Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH2:11])[C:5]=2[N:4]=[CH:3][CH:2]=1.CO.[NH4+].[OH-].[CH3:16][CH2:17][O:18]C(C)=O>>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C@@H:6]([NH:11][C:17](=[O:18])[CH3:16])[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: NC1CCCc2nccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H]1CCCc2nccnc21
Reaction time: 2 h

Procedure:
Following the general procedure, 5,6,7,8-tetrahydroquinoxalin-5-ylamine (263 mg, 1.76 mmol), CALB (45 mg) and EtOAc (7.0 mL) were stirred for 2 hours. The conversion determined from 1H NMR by integration of the peaks at 4.94 ppm (CHNHAc) and 4.01 ppm (CHNH2) was 50%. Flash chromatography of the material on silica gel using 1:4 MeOH:EtOAc followed by 1:1:4 NH4OH:MeOH:EtOAc furnished the (R)-N-(5,6,7,8-tetrahydroquinoxalin-5-yl)acetamide ((157 mg, 47%) in 98% ee (chiral GC method: 130° C. for 180 min, (S)-enantiomerrt=183.5 min, (R)-enantiomerrt=183.7 min); [α]D=−78° (c 1.40, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.62-1.75 (m, 1H), 1.85-2.04 (m, 2H), 2.06 (s, 3H), 2.48-2.57 (m, 1H), 2.90-3.13 (m, 2H), 4.96-5.03 (m, 1H), 6.34 (br s, 1H), 8.35 (d, 1H, J=2.4 Hz), 8.39 (d, 1H, J=2.4 Hz); 13C NMR (CDCl3) δ 19.9, 23.6, 29.7, 31.8, 50.6, 142.1, 143.3, 152.0, 154.0, 170.7; MS m/z: 214 (M+Na+). The unreacted (S)-5,6,7,8-tetrahydroquinoxalin-5-ylamine (was isolated in 45% yield (118 mg) and 99% ee ((S)-enantiomern=25.9 min, (R)-enantiomerrt=29.0 min); [α]D=+61° (c 0.71, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 1.62-1.79 (m, 1H), 1.80-2.18 (m, 4H), 2.18-2.30 (m, 1H), 2.91-3.01 (m, 2H), 4.07 (dd, 1H, J=8.4, 5.4 Hz), 8.32-8.38 (m, 2H); 13C NMR (CDCl3): δ 19.7, 31.7, 32.2, 51.5, 142.0, 142.5, 152.6, 155.4; MS m/z: 150 (M+H+), 133 (M−NH2).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([NH2:28])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:31][NH:28][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:10][CH2:11]2)=[CH:20][C:19]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 10.1 %

Procedure:
A suspension of 5-(4-benzoylpiperazin-1-yl)-N1-phenylbenzene-1,2-diamine (0.2 g, 0.54 mmol), paraformaldehyde (0.025 g, 1.01 mmol), and 6 drops of acetic acid in 10 ml 1,2-dichloroethane was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (0.45 g, 2.2 mmol) was added and stirred overnight before quenching with 10 ml water. The mixture was extracted with ethyl acetate (3×20 ml) and dried over anhydrous sodium sulfate. ((4-(4-(Methylamino)-3-(phenylamino)phenyl)piperazin-1-yl)(phenyl)methanone (0.021 g, 10%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) 8 (ppm) 2.86 (s, 3H), 2.97 (s, br, 4H), 3.58 (s, br, 2H), 3.94 (s, br, 3H), 5.18 (s, 1H), 6.88 (m, 6H), 7.25 (m, 2H), 7.47 (m, 6H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14]>>[CH2:3]([N:2]([CH3:1])[S:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][Cl:7])(=[O:15])=[O:14])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNC
Reactant: O=S(=O)(Cl)CCCCCCl
Product: CCCCN(C)S(=O)(=O)CCCCCCl
Yield: 92.8 %

Procedure:
The reaction was carried out in the same manner as in Preparation Example 11 except for using N-methyl-n-butylamine (5.75g, 66 mmol) in place of diethylamine, and 5-chloropentanesulfonyl chloride (6.15g, 30 mmol) in place of 6-chlorohexanesulfonyl chloride in Preparation Example 11, to give N-n-butyl-N-methyl-5-chloropentanesulfonamide (7.12 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3](=[CH:8][CH3:9])[CH:4]=[CH:5][CH2:6][NH2:7])[CH3:2].[C:10]([N:12]=[C:13]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)OC(C)C)#[N:11].C[O-].[Na+]>CO.O>[C:10]([NH:12][C:13]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[N:7][CH2:6][CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH3:9])#[N:11]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: CC=C(C=CCN)CC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC=C(C=CCN=C(NC#N)c1cccnc1)CC
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of crude 4-ethyl-2,4-hexadien-1-ylamine (1.38 g) and isopropyl N-cyano-3-pyridinecarboximidate (1.74 g) in methanol (35 ml) at room temperature was added 28% sodium methoxide in methanol (2.13 g). After 10 minutes, the mixture was diluted with water and extracted three times with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (5% methanol in dichloromethane) to give N-cyano-N'-(4-ethyl-2,4-hexadien-1-yl)-3-pyridinecarboximidamide (1.89 g) as an oil.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([N:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH2:5][CH2:4][S:3]1)([O-:16])=[O:15]
Reactant: N=C1SCCN1Cc1ccncc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])N=C1SCCN1Cc1ccncc1
Reaction time: 0.5 h

Procedure:
5.8 g of 2-imino-3-(4-pyridylmethyl)thiazolidine was added to 20 ml of conc. sulfuric acid at -5°~0° C. 6 ml of fuming nitric acid was then added dropwise to the solution at the same temperature. After stirring for 30 minutes at 0°~5° C., the reaction mixture was poured onto crushed ice. Twice extract with dichloromethan followed by treating in the usual way yielded 1.4 g of desired 2-nitroimino-3-(4-pyridylmethyl)thiazolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](Cl)[CH:5]=[C:6]([NH2:8])[CH:7]=1.O.[NH3:11]>>[NH2:1][C:2]1[CH:3]=[C:4]([NH2:11])[CH:5]=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc(N)cc(Cl)c1
Reactant: N
Solvent: O
Product: Nc1cc(N)cc(N)c1

Procedure:
In an autoclave, 28.6 g. of 3,5-diaminochlorobenzene, 85 g. of 20% ammonia water and 1.0 g. of cuprous chloride were charged to react them at 175° to 180° C. for 8 hours to obtain 1,3,5-triaminobenzene. Ammonia was discharged and the product was recrystallized to obtain 20 g. of 1,3,5-triaminobenzene.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[C:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:4]=1)=O.[CH3:16][C:17]([S@@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].O>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:17]([S@@:20](/[N:22]=[CH:1]/[C:3]1[N:7]([CH3:8])[CH:6]=[C:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:4]=1)=[O:21])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: Cn1cc(C(=O)OC(C)(C)C)cc1C=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: ClCCl
Product: Cn1cc(C(=O)OC(C)(C)C)cc1/C=N/[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
To a solution of tert-butyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate (3.0 g, 14.5 mmol), (S)-2-methylpropane-2-sulfinamide (2.6 g, 21.8 mmol) in DCM (200 mL) was added titanium isopropoxide (24.8 g, 87 mmol). The mixture was stirred at rt for 20 h then water (30 mL) was added to quench the reaction. The solid precipitate was filtered and the filtrate was concentrated and purified by flash column chromatography (petroleum ether:EtOAc, 5:1) to give (S,E)-tert-butyl 5-((tert-butylsulfinylimino)methyl)-1-methyl-1H-pyrrole-3-carboxylate (2.9 g, 63%). 1H NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 7.29 (s, 1H), 7.02 (s, 1H), 3.89 (s, 3H), 1.48 (s, 9H), 1.16 (s, 9H).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[N:14]1([C:20]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)CC(C)C.C(#N)C>[N:22]1([C:20]([N:14]2[CH2:15][CH2:16][N:17]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:18][CH2:19]2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C(N1CCCCC1)N1CCNCC1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Solvent: CC(C)CCO
Solvent: CC#N
Product: O=C(N1CCCCC1)N1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and piperazin-1-ylpiperidin-1-ylmethanone (100.5 mg; 0.51 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1. After a reaction time of 4 h, piperazin-1-ylpiperidin-1-ylmethanone (50.3 mg; 0.26 mmol) and isoamyl alcohol (0.5 ml) are again added, and the mixture is again irradiated in the microwave for 4 h. The crystals obtained after conventional work-up are dissolved in acetonitrile and water and freeze-dried; yield: 17 mg (9%), crystals;
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]=O)[CH2:10][C:9]1=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(=[CH:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Si:1]([N:8]1[C:9](=[O:15])[CH2:10][CH:11]1[CH2:12][CH:13]=[CH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=O
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=CC(=O)OCc1ccccc1
Yield: 98.3 %

Procedure:
A mixture of (4RS)-1-(tert-butyl-dimethylsilyl)-4-(2-oxoethyl)-2-oxoazetidine (240 mg) and benzyl triphenylphosphoranylidene-acetate (521 mg) in dichloromethane (5 ml) was heated under refluxing for one hour. After removal of the solvent, the residue was chromatographed on silica gel (7 g) eluting with a mixture of dichloromethane and acetone (50:1) to give benzyl 4-[(2RS)-1-(tert-butyl-dimethylsilyl)-4-oxoazetidin-2-yl]but-2-enoate (373 mg) as an oil.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:18]=[C:17]2[C:8]([CH2:9][C:10]3([C:16]2=[O:19])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[CH2:21].C([O-])(=O)C.[Na+].O>CO>[N+:2]([C:5]1[CH:18]=[C:17]2[C:8]([CH2:9][C:10]3([C:16]2=[O:19])[CH2:15][CH2:14][N:13]([CH2:21][CH2:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:12][CH2:11]3)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: C=Cc1ccccn1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CC12CCNCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1c2cc([N+](=O)[O-])ccc2CC12CCN(CCc1ccccn1)CC2
Yield: 66 %

Procedure:
A solution of 0.150 g (0.53 mmole) 1,3-dihydro-6-nitro-1-oxospiro[2H-indene-2,4'-piperidine] hydrochloride, 0.116 g (1.1 mmoles) 2-vinylpyridine, and 0.090 g (1.1 mmoles) sodium acetate in 1.5 ml of 1:1 methanol: water was heated at reflux for 8 hours. Ethanol was removed in vacuo. The aqueous residue was diluted with 3 ml saturated sodium bicarbonate solution and extracted with 2×10 ml ethyl acetate. The combined extracts were washed with 3 ml water brine, dried, and the solvent was removed in vacuo to give 0.195 g crude product. This was recrystallized from ethyl acetate to give 0.123 g (66%) product, m.p. 142°-144° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[OH-:12].[K+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][OH:12])=[C:9]([CH:10]=1)[C:8]([OH:7])=[O:11]
Reactant: [OH-]
Reactant: O=C1OCc2ccc(F)cc21
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(F)ccc1CO
Yield: 78.1 %

Procedure:
To a solution of 6-fluoroisobenzofuran-1(3H)-one (0.549 g, 3.61 mmol) in methanol (12 mL) and water (3 mL) at room temperature was added potassium hydroxide (0.350 g, 6.24 mmol). The mixture was heated at reflux for 1.5 hr. The mixture was concentrated under vacuum to a volume of about 3 mL. The residue was acidified with 1 M KHSO4 solution to pH 3-4. The insoluble material (inorganic salt) was removed by suction filtration and the filtrate was extracted with ethyl acetate (5×30 mL). The combined extract was dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.479 g, 2.82 mmol, 78% yield) as a white solid.
Reaction SMILES: OC1C=CC(OC)=CC=1C(=O)C.C[Mg]Cl.O[C:17]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[OH:28])([CH3:19])[CH3:18].Cl>C1COCC1.[Pd].CC(=O)CC.O>[CH:17]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[OH:28])([CH3:19])[CH3:18]
Reactant: COc1ccc(O)c(C(C)(C)O)c1
Agent: [Pd]
Agent: COc1ccc(O)c(C(C)=O)c1
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCC(C)=O
Solvent: O
Product: COc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled solution of 1-(2-hydroxy-5-methoxy-phenyl)-ethanone (10.0 kg) in 79.0 kg of THF was gradually added 46.4 kg of 3M solution of MeMgCl in THF at a rate such that the reaction mixture temperature did not exceed 25 degrees C. Following addition of the MeMgCl solution, the reaction mixture was stirred at ambient temperature for 18 hours, at which point HPLC analysis showed more than 98% conversion of 1-(2-hydroxy-5-methoxy-phenyl)-ethanone to 2-(1-hydroxy-1-methyl-ethyl)-4-methoxy-phenol (not shown in Scheme D). To the stirred solution was then added 10% palladium on carbon (1.02 kg, 50% water wet) suspended in 3.5 Kg of THF. The reaction mixture was cooled and placed under a hydrogen atmosphere at 5 psig, and concentrated HCl (19.5 kg) was added while maintaining the reaction temperature at 25° C. The resultant mixture was stirred at ambient temperature for 18 hours, then treated with 44.4 kg water and filtered through a bed of Celite to remove suspended catalyst. The filter cake was rinsed with EtOAc and the combined filtrate was separated. The organic phase was washed with water, then concentrated by distillation to provide an oil. This oil was dissolved in 2-butanone (20.4 kg) and the crude solution was employed directly in the next step. A 161.8 g aliquot of the solution was concentrated under vacuum to provide 49.5 g of 2-isopropyl-4-methoxyphenol as an oil, projecting to 10.4 kg crude contained product in the bulk 2-butanone solution. 1H nmr (DMSO) delta: 1.14 (d, 6H, J=6.9 Hz), 3.18 (septet, 1H, J=6.9 Hz), 3.65 (s, 3H), 6.56, (dd, 1H, J=8.6 Hz, 3.1 Hz), 6.67 (d, 1H, J=3.1 Hz), 6.69 (d, 1H, 8.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8](=[S:10])[NH2:9])=[C:5]([NH2:7])[N:6]=1.OO>C(O)(=O)C>[NH2:9][C:8]1[S:10][N:7]=[C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=12
Reactant: Cc1nc(N)c(C(N)=S)s1
Agent: OO
Solvent: CC(=O)O
Product: Cc1nc2nsc(N)c2s1
Temperature: 22 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
3.4 parts of 2-methyl-4-amino-5-thiocarbamoyl-thiazole are suspended in 50 parts of glacial acetic acid and one part of 30 percent strength by weight hydrogen peroxide is added. After stirring for 12 hours at 22° C., the product is filtered off. 1.7 parts of 3-amino-5-methyl-thiazolo-(4,5-c)-isothiazole (50% of theory) of melting point 164°-167° C. are obtained.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8].[ClH:19].[C:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH2:33][C:34](=[O:36])[NH2:35])=[C:28](O)[CH:27]=[CH:26]2)(=[NH:22])[NH2:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[ClH:19].[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([C:20](=[NH:21])[NH2:22])[CH:24]=3)[C:29]=2[CH2:33][C:34](=[O:36])[NH2:35])=[O:15])=[CH:17][CH:18]=1)([O-:9])=[O:8]
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc([N+](=O)[O-])cc3)ccc2c1
Reaction time: 2 h
Yield: 29.4 %

Procedure:
30 Milliliters of anhydrous pyridine and 10 ml of DMF were added to 1.8 g of 4-nitrobenzoic acid, 3.0 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 2.7 g of DCC and 130.9 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. Then, the precipitate was collected by filtration and washed with a small amount of DMF. To this collected precipitate was added 100 ml of DMF, to dissolve the precipitate with heating, followed by stirring for 2 hours under cooling with ice. Then, insoluble matter was filtered off and the filtrate was concentrated to 20 ml under reduced pressure. The residue was added dropwise to 400 ml of acetone, followed by stirring for 24 hour under cooling with ice. The precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using chloroformmethanol-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. The residue was suspended with addition of 20 ml of methanol and 0.6 ml of concentrated hydrochloric acid, and the suspension was added dropwise to a mixed liquid of 200 ml of ether and 20 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 1.35 g of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-nitrobenzoate.hydrochloride.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH:27]1[CH2:30][N:29]([CH2:31][C@H:32]([O:43][C:44]2[N:49]=[CH:48][N:47]=[C:46]3[N:50]([C:53]4[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][N:54]=4)[N:51]=[CH:52][C:45]=23)[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])[CH2:28]1)(C(C)(C)C)(C)C.[Cl-].[NH4+]>C1COCC1.C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([NH:35][C:33](=[O:34])[C@@H:32]([O:43][C:44]2[C:45]3[CH:52]=[N:51][N:50]([C:53]4[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][N:54]=4)[C:46]=3[N:47]=[CH:48][N:49]=2)[CH2:31][N:29]2[CH2:28][CH:27]([OH:26])[CH2:30]2)=[N:37][CH:38]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](Oc2ncnc3c2cnn3-c2ncccc2Cl)C(=O)Nc2ccc(Cl)cn2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cn1)[C@H](CN1CC(O)C1)Oc1ncnc2c1cnn2-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.9 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (5.96 mL, 5.96 mmol) was added to (2S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-N-(5-chloropyridin-2-yl)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (Intermediate AD1) (3.67 g, 5.96 mmol) in THF (75 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 20 hours, saturated ammonium chloride (50 mL) added, diluted with DCM (100 mL) and poured onto a phase separator. The organic layer was evaporated and the crude product was purified by flash silica chromatography, eluting with 0 to 10% MeOH in EtOAc to afford the product (1.7 g, 57%). 1H NMR (400 MHz, DMSO) δ 2.95-3.10 (3H, m), 3.10-3.15 (1H, m), 3.60-3.70 (2H, m), 4.14-4.21 (1H, m), 5.26 (1H, d), 5.73-5.75 (1H, m), 7.74 (1H, dd), 7.88 (1H, dd), 8.01-8.07 (1H, m), 8.33 (1H, dd), 8.39-8.40 (1H, m), 8.55 (1H, s), 8.66 (1H, s), 8.68 (1H, dd), 11.13 (1H, s); m/z (ESI+) (M+H)+=501; HPLC tR=1.27 min.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH:37]C=O)[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3].Cl>CO>[CH2:1]([O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3]
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC=C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC=C)CS[C@H]12)c1csc(N)n1
Yield: 75.1 %

Procedure:
To a solution of 7-[2-(2-propynyl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) in methanol (14 ml) was added conc.hydrochloric acid (0.3 g) and the mixture was stirred for 3.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate and adjusted to pH 2.8 with conc.hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-propynyl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.43 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])=[C:4]([F:14])[CH:3]=1.[N+](=[CH2:17])=[N-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:17])=[O:12])=[C:4]([F:14])[CH:3]=1
Reactant: O=C(O)C1CC1c1ccc(Br)cc1F
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)C1CC1c1ccc(Br)cc1F

Procedure:
To a solution of (+)-2-(4-bromo-2-fluorophenyl)cyclopropanecarboxylic acid from step 7 (1 eq) in methylenechloride was added an ethereal solution of diazomethane until reaction is completed by TLC. The resulting mixture was concentrated. The crude ester was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:26]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]([C:29]2([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][N:19]=3)[S:17][C:10]=12.[CH3:41][O:42][CH2:43][CH2:44][NH2:45].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:26]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:27]([C:29]2([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][NH:45][CH2:44][CH2:43][O:42][CH3:41])=[CH:20][N:19]=3)[S:17][C:10]=12
Reactant: COCCN
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(-c5ccc(C=O)cn5)sc34)c(F)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccccc5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Aldehyde 141 (0.20 g, 0.362 mmol) and 2-methoxyethylamine (0.158 mL, 1.810 mmol) were dissolved in THF (50 mL) to give a colorless solution. Sodium trisacetoxyborohydride (0.384 g, 1.810 mmol) was added and the mixture was stirred at r.t. for 20 h. Additional 2-methoxyethylamine (0.158 mL, 1.810 mmol) and sodium trisacetoxyborohydride (0.384 g, 1.810 mmol) were added, and the mixture was stirred for a further 20 h. It was then concentrated, partitioned between water and dichloromethane. Organic phase was collected, washed with H2O, 1M NaOH, and brine, dried (MgSO4), filtered and concentrated. The residue was purified by Gilson Reverse Phase HPLC (Aquasil C18, 40-90% MeOH/water, 30 min, elutes ˜20 min) and lyophilized, to afford title compound 142. Starting material (50 mg) was also isolated.