Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5](I)[CH:4]=1)#[N:2].C(N(CC)CC)C.[C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[N:31][CH:32]=1)#[CH:26]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:12]([O:11][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[C:26]#[C:25][C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH:30]=[N:31][CH:32]=1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: C#Cc1cncc(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc(C#N)ccc2NC(=O)OC(C)(C)C)c1
Reaction time: 0.08 h
Yield: 52.8 %

Procedure:
Into a reaction flask were added tert-butyl (4-cyano-2-iodophenyl)carbamate (1.4 g, 4.1 mmol), copper(I) iodide (31 mg, 0.16 mmol), bis(triphenylphosphine)palladium(II) chloride (0.12 g, 0.16 mmol), tetrahydrofuran (10 mL), and triethylamine (0.63 mL, 4.5 mmol). The mixture was stirred under N2 bubbling for 5 minutes and tert-butyl (5-ethynylpyridin-3-yl)carbamate (0.90 g, 4.1 mmol) (prepared according to Example 17, Step B) was then added. The reaction mixture was stirred at 65° C. for 2 hours. The solvent was removed under vacuum and the residue was diluted with EtOAc and water. After separation, the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude was purified by silica gel column chromatography to give the desired product (0.94 g, 52%). LCMS for C24H27N4O4 (M+H)+: m/z=435.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH2:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[CH:14]1.[Br:24]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH2:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]1[Br:24]
Reactant: Nc1c(SC(F)(F)F)ncn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Nc1c(SC(F)(F)F)nc(Br)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
To a solution of 1.35 g (3.40 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-amino-4-trifluoromethylsulfenylimidazole in 20 ml of chloroform was added 0.5 ml (9.76 mmole) of bromine. The resulting mixture was stirred at RT under a nitrogen atmosphere for 2 hr. The mixture was then evaporated to remove the excess of bromine and the residue was partioned between water and methylene chloride. The organic layer was dried over anhydrous sodium sulfate and solvent was removed. The residue was purified by flash column chromatography on silica gel using 7% ethyl acetate in hexane to give 200 mg (13.62% yield) of the desired product, mp 154° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[C:20]([O:19][C@@H:18]1[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[O:29][C@H:17]1[N:6]1[C:5]2[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([Cl:11])[C:4]=2[N:3]=[C:2]1[Cl:1])(=[O:22])[CH3:21]
Reactant: Clc1cc(Cl)c2[nH]c(Cl)nc2c1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3c(Cl)cc(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
To a suspension of 1.362 g (6.15 mmol) of 2,4,6-trichlorobenzimidazole in 31 mL of MeCN, was added 1.52 mL (6.15 mmol) of BSA. The reaction mixture was stirred at 80° C. for 15 min to give a clear solution. This solution was treated with 2.153 g (6.675 mmol) of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose and 1.426 mL (7.380 mmol) of TMSOTf at 80° C. for 1 h. The reaction mixture was cooled and diluted with EtOAc (150 mL). The EtOAc solution was washed with sat. NaHCO3 solution (150 mL×2), sat. NaCl solution (150 mL), dried (Na2SO4), and evaporated. The residue was coevaporated with MeOH and then suspended in 50 mL of hot MeOH. The suspension was cooled, filtered, and the solid product was washed with MeOH to give 2.103 g of 80 as white crystals (This product showed one spot on TLC). The mother liquor was evaporated and the residue was chromatographed on a silica column (2.5×20 cm, eluted with CHCl3 and 0.5% MeOH/CHCl3). Evaporation of fractions 20-24 (20 mL per fraction) and recrystallization from MeOH gave an additional 0.258 g of 80 as white crystals. The total yield of 80 was 2.361 g (80%). MP: 198°-200° C. MS: (El) m/e 480.0069 (4%, for C18H1735ClN237ClN2O7 : M+ =480.0072). 1 H NMR (DMSO-d6): δ7.89 (d, 1, 7-H, J7-5 =2.0 Hz), 7.58 (d, 1, 5-H), 6.26 (d, 1, 1'-H, J1'-2' =7.0 Hz), 5.54 (t, 1, 2'-H, J2'-3' =7.0 Hz), 5.44 (dd, 1, 3'-H, J3'-4' =4.5 Hz), 4.48, 4.38 (2×m, 3, 4'-H and 5'-H), 2.14, 2.02 (2×s, 9, 3×Ac). 13H NMR (DMSO-d6): δ169.84, 169.37, 169.09 (3×COCH3), 140.91 (C2), 137.39 (C3a), 134.14 (C7a), 128.47 (C6), 123.66 (C4), 123.25 (C5), 111.06 (C7), 86.91 (C1'), 79.58 (C4'), 70.54 (C2'), 68.55 (C3'), 62.47 (C5'), 20.48, 20.19, 19.90 (3×COCH3). Anal. Calcd. for C18H17Cl3N2O7 : C, 45.07; H, 3.57; N, 5.84. Found: C, 45.08; H, 3.62; N, 5.87.
Reaction SMILES: [NH2:1][OH:2].C[O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]2[CH:18]=[N:19][CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1)=O>CO>[OH:2][NH:1][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]2[CH:18]=[N:19][CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: NO
Reactant: COC(=O)CCCCCc1cccc2cncn12
Solvent: CO
Product: O=C(CCCCCc1cccc2cncn12)NO
Reaction time: 20 h

Procedure:
A solution of hydroxylamine (from 2.06 g of hydroxylamine hydrochloride and 2.02 g of sodium hydroxide) and 5-(5-methoxycarbonylpentyl)imidazo[1,5-a]pyridine (6.08 g) in 25 ml of methanol is allowed to stand at room temperature for 20 hours. The methanol is evaporated and the residue is taken up in 5 ml of water and adjusted to pH=7. The resulting oil crystallizes and the solid is collected, yielding 5-[5-(hydroxycarbamoyl)pentyl]-imidazo[1,5-a]-pyridine, m.p. 138°-140°.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:31]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>C(#N)C>[CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][Br:31])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Solvent: O
Solvent: CC#N
Product: BrCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a solution of 4′-(2-benzylbenzofuran-3-yl)biphenyl-4-methanol (5.01 g, 12.7 mmol) in anhydrous acetonitrile (75 mL) was added dibromtriphenylphosphorane (5.45 g, 12.7 mmol) as a solid portionwise over 15 mins. The reaction was stirred for 2 hours (TLC control) and then poured into water (100 mL) and extracted with diethyl ether (3×100 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the title compound as an off-white solid (4.98 g, 87%): 1H NMR (CDCl3, 300 MHz): δ 7.70 (2H, m, Ar—H), 7.63 (4H, m, Ar—H), 7.50 (3H, m, Ar—H), 7.30 (4H, m, Ar—H), 7.25 (4H, m, Ar—H), 4.57 (2H, s, CH2Br), 4.26 (2H, PhCH2).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH2:8])[CH2:5][CH2:6][CH3:7].C([O:11][C:12](=O)[C:13]([C:15]1[CH:23]=[CH:22][C:18]2[O:19][CH2:20][O:21][C:17]=2[CH:16]=1)=[O:14])C>C(O)C>[O:19]1[C:18]2[CH:22]=[CH:23][C:15]([C:13](=[O:14])[C:12]([NH:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])=[O:11])=[CH:16][C:17]=2[O:21][CH2:20]1
Reactant: CCCC(N)CCC
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)OCO2
Solvent: CCO
Product: CCCC(CCC)NC(=O)C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
4-Heptylamine (2.5 g, 22 mmol) was added to a stirred solution of benzo[1,3]dioxol-5-yl-oxo-acetic acid ethyl ester (2 g, 9 mmol)) in ethanol (40 ml)) at room temperature. The resulting reaction mixture was heated to reflux for 4 hours. Then ethanol was distilled off and stirring was continued at 110° C. for 2 hours. The reaction mixture was cooled to room temperature and then 50 ml of THF and 100 ml of aqueous HCl solution were added and stirred for 30 minutes. The mixture was extracted twice with DCM (50 ml). The organic layer was washed twice with water (50 ml) and concentrated in vacuum. The crude product was chromatographed on a silica gel column using ethylacetate/heptane (2:3) as eluent to provide the title compound (0.5 g, 29% yield) as red crystals.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([N:15]([CH2:24][CH3:25])[CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]([OH:23])=O)[CH3:14].[NH2:26][C:27]1[CH2:33][N:32]=[C:31]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])[C:30]2[CH:42]=[C:43]([N+:46]([O-:48])=[O:47])[CH:44]=[CH:45][C:29]=2[N:28]=1>O1CCCC1.CN(C)C=O>[N+:46]([C:43]1[CH:44]=[CH:45][C:29]2[N:28]3[C:19]([CH2:18][CH2:17][CH2:16][N:15]([CH2:13][CH3:14])[CH2:24][CH3:25])=[CH:20][C:21](=[O:23])[N:26]=[C:27]3[CH2:33][N:32]=[C:31]([C:34]3[C:35]([F:41])=[CH:36][CH:37]=[CH:38][C:39]=3[F:40])[C:30]=2[CH:42]=1)([O-:48])=[O:47]
Reactant: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2c(F)cccc2F)=NC1
Reactant: CCN(CC)CCCC#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN(CC)CCCc1cc(=O)nc2n1-c1ccc([N+](=O)[O-])cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 21, carbonyldiimidazole, 6-diethylamino-2-hexynoic acid and 2-amino-7-nitro5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine was stirred in tetrahydrofuran-dimethylformamide to give 9-nitro-1-(3-diethylaminopropyl)-7-(2,6-difluorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11][C@H:10]1[CH2:25][N:26]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[O:50][CH3:51])[CH2:27][C:28](=O)[CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)(C)(C)C.[C:52]([O:55][CH2:56][CH3:57])(=[O:54])C>>[CH2:56]([O:55][C:52]([N:12]1[CH2:13][CH2:14][N:9]2[C@H:28]([CH:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:27][N:26]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[O:50][CH3:51])[CH2:25][C@@H:10]2[CH2:11]1)=[O:54])[C:57]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1CN(CC(=O)C(c1ccccc1)c1ccccc1)C[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: COc1ccccc1CN1C[C@@H]2CN(C(=O)OCc3ccccc3)CCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h

Procedure:
4N Hydrogen chloride in ethyl acetate solution (3 ml) was added to a solution of (2R)-2-[[N-(2-methoxybenzyl)-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (160 mg) in ethyl acetate (3 ml) at room temperature. After being stirred for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved into dichloromethane (4 ml). Sodium triacetoxyborohydride (150 mg) was added to the stirred mixture and the whole was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (3:4) as an eluent to give (6R,9aR)-6-benzhydryl-8-(2-methoxybenzyl)octahydropyrazino[1,2-a]pyrazine-2-carboxylic acid benzyl ester (108 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][NH:26][N:25]=2)=[CH:20][CH:19]=1>C(OCC)C>[F:1][C:2]([F:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:26]2[CH2:27][CH:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:24]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)=[N:25]2)=[O:15])=[CH:9][CH:8]=1)[CH:3]([F:4])[F:5]
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Reactant: O=C=Nc1ccc(OC(F)(F)C(F)F)cc1
Solvent: CCOCC
Product: O=C(Nc1ccc(OC(F)(F)C(F)F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.7 g of 4-(1,1,2,2-tetrafluoroethoxy)phenylisocyanate were added, while stirring, to a suspension of 1.8 g of 3-(4-chlorophenyl)-4-phenyl-2-pyrazoline in 40 ml of dry diethyl ether. After stirring at room temperature for approximately 1 hour 40 ml of petroleum ether (40-60) were added to the reaction mixture, after which stirring at room temperature was continued for another 3 hours. The precipitate formed was sucked off and washed with petroleum ether (40-60). The desired product was obtained in a yield of 3.1 g; melting-point 178°-180° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:23][N:24](C)[CH:25]=[O:26]>>[CH3:23][NH:24][C:25](=[O:26])[NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
5-(4-Aminophenyl)-2(1H)-pyrazinone hydrochloride (1.0 g) was suspended in dimethylformamide (30 ml) and triethylamine (1.2 ml) was added. The dark solution was filtered. Methyl isocyanate (0.53 ml) was added and the mixture was stirred for 17 hours at room temperature. The mixture was evaporated to dryness and the black residue washed with water; the insoluble material was collected by filtration and then reprecipitated from dimethylformamide solution with water. The precipitate was filtered off and the filtrate evaporated to dryness. The cream-coloured residue was collected to afford the title compound, m.p. >300° C.; C12H12N4O2Calculated: C 59.01; H 4.95; N 22.94: Found: C 59.09; H 4.94; N 22.90: νmax (liquid paraffin) 1675, 1642 cm-1 ; N.m.r. δ(DMSO-d6) 2.76 (d, 3H, CH3), 5.98 (q 1H, --NHCH3), 7.91, 8.08 (2d, 2H, pyridine H's).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:6]=[CH:5]2.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]#[CH:41])=[CH:36][CH:35]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]#[C:41][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:6]=[CH:5]3)=[CH:38][CH:39]=1
Reactant: C#Cc1ccc(OCCCCCCOC2CCCCO2)cc1
Reactant: OCCCCCCOc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCCCCCOc1ccc2cc(C#Cc3ccc(OCCCCCCOC4CCCCO4)cc3)ccc2c1
Yield: 51.5 %

Procedure:
A degassed mixture of pure 6-(6-bromonaphthalen-2-yloxy)hexan-1-ol (5.88 g), 4-[6-(tetrahydropyran-2-yloxy)hexyloxy]phenyl acetylene (6.05 g), triphenylphosphine (0.21 g), copper(I) iodide (0.04 g) and bis(triphenylphosphine)palladium dichloride (0.14 g) in 60 ml of triethylamine was refluxed for 2 hours under an atmosphere of argon. The reaction mixture was cooled and filtered though celite to give a yellowish solution which was then evaporated to dryness to give a yellow residue, which was purified by chromatography using a silica gel column and cyclohexane/ethyl acetate (2:1, 1:1) as eluent, followed by recrystallisation of the resulting solid from cyclohexane/ethyl acetate (100 ml/3 ml) to give 5.10 g of 6-[6-[4-[6-(tetra-hydropyran-2-yloxy)hexyloxy]phenylethyny]naphthalen-2-yloxy]hexan-1-ol as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:22])=[CH:6][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[Cl:22][C:5]1[N:4]=[N:3][C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:9])[CH:6]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CNC(=O)c2cc(Cl)nnc2Cl)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNC(=O)c2cc(Cl)nnc2N2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3,6-dichloro-N-(3,4-dimethoxybenzyl)pyridazine-4-carboxamide (1-2, 0.100 g, 0.292 mmol, 1.0 equiv) in chloroform (0.97 mL) at 25° C. was added morpholine (0.0252 g, 0.292 mmol, 1.0 equiv) and the reaction mixture was stirred for 24 hours at 25° C. The reaction mixture was directly purified by normal phase column chromatography (15 to 100% EtOAc in hexanes) to give the product as a yellow solid. ESI+MS [M+H]+ C18H21ClN4O4: 393.2 found, 393.1 required.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:5][CH:6]=1.[N:21]1([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]3)[CH:25]=[N:24][CH:23]=[N:22]1>>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([O:7][C:4]2[S:5][CH:6]=[C:2]([N:31]3[C:32]4[C:28](=[CH:27][C:26]([N:21]5[CH:25]=[N:24][CH:23]=[N:22]5)=[CH:34][CH:33]=4)[CH:29]=[CH:30]3)[N:3]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc(Br)cs2)CC1
Reactant: c1ncn(-c2ccc3[nH]ccc3c2)n1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(-n3ccc4cc(-n5cncn5)ccc43)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-Butyl 4-((4-bromothiazol-2-yl)oxy)piperidine-1-carboxylate (intermediate 46) and 5-(1H-1,2,4-triazol-1-yl)-1H-indole (intermediate 58).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=3[CH:24]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:9][N:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=3[CH:24]=2)[C:11](=[O:13])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
[5-Oxo-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (1.02 g, 2.94 mmol) was added to a solution mixture of trifluoroacetic acid (10 ml) and dichloromethane (10 ml), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in water and neutralized by adding a saturated sodium hydrogen carbonate aqueous solution. The solvent of the mixture was removed under reduced pressure and the obtained residue was purified by NH-silica gel column chromatography (chloroform/methanol) to yield 642 mg (88%) of the title compound in the form of a light brown solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([CH2:15][CH2:16][OH:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:7]([CH2:15][CH2:16][O:17][CH3:26])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1
Reactant: COCOc1cc(CCO)c(-c2ccccc2)c(OCOC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCc1cc(OCOC)cc(OCOC)c1-c1ccccc1
Temperature: 4 °C
Reaction time: 0.07 h
Yield: 89.4 %

Procedure:
2-[3,5-Bis(methoxymethoxy)-2-phenylphenyl]ethanol (1.2 g, 3.7 mmol) obtained in Example 3, Step 3 was dissolved in N,N-dimethylformamide (15 mL), and a 60% sodium hydride dispersion in mineral oil (0.30 g, 7.5 mmol) was added thereto in an atmosphere of nitrogen, followed by stirring at 4° C. for 4 minutes. After methyl iodide (0.70 mL, 11 mmol) was added dropwise to the reaction mixture, the mixture was stirred at 4° C. for 1 hour, followed by further stifling for 48 hours, while the temperature of the mixture was raised to room temperature. To the reaction mixture was added water (10 mL) and a saturated aqueous solution of ammonium chloride (20 mL), and the mixture was extracted with ethyl acetate (0.10 L). The organic layer was washed with water (0.10 L) and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain 3,5-bis(methoxymethoxy)-1-(2-methoxyethyl)-2-phenylbenzene (1.1 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:26](O)([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:26]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1ccc(CC(=O)O)c(OCc2ccccc2)c1
Reactant: CC(C)(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(CC(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
To a solution of [4-methyl-2-(phenylmethoxy)phenyl]acetic acid (10.25 g, 40 mmol) in toluene (70 ml containing 2 drops of DMF) was added oxalyl chloride (4.0 ml, 46 mmol, 1.15 equivalents) dropwise, the mixture was stirred at room temperature for 5 hr then 44 ml of tert-butanol was added, the resulting solution was stirred at room temperature for 20 hr. The solvents were evaporated and the residue obtained was purified by chromatography on silica gel (EtOAc-hexanes, 1:40 to 1:25) to provide the desired product [4-methyl-2-(phenylmethoxy)-phenyl]acetic acid tert-butyl ester as an oil (11.70 g, 92.80% yield). 1H NMR (CDCl3) δ: 7.521˜7.364 (5H, m), 7.147 (1H, d, J=7.81 Hz), 6.810 (2H, m), 5.118 (2H, s), 3.629 (2H, S), 2.391 (3H, s), 1.461 (9H, s) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[S:37]1[CH:41]=[CH:40][C:39](C2C=C(B(O)O)C=CC=2)=[CH:38]1>>[C@@H:24]1([N:6]([CH2:5][C:4]2[CH:34]=[CH:35][CH:36]=[C:2]([C:39]3[CH:40]=[CH:41][S:37][CH:38]=3)[CH:3]=2)[C:7]([C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[C:21]([OH:23])=[O:22])=[O:8])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: OB(O)c1cccc(-c2ccsc2)c1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(-c3ccsc3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 3-(3-thienyl)phenylboronic acid were processed as described in Example 85 to provide the title compound.