Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:28])[C:9]([C:11]1[S:27][C:14]2[C:15]3[CH:23]=[C:22]([C:24]([NH2:26])=[O:25])[CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[C:29](O)([C:31](F)(F)F)=O.C([SiH](CC)CC)C.C(=O)C>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:28])[C:9]([C:11]1[S:27][C:14]2[C:15]3[CH:23]=[C:22]([C:24]([NH:26][CH2:29][CH3:31])=[O:25])[CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(N)=O)ccc1OCC2)c1ccccc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: CC=O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: CCNC(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccccc3Cl)cc1CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N2-(2-chlorophenyl)-N2-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,9-dicarboxamide 119 (70 mg), TFA (37.5 μL), triethylsilane (80 μL) and acetaldehyde (28 μL) in dry MeCN (Dube et al (1999) Tet. Letters 40(12):2295-2298) was stirred at room temperature overnight then concentrated in vacuo. Purification on silica yielded 300. NMR: (CDCl3 δ 7.19 ppm): 1.21 (t, 3H, CH3, J=7.28 Hz), 2.93 (t, 2H, CH2, J=5.07 Hz), 3.32 (s, 3H, CH3), 3.43 (m, 2H, CH2), 4.17 (t, 2H, CH2, J=5.10 Hz), 5.94 (m, H, NH), 6.59 (s, H, ArH), 6.91 (d, H, ArH, J=8.41 Hz), 7.29-7.36 (m, 3H, 3×ArH), 7.44-7.47 (m, 2H, 2×ArH), 7.81 (m, H, ArH). MS: (ESI+) MH+ 482.15
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([NH:19][C@:20]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][C@H:21]1C=C)=[O:18])=[O:10])[CH:2]=[CH2:3]>C1(C)C=CC=CC=1.ClC1C=CC(OC(C)C)=C(C=1)C=[Ru](Cl)(Cl)C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C>[C:34]([O:33][C:31]([NH:30][C@H:8]1[CH2:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]=[CH:3][C@@H:21]2[CH2:22][C@@:20]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:19][C:17](=[O:18])[C@@H:12]2[CH2:13][C@@H:14]([OH:16])[CH2:15][N:11]2[C:9]1=[O:10])=[O:32])([CH3:36])([CH3:37])[CH3:35]
Reactant: C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2[Ru](Cl)(Cl)=Cc2cc(Cl)ccc2OC(C)C)c(C)c1
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\COCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@]12C[C@H]1C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Temperature: 68 °C
Reaction time: 4 h

Procedure:
(1R,2S)-ethyl 1-((2S,4R)-1-((S)-5-(allyloxy)-2-(tert-butoxycarbonylamino)pentanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (3.55 g, 6.78 mmol) in toluene (750 mL) was degassed by bubbling a stream of nitrogen through the reaction for 1 hr at rt. (5-chloro-2-isopropoxybenzylidene)(1,3-dimesitylimidazolidin-2-yl)ruthenium(V)chloride (0.090 g, 0.14 mmol) was added to the mixture and the mixture was heated to 68° C. (oil bath) and stirred at this temperature for 4 hrs. After removal of solvent, the residue was purified by chromatography (Ethyl acetate:MeOH=40:1) to give (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-hydroxy-5,16-dioxo-2,3,5,6,7,8,9,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecine-14a-carboxylate as off white solid (0.84 g, 25%). MS: Calcd.: 495; Found: [M+H]+ 496. 1H NMR (400 MHz, d6-DMSO) δ8.42 (s, 1H), 6.89 (d, J=7.6 Hz, 1H), 5.48-5.60 (m, 2H), 5.10 (d, J=3.6 Hz, 1H), 4.41 (s, 1H), 4.27 (m, 2H), 4.17 (m, 1H), 4.02 (m, 2H), 3.72 (m, 2H), 3.62 (m, 1H), 3.35 (m, 1H), 3.28 (m, 1H), 2.42 (m, 1H), 1.98 (m, 2H), 1.78 (m, 1H), 1.62 (m, 1H), 1.52 (m, 2H), 1.42 (m, 2H), 1.36 (s, 9H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: O.[OH:2]OS([O-])=O.[K+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([C@H:34]2[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]2)[C:19](=[O:33])[NH:20][C:21]2[S:22][C:23]([S:26][C:27](C)(C)[C:28]([OH:30])=[O:29])=[CH:24][N:25]=2)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([C@H:34]2[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]2)[C:19](=[O:33])[NH:20][C:21]2[S:22][C:23]([S:26]([CH2:27][C:28]([OH:30])=[O:29])=[O:2])=[CH:24][N:25]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CCN(C(=O)Nc2ncc(S(=O)CC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1
Temperature: 25 °C

Procedure:
To Montmorinonite (415 mg) was added H2O (98 μL) the mixture was stirred for 10 min before DCM (0.5 mL), oxone (428 mg, 0.70 mmol) and 2-{2-[3-[2-(4-methoxy-phenyl) -ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid (129 mg, 0.278 mmol) suspended in DCM (2.6 mL) was added in seqence. The mixture was stirred at rt for 1.5 hs. LCMS showed a 1:1 mixture of the sulfoxide and sulfone. The reaction mixture was filtered, washed with DCM and the filtrate was concentrated in vacuo. The mixture was purified by HPLC to give37 mg of {2-[3-[2-(4-methoxy-phenyl)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfinyl}-acetic acid.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([NH:22][CH3:23])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([N:22]([CH3:23])[S:33]([CH3:32])(=[O:35])=[O:34])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(NC)nc3C)c(C)nc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N(C)S(C)(=O)=O)nc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
60 mg of N-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-methylamine (0.17 mmol) and 86 mg of triethylamine (0.85 mmol) are dissolved in 3.0 ml of CH2Cl2 and 23 mg of methanesulfonyl chloride (0.2 mmol) is added. The vial is capped with a Teflon® lined cap and shaken at room temperature for 2 h. The reaction mixture is concentrated and applied to silica-gel chromatography (Hexane:AcOEt=2:1) to give 53.8 mg of the title compound. Yield 75%. mass spectrum (m/e): 422 (M+1); 1H-NMR (CDCl3): 6.96 (s, 1H), 3.60 (s, 3H), 3.34 (m, 1H), 3.19 (s, 3H), 2.56 (s, 3H), 2.48 (s, 3H), 2.29 (s, 3H), 1.86 (m, 4H), 0.90 (t, 6H, J=7.4 Hz).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12].Cl>[Cu].ClCCl>[F:10][C:8]1[CH:7]=[CH:6][C:5]([C:11](=[O:13])[CH3:12])=[C:4]([NH:2][CH3:1])[CH:9]=1
Reactant: CN
Reactant: CC(=O)c1ccc(F)cc1Cl
Agent: [Cu]
Agent: Cl
Solvent: ClCCl
Product: CNc1cc(F)ccc1C(C)=O
Reaction time: 2 h

Procedure:
A mixture of a solution of methylamine in industrial methylated spirit (33% w/w; 315.8 ml), industrial methylated spirit (291.6 ml), 2'-chloro-4'-fluoroacetophenone (203.4 g) and copper powder (2.8 g) was heated to 80° in a glass autoclave over a period of 1 hour. The mixture was stirred at 80° for a further 2 hours and then allowed to cool to 45° over a period of 1 hour. The mixture was transferred to a second vessel and the autoclave rinsed with industrial methylated spirit (50 ml) which was then added to the second vessel. The mixture was heated to 50°. A solution of sodium sulphide nonahydrate (11.2 g) in water (117 ml) was added and the mixture was heated at 50° for a further 15 minutes. The mixture was filtered and the residue washed with industrial methylated spirit (100 ml). The filtrate and washings were combined and evaporated to give a brown oil. The brown oil was stirred with hydrochloric acid (5M; 800 ml) for 2.5 hours and then dichloromethane (600 ml) added. The layers were separated and the aqueous phase further extracted with dichloromethane (2×300 ml). The organic phases were combined and evaporated to give 4'-fluoro-2'-(methylamino)acetophenone as a brown oil which solidified at ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1.C(N(CC)CC)C.FC(F)(F)S(O[Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])(=O)=O.[Cl-].[NH4+]>ClCCl>[CH:31]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:16][C:13]1[CH2:12][CH2:11][CH:10]([C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:15][CH:14]=1)([CH3:33])[CH3:32]
Reactant: O=C1CCC(c2cc(F)c(F)cc2F)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC1=CCC(c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A three-neck flask (1 L) containing a stirred solution of 4-(2,4,5-trifluorophenyl)cyclohexanone (15.8 g) in dichloromethane (160 mL) under a nitrogen atmosphere was cooled to 0° C. and then treated with triethylamine (22 mL) followed by triisopropylsilyl trifluoromethanesulfonate (25.4 g) while maintaining the temperature below 5° C. The solution was stirred at 0° for 30 min and then allowed to rise to ambient temperature over a period of 0.5 h. It was then treated with saturated aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The crude product was chromatographed (silica gel, 3% ether in hexane) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:36][C:37]([NH2:39])=[O:38].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([O:26][CH2:36][C:37]([NH2:39])=[O:38])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)CI
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(O)ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(OCC(N)=O)ccc2c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
To a solution of tert-butyl[4-(4-chlorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.45 g, 1 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (48 mg, 1.2 mmol) (60% in oil) at 0° C., and the mixture was stirred at 0° C. for 10 min. To the obtained mixture was added 2-iodoacetamide (0.22 g, 1.2 mmol) and the mixture was stirred at 0° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(2-amino-2-oxoethoxy)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.27 g, 52.9%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[NH2:11][NH2:12]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:11][NH2:12])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: NN
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(NN)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
33 g (169.2 mmol) of 4,6-dichloro-2-(methylthio)pyrimidine are introduced into 300 ml of THF at −20° C., and 169 ml of a 1M solution of hydrazine in THF is added dropwise at a rate such that the temperature does not rise above −15° C. The mixture is stirred at 0° C. for a further 2 h. After the reaction is complete, the solvent is distilled off and the residue is stirred with diethyl ether. 18.4 g (57% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([NH:10][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:19]=2[F:18])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](NCc2ccc(F)cc2F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2 mmol, 1 equvi) was dissolved in dry DCM (20 ml) cooled to 0 centigrade was added 2,4-difluorobenzaldehyde (1.05 equiv), then NaBH(OAc)3 (2 equiv) and 5 drops of HOAc. The mixture was warmed to room temperature and stirred overnight. The mixture was diluted with DCM, washed with brine, and dried over anhydrous sodium sulfate. After removal of solvent, the crude product was used for the next step without further purification. MS m/e=371.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:11].[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=O.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>O>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]1[S:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1S
Reactant: O=C(O)c1ccccc1Cl
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc2sc(-c3ccccc3Cl)nc2c1
Temperature: 130 °C
Yield: 98.5 %

Procedure:
2-Amino-4-nitrobenzenethiol (315 mg, 1.85 mmol), 2-chlorobenzoic acid (290 mg, 1.85 mmol) and Eaton's reagent (5 mL) were combined and heated in the microwave at 130° C. for 10 min. After cooling, the mixture was poured into water and basified with 5M aqueous sodium hydroxide to give a precipitate, which was filtered off and dried to afford 530 mg (98%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH:13]=[O:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][CH2:16][Mg+].[Br-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH:13]([OH:14])[CH2:15][CH3:16])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ncc(-c2ccc(F)cc2)s1
Reactant: CC[Mg+]
Agent: [Br-]
Product: CCC(O)c1ncc(-c2ccc(F)cc2)s1
Yield: 72.7 %

Procedure:
Using 5-(4-fluorophenyl)thiazole-2-carbaldehyde (0.12 g, 0.58 mmol) and EtMgBr (0.577 mL, 1.73 mmol) and following the procedure described for example 7 and step 2, the crude compound was obtained and further purified by column chromatography (using 100-200μ silica gel and 38% ethyl acetate and hexane) to give 1-(5-(4-fluorophenyl)thiazol-2-yl)propan-1-ol as pale yellow liquid (0.1 g, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.68-7.65 (m, 2H), 7.25 (t, 2H), 6.11 (d, 1H), 4.72-4.67 (m, 1H), 1.84 (m, 1H), 1.88-1.67 (m, 1H), 0.91 (t, 3H); LC-MS m/z calculated for [M+H]+ 238.06, found 238.5.
Reaction SMILES: [CH2:1]([CH:3]1[NH:16][CH:15]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[C:22](Cl)(=[O:32])[C:23]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:26][C:25]=2[CH:24]=1>>[CH2:1]([CH:3]1[N:16]([C:22](=[O:32])[C:23]2[CH:31]=[CH:30][C:29]3[O:28][CH2:27][O:26][C:25]=3[CH:24]=2)[CH:15]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C1=CNC(CC)Cc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Product: CCOC(=O)C1=CN(C(=O)c2ccc3c(c2)OCO3)C(CC)Cc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 2-ethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and piperonyloyl chloride. 1H-NMR (CDCl3): δ 10.38 (1H, br s), 8.15 (1H, s), 7.52 (1H, d), 7.37 (1H, d), 7.10 (4H, m), 6.88 (1H, d), 6.07 (1H, d), 6.06 (1H, d), 5.34 (1H, m), 4.16-4.33 (2H, m), 3.53 (1H, dd), 3.00 (1H, dd), 1.29-1.45 (2H, m), 1.24 (3H, t), 0.81 (3H, t); MS (ES): 433 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:30][C:31](=[O:43])[C:32]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1)([CH3:34])[CH3:33]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:41][C:38]1[CH:37]=[CH:36][C:35]([C:32]([CH3:34])([CH3:33])[C:31]([OH:43])=[O:30])=[CH:40][CH:39]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)C(C)(C)c1ccc(CBr)cc1
Product: CC(C)(C(=O)O)c1ccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
Prepared using the procedure in Example 56 except using 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 2-(4-Bromomethyl-phenyl)-2-methyl-propionic acid methyl ester as the halide. MS (ESI) m/z 556.
Reaction SMILES: [C:1]([S:4][C@H:5]1[CH2:9][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])[C@H:7]([C:23]([N:25]([CH2:34][C:35]([OH:37])=[O:36])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:24])[CH2:6]1)(=[O:3])[CH3:2].[CH3:38][CH2:39]O.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:38]([O:36][C:35](=[O:37])[CH2:34][N:25]([C:23]([C@@H:7]1[CH2:6][C@@H:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:9][N:8]1[S:10]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(=[O:12])=[O:11])=[O:24])[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH3:39]
Reactant: CC(=O)S[C@@H]1C[C@@H](C(=O)N(CCc2ccccc2)CC(=O)O)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CN(CCc1ccccc1)C(=O)[C@@H]1C[C@@H](SC(C)=O)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 0 %

Procedure:
A suspension of 700 mg (1.29 mmol) (2S,4R)-{[4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-phenethyl-amino}-acetic acid and 0.1 ml (1.68 mmol) EtOH in 12 ml CH2Cl2 was treated at 0° C. with 273 mg (1.42 mmol) EDCI and 16 mg (0.13 mmol) DMAP. After warming up to RT (1 h), the reaction was partitioned between aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated KHCO3, 10% NaCl and dried over Na2SO4. Purification by flash-chromatography on silicagel (Hexane/EtOAc 9:1 to 4:1) gave 0.254 mg (34%) (2S,4R)-{[4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-phenethyl-amino}-acetic acid ethyl ester, mp: 119-120° C., MS: 569 (MH+).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:29][CH:30]2[C:45](=[O:46])[N:32]3[C:33]([C:42]([OH:44])=[O:43])=[C:34]([CH2:37]OC(=O)C)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:52]([O-:55])(=[S:54])[CH3:53].[K+].O>C(O)(=O)C.CC(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:29][CH:30]2[C:45](=[O:46])[N:32]3[C:33]([C:42]([OH:44])=[O:43])=[C:34]([CH2:37][S:54][C:52](=[O:55])[CH3:53])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC([O-])=S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 90 °C

Procedure:
A mixture of 1.63 of the product of Step B, 0.21 g of sodium bicarbonate, 0.66 g of potassium thioacetate, 10 ml of water and 5 ml of acetone was heated at 90° C for 21/2 hours and was then acidified with 1 ml of acetic acid. The mixture was vacuum filtered and the solid product was washed and chromatographed over silica gel. Elution with a 1-1 methylene chloride-ether mixture and then with a 5-1-4 acetone-water-ether mixture yielded 830 mg of 7-[2-(2-tritylamino-4-thiazolyl)-acetamido]-3-acetylthiomethyl-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [I-:1].[Na+].Cl[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1.C(Cl)(=O)C>C(#N)C>[I:1][C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Clc1cc(C2=CCCC2)ccn1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Ic1cc(C2=CCCC2)ccn1
Temperature: 25 °C

Procedure:
A flask was charged with sodium iodide (3.75 g, 25.0 mmol), 2-chloro-4-cyclopent-1-enyl-pyridine (450 mg, 2.5 mmol) and acetonitrile (8 mL). Acetyl chloride (0.27 mL, 3.76 mmol) was slowly added and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and quenched with water. Saturated Na2CO3 and 10% Na2S2O3 were added and the mixture was extracted with EtOAc (3×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by chromatography (0% to 10% EtOAc/hexanes) to afford 2-iodo-4-cyclopent-1-enyl-pyridine as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([OH:21])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Br-].[CH2:23]([Zn+])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH2:23]([C:2]1[C:3]([OH:21])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c(O)n2)CC1
Reactant: [Zn+]Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1nc(N2CCNCC2)ncc1Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of tert-butyl 4-(5-bromo-4-hydroxypyrimidin-2-yl)piperazine-1-carboxylate (20 g, 56 mmol) and Pd(Amphos)Cl2 (4.0 g 5.6 mmol) in THF (200 mL, dry) was added benzylzinc(II) bromide (168 mL, 168 mmol) under argon and the mixture was stirred at 60° C. overnight. The reaction mixture was diluted with ethyl acetate (1.5 L), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=1:1 to 100% ethyl acetate) to give 5-benzyl-2-(piperazin-1-yl)pyrimidin-4-ol (8.2 g, 54%) as a pale yellow solid. MS (ES+) C15H18N4O requires: 270, found: 271 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:28][CH3:29])=[C:7]([CH:18]=[C:19]([C:21]2[C:22](=[O:27])[NH:23][CH:24]=[CH:25][CH:26]=2)[CH:20]=1)[C:8]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14])=[O:9])([CH3:4])([CH3:3])[CH3:2]>[Ni]>[NH2:14][CH2:13][C:12]1[CH:11]=[C:10]([CH:17]=[CH:16][CH:15]=1)[C:8]([C:7]1[CH:18]=[C:19]([C:21]2[C:22](=[O:27])[NH:23][CH:24]=[CH:25][CH:26]=2)[CH:20]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[O:28][CH3:29])=[O:9]
Reactant: COc1c(C(=O)c2cccc(C#N)c2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C
Agent: [Ni]
Product: COc1c(C(=O)c2cccc(CN)c2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C

Procedure:
I-66 is prepared by catalytic hydrogenation of 41 with Raney Nickel (MeOH/NH40H) to afford 3-[3-(3-aminomethyl-benzoyl)-5-tert-butyl-4-methoxy-phenyl]-1H-pyridin-2-one. Conversion of the amine to a sulfonamide and cleavage of the pyridinyl ether are carried out in accord with the procedures in step 3 and 4 of example 6.