Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([CH3:16])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8].[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>C(O)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[C:5]([CH3:16])=[C:4]([CH3:17])[S:3][C:2]=2[N:1]2[C:21](=[O:22])[C:20]3[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]2=[O:23])=[O:8])=[CH:10][CH:11]=1
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: Cc1sc(N2C(=O)c3ccccc3C2=O)c(C(=O)c2ccc(Cl)cc2)c1C
Reaction time: 1 h

Procedure:
To a solution of (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (532 mg, 2 mmol; prepared as described in U.S. Pat. No. 6,323,214) in acetic acid (15 mL) is added phthalic anhydride (360 mg, 2.4 mmol) and the mixture is heated to reflux for 15 h. The solvent is evaporated in vacuo and the residual material is dissolved in ethyl acetate (20 mL). The organic solution is washed with a saturated aqueous solution of NaHCO3 (5 mL), water (5 mL), then brine (5 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product is stirred for 1 h in petroleum ether (20 mL), then filtered, affording (2-[3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl]isoindoline-1,3-dione as a yellow powder. 1H NMR (CDCl3) δ: 2.10 (s, 3H), 2.43 (s, 3H), 7.24 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.78 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]2[CH2:10][CH2:9][O:8][C:6]=2[N:7]=1.[Cl:12][C:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[CH:14][Cl:15].ClCCCC>C(Cl)Cl>[Cl:12][C:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]([NH:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]2[CH2:10][CH2:9][O:8][C:6]=2[N:7]=1)=[O:28])(=[O:24])=[O:25])=[CH:14][Cl:15]
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reactant: Cc1nc(N)nc2c1CCO2
Solvent: CCCCCl
Solvent: ClCCl
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(Cl)=CCl)nc2c1CCO2
Reaction time: 8 h

Procedure:
To 300 mg of 2-amino-5,6-dihydro-4-methylfuro[2,3-d]pyrimidine in 25 ml of methylene chloride was added 20 ml of 2-(1,2-dichloroethen-1-yloxy)benzenesulfonyl isocyanate in methylene chloride from the previous example. After heating to reflux, the mixture was stirred overnight at room temfperature. Removal of the solvent in vacuo yielded an amber oil. Trituration of this oil with 1-chlorobutane gave a tan solid. After filtration and washing with ethyl ether, a yield of 0.8 g of a tan solid melting at 208°-210° was obtained.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:6]=[CH:5][CH:4]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:24].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Cl:24][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1cnc(Nc2cccc(CO)n2)s1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnc(Nc2cccc(CCl)n2)s1

Procedure:
2-(6-Hydroxymethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.300 g, 0.29 mmol) was stirred in 5 mL anh DCM under N2. Anhydrous DMF (0.100 mL, 1.29 mmol) and POCl3 (0.120 mL, 1.29 mmol) were added. After 15 h the reaction was diluted with water and the pH was adjusted to 9 with sat NaHCO3 (aq). The dCM was removed in vacuo and the precipitate which formed was filtered and washed with water to provide the titled compound. 1H NMR (DMSO-d6) δ12.35 (s, 1H), 8.29 (s, 1H), 7.85 (t, 1H, J=7.8 Hz, 7.21 (d, 1H, 7.3 Hz), 7.11 (d, 1H, 8.2 Hz), 4.85 (s, 2H).
Reaction SMILES: Br.[NH2:2][C@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:5](/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:4]1.C(N(CC)CC)C.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[CH3:23][O:22][C:20]([CH2:19][CH2:18][CH2:17]/[CH:16]=[CH:15]\[C@@H:5]1[CH2:4][C@@H:3]([NH:2][S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:7][N:6]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:21]
Reactant: COC(=O)CCC/C=C\[C@@H]1C[C@@H](N)CN1Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(C)cc2)CN1Cc1ccccc1
Reaction time: 1.5 h
Yield: 56.3 %

Procedure:
To a solution of (2S,4R)-4-amino-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1-(phenylmethyl)pyrrolidine hydrobromide (371 mg) in dichloromethane (4 ml) were added triethylamine (0.67 ml) and p-toluenesulfonyl chloride (200 mg) at 0° C. and the mixture was stirred at the same temperature for 1.5 hours. The solution was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of ethyl acetate and n-hexane (1:2) as an eluent to give (2S,4R)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-4-(4-methylphenylsulfonylamino)-1-(phenylmethyl)pyrrolidine (249 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](O)[C:5](=[CH:7][CH:8]=1)[OH:6].Cl[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+].O>CN(C)C=O.ClCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[C:7]([O:21][C:18]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH:8]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)c(O)c1
Agent: [K+]
Solvent: CCCCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(Cl)cn2)c(Oc2ccc(Cl)cn2)c1
Yield: 45 %

Procedure:
In 40 ml of dimethylformamide, a mixture of 4.0 grams (0.032 mole) 4-methylcatechol, 12.0 grams 2,5-dichloropyridine, and 12.0 grams of potassium carbonate was heated between 140° and 145° overnight. To the reaction mixture at room temperature was added excess H2O and the resulting aqueous mixture was extracted with ethyl ether (200 ml) which was washed with H2O (2X), saturated NaHCO3, brine, dried (MgSO4), filtered, and the solvent evaporated to yield an oil. Chromatography on a silica gel column using 1-chlorobutane as the eluent gave 5.0 grams of a white solid, m.p. 87°-90°; ir (Nujol): 6.30 (C=N), 9.10, 12.25 microns; NMR (CDCl3): δ2.35 (s, 3H, CH3), 6.60 (d, 2H, pyridine ring protons), 7.00 (broads, 3H, ArH), 7.45 (AB quartet, 2H, pyridine ring protons), 7.95 (d, 2H, pyridine ring protons).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[Cl:11][C:9]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]([NH2:8])[N:6]=[C:5]([N:2]([CH3:3])[CH3:1])[CH:10]=1
Reactant: CNC
Reactant: Clc1cc(Cl)nc(Nc2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C1=NC(N)N(c2ccccc2)C(Cl)=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Dimethylamine in tetrahydrofuran (2M, 15 mL) was added to a solution of 4,6-dichloro-N-phenyl-2-pyrimidinamine (0.715 g, 2.97 mmol) in tetrahydrofuran (30 mL) and N,N-diisopropylethylamine (0.52 mL). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the crude material was purified by flash chromatography on silica gel, eluting with ethyl acetate/hexane (1:9). The eluent was removed, giving 6-chloro-N4, N4-dimethyl-1-phenyl-2,4-pyrimidinediamine (0.592 g, 2.39 mmol, 80%, Rf=0.3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[C:14]1(C)C=CC(CC(OCC)=O)=CC=1.[Li+].CC([N-]C(C)C)C.CI>C1COCC1.CN1C(=O)N(C)CCC1>[C:10]1([CH3:14])[CH:11]=[CH:12][C:7]([CH:5]([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(C)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(C)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(C)cc1
Yield: 86 %

Procedure:
According to the procedure given for the synthesis of 202, ethyl p-tolylacetate (2.72 g, 15.2 mmol) was reacted with LDA (7.6 mL, 15.25 mmol) and methyl iodide (3.03 g, 21.30 mmol) in anhydrous THF (70 mL) and DMPU (1 mL). After aqueous workup and extraction, the residue was distilled in high vacuo to give 203 (2.5 g, 86.0%) as an oil. Bp 59-63° C./0.2 mmHg. 1H NMR (CDCl3): δ (ppm) 7.18 (d, 2H, J=8.1), 7.10 (d, 2H, J=8.1), 4.09 (m, 2H), 3.67 (q, 1H, J=7.2), 2.29 (s, 3H), 1.47 (d, J=7.2 Hz, 3H), 1.20 (t, J=5.7 Hz, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 174.71, 137.80, 136.63, 129.33, 129.14, 127.36, 60.66, 45.18, 21.05, 18.70, 14.15.
Reaction SMILES: CN(/[CH:4]=[C:5]1\[CH2:6][CH2:7][CH2:8][C:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][N:11]([CH3:19])[C:10]=2[C:20]\1=O)C.CN(C=O)C.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[NH:36])=[C:30]([O:38][CH3:39])[CH:29]=1>>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]2[N:37]=[C:20]3[C:10]4[N:11]([CH3:19])[N:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]=4[CH2:8][CH2:7][CH2:6][C:5]3=[CH:4][N:36]=2)=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCC/C(=C\N(C)C)C2=O
Reactant: COc1cc(Br)ccc1NC(=N)N
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(Br)cc3OC)nc1-2
Temperature: 120 °C
Reaction time: 4 h
Yield: 82.3 %

Procedure:
To a suspension of ethyl (7E)-7-[(dimethylamino)methylidene]-1-methyl-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylate 1.72 g (5.92 mmol) in 20 mL of DMF N-(4-Bromo-2-methoxy-phenyl)-guanidine 1.60 g (6.511 mmol) was added. The mixture was stirred at 120° C. for 4 h. The resulting mixture was cooled at room temperature and dried to dryness. The crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/hexane 4/6) to afford 2.30 g (82% yield) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[N:13]([O-])=O.[Na+].[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=1)[N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][OH:27])(=[O:19])[CH3:18].C([O-])(=O)C.[Na+]>O.COCCO>[CH2:28]([N:24]([CH2:25][CH2:26][OH:27])[C:23]1[CH:30]=[CH:31][C:32]([N:13]=[N:5][C:4]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=2[O:2][CH3:1])=[C:21]([NH:20][C:17](=[O:19])[CH3:18])[CH:22]=1)[CH3:29]
Reactant: CCN(CCO)c1cccc(NC(C)=O)c1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: CCN(CCO)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2OC)c(NC(C)=O)c1
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
8.3 g of 2-methoxy-4-nitroaniline was diazotized in a conventional manner using 4 g of sodium nitrite. The diazotized solution thus obtained was added to a mixture composed of 12 g of 3-acetylamino-N-ethyl-N-hydroxyethylaniline, 20 g of sodium acetate, 70 ml of methyl Cellosolve and 50 ml of water at a temperature of not more than 10° C. The mixture was stirred at a temperature range between 10° C. and 15° C. for 30 minutes, the crystals thus deposited were collected by filtration and washed with water. The crude product was recrystallized from acetonitrile to obtain 16 g of Compound [1-g].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20]2[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:21]=2[N:22]=[CH:23][N:24]=1>>[ClH:18].[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:19]3[C:20]4[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Product: Cl
Product: Clc1cc2c(Nc3ccc4c(ccn4Cc4ccccc4)c3)ncnc2cn1

Procedure:
Prepared according to Procedure A from 1-benzyl-1H-indol-5-ylamine and 4,6-dichloro-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.45(1H,s), 9.08(1H,s), 8.95(1H,s), 8.80(1H,s), 7.98(1H,d), 7.60(2H,m), 7.30(6H,m), 6.60(1H,d), 5.48(2H,s), m/z (M+1+) 386.
Reaction SMILES: [F:1][C:2]([F:8])([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:4][CH2:3][C:2]([F:8])([F:1])[CH2:5][CH2:6][O:7][S:16]([CH3:15])(=[O:18])=[O:17])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(F)(F)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(F)(F)COS(C)(=O)=O
Reaction time: 8 h

Procedure:
To a stirred mixture of 2,2-difluoro-1,4-butanediol (12.97 g, 103 mM), dry pyridine (65 mL) and dichloromethane (200 mL) is slowly added a solution of methanesulfonylchloride (23.6 g) in dichloromethane (50 mL). Stirring is continued overnight. The reaction mixture is washed with 2N HCl (twice), followed by 10% aqueous NaHCl3 until neutral, and then with water. The organic layer is dried (MgSO4) and upon evaporation of the solvents, a slightly yellow oil is obtained. Crystallization is induced by scratching the oil with dry ether, to yield the compound 1,4-bis-methanesulfonyloxy-2,2-difluorobutane as white crystals: 22.3 g (77%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:9]([F:12])([F:11])[C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: Nc1ncc(Br)cc1C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Yield: 86.9 %

Procedure:
A mixture of 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (11.5 g, 48 mmol) with 4-trifluormethylphenylboronic acid (9.97 g, 52 mmol) , Pd(PPh3)4 (551 mg, 1 mol %) and 1M aq. Na2CO3 soln. (111 mL, 111 mmol) in DME (250 mL) at reflux for 1 h. Poured on ice water, extracted with EtOAc, dried over Na2SO4 and concentrated. Purified by column chromatography (heptane/AcOEt 2:1), then triturated the collected solids with heptane and a few drops of ether, ultrasound sonication for 10 min, filtrated and dried in to give the product as a white crystalline solid (12.77 g, 87%). MS (ISP) 307.2 [(M+H)+].
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]1([CH2:17][NH:18][C:19]2[O:20][C:21]3[CH:27]=[C:26]([O:28][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]([NH2:37])=O)[CH:30]=4)[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([CH2:17][NH:18][C:19]2[O:20][C:21]3[CH:27]=[C:26]([O:28][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:37])[CH:30]=4)[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: NC(=O)c1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#Cc1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Reaction time: 0.25 h

Procedure:
To a solution of the methylsulfoxide (32 mg, 0.41 mmol, 6.0 eq) in 1 mL of methylene chloride was added oxalyl chloride (2M, 0.135 mL, 0.27 mmol, 4.0 eq) at −78° C. After 15 minutes, the 4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carboxamide (25 mg, 0.068 mmol, 1.0 eq) in 2 mL of methylene chloride was added to the reaction mixture. After being stirred at that temperature for 20 minutes, triethyl amine (83 mg, 0.83 mmol, 12 eq) was added to mixture. The reaction mixture was stirred at −78° C. for 2 hours, and then was quenched with aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was purified by reverse phase prep HPLC to give the title compound. MH+=349.0.
Reaction SMILES: [NH2:1][OH:2].Cl.S([O-])([O-])(=O)=O.[Na+].[Na+].ClC(Cl)(Cl)C([O:15][CH2:16][CH3:17])O.[Cl:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23]>O.Cl>[Cl:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH:23][C:16](=[O:15])/[CH:17]=[N:1]/[OH:2]
Reactant: Nc1ccc(F)cc1Cl
Reactant: NO
Reactant: CCOC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(/C=N/O)Nc1ccc(F)cc1Cl
Temperature: 25 °C
Yield: 3437 %

Procedure:
A solution containing NH2OH.HCl (3.2 g, 46 mmol), anhydrous sodium sulphate (13 g, 93 mmol), and 2.2.2-trichloro-1-ethoxy ethanol (4.1 g, 21.2 mmol) in water (60 mL) was added to a solution of 2-chloro-4-fluroaniline (2 g, 0.27 mmol) in 4 M HCl (25 mL). The solution was refluxed for 40 minutes forming a white precipitate in the process. The mixture was cooled to room temperature, extracted with ethyl acetate three times, dried over sodium sulfate, filtered and concentrated in vacuo to provide 2.01 g of N-(2-chloro-4-fluoro-phenyl)-2-((E)-hydroxyimino)-acetamide: 1H NMR (300 MHz, CDCl3) δ 8.8 (bs, 1H), 8.4 (dd, 1H), 7.9 (s, 1H), 7.6 (s, 1H), 7.2 (dd, 1H), 7.0 (ddd, 1H).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C.O>O1CCCC1>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:16]2[CH2:17][CH2:18][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (10.0 g, 34.3 mmol), 4-bromobenzoyl chloride (8.2 g, 37.4 mmol) and triethylamine (16.7 mL, 120.0 mmol) in tetrahydrofuran (200 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 50:50 to 0:100). Solvent was removed to obtain a solid (14.2 g, quant.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O>[N:1]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=3)=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: CCOC(=O)c1coc(-c2ccc(CCl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc(-c2ccc(Cn3ncc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of indazole (0.244 g, 2.07 mmol) in DMF at 0° C. was treated with sodium hydride (0.076 g, 1.98 mmol), stirred for 10 minutes at room temperature, treated with ethyl 2-[4-(chloromethyl)phenyl]-1,3-oxazole-4-carboxylate (0.5 g, 1.88 mmol) and stirred at 80° C. overnight. The reaction mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo to give a solid residue. The resultant residue was purified by column chromatography (silica, EtOAc:hexanes, 50%) to give ethyl 2-[4-(1H-indazol-1-ylmethyl)phenyl]-1,3-oxazole-4-carboxylate as white solid. The resulting solid (0.45 g, 1.29 mmol) was dissolved in 1:1 MeOH:THF treated with 1.0 M LiOH for 3 hours at 60° C. and concentrated in in vacuo. The resulting residue was diluted with water, treated with 1.0 M HCl and filtered to afford the title product 92% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 320 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]([NH2:14])=O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.S.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12](=[S:17])[NH2:14])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2C(N)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: c1ccncc1
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 0 °C
Yield: 180.7 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (27.9 g. 0.14 m) in dry pyridine (300 ml.), saturated with H2S gas, was treated with P2S5 (26 g., 0.14 m) and heated at reflux for 45 min. Whilst maintaining a slow stream of H2S gas. The reaction mixture was evaporated to dryness in vacuo and cooled to 0° C, made alkaline with 10% sodium hydroxide and the solution extracted with chloroform (3 × 100 ml.). The combined extracts were washed with brine, dried and evaporated in vacuo. The residual oil was triturated with benzene and the solid filtered and recrystallised from benzene to give the title compound as pale yellow needles m.p. 149° (21.8 g., 87%). The hydrochloride was prepared as already described in Example 18 and isolated as colourless needles m.p. 219° C.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:43])[CH:24]([NH:25][C:26](=[O:42])[CH:27]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[NH:28]C(OC(C)(C)C)=O)[C@H:21]3[S:20][CH2:19][C:18]=2[CH:44]=[N:45][O:46][CH3:47])=[O:16])C2C=CC=CC=2)C=CC=CC=1.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].C1(OC)C=CC=CC=1>CCOCC>[F:48][C:49]([F:54])([F:53])[C:50]([O-:52])=[O:51].[CH3:47][O:46][NH+:45]=[CH:44][C:18]1[CH2:19][S:20][C@@H:21]2[CH:24]([NH:25][C:26](=[O:42])[CH:27]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH2:28])[C:23](=[O:43])[N:22]2[C:17]=1[C:15]([OH:16])=[O:14]
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)[C@H]2SC1
Reactant: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: COc1ccccc1
Product: CO[NH+]=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2SC1
Product: O=C([O-])C(F)(F)F
Reaction time: 0.42 h
Yield: 93.3 %

Procedure:
A solution of diphenylmethyl-3-methoxyiminomethyl-7-(N-tertiary butoxycarbonyl-α-phenylglycyl)amino-3-cephem-4-carboxylate (64 mg) in ice-cooled trifluoroacetic acid (0.6 ml) and anisole (0.3 ml) is kept at room temperature for 25 minutes, and diluted with ether (5 ml) and petroleum ether (15 ml). The resulting crystals are collected by filtration and dried to give 3-methoxyiminiomethyl-7-(α-phenylglycyl)amino- 3-cephem-4-carboxylic acid trifluoroacetate (46 mg; 93.3 %). m.p. about 270° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]#[N:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CC(O)=[O:28].C([O-])([O-])=O.[Na+].[Na+].CCCCCC>Br.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:24]([NH2:25])=[O:28])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CC(=O)O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 2 h

Procedure:
A suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbonitrile (143 mg) in 25% hydrogen bromide solution of AcOH (1.5 ml) was stirred at 25-30° C. for 2 hours. The reaction mixture was poured into a mixture of Na2CO3 (2 g) and ice-water (30 g), extracted with CHCl3, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarboxamide as a solid (136 mg).