Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][S:24]([CH3:27])(=[O:26])=[O:25])[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:28](SCC(CO)OCC)CCCCCCCCCCCCCCC.CS(Cl)(=O)=O>>[CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][S:24]([CH3:27])(=[O:26])=[O:25])[O:20][CH2:21][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(CO)OCC
Reactant: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)OC
Agent: CS(=O)(=O)Cl
Product: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)OCC
Yield: 94 %

Procedure:
This compound was prepared in an analogous manner to that of (±)-1-S-hexadecyl-2-O-methyl-3-O-mesylthioglycerol from 5.5 grams (0.016 mole) of (±)-1-S-hexadecyl-2-O-ethylthioglycerol and 2.2 grams (0.019 mole) of methanesulfonyl chloride. This resulted in 6.2 grams of product (94%) as an oil. 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 31H, (CH2)14, CH3 --CH2 --O], 2.58(m, 2H, S--CH2), 2.62(m, 2H, CH--CH2 --S), 3.08(s, 3H, SO2 --CH3), 3.40-3.50(m, 3H, CH, CH3 --CH2 --O), 4.35(m, 2H, CH2 --OSO2).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([NH2:13])[N:6]=1)=O.[CH3:14][NH2:15]>O1CCCC1>[CH3:14][NH:15][C:3]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([NH2:13])[N:6]=1)=[O:2]
Reactant: CN
Reactant: COC(=O)c1cc(SC)cc(N)n1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(SC)cc(N)n1

Procedure:
A solution of 0.099 g 6-amino-4-methylsulfanyl-pyridine-2-carboxylic acid methyl ester in 2 ml methylamine 2M in tetrahydrofuran was kept at room temperature for 24 h. The solvents were evaporated and the residue was recrystallized from water to yield 0.054 g of the title compound as white crystals melting at 89-91° C.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]=2[N:13]=1)[CH3:2].C(O)(=O)C.[CH3:28][C:29]1[N:30]=[CH:31][C:32]([CH:35]=O)=[N:33][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH2:1]([C@@H:3]1[CH2:7][N:6]([CH2:28][C:29]2[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][N:30]=2)[CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[C:12]=2[N:13]=1)[CH3:2]
Reactant: Cc1cnc(C=O)cn1
Reactant: CC[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC[C@@H]1CN(Cc2cnc(C)cn2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of 6-[(3S,4S)-4-ethylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (4.4 g) in dimethylformamide (62 mL) was added acetic acid (2.4 mL), 5-methylpyrazine-2-carbaldehyde (2 g) and sodium triacetoxyborohydride (5.27 g). The reaction mixture stirred for 2 h at ambient temperature and was carefully quenched with saturated sodium bicarbonate solution, extracted 3× with methylene chloride, dried with magnesium sulfate, filtered and concentrated. Purification via Biotage MPLC chromatography eluting with 1-4% methanolmethylene chloride/0.5% saturated ammonium hydroxide provided the title compound (3.9 g). 400 MHz 1H NMR (CDCl3) δ 8.52-8.48 (m, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 4.81-4.75 (m, 1H), 4.11-4.01 (m, 3H), 3.79-3.75 (m, 1H), 3.60-3.53 (m, 2H), 3.40-3.32 (m, 1H), 3.10-3.08 (m, 1H), 2.94 (m, 1H), 2.63-2.57 (m, 1H), 2.53 (d, J=7.5 Hz, 1H), 2.37-2.18 (m, 4H), 1.90-1.83 (m, 2H), 1.67-1.60 (m, 1H), 1.54-1.47 (m, 1H), 0.95-0.92 (m, 3H). MS: (M+H m/z 424.2).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1>O>[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:22][CH2:21]1
Reactant: Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Product: Nc1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3ccnc23)cc1
Reaction time: 72 h

Procedure:
To N1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine (0.2 g, 0.77 mmol) from 1a was added trans-1,4-diaminocyclohexane (1.7 g, 15.0 mmol). The mixture was allowed to melt at 160° C. for 3 days. The melt was then cooled, diluted with water and extracted with dichloromethane. The organic layer was then concentrated in vacuo to give 0.4 g of crude N6-(trans-4-aminocyclohexyl)-N8-(4-aminophenyl)imidazo[1,2-b]pyridazine-6,8-diamine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]2[C:23]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[NH:13][S:12](=[O:25])(=[O:24])[N:11]2[CH3:26])=[CH:6][C:3]=1[CH:4]=O.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]2[C:23]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[NH:13][S:12](=[O:25])(=[O:24])[N:11]2[CH3:26])=[CH:6][C:3]=1[CH2:4][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: CN1C(c2ccc(F)c(C=O)c2)c2ccc3cccnc3c2NS1(=O)=O
Reactant: C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1C(c2ccc(F)c(CN3CCNCC3)c2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 10.5 %

Procedure:
In a similar fashion using route 37 general procedure 90, 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzaldehyde 422 (50 mg, 0.13 mmol), piperazine (12 mg, 0.13 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) in DCE (2 ml) gave the title compound (6 mg, 10%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:20][C:21]([NH2:23])=[O:22].[C:24](OCC)(=[O:30])[C:25](OCC)=[O:26].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[C:20]1[C:21](=[O:22])[NH:23][C:25](=[O:26])[C:24]=1[OH:30]
Reactant: CC1(CC2CCCC2)Cc2cc(CC(N)=O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(CC2CCCC2)Cc2cc(C3=C(O)C(=O)NC3=O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
(6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide (5 g., 0.0141 mole) and diethyl oxalate (2.19 g., 0.015 mole) are dissolved in dry dimethylformamide (30 ml.) and stirred in an ice bath under nitrogen for 20 minutes. Potassium t-butoxide (3.53 g., 0.0315 mole) is then added in two portions 15 minutes apart. The mixture is stirred while cooling in the ice bath for another 45 minutes, then stirred at room temperature for 18 hours and poured into ice water (500 ml.) The mixture is acidified with hydrochloric acid and extracted with ether (4×125 ml.). The combined organic extracts are washed with water and then repeatedly extracted with dilute sodium carbonate. The combined aqueous extracts are acidified with hydrochloric acid, extracted with methylene chloride and then with ether. The combined organic extracts are washed with water, dried over magnesium sulfate and concentrated under vacuum. The residue is chromatographed on silica (175 g.) with a mixture of toluene, dioxane and acetic acid (50:5:1). The appropriate product fractions are concentrated under vacuum and the residue is dissolved in ether and extracted with dilute sodium bicarbonate. The aqueous extracts are acidified with hydrochloric acid and extracted with methylene chloride and then with ether. The combined organic extracts are washed with water, dried over magnesium sulfate and concentrated under vacuum to obtain the 3-(6,7-Dichloro-2-cyclopentylmethyl-2,3 -dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione as a foam which was then dried under high vacuum at 90° C. for 2 hours to give 3.6 g. (63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25]Cl)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH3:28][NH:29][CH3:30]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25][N:29]([CH3:30])[CH3:28])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: Cc1nnc(CNC(=O)CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CNC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nnc(CNC(=O)CN(C)C)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
To a solution of 5-chloro-2-[3-(2-chloroacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (0.4 g) in methanol (4 ml) and chloroform (8 ml), 40% aqueous dimethylamine (0.5 g) is added, and the resultant mixture is stirred at room temperature for 24 hours. The reaction mixture is evaporated under reduced pressure, and the residue is shaken with methylene chloride (20 ml). The methylene chloride layer is washed with aqueous sodium bicarbonate and water in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, whereby 5-chloro-2-[3-(2-dimethylaminoacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone is obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 75.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.120 g; 0.328 mmol), LHMDS 1N in THF (0.362 mL; 0.362 mmol), 1-iodopropane (0.054 mL; 0.554 mmol) in DMF (5 mL) for 3.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.101 g (75%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N:22]([CH3:24])[CH3:23])[C:15]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:6](O)CS(C)(=O)=O.C[O-].[Na+].[NH:29]([CH2:36][CH2:37][C:38]#[N:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CS(C)=O>[NH:29]([CH:36]=[C:37]([CH2:6][C:5]1[CH:13]=[C:14]([N:22]([CH3:23])[CH3:24])[C:15]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:3]([N:2]([CH3:1])[CH3:25])[CH:4]=1)[C:38]#[N:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#CCCNc1ccccc1
Reactant: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1N1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C)c1N1CCCCC1

Procedure:
A mixture of 7.4 g. of 3,5-bis(dimethylamino)-α-[(methylsulfonyl)methyl]4-piperidinobenzyl alcohol, 1.64 g. of sodium methylate and 4.4 g. of β-anilinopropionitrile in 40 ml. of dimethylsulfoxide was stirred for 2 hours at 50° C. under nitrogen. The mixture was poured into 250 ml. of water, the precipitated product extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained α-(anilinomethylene)-3,5-bis(dimethylamino)-4-piperidinohydrocinnamonitrile having a melting point of 200°-202° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl.[Cl:11][C:12]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:13]=1[NH2:14]>>[Cl:11][C:12]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:13]=1[NH:14][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Product: COc1ccc(Cl)c(Nc2cc(C)nc(N)n2)c1

Procedure:
The title compound was prepared from a mixture of 2-amino-4-chloro-6-methyl-pyrimidine (100 mg, 0.696 mmol) and 2-chloro-5-methoxyaniline hydrochloride (203 mg, 1.05 mmol) similar to Example 117 and isolated as a white solid (132 mg, 72%). 1H NMR (CDCl3): 7.77 (d, J=2.7 Hz, 1H), 7.28 (d, J=9.0 Hz, 6.74 (s, 1H), 6.57 (dd, J=3.0, 8.7 Hz, 1H), 6.04 (s, 1H), 4.81 (s, 2H), 3.82 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][CH2:6][C:5]([N+:13]([O-])=O)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][O:3]1.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>C(O)(=O)C.[Zn]>[CH2:30]([O:29][C:27]([NH:13][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][O:7][C:2]([CH3:16])([CH3:1])[O:3][CH2:4]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1([N+](=O)[O-])COC(C)(C)OC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C1(NC(=O)OCc2ccccc2)COC(C)(C)OC1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a solution of 5.0 g of ethyl 2,2-dimethyl-5-nitro-1,3-dioxane-5-carboxylate in 50 ml of acetic acid was added 7 g of zinc powder in four divided portions at room temperature, followed by stirring at 45° C. for 4 hours. The insoluble materials of the reaction mixture were separated by filtration and washed with chloroform. The filtrate was concentrated under reduced pressure and neutralized by the addition of a saturated aqueous sodium hydrogen carbonate solution. To a mixture formed by adding 100 ml of chloroform thereto were added 2.7 g of sodium hydrogen carbonate and 3.7 ml of benzyl chloroformate at 0° C., followed by stirring at room temperature for 2 hours. The obtained organic layer was dried over anhydrous sodium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6.6 g of ethyl 5-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-1,3-dioxane-5-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[CH:16]=1)[C:10](=[O:30])[NH:9]2)=[O:4].O.C(=O)([O-])[OH:33].[Na+].OOS([O-])=O.[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])=[O:33])[CH:16]=1)[C:10](=[O:30])[NH:9]2)=[O:4]
Reactant: COC(=O)c1scc2[nH]c(=O)n(-c3cccc(SC(C)c4ccccc4)c3)c(=O)c12
Reactant: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1scc2[nH]c(=O)n(-c3cccc(S(=O)C(C)c4ccccc4)c3)c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-methoxycarbonyl-3-[3-(1-phenyl -ethylthio)phenyl]thieno[3,4-d]pyrimidine-2,4(1H,3H)-dione (50 mg) in acetone (3 mL)-water (0.6 mL) were added sodium hydrogen carbonate (24 mg) and OXONE (registered trademark) (84 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].CCO[C:22]([CH3:24])=O>C1(C)C=CC=CC=1.O>[CH:9]1[C:10]2[C:5](=[C:22]([CH2:24][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]([CH3:15])=[N:8][C:7]=3[OH:16])[CH:3]=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: CCOC(C)=O
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(C)nc(O)c(Cc3cccc4cnccc34)c2cc1OC
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (158 mg, 721 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.86 mL, 1.72 mmol) at RT followed by MDE 32016 (185 mg, 864 μmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) gave 48 mg of 4-(isoquinolin-5-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol. The free base was dissolved in MeOH (3 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (4.5 mL). The reaction mixture solution was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(isoquinolin-5-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 22 as a brown solid (58 mg, 19% yield).
Reaction SMILES: BrC1C=CC(Br)=CC=1C1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=2)=[N:12][N:13]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Br:39])[CH:38]=1)[C:33](Cl)=[O:34].C(OC1C=CC(C(NN)=O)=CC=1)CCCCCCC>>[Br:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Br:39])[CH:38]=1)[C:33]([NH:13][NH:12][C:11](=[O:10])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1)=[O:34]
Reactant: O=C(Cl)c1cc(Br)cc(Br)c1
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)ccc3Br)o2)cc1
Agent: CCCCCCCCOc1ccc(C(=O)NN)cc1
Product: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Br)cc(Br)c2)cc1
Yield: 36 %

Procedure:
By the general method for the synthesis of 2-(2,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole in Example 1, the reaction of 3,5-dibromobenzoyl chloride (20.13 g, 0.06747 mole) with 4-octyloxybenzoic acid hydrazide (17 g, 0.06747 mole) gave the intermediate 3,5-dibromo-N′-[4-(octyloxy)benzoyl]benzohydrazide (12.87 g, 36% yield). Cyclocondensation of the intermediate 3,5-dibromo-N′-[4-(octyloxy)benzoyl]-benzohydrazide (12.17 g) with POCl3 (63 mL) gave the required 2-(3,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (6.12 g, 52% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[N:12]=[C:11]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:29][S:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(=O)([O-])[O-].[Na+].[Na+].C(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.CN(C)C=O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[N:13]1[CH:9]([C:4]2[CH:3]=[C:2]([C:36]3[CH:37]=[CH:38][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:34][CH:35]=3)[C:7]([F:8])=[CH:6][CH:5]=2)[CH2:10][C:11]([C:22]([F:27])([F:28])[C:23]([F:26])([F:25])[F:24])=[N:12]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(F)c(Br)c2)c(F)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
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: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccc2F)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
5-(3-Bromo-4-fluoro-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (250.0 mg, 0.53 mmol) prepared in Step 5 of Preparation 7, 4-methylsulfonylphenylboronic acid (116.0 mg, 0.58 mmol), Pd(PPh3)4 (61.0 mg, cat.) and a 2N sodium carbonate solution (3.5 mL) were added to a mixed solvent of ethanol (3.5 mL) and N,N-dimethylformamide (15.0 mL). The reaction mixture was stirred at 90° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 150.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:3]=1[CH:4]=[N:5][NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[K].[O-]CCCC.Cl>CN1C(=O)CCC1.O>[I:20][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][CH:18]=1)[N:6]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])[N:5]=[CH:4]2
Reactant: O=C(O)c1cccc(NN=Cc2cc(I)ccc2F)c1
Agent: CCCC[O-]
Agent: Cl
Agent: [K]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1cccc(-n2ncc3cc(I)ccc32)c1
Yield: 107.4 %

Procedure:
3-(2-(2-Fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (I1b, 3.47 g, 9 mmol) and potassium tert, butoxide (2.3 g, 20.5 mmol) was stirred under argon atmosphere in NMP (45 mL) at 150° C. for 30 minutes. After cooling, the mixture was diluted with water (100 mL), acidified with aqueous HCl (1.7 M) and extracted trice with EtOAc. The combined organic phases were washed twice with water and then with brine. Evaporation of the organic phase afforded crude title compound (3.52 g, quant.) as a light brown, amorphous, gummy solid.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].Cl[C:14](=[CH2:17])[C:15]#[N:16]>C(O)C>[C:2]([N:6]1[CH:17]=[CH:14][C:15]([NH2:16])=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: C=C(Cl)C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)n1ccc(N)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a 600 ml of ethanol were added 59.94 g of tert-butylhydrazine hydrochloride, 79.3 g of sodium acetate and 2-chloroacrylonitrile followed by stirring at 80° C. for 12 hours. After removal of the solvent, water was added and then was neutralized with sodium hydrogen carbonate followed by extracting with ethyl acetate. The resulting organic layer was washed with saturated brine, and then dried over magnesium sulfate. The organic layer was filtered and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1 to 1/2) to give the title compound.
Reaction SMILES: [Cl-].[Cl-].[Ca+2].[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=O)[CH:11]=[CH:12][NH:13]2)=[N:8][CH:7]=1.O=P(Cl)(Cl)[Cl:19]>CCOC(C)=O>[Cl:19][C:10]1[CH:11]=[CH:12][N:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:15]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc2c(=O)cc[nH]c2c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: COc1cnc2c(Cl)ccnc2c1
Temperature: 120 °C
Reaction time: 0.29 h

Procedure:
A two-necked round bottomed flask equipped with an air condenser (protected with CaCl2 guard tube) was charged with 7-Methoxy-1H-[1,5]naphthyridin-4-one (13 g) and POCl3 (65 mL). The reaction mixture was allowed to reflux at 120° C. for 12 h. The POCl3 was removed in vacuo and azeotroped twice with toluene. EtOAc (75 mL) was added and the reaction mixture was stirred at 50-60° C. for 15-20 min. EtOAc removed separated by decantation. The organic layers were combined and concentrated. The obtained crude was dissolved in EtOAc (50 ml) and a washed with satd. aqueous sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated. The resulting solids were suspended in hexane, stirred for 15 min, filtered and dried under vacuum.