Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[Na].[Na].[Na].[C:5]([C:8]1[N:9]=[N:10][NH:11][C:12]=1[SH:13])([OH:7])=[O:6].CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O.O.Cl>CC(C)=O>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:13][C:12]3[NH:11][N:10]=[N:9][C:8]=3[C:5]([OH:7])=[O:6])[CH2:28][S:27][C@H:22]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)c1nn[nH]c1S
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3[nH]nnc3C(=O)O)CS[C@H]12

Procedure:
4-Carboxy-1,2,3-triazole-5-thiol trisodium salt hydrate (4.4 g., 20 mmol.) was added to a stirred suspension of 4.08 g. (15 mmol.) of 7-aminocephalosporanic acid in 30 ml. of water and 15 ml. of acetone. The reaction mixture was quickly acidified to pH 7.3 with dilute hydrochloric acid, then heated at 65° for 4.5 hours. The mixture was cooled (ice bath), brought to pH 2.4 with dilute hydrochloric acid and the precipitate was collected, washed with water and acetone and dried in vacuo over phosphorus pentoxide to give the title compound.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[C:20](=[C:28]([C:32]([OH:34])=O)[CH:29]=[CH:30][CH:31]=2)[C:21](=[O:27])[NH:22]3)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35]1[N:39]=[CH:38][N:37]([C:40](N2C=NC=C2)=O)[CH:36]=1.CN(C)CCN>CN(C=O)C.O>[CH3:38][N:37]([CH3:40])[CH2:36][CH2:35][NH:39][C:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:19]2[C:18]3[C:23](=[N:24][CH:25]=[CH:26][C:17]=3[NH:16][C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:15][CH:14]=3)[NH:22][C:21](=[O:27])[C:20]=12)=[O:34]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4c(C(=O)O)cccc4c23)cc1)c1ccccc1
Agent: CN(C)CCN
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cccc2c1c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Reaction time: 2 h

Procedure:
434 (20 mg, 0.04 mmol), and CDI (14 mg, 0.09 mmol) were suspended in DMF (1 mL), and stirred for 2 h. N,N-dimethylethane-1,2-diamine (8 mg, 0.09 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with H2O. The resulting precipitate was filtered, washed with MeOH, and dried under vacuum to provide 435. LC-MS (M+H=521, obsd.=521). 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 6H), 2.49 (4H), 6.93 (d, 1H), 7.20 (d, 2H), 7.54 (m, 3H), 7.76 (m, 3H), 7.97 (d, 1H), 8.10 (d, 1H), 8.27 (s, 1H), 8.85 (d, 1H), 9.18 (s, 1H), 10.27 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31]>CN1C(=O)CCC1>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][NH:27][C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1
Reactant: CN(C)CCN
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(CNC(=O)c2cc(NCCN(C)C)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 67.1 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and (2-aminoethyl)dimethylamine (37.7 mg, 0.43 mmol) in NMP (2 mL). The vessel was sealed and the reaction mixture was irradiated (microwave) at 150° C. for 1 h. The mixture was evaporated under vacuum, and the resulting residue was partitioned between EtOAc and water. The contents were extracted with EtOAc, DCM and DCM/isopropanol (70:30). The combined organics were washed with water (2×) and brine, dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated yellow oil was treated with EtOAc and sonicated. Solids that precipitated were filtered, washed with hexanes, and dried to afford the title compound (60 mg, 65%) as a white solid. LCMS E-S (M+H)=425.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (br. s., 1 H) 8.43 (t, J=5.05 Hz, 1 H) 7.84 (s, 1 H) 7.08 (t, J=5.05 Hz, 1 H) 6.67 (s, 1 H) 5.89 (s, 1 H) 4.94 (quin, J=6.63 Hz, 1 H) 4.32 (d, J=5.05 Hz, 2 H) 3.44 (q, J=6.48 Hz, 2 H) 2.44 (t, J=6.69 Hz, 2 H) 2.17-2.22 (m, 9 H) 2.12 (s, 3 H) 1.43 (d, J=6.57 Hz, 6 H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.Cl[CH2:10][C:11]([NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=O.P([O-])([O-])(O)=O.[Na+].[Na+].O>CN(C)C(=O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])[N:1]=2)[N:4]=1
Reactant: Nc1ccc(I)nn1
Reactant: CCOC(=O)NC(=O)CCl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)Nc1cn2nc(I)ccc2n1
Temperature: 110 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of 3-amino-6-iodopyridazine (27.0 g, 122 mmol) in N,N-dimethylacetamide (270 mL) were added ethyl (chloroacetyl)carbamate (32.4 g, 195 mmol) and disodium hydrogenphosphate (43.4 g, 305 mmol), and the mixture was stirred at 110° C. for 3 hr. After cooling the mixture to room temperature, water (810 mL) was added, and the precipitated crystals were filtrated, and washed with acetonitrile and ether to give the title compound (33.0 g, 81%) as a dark brown powder.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH:4]=[C:3]1[CH2:13]O.P(Br)(Br)[Br:16].C(Cl)Cl>CN(C=O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH:4]=[C:3]1[CH2:13][Br:16]
Reactant: BrP(Br)Br
Reactant: Cn1c(CO)cc(=O)c2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(CBr)cc(=O)c2ccccc21

Procedure:
A solution of 1-methyl-4-oxo-1,4-dihydroquinolin-2-ylmethanol (112 mg, 0.592 mmoles, Coppola, G. M. J. Heterocyclic Chem., 1986, 23, 1717) and phosphorous tribromide (56.2 uL, 0.592 mmoles) in 3:1 CH2Cl2: DMF (20 mL) is stirred 18 hours and another portion (20 mL) of phosphorous tribromide is added. After 24 hours distilled water (10 mL) is added and extracted with EtOAc. The organic layer is concentrated and the resulting residue purified by column chromatography (silica, 20:1 CH2Cl2:MeOH) to yield the title compound as a white solid. MS (ESI) 252, 254 (M+H)+, Br pattern.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[C:11]([NH2:29])=[N:12][CH:13]=[C:14]([C:16]3[N:20]([CH2:21][CH3:22])[N:19]=[C:18]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[N:17]=3)[N:15]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1([CH3:39])[O:35][C@H:34]([C:36]([O-])=[O:37])[CH2:33][O:32]1.[K+].CCN=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[NH2:29][C:11]1[N:12]=[CH:13][C:14]([C:16]2[N:20]([CH2:21][CH3:22])[N:19]=[C:18]([CH:23]3[CH2:28][CH2:27][N:26]([C:36]([C@@H:34]4[CH2:33][O:32][C:31]([CH3:39])([CH3:30])[O:35]4)=[O:37])[CH2:25][CH2:24]3)[N:17]=2)=[N:15][C:10]=1[C:8]1[O:9][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[N:6][N:7]=1
Reactant: CC1(C)OC[C@@H](C(=O)[O-])O1
Reactant: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(C2CCN(C(=O)[C@@H]3COC(C)(C)O3)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.8 %

Procedure:
To a mixture of 3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (257 mg, 0.50 mmol, TFA salt), potassium (S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (101 mg, 0.55 mmol) and EDCI (105 mg, 0.55 mmol) in DCM (5 mL) were added 1-hydroxy-1H-benzotriazol hydrate (85 mg, 0.56 mmol) and DIPEA (194 mg, 1.50 mmol). The mixture was stirred for 16 hours at room temperature. Water was added to the mixture and the mixture was extracted with DCM. The organic layers were washed with brine and dried over Na2SO4, filtered and concentrated to give (S)-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)(2,2-dimethyl-1,3-dioxolan-4-yl)methanone (320 mg). Mass Spectrum [M+H]+=526. To a mixture of (S)-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)(2,2-dimethyl-1,3-dioxolan-4-yl)methanone (320 mg) in DCM (10 mL) at r.t was added dropwise TFA (1.6 ml, 20.77 mmol). The mixture was stirred for 16 h at r.t, concentrated and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as the eluant. The fractions containing the desired compound were evaporated to dryness to afford the title compound (142 mg, 48%) as a white solid. 1H NMR Spectrum (400 Hz, DMSO-d6, 30° C.): 1.45 (12H, m), 1.56 (1H, m), 1.70 (1H, m), 1.98 (2H, m), 2.85 (1H, m), 3.00 (1H, m), 3.20 (1H, m), 3.45 (1H, s), 3.55 (1H, s), 4.05 (1H, m), 4.35 (2H, m), 4.60 (2H, m), 4.70 (1H, m), 4.85 (1H, m), 7.90 (2H, m), 8.85 (1H, s); Mass Spectrum [M+H]+=486.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:17][C:18]([F:21])([F:20])[F:19].B1C2CCCC1CCC2.[OH-:31].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:31])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:17][C:18]([F:20])([F:19])[F:21]
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
To the solution of 1-chloro-2-(trifluoromethoxy)-4-(4-vinylphenoxy)benzene (1.2 g, 3.81 mmol) in dry THF (10 mL), was added 9-BBN (15.25 mL, 7.63 mmol) at 0° C. The mixture was stirred at room temperature overnight. aq. NaOH (6.5 mL, 19.50 mmol), and 30% H2O2 (2.0 mL, 19.58 mmol) were added. The reaction mixture was heated at 55° C. for 4 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (450 mg, 1.353 mmol, 35.5% yield) as a white oil.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:19](=[O:21])C)[C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14]C=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22]OC(C)(C)C>C(Cl)(Cl)Cl>[C:1]1([NH:7][N:8]=[C:9]([CH2:10][C:11]2[CH:12]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]([Cl:22])=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)C(=NNc1ccccc1)C(=O)Cc1ccccc1
Reactant: CC(C)(C)OCl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)C(Cc1ccccc1)=NNc1ccccc1

Procedure:
The foregoing procedure was repeated, but using 12.1 gms. 1-phenyl-2,3,4-pentanetrione-3-phenylhydrazone, 100 ml. chloroform, and 6 ml. tert-butyl hypochlorite. Upon recrystallization from 100 ml. methanol there was obtained 6.3 gms. of compound having a melting point at 132° to 134°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=1)[C:6]([CH3:25])=[C:5]2[CH:26]=O.Cl.[NH2:29][OH:30].CO>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=1)[C:6]([CH3:25])=[C:5]2[CH:26]=[N:29][OH:30]
Reactant: NO
Reactant: Cc1c(C=O)c2cc(F)ccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1c(C=NO)c2cc(F)ccc2n1-c1ccc(OCc2ccccc2)cc1
Yield: 88 %

Procedure:
A mixture of 5-fluoro-1-(4-benzyloxyphenyl)-2-methyl-1H-indole-3-carbaldehyde (0.97 g, 2.7 mmol), hydroxylamine hydrochloride (0.25 g, 3.6 mmol), methanol (25 mL) and pyridine (1 mL) was reacted according to the procedure in Example 3a to afford white solid (88%): mp 183-185° C.; 1H NMR (DMSO-d6): δ 2.30 (3H, s), 5.20 (2H, s) d, 6.94-6.97 (2H, m), 7.23 (2H, d, J=8.9 Hz), 7.37-7.46(5H, m), 7.52(2H, d, J=6.8 Hz), 7.71 (1H, d, J=10.1 Hz), 8.41 (1H, s), 10.72 (1H, s); MS m/z (M+H)+ 375. Anal. for C23H19FN2O2: Calc'd: C, 73.78; H, 5.11 N, 7.48. Found: C, 73.55; H, 5.03; N, 7.35.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH:18](=O)[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O>C(COC)OC>[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([CH:18]=[C:8]([CH3:9])[C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:20][CH:21]=1)=[O:24]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccc(C=O)cc1

Procedure:
To a suspension of 10.0 g of 50% sodium hydride (dispersion in mineral oil) in freshly distilled dimethoxyethane (DME, 350 ml) stirred under nitrogen at 10° is added 53.6 ml of triethyl 2-phosphonopropionate in ca. 40 minutes. The mixture is stirred for 0.5 hour at 10° and for an additional 1.5 hours during which time the temperature is allowed to rise to room temperature. This solution is transferred under nitrogen by cannula to a 500 ml addition funnel and is added dropwise to a solution of terephthalaldehyde (33.53 g) in dry DME (475 ml) over a period of 1 hour at 22°-34°. After addition is complete the reaction mixture is stirred mechanically at room temperature for 2 hours, poured into 1L of water and extracted with 4×500 ml of ether. The ether extract is washed with a saturated sodium chloride solution (700 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow oil which partially crystallizes on standing. This crude mixture is purified by suspending in petroleum ether and ethyl acetate (93:7). The filtrate, after removal of unreacted dialdehyde, is concentrated in vacuo to give a mixture which is further purified by high pressure liquid chromatography (using petroleum ether/ethyl acetate 93:7). There is obtained pure ethyl 4-formyl-α-methylcinnamate. A solution of the aldehyde (34.80 g) in 820 ml of absolute ethanol is treated with 12.11 g of granular sodium borohydride at room temperature under nitrogen. The resulting mixture is stirred at room temperature for 3 hours (or until all borohydride has dissolved) and then concentrated to ca. 200 ml volume, diluted with 400 ml of water, and extracted with 3×200 ml of ether. The ether extract is washed with 100 ml of water and brine (100 ml), is dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo to give ethyl 3 (p-hydroxymethylphenyl)-2-methylacrylate. To a solution of this product in 350 ml of methylene chloride is added at room temperature 11.53 ml of thionyl chloride dropwise over 25 minutes. The clear, colorless solution is stirred for 2 hours. The solution is washed with 100 ml of water, 200 ml of saturated sodium bicarbonate, 100 ml of water, and 100 ml of brine. The organic layer after drying and removal of solvent yields ethyl 3-(p-chloromethylphenyl)-2-methylacrylate, used without further purification.
Reaction SMILES: CC(S([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16])=O)(C)C.Cl>CO.O1CCOCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26](/[CH:25]=[CH:24]/[C:21]2[CH:22]=[CH:23][C:18]([S:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][NH2:7])(=[O:17])=[O:16])=[CH:19][CH:20]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)S(=O)NCc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1

Procedure:
2-Methyl-N-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)benzyl]propane-2-sulfinamide (Example 177, 285 mg, 0.6 mmol) was dissolved in methanol (5 mL) and 4N HCl in dioxane (5 mL) and stirred overnight at room temperature. The solvent was removed in vacuo and the residue triturated with diethyl ether to give the title compound as the hydrochloride salt (221 mg, 90%). δH (500 MHz, d6 DMSO): 8.46-8.38 (3H, m), 8.13 (1H, d, J=7.8 Hz), 7.89 (2H, d, J=8.3 Hz), 7.84-7.78 (3H, m), 7.71-7.67 (4H, m), 7.45 (1H, d, J=16.5 Hz), 7.30 (1H, d, J=16.5 Hz), 7.23 (2H, t, J=8.7 Hz), 4.28 (2H, s).
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH3:16][O:17][N:18]=[C:19]([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1O.N(C(OCC)=O)=NC(OCC)=O>CCOCC>[CH3:16][O:17][N:18]=[C:19]([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH3:9]
Reactant: CCC(O)c1ccccc1
Reactant: CON=C(c1ccccc1O)n1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(Oc1ccccc1C(=NOC)n1ccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thriphenylphosphine (1.05 g), 1-phenylpropyl alcohol 0.54 g) and THF (20 ml) were added to 2-hydroxy-α-(1-imidazolyl)benzaldehyde O-methyloxime (0.43 g), and diethyl azodicarboxylate (0.70 g) was added under ice-cooling over 10 minutes. then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, ether (100 ml) was added, the mixture was washed with water (80 ml) twice, and the ether layer was concentrated under reduced pressure. the resulting crude product was purified by silica gel chromatography to α-(1-imidazolyl)-2-(1-phenylpropyloxy)benzaldehyde O-methyloxime (0.63 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[CH:4]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[S:26].[C:37](#N)C>C(OCC)(=O)C>[CH3:37][S:26][C:25]1[O:24][N:23]=[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[C:5]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:16])[CH2:11][CH2:10]3)[CH:4]=2)[N:1]=1
Reactant: CC#N
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: CSc1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-Dimethylpropyl 4-{4-[amino(hydroxyimino)methyl]pyridin-2-yl}piperazine-1-carboxylate (340 mg) obtained in Example 26-1) was dissolved in acetonitrile (2 mL), and 1,1′-thiocarbonyldiimidazole (231 mg) was added thereto and stirred at room temperature for 2 hours. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was dissolved in dimethylformamide (2 mL), and methyl iodide (0.080 mL) and potassium carbonate (198 mg) were added thereto and stirred at room temperature for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=7/3) to obtain 25.2 mg of the entitled compound as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:57]([C:59]1[CH:64]=[CH:63][C:62]([N:65]2[CH2:69][CH2:68][CH:67]([C:70](O)=[O:71])[C:66]2=[O:73])=[CH:61][CH:60]=1)#[N:58]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:70]([CH:67]1[CH2:68][CH2:69][N:65]([C:62]2[CH:63]=[CH:64][C:59]([C:57]#[N:58])=[CH:60][CH:61]=2)[C:66]1=[O:73])=[O:71]
Reactant: N#Cc1ccc(N2CCC(C(=O)O)C2=O)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 3.4 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.434 mmol), PyBOP (0.340 g; 0.651 mmol), N,N-diisopropylethylamine (0.224 mL; 1.30 mmol) and 1-(4-cyanophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.434 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified preparative HPLC (method 1) to yield 0.006 g (3%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[N:4]2[C:3]1=[O:14].O=[C:16]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17]([OH:19])=[O:18].[OH-].[Na+].C([BH3-])#N.[Na+]>O>[C:17]([CH:16]([NH:1][CH:2]1[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[N:4]2[C:3]1=[O:14])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:19])=[O:18]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: NC1CN2CCCC(C(=O)O)N2C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(CCc1ccccc1)NC1CN2CCCC(C(=O)O)N2C1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 22.1 %

Procedure:
0.896 g of 2-amino-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (racemate A) was dissolved in 6 ml of water. 2.4 g of 2-oxo-4-phenylbutyric acid were added and the mixture was adjusted to pH 6 with 2N aqueous sodium hydroxide solution. 0.504 g of sodium cyanoborohydride was then added and the mixture was stirred at room temperature for 22 hours. The resulting solution was applied to 10 g of Zerolit 225 ion-exchange resin (H+ form). Elution with water containing 2% pyridine gave 0.98 g of a crude diastereomeric product. Crystallization from water gave a solid which was recrystallized from methanol to yield 0.36 g (22%) of 2-(1-carboxy-3-phenylpropylamino)-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (racemate A) in the form of a white solid of melting point 233°-235° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](O)=[O:29].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:28]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)=[O:29])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccco1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(N)c2)COC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(NC(=O)c3ccco3)c2)COC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
[5-(3-Amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (264 mg, 0.865 mmol), furan-2-carboxylic acid (107 mg, 0.951 mmol) and HOBT (172 mg, 1.124 mmol) were dissolved in dichloromethane under N2 at 0° C. DIPEA (112 mg, 0.865 mmol) and EDC (182 mg, 0.951 mmol) were added. The mixture was stirred at 0° C. for 10 min, then allowed to warm to room temperature, stirred for 17 h at room temperature, quenched with 1M aqueous KHCO3 solution and extracted with dichloromethane. The organic phase was washed with water and brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc) to yield the title compound in the form of a colourless solid. 1H-NMR (400 MHz, DMSO-d6): 9.86 (br, 1H), 9.27 (br, 1H), 7.83 (d, 1H), 7.69 (m, 2H), 7.30 (m, 2H), 7.15 (dd, 1H), 6.65 (m, 1H), 4.40-4.30 (m, 2H), 3.75-3.55 (m, 2H), 1.52 (s, 3H), 1.44 (s, 9H); MS: 400 [(M+H)+].