Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH3:23])[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]2[C:19]([O:21][CH3:22])=[O:20])[CH:7]=[CH:8][C:9]=1[Cl:10].[P:24](Cl)([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25].[Cl-].[NH4+]>C(OCC)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH3:23])[C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:13]([O:18][P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][CH:15]([CH3:17])[CH2:16]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)C1C(=O)CC(C)CC1(C)c1ccc(Cl)c(Cl)c1
Reactant: CCOP(=O)(Cl)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOP(=O)(OCC)OC1=C(C(=O)OC)C(C)(c2ccc(Cl)c(Cl)c2)CC(C)C1
Reaction time: 0.17 h

Procedure:
A stirred suspension of sodium hydride (60% in mineral oil, 13 mg) in diethyl ether (2 mL) was treated at rt with methyl (2RS,4RS)-2-(3,4-dichlorophenyl)-2,4-dimethyl-6-oxocyclohexanecarboxylate (100 mg). The mixture was stirred for 10 min and then a solution of diethyl chlorophosphate in diethyl ether (2 mL) was added. Upon completion of addition, the resulting mixture was stirred at rt for 3 h. After this time, solid ammonium chloride was added and stirring was continued for an additional 30 min. At the conclusion of this period, the resulting suspension was filtered through Celite and the filtrate was concentrated under vacuum to provide methyl (4RS,6SR)-6-(3,4-dichlorophenyl)-2-(diethoxyphosphoryloxy)-4,6-dimethyl-cyclohexen-1-carboxylate in quantitative yield. Mass spectrum m/z 465.19 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21](=[O:23])[C:20]3([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:19]=2)=[CH:14][CH:13]=1>CN1CCOCC1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([NH:19][C:20]2([C:21]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:23])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22])=[CH:16][CH:17]=1
Reactant: CSCC[C@H](N)C(=O)O
Reactant: COc1ccc(C2=NC3(CCCCC3)C(=O)O2)cc1
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)NC2(C(=O)N[C@@H](CCSC)C(=O)O)CCCCC2)cc1
Yield: 12.7 %

Procedure:
10 ml of N-methylmorpholine was added to 298 mg (2 mmol) of L-methionine and 259 mg (1 mmol) of 2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and refluxed under heating overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium hydrogensulfate and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 52 mg (13%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:1]=[C:2]2[CH:11]=1
Reactant: COc1cc(N)nc2ccccc12
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cn2c(cc(OC)c3ccccc32)n1
Reaction time: 8 h

Procedure:
To 75 ml. of acetone was added 3.5 g. (0.20 mole) of 2-amino-4-methoxyquinoline, 4.3 g. (0.22 mole) of ethyl bromopyruvate and 3.0 g. (0.20 mole) potassium carbonate. The resulting mixture was heated at reflux for 5.5 hours and the resulting dark slurry allowed to stand at room temperature overnight. The solvent was removed by evaporation in vacuo and 200 ml. of water added to the residue to afford a gummy precipitate. This was extracted twice with 200 ml. portions of ethyl acetate, the extracts dried over anhydrous sodium sulfate, decolorized with active carbon (Darco), filtered and the solvent removed in vacuo to afford 3.5 g. of crude product. Filtration of the aqueous phase from the extraction step afforded another 1.0 g. of crude material. The combined crops were recrystallized from 100 ml. of 1:1 (by volume) isopropanol-water to afford 900 mg. of the title compound, M.P. 175°-176.5° C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29][CH2:30][CH3:31])=[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-].[K+].[K+].[CH3:40][N:41]1[CH2:45][CH2:44][CH:43](Br)[C:42]1=[O:47].O>CS(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:43]2[CH2:44][CH2:45][N:41]([CH3:40])[C:42]2=[O:47])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC(Br)C1=O
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)/C(=N\OC1CCN(C)C1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
2.7 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate are dissolved in 12 ml of dimethylsulfoxide, and 1.0 g of anhydrous potassium carbonate is added thereto under nitrogen gas atmosphere. The mixture is stirred at room temperature for 10 minutes. 1.2 g of 1-methyl-3-bromo-2-pyrrolidone are added to the mixture, and the mixture is stirred at room temperature for 5 hours. The reaction mixture is poured into 100 ml of water, and crystalline precipitates are collected by filtration. The crystals are dissolved in ethyl acetate, and the solution is washed with water and then dried. The solution is concentrated under reduced pressure to remove solvent. Then, the residue is crystallized with isopropyl ether and collected by filtration. 2.1 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetate are obtained.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[C:19]([I:20])=[CH:18][N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]=2[N:16]=1>C1COCC1>[Cl:10][C:11]1[N:12]=[C:13]([O:9][CH:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)[C:14]2[C:19]([I:20])=[CH:18][N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]=2[N:16]=1
Reactant: OC1CCOCC1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a suspension of sodium hydride (1 equiv) in dry THF (0.42 M) under nitrogen atmosphere was added tetrahydro-2H-pyran-4-ol (1 equiv) at 0° C. The reaction mixture was stirred at room temperature for 30 min before a solution of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.67 equiv) in dry THF (0.75 M) was added at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction was monitored by thin layer chromatography. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography (5% ethyl acetate in petroleum ether) to afford the title compound as a yellowish oil (84% yield). MS (ESI) m/z 510.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([O:7][CH3:8])([O:5][CH3:6])[CH3:4].[Cl:9]Cl>>[Cl:9][CH2:4][C:3]([O:7][CH3:8])([O:5][CH3:6])[O:2][CH3:1]
Reactant: COC(C)(OC)OC
Reactant: ClCl
Product: COC(CCl)(OC)OC
Reaction time: 4 h
Yield: 85.1 %

Procedure:
A 1000 ml flask equipped with a stirrer and gas inlet tube was initially charged at 10° C. with 480 g (4 mol) of 1,1,1-trimethoxyethane. Within 4 hours, 220 g (3.14 mol) of chlorine were introduced into the flask in gaseous form, and the internal temperature of the flask did not rise above 15° C. Once the entire amount of chlorine had been introduced into the flask, the mixture was worked-up by distillation. A distillation apparatus having approx. 5 theoretical plates was used to remove low boilers such as methanol and methyl acetate in the first stages at a reflux ratio of 5:1. In the main fraction, 413 g of 2-chloro-1,1,1-trimethoxyethane in a purity of >99.0% were obtained at a reflux ratio of 2:1. This amount of product corresponds to a yield of approx. 67%.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:44]([C:60](=[O:84])[NH:61][CH:62]2[CH2:67][CH2:66][N:65]([C:68](=[NH:83])[NH:69]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:64][CH2:63]2)[CH2:43]1>>[C:68]([N:65]1[CH2:66][CH2:67][CH:62]([NH:61][C:60]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][NH:45]2)=[O:84])[CH2:63][CH2:64]1)(=[NH:69])[NH2:83]
Reactant: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCC(NC(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)NC4CCN(C(=N)N)CC4)C3)[C@H](C)[C@H]12

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 32) and (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonylamidino)piperidin-4-ylcarbamoyl]pyrrolidine (prepared as described in Preparation 110) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: Br.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11](=[NH:13])[NH2:12].C[O-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([CH2:31][C:32]3[CH:33]=[C:34]([C:38]([O:40][CH3:41])=[O:39])[CH:35]=[CH:36][CH:37]=3)[C:29](=[O:42])[N:28]([CH2:43][C:44]([NH:46]N)=O)[N:27]=2)=[CH:22][CH:21]=1>CO>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([CH2:31][C:32]3[CH:33]=[C:34]([C:38]([O:40][CH3:41])=[O:39])[CH:35]=[CH:36][CH:37]=3)[C:29](=[O:42])[N:28]([CH2:43][C:44]3[NH:12][C:11]([CH2:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([F:14])([F:15])[F:2])=[N:13][N:46]=3)[N:27]=2)=[CH:22][CH:21]=1
Reactant: N=C(N)Cc1ccccc1C(F)(F)F
Reactant: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)NN)c2=O)c1
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(Cc3nnc(Cc4ccccc4C(F)(F)F)[nH]3)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
77 mg (0.27 mmol) of 2-[2-(trifluoromethyl)phenyl]ethaneimidamide hydrobromide were dissolved in 1 ml of dry methanol, 74 μl (0.27 mmol) of a 25% strength methanolic sodium methoxide solution were added and the mixture was stirred for 30 min 75 mg (0.18 mmol) of the compound from Example 16A were then added, and the mixture was stirred initially at RT for 16 h and then under reflux for 5 h. The mixture was then directly purified chromatographically [Method 19]. This gave 67 mg (64% of theory) of the target compound as a colorless foam.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]1[N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]2=[C:15]([C:18]([O:20]CC)=O)[N:16]=[CH:17][N:8]2[C:7]2[CH:23]=[CH:24][S:25][C:6]1=2>C(O)C>[O:4]=[C:5]1[N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]2=[C:15]([C:18]([NH:2][NH2:3])=[O:20])[N:16]=[CH:17][N:8]2[C:7]2[CH:23]=[CH:24][S:25][C:6]1=2
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Yield: 94 %

Procedure:
8 ml of hydrazine hydrate were added to a suspension of 4.0 g (12.6 mmol) of ethyl (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylate in 40 ml of ethanol and the mixture was heated at reflux for 3 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 3.6 g (94%) of (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide as colourless needles of m.p. >260°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[CH:7](O)[CH2:6][CH2:5]2.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>O.C(C1C=C(O)C(=CC=1)O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[CH2:7][CH:6]=[CH:5]2
Reactant: OC1CCc2cc(Cl)c(Cl)cc21
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cc2c(cc1Cl)CC=C2
Yield: 56.5 %

Procedure:
A mixture of 17.48 g of the product of Step B, 470 ml of toluene, 0.57 g of 4-tert.-butyl-catechol and 1.63 g of p-toluene sulfonic acid was refluxed for 2 hours and then was diluted with water. 10 ml of N sodium hydroxide solution were added and the mixture was extracted with toluene. The organic phase was evaporated to dryness under reduced pressure and the residue was taken up in hexane. The mixture was vacuum filtered and the crystalline product was dried to obtain 9 g of the desired product melting at 76° C.
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:24])[CH2:22]Cl.[H-].[Na+].Cl>CN(C)C=O>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:22]=1[C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)=[O:24]
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Reactant: O=C(CCl)Nc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a solution of 590 mg. (3 mmole) of N-methylsaccharin and 1.02 g. (6 mmole) of N-(2-pyridyl)chloroacetamide in 3 ml. of dimethylformamide at 40° C. was added 250 mg. (10.3 mmole) of 99% sodium hydride portionwise over a period of one hour. The reaction mixture was allowed to stir at 40° C. for 2.5 hours and was then added to 100 ml. of 5% hydrochloric acid solution and 300 ml. of ice. The precipitate was filtered and dried to give 24 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[N+:19]([O-])=O>CCOC(C)=O>[NH2:19][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:3]=1[O:2][CH3:1])[CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1N
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Tert-Butyl 4-methoxy-3-nitrobenzyl(methyl)carbamate (333 mg, 1.124 mmol) was dissolved in EtOAc (20 ml), Pt2O (33 mg, 0.145 mmol) was added, and the mixture was hydrogenated in a Parr apparatus at 20 psi for 3 hours. The solution was filtered and evaporated to dryness to give tert-butyl 3-amino-4-methoxybenzyl(methyl)carbamate (265.3 mg, 0.996 mmol, 89% yield, MS/ESI+ 289.2 [MNa]+) that was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>CN(C)C=O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30]([N:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:9]2=[O:10])(=[O:31])=[O:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: O=c1[nH]c(-c2ccccc2)cc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2c(-c3ccccc3)cc3ccccc3c2=O)cc1OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46.7 %

Procedure:
A solution of 3-phenylisocarbostyril (0.1 g) in N,N-dimethylformamide (2 ml) was cooled to 0° C. under an inert atmosphere. Sodium hydride (0.019 g) was added and the resulting mixture stirred at 0° C. for 5 minutes. 3,4-Dimethoxybenzenesulphonylchloride (0.107 g) was added over a 3 minute period, with continued stirring at 0° C. for a further 15 minutes. The reaction mixture was warmed to room temperature and stirred for 24 hours. The DMF was evaporated under high vacuum and the residue partitioned between ethyl acetate (2×12 ml) and water (12 ml). The combined organic phases were dried over magnesium sulphate and concentrated in vacuo to yield a yellow oil. Purification using column chromatography eluting with 50% ethyl acetate in hexane yielded an oil which was crystallized from ethyl acetate/hexane to furnish the title compound as white crystals (0.089 g).
Reaction SMILES: [C:1]([C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>CN(C=O)C.CCN(CC)CC>[OH:8][C:3]1([C:1]#[C:2][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:20]/[C:21]2[NH:22][CH:23]=[CH:24][C:25]=2[O:26][CH3:27])/[C:13](=[O:19])[NH:14]3)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC1(O)CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC3(O)CCCC3)c21

Procedure:
Using Method D above, 1-ethynyl-cyclopentanol (86.3 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.31 mmol) (Starting Material 1 above) using DPPFPdCl2 (12.6 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 2 days to yield (Z)-1,3-dihydro-4-[(1-hydroxycyclopentyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 43 mg, 40%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Cl)[CH3:2].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.[Na]>CC(N(C)C)=O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][S:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(CCl)OCC
Reactant: Cc1ccc(S)cc1
Agent: [Na]
Solvent: CC(=O)N(C)C
Product: CCOC(CSc1ccc(C)cc1)OCC

Procedure:
152.5 Grams (1 mole) of chloroacetaldehyde-diethylacetal were heated at 100° C for 6 hours on the steam bath, together with 162 g (1 mole) of 4-methylthiophenol-sodium salt in 200 ml of dimethylacetamide (in a manner analogous to Comptes Rendus 194, 617 (1932)). After the precipitated sodium chloride had been suction-filtered, the solvent was removed by distillation under reduced pressure. 4-Methylthio-phenoxyacetaldehyde-diethylacetal was obtained as an oily residue which was directly further reacted.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:14]([CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:13][CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C>>[C:1]([O:5][C:6]([N:8]1[C@H:14]([CH2:15][NH2:16])[CH2:13][CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN2C(=O)c3ccccc3C2=O)CC[C@H]2C[C@H]21
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@H](CN)CC[C@H]2C[C@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of D8 (11 g, 30.9 mmol) in ethanol (200 mL) hydrazine hydrate (7.28 mL, 150 mmol) was added and the mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and the filtrate was concentrated. Then i-Pr2O was added, the precipitate was discarded and the filtrate was concentrated to give the title compound as yellow oil. Yield (6.7 g, 96%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)=[O:21]>N1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[O:21])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: O=C(Cl)Oc1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)Oc2cccc([N+](=O)[O-])c2)N(c2nnc(C(C)(C)C)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H) -pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C and 3-nitrophenyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6 -(3-nitrophenoxycarbonyloxy)-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:10](=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:33](CC1C=CC=CC=1)[CH:34]([CH2:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=1)[CH:35]=[O:36])C1C=CC=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[C:10](=[O:25])[C@@H:9]1[C@@H:35]([OH:36])[C@@H:34]([NH2:33])[CH2:37][C:38]1[CH:39]=[C:40]([F:45])[CH:41]=[C:42]([F:44])[CH:43]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CC(Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)CCc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1=O
Product: CC(C)CCc1ccccc1N1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)C1=O

Procedure:
The title is prepared by reacting 4-[2-(3-methyl-butyl)-phenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester with 2-(dibenzylamino)-3-(3,5-difluorophenyl)-propanal essentially as described in Preparation 41.
Reaction SMILES: C=O.[C:3]([O:7][C:8]([N:10]([CH3:26])[C@@H:11](C)[C:12](N[C@@H](C1CCCCC1)C(O)=O)=O)=[O:9])([CH3:6])([CH3:5])[CH3:4].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CCOC(C)=O>[C:3]([O:7][C:8](=[O:9])[N:10]([CH2:11][CH3:12])[CH3:26])([CH3:6])([CH3:5])[CH3:4]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Agent: C=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(C)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 299.1 %

Procedure:
To a solution of 4-fluoro-phenyl)-(S)-5-pyrrolidin-2-yl-pyridin-3-yl) -methanone (2.57 g, 9.5 mmole) and (S)-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-cyclohexyl-acetic acid (5) (3.58 g, 10.5 mmole) in 75 mL of THF at 0° C., is added 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholinium chloride hydrate (2.97 g, 10.7 mmole) in one portion. After stirring at 20° C. for 2 hours, the reaction mixture is diluted with 100 mL of EtOAc, and washed with 3×20 mL of water. After concentration, the crude product is purified by flash column chromatography (CH2Cl2 95%, MeOH 5%) to give (S) -1-(S)-1-cyclohexyl-2-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethylcarbamoyl)-ethylmethyl-carbamic acid tert-butyl ester (6) (5.0 g, yield 88%) as pale yellow solid.