Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O.Cl.[NH2:29][CH:30]1[C:55](=[O:56])[N:32]2[C:33]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:34]([CH:37]=[CH2:38])[CH2:35][S:36][C@H:31]12.C[Si](CC(N)=O)(C)C.C(OC(C)C)(C)C>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([NH:29][CH:30]1[C:55](=[O:56])[N:32]2[C:33]([C:39]([O:41][CH:42]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:40])=[C:34]([CH:37]=[CH2:38])[CH2:35][S:36][C@H:31]12)=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 93.9 %

Procedure:
The activated acid, which was prepared from 2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (13.8 g), N,N-dimethylformamide (3.66 g) and phosphorus oxychloride (7.7 g) in tetrahydrofuran (80 ml) in a conventional manner, was added to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (15 g) and trimethylsilylacetamide (32 g) in ethyl acetate (150 ml) at -20° C. with stirring, and the stirring was continued at the same temperature for half an hour. After addition of water (100 ml), the ethyl acetate layer was separated out, and washed with an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and then an aqueous solution of sodium chloride in turn, followed by drying over anhydrous magnesium sulfate. Removal of the solvent gave an oil, which was pulverized with diisopropyl ether and washed with the same to obtain benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (23.1 g), mp 101° C. (dec.).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8]1[C:9]([F:21])=[C:10]([C:13]([CH2:19]O)=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[C:11]#[N:12])[CH3:6].C(OCC)(=O)C.O>COCCOC>[Br:2][CH2:19][C:13]1[C:10]([C:11]#[N:12])=[C:9]([F:21])[C:8]([O:7][CH2:5][CH3:6])=[C:15]([O:16][CH2:17][CH3:18])[CH:14]=1
Reactant: BrP(Br)Br
Reactant: CCOc1cc(CO)c(C#N)c(F)c1OCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(CBr)c(C#N)c(F)c1OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 180.4 %

Procedure:
Phosphorus tribromide (PBr3, 1.57 mL, 16.7 mmol) was added to a solution of 3,4-diethoxy-2-fluoro-6-(hydroxymethyl)benzonitrile (38.0 g, 33.4 mmol) in 1,2-dimethoxyethane (DME) (80 mL) on ice, followed by 3 hours of stirring at room temperature. After the reaction solution was cooled on ice, ethyl acetate and water were added. The organic layer was separated, and the aqueous layer was extracted further with ethyl acetate. The combined extract solutions were washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and after addition of activated charcoal, were dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, followed by addition of n-heptane (100 mL) to the residue, and the solvent was distilled off again. n-Heptane (100 mL) was added to the residue, and this was cooled on ice. Precipitated crystals were collected by filtration, and washed with n-heptane to give 9.1 g of the subject compound (yield: 90.1%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:13][C:14]1[N:19]=[C:18]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:17]=[C:16]2[N:35]([CH2:46][C:47]3[C:52]([CH3:53])=[C:51]([O:54][CH3:55])[C:50]([CH3:56])=[CH:49][N:48]=3)[N:36]=[C:37]([CH2:38][CH:39]3[CH2:43][O:42]C(C)(C)[O:40]3)[C:15]=12>CO.[Cl-].[Na+].O>[Cl:13][C:14]1[N:19]=[C:18]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[N:17]=[C:16]2[N:35]([CH2:46][C:47]3[C:52]([CH3:53])=[C:51]([O:54][CH3:55])[C:50]([CH3:56])=[CH:49][N:48]=3)[N:36]=[C:37]([CH2:38][CH:39]([OH:40])[CH2:43][OH:42])[C:15]=12
Reactant: COc1c(C)cnc(Cn2nc(CC3COC(C)(C)O3)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C)cnc(Cn2nc(CC(O)CO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 82 %

Procedure:
p-Toluenesulfonic acid monohydrate (3.76 g) was added to a solution of di-tert-butyl {4-chloro-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate of 6) above (12.52 g) in methanol (250 mL), and the mixture was stirred at room temperature for seven hours. The reaction mixture was poured into brine, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain the title compound (9.64 g, 82%) as an amorphous substance.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36]>>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH:5]1[N:6]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([OH:37])=[O:36])=[C:4]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Yield: 41.4 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(3-fluoropyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.34 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C1COCC1.CO.C[O:9][C:10](=[O:40])[C@H:11]([CH2:36][CH2:37][S:38][CH3:39])[NH:12][C:13](=[O:35])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:16][C:15]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].O.[OH-].[Li+]>O>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][O:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C@H:11]([C:10]([OH:40])=[O:9])[CH2:36][CH2:37][S:38][CH3:39])=[O:35])=[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COCc2cccs2)cc1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CSCC[C@H](NC(=O)c1ccc(COCc2cccs2)cc1-c1ccccc1C)C(=O)O
Reaction time: 3.5 h

Procedure:
To a solution in 1:1 THF-methanol of [4-(2-thienylmethoxymethyl)-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 272C was added a solution of lithium hydroxide hydrate (40 mg, 0.95 mmol) in water (0.5 mL) and the reaction mixture was stirred for 3.5 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ether and water. Aqueous 2N HCl (1 mL) was added to the aqueous phase. The aqueous phase was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give [4-(2-thienylmethoxymethyl)-2-(2-methylphenyl)benzoyl]methionine. The acid was dissolved in acetonitrile (5 mL) and a solution of lithium hydroxide hydrate (18 mg, 0.43 mmol) in water (8 mL) was added. The mixture was concentrated and the residue was dissolved in water, frozen and lyophilized to give [4-(2-thienylmethoxymethyl)-2-(2-methylphenyl)benzoyl]methionine lithium salt (204 mg) as a light-yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:34][CH:35]5[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]5)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(CCO)CC1
Product: COc1cc(C(=O)NC2CCN(CCO)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 2-(4-aminopiperidin-1-yl)ethanol as described in the General procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.86 (m, 12 H) 1.88-2.10 (m, 5 H) 2.33-2.42 (m, 2 H) 2.84 (d, J=11.4 Hz, 2 H) 3.48 (q, J=6.2 Hz, 2 H) 3.73 (d, J=4.6 Hz, 1 H) 4.08 (t, J=14.0 Hz, 2 H) 4.37 (t, J=5.4 Hz, 1 H) 4.82 (t, J=8.2 Hz, 1 H) 7.18 (d, J=6.6 Hz, 1 H) 7.90 (dd, J=7.7, 3.4 Hz, 1 H) 8.04 (s, 1 H) 8.18-8.34 (m, 2 H). [M+H] calc'd for C28H36F3N7O4, 592; found 592.
Reaction SMILES: C[C:2](C)([O-:4])C.[Na+].[CH3:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:38])(=[O:37])[NH:27][CH2:28][CH2:29]CN4CCCC4=O)=[CH:22][CH:21]=3)[N:14]=2)=[CH:11][N:10]=[C:9]1[CH3:39].COCCNS(C1C=CC(I)=CC=1)(=O)=O.CO>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([S:26](=[O:37])(=[O:38])[NH:27][CH2:28][CH2:29][O:4][CH3:2])=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][N:10]=[C:9]1[CH3:39]
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NCCCN4CCCC4=O)cc3)n2)n1C
Reactant: CC(C)(C)[O-]
Agent: [Pd]
Agent: COCCNS(=O)(=O)c1ccc(I)cc1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: COCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3C)n2)cc1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
Sodium t-butoxide (1.04 g, 10.8 mmol) was added to a degassed solution of 2-amino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 26; 567 mg, 3 mmol), N-(2-methoxyethyl)-4-iodobenzenesulphonamide (Method 40; 1.54 g, 4.5 mmol), tris(dibenzylideneacetone) dipalladium (0) (72 mg, 0.15 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (102 mg, 0.15 mmol) in dioxane (36 ml) and the mixture heated at 80° C. overnight. The reaction was cooled to room temperature and MeOH (5 ml) was added and the mixture poured onto an Isolute SCX-2 column, eluted first with MeOH (10×30 ml) and the product was then eluted with 2% methanolic ammonia (10×30 ml). The solvent was removed by evaporation and the residue was dissolved in EtOAc (100 ml), washed with water (3×100 ml) and then brine (100 ml), dried and the solvent removed by evaporation to give the title compound (1.01 g, 84%) as a foam. NMR 2.40 (s, 3H), 3.07 (q, 2H), 3.20 (s, 3H), 3.38 (t, 2H), 3.86 (s, 3H), 5.00 (t, 1H), 6.95 (d, 1H), 7.47 (s, 2H), 7.71 (m, 4H), 8.36 (d, 1H); m/z 403.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[Br:20][C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=[C:17]([I:19])[CH:16]=1
Reactant: O=C(NC(=S)Nc1cc(Br)cc(I)c1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=S)Nc1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
A stirred suspension of 1-Benzoyl-3-(3-bromo-5-iodophenyl)-thiourea (20.70 g, 0.0449 mol) in methanol (303 ml) was treated with sodium methoxide (2.42 g, 0.0449 mol) and stirred at ambient temperature for 4 h. The resultant suspension was evaporated to dryness at reduced pressure. The residue was mixed with water (500 ml) and extracted with ethyl acetate (3×200 ml) which was dried (MgSO4) and the solvent removed in vacuo to give a residue which was triturated with 40-60° petroleum ether/diethyl ether (1:1) to afford (3-Bromo-5-iodophenyl)-thiourea as an off-white solid (14.35 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7]C(OC(C)(C)C)=O)=[N:4][C:3]=1/[C:15](=[CH:19]/[CH3:20])/[C:16]([OH:18])=[O:17]>FC(F)(F)C(O)=O>[NH2:7][C:5]1[S:6][C:2]([Cl:1])=[C:3](/[C:15](=[CH:19]/[CH3:20])/[C:16]([OH:18])=[O:17])[N:4]=1
Reactant: C/C=C(\C(=O)O)c1nc(NC(=O)OC(C)(C)C)sc1Cl
Solvent: O=C(O)C(F)(F)F
Product: C/C=C(\C(=O)O)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.7 g of Z-2-(5-chloro-2-tert.-butoxycarbonylaminothiazol-4-yl)but-2-enoic acid are dissolved in 5 ml of trifluoroacetic acid at 0° C. under nitrogen. The mixture is stirred at room temperature for one hour and evaporated in the cold and the residue is suspended in ethyl acetate. The pH is brought to 3.5 with saturated sodium bicarbonate solution, while stirring, the product first dissolving and then precipitating again. The product is filtered off with suction, washed with ethyl acetate and dried.
Reaction SMILES: C([Li])CCC.CCCCCC.C(C(C1C=CC(Cl)=CC=1)=[C:20]1[C:32]2[C:24]([CH:25]=[C:26]3[C:31]=2[CH:30]=[C:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:27]3)=[C:23](C2C=CC=C2)[C:22]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[C:21]1[C:54]([CH3:57])([CH3:56])[CH3:55])C1C=CC=CC=1.[CH3:65][C:66]([C:72]1[CH:77]=[CH:76][C:75]([CH3:78])=[CH:74][CH:73]=1)=[C:67]1[CH:71]=[CH:70][CH:69]=[CH:68]1>O1CCCC1>[CH3:65][C:66]([C:72]1[CH:73]=[CH:74][C:75]([CH3:78])=[CH:76][CH:77]=1)([CH:67]1[CH:68]=[CH:69][CH:70]=[CH:71]1)[C:23]1[C:24]2[CH2:25][C:26]3[C:31](=[CH:30][C:29]([C:33]([CH3:34])([CH3:36])[CH3:35])=[C:28]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:27]=3)[C:32]=2[CH:20]=[C:21]([C:54]([CH3:56])([CH3:55])[CH3:57])[C:22]=1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(=C1C=CC=C1)c1ccc(C)cc1
Reactant: CC(C)(C)c1cc2c(cc1-c1ccccc1)=Cc1c(C3C=CC=C3)c(-c3ccccc3)c(C(C)(C)C)c(=C(Cc3ccccc3)c3ccc(Cl)cc3)c1=2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(C)(c2c3c(cc(C(C)(C)C)c2-c2ccccc2)-c2cc(C(C)(C)C)c(-c4ccccc4)cc2C3)C2C=CC=C2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under a nitrogen atmosphere, a solution of n-butyllithium in hexane (6.3 ml, 10.2 mmol) was dropped into a solution of 2,7-diphenyl-3,6-di-tert-butylfluorene (4.0 g, 9.3 mmol) in dry tetrahydrofuran (50 ml) at −10° C., and then the product was stirred at room temperature for 20 hours. Then, 6-methyl-6-(p-tolyl)fulvene (1.9 g, 10.2 mmol) was dropped into this solution at −10° C., and the product was stirred at room temperature for 2 hours to induce a reaction. After the reaction was terminated, dilute aqueous hydrochloric acid was added thereto, the product was subjected to extraction with hexane, the organic layer was subsequently washed with water and then dehydrated with anhydrous magnesium sulfate, and then the solvent was distilled off to produce a light brown solid. The produced solid was recrystallized with methanol to obtain 5.1 g of an objective. The analytical values were as follows.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])[CH2:5][C:6]([F:15])([F:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.O.O>[F:15][C:6]([F:14])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][C@H:4]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)=[O:18])[C:3]([OH:25])=[O:2]
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Solvent: CO
Solvent: O
Product: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a solution of (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid methyl ester (2.81 g, 7.88 mmol) in MeOH:H2O (2:1 vol, 40 mL) is added LiOH mono hydrate (662 mg, 15.76 mmol). The mixture is stirred at room temperature for 2.5 h, and then diluted with water (30 mL). Methanol is removed in vacuum. The pH is adjusted to pH 1 with 6N HCl and the aqueous layer is extracted with dichloromethane (2×30 mL). The organic layers are dried over magnesium sulfate and concentrated in vacuum to afford (S)-4,4-Difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid (2.509 g, 93%).
Reaction SMILES: C(OCC)(=O)C.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N+:31]([O-])=O)=[C:12]([CH:30]=1)[O:13][C:14]1[CH:15]=[C:16]([C@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[CH:17]=[CH:18][CH:19]=1.Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+]>[C].[Pd].O.CN(C)C=O>[C:25]([O:24][C:23]([NH:22][C@@H:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][C:12]1[CH:30]=[C:8]([Cl:7])[CH:9]=[CH:10][C:11]=1[NH:31][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:21])=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)CCCBr
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc([C@@H](C)NC(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 56.5 %

Procedure:
5% carbon-palladium (1.I g) was added to an ethyl acetate (50 ml) solution of tert-butyl(1R)-(-)-1-[3-(5-chloro-2-nitrophenoxy)phenyl]ethylcarbamate (3.5 g, 8.9 mmols). The resulting mixture was hydrogenated at room temperature under atmospheric pressure for 1 hour. The catalyst was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was stirred with ethyl 4-bromobutyrate (7 g, 36 mmols), potassium carbonate (3.7 g, 27 mmols) and N,N-dimethylformamide (50 ml) at 80° C. for 72 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[N-[2-[3-[(1R)-1-tert-butoxycarbonylaminoethyl]phenoxy]-4-chlorophenyl]]aminobutyrate (2.4 g, 56%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]([F:28])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH2:22][CH2:23][CH2:24][NH2:25])[N:16]=1.CCO>C(N(CC)CC)C>[F:28][C:10]([F:9])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH2:22][CH2:23][CH2:24][NH:25][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[N:16]=1
Reactant: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: O=C(Cl)c1ccco1
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NCC(F)(F)F)Nc1ccnc(SCCCNC(=O)c2ccco2)n1
Reaction time: 2 h
Yield: 74.6 %

Procedure:
2-Furoyl chloride (145 mg.) was added to a mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylthio)pyrimidine (308 mg.), EtOH (10 ml.) and triethylamine (0.5 ml.), the mixture left at room temperature for 2 hours and then evaporated to dryness. The residue was dissolved in N aqueous HCl and the solution washed with EtOAc. The aqueous phase was basified with 10N aqueous NaOH and then extracted with EtOAc, and the extract was dried amd evaporated to dryness. The residue was recrystallised from EtOAc to give N-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimidin-2-yl-thio)propyl]-2-furamide (300 mg.), m.p. 127°-129°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[I:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[I:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: CN1CCC(c2c[nH]c3ccc(NS(=O)(=O)c4ccc(I)cc4)cc23)CC1

Procedure:
Following the procedure described in detail in Example 39, 0.791 gm (3.45 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 1.1 gm (3.62 mMol) 4-iodobenzenesulfonyl chloride were used to prepare 0.809 (47.3%) of the title compound as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][N:23](C1CCCCO1)[OH:24].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][NH:23][OH:24]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCN(O)C3CCCCO3)c3cc(F)ccc32)cc1
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: CSc1ccc(/C=C2/C(C)=C(CCNO)c3cc(F)ccc32)cc1

Procedure:
A mixture of the indene intermediate from Step 3 (1 g, 2.35 mmol) and (1R)-(−)-l0-camphorsulfonic acid (546 mg, 2.35 mmol) in methanol (30 mL) was refluxed for 3 hours. The methanol was evaporated, the residue dissolved in ethyl acetate and the solution washed successively with water, twice with saturated aqueous sodium bicarbonate, and with water. After drying over Na2SO4, the residue obtained on evaporation of the solvent was triturated with ether and filtered to obtain the title compound as a yellow solid, mp: dec 126° C. which was identical to the product obtained in Method A, Step 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:22][C:20]1[C:19]([CH:25]2[CH2:27][CH2:26]2)=[CH:18][C:11]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH:21]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc([N+](=O)[O-])c(C3CC3)cc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N)c(C3CC3)cc12
Yield: 114.3 %

Procedure:
To a solution of ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3-carboxylate (8 g, 18.2 mmol) in ethyl acetate (450 mL) was added 10% palladium on carbonate (1.83 g), 1N HCl solution (2.5 mL), and stirred with under 0.4 MPa of hydrogen at room temperature for 8 hrs. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give ethyl 6-amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate as a brown solid (7.4 g, 99%).