Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([OH:32])[CH:30]=3)[N:25]([S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:24]=2)[CH:3]=1.[CH2:42](O)[C:43]#[CH:44].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH2:44][C:43]#[CH:42])[CH:30]=3)[N:25]([S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:24]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(O)cc34)cc(Cl)n2)CC1
Reactant: C#CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#CCOc1cnc2c(c1)c(-c1cc(Cl)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c1)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Example 224a (0.075 g, 0.125 mmol), propargyl alcohol (0.018 mL, 0.313 mmol), di-tert-butyl azodicarboxylate (0.072 g, 0.313 mmol), and triphenylphosphine (3 mmol/1 g)-polymer supported (0.105 g, 0.4 mmol) in THF (3.0 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and dichloromethane, filtered through celite, concentrated and purified on 12 g column, using Analogix System, eluted with 0-30% EtOAc in hexanes to give 56.0 mg (70%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[NH:9][CH2:10][C:4]=2[CH:3]=1.[CH3:16][N:17]([CH2:22][C:23]1[O:24][C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27]=1[CH3:28])[C:18](=[O:21])[CH:19]=[CH2:20].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:8]1([CH3:12])[C:7](=[O:13])[NH:6][C:5]2[N:14]=[CH:15][C:2](/[CH:20]=[CH:19]/[C:18]([N:17]([CH3:16])[CH2:22][C:23]3[O:24][C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[C:27]=3[CH3:28])=[O:21])=[CH:3][C:4]=2[CH2:10][NH:9]1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCC#N
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)oc2ccccc12
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
A suspension of 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.27 g, 1.0 mmol) and N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.31 g, 1.4 mmol) in propionitrile (5 mL) and DMF (1.3 mL) was de-oxygenated with Ar for 10 min. The mixture was treated with (i-Pr)2EtN (0.37 mL, 2.1 mmol) and was de-oxygenated with Ar for 10 min. Pd(OAc)2 (22 mg, 0.098 mmol) and P(o-tol)3 (61 mg, 0.20 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight, then allowed to cool. The resulting precipitate was isolated by filtration, washed with EtOAc, dissolved in CH2Cl2/MeOH (1:1) and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3) gave the title compound (0.25 g, 60%) as a white solid: MS (ESI) m/e 419 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH:16]3[NH:19][C:20](=[O:41])/[C:21](=[CH:26]/[C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]4)=[C:29]([O:39][CH3:40])[CH:28]=3)/[CH2:22][CH2:23][CH2:24]Cl)=[CH:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.O.C(OCC)(=O)C>CN(C=O)C>[CH3:40][O:39][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1)/[CH:26]=[C:21]1/[C:20](=[O:41])[N:19]([CH:16]2[C:17]3[C:12](=[CH:11][CH:10]=[C:9]([N:3]4[CH2:8][CH2:7][O:6][CH2:5][CH2:4]4)[CH:18]=3)[CH2:13][CH2:14][CH2:15]2)[CH2:24][CH2:23][CH2:22]/1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NC2CCCc3ccc(N4CCOCC4)cc32)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCCN(C3CCCc4ccc(N5CCOCC5)cc43)C2=O)ccc1-n1cnc(C)c1
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
Sodium hydride (containing mineral oil at 40%, 37.8 mg) was added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)-benzylidene)valeric acid (7-morpholin-4-yl-1,2,3,4-tetrahydronaphthalen-1-yl)amide (213 mg) in DMF (5.0 mL) at 0° C., and the reaction solution was stirred for 30 minutes. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system→ethyl acetate-methanol system) to obtain 195 mg of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-1-(7-morpholin-4-yl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin-2-one as a racemate.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:39]([CH3:51])[C:40](=[O:50])[CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH:33]=2)=[CH:28][CH:27]=1)=O>C(Cl)(Cl)Cl.ClCCl>[OH:5][CH2:4][CH2:3][N:2]([CH2:24][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:39]([CH3:51])[C:40](=[O:50])[CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:46])[CH3:47])[CH:33]=2)=[CH:28][CH:27]=1)[CH3:1]
Reactant: CNCCO
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CN(CCO)Cc1ccc(-c2cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c2)cc1
Reaction time: 5 h
Yield: 99.6 %

Procedure:
To a mixture of 2-(methylamino)ethanol (41 mg), sodium triacetoxyborohydride (166 mg), acetic acid (9 mg), and dichloromethane (4 ml) was added tert-butyl (2-{[(4′-formylbiphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (200 mg), followed by stirring for 5 hours. To the reaction mixture was added CHCl3-saturated aqueous sodium hydrogen carbonate solution, the organic layer was dried over Na2SO4, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (3% MeOH/chloroform) to obtain tert-butyl (2-{[(4′-{[(2-hydroxyethyl)(methyl)amino]methyl}biphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (230 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15])[CH3:11].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:14]([CH3:16])([CH3:15])[C:13]([O:12][CH2:10][CH3:11])=[O:18]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1Br
Temperature: 120 °C

Procedure:
A mixture of 2-bromo-4-chlorophenol (250 mg; 1.21 mmol) and ethyl-2-bromoisobutyrate (450 μl; 3.0 mmol) in DMF (5 mL) was treated with K2CO3 (250 mg, 1.81 mmol) and heated at 120° C. for 4.5 hours. Water was added and the reaction mixture was extracted 3 times with EtOAc. The combined organic phases were dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica), eluting with heptane containing increasing amounts of EtOAc. The title compound was obtained as a yellow sticky solid (320 mg; 83%).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH2:1]([NH:4][C:20](=[O:21])[O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNC(=O)OCc1ccccc1
Reaction time: 0.03 h

Procedure:
To a solution of allylamine (58 mmoles, 3.34 g) at 0° C. in dichloromethane (100 mL) was added triethylamine (120 mmoles, 16 mL). The mixture was stirred for two minutes, then benzylchloroformate (58 mmoles, 8.25 mL) added dropwise. The resulting solution was stirred at 0° C. for 2 hours, and at ambient temperature for an additional 90 minutes. A white precipitate formed, which was filtered off. Solvent was removed from the filtrate under reduced pressure, and the residue chromatographed on a silica gel column, eluting with 20% ethyl acetate/hexanes, to give benzyl allylcarbamate, a compound of formula (2), as a clear oil. Yield: 5.0 g.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][C:36]#[N:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO.O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][C:36]#[N:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(N)n3)[C@H]2SC1
Yield: 64.2 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.05 g.) and conc. hydrochloric acid (1.52 g.) in methanol (30 ml.) and tetrahydrofuran (20 ml.) was stirred at room temperature for 2 hours. After the solvent was evaporated in vacuo, the residue was dissolved in 10% aqueous solution of sodium hydroxide. After filtration, the filtrate was adjusted to pH 3.0 with 10% hydrochloric acid and stirred under ice-cooling for 30 minutes. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.25 g.).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[N-:7]=[N+:8]=[N-:9].[Li+].O>CN(C)C=O>[N:7]([CH:2]1[CH2:3][CH2:4][O:5][C:1]1=[O:6])=[N+:8]=[N-:9]
Reactant: O=C1CCCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCOC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.56 g (10 mmol) of 2-bromo-,γ-butyrolactone are dissolved in 2 ml of dimethylformamide, and 612 mg (12.5 mmol) of lithium azide are added at 0° C. The mixture is stirred at room temperature for 2 hours, water is added and the mixture is extracted three times with methylene chloride. The combined organic phases are washed three times with water, dried over sodium sulphate and concentrated. 1.10 g (86.6% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[O:22][C:21]([CH2:23]O)=[CH:20][CH:19]=4)[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:50]1[CH2:53][CH:52]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:51]1.C(N(CC)C(C)C)(C)C>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[O:22][C:21]([CH2:23][N:50]5[CH2:53][CH:52]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:51]5)=[CH:20][CH:19]=4)[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1CNC1
Reactant: OCc1ccc(-c2noc(-c3ccc(C4CCCCC4)cc3)n2)o1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(C5CCCCC5)cc4)n3)o2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using {5-[5-(4-cyclohexylphenyl)-1,2,4-oxadiazol-3-yl]-2-furyl}methanol (0.18 g, 0.55 mmol) that was obtained in Example 2 (2c), carbon tetrabromide (0.22 g, 0.67 mmol), triphenylphosphine (0.18 g, 0.67 mmol), ethyl 3-azetidinecarboxylate hydrochloride (0.14 g, 0.83 mmol) and N,N-diisopropylethylamine (0.30 ml, 1.7 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1) as the eluent to afford the title compound (0.23 g) in a yield of 96% as a white crystalline solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([O:52][Si](CC)(CC)CC)[CH2:16][CH:15]1[O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][CH:51]=[C:25]23)[CH2:20][CH2:19]1>C(OCC)(=O)C>[OH:52][C@@:14]1([CH3:13])[CH2:16][C@H:15]1[O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:45][C:4](=[O:7])[O:5][N:3]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][CH:51]=[C:25]23)[CH2:20][CH2:19]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC3CC3(C)O[Si](CC)(CC)CC)CC2)c2ccnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](O[C@@H]3C[C@]3(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.56 g), sodium hydrogen carbonate (0.84 g) and dimethyl sulfoxide (3.5 mL) was stirred at 50° C. for 30 min, 4′-({4-[trans-4-({2-methyl-2-[(triethylsilyl)oxy]cyclopropyl}oxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.44 g) was added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 1.5 mL), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.11 g, 28%).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].B(F)(F)F.CCOCC.[CH3:17][O:18][N:19]=[C:20]([C:37](=[O:40])[CH2:38][Br:39])[C:21]([NH:23][CH:24]1[C:35](=[O:36])[N:26]2[CH:27]([C:32]([OH:34])=[O:33])C(O)C[S:30][C@H:25]12)=[O:22].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:17][O:18][N:19]=[C:20]([C:37](=[O:40])[CH2:38][Br:39])[C:21]([NH:23][CH:24]1[C:35](=[O:36])[N:26]2[CH:27]([C:32]([OH:34])=[O:33])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][S:30][C@H:25]12)=[O:22]
Reactant: CC(=O)OC(C)=O
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(OC(C)=O)CS[C@H]12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (22.5 ml.) and boron trifluoride etherate (7.5 ml.) were added to a stirred solution of 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer 31.8 g.) in dry tetrahydrofuran (150 ml.) at room temperature, and stirred at the same temperature for 30 minutes and at 50° C. for an hour. To the resultant solution was added a saturated aqueous solution of sodium chloride (100 ml.) and stirred for 30 minutes. Ethyl acetate (150 ml.) was added to the solution, and the ethyl acetate layer was separated, and washed with a saturated aqueous solution of sodium chloride. The aqueous layer was extracted with ethyl acetate (100 ml.). The ethyl acetate layer and the extract were combined, treated with activated charcoal and evaporated. After adding diisopropyl ether (500 ml.) to the residue, the solvent was decanted. The residue was pulverized with diisopropyl ether, and the precipitates were collected by filtration and dried to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-acetoxycepham-4 -carboxylic acid (syn isomer, 35.3 g.)
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH3:16][C:17]([CH3:19])=O.[C:20]1(C)[CH:25]=CC=C[CH:21]=1>[Pt]>[CH:17]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][CH:20]([CH3:25])[CH3:21])=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)([CH3:19])[CH3:16]
Reactant: CC(C)=O
Reactant: Cc1ccccc1
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Agent: [Pt]
Product: CC(C)Nc1ccc(Cc2ccc(NC(C)C)cc2)cc1
Temperature: 22 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
4,4′-Methylenebis(benzeneamine) (8.0 g, 40 mmol), acetone (10.0 g, 172 mmol), Pt(S)/C (0.5 g), and toluene (50.0 g) were charged into reactor. The reactor was purged 3 times with 110 psig (8.60×105 Pa) of H2 at 22° C. The reaction mixture was then stirred at 22° C. under 110 psig of H2 overnight. GC (conditions: 180° C./5 minutes/10° C.-minutes rate/270° C./RT=9.37 minutes) showed 100% conversion of 4,4′-methylenebis(benzeneamine), and a 98% yield of N,N′-diisopropyl-4,4′-methylenebis(benzeneamine). The structure of the product was confirmed by GC-MS. No tertiary diamine was detected either by GC or by GC-MS.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:27](OC1C=CC([N+]([O-])=O)=CC=1)=[O:28].N1C=CC=CC=1.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>C(Cl)Cl>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH2:20][CH3:21])=[CH:13][CH:14]=2)[N:9]([CH:22]2[CH2:23][CH2:24][CH2:25]2)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:28])=[CH:7][CH:6]=1)#[N:18]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Reactant: C1COCCN1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ccc2c(C#N)c(-c3ccc(NC(=O)N4CCOCC4)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
2-(4-aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (40 mg, 0.12 mmol), 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), CH2Cl2 (400 μL), and pyridine (25 μL, 0.31 mmol) are stirred at room temperature for 1 hour. Morpholine (60 μL, 0.70 mmol) is added. After stirring at room temperature for an additional 30 minutes, the reaction mixture is diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol byproduct. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2/EtOAc, 7/3) yields morpholine-4-carboxylic acid [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-amide (53 mg, 100%) as a white solid.
Reaction SMILES: C(=O)CCCCCC.ClC(Cl)(Cl)C([O-])=O.[Na+].C(=O)([O-])[O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:20]([Cl:23])([Cl:22])[Cl:21].[Na+]>O>[Cl:21][C:20]([Cl:22])([Cl:23])[CH:19]([OH:18])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCC(OC(=O)[O-])C(Cl)(Cl)Cl
Agent: O=C([O-])C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCCCCCC=O
Solvent: O
Product: CCCCCCC(O)C(Cl)(Cl)Cl
Reaction time: 8 h

Procedure:
The contents of a flask charged with n-heptanal (2.5 mmol), sodium trichloroacetate (2.7 mmol) and a solvent (10 g) were stirred for 16 hours. At the end of this period, when the reaction mixture contained sodium 1,1,1-trichloro-2-octyl carbonate (compound 24), ##STR35## water (50 ml) was added and the mixture was extracted with two portions (each of 25 ml) of n-pentane. Six experiments were thus carried out, each with another solvent. Table I shows which solvents and temperatures were used and presents the conversion of the n-heptanal and the selectivity to the title alcohol. These conversions and selectivities were already obtained after one hour stirring, stirring being continued overnight.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27](Cl)[CH:26]=[N:25]1)([CH3:23])([CH3:22])[CH3:21].C(OC(C)C)(C)C>CN(C)C=O>[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27]([O:15][CH2:14][C:11]2[CH:12]=[N:13][C:8]([O:7][CH2:6][C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH:26]=[N:25]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: OCc1ccc(OCc2ccc(F)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(OCc2ccc(OCc3ccc(F)cc3)nc2)c(Cl)c1=O
Temperature: 0 °C
Yield: 77.7 %

Procedure:
To a solution of 2.3 g of 6-(4-fluorobenzyloxy)-3-pyridine methanol in 20 ml of N,N-dimethylformamide was added under stirring at 0° C. 0.5 g of 55% sodium hydride (in mineral oil). After stirring for 30 minutes at room temperature, thereto was added 2.2 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone. The reaction mixture was stirred at room temperature for additional 8 hours, poured into 50 ml of ice water and extracted twice with 50 ml of benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to give 4.1 g of a crude product. The crude product was added with isopropyl ether and recrystallized therefrom to obtain 3.2 g of 2-t-butyl-4-chloro-5-[{6-(4-fluorobenzyloxy)-3-pyridyl}-methyloxy]-3(2H)-pyridazinone, m.p. 121.0°~124.0° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41]>>[CH3:38][N:39]([CH3:43])[C:40]([N:29]1[CH2:28][CH2:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30]1)=[O:41]
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Reactant: CN(C)C(=O)Cl
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)N(C)C)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with dimethylcarbamic chloride to give the title compound. LC/MS (M+H)+: 606. Ret. time: 1.53 min. (Condition G); analytical HPLC Ret. time: 7.53 min (Condition H).