)ethanone (39B, 110 mg, 0.235 mmol) was dissolved in THF (2.0 ml) cooled to −78° C. and charged with methylmagnesium bromide (0.470 ml, 0.470 mmol). The reaction was allowed to stir for 1 hr, eventually reaching 0° C. The reaction was slowly quenched with saturated ammonium chloride (3 mL) and partioned between EtOAc 2×10 mL, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 2-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)propan-2-o (Intermediate 40B). The products were carried forward without purification. MS: [M+H]+ m/z 484.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=[C:11]([O:23]CC2C=CC=CC=2)[N:10]=1)C1C=CC=CC=1.II.S([O-])([O-])(=O)=S.[Na+].[Na+].[C:40]1([CH3:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:46]([N:14]1[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:12][C:11](=[O:23])[N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:8])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: c1ccc(COc2nc(OCc3ccccc3)nc(OCc3ccccc3)n2)cc1
Reactant: Cc1ccccc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: O=c1nc(OCc2ccccc2)n(Cc2ccccc2)c(=O)n1Cc1ccccc1
Yield: 21 %

Procedure:
Furthermore, a synthesis method of the hydroxy group-protecting agent 5 will be explained. To a 10 mL eggplant flask, 599.2 mg (1.50 m mol) of 2,4,6-tribenzyloxy-1,3,5-triazine, 5.00 mL of toluene and 38.8 mg (030 m mol) of iodine were added, heat-perfused, and reacted for 31 hours. After the reaction, 5 mL of an aqueous solution of saturated sodium thiosulfate was added, which was washed with 5 mL of 1 N sodium bicarbonate water, 5 mL of 1 N hydrochloric acid, 5 mL of water and 5 mL of saturated salt water. A resulting organic phase was dried by magnesium sulfate, from which the solvent was distilled away, and the residue was isolated and purified by silica-gel chromatography to obtain 126.2 mg of 1,3-dibenzyl-6-(benzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione (yield: 21%).
Reaction SMILES: [NH2:1]C1C=CC(CC2C=C(CC3C=CC(N)=CC=3)C=CC=2N)=CC=1.[C:24]1(=O)[O:29][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>O>[C:24]1(=[O:29])[NH:1][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12
Reactant: Nc1ccc(Cc2ccc(N)c(Cc3ccc(N)cc3)c2)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Product: O=C1NC(=O)c2ccccc21

Procedure:
A phthalimide-amine was prepared by mixing in a 2 liter glass resin kettle equipped with a mechanical stirrer, a heating mantle, a thermocouple connected to a temperature recorder, and an overhead water trap with a vertical condenser, 2.0 moles (600 grams) of BABA (a product of the E. I. duPont de Nemours & Company containing primarily 2,4-Bis(p-aminobenzyl)aniline) and 3.0 moles (444 grams) of phthalic anhydride. Heat was applied, and at about 100° C., the BABA melted and phthalic anhydride started slowly to react. The temperature was slowly allowed to rise to 150° C., at which time water began to condense overhead. Heating continued until 3.0 moles (54 grams) of water were collected. Since 2.0 moles of BABA contain 6 primary amines and three of them reacted with phthalic anhydride to form phthalimide linkages, 3 primary amine groups remained per 2 moles of BABA phthalimide. Since the molecular weight of this BABA phthalimide is 300+222-27=495, and contains 3 aminic hydrogens, its amine equivalent is 495/3=165, which corresponds to one epoxide equivalent or 180 grams of EPON-828 or 826 (the diglycidel ether of bisphenol-A such as is produced by the Shell Corporation). In other words, 47 grams of the aromatic amine of this example correspond to 51.3 grams of EPON-828.
Reaction SMILES: OCCCCC[CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1.N1CCC([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])CC1>>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH:12]1[CH2:7][CH2:8][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH2:10][CH2:11]1
Reactant: OCCCCCCC1CCNCC1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCCCO)C1
Product: O=C(OCc1ccccc1)N1CCC(CCCCCCO)CC1

Procedure:
Prepared similarly to Intermediate 64 from 6-(4-piperidinyl)-1-hexanol. LCMS (System B): tRET=3.00 min; MH+ 320
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:18]([O:20][P:21](C#N)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:19].C(N(CC)CC)C>ClCCl.O>[CH2:18]([O:20][P:21]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[CH:12][CH:13]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(OCC)Oc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
1.2 g (5 mmol) of N-Boc tyramine, 0.9 g (5.5 mmol) of diethylcyanophosphonate and 1.4 ml (10 mmol) of triethylamine are placed in solution in 5 ml of dichloromethane at 0° C. under an argon atmosphere. The reaction mixture is stirred for 30 minutes at 0° C. followed by diluting with 25 ml of water and extracting with twice 30 ml of dichloromethane. The organic phases are combined followed by washing with 50 ml of water then 25 ml of a saturated solution of sodium chloride. The organic phase is dried over magnesium sulphate, followed by filtering and concentrating under vacuum. The expected product is obtained in the form of a clear oil with a yield of 92% (1.73 g).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[O:32][CH3:33])(=[O:23])=[O:22].CO[C:36]1C=CC(OC)=C[C:37]=1S(Cl)(=O)=O>>[CH2:36]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[O:32][CH3:33])(=[O:23])=[O:22])[CH:4]=2)=[CH:10][CH:11]=1)[CH3:37]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: COc1ccc(OC)c(S(=O)(=O)Nc2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc2Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cc(OC)ccc3OC)c2)cc1

Procedure:
4-[4-Chloro-3-(2,5-dimethoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=489.2 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 2,5-dimethoxy-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(2,5-dimethoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH3:18])[N:8]=1)=[O:6].Cl[C:31]1[N:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN(C)C=O>[NH2:39][C:37]([C:35]1[CH:34]=[CH:33][N:32]=[C:31]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH3:18])[N:8]=2)=[O:6])[N:36]=1)=[O:38]
Reactant: NC(=O)c1ccnc(Cl)n1
Reactant: COc1ccccc1OCCN(C)CCCNc1nccc(C(=O)NCCN)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OCCN(C)CCCNc1nccc(C(=O)NCCNc2nccc(C(N)=O)n2)n1
Temperature: 60 °C

Procedure:
3.0 g (7.45 mmol) of N-(2-aminoethyl)-2-[[3-[[2-(2-methoxyphenoxy) ethyl]methylamino]propyl]amino]-pyrimidine-4-carboxamide, 1.23 g (7.8 mmol) of 2-chloropyrimidine-4-carboxamide, 1.55 g (11.2 mmol) of potassiumcarbonate and 0.1 g of sodium iodide are introduced into 40 ml of N,N-dimethylformamide in a 0.25 l, three-necked, round-bottomed flask and the reaction mixture is heated at 60° C. for 15 h. The mixture is cooled to room temperature and the reaction product is poured onto 100 ml of water and extracted with ethyl acetate (3×100 ml). The organic phase is washed with water, dried over sodium sulphate, filtered and the solvents are evaporated under reduced pressure. After recrystallisation from ethyl acetate, 1.95 g of compound are obtained.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]=[CH:3][CH2:4][OH:5].N1C=CN=C1.[C:12]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13].C(OCC)(=O)C>ClCCl.CN(C)C=O>[Si:16]([O:5][CH2:4][CH:3]=[CH:2][CH2:1][OH:6])([C:12]([CH3:15])([CH3:14])[CH3:13])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC=CCO
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC=CCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 41.5 %

Procedure:
In a dichloromethane/N,N-dimethylformamide (200 ml/200 ml) mixture were dissolved 2-buten-1,4-diol (10.0 g, 113 mmol) and imidazole (4.70 g, 69.0 mmol), followed by the dropwise addition of t-butylchlorodiphenylsilane (30.0 ml, 115 mmol) at room temperature. After completion of the dropwise addition, the mixture was stirred at room temperature for 4 days. The residue obtained by concentrating the reaction mixture under reduced pressure was added with diethyl ether. From the resulting mixture, the insoluble matter was filtered off. The diethyl ether layer was washed with water and then, the organic layer was dried over anhydrous magnesium sulfate. After fitration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure, whereby the title compound (15.3 g, 46.9 mmol, 42%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br.N.CO>CC(O)=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[C:16]([Br:18])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(c1)ncn2Cc1ccccc1
Reactant: BrBr
Agent: N
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc2c(ncn2Cc2ccccc2)c1Br
Yield: 60 %

Procedure:
To a solution of 1-benzyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in 40 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitate. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CHC13) to provide 0.90g (2.5 mmol, 60%) of the product.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH2:9]([O:12][C:13](=[O:23])[C@H:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:15])[CH:10]=[CH2:11].C>O1CCOCC1>[N-:15]=[C:4]=[O:3].[CH2:9]([O:12][C:13](=[O:23])[C@H:14]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:15])[CH:10]=[CH2:11]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: C=CCOC(=O)[C@@H](N)Cc1ccccc1
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of phenylalanine allyl ester, prepared as described by H. Waldmann and H. Kunz in Liebigs Ann. Chem., 1983, 1712-1725, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give phenylalanine allyl ester isocyanate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=1>>[F:18][C:15]1[CH:14]=[N:13][C:12]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:17][CH:16]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Fc1cnc(Cl)nc1
Product: Oc1ccc(-c2ncc(F)cn2)cc1
Yield: 42 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 4-hydroxybenzene boronic acid and 2-chloro-5-fluoro-pyrimidine to afford the title compound as a white solid (575 mg, 42%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:16]3[CH2:15][CH:14]=[CH:13][CH2:12][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.[OH-:21].[Na+].O.OO>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:12][CH:13]([OH:21])[CH2:14][CH2:15][C:16]=3[C:17]2=[O:18])=[C:4]([F:20])[CH:3]=1
Reactant: [OH-]
Reactant: O=C1C2=C(CC=CC2)C(=O)N1c1cc(O)c(Cl)cc1F
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C2=C(CC(O)CC2)C(=O)N1c1cc(O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 500 mg(1.61 mmol) of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,7-dihydro-1H-isoindole-1,3(2H)-dione in 10 mL of tetrahydrofuran (THF) was added 1.94 mL of a 1M solution of BH3 in THF at 0° C. The mixture was then stirred at the same temperature for 1 h. Then, the mixture was warmed to room temperature. A solution of 3.0 mL of 6N aqueous sodium hydroxide, 1.8 mL of water, and 2.1 mL of 30% aqueous hydrogen peroxide were added subsequently. The mixture was stirred at the same temperature for 4 h. The crude product was diluted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel, eluting with a 1:2 v:v mixture of ethyl acetate and n-hexane to give 62 mg of the title product of Step B, a compound of the invention, as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 1.8 (br s, 1H), 1.95 (m, 2H), 2.8-2.4 (m, 4H), 4.4 (m, 1H), 5.85 (br s, 1H), 6.9 (s, 1H), 7.5 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[CH2:19][CH:18]([C:22]([OH:24])=O)[CH2:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:29][NH2:30].O>ClCCl.C(O)C>[CH3:29][NH:30][C:22]([CH:18]1[CH2:19][C:20](=[O:21])[N:16]([C:13]2[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:11][CH:12]=2)[CH2:17]1)=[O:24]
Reactant: CN
Reactant: O=C(O)C1CC(=O)N(c2ccc(/C=C/c3cccc(F)c3)cc2)C1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)C1CC(=O)N(c2ccc(/C=C/c3cccc(F)c3)cc2)C1
Temperature: 45 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A suspension of 300 mg (0.92 mmol) of (E)-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid in 5 ml of dichloromethane is treated with 549 mg (4.6 mmol) of thionylchloride and heated to 45° C. for 18 hours. Thereafter, the reaction mixture is evaporated to dryness under reduced pressure. The crude acid chloride obtained is dissolved in 5 ml of dry dichloromethane, then, at RT, 0.58 ml (4.61 mmol) of a solution of methylamine in ethanol (33%) is added and stirring continued for 3 hours. For the working-up, the reaction mixture is treated with water and dichloromethane. The organic layer is separated, dried over magnesium sulfate and evaporated. For purification, the crude product is chromatographed on silica gel using a 95:5-mixture of dichloromethane and methanol as the eluent. After crystallization from a mixture of dichloromethane and ether, there are obtained 207 mg (66% of theory) of (RS)-(E)-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a light brown solid; MS: m/e=339 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:20]=[C:14]([O:13][CH3:12])[CH:15]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Product: COc1cc(NC(=O)c2cc(Br)ccc2O)cc(C(F)(F)F)c1
Yield: 58.8 %

Procedure:
Using 5-bromosalicylic acid and 3-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH:17]2[C:21]([OH:23])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:38]([C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1)([O-:40])=[O:39].Cl>CN(C)C=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([S:24]([C:27]([F:28])([F:29])[F:30])(=[O:25])=[O:26])[CH:17]2[C:21]([O:23][CH2:45][C:44]1[CH:47]=[CH:48][C:41]([N+:38]([O-:40])=[O:39])=[CH:42][CH:43]=1)=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 46.6 %

Procedure:
To a solution of 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylic acid (547 mg.) in N,N-dimethylformamide (4 ml.) were added triethylamine (160 μl) and 4-nitrobenzyl bromide (276 mg.) at 0° C., and the mixture was stirred at room temperature for 18.5 hours. The reaction mixture was poured into a chilled dilute hydrochloric acid and then extracted with ethyl acetate (50 ml.). The extract was washed with water (×3), a dilute aqueous solution of sodium bicarbonate (×2), water and an aqueous solution of sodium chloride, successively. Drying over magnesium sulfate and removal of the solvent gave a residue (610 mg.), which was chromatographed on silica gel (9.5 g.) with a mixed solvent of benzene and ethyl acetate (10:1 to 5:1 by volume) to give an amorphous solid (328 mg.) of 4-nitrobenzyl 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate.