Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H]([C:5](O)=[O:6])C[SeH].[Li]CCCC.[Si:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(CCN(C)C)C.CN(C=O)C.Cl>C1COCC1>[Si:13]([O:20][C:21]1[C:22]([F:27])=[C:23]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[O:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1F
Reactant: N[C@@H](C[SeH])C(=O)O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1F
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
Sec-BuLi (1.3M solution in cyclohexane, 75 mL, 98 mmol) was added slowly at −78° C. to a solution of Intermediate 31, 1-(tert-Butyldimethylsilyl)oxy-2-fluorobenzene (20.1 g, 89 mmol) and TMEDA (14.8 mL, 98 mmol) in THF (200 mL) and the mixture was stirred at the same temperature for 30 min. DMF (7.5 mL, 98 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for 1.5 h. Then 10% aqueous HCl was added to attain pH˜4-5 (200 mL), and the reaction mixture was stirred at RT for 30 min. The organic layer was separated. Aqueous layer was extracted with EtOAc (200 mL). The organic layers was washed with sat. NaHCO3, brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (16.7 g, 74%, 66 mmol) as a yellow oil. 1H NMR data (dmso-d6): 10.21 (s, 1H, CHO), 7.39-7.45 (m, 1H, H—Ar), 7.32-7.38 (m, 1H, H—Ar), 7.22-7.28 (m, 1H, H—Ar), 0.97 (s, 9H, t-Bu), 0.20 (s, 6H, 2CH3).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[CH2:10]2)[NH:5][C:4]1=[O:22].B(Br)(Br)Br>ClCCl>[OH:1][CH2:2][CH:3]1[CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH:9]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)[CH2:10]2)[NH:5][C:4]1=[O:22]
Reactant: COc1ccc(CC2CCC3NC(=O)C(CO)CC3C2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1NC2CCC(Cc3ccc(O)cc3)CC2CC1CO
Yield: 14.1 %

Procedure:
3,4,4a,5,6,7,8,8a,-Octahydro-3-hydroxymethyl-6-((4-methoxyphenyl)methyl)-quinolin-2[1H]-one (0.26 g) (prepared according to Example 7) was dissolved in dichloromethane and cooled to ice temperature. 1M Boron tribromide in dichloromethane (4.3 ml) was added and the mixture was left 2 hours after which a further 75 ml of dichloromethane was added. After a further 1 hour the reaction mixture was quenched by addition of water (2 ml) and evaporated under reduced pressure. The residue was dissolved in methanol (100 ml) containing conc. HCl (1 ml) and the methanol was evaporated under reduced pressure; the process being repeated three time. The residue was basified with saturated sodium bicarbonate solutions and was extracted into chloform. The chloroform layer was dried (MgSO4) and evaporated. The residue was recrystallised from isopropanol/diisopropyl ether to give the title compound (0.035 g) mp 126°-128° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].CO[CH2:11][N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:7][O:6][C:4]([C:3]1([O:2][CH3:1])[CH2:8][CH2:11][N:12]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:13]1)=[O:5]
Reactant: C=C(OC)C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(OC)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a stirred solution of methyl 2-methoxyacrylate (20.8 g, 179 mmols) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (55 ml, 215 mmols) in dichloromethane (160 ml) was added at 0 C a solution of trifluoroacetic acid (2 ml) in dichloromethane (10 ml). The resulting solution was warmed to room temperature and stirred overnight. After concentration, the crude product was purified by column chromatography on silica gel eluting with a solution of ethyl acetate/hexanes/Et3N (1000:3000:4 to 1000:1000:3) to give the title compound (17.7 mg, 40%).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]4[C:28]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][S:26][C:25]=4[CH:34]=3)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C>C1COCC1>[N:16]1[C:17]2[NH:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[CH:14][C:15]=1[CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[C:28]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][S:26][C:25]=2[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4c(CCC(=O)O)csc4c3)nc21
Solvent: C1CCOC1
Product: O=C(O)CCc1csc2cc(OCCc3ccc4c(n3)NCCC4)ccc12
Yield: 23.9 %

Procedure:
7-{2-[3-(2-Carboxy-ethyl)-benzo[b]thiophen-6-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (168 mg, 0.35 mmol) was dissolved in THF (10 ml). Hydrogen chloride gas was bubbled through the solution until the starting material disappears by TLC. Then the solvent was evaporated under vacuum and the crude was chromatographied over silica gel using 5% methanol/ methylene chloride as solvent to yield 32 mg (24%) of 3-{6-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-benzo[b]thiophen-3-yl}-propionic acid. NMR 1H Cl3CD δ: 7.55 (d, 1H, J=8.7 Hz), 7.25 (m, 2H), 6.93 (s, 1H), 6.88 (dd, 1H, J=2.1, 8.7 Hz), 6.43 (d, 1H, J=7.2 Hz), 4.24 (t, 2H, J=6.1 Hz), 3.45 (m, 2H), 3.10 (m, 4H), 2.71 (m, 4H), 1.88 (m, 2H). Mass Spectrum (LCMS, ESI) calculate for C21H23N2O3S 383.14 (M+H) found: 383.3.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[F:34][C:35]([F:47])([F:46])[C:36]1[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=O)[CH:39]=[CH:40][CH:41]=1.C(N(CC)C(C)C)(C)C.[Cl:57][C:58]1[S:62][C:61]([C:63]2[N:67]([CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[F:75])[C:66](=[O:76])[N:65]([CH2:77]/[C:78](=[N:80]/O)/[NH2:79])[N:64]=2)=[CH:60][CH:59]=1>CN(C=O)C.O>[Cl:57][C:58]1[S:62][C:61]([C:63]2[N:67]([CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[F:75])[C:66](=[O:76])[N:65]([CH2:77][C:78]3[N:80]=[C:43]([CH2:42][C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([C:35]([F:34])([F:47])[F:46])[CH:37]=4)[O:45][N:79]=3)[N:64]=2)=[CH:60][CH:59]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: N/C(Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O)=N\O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1n(Cc2noc(Cc3cccc(C(F)(F)F)c3)n2)nc(-c2ccc(Cl)s2)n1Cc1ccccc1F
Reaction time: 0.5 h

Procedure:
Under argon, 81 mg (0.16 mmol) of benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate were added to a solution of 29 mg (0.14 mmol) of 3-(trifluoromethyl)phenylacetic acid and 27 μl (0.16 mmol) of N,N-diisopropylethylamine in 1.3 ml of dry DMF. After 30 min of stirring, 50 mg (0.13 mmol) of the compound from Example 25A were added and the mixture was stirred at RT for 18 h. 2 ml of water were then added, and the mixture was extracted three times with in each case 5 ml of ethyl acetate. The combined organic phases were washed with in each case 5 ml of water and sodium chloride solution, filtered though Extrelut and concentrated under reduced pressure. The residue was dissolved in 2 ml of DMF and stirred in a microwave oven at 250° C. for 15 min. After cooling, the solvent was removed under reduced pressure on a rotary evaporator and the crude product was purified by chromatography [Method 15]. This gave 25 mg (34% of theory) of the target compound as a dark-yellow resin.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:15][CH3:16])[C:7](=[O:14])[CH:8]([N:11]([CH3:13])[CH3:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:19][CH3:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[N:27][C:22]([NH:1][C:2]2[CH:18]=[CH:17][C:5]3[N:6]([CH2:15][CH3:16])[C:7](=[O:14])[CH:8]([N:11]([CH3:12])[CH3:13])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:19][CH3:20])=[N:23][CH:24]=1
Reactant: CCN1C(=O)C(N(C)C)CCc2c1ccc(N)c2OC
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: CCN1C(=O)C(N(C)C)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)c2OC
Yield: 9.3 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-3-dimethylamino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (78 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (78 mgs) were converted to the title compound as a white foam (13 mgs). 1H-NMR (CDCl3): 1029 (s, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.31 (d, J=7.5 Hz, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.44-7.41 (m, 3H), 7.28-7.26 (m, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.54 (s, 1H), 4.33-4.25 (m, 1H), 3.81 (s, 3H), 3.54-2.10 (complex series of m, 10H), 1.15 (t, J=7.1 Hz, 3H). LC/MS found (M+H)+=547.21
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH2:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].O=[CH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:4]([C@H:3]1[C:8](=[O:9])[NH:10][CH:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[NH:2]1)[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: CC(C)COC(=O)CCC=O
Agent: Cl
Product: CC(C)COC(=O)CCC1NC(=O)[C@H](CC(C)C)N1

Procedure:
L-Leucinamide hydrochloride (3.2 g, 19.2 mmol) and isobutyl 4-oxobutanoate (3 g, 18.96 mmol) were reacted together according to the procedure of example 5A to give the title compound, 1.7 g (33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1C=O.ClC1C=C(C=CC=1)C(OO)=[O:20].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[OH:20]
Reactant: COc1cc(C(F)(F)F)ccc1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
To a solution of 2-methoxy-4-(trifluoromethyl)benzaldehyde (1.0 g, 4.90 mmol) in dichloromethane (15 mL) was added m-chloroperoxybenzoic acid (1.48 g, 6.61 mmol). The resulting clear solution was stirred for 16 hours at room temperature. Overnight a white precipitate had formed that was filtered off. The filtrate was evaporated to a white solid, which was dissolved in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulphate, and evaporated to a white solid. This solid was redissolved in methanol (15 mL), and treated with triethylamine (2 mL, 10 mmol). After stirring for two hours, the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (25 mL), and washed with 1N citric acid solution (20 mL) and brine (20 mL). The organic layer was dried over sodium sulphate, and evaporated to an oil. This crude material was then purified by eluting through a short pad of silica with dichloromethane, which afforded the title compound as a clear oil (536 mg, 57%)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.[CH3:21][OH:22].C[O-].[Na+]>O>[CH3:21][O:22][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:5]=[C:4]([S:19][CH3:20])[N:3]=1
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2ccc(C)nc2)n1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(SC)nc(Nc2ccc(C)nc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-6-[(6-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (Preparation Example 303) (51 mg) and methanol (1 mL), sodium methoxide (11 mg) was added under ice cooling and stirred overnight at room temperature. Water was added to the reaction liquid, and the solid was collected by filtration to give 4-methoxy-6-[(6-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (41 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[C:20](=[N:25][OH:26])[C:21](=[O:24])[CH2:22][Br:23])[C@H:4]2[S:3]1.[N+](=[CH2:31])=[N-]>C(O)C.C(OCC)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:13])([Cl:14])[Cl:15])=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[C:20](=[N:25][O:26][CH3:31])[C:21](=[O:24])[CH2:22][Br:23])[C@H:4]2[S:3]1
Reactant: C=[N+]=[N-]
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]2S1
Solvent: CCO
Solvent: CCOCC
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-hydroxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (a mixture of syn and anti isomers) (1.2 g.) in ethanol (20 ml.) was added dropwise a solution of diazomethane (0.1 mole) in diethyl ether under stirring and ice-cooling to complete the reaction. After the reaction mixture was concentrated under reduced pressure, the residue was pulverized in diisopropyl ether, collected by filtration and then dried to give brown powder of 2,2,2-trichloroethyl 2-methyl-7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (a mixture of syn and anti isomers) (1.1 g.), mp 80° to 83° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)=[O:10].[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[NH2:17])=[O:10]
Reactant: COc1ccccc1S(=O)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccccc1S(=O)c1cccc(N)c1
Temperature: 25 °C

Procedure:
1-Methoxy-2-(3-nitrophenylsulfinyl)benzene (217 mg, 0.78 mmol) was dissolved in ethyl alcohol (5.0 ml) and water (1.75 ml), to which was added iron powder (488 mg, 8.7 mmol) and ammonium chloride (77 mg, 1.4 mmol). This mixture was heated to reflux for four hours, cooled to room temperature and the supernatant decanted. The insoluble material was rinsed with methylene chloride, followed by aqueous 1M potassium carbonate. All decanted solutions were combined and the organic layer separated. The aqueous layer was extracted again with methylene chloride, and the combined organics washed once with brine. After drying over magnesium sulfate and concentration in vacuo, the title compound was obtained as a white solid (145 mg, 75%). 1H NMR(400 MHz): 3.89(3H,s), 6.69-6.74(1H,m), 6.86(1H,d,J=8.4), 7.03-7.09(2H,m), 7.10-7.20(2H,m), 7.38(1H,dt,J=8.3, 1.5), 7.86(1H,dd,J=7.8, 1.5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.BrNC(=O)CCC(N)=O.NC1C(Br)=CC(C)=CN=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.CS(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(N)nc1
Agent: Cl[Pd]Cl
Agent: Cc1cnc(N)c(Br)c1
Agent: NC(=O)CCC(=O)NBr
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1cnc(N)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-amino-3-phenyl-5-methylpyridine was prepared as follows: 2-amino-5-picoline (10.8 g, 0.1 M) was dissolved in glacial acetic acid (200 ml), and N-bromosuccinamide (20 g, 0.11 M) was added. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was poured onto ice/water and the solid removed by filtration. The filtrate was basified with solid sodium hydroxide, and the resulting precipitate was isolated by filtration (12.8 g). The product, 2-amino-3-bromo-5-methylpyridine (3.7 g, 20 mmol), was dissolved in anhydrous DMSO (100 ml) under an atmosphere of nitrogen. Phenylboronic acid (2.66 g, 22 mmol) was added, followed by the addition of potassium carbonate (9.66 g, 70 mmol) and bis(triphenylphosphine)-palladium(II)chloride (426 mg, 0.6 mmol). The reaction mixture was heated to 80° C. with stirring for 15 hours. The reaction was cooled, poured into ice/water, and the crude product was collected by filtration. The resultant material was treated with 1 M aqueous hydrochloric acid (200 ml), stirred for 10 minutes, and filtered to remove insoluble residues. The filtrate was basified with solid sodium hydroxide, and the resultant yellow precipitate was filtered and dried to provide the product, 2-amino-3-phenyl-5-methylpyridine, as a pale yellow solid (2.25 g).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[CH:4]=1.[ClH:12].[N:13]([O-])=O.[Na+].NC1C=CC=CC=1>C(O)C.[Fe].C(OCC)C.O>[ClH:12].[ClH:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:13])=[C:5]([CH2:9][CH3:10])[CH:4]=1
Reactant: CCc1cccc(N(C)C)c1
Reactant: O=N[O-]
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: CCc1cc(N(C)C)ccc1N
Temperature: 5 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a 250 cm3 round bottom flask was added N,N-dimethyl-m-ethylaniline (4.68 g, 31.3 mmol), water (100 cm3) and hydrochloric acid (8.5 cm3, 37%) and the solution was cooled to 5° C. An aqueous (80 cm3) solution of sodium nitrite (2.46 g, 3.57 mmol) was then added dropwise to the aniline mixture and stirred for 3 hours at room temperature. Iron (Fe) fillings (5.24 g, 94 mmol) and hydrochloric acid (8.5 cm3, 37%) were added and the mixture was stirred at room temperature for 3 hours. The suspension was filtered and the filtrate adjusted to pH 7 with sodium bicarbonate solution before extraction into ethyl acetate (3×50 cm3). The combined extracts were dried over magnesium sulphate, filtered, and concentrated to yield a brown oil. The oil was dissolved in ethanol (100 cm3) and diethyl ether (80 cm3) and hydrochloric acid (7 cm3, 37%) was added carefully to give the title compound (7.42 g, 72%) as a light tan solid. νmax (KBr)/cm−1: 2976 (CH), 2894 (CH), 2859 (CH), 2753 (CH), 1583 (C═N), 1508 (CH), 1486 (CH), 1459 (CH), 1183 (CH); dH (250 MHz; D2O): 7.66 (1H, s, ArH), 7.56 (2H, s, ArH), 3.29 (6H, s, NCH3), 2.74 (2H, q, 7.5, CH2), 1.25 (3H, t, 7.5, CH3); dC (62.9 MHz; CDCl3): 15.5 (CH3) 25.6 (NCH2), 48.9 (NCH3), 122.1 (ArC), 124.6 (ArC), 128.1 (ArC), 132.6 (ArC), 143.3 (ArC), 144.9 (ArC).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[Cl:38])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[Cl:38][C:32]1[C:33]([Cl:37])=[CH:34][CH:35]=[CH:36][C:31]=1[N:30]1[C:18](=[O:19])[C:11]2[C@@H:12]3[C:15]([CH3:17])([CH3:16])[C@@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:29]1[CH3:27]
Reactant: CN(Nc1cccc(Cl)c1Cl)C(=O)OC(C)(C)C
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1c2c(c(=O)n1-c1cccc(Cl)c1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
Triethylamine (1.3 mL, 9.33 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 905 mg, 4.22 mmol) in 1,2-dichloroethane (8 mL) over 1 min. A solution of N′-(2,3-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (775.8 mg, 2.66 mmol) in 1,2-dichloroethane (14 mL) was added. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 15 min, and then in an oil bath at 50° C. for 30 min. The reaction mixture was cooled. A solution of HCl in dioxane (4 M; 10 mL, 40 mmol) was added and the mixture was heated at reflux for 1 h and allowed to cool. Dichloromethane (150 mL) was added and the mixture was washed with 1:1 water/brine (30 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 120 g column, eluting with 20-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated with methanol and then diethyl ether. The residue was dried under high vacuum at 70° C. overnight to give (4S,7R)-2-(2,3-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (332 mg, 36%) as a white solid. ES(+)-MS (M+H) 351.
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)(Cl)=O.[CH:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH2:25][CH2:26][O:27][CH:28]=[O:29])[C:20]([OH:22])=O)[N:18]=1)=[O:12].[NH2:30][CH:31]1[C:46](=[O:47])[N:33]2[C:34]([C:43]([OH:45])=[O:44])=[C:35]([CH2:38][O:39][C:40](=[O:42])[NH2:41])[CH2:36][S:37][C@H:32]12>O.CC(C)=O.C(N(CC)CC)C.C(OCC)(=O)C>[CH:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH2:25][CH2:26][O:27][CH:28]=[O:29])[C:20]([NH:30][CH:31]2[C:46](=[O:47])[N:33]3[C:34]([C:43]([OH:45])=[O:44])=[C:35]([CH2:38][O:39][C:40](=[O:42])[NH2:41])[CH2:36][S:37][C@H:32]23)=[O:22])[N:18]=1)=[O:12]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1nc(C(=NOCCOC=O)C(=O)O)cs1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCOC=O)c3csc(NC=O)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
N,N-Dimethylformamide (0.4 g.), dry ethyl acetate (11.6 ml.), phosphoryl chloride (0.9 g.) and 2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetic acid (syn isomer, 1.6 g.) were treated in a similar manner to that of Example 1-(1) to give an activated acid solution. On the other hand, a suspension of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (1.5 g.) in a mixture of water (10 ml.) and acetone (20 ml.) was adjusted to pH 8.0 with triethylamine at -3° C. The activated acid solution was added to the stirred solution over 15 minutes while keeping at pH 7.5 to 8.0, and stirred at -3° to 3° C. for 30 minutes. After removing the solvent from the resultant solution in vacuo at pH 7.0, water (20 ml.) was added to the residue. The aqueous solution was washed with ethyl acetate and diethyl ether in turn, and the remaining organic solvent was removed from the solution by bubbling nitrogen gas. After adjusting the solution to pH 2.5 with 10% hydrochloric acid, the precipitates were collected by filtration, washed with water and dried over phosphorous pentoxide under reduced pressure to give 7-{2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)-acetamido}-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 1.05 g.). The mother liquid was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diisopropyl ether. The pricipitates were collected by filtration, washed with diisopropyl ether and dried to give the same object compound (0.6 g.). Total yield 1.65 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH3:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:11])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CNCCc1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(C)CCc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A solution of [2-(4-fluoro-2-nitro-phenyl)-ethyl]-methyl-amine (10.4 g, 0.053 mole) and ethyl bromoacetate (8.8 g, 0.053 mole) in acetonitrile (200 mL) containing potassium carbonate (3.64 g, 0.026 mole) was stirred at room temperature overnight. The mixture was evaporated in vacuo, water was added to the residue and then extracted with dichloromethane (2×200 mL). The combined organic layers were washed with saturated sodium chloride (300 mL), dried and concentrated. Purification by flash column chromatography (silica gel, methylene chloride:hexanes 1:1 to methylene chloride) provided 10.0 g of the title compound as a light brown oil. 1H NMR (CDCl3): 7.65 δ (dd, 1H); 7.40 δ (dd, 1H); 7.25 δ (dd, 1H); 4.20 δ (m, 2H); 3.30 δ (s, 2H); 3.05 δ (t, 2H); 2.80 δ (t, 2H); 2.45 δ (s, 3H); 1.25 δ (t, 3H).