Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([N+:14]([O-])=O)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1>CO>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ncccc1N1CCC(F)CC1
Solvent: CO
Product: Nc1ncccc1N1CCC(F)CC1
Reaction time: 5 h

Procedure:
To a solution of 3-(4-fluoropiperidin-1-yl)-2-nitropyridine (2.0 g, 8.9 mmol) in methanol (25 mL) was added a generous spoon of rainey-nickel and the mixture stirred under an atmosphere of hydrogen for 5 hours. The reaction was then filtered over Hyflo and the solvent was evaporated in vacuo to afford the product used without need for further purification. The title compound was obtained as a dark brown solid (1.7 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][O:29][CH3:32])=[CH:26][CH:27]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CO)cc3)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-(4-hydroxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (133 mg, 0.306 mmol) in anhydrous DMF (2 mL) under nitrogen, add sodium hydride (60% dispersion, 13-15 mg, 0.375 mmol) at ambient temperature and continue sting for 30 min. Add methyl iodide (80 □L, 1.28 mmol). After 15 min, dilute with water, extract three times with EtOAc, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (15:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(4-methoxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil, which crystallizes on standing to a white solid (87 mg, 63%), along with recovered starting material (22 mg, 17%). Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 348 (M+H−Boc)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:11]1[NH:16][C:15](=[O:17])[C:14]([CH2:18][C:19]2[CH:20]=[N:21][C:22]([O:25]C)=[CH:23][CH:24]=2)=[CH:13][N:12]=1.[ClH:27]>C(O)C>[ClH:27].[ClH:27].[ClH:27].[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:11]1[NH:16][C:15](=[O:17])[C:14]([CH2:18][C:19]2[CH:20]=[N:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[CH:13][N:12]=1
Reactant: COc1ccc(Cc2cnc(NCCSCc3nccs3)[nH]c2=O)cn1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c(NCCSCc2nccs2)ncc1Cc1ccc(O)nc1

Procedure:
2-[2-(2-Thiazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone in 2N hydrogen chloride in ethanol was boiled under reflux for 24 hours. The mixture was evaporated to dryness and the residue was recrystallised from 2-propanol/ethanol containing hydrogen chloride to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(6-hydroxy-3-pyridylmethyl)-4-pyrimidone trihydrochloride, m.p. 200-204°.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[C:22](=[O:38])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]2=[O:36])=[CH:26][C:25]=1[F:37])=O)(C)(C)C.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[F:37][C:25]1[CH:26]=[C:27]([N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]2=[O:36])[CH:28]=[CH:29][C:24]=1[NH:23][C:22]([C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:12][NH:8]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CN[C@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,4S)-4-[(5-Chloro-thiophene-2-carbonyl)-amino]-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (30 mg) was dissolved in CH2Cl2 (1 ml) and TFA is added (1 ml). The mixture was stirred for 1 h at 25° C. and evaporated to dryness to yield (2S,4S)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide trifluoro-acetate (31 mg) as a colorless solid. MH+=461.3 (Cl-isotopes).
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1.[NH2:13][C:14]1[CH:15]=[C:16]([C:21]2[C:25]([Cl:26])=[C:24]([O:27][CH:28]([F:30])[F:29])[N:23]([CH3:31])[N:22]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]>O1CCCC1>[Cl:26][C:25]1[C:21]([C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([NH:13][C:10]([CH:7]3[CH2:9][CH2:8]3)=[O:11])[CH:15]=2)=[N:22][N:23]([CH3:31])[C:24]=1[O:27][CH:28]([F:30])[F:29]
Reactant: O=C(Cl)C1CC1
Reactant: Cn1nc(-c2ccc(Cl)c(N)c2)c(Cl)c1OC(F)F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1nc(-c2ccc(Cl)c(NC(=O)C3CC3)c2)c(Cl)c1OC(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1.0 g (13 mmol) of pyridine and 0.7 g (6.5 mmol) of cyclopropanecarbonyl chloride were added to a solution of 2.0 g (6.5 mmol) of 3-(3-amino-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole in 30 ml of tetrahydrofuran. The solution was stirred at room temperature overnight and at 50° C. for 2 hours, an then concentrated. The residue was taken up in ethyl acetate. The ethyl acetate was washed in succession with cold 1N hydrochloric acid, water and saturated sodium chloride solution, then dried over magnesium sulfate and finally concentrated. Yield: 2.2 g.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[K+]>CS(C)=O.C(OCC)C>[N:8]1[CH:9]=[CH:10][C:11]([O:14][N:20]2[CH2:21][CH2:22][CH2:17][CH2:18][CH2:19]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccncc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: c1cc(ON2CCCCC2)ccn1
Reaction time: 16 h
Yield: 159.7 %

Procedure:
To a solution of N-BOC-4-hydroxypiperidine (3.00 g, 14.9 mmol) in dimethylsulfoxide (10 mL) are sequentially added 4-chloropyridine hydrochloride (2.35 g, 15.6 mmol) and potassium-t-butoxide (30.5 mL of a 1.0 M solution in tetrahydrouran, 30.5 mmol). After 16 hr at ambient temperature, the reaction mixture is diluted with diethyl ether (100 mL) and washed with H2O (3×) and brine, and then dried over sodium sulfate Na2SO4). Concentration of the organic solution gives the desired 4-pyridyloxypiperidine (4.24 g, 100%) as a white solid. Analytical calculation for C15H22N2O3: C, 64.73; H, 7.97; N, 10.06. Found: C, 64.48; H, 8.14; N, 9.82.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:29])[C@H:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:28])=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:15][CH:14]=1)[CH3:11].[H-].[Na+].[CH3:32]I>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:32])[C:9](=[O:29])[C@H:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:28])=[CH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)[CH3:11]
Reactant: CI
Reactant: C[C@@H](Oc1ccc(OC(F)=Cc2ccccc2)cc1)C(=O)Nc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(OC(F)=Cc2ccccc2)cc1)C(=O)N(C)c1ccccc1F
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.3 %

Procedure:
0.4 g (1 mmol) of the compound obtained in Example 38 was dissolved in anhydrous tetrahydrofuran, and the mixture was cooled to 0° C. 40 mg (1 mmol) of 60% NaH and 0.14 g (1 mmol) of methyliodide were sequentially added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. Ice was added to the reaction mixture and resulting mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate:n-hexane=1:2) to obtain the title compound (300 mg, 73.3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17]Cl)[CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-n2c(CCl)nc3ccccc32)c1
Reactant: Nc1ccncc1
Solvent: CCO
Product: Fc1cccc(-n2c(CNc3ccncc3)nc3ccccc32)c1
Yield: 20.5 %

Procedure:
A ethanol (8 ml) solution of 1-(3-fluorophenyl)-2-chloromethylbenzimidazole (1.0 g, 4 mmol) prepared in the preceding step (b) and 4-aminopyridine (1.3 g, 7.4 mmol) was refluxed for 1.5 hours. The reaction mixture was concentrated in vacuo and crystallized from acetone and recrystallized from ethanol-acetone, then the objective compound (0.3 g, 0.82 mmol) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH:8]([OH:23])[CH:9]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1.Cl[CH2:25][CH2:26][CH3:27].[OH-].[Na+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][C:2]1([CH:8]([O:23][CH2:25][CH2:26][CH3:27])[CH:9]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:3][O:4][CH2:5][O:6][CH2:7]1
Reactant: CC1(C(O)C(Cc2ccc(Cl)cc2)n2cncn2)COCOC1
Reactant: CCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CCCOC(C(Cc1ccc(Cl)cc1)n1cncn1)C1(C)COCOC1
Temperature: 30 °C
Yield: 70.2 %

Procedure:
A mixture of 15.2 g (0.045 mole) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-3-(4-chlorophenyl)-propan-1-ol, 100 g of 1-chloropropane, 3 g of tetrabutylammonium bisulfate and 65 g of 50% strength sodium hydroxide solution is heated for 36 hours at 30° C., with vigorous stirring. 300 ml of water are then added and the batch is extracted with twice 150 ml of methylene chloride. The combined extracts are extracted by shaking with eight time 100 ml of water, dried over magnesium sulfate and evaporated down. The residue crystallizes after addition of 20 ml of petroleum ether and 5 ml of ether. 12 g (70.3%) of 1-(5-methyl-1,3-dioxan-5-yl)-1-n-propoxy-2-(1,2,4-triazol-1-yl)-3-(4-chlorophenyl)-propane are obtained as white crystals of melting point 94°-96° C.
Reaction SMILES: [CH2:1]([NH:19][CH2:20][C:21]([NH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=1[O:34][CH3:35])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1.[K+].[Br-]>C(OCC)(=O)C>[CH3:53][C:43]1[CH:48]=[CH:47][C:46]([S:49]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][C:21]([NH:23][C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=2[O:34][CH3:35])=[O:22])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCC/C=C\CCCCCCCCNCC(=O)Nc1c(OC)cc(OC)cc1OC
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCCN(CC(=O)Nc1c(OC)cc(OC)cc1OC)S(=O)(=O)c1ccc(C)cc1
Reaction time: 72 h

Procedure:
To a mixture of 0.50 g of the product of Example 7, excess triethylamine, and ethyl acetate at room temperature was added 0.25 g p-toluene sulfonyl chloride and this was allowed to sit 3 days at room temperature. The reaction mixture was then washed with H3PO4, NaHCO3, and NaCl solutions, dried over MgSO4, filtered, and stripped to an oil. This oil was purified by chromatography on silica gel (70-230 mesh) using 1/1 hexane/EtoAc as eluant. The product was obtained as a viscous oil. 0.28 g (42%). NMR (CDCl3) δ 0.88 (3H, z), δ 1.26 (24H, m), δ 1.66 (2H, m), δ 2.01 (4H, m), δ 2.44 (3H, s), δ 3.21 (2H, m), δ 3.79-3.88 (9H, m), δ 5.34 (2H, m), δ 6.15 (2H, s), δ 7.26-7.75 (5H, m). IR (KBr) 3019, 2925, 1599, 1466, 1206 cm-1.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]#N)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3]C=1.C(OC([C:31]1C2C(=CC=CC=2)C=C[N:32]=1)(C)C)(=O)C1C=CC=CC=1>>[CH:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:31]#[N:32])[C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(OC(=O)c1ccccc1)c1nccc2ccccc12
Reactant: N#Cc1cccc2c(-c3ccccc3)nccc12
Product: N#CCc1cccc2c(C3CCCC3)nccc12

Procedure:
1-Cyclopentylisoquinoline (obtained from 1-cyano-2-benzoyl-1,2-dihydroisoquinoline and cyclopentyl bromide) and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to obtain 1-cyclopentyl-5-dichloroacetylaminomethylisoquinoline having a melting point of 151.0° to 152.3° C. The product was successively reacted in the same way as in steps (c), (d), (e), and (f) of Example 18 to afford 1-cyclopentylisoquinoline-5-acetonitrile having a melting point of 99.4° to 100.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:14][CH2:15][C:16]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.[C:22](Cl)(=O)[C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:26]1[N:14]([CH2:15][C:16]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:9])=[O:10])=[CH:7][C:2]=2[N:1]=1)([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2(O)CCCC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1(O)CCCC1

Procedure:
The title compound was prepared according to the procedure described in Step C of Example 17 from 1-({[2-amino-4-(isopropylsulfonyl)phenyl]amino}methyl)cyclopentanol (Step B) and pivaloyl chloride.
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[C:9](=[C:16]=[CH2:17])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:24]1(I)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([CH:7]2[O:11][CH:10]3[C:9]([C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH2:17])([O:14][C:13](=[O:15])[CH2:12]3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Ic1ccccc1
Reactant: C=C=C1CC(c2ccccc2)OC1CC(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(c1ccccc1)C12CC(c3ccccc3)OC1CC(=O)O2
Temperature: 85 °C
Reaction time: 4 h

Procedure:
(5-phenyl-3-vinylidene-tetrahydro-furan-2-yl)acetic acid (32 mg, 0.12 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol) and K2CO3 (84 mg, 0.61 mmol) were dissolved in 3 mL of dimethylformamide, followed by addition of PhI (68 μL, 0.61 mmol). The solution was stirred for 4 hours at 85° C. When the reaction was completed, H2O was added and the solution was stirred for 5 minutes. The mixture was diluted with ethyl acetate, washed with H2O and NaCl. Organic layer was separated and dried with anhydride MgSO4. Solvent was removed under reduced pressure, and the remnant was purified through silica gel tube chromatography (EtOAc:n-Hexane=1:15, v/v), thus providing products (26 mg, 62%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2.CN1CCCC1=O.N1C=CC=CC=1.[C:38]1(=[O:52])[N:42]([CH2:43][C:44](Cl)=[O:45])[C:41](=[O:47])[C:40]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:39]12>CN(C)C1C=CN=CC=1.O>[Cl:24][C:5]1[C:4]([NH:3][C:44](=[O:45])[CH2:43][N:42]2[C:41](=[O:47])[C:40]3=[CH:48][CH:49]=[CH:50][CH:51]=[C:39]3[C:38]2=[O:52])=[CH:22][CH:21]=[C:20]([Cl:23])[C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N)c3Cl)c2n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(NC(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 85.5 %

Procedure:
To a mixture of 8-(3-amino-2,6-dichlorobenzyloxy)-2-methylquinoline dihydrochloride (4.06 g), 4-dimethylaminopyridine (120 mg), N-methylpyrrolidone (30 ml) and pyridine (10 ml) was added phthalimidoacetyl chloride (3.35 g) at ambient temperature. The mixture was stirred at 50° C. for 1.5 hours and cooled in an ice-water bath. Water (40 ml) was added therein and the mixture was stirred for 30 minutes in an ice water bath. The precipitate was collected by vacuum filtration and washed with water and ethyl acetate to give 8-[2,6-dichloro-3-(phthalimidoacetylamino)benzyloxy]-2-methylquinoline (4.45 g) as a yellowish powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][C:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][NH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[C:32]([CH3:31])=[N:33][NH:34][CH:35]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1n[nH]cc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), 3-methyl-1H-pyrazole-4-boronic acid pinacol ester (135 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=30:70) to obtain the title compound (213 mg, 71%) in an orange oily form.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CCO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8]/[N:9]=[CH:22]/[C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH2:17][CH2:16][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:20]=2)=[N:6][CH:7]=1
Reactant: NNc1ccc(I)cn1
Reactant: O=Cc1cccc(OCCN2CCOCC2)c1
Solvent: CCO
Product: Ic1ccc(N/N=C/c2cccc(OCCN3CCOCC3)c2)nc1
Temperature: 25 °C
Yield: 86306.9 %

Procedure:
To a suspension of 5-iodo-2-hydrazinopyridine (6.62 g, 0.028 mmol) in EtOH (90 mL) was added 3-(2-morpholin-4-yl-ethoxy)-benzaldehyde (6.63 g, 0.028 mmol). The reaction was heated at reflux for 2 h under nitrogen, then cooled to RT. The resulting precipitate was collected by filtration and washed with EtOH to afford the title compound (10.93 g, 86%) as a white solid. LCMS (Method 1): Rt 2.37 min, m/z 453 [MH+]. 1H NMR (300 MHz, CD3OD): δ 8.24 (1 H, d, J 2.2), 7.90-7.84 (2 H, m), 7.36-7.18 (3 H, m), 7.12 (1 H, d, J 8.8), 6.94-6.89 (1 H, m), 4.19 (2 H, t, J 5.4), 3.72 (4 H, t, J 4.6), 2.83 (2 H, t, J 5.4), 2.62 (4 H, t, J 4.6).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH2:7][CH2:8][OH:9])=[O:5])#[N:2].[C:10]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1.O>[C:1]([C:3](=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:4]([NH:6][CH2:7][CH2:8][OH:9])=[O:5])#[N:2]
Reactant: N#CCC(=O)NCCO
Reactant: O=C1CCCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: N#CC(C(=O)NCCO)=C1CCCCC1

Procedure:
2-Cyano-N-(2-hydroxyethyl)acetamide (4.62 g, 36.1 mmol), cyclohexanone (3.89 g, 4.10 mL, 39.7 mmol), acetic acid (0.433 g, 0.413 mL, 7.21 mmol) and ammonium acetate (2.78 g, 36.1 mmol) were suspended in toluene (150 mL) and the mixture heated to reflux under Dean-Stark conditions until no more water was collected (˜1.5 h). The mixture was concentrated to remove toluene before partitioning between EtOAc/Water. The organic phase was collected, dried and concentrated to a lower volume before addition of small quantities of heptane. The glass was etched until precipitation occurred and the solid collected by filtration. The desired product was isolated in 3 batches (4.2 g, 20.2 mmol, 56%). The sample was used directly in the next step without any further purification.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)C(=O)c1ccc(OCCCc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCc2ccc3ccccc3c2)cc1
Yield: 86.8 %

Procedure:
A mixture of 4-[[3-(2-naphthalenyl)propyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.6 g) in methanol (10 mL) and 0.5N sodium hydroxide (4 mL) was treated as in Example 19. Extraction with dichloromethane provided material which was crystallized from dichloromethane-hexane to give 0.5 g of colorless 4-[[3-(2-naphthalenyl)propyl]oxy]-alpha-oxobenzeneacetic acid, mp 123°-124° C.
Reaction SMILES: [CH2:1]([C:8]([CH2:19][CH2:20][C:21]([F:33])([F:32])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])(C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[Cl-].[Li+].O>CS(C)=O>[F:32][C:21]([F:33])([C:22]([F:30])([F:31])[C:23]([F:28])([F:29])[C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Yield: 88.5 %

Procedure:
A solution of diethyl 2-(6-heptenyl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)malonate (1.05 g, 2.1 mmol) in dimethyl sulfoxide (10 ml) was stirred with lithium chloride (0.18 g, 4.2 mmol) and water (0.038 ml, 2.1 mmol) for 5 hours at a temperature of 170° C. to 180° C. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/40) to give ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate (0.80 g, Yield 89%).