Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[O:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: Cc1cc2c(o1)CN(C)CCC2Oc1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)=[C:7]([N+:13]([O-])=O)[CH:8]=2)[N:3]1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C1COCC1.[H][H]>[C].[Pd].CO>[NH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[N:3]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:2](=[O:1])[C:11](=[O:12])[NH:10]2
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(N)c(-n3ccnc3)cc21
Yield: 85.6 %

Procedure:
A mixture of 1.30 g of ethyl 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate, 80 ml of THF, 20 ml of methanol and 600 mg of 10% palladium-carbon was stirred in a hydrogen gas atmosphere for 36 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 1.02 g (86%) of ethyl 2-[6-amino-2,3-dioxo-7-(1H-imidazol-1-yl)-l,2,3,4-tetrahydroquinoxalin-1-yl]acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[O:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[N:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C(OCC)(=O)C.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[C:32](=[O:36])[N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][CH:22]=3)=[CH:26][CH:27]=2)[CH:35]=[N:34]1)[CH3:12]
Reactant: Cc1nc(-c2ccc(-n3cn[nH]c3=O)cc2)co1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2ccc(-n3cnn([C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)c3=O)cc2)co1
Temperature: 90 °C
Reaction time: 20 h
Yield: 33.6 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (0.50 g), 4-[4-(2-methyl-4-oxazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (0.56 g) and potassium carbonate (powder: 1.38 g) were added to a mixture of 1-methyl-2-pyrrolidone (5 ml) and N,N-dimethylformamide(4 ml), and the mixture was heated with stirring at 90° C. for 20 hours. After cooling, the reaction solution was diluted with ethyl acetate (40 ml). Ice water (40 ml) was added thereto to separate the ethyl acetate layer. The ethyl acetate layer was washed with 0.5N-sodium hydroxide (40 ml), 1N-hydrochloric acid (40 ml) and a saturated aqueous solution of sodium chloride (40 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate to ethyl acetate/methanol=9/1) and crystallized from ethyl acetate-diisopropyl ether to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2-methyl-4-oxazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 36, 0.33 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[S:12])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Br[CH:44]([CH3:49])[C:45](OC)=[O:46]>CCO.C(Cl)Cl>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[C:45](=[O:46])[CH:44]([CH3:49])[S:12]/[C:11]/2=[N:13]/[N:14]=[CH:15]\[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:37])[F:36])=[CH:31][CH:32]=4)[N:23]=3)=[CH:20][CH:21]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(/C=N/NC(=S)Nc4ccccc4C4CC4)cc3)n2)cc1
Reactant: COC(=O)C(C)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC1S/C(=N/N=C\c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)N(c2ccccc2C2CC2)C1=O
Temperature: 60 °C
Yield: 29.3 %

Procedure:
To (E)-N-(2-cyclopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (100 mg, 0.191 mmol) and sodium acetate (63.0 mg, 0.765 mmol) in EtOH (4 mL) was added methyl 2-bromopropanoate (0.026 mL, 0.230 mmol). The reaction was heated to 60° C. overnight. The reaction was then heated to 85° C. for 72 hours. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided the title compound as a white solid (32.5 mg, 0.056 mmol, 30%): mp 112-115° C.; 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.32 (s, 1H), 8.22 (d, J=8.3 Hz, 2H), 7.87-7.75 (m, 4H), 7.43-7.32 (m, 4H), 7.26-7.24 (m, 2H), 4.23 (q, J=7.3 Hz, 1H), 1.85-1.78 (m, 4H), 0.90-0.78 (m, 2H), 0.78-0.69 (m, 1H), 0.65-0.55 (m, 1H); ESIMS m/z 578 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:40])[CH2:6][CH2:5][CH:4]=[C:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:37])[N:19]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C@@H:20]4[C@H:25]([C:26]=3[OH:27])[C@@H:24]3[CH2:28][C@H:21]4[CH2:22][CH2:23]3)=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1>CO.[Pd]>[O:40]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:37])[N:19]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[C@@H:20]4[C@H:25]([C:26]=3[OH:27])[C@@H:24]3[CH2:28][C@H:21]4[CH2:22][CH2:23]3)=[N:13][S:14](=[O:15])(=[O:16])[C:9]=2[CH:8]=1.[O:40]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C@@:21]34[CH2:28][C@H:24]([CH2:23][CH2:22]3)[C@@H:25]3[C@@H:20]4[N:19]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:18](=[O:37])[CH:17]=[C:26]3[OH:27])=[N:13][S:14](=[O:15])(=[O:16])[C:9]=2[CH:8]=1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: O=C1C(C2=NS(=O)(=O)c3cc(C4CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Product: O=C1C=C(O)[C@@H]2[C@H]3CC[C@@](C4=NS(=O)(=O)c5cc(C6CCCS6(=O)=O)ccc5N4)(C3)[C@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 176 %

Procedure:
(1R,2S,7R,8S)-5-[7-(1,1-Dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 20, 30 mg, 0.05 mmol) was dissolved in methanol (15 mL) and 5% palladium on charcoal (100 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite, rinsed with 10% methanol/dichloromethane, and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (1R,2S,7R,8S)-[7-(1,1-dioxo-tetrahydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (26 mg, 0.044 mmol, 86%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.19 (2H, m), 1.40-1.60 (4H, m), 2.12 (1H, m), 2.67 (1H, m), 2.36 (1H, m), 2.50 (1H, m), 2.65 (1H, m), 3.03 (1H, m), 3.23 (1H, m), 3.32 (1H, m), 3.53 (1H, d, J=10.0 Hz), 4.42 (1H, d, J=15.2 Hz), 4.56 (1H, dd, J=11.6, 6.8 Hz), 4.97 (1H, d, J=15.6 Hz), 7.14 (2H, m), 7.33 (2H, m), 7.58 (1H, d, J=8.8 Hz), 7.69 (1H, dd, J=8.8, 2.4 Hz), 7.82 (1H, d, J=2.4 Hz); LC-MS (ESI) calcd for C28H28FN3O6S2 585.14, found 586.3 [M+H+].
Reaction SMILES: O[CH:2](O)[CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[O:10][C:11]([CH3:13])=[CH:12][C:6]=2[C:5]1=[O:14].[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22].S([O-])(O)=O.[Na+].O>C(O)C>[NH:22]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:23]=[C:2]1[CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[O:10][C:11]([CH3:13])=[CH:12][C:6]=2[C:5]1=[O:14]
Reactant: Nc1ccccc1N
Reactant: Cc1cc2c(=O)n(CC(O)O)ccc2o1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(=O)n(Cc3nc4ccccc4[nH]3)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
5-(2,2-Dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (2.1 g) and o-phenylenediamine (1.1 g) were suspended in ethanol (20 ml). Sodium hydrogensulfite (5.2 g) was added, and the mixture was heated and stirred overnight under reflux. The reaction mixture was cooled to room temperature. Water was added thereto and the precipitated insoluble matter was separated, washed with water, and dried to give the title compound (2.25 g).
Reaction SMILES: ClC1C(Cl)=CC=CC=1N[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18](=[O:31])[N:19]([C@H:22]3[CH2:24][C@@H:23]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:21])[C@@H:14]2[CH2:13]1)=O.Cl.[C:33]1([C@H:39]2C[C@@H]2N2C(=O)[C@@H]3CNCCN3C2=O)[CH:38]=CC=C[CH:34]=1.C(Cl)(=O)C(C)(C)C>C(Cl)Cl>[CH3:34][C:33]([CH3:39])([CH3:38])[CH2:10][N:12]1[CH2:17][CH2:16][N:15]2[C:18](=[O:31])[N:19]([C@H:22]3[CH2:24][C@@H:23]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:21])[C@@H:14]2[CH2:13]1
Reactant: O=C1[C@@H]2CNCCN2C(=O)N1[C@H]1C[C@@H]1c1ccccc1
Reactant: O=C(Nc1cccc(Cl)c1Cl)N1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)[C@@H]2C1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)CN1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of Example 4, D2 (1 eq) and TEA (1.1 eq) in DCM (0.08M) was added pivaloyl chloride (2.1 eq) and the reaction mixture was stirred at 25° C. for 2 h. The crude product was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents, affording the title compound. 1H NMR (400 MHz, DMSO-d6, 300K) 7.48-7.18 (5H, m), 4.75-4.63 (1H, m), 4.42-4.33 (1H, m), 4.05-3.93 (2H, m), 3.15-2.80 (3H, m), 2.72-2.63 (1H, m), 2.50-2.38 (1H, m), 1.58-1.51 (1H, m), 1.48-1.38 (1H, m), 1.35 (9H, s). MS (ES) C20H25N3O3 requires: 354 found: 355 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17]>CO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:2][NH2:3])=[O:17]
Reactant: NN
Reactant: COC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NN)c1Cl
Temperature: 60 °C
Yield: 92 %

Procedure:
Hydrazine hydrate (2 ml) is added dropwise to a suspension of methyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate (227.1 mg, 0.73 mmol) in 10 ml of methanol. The reaction mixture is heated at 60° C. for seven hours under an atmosphere of nitrogen and then allowed to cool to room temperature overnight. The now clear colorless solution is concentrated in vacuo and chromatographed, eluting with ethyl acetate and hexane (gradient of 1:2 to 1:1), providing 208.6 mg (92%) of a white solid, mp 158°-160° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[CH:8]([N:14]([CH:16]3[CH2:18][CH2:17]3)[CH3:15])[CH2:7][CH2:6][C:5]([CH3:20])([CH3:19])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:16]1([N:14]([CH3:15])[CH:8]2[CH2:7][CH2:6][C:5]([CH3:20])([CH3:19])[C:4]3[C:3]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:2][CH:11]=[C:10]([O:12][CH3:13])[C:9]2=3)[CH2:18][CH2:17]1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(Br)cc2c1C(N(C)C1CC1)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COc1ccc(C#C[Si](C)(C)C)c2c1C(N(C)C1CC1)CCC2(C)C
Yield: 76.5 %

Procedure:
Following General Procedure D and using 2-bromo-5-(cyclopropyl-methylamino)-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 79, 1.08 g, 3.2 mmol), triethyl amine (5 mL), copper(I)iodide (0.061 g, 0.32 mmol), trimethylsilyl acetylene (3 mL, 21.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.225 g, 0.32 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane-10% ethyl acetate in hexane as the eluent, the title compound (0.87 g, 80%) was obtained.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]4[C:21]5[NH:22][CH2:23][CH2:24][C:25](=[O:26])[C:20]=5[C:19]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[N:18][C:17]=34)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:33]1[CH:37]=[N:36][C:35]([C:38](O)=[O:39])=[N:34]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[N:33]1[N:34]=[C:35]([C:38]([N:30]2[CH2:31][CH2:32][CH:27]([C:19]3[C:20]4[C:25](=[O:26])[CH2:24][CH2:23][NH:22][C:21]=4[N:16]4[N:15]=[CH:14][C:13]([C:10]5[CH:11]=[N:12][C:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)=[CH:8][CH:9]=5)=[C:17]4[N:18]=3)[CH2:28][CH2:29]2)=[O:39])[NH:36][CH:37]=1
Reactant: O=C1CCNc2c1c(C1CCNCC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn21
Reactant: O=C(O)c1nc[nH]n1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCNc2c1c(C1CCN(C(=O)c3nnc[nH]3)CC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one (70 mg, 0.17 mmoL), 1H-1,2,4-triazole-3-carboxylic acid (20.5 mg, 0.18 mmoL), EDC (63 mg, 0.33 mmoL), HOBt (44.6 mg, 0.33 mmoL) and DIEA (172.2 uL, 0.99 mmoL) in DMF (3 mL) was stirred at room temperature for 2 h. Purification with prep-LC provided 5-(1-(4H-1,2,4-triazole-3-carbonyl)piperidin-4-yl)-3-(6-phenylpyridin-3-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one: LCMS tR=3.15 Min (10 min run, UV254nm). Mass calculated for, M+ 519.2, observed LC/MS m/z 519.97 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C@H:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH3:2].[CH3:18][C:19]([CH3:21])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CCO>[CH2:1]([N:3]([CH:19]([CH3:21])[CH3:18])[C@H:4]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH3:2]
Reactant: CCN[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCN(C(C)C)[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of product from example 122A (0.098 g, 0.416 mmol) in EtOH (5 mL) was added acetone (0.031 mL, 0.416 mmol), acetic acid (0.024 mL, 0.416 mmol), and sodium cyanoborohydride (0.039 g, 0.625 mmol), and the resulting mixture and stirred at rt for 8 hrs. The mixture was partitioned between CH2Cl2 and saturated aq. NaHCO3, and the organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-1% MeOH in CH2Cl2 to give the title compound (0.0352 g, 31%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]2[N:27]=[C:28]([NH:31][C:32](=[O:34])[CH3:33])[S:29][CH:30]=2)=[CH:20][CH:19]=1)[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[Br:41]N1C(=O)CCC1=O>CO>[C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]2[N:27]=[C:28]([NH:31][C:32](=[O:34])[CH3:33])[S:29][C:30]=2[Br:41])=[CH:22][CH:23]=1)[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c(Br)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
Di-tert-butyl{[(4-(2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl)phenyl)amino]methylidene}biscarbamate (310 mg) prepared in a similar manner according to Step 5 of the following Production Example 18 was dissolved in methanol (6 ml) and tetrahydrofuran (3 ml) under nitrogen atmosphere. Then N-bromosuccinimide (164 mg) was added to the solution at 0° C. The reaction mixture was stirred at room temperature for 4 hours, and concentrated in vacuo. Chloroform and saturated sodium hydrogen carbonate solution were added to the residue. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with n-hexane/ethyl acetate (2:1) as an eluent to give di-tert-butyl{[(4-{2-[2-(acetylamino)-5-bromo-1,3-thiazol-4-yl]ethyl}phenyl)amino]-methylidene)biscarbamate (271.4 mg) as a colorless amorphous substance.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.P(Cl)(Cl)(Cl)=O.[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>CN(C)C1C=CC=CC=1>[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH:17]1[NH:16][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12
Reactant: Oc1ncnc2[nH]ncc12
Reactant: NC1Cc2ccccc2C1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)CC(Nc1ncnc3[nH]ncc13)C2
Yield: 56 %

Procedure:
Using 4-hydroxypyrazolo[3,4-d]pyrimidine (140 mg, 1.0 mmol), phosphorus oxichloride (3.0 ml), and dimethylaniline (0.39 ml, 3.1 μmol), and then 2-aminoindan (400 mg, 3.0 mmol), a similar procedure to Preparation Example 5 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=5:2) to obtain the title compound (150 mg, 0.56 mmol) having the following physical properties:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[C:4]([C:10]([OH:12])=[O:11])[O:12][C:10]2=[O:11])=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Br)cc1C(=O)O
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2ccc(Br)cc2c(=O)o1

Procedure:
7- Bromoisocoumarin -3- carboxylic acid, mp. (EtOH-H2O) 320-4°, (Found: C, 44.72; H, 1.86; Br. 29.41. C10H5BrO4 requires C, 44.64; H, 1.87; Br. 29.70), was prepared from 4- bromo -2- carboxybenzaldehyde by an analgous procedure to that described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13](/[CH:16]=[CH:17]\[CH2:18]Cl)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:38].[Na+]>CC(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13](/[CH:16]=[CH:17]/[CH2:18][I:38])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of diphenylmethyl 7-t-butoxycarbonylamino-3- [(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate (IIIa) (541 mg, 1 mmol) and sodium iodide (450 mg, 3 mmol) in acetone (5.4 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 ml), washed with aqueous sodium thiosulfate and water successively, dried with MgSO4 and concentrated to yield 632 mg of the title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:13]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.CN1CCCC1=O>>[CH2:21]([N:20]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(N(Cc2ccccc2)Cc2ccccc2)nc1Cl
Temperature: 120 °C
Yield: 86 %

Procedure:
A mixture of 2,6-dichloro-3-(trifluoromethyl)pyridine (1.0 g, 4.63 mmol), dibenzylamine (913 mg, 890 μL, 4.63 mmol), triethylamine (1.2 mL, 8.61 mmol) and 1-methyl-2-pyrrolidone (6 mL, 62.22 mmol) was heated at 120° C. for 9 h. The reaction mixture was cooled to the room temperature and poured into ice-water, extracted with EtOAc (20 mL×3), the combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (2%-10% EtOAc in petroleum ether as eluant) to give N,N-dibenzyl-6-chloro-5-(trifluoromethyl)pyridin-2-amine (1.5 g, 86%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.7 Hz, 1H), 7.37-7.21 (m, 10H), 6.32 (d, J=8.7 Hz, 1H), 4.80 (s, 4H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]([CH3:16])[CH2:13][CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[ClH:3].[CH2:5]([N:12]([CH2:13][CH2:14][Cl:3])[CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCO
Product: CN(CCCl)Cc1ccccc1
Product: Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
The procedure of Hall, et al.[Organic Syntheses Coll. Vol. 4, 1963, 333-335]was used. To thionyl chloride (22.92 mL, 03.14 mol) at 0° C. was added dropwise N-benzyl-N-methyl ethanolamine (50 g, 0.303 mol). The creamy, off-white material was stirred for 1 hour at 0° C. and then 1 hour at room temperature. Anhydrous ethanol (129 mL) was added to the material. The solution was refluxed for 20 minutes and then was concentrated to an off-white solid. The solid was triturated with Et2O to give the title compound as a white solid (62.51 g, 94% yield, mp 136°-138° C.).
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:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH:23]=1)[CH2:21]Br.O>C(#N)C>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH:23]=1)[CH2:21][N:4]1[C:3]([O:2][CH3:1])=[N:7][NH:6][C:5]1=[O:8]
Reactant: COc1n[nH]c(=O)[nH]1
Reactant: Clc1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1n[nH]c(=O)n1Cc1cc(Br)ccc1Cl
Temperature: 55 °C
Reaction time: 5 h
Yield: 35.6 %

Procedure:
To a solution of 0.91 g (7.93 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 8 ml of dry acetonitrile was added 0.96 g (6.94 mmol) of potassium carbonate. To the mixture was added dropwise a solution of 1.88 g (6.61 mmol) of 5-bromo-2-chlorobenzylbromide in 20 ml of dry acetonitrile at 55° C. After the mixture was stirred at 55° C. for 5 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. To the resultant solid residue (1.90 g) was added cold tert-butyl methyl ether and the solid was thoroughly washed, collected by filtration and dried to obtain 0.75 g of 4-(5-bromo-2-chlorobenzyl)-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.