Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]2[CH:32]=[CH:31][C:19]([C:20]([N:22]3[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([OH:30])=[O:29])[CH2:23]3)=[O:21])=[CH:18][CH:17]=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:33])[CH:3]=1.[C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)#[N:35].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:22]4[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([OH:30])=[O:29])[CH2:23]4)=[O:21])=[CH:31][CH:32]=3)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:33])[CH:3]=2)=[CH:38][CH:37]=1)#[N:35]
Reactant: Cc1cc(Br)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccc(C#N)cc2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Yield: 17.8 %

Procedure:
To (3R)-1-(4-((1-(4-bromo-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoyl)piperidine-3-carboxylic acid (42 mg) was added a solution of 4-cyanophenylboronic acid (24 mg) in DME (0.5 mL), polymer-supported triphenylphosphinepalladium(0) (0.1 mg), and a solution of potassium carbonate (16 mg) in water (0.2 mL), and the mixture was stirred at 80° C. overnight. The reaction solution was passed through a filter, and washed twice with THF (2 mL). The solvent was evaporated from the obtained solution by an air blowing apparatus. The residue was purified by HPLC (C18, mobile phase: water/acetonitrile (0.1% TFA-containing system)), and the solvent was evaporated from the obtained solution by an air blowing apparatus. The residue was purified by HPLC (C18, mobile phase: water/acetonitrile (10 mM ammonium acetate-containing system)) to give the title compound (7.8 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH3:12])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.C(O)(=O)C.[OH-].[Na+]>[Fe].C(O)C>[Cl:1][C:2]1[C:3]([NH:11][CH3:12])=[N:4][CH:5]=[C:6]([NH2:8])[CH:7]=1
Reactant: CNc1ncc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1ncc(N)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A suspension of 329 mg of 3-chloro-N-methyl-5-nitropyridin-2-ylamine, 489 mg of iron powder, and 9 ml of acetic acid was stirred at 60° C. for 2 hours. After the reaction solution was cooled to room temperature, ethanol was added thereto and the solution was filtrated through celite. The filtrate was concentrated under reduced pressure and ethyl acetate and a saturated aqueous sodium bicarbonate solution were added thereto. To the organic layer obtained by an operation of separation was added a 1M aqueous sodium hydroxide solution, followed by an operation of separation. The resulting organic layer was dried over anhydrous sodium sulfate and filtrated and then the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain 193 mg of 3-chloro-2-methylamino-5-aminopyridine as a brown oil.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:4]1)#[N:2].[N:38]([Si](C)(C)C)=[N+:39]=[N-:40].C([Sn](CCCC)=O)CCC>O1CCCC1>[CH3:26][O:25][CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]=[C:16]1[C:14]([N:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C@H:7]1[CH2:8][C@@H:3]([C:1]2[NH:40][N:39]=[N:38][N:2]=2)[CH2:4][N:5]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:6]1)=[O:15]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C#N)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: C1CCOC1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3nnn[nH]3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reaction time: 43 h

Procedure:
tert-Butyl (3R,5S)-3-cyano-5-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate (320 mg) was dissolved in tetrahydrofuran (20 ml), azido(trimethyl)silane (1.5 ml) and dibutyl(oxo)stannane (100 mg) were added, and the mixture was heated under reflux with stirring for 43 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-ethyl acetate-methanol (8:2) was concentrated under reduced pressure to give the object product (304 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][NH2:10])[CH:4]=1.N=[C:12]([CH3:16])[CH2:13][C:14]#[N:15].C(O)C>C(OCC)(=O)C>[CH3:16][C:12]1[CH:13]=[C:14]([NH2:15])[N:9]([C:5]2[CH:4]=[C:3]([S:2][CH3:1])[N:8]=[CH:7][N:6]=2)[N:10]=1
Reactant: CSc1cc(NN)ncn1
Reactant: CC(=N)CC#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1cc(-n2nc(C)cc2N)ncn1
Temperature: 85 °C

Procedure:
The mixture of (6-Methylsulfanyl-pyrimidin-4-yl)-hydrazine (1.0 g, 6.4 mmol), 3-Imino-butyronitrile (1.1 g, 12.8 mmol), and ethanol (30 mL) is heated to 85° C. for overnight. The reaction mixture is then cooled to room temperature, condensed, and treated with 75 mL ethyl acetate. The reaction mixture is partitioned between ethyl acetate and aqueous layer. The organic layer is dried over Na2SO4 and concentrated. The crude product is purified by ISCO chromatography eluting with ethyl acetate in hexanes from 10% to 80% to afford 5-Methyl-2-(6-methylsulfanyl-pyrimidin-4-yl)-2H-pyrazol-3-ylamine: 1H NMR 400 MHz (d6-DMSO) δ 8.72 (s, 1H), 7.53 (s, 1H), 6.90 (s, 1H), 5.26 (s, 1H), 2.57 (s, 3H), 2.08 (s, 3H); MS m/z 222.07 (M+1).
Reaction SMILES: O=O.[Si:3]([OH:7])([OH:6])([OH:5])[OH:4].[OH-].[Na+:9]>>[Si:3]([O-:7])([O-:6])([O-:5])[O-:4].[Na+:9].[Na+:9].[Na+:9].[Na+:9].[Si:3](=[O:5])=[O:4]
Reactant: O[Si](O)(O)O
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Product: O=[Si]=O
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
Oxygen cleaning agent according to the invention was made as follows: a highly concentrated sodium silicate solution was prepared by reacting 45.4 kilograms of 99.9% silicic acid with 93.0 kilograms of 50% sodium hydroxide solution at 104.4° C. to 126.7° C. This temperature was maintained for four hours under reflux conditions not allowing the temperature to exceed 126.7° C. This material was then quenched with 68.0 kilograms of ASTM D1193 Type 1 demineralized water. Two hundred and twenty five grams of this 44% active polysilicate anion sodium silicate solution was mixed with one liter of ASTM D1193 Type 1 demineralized water to obtain a silicon dioxide:disodium oxide mole ratio of 1.83, a polysilicate anion concentration of 9.5% by weight and a pH of 12.4. This solution was then heated to 82.2° C. for two hours and filtered in steps through 50 micron, 10 micron and 3 micron filters. The solution was allowed to cool to room temperature, and five grams of 99.9% sodium molybdate was added as a corrosion inhibitor. Then 15 grams of 48 to 50% fluoroboric acid was added as an additional corrosion inhibitor reducing the pH to 11.93 and forming in situ sodium fluoroborate.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][S:7][C:8]1[C:9]([CH3:17])=[CH:10][C:11]2[N:12]([N:14]=[CH:15][N:16]=2)[N:13]=1.[C:18]1([CH:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:38](=[O:41])([O-:40])[O-].[K+].[K+]>CN(C)C=O>[C:24]([OH:4])(=[O:25])/[CH:32]=[CH:37]/[C:38]([OH:40])=[O:41].[C:32]1([CH:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][S:7][C:8]3[C:9]([CH3:17])=[CH:10][C:11]4[N:12]([N:14]=[CH:15][N:16]=4)[N:13]=3)[CH2:28][CH2:27]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C([O-])[O-]
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: Cc1cc2ncnn2nc1SCCOCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2ncnn2nc1SCCOCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 23 h
Yield: 80.1 %

Procedure:
1.09 g of 6-[2-(2-bromoethoxy)ethylthio]-7-methyl[1,2,4]triazolo[1,5-b]pyridazine and 840 mg of 4-(diphenylmethoxy)piperidine were dissolved in 10 ml of N,N-dimethylformamide; 520 mg of potassium carbonate was added, followed by stirring at room temperature for 23 hours. Ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with dichloromethane:ethyl acetate:methanol (5:5:1). The desired fraction was collected; the residue was dissolved in 10 ml of ethanol; 200 mg of fumaric acid was added, followed by concentration. Ethyl ether was added to the residue; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 0.78 g of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])C.C(OC(C1(NC(C2CC(OC3C4C(=CC(OC)=CC=4)N=C(C4C=CC=CC=4)C=3)CN2[C:75](=[O:95])[NH:76][CH:77]([C:82](=[O:94])[NH:83][CH:84]2[C:92]3[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=3)C[CH:85]2[OH:93])[C:78]([CH3:81])([CH3:80])[CH3:79])=O)CC1C=C)=O)C.OC1CC2C(=CC=CC=2)[CH:98]1[NH:106]C(C(N1CC(OC2C3C(=CC(OC)=CC=3)C=C(C3C=CC=CC=3)C=2)CC1C1(C(O)=O)CC1C=C)C(C)(C)C)=O>>[CH:92]1([C@H:84]([NH:83][C:82]([C@@H:77]([NH:76][C:75]([N:15]2[CH2:16][C@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:18][C@H:14]2[C:12]([NH:11][C@:6]2([C:4]([OH:3])=[O:5])[CH2:8][C@H:7]2[CH:9]=[CH2:10])=[O:13])=[O:95])[C:78]([CH3:79])([CH3:80])[CH3:81])=[O:94])[C:85](=[O:93])[NH:106][CH3:98])[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]1
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Reactant: C=CC1CC1(C(=O)O)C1CC(Oc2cc(-c3ccccc3)cc3cc(OC)ccc23)CN1C(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)O
Yield: 18 %

Procedure:
Compound 12 was treated as described for the preparation of 13 but with the use of 21 instead of 2-amino-N-(2-hydroxy-indan-1-yl)-3,3-dimethyl-butyramide followed by ester hydrolysis as described for the preparation of compound 14 which, after purification by HPLC, gave the title compound (8.6 mg, 18% yield). Purity by HPLC >95%. M+H+783.3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH3:7].Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[C:27]1C(C2NC=CN=2)=[CH:31][N:30]=[C:29]([NH:38][CH2:39][CH2:40][NH:41]C2C=CC([N+]([O-])=O)=CN=2)[N:28]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[C:27]1[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[CH:31][N:30]=[C:29]([NH:38][CH2:39][CH2:40][NH:41][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[N:28]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1nccn1C
Product: Cn1ccnc1-c1cnc(NCCNc2ccc(C(F)(F)F)cn2)nc1-c1ccc(Cl)cc1Cl

Procedure:
[4-(2,4-dichlorophenyl)-5-(1-methylimidazol-2-yl)pyrimidin-2-yl](2-{[5-(trifluoro-methyl)(2-pyridyl)]amino}ethyl)amine was prepared from 1,2-dimethylimidazole and 2-chloro-5-(trifluoromethyl)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[O-:13][C:14]#[N:15].[Na+]>C(O)(=O)C>[CH:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:14]([NH2:15])=[O:13])([CH3:3])[CH3:2]
Reactant: COc1ccc(NC(C)C)cc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(N(C(N)=O)C(C)C)cc1

Procedure:
To a solution of 4.47 g (27.1 mmol) isopropyl-(4-methoxy-phenyl)-amine in 70 ml acetic acid are added in small portions 1.72 g (25.4 mmol) sodium cyanate while keeping the temperature below 15° C. by means of an ice bath. After stirring for 2 h at room temperature the acetic acid is evaporated and the residue is taken up in dichloromethane and washed with aqueous sodium hydroxide solution (1M). The organic phase is evaporated and the crude product is purified by recrystallization from dichloromethane/hexanes to yield 1-isopropyl-1-(4-methoxy-phenyl)-urea.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1)c1ccccc1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (35 mg) was reacted with 30 μL of benzoyl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 7 h
Yield: 75 %

Procedure:
1-Benzylpiperazine (2.8 ml; 16 mmol) and potassium carbonate (2.3 g; 17 mmol) were added to a solution of 1-chloro-4-nitrobenzene (2.0 g; 13 mmol) in dimethylformamide (0.5 ml), and the mixture was stirred for 7 hours in a bath controlled at 100° C. Water was added to the reaction mixture to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 2.9 g (yield: 76%) of 4-(4-benzyl-1-piperazinyl)-1-nitrobenzene as a colorless oil.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[CH3:9][C:10]1[N:11]=[C:12]([C:15]2([CH3:19])[CH2:18][O:17][CH2:16]2)[NH:13][CH:14]=1>C(#N)C>[I:8][C:14]1[NH:13][C:12]([C:15]2([CH3:19])[CH2:16][O:17][CH2:18]2)=[N:11][C:10]=1[CH3:9]
Reactant: Cc1c[nH]c(C2(C)COC2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1nc(C2(C)COC2)[nH]c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
NIS (2.61 g, 11.58 mmol) was added portion-wise to a solution of 4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.1, 1.76 g, 11.58 mmol) in acetonitrile (60 mL). The mixture was stirred at room temperature for 1 hour, then was partitioned between EtOAc (300 mL) and water (80 mL). The organic layer was washed with saturated sodium thiosulfate (50 mL), brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to give the title compound as a light yellow solid (3.0 g, 93%). m/z (ES+) 279 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=4[CH3:33])[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(F)cc3)CCCCC2)CC1

Procedure:
Example 92 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.46–7.43 (m, 3H), 7.26–7.22 (m, 2H), 7.10 (d, 1H, J=8.4 Hz), 7.06–7.01 (m, 2H), 6.74 (br s, 1H), 3.31 (dd, 2H, J=6.0, 12.0 Hz), 2.96 (d, 2H, J=11.6 Hz), 2.68 (m, 1H), 2.52 (m, 1H), 2.36–2.32 (m, 4H), 2.29 (s, 3H), 2.03–1.90 (m, 4H), 1.74–1.61 (m, 12H), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 522.3 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:25]2[N:29]=[CH:28][CH:27]=[N:26]2)=[C:20]([CH:24]=1)[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:25]2[N:29]=[CH:28][CH:27]=[N:26]2)=[C:20]([CH:24]=1)[C:21]([NH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:22]
Reactant: O=C(O)c1cc(Cl)ccc1-n1nccn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1NC(=O)c1cc(Cl)ccc1-n1nccn1

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 120 mg, 0.60 mmol), 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 38a; CAS number 1293284-54-4; 134 mg, 0.60 mmol), TBTU (231 mg, 0.72 mmol) and DIPEA (0.116 g, 0.9 mmol) in DMF (3 ml) was stirred at room temperature for 2 hours. The reaction was diluted with water (30 ml) and extracted with ethyl acetate (3×30 ml). The combined organics were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-30% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: [SH-:1].[C+4:2].[SH-:3].[SH-].[SH-].[OH-].[K+:7].[N+:8]([CH3:11])([O-:10])=[O:9]>>[N+:8]([CH:11]=[C:2]([S-:3])[S-:1])([O-:10])=[O:9].[K+:7].[K+:7]
Reactant: [SH-]
Reactant: [C+4]
Reactant: C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])C=C([S-])[S-]
Reaction time: 6 h

Procedure:
A mixture of nitromethane and carbon bisulfide dissolved in alcohols is added dropwise to the solution of potassium hydroxide in alcohol at room temperature. The reaction is carried out at the temperature range of 0-35° C. for 2-10 hours. The solid is filtered out to afford a crude product potassium 2-nitroethene-1,1-bis(thiolate) which is a brown yellow powder.
Reaction SMILES: [CH:1]1([NH:11][CH:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br.[O:15]=O.[Cl-].[Na+]>C(O)(=O)C.O.C(C(C)=O)C(C)C>[O:15]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]([NH:11][CH:12]=[O:13])[CH2:2][CH2:3]1
Reactant: O=CNC1CCCc2ccccc21
Reactant: O=O
Agent: Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Solvent: CC(=O)O
Product: O=CNC1CCC(=O)c2ccccc21
Temperature: 76 °C

Procedure:
A mixture of N-(1,2,3,4-tetrahydro-1-naphthyl)-formamide (2.0 g), cobaltous acetate tetrahydrate (0.95 g), a 30% solution of hydrobromic acid in acetic acid (0.925 g) and a 1:1 mixture of acetic acid: methyl isobutyl ketone (40 ml) is stirred and oxygen introduced via a capillary gas delivery tube. The blue reaction mixture is gradually heated to 76° C. in 42 minutes during which time the color changes to purple. The reaction mixture is then allowed to cool to room temperature. Water (40 ml) is added and the mixture saturated with sodium chloride. The mixture is extracted with chloroform (3×20 ml), the combined extracts are washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The residual red oil is triturated with ether and after cooling the title compound (0.4 g) collected. Further work-up of the mother liquor affords an additional 0.6 g of title compound.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24](NC(=O)/C(/C4N=C(NC(OC(C)(C)C)=O)SC=4)=N\OC(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20](=[O:64])[CH2:19][C:18]=2[S:65][CH:66](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:67][C:68]2[N:72]=[CH:71][NH:70][N:69]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C(OCC)(=O)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[CH2:24][C@H:21]3[S:20](=[O:64])[CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:72]=[CH:71][NH:70][N:69]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4nc[nH]n4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS(=O)[C@H]23)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SCSc2nc[nH]n2)CS(=O)[C@@H]2CC(=O)N12
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.8 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol -4-yl)- 2-trityloxyiminoacetylamino]-3-(trityl-1,2,4-triazol -3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (11.3 g) in acetone (60 ml) under ice cooling is added toluene-p-sulfonic acid monohydrate (1.68 g : 8.83 mMol.), and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with aqueous 5% sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene : ethyl acetate=1:1-1:2) to give 7β-(Z)-2-(2-t butoxycarbonylaminothiazol-4-yl) -2-trityloxyiminoacetylamino]-3-(1,2,4-triazol-3-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (2.84 g) as brown foam. Yield: 31%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH:34]([CH2:38][CH2:39][OH:40])[CH2:35][CH2:36][OH:37].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([N:34]([CH2:38][CH2:39][OH:40])[CH2:35][CH2:36][OH:37])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: OCCNCCO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N(CCO)CCO)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (50 mg, 101 μmol) was dissolved in absolute THF (2.5 ml), diethanolamine (29 μl, 303 μmol; 3 eq.) and triethylamine (10.2 mg, 101 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (4.9 mg, 9% of theory).