Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH3:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][C:19](=[CH2:22])[CH2:18][CH2:17]2)[C:13]([N+:23]([O-:25])=[O:24])=[CH:12][CH:11]=1>>[CH3:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][C:19]3([O:24][N:23]=[C:13]([C:12]#[C:8][C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][N:3]=4)[CH2:22]3)[CH2:18][CH2:17]2)[C:13]([N+:23]([O-:25])=[O:24])=[CH:12][CH:11]=1
Reactant: C=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Reactant: Cc1cccc(Br)n1
Product: Cc1ccc([N+](=O)[O-])c(N2CCC3(CC2)CC(C#Cc2ccccn2)=NO3)n1
Yield: 49.6 %

Procedure:
The title product was prepared replacing 2-iodopyridine for 2-bromo-6-methylpyridine following the procedure reported above for the compound of Example 3. Purification of the residue by automated flash liquid chromatography (Horizon®TM-Biotage) (Petroleum Ether-EtOAc gradient from 9:1 to 4:6). Yield: 49.6%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[C:10]2([CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[C:9](=[O:19])[NH:8][C:7]1=[O:20]>O>[CH3:5][N:6]1[C:10]2([CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[C:14]([N+:1]([O-:4])=[O:2])[CH:13]=3)[CH2:18]2)[C:9](=[O:19])[NH:8][C:7]1=[O:20]
Reactant: CN1C(=O)NC(=O)C12Cc1ccccc1C2
Reactant: O=[N+]([O-])O
Solvent: O
Product: CN1C(=O)NC(=O)C12Cc1ccc([N+](=O)[O-])cc1C2

Procedure:
To stirred fuming nitric acid (100 ml) was slowly added (±)-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (4.5 g, 20.9 mmol) in portions over 30 min. The reaction mixture was diluted with H2O (200 mL) and the precipitate was collected by filtration, washed with H2O and dried in vacuo to give the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [OH:1][CH:2]1[C:7](/[CH:8]=[CH:9]/[C:10]#[C:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:6]([CH3:23])[CH2:5][CH2:4][CH2:3]1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([O:1][CH:2]1[C:7](/[CH:8]=[CH:9]/[C:10]#[C:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:6]([CH3:23])[CH2:5][CH2:4][CH2:3]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1ccc(C#C/C=C/C2=C(C)CCCC2O)cc1
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)c1ccc(C#C/C=C/C2=C(C)CCCC2OC(=O)c2ccccc2)cc1

Procedure:
The title compound, a colorless oil, was prepared from ethyl (+)-(E)-4-(4-(6-hydroxy-2-methylcyclohex-1-enyl)but-3-en-1-ynyl)benzoate (Compound 1b, 30 mg, 0.097 mmol) and benzoyl chloride (0.041 mL, 0.35 mmol) as described in General Procedure D.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH2:17][CH2:18][OH:19])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][N:11]([CH2:17][CH2:18][OH:19])[CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: OCCN1CCNCC1
Product: Cn1ncc([N+](=O)[O-])c1N1CCN(CCO)CC1
Yield: 95 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 2-(piperazin-1-yl)ethanol gave 2-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazin-1-yl)ethanol as a cream solid (0.30 g, 95%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.78 (s, 3H), 3.67 (t, J=5.3 Hz, 2H), 3.26 (t, J=4.6 Hz, 4H), 2.72-2.62 (m, 6H). OH not seen
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][Cl:25])=[CH:22][CH:21]=1>CCO>[ClH:25].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][S:18][C:9]2[NH:8][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[CH:22][CH:21]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: Fc1ccc(CCl)cc1
Solvent: CCO
Product: Cl
Product: Fc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Temperature: 25 °C

Procedure:
A mixture of intermediate 25 (0.50 g, 1.9 mmol) and 4-fluorobenzyl chloride (0.47 mL, 0.3.93 mmol) in abs. EtOH (20 mL) is heated at 90° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 0.70 g of the product 197. 1H NMR (DMSO-d6) δ 11.37 (s, 2H), 7.75-7.65 (m, 2 H), 7.40-7.25 (m, 2 H), 7.15-6.95 (m, 6 H), 6.90-6.70 (m, 4 H), 5.78 (s, 2 H), 4.84 (s, 2 H); MS: m/z 363 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=2)[O:14][CH:15]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37].O>ClCCl>[C:36]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]([CH3:26])[CH3:27])[CH:17]=2)[O:14][CH:15]=1)(=[O:38])[CH3:37]
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3O)co2)cc1OC(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3OC(C)=O)co2)cc1OC(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 0.2 g quantity of the compound obtained in Example 223 and 0.1 ml of triethylamine were dissolved in 5 ml of dichloromethane, 0.1 ml of acetyl chloride was added to the obtained solution, and the mixture was stirred for 6 hours at room temperature. At the completion of the reaction, water was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate. The organic layer was washed twice with water, and the solvent was distilled off. The residue was purified using a silica gel column (n-hexane:ethyl acetate=2:1), and the obtained crude crystals were recrystallized with ethanol, thereby yielding 15 mg of white powdery 2-{3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propionyl}phenyl acetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH2:16][C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: CC#CCO
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 280 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 96 mg of 2-butyn-1-ol, to which 55 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 212 mg of 4-(2,3-difluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (83)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][C@@H:33]4[CH3:38])[C:25]4[CH2:31][CH2:30][NH:29][CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.N1([O:53][C:54](N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(O)=O.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:23]=[C:24]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][C@@H:33]4[CH3:38])[C:25]4[CH2:31][CH2:30][N:29]([CH:54]=[O:53])[CH2:28][C:26]=4[N:27]=3)=[CH:20][CH:21]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCNC2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=CO
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCN(C=O)C2
Reaction time: 1 h

Procedure:
(S)-6-(benzyloxy)-N-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyridin-2-amine (0.2684 g, 0.5277 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.226 g, 0.704 mmol) and Formic acid (0.0294 mL, 0.779 mmol) were combined then added dry N,N-Dimethylformamide (2.20 mL, 28.4 mmol) followed by N,N-Diisopropylethylamine (0.507 mL, 2.91 mmol). The reaction mixture stirred for 1 hour then concentrated and chromatographed through silica gel (12 g, 0-5% MeOH in dichloromethane). 1H NMR (500 MHz, DMSO) δ 9.33 (s, 1H), 8.20 (dd, J=7.4, 5.2, 2H), 7.70-7.65 (m, 2H), 7.54 (t, J=7.9, 1H), 7.47 (d, J=7.7, 2H), 7.39 (t, J=7.5, 2H), 7.32 (t, J=7.2, 1H), 6.47 (d, J=7.9, 1H), 6.27 (d, J=7.7, 1H), 5.39 (s, 2H), 4.58 (dt, J=18.2, 12.9, 2H), 4.41 (d, J=19.0, 1H), 4.08 (s, 1H), 3.89 (d, J=11.5, 1H), 3.80-3.51 (m, 5H), 3.44 (s, 1H), 2.73 (s, 1H), 2.69 (s, 1H), 1.30-1.18 (m, 3H). LC/MS-m/z+537.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([Si:15]([CH3:30])([CH3:29])[O:16][CH2:17][CH2:18]OC1C=CC(I)=CC=1C=O)(C)(C)C.C[Si]([NH:35][Si](C)(C)C)(C)C.C([Li])CCC.C[Si](Cl)(C)C.C(N(CC)CC)C.C(Cl)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:7]=[N:35][C:17]([O:16][Si:15]([CH3:30])([CH3:29])[CH3:11])=[CH2:18])[CH:9]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(I)cc1C=O
Reactant: O=Cc1cc(Cl)ccc1I
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: C=C(N=Cc1cc(Cl)ccc1I)O[Si](C)(C)C

Procedure:
In a manner similar to the method described in example 190b, 5-chloro-2-iodobenzaldehyde prepared in example 208a (3.97 g, 15 mmol) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (2.4 g, 15 mmol), n-butyllithium (2.5 M, 6 mL, 15 mmol), trimethylsilyl chloride (1.6 g, 15 mmol), triethylamine (2 g, 20 mmol) and acetyl chloride (1.5 g, 20 mmol) to give crude 1-(5-chloro-2-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.
Reaction SMILES: C([C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)(O)=O.[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)C=O)([O-:16])=[O:15].CC1C=CC(C(C)C)=CC=1>>[N+:14]([C:17]1[CH:24]=[C:23]([CH:13]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[C:10](=[O:11])[O:12]2)[CH:22]=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)c1cccnc1C(=O)O
Solvent: Cc1ccc(C(C)C)cc1
Product: O=C1OC(c2cccc([N+](=O)[O-])c2)c2ncccc21
Temperature: 180 °C
Yield: 37.2 %

Procedure:
A solution of 2,3-pyridinyldicarboxylic anhydride (20 g, 134 mmoles) in 25 ml of anhydrous methanol was refluxed for 30 minutes. The methanol was removed and the two positional isomers (2-carboxy-3-methoxycarbonylpyridine and 2-methoxycarbonyl-3-carboxypyridine) are isolated and separated. The 2-carboxy-3-methoxycarbonyl pyridine was added to a solution of 3-nitrobenzaldehyde (101.35 g, 670 mmoles) in p-cymene (105 ml, 670 mmoles) and heated at 180° C. for 13.5 hours. The solution was cooled, filtered and the excess 3-nitrobenzaldehyde and p-cymene removed by bulb to bulb distillation using a Kugelrohr apparatus. The residue was triturated with methylene chloride and the solid residue was discarded. The product was isolated from the filtrate yielding 12.7 g of 7-(3-nitrophenyl)-furo[3,4-b]pyridin-5-one (37.2%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][C:13]([OH:15])=O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].C(N1[CH:27]=[CH:26]N=C1)(N1C=CN=C1)=O.[OH-].[NH4+:29]>O1CCCC1.O>[C:10]1(=[O:11])[N:9]([CH:12]([C:27]2[CH:26]=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:13]([NH2:29])=[O:15])[C:7](=[O:8])[C:5]2=[CH:6][CH:1]=[CH:2][CH:3]=[C:4]12
Reactant: [NH4+]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C(c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirred solution of N-phthaloylglycine (2.50 g, 8.89 mmol) in tetrahydrofuran (50 mL) is added carbonyldiimidazole (1.50 g, 9.25 mmol) and a few crystals of 4-N,N-dimethylaminopyridine. The reaction is then heated to 50° C. for 45 minutes. After the reaction mixture had cooled to room temperature, 1 mL of concentrated ammonium hydroxide is added via syringe. The reaction is stirred for 1 hour, then diluted with 50 mL of water and partially concentrated to remove the majority of the tetrahydrofuran. The resulting slurry was filtered and the solid washed with copious amounts of water. The solid was dried in vacuo (60° C., <1 mm) to afford 1.9 g (76%) of α-phthalimidophenylacetamide as an off-white powder: mp 218°-220° C.; 1H NMR (DMSO-d6) δ 9.00-7.75 (m, 4 H, Ar), 7.61 (br s, 1 H, CONH2), 7.55-7.20 (m, 6 H, Ar, CONH2), 5.82 (s, 1 H, CHCO2); 13C NMR (DMSO-d6) δ 168.2, 167.1, 135.6, 134,5, 131.4, 129.4, 127.9, 127.7, 123.1, 56.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:28])[C:12]([NH:15][CH2:16][C:17]2[CH:27]=[CH:26][C:20]3[N:21]=[C:22]([S:24][CH3:25])[S:23][C:19]=3[CH:18]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](OC(OCC)OCC)C>C(O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]([CH2:16][C:17]3[CH:27]=[CH:26][C:20]4[N:21]=[C:22]([S:24][CH3:25])[S:23][C:19]=4[CH:18]=3)[CH:29]=[N:28][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CSc1nc2ccc(CNc3ccc(OCc4ccccc4)cc3N)cc2s1
Solvent: O=CO
Product: CSc1nc2ccc(Cn3cnc4cc(OCc5ccccc5)ccc43)cc2s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of 4-(benzyloxy)-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (2.49 g, 6.1 mmol) from the previous step, triethylorthoformate (60 mL), and formic acid (1.22 g) was stirred at 90° C. for 2 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 50% EtOAc in petroleum ether to 100% EtOAc to afford 6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.6 g, 62%) as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.50 (s, 1H), 7.44-7.49 (m, 2H), 7.30-7.40 (m, 4H), 7.26 (m, 1H), 7.13 (d, J=9.0 Hz, 1H), 6.98 (m, 1H), 5.41 (s, 2H), 5.10 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 418 (M+H)+.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[CH3:41][C:42]1[O:43][CH:44]=[CH:45][C:46]=1[S:47](Cl)(=[O:49])=[O:48]>O1CCCC1.O>[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21][N:22]([S:47]([C:46]2[CH:45]=[CH:44][O:43][C:42]=2[CH3:41])(=[O:49])=[O:48])[C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1occc1S(=O)(=O)Cl
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1occc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a suspension of sodium hydride (60% in oil, 34 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (0.17 mL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (210 mg) in tetrahydrofuran (1 mL) and 2-methylfuran-3-sulfonyl chloride (176 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:3) and basic silica gel column chromatography (eluent: hexane-ethyl acetate=17:3→1:1) to give the title compound as a pale-yellow oil (yield 187 mg, 61%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cu:9](I)I>C(O)C.[NH4+].[OH-].O>[C-:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cu+:9]
Reactant: I[Cu]I
Reactant: C#Cc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: [C-]#Cc1ccccc1
Product: [Cu+]
Reaction time: 0.5 h

Procedure:
To a solution of 10.7 g of phenylacetylene in 500 ml of absolute ethanol was added a solution of 20 g of copper iodide in 250 ml of conc. NH4OH and 100 ml of water. The solution was stirred 30 minutes and then filtered. The solid that was collected was washed with water, 95% aq. Ethanol and then ether. The solid was then collected and dried under vacuum to provide the title compound as a bright yellow solid.
Reaction SMILES: [C:1]([O:6]C(C12CC3CC(CC(C(OC(=O)C(C)=C)(C)C)(C3)C1)C2)(C)C)(=[O:5])C(C)=C.[CH:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2.[OH:39][C:40]12[CH2:49][CH:44]3[CH2:45][CH:46]([CH2:48][C:42]([OH:50])([CH2:43]3)[CH2:41]1)[CH2:47]2.S(=O)(=O)(O)[OH:52]>C(O)=O.ClCCCl>[OH:39][C:40]12[CH2:49][CH:44]3[CH2:45][CH:46]([CH2:48][C:42]([OH:50])([CH2:43]3)[CH2:41]1)[CH2:47]2.[C:29]12([C:42]([OH:50])=[O:52])[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][C:31]([C:1]([OH:6])=[O:5])([CH2:32]3)[CH2:30]1)[CH2:36]2
Reactant: O=S(=O)(O)O
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: C=C(C)C(=O)OC(C)(C)C12CC3CC(C1)CC(C(C)(C)OC(=O)C(=C)C)(C3)C2
Agent: OC12CC3CC(C1)CC(O)(C3)C2
Solvent: O=CO
Solvent: ClCCCl
Product: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2

Procedure:
The synthesis of 2-methacryloyloxy-2-(3-(2-methacryloyloxy-2-propyl)-1-adamantyl)propane was performed by the following method. First, according to the method described in Japanese Patent Application Laid-open No. 2002-167342, 100 g of 1,3-dihydroxyadamantane was synthesized from adamantane. Next, a four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a Dimroth condenser was charged with 100 g of 1,3-dihydroxyadamantane, 500 mL of 1,2-dichloroethane and 800 g of 96% sulfuric acid, and further 300 g of formic acid was dropped into the flask for 1 h. Thereafter, the contents of the flask were reacted at 25° C. for 10 h. The resultant reaction solution was filtered to separate precipitated crystals therefrom. The thus separated crystals were washed with water to obtain 140 g of 1,3-adamantanedicarboxylic acid.
Reaction SMILES: [CH:1]([O:14][C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[C:28](O)=[C:27]([Cl:30])[C:26]([Cl:31])=[C:25]([Cl:32])[C:24]=1[Cl:33].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[Cl:22][C:23]1[C:28]([O:20][C:19](=[O:21])[CH2:18][NH:17][C:15]([O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])=[C:27]([Cl:30])[C:26]([Cl:31])=[C:25]([Cl:32])[C:24]=1[Cl:33]
Reactant: O=C(O)CNC(=O)OC(c1ccccc1)c1ccccc1
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)OC(c1ccccc1)c1ccccc1)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
To a mixture consisting of 10 g. of N-benzhydryloxycarbonylglycine [this compound is reported in J. Am. Chem. Soc., 87, 3969 (1965)], 9.4 g. of pentachlorophenol, and 150 ml. of ethyl acetate, at 5° C., is added 7.3 g. of dicyclohexylcarbodiimide, and the resulting solution is kept at 5° C. for 5 hours and filtered. The filtrate is evaporated, and the residue is triturated with petroleum ether to give a solid precipitate of N-benzhydryloxycarbonylglycine pentachlorophenyl ester, which is isolated and dried; m.p. 171°-172° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.[OH:23][C:24]1([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:23][C:24]2([C:27]([O:29][CH3:30])=[O:28])[CH:26]=[CH:25]2)=[O:21])=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COC(=O)C1(O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1(OC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)C=C1
Reaction time: 14 h
Yield: 78.3 %

Procedure:
To a stirred solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetyl chloride (2.0 g, 6.557 mmol) in DCM (50 mL), DMAP (1.4 g, 13.114 mmol) was added followed by methyl 1-hydroxycyclopropanecarboxylate (1.1 g, 9.836 mmol) under a nitrogen atmosphere at RT and the mixture was stirred for 14 h. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with a saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude methyl 1-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetoxy)cyclopropenecarboxylate (2.0 g,) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]=[O:13])[CH:6]=1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[I:23].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C(#N)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[I:23])=[C:7]([CH:12]=[O:13])[CH:6]=1
Reactant: ClCc1ccccc1I
Reactant: COC(=O)Cc1ccc(O)c(C=O)c1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(OCc2ccccc2I)c(C=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (3-formyl-4-hydroxy-phenyl)-acetic acid methyl ester (17.2 g, 85.9 mmol) in acetonitrile was slowly added to a solution of 1-chloromethyl-2-iodo-benzene (13.06 g, 94.5 mmol) and Nal (3.22 g, 21.5 mmol) in acetonitrile (273 ml) at reflux temperature and the mixture was mantained at this temperature for 3 hours. Once the mixture reached room temperature, the residue that had formed was filtered, washed with acetonitrile and concentrated to obtain a residue that was then dissolved in toluene (330 ml) and washed with NaOH 0.1N and water. The organic layer was concentrated to dryness, diluted with acetone (330 ml) and was stirred into water (500 ml) at room temperature. The mixture was filtered and washed with water to obtain 33.959 (96%) of [3-Formyl-4-(2-iodo-benzyloxy)-phenyl]-acetic acid methyl ester, which was purified by crystallization in toluene-cyclohexane (99% HPLC)
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CO>[F:10][C:11]1[N:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccc(F)nc2)cc1
Temperature: 110 °C
Yield: 78 %

Procedure:
A mixture of 4-bromobenzonitrile (0.20 g, 1.1 mmol), (6-fluoropyridin-3-yl)boronic acid (0.15 g, 1.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (1:1) complex (0.04 g, 0.05 mmol) and potassium carbonate (0.46 g, 3.3 mmol) in 1,4-dioxane (7 mL), and water (3 mL) was heated at 110° C. for 2 h. After cooled to r.t., the mixture was diluted with MeOH, filtered, concentrated under reduced pressure and purified by flash chromatography on a silica gel column eluting with 5% MeOH in DCM to afford the desired product (0.17 g, yield: 78%). Analytic LCMS (M+H)+: m/z=199.2.