Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[C:28]4[C:23](=[CH:24][N:25]=[C:26](Br)[CH:27]=4)[N:22]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[N:21]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:42][CH2:43][CH3:44])(=[O:41])[CH2:37][C:38]([O-:40])=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+].N1C=CC=[CH:53][C:52]=1C(O)=O>O1CCOCC1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[C:16]([C:20]3[C:28]4[C:23](=[CH:24][N:25]=[C:26]([CH:37]([C:38]([O:40][CH2:52][CH3:53])=[O:39])[C:36]([O:42][CH2:43][CH3:44])=[O:41])[CH:27]=4)[N:22]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[N:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccccn1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(Br)cc34)n2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1cc2c(-c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)n3)nn(C3CCCCO3)c2cn1
Temperature: 100 °C
Yield: 47 %

Procedure:
A mixture of 218 mg (0.40 mmol) of 4-{6-[5-Bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester, 1.22 mL (8.02 mmol) of Ethyl malonate, 76 mg (0.40 mmol) of copper(I) iodide, 654 mg (2.006 mmol) of cesium carbonate and 99 mg (0.80 mmol) of picolinic acid in 4.0 ml of 1,4-dioxane was degassed and then heated for 24 hours at 100° C. The mixture was filtered and the filtrate concentrated in vacuum. The residue was partitioned between ethyl acetate and water, the organic extracts were washed consequently with saturated aqueous NaHCO3, 5% aqueous citric acid, water, brine, dried over MgSO4 and concentrated. The residue was purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 117 mg (47%) of Diethyl 2-(3-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)malonate. ESI MS m/z 623.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:26]([O:33][CH2:34]I)(=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[I-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH2:34][O:33][C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reactant: CCCCCC(=O)OCI
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OCOC(=O)CCCCC)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.9 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate (2.0 g) in N,N-dimethylformamide (20 ml) were added iodomethyl hexanoate (3.4 g) and sodium iodide (3.1 g) in a stream of nitrogen, and the mixture was stirred at ambient temperature for 1.5 hours. After the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (200 ml), the organic layer was separated out, washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate, followed by treating with charcoal. The filtrate was concentrated, and thereto was added diisopropyl ether, followed by collecting the precipitated substance by filtration to obtain hexanoyloxymethyl 7-[2-(2-aminothiazol-4-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate (1.5 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[N:12]1([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.C(O)CO>O>[N:4]1[C:3]([CH2:2][N:15]2[CH2:16][CH2:17][N:12]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:13][CH2:14]2)=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: OCCO
Product: NS(=O)(=O)c1ccc(N2CCN(Cc3cn4ccccc4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 62.5 %

Procedure:
A mixture of 2-(chloromethyl)imidazo[1,2-a]pyridine (0.495 g), 4-(piperazin-1-yl) benzenesulfonamide (0.717 g), triethylamine (0.456 mL), and ethylene glycol (6 mL) is stirred at 80° C. for 1.5 h. After cooling, water is added and the resulting solid is collected and washed with water and toluene. Chromatography on silica gel using methanol/dichloromethane (6/94) yields 0.69 g of the title compound; mp 238-242° C.; IR (mineral oil) 1150, 1152, 1331, 1308, 1508 cm-1. 1H NMR (DMSOd6) δ2.61. 3.28, 3.66, 6.86, 7.02, 7.06, 7.20, 7.49, 7.61, 7.85, 8.50.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH:15]([NH:18][C:19]([C@@H:21]1[C@H:26]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[C:29]=2[NH2:36])[C@@H:25]2[CH2:37][C@H:22]1[CH:23]=[CH:24]2)=[O:20])([CH3:17])[CH3:16].C([O-])(=O)C.[NH4+]>>[CH:15]([NH:18][C:19]([C@@H:21]1[C@H:26]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30]3[N:35]=[C:7]([C:6]4[S:5][C:4]([N:9]5[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10]5)=[N:3][C:2]=4[Cl:1])[NH:36][C:29]=23)[C@@H:25]2[CH2:37][C@H:22]1[CH:23]=[CH:24]2)=[O:20])([CH3:17])[CH3:16]
Reactant: O=Cc1sc(N2CCC(O)C2)nc1Cl
Reactant: CC(C)NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(C)NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3nc(-c4sc(N5CC[C@@H](O)C5)nc4Cl)[nH]c23)[C@H]2C=C[C@@H]1C2
Yield: 7 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-(3-hydroxy-pyrrolidin-1-yl)-thiazole-5-carbaldehyde (180.77 mg, 0.77687 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid isopropylamide (208.72 mg, 0.62149 mmol), and Ammonium acetate (95.813 mg, 1.2430 mmol) were reacted to produce 23.87 mg (7%) of the title compound. (300 MHz, DMSO-d6) 12.60 (s, 1H), 8.10 (d, J=7 Hz, 1H), 7.92 (s, 1H), 6.38-6.31 (m, 2H), 5.16 (m, 1H), 5.02 (T, J=17 Hz, 9 Hz, 1H), 4.44 (s, 1H), 3.88 (m, 1H), 3.54 (m, 3H), 2.83 (s, 1H), 2.76 (s, 1H), 2.55 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 2.10 (m, 1H), 1.96 (m, 1H), 1.38 (d, J=8 Hz, 1H), 1.06 (d, J=7 Hz, 3H), 0.99 (d, J=7 Hz, 3H). MS=548 (M+H), HPLC: 2.52 min. (G Method)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].[C:18]([OH:21])(=[S:20])[CH3:19].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][S:20][C:18](=[O:21])[CH3:19]
Reactant: CC(O)=S
Reactant: C=Cc1cccc(CC(=O)OC)c1C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)Cc1cccc(CCSC(C)=O)c1C(=O)OC
Temperature: 25 °C
Yield: 31.9 %

Procedure:
Nitrogen was bubbled through a solution of 2-methoxycarbonylmethyl-6-vinyl-benzoic acid methyl ester (1.31 g, 5.60 mmol), thioacetic acid (4.00 mL, 56.0 mmol), and AIBN (0.184 g, 1.10 mmol) in benzene (30 mL) for 3 h at rt to remove oxygen. The mixture was heated at reflux for 3 h. The solution was allowed to cool to rt and saturated aqueous NaHCO3 (100 mL) was added. The mixture was extracted with EtOAc (100 mL) and the organic layer was washed with H2O (100 mL) and brine (100 mL), then dried over MgSO4 and concentrated in vacuo. Flash chromatography on SiO2 (10% EtOAc/hexanes) provided 2-(2-acetylsulfanyl-ethyl)-6-methoxycarbonylmethyl-benzoic acid methyl ester as a yellow solid (0.555 g, 33%): 1H NMR (CDCl3): δ 2.40 (s, 3H), 2.94–2.99 (m, 2H), 3.13–3.18 (m, 2H), 3.75 (s, 3H), 3.78 (s, 2H), 3.99 (s, 3H), 7.25 (d, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=C[CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].CC[O:12]CC.[Li]CCCC.[CH3:20][N:21](C=O)C>C1COCC1>[Br:8][C:4]1[C:3]([CH3:9])=[C:2]([CH:7]=[O:12])[CH:20]=[N:21][CH:5]=1
Reactant: CN(C)C=O
Reactant: CCOCC
Reactant: Cc1c(Br)cccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(Br)cncc1C=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,6-Dibromotoluene (9.8 g, 39 mmol) in THF (300 mL) was stirred under N2 and was then cooled to −100° C. (ether/liquid N2). n-BuLi (16.4 mL, 41 mmol, 2.5 M in hexane) was then added drop wise and after stirring for 5 minutes DMF (4.5 mL, 58.6 mmol) was added. The reaction was stirred for a further 20 minutes and then for an hour at −78° C. The reaction was quenched with saturated aqueous NH4Cl and allowed to warm up to room temperature. The reaction was diluted with water and the pH adjusted to pH 7-8 with sat. aqueous NaHCO3. The mixture was evaporated in vacuo to remove the THF, and the product was then extracted with Et2O (×3). The combined organic layers were washed with brine and dried (MgSO4). The product was filtered and evaporated on vacuo to give 5-bromo-4-methyl-pyridine-3-carbaldehyde as a colourless solid which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]1([C:25]2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][NH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C)C=O>O>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:27]2[CH:28]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:26]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
Sodium hydride (60%, oily, 1.85 g) was added to a mixture of 4-benzyloxybenzyl chloride (10.8 g), ethyl 3-phenyl-1H-pyrazole-4-carboxylate (10.0 g) and N,N-dimethylformamide (50 ml) at 0° C., and the mixture was stirred for 1.5 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield ethyl 1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylate (15.3 g, yield: 80%). This was crystallized from ethyl acetate-diisopropyl ether. Melting point: 102–103° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])=[CH:21][C:22](Cl)=[O:23].COC1C=CC(C=O)=CC=1>ClCCl.O>[CH3:25][C:20](=[CH2:19])[CH2:21][C:22]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])=[O:23]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC(C)=CC(=O)Cl
Agent: COc1ccc(C=O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)CC(=O)OC/C=C(\C)CCC=C(C)C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of geraniol (225 ul, 1.29 mmol, 1.0 equivalent) and triethylamine (271 ul, 1.94 mmol, 1.5 equivalent) in dry dichloromethane (I ml) was cooled to −78 C and treated dropwise with 3,3-dimethylacryloyl chloride (159 ul, 1.43 mmol, 1.1 equivalent). After 3 h, the solution was diluted with water (1 ml) and dichloromethane (1 ml), and the cooling hath was removed. The mixture was extracted with dichloromethane (3×20 ml), and the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by radial chromatography (4 mm SiO2 plate; elute, 7% EatOAc-hexanes; product, fractions 4-6; 30 ml/fraction) afforded ##STR3## (301 mg, 1.27 mmol, 99% yield) as a clear oil: Rf starting material, 0.14; product, 0.51 (5:1 hexanes-EtOAc, anisaldehyde); FTIR (film) 2970, 2919, 2858, 1738, 1653, 1445, 1377, 1206, 1153, 987, 896 cm-1; sup. 1H NMR (400 MHz, CDCl3) δ 5.31-5.35 (m, 1H), 5.04-5.08 (m, 1H), 4.88 (bs, 1H), 4.83 (bs, 1H), 4.60 (s, 1H), 4.58 (s, 1H), 3.01 (s, 2H), 2.00-2.09 (m, 4H), 1.79 (s, 3H), 1.69 (s, 3H), 1.66 (s, 3H), 3.01 (s, 2H), 2.00-2.09 (m, 4H), 1.79 (s, 3H), 1.69 (s, 3H), 1.66 (s, 3H), 1.58 (s, 3H); .sup.13 C NMR (101 Mhz, CDCl3) δ 171.2, 142.2, 138.6, 131.7, 123.7, 118.2, 114.5, 61.4, 43.4, 39.4, 26.2, 25.6, 22.3, 17.6, 16.4; HRMS (EI, Pos) m/z calculated for [C15H24O2]+236.1776, found 236.1768.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].O=[C:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl[Sn](Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:8][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:18])[N:1]=[C:2]2[S:3][C:4]([CH3:9])=[CH:5][C:6]=12
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(C#N)c(N)s1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2sc(C)cc2c1N
Yield: 71.5 %

Procedure:
To a solution of 2-amino-5-methyl-3-thiophenecarbonitrile (5 g, 36.2 mmol), ethyl 3-oxobutanoate (5.49 mL, 43.4 mmol) in toluene (200 mL) was added SnCl4 (5.10 mL, 43.4 mmol). The resulting mixture was refluxed for 2 h after which the heater was switched off. SnCl4 (2.123 mL, 18.09 mmol) was added and the mixture refluxed for another 4 h. The solution was cooled and aqueous NaOH (5M) was added until the solution turned basic. Ethyl acetate (100 mL) was added and washed with water (3×30 mL). The organic layer was dried over MgSO4, filtered and solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane afforded the title compound (6.48 g). LCMS (A) m/z: 251 [M+1]+, Rt 0.74 min (acidic).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]1[C:8](=[O:9])[CH:7]=[CH:6][CH2:5]1.[C:10](=[O:20])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:11].O.O.O.O.O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Bi+3].O>ClCCl>[CH2:3]([CH:4]1[C:8](=[O:9])[CH2:7][CH:6]([NH:11][C:10](=[O:20])[O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:5]1)[CH:2]=[CH2:1]
Reactant: C=CCC1CC=CC1=O
Reactant: NC(=O)OCc1ccccc1
Agent: O=[N+]([O-])[O-]
Agent: [Bi+3]
Solvent: O
Solvent: ClCCl
Product: C=CCC1CC(NC(=O)OCc2ccccc2)CC1=O
Reaction time: 18 h

Procedure:
A solution of 5-(propene-3-yl)cyclopent-2-enone (4.28 g, 35 mmol) in dichloromethane (15 mL) was treated with benzyl carbamate (10.6 g, 70 mmol) and bismuth trinitrate pentahydrate (2.2 g, 4.5 mmol), stirred rapidly for 18 h, then diluted with dichloromethane (50 mL). The mixture was filtered through Celite® (rinse with dichloromethane) and the filtrate added directly to a silica gel column (˜550 cc). Elution first with 3:2 petroleum ether/dichloromethane afforded recovered starting material (1.01 g), then 4:1 heptane/ethyl acetate gave the subject compound (4.54 g, 47.5% uncorrected yield) as a pale yellow oil. NMR (CDCl3): δ 7.28 (br s, 5 H), 5.55-5.70 (m, 1 H), 5.03 (br s, 2 H), 4.90-5.10 (m, 2 H), 4.75-4.90 (m, 1 H), 4.10-4.30 (m, 1 H), 2.40-2.80 (m, 2 H), 2.15-2.40 (m, 2 H), 1.85-2.15 (m, 3 H). MS (M+Na): 296.0; MS (M−H2O+1): 256.0 (no M+1 visible).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:49]=[CH:48][C:12]([CH2:13][NH:14][C:15]2[N:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:18]=[C:17]([NH:27][C:28]3[CH:47]=[CH:46][C:31]([C:32]([NH:34][CH:35]([CH:40]4[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]4)[C:36]([O:38]C)=[O:37])=[O:33])=[CH:30][CH:29]=3)[N:16]=2)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].O.Cl>CC(C)=O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15]2[N:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:18]=[C:17]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH:35]([CH:40]4[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]4)[C:36]([OH:38])=[O:37])=[O:33])=[CH:46][CH:47]=3)[N:16]=2)=[CH:48][CH:49]=1
Reactant: COC(=O)C(NC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCCCCN)cc3)nc(OCC(F)(F)F)n2)cc1)C1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NCCCCCCOc1ccc(CNc2nc(Nc3ccc(C(=O)NC(C(=O)O)C4CCCNC4)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 85 °C
Yield: 81.7 %

Procedure:
A mixture of methyl 2-(4-(4-(4-(6-aminohexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-(piperidin-3-yl)acetate (50 mg) and K2CO3 (50.2 mg) in acetone (2 mL)/water (2 mL) was heated at 85° C. for 4 hours. After cooling to room temperature, the mixture was acidified with 1N HCl to pH=3. All the solvents were removed under vacuum. The residue was purified by preparative HPLC to give 2-(4-(4-(4-(6-aminohexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-(piperidin-3-yl)acetic acid (40 mg).
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[C:33]([O:36][CH2:37][C@@H:38]1[C@:46]2([CH3:47])[C@@:41]([OH:49])([CH2:42][C:43](=O)[CH2:44][CH2:45]2)[CH2:40][CH2:39]1)(=[O:35])[CH3:34]>C1COCC1.CCCCCC.O>[C:33]([O:36][CH2:37][C@@H:38]1[C@:46]2([CH3:47])[C@@:41]([OH:49])([CH2:42]/[C:43](=[CH:8]\[CH2:7][CH:3]3[O:2][CH2:6][CH2:5][O:4]3)/[CH2:44][CH2:45]2)[CH2:40][CH2:39]1)(=[O:35])[CH3:34].[C:33]([O:36][CH2:37][C@@H:38]1[C@:46]2([CH3:47])[C@@:41]([OH:49])([CH2:42]/[C:43](=[CH:8]/[CH2:7][CH:3]3[O:2][CH2:6][CH2:5][O:4]3)/[CH2:44][CH2:45]2)[CH2:40][CH2:39]1)(=[O:35])[CH3:34]
Reactant: c1ccc([P+](CCC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)OC[C@H]1CC[C@]2(O)CC(=O)CC[C@]12C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OC[C@H]1CC[C@]2(O)C/C(=C/CC3OCCO3)CC[C@]12C
Product: CC(=O)OC[C@H]1CC[C@]2(O)C/C(=C\CC3OCCO3)CC[C@]12C
Temperature: -25 °C
Reaction time: 1 h

Procedure:
To a suspension of 26.0 g of [2-(1,3-dioxolan-2-yl)ethyl]-triphenylphosphonium bromide in 300 ml of anhydrous THF, cooled at -25° C., 36 ml of 1.6N n-butyllithium in n-hexane were added, under a nitrogen atmosphere. After stirring for 1 hr, a solution of 5.0 g of (1S,3aS,7aR)-1-acetoxymethyl-3a-hydroxy-7a-methyl-5-perhydroindenone in 50 ml of anhydrous THF was added and the resulting mixture was stirred at -20° C. for 4 hrs, then at room temperature per 3 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) with methylene chloride/acetone 95:5 as the eluant to give 1.88 g of (1S,3aS,7aR)-1-acetoxymethyl-5-[(Z)-2-(1,3-dioxolan-2-yl)ethyliden]-7a-methyl-perhydroinden-3a-ol and 1.46 g of (1S,3aS,7aR)-1-acetoxymethyl-5-[(E)-2-(1,3-dioxolan-2-yl)ethyliden]-7a-methylperhydroinden-3a-ol as pale yellow oils.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([OH:10])[CH:7]([CH3:9])[CH3:8].[H-].[Na+].[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])C(=O)C=2C=1CBr>O>[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:5](=[O:1])[C:4]=2[C:3]=1[CH2:2][O:10][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CO
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)COCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To 5 ml of dehydrated tetrahydrofuran solution containing 1 ml of isobutanol was added 0.49 g of sodium hydride (60% dispersed material in mineral oil) under cooling in ice-bath, and the mixture was stirred at room temperature for 15 minutes. Then, 0.99 g (1.75 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added to the mixture under cooling in ice-bath, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.66 g of the title compound as a colorless oil. (Yield: 67%)
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:6]([N+:15]([O-])=O)=[CH:5][CH:4]=1.C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>CO.[Pd]>[CH3:1][N:2]([CH3:18])[C:3]1[N:8]=[C:7]2[N:9]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:24]([OH:25])=[N:15][C:6]2=[CH:5][CH:4]=1
Reactant: CCC(CC)Nc1nc(N(C)C)ccc1[N+](=O)[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Pd]
Solvent: CO
Product: CCC(CC)n1c(O)nc2ccc(N(C)C)nc21
Temperature: 25 °C
Yield: 57.4 %

Procedure:
To a solution of N6,N6-dimethyl-3-nitro-N2-(pentan-3-yl)pyridine-2,6-diamine (100 mg, 0.40 mmol) in MeOH (4 mL) was added a catalytic amount of Pd/C. The mixture was purged with hydrogen from a balloon fitted with a needle for 1 h. The resulting mixture was filtered through a pad of celite and concentrated in vacuo. The solid was then dissolved in THF (2 mL) and CDI (100 mg, 1.17 mmol) was added as a solid. After heating for 3 h, the reaction was cooled to room temperature. The excess CDI was quenched by the careful addition of water. The mixture was diluted with EtOAc and washed three times with water and once with brine. The solution was then dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (5%-25% EtOAc/hexanes) provided the title compound as a white solid (57 mg, 57%). m/z=249.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.C(OC[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C1OC1.O1CC1COC1CC2C(=CC=CC=2)C1>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH2:22][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:14][CH2:13]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Reactant: c1ccc(COCC2CO2)cc1
Agent: c1ccc2c(c1)CC(OCC1CO1)C2
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COCc2ccccc2)CC1

Procedure:
Compound 11 was prepared in a similar manner to compound 7, substituting the commercially available benzyl glycidyl ether for 2-(oxiran-2-ylmethoxy)indane in part D to afford 11. Mass Spectrum (M+1)=412.36.