Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClN1[C:42](=[O:43])CCC1=O>CO.C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:20])=[C:15]([CH3:18])[C@@H:16]([O:43][CH3:42])[S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CO
Product: CO[C@H]1S[C@@H]2[C@@H](NC(=O)Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a solution of diphenylmethyl 7α-phenyl-acetamido-3-methyl-3-cephem-4-carboxylate (2.88 g, 5.8 mmole) in 40 ml of methanol and 60 ml of methylene chloride, was added N-chlorosuccinimide (882 mg, 6.6 mmol) and the mixture was stirred for 90 minutes at room temperature. The reaction solution was then washed with brine (2X) and dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The resultant yellow foam (2.84 g) was chromatographed over 100 grams of silica gel employing 10-15% of ethyl acetate in toluene as the eluting solvent. The first fraction to elute from the column was the desired 2α-methoxy cephem compound which was subsequently recrystallized from a mixture of ethyl acetate and cyclohexane to give pure diphenylmethyl 7α-phenylacetamido-2α-methoxy-3-methyl-3-cephem-4-carboxylate. (638 mg, 21% yield) (m.p. 144°-145° C.) i.r. (CHCl3) 1780, 1725 and 1680 cm-1 ; n.m.r. (CDCl 3) δ1.95 (s, 3, CH3) 3.35 (s, 3, OCH3), 3.45 (s, 2, CH2Ph), 4.60 (s, 1, C2 --H), 4.70 (d, J=2 and 8 Hz, 1, C7 --H), 4.85 (d, J=2 Hz, 1, C6 --H), 6.95 (s, 1, CH2Ph), 7.3 (m, 16, aromatic H and N-H); u.v. (CHCl3) λmax 264 nm (ε=9726).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[C:5]([C:20](=[O:28])[NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:4][N:3]=1.[CH2:29]([NH:31][C:32]([NH2:34])=[O:33])[CH3:30].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1>[CH2:29]([NH:31][C:32](=[O:33])[NH:34][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[C:5]([C:20](=[O:28])[NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:4][N:3]=1)[CH3:30]
Reactant: CCOC(=O)c1ccc(Nc2cc(Cl)ncc2C(=O)Nc2cccnc2)cc1
Reactant: CCNC(N)=O
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(Nc2ccc(C(=O)OCC)cc2)c(C(=O)Nc2cccnc2)cn1
Temperature: 120 °C

Procedure:
Compound ii (210 mg, 0.53 mmol) and N-ethylurea (93 mg, 1.1 mmol) were dissolved in degassed dioxane (2 mL) under an atmosphere of nitrogen. Sodium tert-butoxide (102 mg, 1.1 mmol), X-phos (2-(Dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl, 50 mg, 0.1 mmol) and palladium(0)bis(dibenzylideneacetone) (50 mg, 0.05 mmol) were added sequentially. The mixture was heated at 120° C. in a microwave reactor for 60 min. The mixture was cooled to RT, filtered then evaporated to dryness. The residue was purified by flash chromatography (40 g GraceResolv silica cartridge, 0-15% MeOH in DCM) to yield Compound 15 as an off white solid (160 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 10.06 (s, 1H), 9.24 (s, 1H), 8.86 (s, 1H), 8.64 (s, 1H), 8.32 (d, J=4.8 Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.80 (m, 1H), 7.55 (s, 1H), 7.40 (d, J=8.8 Hz, 311), 4.32-4.27 (m, 2H), 3.17-3.14 (m, 2H), 1.34 (t, J=7.2 Hz, 3H), 1.12-1.09 (m, 3H). [M+H]+ m/z=449.16.
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH2:18]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C(C2C=CC=CC=2)N2CCN(C([C@@H](NC(=O)OC(C)(C)C)CC(C)C)=O)CC2)C=CC=CC=1>>[CH2:18]([N:27]1[CH2:32][CH2:31][N:30]([C:15]([C@@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:17])[CH2:29][CH2:28]1)[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C(=Cc1ccccc1)CN1CCNCC1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(CC=Cc2ccccc2)CC1
Yield: 86 %

Procedure:
Tert-butoxycarbonyl-L-leucine monohydrate (7.47 g) and 1-cinnamylpiperazine (6.06 g) were condensed in the same manner as employed in the preparation of tert-butyl (s)-1-(4-diphenylmethylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate to yield 10.7 g of tert-butyl (s)-1-(4-cinnamylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate as a colorless amorphous substance (yield: 86%).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=1[CH3:22])[OH:11])[CH2:2]2.[CH3:23][C:24]1[C:32]2[CH2:31][O:30][C:29](=[O:33])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH:34]1[CH2:36][O:35]1>CS(C)=O.O>[CH:1]12[N:8]([CH2:36][CH:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:29](=[O:33])[O:30][CH2:31][C:32]=4[C:24]=3[CH3:23])[OH:35])[CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=1[CH3:22])[OH:11])[CH2:2]2
Reactant: Cc1c(C(O)CN2CC3CCC(C2)N3)ccc2c1COC2=O
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C(O)CN2CC3CCC(C2)N3CC(O)c2ccc3c(c2C)COC3=O)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of isomer (37B) of 5-[2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one (45 mg, 0.149 mmol) and 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (57 mg, 0.210 mmol) in 2 mL DMSO was heated under microwave condition (150° C.) for 1 hr. After cooling to rt., the mixture was diluted with water (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated. The residue was purified by prep-TLC (MeOH/DCM=1:15) and then separated by SFC chiral chromatography to obtain two separated isomers C and D of 5,5′-[3,8-diazabicyclo[3.2.1]octane-3,8-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=2)[CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=2)[CH:12]=[C:13]([CH2:15][O:16][CH3:24])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1nc2c(OCc3ccccc3)cc(CO)cn2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of inert gas, a suspension of 1.2 g of 8-benzyloxy-6-hydroxymethyl-2,3-dimethylimidazo[1,2-a]pyridine in 12 ml of dimethylformamide is admixed with 0.36 g of 60% sodium hydride in paraffin, and the mixture is stirred at room temperature for 30 minutes, until the generation of gas has ceased, and then, at room temperature, admixed with 0.56 ml of methyl iodide. After a reaction time of one hour, the mixture is poured into 100 ml of ice-water and extracted three times with in each case 100 ml of ethyl acetate. The organic phases are combined and washed with water. The solvent is removed in vacuo and the oily residue is chromatographed on silica gel (mobile phase: methylene chloridelmethanol=100/1). This gives 0.34 g of the title compound of melting point 107° C. (diethyl ether).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CC([O-])(C)C.[K+].[C:18]([O:22][C:23](=O)[O:24]C(C)(C)C)([CH3:21])([CH3:20])[CH3:19].Cl>CN(C=O)C.O>[C:18]([O:22][C:23]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[C:10]([F:11])[CH:9]=2)[CH:5]=[CH:6]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Fc1cc2[nH]ccc2cc1Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2cc(Br)c(F)cc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of 2.1 g (9.81 mmol) 5-Bromo-6-fluoro-indole in 35 ml of DMF were added 1.54 g (13.76 mmol) KOtBu and 3.0 g (13.76 mmol) Di-tert.butylcarbonate, and the solution was stirred for 1 hr at room temperature and 30 min at 60° C. The mixture was poured into water, acidified with 2M aqueous HCl and extracted with Et2O. Drying of the organic layers with MgSO4, evaporation of the solvent, and chromatography on silica gel with hexane/EtOAc 49:1 gave 2.6 g (84%) 5-Bromo-6-fluoro-indole-1-carboxylic acid tert-butyl ester as a colorless liquid, MS: 313 (M, 1Br).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3](C)C.[C:7](Cl)(=[O:18])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.N1C(C)=CC(C)=C[C:21]=1C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:7](=[O:18])([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[O:6][CH:1]([CH2:2][CH3:3])[CH3:21]
Reactant: CC(C)CCO
Reactant: Cc1cc(C)nc(C)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
To a solution of isoamyl alcohol (1.0 g, 13.5 mmol) in CH2Cl2 (30 ml) is added 4-nitrophenyl carbonochloridate (3.2 g, 16.2 mmol), 2,4,6-collidine (2.14 ml, 16.2 mmol) and a catalytic amount of DMAP. After stirring for 2 h, 1N HCl is added and the aqueous layer is extracted with CH2Cl2, and the combined organic layers washed with 1N HCl, brine, and dried over Na2SO4. Evaporation of solvent and purification by flash chromatography (120 g SiO2, EtOAc/hexanes gradient) yields sec-butyl 4-nitrophenyl carbonate F5a as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ=8.27 (d, J=9.2 Hz, 2H), 7.38 (d, J=9.2 Hz, 2H), 4.85 (sextet, J=6.4 Hz, 1H), 1.82-1.62 (m, 2H), 1.37 (d, J=6.4 Hz, 3H), 1.00 (t, J=7.2 Hz, 3H); MS calcd. for [M+Na]+C11H13NaNO5: 262.1. found: 262.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14](=[O:24])[C:13]([C:25](=[O:56])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([NH:40][CH:41]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)[C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:35]=4[Cl:54])=[C:29]([F:55])[CH:28]=3)=[CH:12]2)=[O:8])[CH2:3][CH2:2]1.C=O.[C:59](O)(=O)C.[BH3-]C#N.[Na+]>C(#N)C>[CH3:59][N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14](=[O:24])[C:13]([C:25](=[O:56])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([NH:40][CH:41]([C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:35]=4[Cl:54])=[C:29]([F:55])[CH:28]=3)=[CH:12]2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccnc(NC(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1cn(COC(=O)C2CCNCC2)cc(-c2ccc(F)cc2)c1=O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: CN1CCC(C(=O)OCn2cc(C(=O)Nc3ccc(Oc4ccnc(NC(c5ccccc5)c5ccccc5)c4Cl)c(F)c3)c(=O)c(-c3ccc(F)cc3)c2)CC1
Reaction time: 0.5 h

Procedure:
To a mixture of (3-(4-(2-(benzhydrylamino)-3-chloropyridin-4-yloxy)-3-fluorophenylcarbamoyl)-5-(4-fluorophenyl)-4-oxopyridin-1(4H)-yl)methyl piperidine-4-carboxylate (60 mg, 0.077 mmol), formaldehyde (37% in water, 0.08 mL, 0.077 mmol) and acetic acid (0.03 mL, 0.077) in acetonitrile (2 mL) at rt was added, NaCNBH3 (50 mg, 0.8 mmol). The resulting mixture was stirred for 30 min. The solvent was removed in vacuo and the crude product residue was used directly in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[C:16]([NH2:29])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of acryloyl chloride (0.057 mL, 0.70 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of N-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine (Intermediate 118, 310 mg, 0.67 mmol) and DIPEA (0.127 mL, 0.73 mmol) in CH2Cl2 (40 mL), which was cooled in an ice/water bath to 0° C. The mixture was stirred while in the ice/water bath for 1 h and was then allowed to warm to r.t. The mixture was then held at r.t. for 18 h, and was then diluted with CH2Cl2 (100 mL). This solution was then washed with sat. NaHCO3 (200 mL) and the aqueous wash solution was extracted with CH2Cl2 (2×100 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound together with an impurity (172 mg, 50%) as a pale yellow solid. 120 mg of this material was purified by crystallisation from CH3CN to give the title compound (85 mg, 0.164 mmol) as a yellow solid without evidence of the impurity by NMR analysis. The mother liquors from the crystallization and a further impure fraction from the FCC (containing a 75:25 mixture of product:starting material) were combined, concentrated in vacuo and was purified by crystallisation from CH3CN to give more of the title compound (40 mg, 12%) as a tan solid; 1H NMR: 2.09 (6H, s), 3.03-3.12 (1H, m), 3.58 (2H, t), 3.78 (3H, s), 3.96 (2H, t), 5.66 (1H, dd), 6.16 (1H, dd), 6.25 (1H, s), 6.46 (1H, dd), 7.07 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 7.48 (1H, s), 8.24 (1H, s), 8.27-8.31 (1H, br s), 8.31 (1H, s), 8.46 (1H, d), 9.22 (1H, s), 11.79 (1H, s); m/z: ES+ MH+ 518.23.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[NH:5][C:4](=[O:8])[CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[C:18]1[O:19][CH:20]=[CH:21][CH:22]=1.[CH3:23][C:24]1([CH3:32])[CH2:29][CH2:28][C:27](=O)[CH2:26][C:25]1=[O:31]>>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[C:26]3[C:25](=[O:31])[C:24]([CH3:32])([CH3:23])[CH2:29][CH2:28][C:27]=3[NH:1][C:2]3[N:6]([CH3:7])[NH:5][C:4](=[O:8])[C:3]2=3)=[CH:12][C:11]=1[C:18]1[O:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(F)c(-c2ccco2)c1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Cn1[nH]c(=O)cc1N
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)C(C)(C)CC1)C2c1ccc(F)c(-c2ccco2)c1
Yield: 68.7 %

Procedure:
5-Amino-1-methyl-1,2-dihydropyrazol-3-one (0.11 g, 1 mmol), 4-fluoro-3-(2-furyl)-benzaldehyde (0.19 g, 1 mmol), and 4,4-dimethyl-1,3-cyclohexanedione (0.14 g, 1 mmol) were processed as described in Example 22 to provide 0.28 g (67%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.92 (s, 3H), 0.99 (s, 3H), 1.78 (t, 2H), 2.65 (m, 2H), 3.45 (s, 3H), 4.88 (s, 1H), 6.62 (m, 1H), 6.76 (m, 1H), 7.06 (m, 1H), 7.1 (t, 1H), 7.55 (dd, 1H), 7.81 (dd, 1H), 9.49 (s, 1H), 9.6 (s, 1H); MS (ESI−) m/z 406 (M−H)−; Anal. calcd for C23H22N3FO3: C, 67.80; H, 5.40; N, 10.3. Found: C, 68.05; H, 5.39; N, 10.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([OH:17])=O)[CH2:10]2)=[CH:5][CH:4]=1.Cl.Cl.N[CH:23]1[CH2:26][NH:25][CH2:24]1.C([N:30](C(C)C)CC)(C)C>C(#N)C.CO>[NH2:30][CH:10]1[CH:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[CH2:13][N:12]([CH3:14])[CH:11]1[C:15]([N:25]1[CH2:26][CH2:23][CH2:24]1)=[O:17]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Reactant: NC1CNC1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: COc1ccc(CSC2CN(C)C(C(=O)N3CCC3)C2N)cc1
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
1.62 g of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-pyrrolidinecarboxylic acid were suspended in 20 ml of dry acetonitrile, and 1.02 g of N,N'-carbonyldiimidazole were added to the suspension, after which the mixture was stirred at 40° C. for 45 minutes. A solution of 1.00 g of 3-aminoazetidine dihydrochloride and 2.40 ml of diisopropylethylamine in 10 ml of methanol was added dropwise to the mixture, whilst ice-cooling, and the mixture was stirred at the same temperature for 90 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The resulting residue was subjected to reverse phase column chromatography (Cosmosil 75C18 -PREP, manufactured by Nacalai Tesque, 145 g) to give 1.21 g of the title compound, as a colorless oil, from the fraction obtained by solution with 30% by volume aqueous acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH:27]1([NH:30][C:24]([C:21]2[CH:22]=[CH:23][C:18]3[N:19]([C:15]([CH2:14][O:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[N:16][N:17]=3)[CH:20]=2)=[O:25])[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: COc1ccc2c(OCc3nnc4ccc(C(=O)O)cn34)ccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(OCc3nnc4ccc(C(=O)NC5CC5)cn34)ccnc2c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.047 g, 0.13 mmol), cyclopropanamine (0.011 ml, 0.16 mmol), 1-hydroxy-7-azabenzotriazole (0.018 g, 0.13 mmol), and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride, (0.039 g, 0.20 mmol) were added to a reaction flask then suspended in DMF (1 mL). N-Ethyldiisopropylamine (0.070 ml, 0.40 mmol) was added to the reaction mixture. The clear reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated under vacuum then triturated with water. The solid was collected on a glass frit, washing with water. The sample was purified by preparative TLC eluting with 8% 7N ammonia in methanol/dichloromethane to afford N-cyclopropyl-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (0.023 g, 44% yield) as a tan solid. MS (ESI pos. ion) m/z: 390.2 (MH+).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])[CH2:2][C:3]#[CH:4].O1CCCC1.[C:21]1([C:27]2[S:28][CH:29]=[C:30](Br)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>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.[Cu](I)I.C(N(CC)CC)C>[C:21]1([C:27]2[S:28][CH:29]=[C:30]([C:4]#[C:3][CH2:2][CH2:1][N:5]3[C:9](=[O:10])[C:8]4[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:6]3=[O:15])[N:31]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Brc1csc(-c2ccccc2)n1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To 221 mg of dichlorobis(triphenylphosphine)palladium, 60 mg of copper iodide, and 1.24 g of N-(3-butynyl)phthalimide were added 15 ml of tetrahydrofuran, 1.50 g of the 2-phenyl-4-bromothiazole obtained in the foregoing stage, and 3.8 ml of triethylamine in a nitrogen atmosphere, and the mixture was stirred under reflux for 4 hours. After the stifling, the reaction mixture was cooled to room temperature and the solids were filtered. After concentrating the filtrate, the residue was purified by column chromatography (Wakogel C-200; toluene:ethyl acetate=9:1) to give 1.24 g of a phthalimide compound.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:30][C:31]([CH2:33][Cl:34])=[O:32])C=CC=CC=1>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])[C:14]2=[CH:30][C:31]([CH2:33][Cl:34])=[O:32])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Reactant: O=C(CCl)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2C(=CC(=O)CCl)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 6.6 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 150 ml of benzene is treated at room temperature with 9 g of triphenylchloroacetonylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (7:3). There is obtained methylene-(2S,5R)-6-(3-chloroacetonylidene)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as an orange oil [Rf: 0.4; cyclohexane/ethyl acetate (6:4); NMR (CDCl3), δ (ppm); 1.21 (9H); 1.51 (3H); 1.57 (3H); 4.25 (2H); 4.65 (1H); 5.9 (m, 2H); 6.1 (1H); 6.93 (1H)].
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].N1C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:22](=[O:23])[NH:21][N:20]=[C:19]1[C:24]1[S:40][C:27]2[C:28]3[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=1>C1COCC1.O>[NH2:3][CH2:2][CH2:1][NH:4][C:37]([C:34]1[CH:35]=[CH:36][C:28]2[C:27]3[S:40][C:24]([C:19]4[N:18]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=5[Cl:11])[C:22](=[O:23])[NH:21][N:20]=4)=[CH:25][C:26]=3[CH2:32][CH2:31][O:30][C:29]=2[CH:33]=1)=[O:38]
Reactant: O=C(Cl)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Reactant: NCCN
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: NCCNC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of ethane-1,2-diamine (82 mg, 1.36 mmol) and pyridine (0.5 mL) in 5 mL of THF was slowly added 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonyl chloride (ca. 417 mg, ca. 0.91 mmol) in 20 mL of THF at 0° C. The mixture was stirred at room temperature overnight, diluted with water and purified by preparative HPLC to afford 66 mg of 533, isolated yield: 20%. ESI-MS: 482. 1H NMR (DMSO-d6, 400 MHz): δ 8.74 (s, 1H, NH), 8.37 (s, 1H, NH), 7.74-7.47 (m, 7H, ArH), 6.47 (s, 1H, ═CH), 4.19 (t, J=4.8 Hz, 2H, CH2), 3.40-3.36 (m, 4H, 2CH2), 2.98 (t, J=5.2 Hz, 2H, CH2), 2.86 (t, J=6.0 Hz, 2H, CH2).