Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@@H:10]([OH:21])[CH2:11][C@@H:12]([C:17]([OH:20])([CH3:19])[CH3:18])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])(C)(C)C.Cl.[C:27]([O:31][C:32]([NH:34][C@H:35](C(O)=O)[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[C:27]([O:31][C:32]([NH:34][C@H:35]([C:6]([NH:8][C@@H:9]([CH2:22][CH:23]([CH3:24])[CH3:25])[C@@H:10]([OH:21])[CH2:11][C@@H:12]([C:17]([OH:20])([CH3:18])[CH3:19])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 274 mg (0.76 mmoles) of (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-4-hydroxy-2-(1-hydroxy-1-methylethyl)-7-methyl-N-methyloctanamide (prepared as described in Preparation 28) in 5 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature and under an atmosphere of nitrogen for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. Diethyl ether was added to the residue, and the solvent was again removed by distillation under reduced pressure. The same operation was repeated, in total, three times. The resulting residue was then dried by evaporation under reduced pressure for 8 hours, after which it was suspended in 5 ml of anhydrous tetrahydrofuran. 248 mg (0.91 mmoles) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were then added to the suspension, after which 0.14 ml (0.92 mmoles) of diethyl cyanophosphate and 0.23 ml (1.65 mmoles) of triethylamine were added to the mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 5 hours, after which the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from hexane to give 356 mg (yield 91%) of the title compound as a white amorphous substance.
Reaction SMILES: C(OC(=O)[NH:7][C@:8]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C@H:12]([CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C@@H:11]([CH3:19])[O:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@:8]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:9][O:10][C@H:11]([CH3:19])[C@H:12]1[CH:13]([OH:18])[C:14]([F:17])([F:15])[F:16]
Reactant: C[C@H]1OC[C@@](NC(=O)OC(C)(C)C)(c2ccccc2F)[C@@H]1C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1OC[C@@](N)(c2ccccc2F)[C@@H]1C(O)C(F)(F)F
Reaction time: 16 h
Yield: 1334.3 %

Procedure:
[(3S,4R,5R)-3-(2-Fluoro-phenyl)-5-methyl-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-tetrahydro-furan-3-yl]-carbamic acid tert-butyl ester (Preparation Example 30-(3)) (1.20 g, 0.23 mmol) was dissolved in DCM (20 ml). TFA (10 ml) was added. The reaction mixture was stirred overnight (16 h). The reaction was then concentrated, 10 ml of aqueous saturated sodium carbonate was added then extracted with DCM (2×40 ml). 900 mg (86%) of a mixture of the title compound (85%) and its epimer at the CF3 position (15%) were isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]3[C:19]=2[CH3:20])=[CH:4][C:3]=1[OH:21].[N:22]#[C:23]Br.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C(OCC)(=O)C>[CH3:20][C:19]1[N:13]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]2=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:23]([NH2:22])[O:21][C:3]=2[CH:4]=1
Reactant: Cc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1
Reactant: N#CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1ccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc2c1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 62.2 %

Procedure:
A mixture of 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (11.0 g) and cyanogenbromide (5.0 g) in ethanol (165 ml) was stirred for 100 minutes at ambient temperature. To the reaction mixture was added a solution of ethyl acetate and water, and the mixture was adjusted to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 8 with 20% aqueous potassium carbonate and the resulting precipitate was collected by filtration. The precipitate was subjected to a column chromatography on alumina eluting with a solution of chloroform and methanol (19:1 V/V). The fractions containing desired product were combined and evaporated to give 6-[2-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-aminobenzoxazole (7.45 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16].[CH3:25][C:26]([CH3:33])([CH:31]=O)[C:27]([O:29][CH3:30])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:25][C:26]([CH3:33])([CH2:31][N:22]1[CH2:21][CH2:20][CH:19]([CH2:18][NH:17][C:15]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[C:2]2=[O:1])=[O:16])[CH2:24][CH2:23]1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: O=C(NCC1CCNCC1)N1C(=O)C2(CCCC2)c2ccccc21
Reactant: COC(=O)C(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)CN1CCC(CNC(=O)N2C(=O)C3(CCCC3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 22.6 %

Procedure:
To a stirred solution of 2′-oxo-N-(piperidin-4-ylmethyl)spiro[cyclopentane-1,3′-indole]-1′(2′H)-carboxamide (480 mg, 1.5 mmol, step 2 of Example 2) and methyl 2,2-dimethyl-3-oxopropanoate (248 mg, 1.7 mmol, Kim, Hwa-Ok et al., Synth. Commun., 1997, 27, 2505) in CH2Cl2 (40 mL) was added sodium triacetoxyborohydride (623 mg, 2.9 mmol) in one portion at room temperature. The mixture was stirred for 20 h at ambient temperature. To the mixture was added sat. NaHCO3 aq. (10 mL), extracted with CH2Cl2 (30 mL×2), dried over MgSO4, filtered and concentrated gave yellow oil. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (9:1) to give 150 mg (23%) of the title compound as clear colorless oil.
Reaction SMILES: [CH2:1]([S:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)[CH2:2][CH3:3].C([Li])CCC.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CCCCCC>[C:16]1([S:22]([N:9]2[CH:5]([S:4][CH2:1][CH2:2][CH3:3])[CH2:6][CH2:7][C:8]2=[O:10])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCSC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCSC1CCC(=O)N1S(=O)(=O)c1ccccc1
Yield: 34.7 %

Procedure:
To 2.3 g of 5-propylthio-pyrrolidin-2-one in solution in 120 cm3 of tetrahydrofuran, there is added at -70° C./-65° C., 9.6 cm3 of a 1.5M solution of butyllithium in hexane. After 20 minutes at this temperature, 2.55 g of benzenesulphonyl chloride is added in 20 cm3 of tetrahydrofuran. After allowing to return slowly to ambient temperature, concentrating and chromatographing on silica (eluent: hexane-ethyl acetate, 3-7), 1.5 g of the expected product is obtained. m.p. 49°-51° C. crystallized from isopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:24][CH2:25][CH2:26]Br>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:24][CH2:25][CH3:26])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: CCCBr
Product: CCCN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) and n-propyl bromide. MS (M−H, 362.1); 1H NMR (400 MHz, CDCl3): δ, ppm: 0.70 (m, 3H), 1.35 (m, 3H), 3.08 (m, 2H), 3.73 (s, 3H), 4.31 (s, 2H), 6.83 (m, 2H), 7.17 (m, 2H), 7.93 (m, 2H), 8.23 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.Cl.[S:9]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1)(=[O:12])(=[O:11])[NH2:10]>>[S:9]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][N:20]=[CH:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:17][CH:18]=1)(=[O:12])(=[O:11])[NH2:10]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccco1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=Cc2ccco2)cc1

Procedure:
A solution of 2-furancarboxaldehyde (5 mmol) and 4-sulfamylphenylhydrazine hydrochloride is subjected to the General Procedure. The title compound is isolated as described in the general procedure.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:8][CH2:9][C:10]([N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](OC)=[O:24])=[CH:19][CH:18]=2)[CH3:14])([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:33]>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][N:13]([C:10]([CH3:12])([CH3:11])[CH2:9][O:8][CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:14])=[CH:18][CH:19]=1)(=[O:24])[NH2:33]
Reactant: COC(=O)c1ccc(CCN(C)C(C)(C)COC(c2ccccc2)c2ccccc2)cc1
Reactant: N
Product: CN(CCc1ccc(C(N)=O)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Yield: 62 %

Procedure:
A solution of 1-diphenylmethoxy-2-[N-(4-methoxycarbonylphenethyl)-N-methylamino]-2-methylpropane (800 mg -- see Example 13) in saturated methanolic ammonia (80 ml) was heated in a steel bomb at 100° for 80 hours and evaporated. The residue was purified by chromatography on silica (40 g) using methylene chloride:methanol:saturated methanolic ammonia (96:4:1) as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil (480 mg, 62%).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:6][CH2:5]1.[N:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C@H:7]3[CH2:8][CH2:9][C@H:4]([NH:3][C:37](=[O:38])[C:36]4[CH:35]=[CH:34][C:33]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:41][CH:40]=4)[CH2:5][CH2:6]3)[CH2:17][CH2:16]2)=[O:19])=[CH:21][CH:22]=1
Reactant: N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)cc3)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)cc3)CC2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
From {1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl}-(4-chloro-phenyl)-methanone dihydrochloride (100 mg) and 4-morpholin-4-yl-benzoic acid. Yield: 56 mg (40%). MS (m/z): 538.5 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[OH-].[Li+].Cl>CO.O>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ncc(Br)nc1C(=O)O
Temperature: 90 °C
Yield: 99 %

Procedure:
A mixture of methyl 3-amino-6-bromo-pyrazine-2-carboxylate (5.11 g, 22.02 mmol) and lithium hydroxide (2.637 g, 110.1 mmol) in MeOH (20 mL) and H2O (20 mL) was heated to 90° C. for 2 hours. The reaction mixture was allowed to cool and neutralised with HCl and the resultant precipitate collected by filtration. Taken on to the next step without further purification (4.80 g, 99% Yield).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[OH-].[NH4+:16]>O>[NH2:16][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 7 h

Procedure:
2-Chloro-3-nitrobenzoic acid (20.6 g, 0.24 mol) was dissolved in ammonium hydroxide solution (120 mL) and the reaction mixture stirred at 120° C. in a sealed vessel for 7 hours. The reaction mixture was diluted with water (250 mL) and acidified to pH 2 with hydrochloric acid. The precipitate formed was filtered off and dried in vacuo to yield the title product, 15.0 g (80%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[C:12]([F:17])[CH:11]=1)(=[O:9])=[O:8].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)=[C:12]([F:17])[CH:11]=1)(=[O:9])=[O:8]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)c(F)c1
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(C(F)(F)F)cc2)c(F)c1

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-3-fluorophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 4-trifluoromethylphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 26.4, 29.5, 43.2, 62.2, 115.4 (d, J 25.4), 123.2, 125.7, 129.4, 130.8 (d, J 22.2), 131.6, 137.6, 141.5 (d, J 6.8) and 159.3 (d, J 253.9).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:12][NH:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[O:4]=[C:3]([N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:2][N:13]([CH3:12])[CH2:14][CH2:15][OH:16]
Reactant: O=C(CCl)N1CCCCCC1
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(CCO)CC(=O)N1CCCCCC1

Procedure:
A mixture of 4.8 g (27 mmol) of 1-(2-chloroacetyl)perhydroazepine, dissolved in 40 ml of 2-butanone, 3.6 g (48 mmol) of 2-(methylamino)ethanol and 6.6 g (48 mmol) of potassium carbonate is heated to 70° C. for 5 h.
Reaction SMILES: [BH4-].[Li+].[N:3]1[C:4]([C:12](OCC)=[O:13])=[CH:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.CO>O1CCCC1.O>[N:3]1[C:4]([CH2:12][OH:13])=[CH:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: CCOC(=O)c1cn2ccccc2n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OCc1cn2ccccc2n1
Reaction time: 8 h
Yield: 7.8 %

Procedure:
3.68 g of lithium borohydride were added at room temperature to a solution of 9.17 g of ethyl imidazo[1,2-a]pyridine-2-carboxylate [described in J. Org. Chem., 30, 2403-2407 (1965)] in 200 ml of tetrahydrofuran, and then 20 ml of methanol were added dropwise to the mixture, which was then allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was diluted with 10 ml of water and then concentrated by evaporation under reduced pressure. The concentrate was mixed with an aqueous solution of sodium chloride, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the eluent. The product was then recrystallized from a mixture of ethyl acetate and hexane, to give 0.56 g of the title compound, melting at 126°-128° C.
Reaction SMILES: Cl.CN.[CH3:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[CH:17][CH3:18])[C:14](Cl)=[O:15].[N:19]1C=CC=C[CH:20]=1>ClCCl>[CH3:20][NH:19][C:14](=[O:15])[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][O:5][CH3:4])=[CH:17][CH3:18]
Reactant: c1ccncc1
Reactant: CC=C(C(=O)Cl)c1ccccc1COC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CC=C(C(=O)NC)c1ccccc1COC
Temperature: 20 °C
Reaction time: 15 h
Yield: 29.7 %

Procedure:
1.7 g of methylamine hydrochloride was added to 5.2 g (23 mmol) of α-(2-methoxymethylphenyl)-β-methylacrylic chloride in 30 ml of dichloromethane, and 4 g of pyridine was dripped in at 0° to 5° C. The mixture was stirred for a further 15 hours at about 20° C. The reaction mixture was diluted with 20 ml of dichloromethane and washed with water. The organic phase was dried over sodium sulfate and evaporated down. The crude product was chromatographed on silica gel with methyl tert-butyl ether/cyclohexane (5/1). Removal of the solvent gave 1.5 g (30%) of the title compound in the form of colorless crystals (m.p.: 58° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N+:10]([CH3:13])([O-:12])=[O:11].[OH-].[Na+].C(O)(=O)C>CCO>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:13][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C(O)C[N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A stirred solution of 4-methylbenzaldehyde (325 mg, 319 μL, 2.71 mmol) and nitromethane (531 μL, 9.89 mmol) in absolute EtOH (20 mL) at 0° C. was treated with 10% aq. NaOH (m/v) (1.14 mL, 2.84 mmol), stirred for 1 h and treated with 2% aq. acetic acid (m/v) (8.54 mL, 2.84 mmol). The reaction was stirred for 1 h at room temperature then partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo to afford 1-(4-methylphenyl)-2-nitroethanol as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.28 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H), 5.42 (dt, J=9.6, 3.3 Hz, 1H), 4.60 (dd, J=13.3, 9.7 Hz, 1H), 4.49 (dd, J=13.3, 3.1 Hz, 1H), 2.79 (d, J=3.7, 1H), 2.36 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([C:8]#[CH:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:24])[N:15]([CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:17][C:18]([CH3:20])=[CH2:19]>CCCCCC>[CH:21]([N:15]([CH:16]1[CH:17]=[C:18]([CH3:20])[CH2:19][CH:9]=[C:8]1[C:6]([C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=1)=[O:7])[C:14]([O:13][CH3:12])=[O:24])([CH3:22])[CH3:23]
Reactant: C#CC(=O)c1ccc(F)cc1
Reactant: C=C(C)C=CN(C(=O)OC)C(C)C
Solvent: CCCCCC
Product: COC(=O)N(C(C)C)C1C=C(C)CC=C1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred suspension of 67,9 g 4-fluorobenzoylacetylene in 160 ml hexane under reflux is added dropwise within 1 hour 78,8 g N-isopropyl-N-(3-methyl-1,3-butadienyl)-carbamic acid methylester in 40 ml hexane. After the addition is completed, the reaction mixture is stirred for additional 6 hours under reflux, and then cooled to room temperature, whereby the heading compound precipitates, m.p. 98°-102° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].CCN(CC)CC.[NH:15]1[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][CH2:16]1.CCOC(C)=O>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([N:15]1[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][CH2:16]1)=[O:7]
Reactant: C1CCC2NCCCC2C1
Reactant: O=C=NCCCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCCCl)N1CCCC2CCCCC21
Yield: 84.6 %

Procedure:
2.5 g (21 mmol) of 3-chloropropylisocyanate are dissolved in 150 mL of anhydrous THF and 6.4 mL (46 mmol) of Et3N. Once dissolved 3.4 mL (23 mmol) of decahydroquinoline are slowly added and it is refluxed for 18 h. AcOEt is then added and the resulting solution is sequentially washed with water, 1N HCl and brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure yielding 4.6 g of intermediate IIIf.1. Method B: tr: 3.58 min; m/z: 259
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[CH2:12]([SiH:16]([CH2:23]F)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH:14]=[CH2:15]>C1COCC1>[CH2:12]([SiH:16]([CH2:23][CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: C1CSCSC1
Reactant: C=CCC[SiH](CF)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC[SiH](CC1SCCCS1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 1,3-dithiane (11.1 g, 91.9 mmol) in THF (150 mL) at −78° C. was added dropwise over 10 min n-butyllithium (1.6 Min hexane, 76.6 mmol), and the solution was stirred for 2 h under argon. A solution of 42 (11.9 g, 61.3 mmol) in THF (120 mL) was added dropwise over 30 min, and the mixture was stirred for 3 h at −78° C. and overnight at rt. The reaction mixture was quenched with water (100 mL) and extracted thrice with 100-mL portions of EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave 43 contaminated with 1,3-dithiane. The latter was removed by sublimation (54° C., 8.0 mm Hg) to provide pure 43 as a yellow oil (9.0 g, 50% for three steps from dichlorosilane):Rf=0.55 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.63-7.61 (m, 2H), 7.42-7.38 (m, 3H), 5.97-5.84 (m, 1H), 5.06-4.90 (m, 2H), 3.95 (s, 1H), 2.93-2.83 (m, 2H), 2.72-2.67 (m, 2H), 2.21-1.97 (m, 4H), 1.18-1.09 (m, 2H), 0.49 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 141.0, 134.5, 134.1, 129.9, 127.9, 113.2, 32.9, 31.1, 31.0, 27.2, 25.8, 10.8, 7.0; MS (FAB) m/e (rel. intentsity) 293 (MH+, 23), 239 (21), 175 (20), 159 (9), 149 (58), 121 (100), 119 (37), 115 (23), 105 (34), 97 (28), 92 (22); HRMS (FAB) calcd for C15H22S2Si: 293.0854, found: 293.0861. Anal. Calcd for C15H22S2Si: C, 61.16; H, 7.53. Found C, 61.31; H, 7.74.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[S:15][CH2:14][CH2:13][S:12]1.[H-].[Na+].Br[CH2:19][C:20]([NH2:22])=[O:21].O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]([NH2:22])=[O:21])[C:6](=[O:11])[C:5]12[S:12][CH2:13][CH2:14][S:15]1
Reactant: Cc1ccc2c(c1)C1(SCCS1)C(=O)N2
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)C1(SCCS1)C(=O)N2CC(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Compound 6 (8 g, 33.7 mmol) was dissolved in dry DMF (80 ml) under a nitrogen atmosphere. The solution was cooled at 0° C. and NaH (1.62 g, 37.13 mmol, 60% dispersion) was carefully added portionwise. When the nitrogen evolution ceased, bromoacetamide (5.6 g, 37.13 mmol) was added. After 30 minutes, the mixture was poured into cold water and the solid filtered off, washed with water and hexane. The crude material was directly cristallized in acetonitrile affording 2-[(5′-methyl-2′-oxospiro[1,3-dithiolane-2,3′-indol]-1′(2′H)-yl]acetamide 15 as a white solid.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[C:19]([C:22](=[N:30][O:31][CH3:32])[CH2:23][N:24]1[C:28]([SH:29])=[N:27][N:26]=[N:25]1)([OH:21])=[O:20].B(F)(F)F.CCOCC.N>C(#N)C.O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:29][C:28]3[N:24]([CH2:23][C:22]([C:19]([OH:21])=[O:20])=[N:30][O:31][CH3:32])[N:25]=[N:26][N:27]=3)[CH2:15][S:14][C@H:9]12
Reactant: CON=C(Cn1nnnc1S)C(=O)O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Agent: N
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: CON=C(Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1)C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a suspension of 7-aminocephalosporanic acid (0.99 g) and 1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazole-5-thiol (0.95 g) in dry acetonitrile (10 ml) was added boron trifluoride etherate (1.55 g) and the resulting solution was stirred at 50° C. for 2 hours. Water (10 ml) was added to the reaction mixture and the solution was adjusted to pH 3.5 with conc. aqueous ammonia under ice-cooling to give precipitates which were filtered, washed with water and dried to give 7-amino-3-[1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.0 g), mp 170° to 180° C. (dec.).