Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(N(CC)CC)C.CCOC(C)=O>CCO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]3[CH:17]4[N:13]([CH2:12][CH2:11][C:6]2=3)[CH2:14][CH2:15][CH2:16]4)=[CH:22][CH:23]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: Clc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Fc1ccc(CCn2c3c(c4cc(Cl)ccc42)C2CCCN2CC3)cc1

Procedure:
A mixture of 7-chloro-2,3,5,10,11,11c-hexahydro-1H-indolizino[7,6-b]indole and 10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (non-separable regioisomers, 500 mg, 2.03 mmol, 1 equiv) and 1-(2-bromoethyl)-4-fluorobenzene (577 mg, 2.84 mmol, 1.4 equiv) were heated at 95° C. with triethyl amine (0.85 mL, 6.09 mmol, 3 equiv) in 6 mL of EtOH for 18 h. The mixture was brought to RT followed by dilution with EtOAc (40 mL), washed with water (2×10 mL), and once with brine, then dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography over 230-400-mesh silica gel using a gradient of MeOH in EtOAc (0 to 50%). The product was further purified by reverse phase HPLC. Column: ZORBAX SB C18, 4.6×250 mm, 5μ, retention time (min): 9.71, purity: 95.20%;
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].O>C(#N)C.C(OCC)(=O)C>[CH:20]([C:19]1[CH:18]=[C:17]([CH:24]=[CH:23][CH:22]=1)[CH2:16][N:4]1[C:3]([O:2][CH3:1])=[N:7][NH:6][C:5]1=[O:8])=[O:21]
Reactant: O=Cc1cccc(CBr)c1
Reactant: COc1n[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COc1n[nH]c(=O)n1Cc1cccc(C=O)c1
Reaction time: 6 h
Yield: 18.8 %

Procedure:
To a solution of 0.92 g (8.0 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 15 ml of dry acetonitrile was added 1.16 g (8.4 mmol) of potassium carbonate. To the mixture was added dropwise a solution of 1.59 g of crude 3-(bromomethyl)benzaldehyde in 30 ml of dry acetonitrile at 55° C. under an atmosphere of nitrogen. After the mixture was stirred at the same temperature for additional 6 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue (1.31 g) was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=1:1 and then 1:2) to obtain 0.35 g (1.50 mmol) of 4-(3-formylbenzyl)-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: C([O:8][C:9]1[C:14]([NH:15]C(=O)OCC2C=CC=CC=2)=[CH:13][N:12]=[C:11]([N:26]2[CH:30]=[CH:29][CH:28]=[N:27]2)[N:10]=1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[NH2:15][C:14]1[C:9]([OH:8])=[N:10][C:11]([N:26]2[CH:30]=[CH:29][CH:28]=[N:27]2)=[N:12][CH:13]=1
Reactant: [H][H]
Reactant: O=C(Nc1cnc(-n2cccn2)nc1OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cnc(-n2cccn2)nc1O
Yield: 93 %

Procedure:
Benzyl 4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidin-5-ylcarbamate, 3-d, (1.96 g, 4.9 mmol) was hydrogenated with hydrogen ballon in THF (20 ml) and Pd/C (200 mg) at room temperature for 12 hours. The mixture was filtered through a celite pad and the filtrate was concentrated under vacuum to provide the compound, 3-e (0.8 g, 93%). 1H NMR (DMSO-d6, 300 MHz): δ 8.39 (s, 1H), 7.80 (s, 1H), 7.20 (s, 1H), 6.56 (m, 1H), 5.00 (br, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[CH:8][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3)nc2c1
Product: Cc1ccn2cc(-c3ccc(OCCCN4CCCCC4)cc3)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (0.2 g) and piperidine (2.0 mL) were heated at reflux temperature for 5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with additional ethyl acetate (10 mL) and the organic portions combined. The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (0.21 g). This compound can also be named as 7-(methyl-2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-imidazo [1,2-a]pyridine. Treatment with 2M HCl in ether afforded the dihydrochloride. 1H NMR (CD3OD) δ 8.67 (d, J=7.5 Hz, 1 H), 8.41 (s, 1 H), 7.84 (m, 2H), 7.71 (s, 1 H), 7.36 (dd, J=6.9 Hz, J=1.4 Hz, 1H), 7.16 (m, 2H), 4.22 (t, J=5.8 Hz, 2H), 3.64 (d, J=12.5 Hz, 2H), 3.35 (m, 2H), 3.04 (m, 2H), 2.62 (s, 3H), 2.34 (m, 2H), 1.99 (m, 2H), 1.86 (m, 3H), 1.59 (m, 1H); 13C NMR (CD3OD) δ 161.0, 147.1, 141.1, 136.2, 128.5, 128.2, 120.3, 119.3, 115.8, 110.6, 109.9, 65.8, 55.0, 53.8, 24.5, 23.6, 22.1, 21.2, MS (M+H)=350.2 Analysis: Calc'd for C22H27N3O 2HCl(2H2O) C, 57.64; H, 7.26; N, 9.17. Found: C, 57.68; H, 7.13; N, 9.16.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[C:12](Cl)[N:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([C@H:31]1[CH2:36][NH:35][CH2:34][CH2:33][N:32]1C(OC(C)(C)C)=O)[CH:28]([CH3:30])[CH3:29]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[C:12]([N:35]3[CH2:34][CH2:33][NH:32][C@@H:31]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:36]3)[N:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1C(=O)c1nc(Cl)ccc1C(F)(F)F
Reactant: CC(C)C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H]1CN(c2ccc(C(F)(F)F)c(C(=O)c3cccnc3N)n2)CCN1
Temperature: 90 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
A microwave vial was charged with (2-aminopyridin-3-yl)(6-chloro-3-(trifluoromethyl)pyridin-2-yl)methanone (2.12 g, 7.028 mmol), potassium carbonate (1.166 g, 8.434 mmol), (S)-tert-butyl 2-isobutylpiperazine-1-carboxylate (1.874 g, 7.731 mmol) and dimethylformamide (4 mL). The reaction mixture was heated under microwave irradiation at 90° C. for 50 minutes. The reaction mixture was cooled down to room temperature and partitioned between a saturated solution of sodium bicarbonate and ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was taken up in dichloromethane (50 ml) and trifluoroacetic acid (8 ml) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and partitioned between dichloromethane and a saturated solution of sodium carbonate. The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a pale yellow oil (2.203 g, 77% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:6][CH2:5][N:4]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])C(=O)OC(C)(C)C)[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:3]1=[O:40].C(OC(=O)C)C.[ClH:48]>CO.C(OCC)(=O)C>[ClH:48].[CH3:1][C:2]1([CH3:41])[CH2:6][CH2:5][N:4]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:34][C:35]([F:36])([F:38])[F:37])[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:3]1=[O:40]
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CCC(C)(C)C2=O)n1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)c(N2CCC(C)(C)C2=O)n1

Procedure:
A solution of tert-butyl (4-(4-((3-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (280 mg) and 4M hydrogen chloride ethyl acetate solution (4.0 mL) in methanol (1.0 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate (3.0 mL), and the precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (195 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12]1[N:13]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]1[N:13]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:14]=[CH:15][N:16]=1
Reactant: Oc1cccc(F)c1F
Reactant: ClCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccc(OCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a stirred solution of 2,3-difluorophenol (109 mg) at room temperature in dimethylformamide DMF (5 ml) under an argon atmosphere were added 2-chloromethyl-1-trityl-1H-imidazole (200 mg) and potassium carbonate (193 mg). The mixture was heated to 80° C. and stirring was continued overnight. The brown suspension was cooled to room temperature, diluted with EtOAc and washed with 1 N NaOH. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient:cyclohexane→cyclohexane/EtOAc 55:45) to give 2-(2,3-difluoro-phenoxymethyl)-1-trityl-1H-imidazole (240 mg) as a light yellow gum. MS (ISP): 453.0 ([M+H]+)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:46]=[CH:45][C:35]2[C:36](=[O:44])[C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:38][O:39][C:34]=2[CH:33]=1>ClCCl>[C:1]([N:4]1[CH2:5][CH2:6][C:7]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:40]([C:37]3[C:36](=[O:44])[C:35]4[CH:45]=[CH:46][C:32]([Cl:31])=[CH:33][C:34]=4[O:39][CH:38]=3)(=[O:42])=[O:41])[CH2:17][C:16]2=[O:21])([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(CN2CCNCC2=O)CCN(C(C)=O)CC1
Reactant: O=c1c(S(=O)(=O)Cl)coc2cc(Cl)ccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(CN2CCN(S(=O)(=O)c3coc4cc(Cl)ccc4c3=O)CC2=O)CCN(C(C)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of 1-(1-acetyl-4-methoxycarbonylpiperidin-4-ylmethyl)-2-piperazinone (850 mg) and diisopropylethylamine (555 mg) in dichloromethane (15 ml) was gradually added dropwise at 0° C. a solution of 7-chloro-4-oxo-4H-benzopyran-3-sulfonyl chloride (960 mg) in dichloromethane (5 ml), and the mixture was stirred at 0° C. for 30 minutes. The reaction solution was diluted with dichloromethane, washed with water, citric acid solution, sodium bicarbonate solution and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate: methanol=10:1) to give pale yellow solid of 1-(1-acetyl-4-methoxycarbonylpiperidin-4-ylmethyl)-4-(7-chloro-4-oxo-4H-benzopyran-3-sulfonyl)-2-piperazinone (1.10 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.B.O1CCCC1.Cl.O>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(CC#N)nc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CCN)nc1
Temperature: 60 °C
Yield: 41 %

Procedure:
To a solution of 18 g of crude 2-(5-methylpyridin-2-yl)acetonitrile in dry THF (100 mL) was added dropwise Borane-tetrahydrofuran complex (1.0 M in THF, 232 mL, 232.5 mmol, 4 eq) at 0° C. under N2 atmosphere. The reaction mixture was then heated to 60° C. overnight. The reaction was cooled to room temperature, aq. HCl (6 N, 40 mL) was added carefully and the reaction mixture was then heated at 70° C. for 2 hrs. After cooling, water was added and the resulting solution was washed with ether. The aqueous layer was basified with aq. NaOH (10 N) at 0° C. and saturated with K2CO3 then extracted with ether (5×100 mL). The organic layer was dried over MgSO4, filtered and evaporated to give 7.6 g of crude 2-(5-methylpyridin-2-yl)ethanamine. (96% crude yield)
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=O)[CH2:13]Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:16][C:17]([NH2:19])=[S:18].O.O.O.C([O-])(=O)C.[Na+].O>C(O)C>[NH2:19][C:17]1[S:18][CH:13]=[C:12]([C:6](=[N:5][O:4][CH2:3][CH2:2][Br:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:16]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOCCBr)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOCCBr)c1csc(N)n1
Temperature: 40 °C
Yield: 27.8 %

Procedure:
A mixture of ethyl 2-(2-bromoethoxyimino)-4-chloro-3-oxobutyrate (syn isomer, 156 g.), thiourea (39.4 g.) sodium acetate trihydrate (70.5 g.), water (300 ml.) and ethanol (500 ml.) was stirred at 40° C. for an hour. The resultant solution was concentrated in vacuo and the residue was extracted twice with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. After adding diethyl ether (1 l.) to the oily residue, the soluble substance was separated by decantation and the solution was concentrated in vacuo. The residue was crystallized with diisopropyl ether and the precipitates were collected by filtration to give ethyl 2-(2-aminothiazol-4-yl)-2-(2-bromoethoxyimino)acetate (syn isomer, 46.4 g.), mp. 111° to 114° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([Cl:7])=[O:6])[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][C:22]1([OH:25])[CH2:24][CH2:23]1)=[CH:16][CH:15]=[CH:14][CH:13]=2>ClCCl>[ClH:7].[CH2:1]([O:3][CH2:4][C:5]([NH:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][C:22]1([OH:25])[CH2:23][CH2:24]1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:6])[CH3:2]
Reactant: Nc1cnc2ccccc2c1NCCC1(O)CC1
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Product: CCOCC(=O)Nc1cnc2ccccc2c1NCCC1(O)CC1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Ethoxyacetyl chloride (0.43 mL) was added to a cooled (0° C.) solution of 1-[2-(3-aminoquinolin-4-ylamino)ethyl]cyclopropanol (3.85 mmol) in dichloromethane (16 mL). The reaction mixture was stirred at 0-5° C. for 60 minutes and then concentrated under reduced pressure to provide crude 2-ethoxy-N-{4-[2-(1-hydroxycyclopropyl)ethylamino]quinolin-3-yl}acetamide hydrochloride.
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].COCCO[AlH2-]OCCOC.[Na+]>ClCCl.C1(C)C=CC=CC=1>[CH3:3][NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)Nc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CNc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A solution of 0.5 g (1.4 mMol) [6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-carbamic acid methyl ester in 3.0 ml dichloromethane was added over 10 minutes to a solution of 1.98 ml (6.9 mMol ) Red-Al® (70% in toluene) and 2.5 ml toluene (exothermic, cool with a water bath to avoid temperature to go >50° C.). The reaction mixture was stirred 2 hours at 50° C. in CH2Cl2, extracted with ethyl acetate and cooled to 0° C. 4 ml Aqueous NaOH 1N were carefully (exothermic) added over 15 minutes, followed by 20 ml ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with deionized water and brine, dried (Na2SO4) and concentrated under reduced pressure to yield 0.37 g (89%) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine as an orange resin.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([C@@H:17]([OH:21])[C:18]([OH:20])=O)[C:12]2=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[F:32].NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([C@@H:17]([OH:21])[C:18]([NH:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=3[F:32])=[O:20])[C:12]2=[O:22])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)O)C2=O)cc1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Product: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3F)C2=O)cc1

Procedure:
According to the Step 1-3 in synthetic method for EXAMPLE 1, a cyclic carbonate analogue (0.2 g) derived from compound 52-4 and 4-amino-3-fluorobenzonitrile (81.7 mg) were used instead of 1-2 and 6-amino-1-bis(tert-butoxy carbonyl)aminoisoquinoline, under high concentration condition (1M), to obtain compound 67-1 (130 mg) as a colorless amorphous solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[N:7]=[C:6]([C:12]([OH:14])=O)[CH:5]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[N:7]=[C:6]([C:12]([Cl:24])=[O:14])[CH:5]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 75 °C
Reaction time: 7 h
Yield: 117.4 %

Procedure:
A 500 mL three neck round bottom flask with thermowell was fitted with a condenser which vented to a trap and then an aqueous 10% NaOH scrubber, magnetic stir bar, two stoppers and a thermometer. To the vessel was added 4,5,6-trichloropicolinic acid (86 g which contained 8.6 g water, 77.4 g active, 0.32 mol), toluene (160 mL), thionyl chloride (85 mL, 1.12 mol) and DMF (0.3 mL). The slurry was heated to 70-80° C., held there for 7 h and then cooled to room temperature and allowed to stir overnight. Approximately 0.2 mL of the pale yellow solution was placed in a vial and concentrated to a solid under a stream of N2. The solid was treated with a mixture of triethylamine/methanol (0.3 mL/2 mL) and then warmed with a heat gun for ca. 1 min. HPLC analysis indicated that less than 1% of the carboxylic acid remained as compared to the methyl ester derivative. The solution was concentrated on a rotary evaporator leaving a pale yellow solid. The solid was dried (40° C./20 mmHg) for about 1 h providing the title compound (92 g): mp 68-70° C.; 1H NMR (CDCl3, 400 MHz) δ 8.12 (s), the solid contained about 4 wt % toluene as determined by integration of the proton signals; 13C NMR (CDCl3, 101 MHz) δ 167.3, 151.0, 145.82, 145.8, 135.7, 125.5.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>O>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)=[CH:12][CH:11]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Fc1cccc(F)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(NCc2ccc(Cl)cc2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To 2,6-difluoro-pyridine (20, 3.80 g, 33.0 mmol) in 20.0 mL ofN-methylpyrrolidone, 4-chloro-benzylamine (21, 5.6 mL, 46.0 mmol) and N,N-diisopropylethylamine (10.0 mL, 57.4 mmol) were added. The reaction was stirred at 90° C. overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 25% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum, and the resulting material was washed with ethyl acetate/hexane to provide the desired compound as a white solid (22, 5.30 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:30]=[N:31][N:32]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH2:11][S:12][C@@H:13]3[CH:20]([NH:21][C:22](=[O:28])[CH2:23][C:24](=[O:27])[CH2:25][Cl:26])[C:19](=[O:29])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=1.[N:33]([O-])=[O:34].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[C:3]2[N:4]([N:30]=[N:31][N:32]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH2:11][S:12][C@@H:13]3[CH:20]([NH:21][C:22](=[O:28])[C:23](=[N:33][OH:34])[C:24](=[O:27])[CH2:25][Cl:26])[C:19](=[O:29])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=1
Reactant: Nc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC(=O)CCl)[C@H]3SC2)nn2nnnc12
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NO)C(=O)CCl)[C@H]3SC2)nn2nnnc12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 3-[(8-amino-6-tetrazolo[1,5-b]pyridazinyl)thiomethyl]-7-(4-chloro-3-oxobutyramido)-3-cephem-4-carboxylic acid (6.72 g; 0.0171 mole) in acetic acid (60 ml), a solution of sodium nitrite (1.65 g; 0.0239 mole) in water (6 ml) was added at 5°-10° C. After stirring for 3.5 hours at room temperature, the reaction mixture was quenched with brine and extracted with ethyl acetate (4×200 ml). The combined extracts were washed with water, dried over NaSO4 and evaporated to a foam. Trituration of this product with diethyl ether afforded the title compound as a beige powder, 6.3 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[N:41]=[CH:40][CH:39]=[CH:38][C:35]=1[C:36]#[N:37].C(=O)([O-])O.[Na+]>COCCOC>[CH3:20][CH2:19][CH2:18][CH:17]([CH3:22])[CH3:16].[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([C:34]2[C:35]([C:36]#[N:37])=[CH:38][CH:39]=[CH:40][N:41]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: N#Cc1cccnc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncccc2C#N)cc1
Product: CCCC(C)C
Reaction time: 2.17 h
Yield: 113.1 %

Procedure:
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (400 mg, 0.913 mmol; prepared as described in international patent publication number wo03/087057, method 13, page 60), 2-bromonicotinonitrile (167 mg, 0.913 mmol), tetrakis(triphenylphosphine)palladium[0] (50 mg, 0.043 mmol), 1,2-dimethoxyethane (4 ml) and a saturated aqueous solution of sodium hydrogen carbonate (2 ml) were stirred at 100° c. under an atmosphere of nitrogen in a microwave for 130 mins. the mixture was allowed to cool before being partitioned between dichloromethane and water. the organics were separated, dried over sodium sulfate, filtered and evaporated. the crude product was purified by chromatography on silica eluting with 60:40 ethyl acetate: isohexane to afford the title compound as a white solid (214 mg, 57%); nmr spectrum: (dmso-d6) 1.45 (s, 9h), 7.18 (m, 2h), 7.57 (m, 1h), 7.66 (dd, 1h), 8.01 (d, 2h), 8.13 (d, 2h), 8.47 (dd, 1h), 8.73 (s, 1h), 8.98 (d, 1h), 9.97 (s, 1h); mass spectrum: m+h+415.