Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=1)=[O:13].[CH3:28][C:29]1[O:33][N:32]=[C:31]([C:34](Cl)=[O:35])[CH:30]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:22][N:21]([CH3:23])[C:17]1[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:9]([NH:8][C:34]([C:31]3[CH:30]=[C:29]([CH3:28])[O:33][N:32]=3)=[O:35])[CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Reactant: Cc1cc(C(=O)Cl)no1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cc(C(=O)Nc3cccc(N(C)C)c3)ccc2C)no1
Yield: 71.2 %

Procedure:
Triethylamine (0.129 ml) was added to a stirred mixture of 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.1 g), 4-dimethylaminopyridine (5 mg), 5-methylisoxazol-3-ylcarbonyl chloride (0.081 g) and methylene chloride (3 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with methylene chloride (10 ml), washed with a saturated aqueous sodium bicarbonate solution and dried over magnesium sulphate. The organic solution was evaporated and the residue was triturated under isohexane. The resultant solid was dried at 55° C. under vacuum to give the title compound as a solid (0.1 g); NMR Spectrum: (CDCl3) 2.42 (s, 3H), 2.55 (s, 3H), 2.97 (s, 6H), 6.55 (m, 2H), 6.89 (d, 1H), 7.23 (m, 2H), 7.36 (d, 1H), 7.72 (d, 1H), 7.84 (broad s, 1H), 8.55 (broad s, 2H); Mass Spectrum: M+H+ 379.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41]C(F)=CC=2)=S)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1.Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1[O:53]C1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1>>[CH:37]1([CH2:36][C:35]([NH:34][C:32]([NH:31][C:6]2[CH:7]=[CH:8][C:9]([O:10][C:11]3[C:16]4=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]5[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]5)=[CH:19][N:15]4[N:14]=[CH:13][N:12]=3)=[C:4]([F:3])[CH:5]=2)=[O:53])=[O:44])[CH2:42][CH2:41]1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)NC(=O)CC4CC4)cc3F)c12

Procedure:
Prepared in a similar manner as Example 264 using Compound B of Example and Compound A of Example 279 (21.0 mg, 81%). 1H NMR (CD3OD) δ 7.81 (s, 1H), 7.74 (d, 1H, J=5.5 Hz), 7.25 (m, 3H), 4.18 (t, 2H, J=5.5 Hz), 3.35 (t, 2H, J=1.7 Hz), 2.90 (t, 2H, J=5.5 Hz), 2.74–2.54 (m, 4H), 2.45 (s, 3H), 2.33 (t, 4H, J=2.8 Hz), 1.12 (m, 1H), 0.67–0.64 (m, 2H), 0.29–0.25 (m, 2H); MS(ESI+) m/z 529.3 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([C@@H:30]([CH3:49])[C@H:31]([N:46]=[N+:47]=[N-:48])[C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:46]([C@H:31]([C:32]1[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[C@@H:30]([NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[CH3:49])=[N+:47]=[N-:48]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@@H](C)[C@H](N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl{(1S,2R)-2-azido-2-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (21.7 mg, 0.030 mmol) in CH2Cl2 (2 mL) was added TFA (200 mL). The reaction was stirred at room temperature for 1 hour and then diluted with CH2Cl2 (25 mL). The CH2Cl2 solution was washed with 1 N NaOH (15 mL) and the aqueous phase was re-extracted with CH2Cl2 (25 mL). The organic extracts were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 15% EtOAc/hexanes afforded (1R,2S)-1-azido-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propan-2-amine. Rf=0.45 (15% EtOAc/hexanes). LCMS=619.2 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][CH3:56])=[CH:51][CH:50]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:55]([C:52]4[CH:53]=[CH:54][C:49]([O:48][CH3:47])=[CH:50][CH:51]=4)[CH3:56])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CNc1ccc(OC)cc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)c2ccc(OC)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-(4-methoxy-phenyl)-N-methyl-amine (Aldrich) to give the title compound. LC-MS (ES+) 784 [(M+H)+].
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.C([O-])([O-])=O.[Cs+].[Cs+].[C:11]([N:18]1[C:30]2[C:29]([OH:31])=[C:28]3[N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][C:38]=4[C:27]3=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[C:22]([F:47])[CH:23]=2)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(#N)C>[C:40]([N:32]1[C:28]2[C:29]([O:31][CH2:3][CH2:2][Br:1])=[C:30]3[N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:19]4[CH:20]=[CH:21][C:22]([F:47])=[CH:23][C:24]=4[C:25]3=[CH:26][C:27]=2[C:38]2[C:33]1=[CH:34][CH:35]=[C:36]([F:39])[CH:37]=2)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(OCCBr)c21
Yield: 77 %

Procedure:
To a solution of 1,2-dibromoethane (>5 equiv) in acetonitrile was added Cs2CO3 (2 equiv) and 5,7-diBOC-2,10-difluoro-6-hydroxyindolo[2,3-b]carbazole (1 equiv) under argon. The suspension was refluxed and the reaction was monitored by TLC. After completion of the reaction (1-3 hours), the solid was removed by filteration and washed with dichloromethane. The combined filtrate was concentrated and the residue was subjected to chromatography on silica gel, eluting with 8% ethyl acetate in hexanes to give 5,7-diBOC-2,10-difluoro-6-(2-bromoethoxy)indolo[2,3-b]carbazole (77%). 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (s, 1H), 8.06 (dd, J=9.0, 4.2 Hz, 2H), 7.68 (dd, J=8.4, 2.8 Hz, 2H), 7.17 (td, J=9.0, 2.8 Hz, 2H), 4.21 (t, J=6.8 Hz, 2H), 3.42 (t, J=7.0 Hz, 2H), 1.74 (s, 18H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][Cl:14])=[CH:7][CH:6]=1)=[O:4].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[Cl:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OCCCl)cc1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(OCC(=O)c2ccc(OCCCl)cc2)cc1
Reaction time: 16 h

Procedure:
A mixture of 27.7 g. (0.1 mol.) of α-bromo-p-(2-chloroethoxy)acetophenone, 12.4 g. (0.1 mol.) of p-methoxyphenol and 13.8 g. (0.1 mol.) of potassium carbonate in 75 ml. of dry acetone is refluxed with stirring for 16 hours. After cooling, the reaction mixture is poured into 500 ml. of water. The product is collected and dissolved in chloroform and the chloroform solution is washed with water, dried (MgSO4) and concentrated to give p-(2-chloroethoxy)-α-(p-methoxyphenoxy)acetophenone.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([NH:70][CH2:71][C:72]([O:74][CH2:75][CH3:76])=[O:73])=[CH:66][CH:65]=1>>[CH2:75]([O:74][C:72](=[O:73])[CH2:71][NH:70][C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([C@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][CH:66]=1)[CH3:76]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCOC(=O)CNc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1ccc(NC(=O)[C@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 29.7 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (100 mg, 0.173 mmol), was reacted with diisopropylethylamine (89 mg, 0.690 mmol), diphenylphosphinic chloride (Alfa Aesar, 106 mg, 0.446 mmol), then reacted with ethyl 2-(4-aminophenylamino)acetate (35 mg, 0.181 mmol) to give rac-(4-{[(2′S,3′R,4′S,5′S)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenylamino)-acetic acid ethyl ester (33 mg, 29%). MS (ES+) m/z [(M+H)+]: 641
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:31]=[CH:30][C:18]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]3)=[O:20])=[CH:17][CH:16]=2)=[N:12][CH:13]=1)=[O:6].[CH2:36]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[C:37]1[CH:45]=[CH:44][C:43]2[O:42][CH2:41][O:40][C:39]=2[CH:38]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:36]([N:46]1[CH2:51][CH2:50][N:49]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:19]([C:18]3[CH:17]=[CH:16][C:15]([O:14][C:11]4[N:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:32]=[CH:33][C:34]([Cl:35])=[C:2]([Cl:1])[CH:3]=5)=[CH:9][CH:10]=4)=[CH:31][CH:30]=3)=[O:20])[CH2:22][CH2:23]2)=[O:28])[CH2:48][CH2:47]1)[C:37]1[CH:45]=[CH:44][C:43]2[O:42][CH2:41][O:40][C:39]=2[CH:38]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCC(C(=O)O)CC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCC(C(=O)N4CCN(Cc5ccc6c(c5)OCO6)CC4)CC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzoyl}piperidine-4-carboxylic acid (7.96 g, 15.5 mmol) in DMF (160 mL) were added 1-piperonylpiperazine (3.75 g, 17.6 mmol), 1-hydroxybenzotriazole monohydrate (2.85 g, 18.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.56 g, 18.6 mmol) under ice cooling, and the resulting solution was stirred for overnight at room temperature. This reaction solution was concentrated under reduced pressure. To the residue were added water and ethyl acetate, and the resulting solution was vigorously stirred. The resulting precipitates were collected by filtration and recrystallized from a dichloromethane-methanol mixed solvent, to thereby yield 7.36 g of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22])=[O:4].COC(C1C=CC(=O)N(C)C=1NC1C=CC(Br)=CC=1F)=O.BrN1C(=O)CCC1=O>CN(C=O)C>[Br:11][C:9]1[C:8](=[O:12])[N:7]([CH3:13])[C:6]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: COC(=O)c1cc(Br)c(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 85 %

Procedure:
Preparation of 5-bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester: To a solution of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.390 g, 1.34 mmol) in DMF (10 mL) was added N-bromosuccinimide (0.263, 1.48 mmol). The reaction mixture was stirred at room temperature for 25 minutes and then quenched with saturated sodium bisulfite. The reaction mixture was diluted with H2O and partitioned between EtOAc/diethyl ether and saturated NaCl. The layers were separated and the aqueous layer was reextracted with EtOAc (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave 0.424 g (85%) pure desired product as a lavender foamy solid.
Reaction SMILES: OC1C=CC=CC=1C=[N:5][CH:6]1[C:39](=[O:40])[N:8]2[C:9]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:10]([CH2:13][S:14]/[CH:15]=[CH:16]\[C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][S:12][C@H:7]12.[ClH:45]>C(OCC)(=O)C>[ClH:45].[ClH:45].[NH2:5][CH:6]1[C:39](=[O:40])[N:8]2[C:9]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[C:10]([CH2:13][S:14]/[CH:15]=[CH:16]\[C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][S:12][C@H:7]12
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CS/C=C\c2cccnc2)CS[C@@H]2C(N=Cc3ccccc3O)C(=O)N12
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3cccnc3)CS[C@H]12
Reaction time: 0.5 h

Procedure:
To a solution of benzhydryl 7-(2-hydroxybenzylideneamino)-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (2.3 g) in ethyl acetate (46 ml) was added concentrated hydrochloric acid (1 ml) at ambient temperature and the mixture was stirred for 30 minutes to give a precipitate of a viscous oil. The upper layer was removed by decantation and the resultant oil was triturated with a mixture of ethanol and diethyl ether to give benzhydryl 7-amino-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate dihydrochloride (2.2 g).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([N:33]2[C:37](=[O:38])[CH2:36][CH2:35][C@@H:34]2[CH2:39][OH:40])[CH:3]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50].O>C(Cl)Cl>[CH3:48][S:49]([O:40][CH2:39][C@H:34]1[CH2:35][CH2:36][C:37](=[O:38])[N:33]1[C:4]1[CH:3]=[C:2]([F:1])[CH:32]=[CH:31][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:30])[CH3:29])=[O:9])(=[O:51])=[O:50]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CO)c(OCc1ccccc1)c2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1COS(C)(=O)=O)c(OCc1ccccc1)c2=O
Temperature: 23 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
To a stirred solution of intermediate 192, (R)-N-(4-fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.160 g, 0.291 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (81 μL, 0.582 mmol) and methanesulfonyl chloride (27 μL, 0.349 mmol). The reaction mixture was stirred at 23° C. for 4 h. Water (50 mL) was then added and the organic material was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (0.178 g, 98% yield). The crude material was used without further purification for the next step: LCMS (M+H)+ m/z 629.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:21][CH2:22][C:23]([F:27])=[C:24]([F:26])[F:25]>CN(C)C=O>[F:27][C:23](=[C:24]([F:26])[F:25])[CH2:22][CH2:21][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: FC(F)=C(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1ccc(OC(F)(F)F)cc1
Yield: 26.2 %

Procedure:
Using 0.50 g of (4-(trifluoromethoxy)benzyl)malononitrile, 9 ml of N,N-dimethylformamide, 96 mg of sodium hydride (60% in oil), and 0.79 g of 4-bromo-1,1,2-trifluoro-1-butene, and according to the process described in the Production Example 1, there was obtained 0.19 g of 2-(3,4,4-trifluoro-3-butenyl)-2-(4-(trifluoromethoxy)benzyl)malononitrile (the present compound (49)).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=1.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=[C:3]1[CH2:2][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: Cc1cccc2nc(CCl)n(-c3ccccc3Cl)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2nc(CSc3ncnc4[nH]cnc34)n(-c3ccccc3Cl)c(=O)c12
Yield: 79.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2g (300 mg, 0.940 mmol), 6-mercaptopurine monohydrate (176 mg, 1.03 mmol), K2CO3 (142 mg, 1.03 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 324 mg of a white crystalline solid (79%), mp 227.8-230.1° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.57 (br s, 1H); 8.49 (s, 1H); 8.47 (s, 1H); 7.69-7.78 (m, 2H); 7.66 (d, J=7.3 Hz, 1H); 7.55 (d, J=7.9 Hz, 1H); 7.39-7.52 (m, 2H); 7.36 (d, J=6.9 Hz, 1H); 4.38-4.50 (m, 2H); 2.74 (s, 3H). 13C NMR (DMSO-d6) ppm: 161.2, 156.3, 152.4, 151.5, 148.6, 143.9, 141.0, 134.6, 134.5, 132.3, 131.7, 131.4, 130.4, 130.2, 128.7, 125.7, 119.0, 32.0, 22.8. MS (ES): m/z 435.0 (M+). Anal. calcd. for C21H15ClN6OS.0.65C2H6O.0.1H2O: C, 57.40; H, 4.13; Cl, 7.60; N, 18.01; S, 6.87. Found: C, 57.11; H, 3.96; Cl, 7.45; N, 17.79; S, 6.90.
Reaction SMILES: C([NH:9][C:10](=[S:32])[NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=2[Cl:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:15]([Br:31])=[CH:14][N:13]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:31][C:15]1[C:16]([O:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=2[Cl:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][C:12]([NH:11][C:10]([NH2:9])=[S:32])=[N:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(NC(=S)NC(=O)c3ccccc3)ncc2Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(NC(N)=S)ncc2Br)c1
Temperature: 40 °C
Reaction time: 6 h
Yield: 55.3 %

Procedure:
A flask was charged with ethyl 3-(2-(3-benzoylthioureido)-5-bromopyridin-4-yloxy)-4-chlorobenzoate (1.37 g, 2.56 mmol), Potassium carbonate (0.496 g, 3.59 mmol) and ethanol (50 mL). The reaction mixture was stirred at 40° C. for 6 hours and then concentrated. The crude material was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexanes to give the desired product (0.61 g, 54% yield) as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:12].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl.CC(C)=O>[Cl:21][CH2:22][C:23]([NH:1][C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:12])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc2cc(N)c(=O)[nH]c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cccc2cc(NC(=O)CCl)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution prepared by 2.9 g of 3-amino-8-methylcarbostyril, 3.5 ml of triethylamine in 50 ml of dichloromethane was added dropwise a solution prepared by 1.9 ml of chloroacetyl chloride in 10 ml of dichloromethane under ice-cooled condition. After the dropwise addition, the reaction mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was concentrated by removing the solvent by evaporation under reduced pressure, the residue thus obtained was suspended in aceton and the suspension was poured in an ice-water. The crystals formed were collected by filtration, washed with water, dried, then recrystallized from acetone-water to obtain 3.6 g of 3-chloroacetylamino-8-methylcarbostyril. White powdery substance. Melting point: 271.5°-272° C. (decomposed).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:6]=1.CO.C(O)(=O)C>[Pd].O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:6]=1
Reactant: Nc1nc(C(=O)c2ccc([N+](=O)[O-])cc2)cs1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(C(=O)c2csc(N)n2)cc1
Reaction time: 7 h
Yield: 87.7 %

Procedure:
A mixture of 2-amino-4-(4-nitrobenzoyl)thiazole g) and 10% palladium on carbon (1 g, 50% wet) in a mixture of tetrahydrofuran (50 ml), methanol (50 ml) and acetic acid (5 ml) was hydrogenated under atmospheric pressure for 7 hours. The reaction mixture was filtered and then, the filtrate was concentrated under reduced pressure. The residue was dissolved in water and adjusted to pH using aqueous sodium bicarbonate. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-4(4-aminobenzoyl)thiazole (0.54 g, yield: 87.7%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:15]O>>[O:1]=[C:2]1[NH:7][C@H:6]([C:8]([O:10][CH3:15])=[O:9])[CH2:5][CH2:4][CH2:3]1
Reactant: CO
Reactant: O=C1CCC[C@@H](C(=O)O)N1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-6-oxopiperidine-2-carboxylic acid (17 g, 120 mmol) in methanol (200 mL) was added thionyl chloride (87 mL, 1.2 mol) and the reaction mixture was stirred at RT overnight, concentrated, combined with the product of a similar preparation, washed with saturated aqueous NaHCO3, and extracted with EtOAc (4×200 mL). The organic layers were combined, dried over sodium sulfate and evaporated to provide crude (S)-methyl 6-oxopiperidine-2-carboxylate (36.5 g).