Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:10]2C3N=C(N)[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH:21]1C=NC(C(N)=O)=N1.[OH-].[K+]>>[CH:11]1[N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[N:21]=[C:13]([C:14]([NH2:16])=[O:15])[N:12]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: NC(=O)c1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1

Procedure:
Bioconversion media were prepared as in Example 1, except the initial amounts of guanosine and 1,2,4-triazole-3-carboxamide were 40 millimoles. The initial pH of each flask was adjusted to pH 7.2 with potassium hydroxide. The bioconversions were initiated as in Example 1, except that the temperature was 70° C. The cells were added promptly as the temperature reached 70° C. to avoid gelling of the bioconversion mixture. Forty millimole additions of both guanosine and 1,2,4-triazole-3-carboxamide were made at 6 and 12 hours into the bioconversion. Thus after the second addition, a total of 120 millimoles of the two reactants had been added. Potassium hydroxide was added at 6 hours to adjust the pH from 6.7 to 7.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[H-].[Na+].Cl[C:18]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:21]=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:19]=1.C(O)(=O)C>CN(C=O)C.O>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:20]1[N:19]=[C:18]([O:11][CH2:10][CH2:9][NH:8][C:6]2[N:7]=[C:2]([NH2:1])[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][CH:5]=2)[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:21]=1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Reactant: Nc1nc(NCCO)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(NCCOc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-[(6-Amino-5-nitropyridin-2-yl)amino]ethanol (Example 48A) is introduced into DMF (3 ml) at 0° C., and sodium hydride (60% oil dispersion, 15 mg, 0.4 mmol) is added. The mixture is stirred at 0° C. for 10 min. 5-Chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine (Example 6A) (125 mg, 0.4 mmol) in DMF (1 ml) is added dropwise, and the reaction mixture is stirred at RT for 12 h. Glacial acetic acid (200 μl) is added, and the reaction mixture is poured into water and extracted with ethyl acetate (3×50 ml). The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The residue is precipitated from acetonitrile, filtered off, washed with acetonitrile and dried. 36 mg (18% of theory) of product are obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.Cl.[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][C@H:20]([NH2:23])[CH2:21][F:22].CN(C)C.C1(N=C=NC2CCCCC2)CCCCC1>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:23][C@H:20]([CH2:21][F:22])[CH2:19][CH2:18][C:17]([O:16][CH3:15])=[O:24])=[O:8]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: COC(=O)CC[C@H](N)CF
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CC[C@@H](CF)NC(=O)COc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.70 g of 2,4-dichlorophenoxyacetic acid, 0.59 g of 4 and 0.44 ml of trimethylamine were mixed with 75 ml of methylene chloride, and the mixture was stirred at room temperature for 30 minutes. Then, 0.65 g of N,N'-dicyclohexylcarbodiimide was added and the mixture was stirred at room temperature overnight. Several drops of glacial acetic acid were added and the mixture was filtered. The filtrate was washed successively with water, 1N hydrochloric acid, and half-saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and stripped of solvent. The residue was triturated with ethyl acetate, the mixture was filtered and the solvent was evaporated from the filtrate under reduced pressure. The solid residue was triturated with hexane, the mixture was filtered and the solvent was evaporated from the filtrate. The solid residue was chromatographed over silica gel, first with a 1:3 v:v mixture of ethyl acetate and hexane as eluent, then with a 1:1 v:v mixture of ethyl acetate and hexane as eluent. On workup, 16 was obtained, as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[C:21]1([CH3:40])[CH:26]=[CH:25][C:24]([O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])=[CH:23][C:22]1(Br)[CH3:38].[C:41]([O-:44])([O-:43])=O.[K+].[K+]>C(#N)C>[C:4]([OH:27])(=[O:8])/[CH:5]=[CH:18]/[C:41]([OH:44])=[O:43].[C:24]([OH:27])(=[O:8])/[CH:25]=[CH:26]/[C:41]([OH:44])=[O:43].[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:38][C:22]5[C:21](=[CH:26][CH:25]=[C:24]([O:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:35]([CH3:36])[CH3:37])[CH:23]=5)[CH2:40]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C([O-])[O-]
Reactant: CC(C)[Si](OC1=CC(C)(Br)C(C)(Br)C=C1)(C(C)C)C(C)C
Agent: [K+]
Solvent: CC#N
Product: CC(C)[Si](Oc1ccc2c(c1)CN(CCN1CCC(c3noc4cc(F)ccc34)CC1)C2)(C(C)C)C(C)C
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (1.52 g, 5.73 mmol), 1,2-dibromo-4-(triisopropylsilyl)oxy-xylene (2.4 g, 5.7 mmol) and K2CO3 (1.8 g, 13 mmol) in acetonitrile (300 ml) was stirred overnight (18 hours) at room temperature. The mixture was filtered and the solvent was stripped. The residue was purified by flash chromatography over a silica gel column (7 gm of SiO2 ; eluted with 1-3% CH3OH in dichloromethane. The product thus purified (weight: 900 mg) was; converted to the fumarate salt by treatment with fumaric acid (194 mg) in hot ethanol. The crystals were collected and weighed 590 mg, m.p. 208°-210° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:7][NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([NH:19][CH2:20][C@H:21]3[CH2:23][C@@H:22]3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:12]=[CH:11][N:10]=2)=O)[CH2:3][CH2:2]1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CCOC(C)=O>[CH:1]1([CH2:4][C:5]2[N:10]3[CH:11]=[CH:12][C:13]([NH:19][CH2:20][C@H:21]4[CH2:23][C@@H:22]4[C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]3=[N:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: O=C(CC1CC1)NNc1nccc(NC[C@H]2C[C@@H]2c2ccc(F)cc2)c1C(F)(F)F
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc([C@H]2C[C@@H]2CNc2ccn3c(CC4CC4)nnc3c2C(F)(F)F)cc1
Reaction time: 6 h
Yield: 78.4 %

Procedure:
To a mixture of 2-cyclopropyl-N′-(4-((((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)amino)-3-(trifluoromethyl)pyridin-2-yl)acetohydrazide (0.06 g, 0.142 mmol) in THF (4 mL) was added Burgess reagent (0.068 g, 0.284 mmol) and the resulting mixture was refluxed stirring for 6 hours. The reaction mixture diluted with EtOAc and extracted with aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with aqueous sodium bicarbonate (2×10 mL) and brine (10 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography to give 3-(cyclopropylmethyl)-N-(((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-amine as a white solid (0.045 g, 74% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.98 (d, J=7.5 Hz, 1H), 7.09-7.01 (m, 2H), 7.00-6.92 (m, 2H), 6.64 (d, J=7.8 Hz, 1H), 5.49 (d, J=4.0 Hz, 1H), 3.39 (tdd, J=19.0, 12.8, 5.6 Hz, 2H), 3.01 (d, J=6.8 Hz, 2H), 1.92 (dt, J=9.1, 4.9 Hz, 1H), 1.46-1.34 (m, 1H), 1.19-0.94 (m, 3H), 0.65-0.54 (m, 2H), 0.37-0.27 (m, 2H). LCMS M+1=405.05.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[CH2:21]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O:35]1CCCC1>>[CH2:19]([O:18][C:13](=[O:17])[C:14]([C:31]1([OH:35])[CH2:32][CH2:33][N:28]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][CH2:30]1)([CH3:16])[CH3:15])[CH3:20]
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: CCOC(=O)C(C)C
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)C1(O)CCN(Cc2ccccc2)CC1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (7.64 mL, 54.5 mmol) in dry tetrahydrofuran (5 mL) at −78° C. was added n-butyl lithium (2.5 M, 20 mL, 50.0 mmol). The mixture was stirred at −65° C. for 30 minutes. Then ethyl isobutyrate (6.09 mL, 45.6 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred at −60° C. for 45 minutes. To this solution was added 1-benzylpiperidone (6.15 g, 32.5 mmol) in 5 mL of tetrahydrofuran. The mixture was allowed to warm up to room temperature and stirred overnight. The mixture was quenched with ammonium chloride solution (30 mL) and extracted with ether (100 mL). The organic layer was first washed with brine and then dried over sodium sulfate. Solvents were evaporated and the residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 2-(1-benzyl-4-hydroxy-piperidin-4-yl)-2-methyl-propionic acid ethyl ester (5.87 g) as an oily material. The NMR spectrum obtained on the sample is compatible with its structure. LC-MS calcd for C18H27NO3 (m/e) 305.43, obsd 306.2 (M+H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([NH2:14])(=[O:13])[CH2:9][C:10]([CH3:12])=O.F[C:16](F)(F)[C:17]([OH:19])=O.B(F)(F)F>CCOCC>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:10]([C:1]2[CH:6]=[CH:16][C:17]([OH:19])=[CH:3][CH:2]=2)([CH3:12])[CH2:9][C:8]([NH2:14])=[O:13])=[CH:3][CH:2]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccccc1
Reactant: CC(=O)CC(N)=O
Agent: FB(F)F
Solvent: CCOCC
Product: CC(CC(N)=O)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 20 °C

Procedure:
A mixture of 63.3 g, (0.6735 mol), of phenol, 8.51 g, (0.0842 mol) of acetoacetamide and 40 ml of trifluoroacetic acid was placed in a 500 ml, 3-necked flask equipped with a gas inlet tube and a condenser. The mixture was stirred under nitrogen and BF3 gas was introduced while the reaction temperature was maintained at 20° C. A total of 17.6 g of BF3 gas was added over a period of 3 hr. The reaction mixture was diluted with 200 ml of ether and the ether solution was washed with water three times. The ether and excess phenol were removed under vacuum maintaining the temperature below 90° C. When the viscous residue was dissolved in 50 ml of methanol, a white precipitate formed. The white solid was filtered, washed with cold methanol and dried. Based on method of preparation, there was obtained 3,3-bis(4-hydroxyphenyl)butyramide referred to below as "bisphenol". The yield of the product was 13.47 g (59.0%), mp=216°-216.5° C. 1H nmr (ppm in DMSO-d6): C-CH3 (s)1.71(3), CH2 (s) 2.79(2), NH2 6.50 & 6.85(2), Haarom (d) 6.95(J=8.55Hz (4), Hbarom (d) 6.85 (J=8.54Hz) (4), OH(s) 9.12 (2) . 13C nmr(ppm in DMSO-d6): C1 139.94, C2 127.83, C3 114.49, C4 154.94, C5 43.68, C6 28.25, C7 46. 83 C8 172. 56.
Reaction SMILES: C(OC1C(CCC=C)=CC=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)C1C=CC=CC=1.CC[C@H]1[C@H]2C[C@H]([C@H](OC3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]([O:57][C@H:58]([C:69]4[CH:78]=[CH:77]N=C5[C:70]=4[CH:71]=[C:72]([O:79]C)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[C:81]([OH:85])(C)(C)C>O>[CH2:50]([O:57][C:58]1[C:69]([CH2:70][CH2:71][C@H:72]([OH:79])[CH2:81][OH:85])=[CH:78][CH:77]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=CCCc1ccc2ncccc2c1OCc1ccccc1
Reactant: CC(C)(C)O
Solvent: O
Product: OC[C@@H](O)CCc1ccc2ncccc2c1OCc1ccccc1

Procedure:
Addition of 5-(benzyloxy)-6-but-3-enylquinoline to a suspension of AD-mix-α in water:tert-butyl alcohol following the procedure described for Example 1, step 2 gives (2S)-4-[5-(benzyloxy)quinolin-6-yl]butane-1,2-diol.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:9][C:10]([NH:12]C(=O)C2C=CC=CC=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Na+]>CCO>[NH2:2][C:1]1[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][C:4]=2[NH:9][C:10](=[O:11])[N:12]=1
Reactant: N#Cc1cccnc1NC(=O)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(=O)[nH]c2ncccc12
Temperature: 25 °C
Yield: 54.8 %

Procedure:
A solution of N-(3-cyanopyridin-2-ylcarbamoyl)benzamide (example 53a) (360 mg, 1.35 mmol) and NaOH (2 N, 1.85 mL) in EtOH (5 mL) was stirred at 100° C. under nitrogen for half an hour. After cooling to room temperature, the clear reaction solution was filtered and the filtrate was carefully neutralized with 10% AcOH with vigorous stirring at 0° C. The resultant precipitate was collected by filtration, and washed with warm 20% EtOH in water to give the final product 4-aminopyrido[2,3-d]pyrimidin-2(1H)-one (120 mg, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.22 (dd, J=4.4 Hz, 4.8 Hz, 1H), 7.29 (dd, J=4.8 Hz, 1H), 8.24 (dd, J=2 Hz, 1.6 Hz, 1H), 8.59 (dd, J=2 Hz, 1.6 Hz, 1H), 8.66-8.71 (m, 2H), 8.70 (d, J=1.2 Hz, 1H). MS 162 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22].CC(C)([O-])C.[K+].O>CN(C)C(=O)C>[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=2)=[CH:16][C:15]=1[CH3:22]
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1cc(O)cc(C)c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNc1cc(Oc2cc(C)c(N)c(C)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of N-(5-chloro-2-nitrophenyl)-N-methylamine (4.0 g) in N,N-dimethylacetamide (56 ml) were added 4-amino-3,5-dimethylphenol (2.9 g) and potassium t-butoxide (2.9 g) with stirring under ice-cooling, and the resulting mixture was stirred at 75-80° C. for 1 hour. After stirring, water (74 ml) was added to the reaction mixture, and the resulting mixture was cooled gradually to room temperature. The crystals precipitated were collected by filtration and dried in vacuo to afford the title compound (4.9 g, yield: 80%) as a yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=3)[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccc(F)cc2)CC1
Reaction time: 2 h
Yield: 85 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 4-fluorobenzoyl chloride, (0.018 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (35 mg, 82%). LCMS calculated for C22H20ClFN3O2 (M+H)+: m/z=412.1; Found: 412.1.
Reaction SMILES: C(OC([N:8]1[CH2:12]C[CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.N[CH2:32][C:33]1[CH:38]=CC=CN=1>>[N:8]1[CH:12]=[CH:38][CH:33]=[CH:32][C:9]=1[CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCc1ccccn1
Product: O=C(NCc1ccccn1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(aminomethyl)pyridine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 350 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (1H, br. s.) 10.25 (1H, s) 8.75 (1H, t, J=5.95 Hz) 8.43-8.49 (1H, m) 8.02 (1H, d, J=5.47 Hz) 7.83 (1H, d, J=5.27 Hz) 7.69-7.77 (1H, m) 7.49 (1H, d, J=5.47 Hz) 7.28-7.34 (2H, m) 7.21-7.27 (1H, m) 6.82 (1H, d, J=5.47 Hz) 6.41 (1H, dd, J=3.51, 1.76 Hz) 4.55 (2H, d, J=6.05 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([C:16]1[CH:26]=[C:25]([C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH:24]=[CH:23][C:17]=1[O:18][CH2:19][C:20](Cl)=[O:21])([CH2:14][CH3:15])([CH3:13])[CH3:12]>N1C=CC=CC=1>[C:11]([C:16]1[CH:26]=[C:25]([C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH:24]=[CH:23][C:17]=1[O:18][CH2:19][C:20]([NH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)=[O:21])([CH2:14][CH3:15])([CH3:13])[CH3:12]
Reactant: CCC(C)(C)c1ccc(OCC(=O)Cl)c(C(C)(C)CC)c1
Reactant: CC(=O)c1cccc(N)c1
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(C)=O)c2)c(C(C)(C)CC)c1

Procedure:
40 grams (0.1 mol) of N-{α-(2,4-di-tert-amylphenoxy)acetyl} -m-aminoacetophenone (m.p.:135°C), obtained by the reaction between m-aminoacetophenone and α-(2,4-di-tert-amylphenoxy)acetyl chloride in pyridine, was dissolved in 200 ml of anhydrous ethyl ether (placed in a three-necked flask), and 0.5 g of anhydrous aluminum chloride powder was added to this solution followed by ice-cooling (about 0°-5°C) under stirring. 16 grams (0.1 mol) of bromine was added dropwise to this mixture. After the completion of the dropwise addition, the temperature was allowed to rise to room temperature (about 20°-35°C). Stirring was continued until the generation of hydrogen bromide stopped. Thus, white crystals were precipitated.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH3:14])[CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH3:14])[CH2:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: CC1CNc2cc([N+](=O)[O-])ccc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CNc2cc(N)ccc2C1
Yield: 91 %

Procedure:
A solution of 7-nitro-1,2,3,4-tetrahydro-3-methylquinoline (8.2 mg, 0.042 mmol) in ethyl acetate (1 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (4 mg) at rt for 2 h. Filtration over Celite™ afforded 6.2 mg (89%) of 7-amino-1,2,3,4-tetrahydro-3-methylquinoline (structure 61A of Scheme XLVIII, where R1-2 =R4 =H, R3 =methyl) that was used without further purification for the next step. Compound 436 was prepared by General Method 13 (EXAMPLE 147) from 7-amino-1,2,3,4-tetrahydro-3-methylquinoline (6.2 mg, 0.038 mmol), ZnCl2 (8.0 mg, 0.057 mmol) and ethyl 4,4,4-trifluoroacetoacetate (5.5 mL, 0.038 mol) to afford 5.8 mg (54%) of Compound 436 as a yellow solid. Data for Compound 436: 1H NMR (400 MHz, DMSO-d6) 11.80 (bs, 1H), 7.11 (s, 1H), 6.95 (s, 1H), 6.37 (s, 2H), 3.26 (m, 1H), 2.83 (m, 2H), 2.51 (dd, J=15.7, 10.3, 1H), 1.88 (s, 1H), 0.97 (d, J=6.6, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:43]1[N:44]=[C:45]([NH:48]C=O)[S:46][CH:47]=1)[C:12]([NH:14][CH:15]1[C:41](=[O:42])[N:17]2[C:18]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:19](/[CH:22]=[CH:23]/[Cl:24])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.Cl.C(=O)(O)[O-].[Na+]>O.O1CCCC1>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:12]([NH:14][CH:15]1[C:41](=[O:42])[N:17]2[C:18]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])=[C:19](/[CH:22]=[CH:23]/[Cl:24])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12)c1csc(N)n1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (syn isomer) (3.0 g) in a mixed solvent of methanol (30 ml) and tetrahydrofuran (5 ml) was added concentrated hydrochloric acid (1.67 ml) at room temperature, and the mixture was stirred for two hours at the same temperature. The reaction mixture was diluted with water (40 ml), adjusted to pH 6.0 with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried and evaporated under reduced pressure. The residue was triturated with diisopropyl ether and collected by filtration to give benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (syn isomer) (2.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:12][C:11]=2[C:21]2[NH:25][CH:24]=[N:23][N:22]=2)O)=[CH:4][CH:3]=1.[N:26]1[CH:31]=CC=C[CH:27]=1.CS(Cl)(=O)=O.CNC>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:12][C:11]=2[C:21]2[NH:25][CH:24]=[N:23][N:22]=2)[N:26]([CH3:31])[CH3:27])=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: OC(c1ccc(Cl)cc1)c1cc(-c2ccncc2)sc1-c1nnc[nH]1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(c1ccc(Cl)cc1)c1cc(-c2ccncc2)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a mixture of (4-chlorophenyl)[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol (141 mg, 0.382 mmol) (synthesized in an analogous way as described in Example 3) in methylene chloride (2.8 mL) was added pyridine (6.0 mL, 74 mmol) and methanesulfonyl chloride (0.148 mL, 1.91 mmol) at 0° C. After the addition, the mixture was warmed to rt and stirred for 30 min and then heated at 60° C. for 20 min. The mixture was cooled in an ice bath and dimethylamine (0.553 mL, 11.5 mmol) in THF was added to the mixture. After the addition, the ice bath was removed and the mixture was stirred at rt for 30 min and then heated at 55° C. for 2 h. The mixture was cooled, concentrated, and the residue was purified by HPLC to afford 1-(4-chlorophenyl)-N,N-dimethyl-1-[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanamine as white powder (115 mg, 76%). LCMS: (AA) ES+ 396.3, 398.1; 1H NMR (400 MHz, d6-DMSO) δ: 14.48-14.27 (m, 1H), 8.71 (s, 1H), 8.57 (dd, J=4.55, 1.62 Hz, 2H), 7.95 (s, 1H), 7.73-7.63 (m, 4H), 7.39-7.30 (m, 2H), 5.53 (s, 1H), 2.13 (s, 6H).