Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH2:29]([NH2:32])[CH2:30][NH2:31].C(N(CC)CC)C.[S:40](Cl)([CH3:43])(=[O:42])=[O:41]>CN1CCCC1=O>[NH2:23][C:20]1[N:19]=[C:18]([CH3:24])[C:17]([C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([NH:31][CH2:30][CH2:29][NH:32][S:40]([CH3:43])(=[O:42])=[O:41])[N:3]3[CH2:25][CH:26]3[CH2:28][CH2:27]3)=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]=2)=[CH:22][N:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Reactant: NCCN
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(NCCNS(C)(=O)=O)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 45.4 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and ethylenediamine (150 mg, 2.49 mmol) and the resulting mixture was stirred at 120° C. for 3.5 hours. The reaction mixture was partitioned with chloroform and saturated brine and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, then triethylamine (100 μl, 0.75 mmol) and mesyl chloride (25 μl, 0.32 mmol) were added to the residue, and the resulting mixture was stirred for 1 hour. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (57 mg, 46%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH:23]=[CH:24][C:25]([O:27][CH2:28]C)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Mg]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C[C@@H]1C[C@@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Agent: [Mg]
Solvent: CO
Product: COC(=O)CC[C@@H]1C[C@@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 110.5 %

Procedure:
In analogy to literature [Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G. Tetrahedron Lett. (1987), 28(44), 5287-90] a solution of 0.35 g (0.84 mmol) (2S,4R)-2-(2-ethoxycarbonyl-vinyl)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 20 ml MeOH was treated with 0.122 g (5.04 mmol) magnesium and stirred at room temperature for 5 h. The reaction was evaporated, suspended twice in EtOAc and filtered to give 0.38 g (quantitative) of (2R,4R)-4-(4-methoxy-benzylsulfanyl)-2-(2-methoxycarbonyl-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 410 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:41][O:42][CH3:43])[C:4]([CH3:40])=[C:5]([C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:30])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[C:7]=1[C:8]([O:10]COC(=O)C(C)(C)C)=[O:9]>C(OC(C)C)(C)C.O>[CH3:1][C:2]1[N:3]([CH2:41][O:42][CH3:43])[C:4]([CH3:40])=[C:5]([C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:36])([CH3:37])[CH3:38])=[O:30])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:26])[F:27])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2ccccc2C(F)(F)F)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: CC(C)OC(C)C
Solvent: O
Product: COCN1C(C)=C(C(=O)O)C(c2ccccc2C(F)(F)F)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 83 %

Procedure:
In 10 ml of isopropyl ether saturated with water was dissolved 613 mg of bis(pivaloyloxymethyl) 1,4-dihydro -2,6-dimethyl-1-methoxymethyl-4-(2-trifluoromethylphenyl)-3,5-pyridinedicarboxylate obtained in Example 8, and 50 mg of Lipase B was added thereto, followed by stirring at room temperature for 7 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was subjected to preparative TLC (acetate/hexane=1/1), and the spot of the desired product was extracted with ethyl acetate. The extract with concentrated under reduced pressure to obtain 414 mg (yield: 84%) of (+)-1,4-dihydro-2,6-dimethyl -1-methoxymethyl-4-(trifluoromethylphenyl)-5-pivaloyloxymethoxycarbonyl -3-pyridinecarboxylic acid as a colorless crystal.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:16](=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](Cl)=[O:43].C(ON(CCCCC#N)C(=O)CCCCCl)C1C=CC=CC=1>>[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:43])[N:24]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16](=[O:33])[N:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: O=C(Cl)CCCCCCCBr
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCCCNOCc1ccccc1
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCCCN(OCc1ccccc1)C(=O)CCCCCCCBr

Procedure:
Compound [III] (1.50 g, 3.32 mmol) was combined with 8-bromooctanoyl chloride (0.963 g, 3.99 mmol) following the conditions used for (3). The crude oil was purified by silica gel column chromatography with 1:1 hexane/EtOAc as the eluant, giving 2.06 g (95%) of [IV] as an oil: NMR δ 1.17-2.00 (m, 24H), 2.23-2.50 (m, 6H), 3.36 (t, 2H, J=6), 3.60 (t, 2H, J=6), 3.63 (t, 2H, J=6), 4.77 (s, 4H), 7.33 (s, 10H). Anal. (C35H50BrN3O4) C, H, N.
Reaction SMILES: CO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[C:6]([O:14][CH:15]([CH:22]2[CH2:24][CH2:23]2)[C:16]#[C:17][Si](C)(C)C)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[C:6]([O:14][CH:15]([CH:22]2[CH2:24][CH2:23]2)[C:16]#[CH:17])[CH:5]=1
Reactant: C[Si](C)(C)C#CC(Oc1cc(Br)ccc1OC(F)F)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CC(Oc1cc(Br)ccc1OC(F)F)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
To 34 ml of methanol solution containing 4.05 g (10.5 mmol) of 4-bromo-2-(1-cyclopropyl-3-trimethylsilyl-2-propynyloxy)-1-difluoromethoxybenzene obtained in Reference example 14-(a) was added 0.48 g (3.5 mmol) of potassium carbonate, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, 50 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 2.8 g of the title compound as colorless liquid. (Yield: 84%)
Reaction SMILES: Br[CH:2]([C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>CN(C)C=O.O>[CH:15]1([NH:18][CH:2]([C:4]2[NH:13][C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH3:3])[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: CC(Br)c1nc2ccccc2c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC1CC1)c1nc2ccccc2c(=O)[nH]1
Reaction time: 18 h

Procedure:
To a suspension of 2-(1-bromoethyl)quinazolin-4(3H)-one (2.53 g) in N,N-dimethylformamide (30 mL) was added cyclopropylamine (3.46 mL), and the mixture was diluted with N,N-dimethylformamide (20 mL) and water (1 mL), and then stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added aqueous sodium hydrogen carbonate solution, and then the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with diisopropyl ether/ethyl acetate (20:1) to give 2-[1-(cyclopropylamino)ethyl]quinazolin-4(3H)-one [REx(33-1)] (1.71 g) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=3)=[N:9][N:8]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:5]2=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:36]=2)O1>>[F:17][C:13]1[N:12]=[C:11]([C:10]2[C:4]3[C:5](=[CH:6][N:7]=[C:2]([C:32]4[CH:33]=[N:34][N:35]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:36]=4)[CH:3]=3)[N:8]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(Br)cc23)n1
Product: CCOC(=O)Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Yield: 56 %

Procedure:
Following the Suzuki coupling procedure of Example 10, 5-bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate, were reacted and purified via silica gel chromatography using a gradient of EtOAc in heptane to afford 100 mg (56%) of Ethyl 2-(4-(3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetate. ESI MS m/z 451.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14])=O.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:5](=[N:22]\[OH:23])/[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14]
Reactant: COc1ccc(C(=O)c2cc(F)ccc2F)c(O)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(/C(=N\O)c2cc(F)ccc2F)c(O)c1Cl

Procedure:
A mixture of 28 g of 3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone and 26 g of hydroxylamine HCl in 250 ml pyridine is refluxed for three hours. Pyridine is evaporated and the residue partitioned between ethyl acetate and 5% HCl. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give a solid product as a mixture of isomers. The solid is heated at 200°-210° C. for approximately 30-45 minutes and recrystallized from toluene giving E-3-chloro-2',5'-difluoro-2-hydroxy4-methoxybenzophenone oxime, mp 209°-210° C.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.Cl.Cl.[CH3:15][S:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1.[C@H:26]1([NH:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH2:46])[CH:42]=3)[N:37]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>>[C@H:26]1([NH:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH:46][C:1]([NH:25][CH:22]4[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][S:16][CH3:15])[CH2:24][CH2:23]4)=[O:12])[CH:42]=3)[N:37]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CSCCN1CCC(N)CC1
Agent: Cl
Product: CSCCN1CCC(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(2-methylsulfanyl-ethyl)-piperidin-4-ylamine dihydrochloride and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=476.7 (M+H+).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[CH2:23]([NH3+:26])[CH2:24][CH3:25]>>[CH2:23]([NH:26]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1)[CH2:24][CH3:25]
Reactant: CCC[NH3+]
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Agent: CC(=O)[O-]
Product: CCCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 68 %

Procedure:
Prepared as in Example 35 from 2-benzoyl-benzo[b]thiophen-3-ol and n-propylammonium acetate with a yield of 68% of theory; m.p. 124°-125° C. (petroleum ether/ethyl acetate 1:1).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.BrC1C=CC=CC=1>COC(C)(C)C>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[NH:16][C:10]([C:4]1[C:3](=[O:15])[N:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=1[OH:9])=[O:12]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Nc1cnccn1
Solvent: COC(C)(C)C
Solvent: Brc1ccccc1
Product: Cc1cc(O)c(C(=O)Nc2cnccn2)c(=O)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
211 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 95 mg of aminopyrazine were added to 6 ml of bromobenzene, and the mixture was stirred for 3 hours under the heat-refluxing condition. The reaction mixture was cooled to room temperature, and t-butyl methyl ether was added to the mixture. The resulting solid was collected by filtration, washed with t-butyl methyl ether, and dried to obtain 258 mg of N-(2-pyrazinyl)-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 1) represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[C:20]=1[O:21]C)[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6].[Cl-].[Li+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6]
Reactant: COc1c(Cl)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1S(C)(=O)=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(Cl)c1O
Temperature: 120 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
3-(3-chloro-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (586 mg) was dissolved in N,N-dimethylformamide (4 mL), and lithium chloride (241 mg) was added to the solution, and then the mixture was stirred at 120° C. for 2 hours. To the reaction solution, 1N hydrochloric acid was added, and the precipitated crystal was washed with water and then crystallized from n-hexane-chloroform to obtain the title compound (310 mg) as a colorless crystal.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]1[CH2:15][OH:16])(=[O:3])[CH3:2].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]1[CH:15]=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1c([N+](=O)[O-])cnc1CO
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: c1ccccc1
Product: CC(=O)OCCn1c([N+](=O)[O-])cnc1C=O

Procedure:
A 6.27 gm. portion of 1-(2-acetoxyethyl)-2-hydroxymethyl-5-nitroimidazole is refluxed with 13.3 gm. of lead tetraacetate in 200 ml. of benzene for 18 hours, cooled, and filtered. The filtrate is washed with 50 ml. of saturated sodium carbonate solution, and the organic phase is separated therefrom. The remaining aqueous phase is twice extracted with 30 ml. of chloroform, and then combined with the above separated organic phase. The combined organic phases are dried under magnesium sulfate, and filtered. The organic solvents are then removed in vacuo, giving the above aldehyde.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][S:11][C:12]2[O:13][C:14]3[C:19]([C:20](=[O:23])[C:21]=2[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH3:22][C:21]1[C:20](=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12]=1[S:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:25][CH:24]=1
Reactant: Cc1c(SCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CSc3oc4ccccc4c(=O)c3C)cc2)cc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
To a solution 2-[4-(4-hydroxy-butyl)-benzylsulfanyl]-3-methyl-chromen-4-one (300 mg, 0.85 mmol) dissolved in anhydrous dichloromethane (8.0 mL) was added TsCl (194 mg, 1.01 mmol), DMAP (124 mg, 1.01 mmol) and TEA (0.213 mL, 1.52 mmol). The reaction mixture continued stirring at room temperature. After 3 hours the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material was purified using silica gel chromatography (1:1 pentane: ethyl acetate) to yield toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-chromen-2-ylsulfanylmethyl)-phenyl]-butyl ester (280 mg, 0.55 mmol) in moderate yield (65%).1H (CDCl3, 600 MHz): δ 8.18 (1H, dd, J=7.9, 1.3 Hz), 7.77 (2H, d, J=8.2 Hz). 7.62 (1H, m), 7.39 (2H, t, J=8.0 Hz), 7.33 (2H, d, J=8.0 Hz), 7.30 (2H, d, J=8.0 Hz), 7.07 (2H, d, J=8.0 Hz), 4.37 (2H, s), 4.02 (2H, t, J=5.8 Hz), 2.55 (2H, t, J=7.3 Hz), 2.05 (3H, s), 1.65 (4H, m); 13C (CDCl3, 150 MHz): δ 175.5, 162.2, 156.7, 144.9, 141.5, 134.1, 133.4, 133.0, 130.0, 129.1, 129.0, 128.1, 126.5 125.3, 122.9, 117.5, 117.0, 70.5, 35.3, 34.9, 28.6, 27.2, 21.8, 10.8.; HRMS calcd for C28H28O5S2 509.1450:, found 509.1441
Reaction SMILES: [F:1][C:2]([F:18])([C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl>[CH3:26][S:27]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:18])([F:1])[C:8]([F:16])([F:17])[C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])(=[O:29])=[O:28]
Reactant: OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 5,5,6,6,7,7,8,8,8-nonafluorooctan-1-ol (7.8 g, 26.70 mmol) in dichloromethane (150 ml) was cooled to 0° C. Triethylamine (9.29 ml, 66.75 mmol) and methanesulfonyl chloride (2.48 ml, 32.04 mmol) were added dropwise to the solution, followed by stirring for 1 hour. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with dichloromethane. 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=1/4) to give 1-methanesulfonyloxy-5,5,6,6,7,7,8,8,8-nonafluorooctane (8.5 g, Yield 86%).
Reaction SMILES: [CH3:1][C:2]1([CH2:5][CH2:6][C:7](Cl)=[O:8])[CH2:4][CH2:3]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[F:39][C:37]([F:38])([F:40])[C:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:7](=[O:8])[CH2:6][CH2:5][C:2]4([CH3:1])[CH2:4][CH2:3]4)=[CH:12][CH:13]=3)=[O:18])[CH2:24][CH2:23]2)=[CH:31][CH:30]=1)([OH:41])[C:33]([F:36])([F:35])[F:34]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reactant: CC1(CCC(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(CCC(=O)Nc2ccc(C(=O)N3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2)CC1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
3-(1-Methylcyclopropyl)propionic acid (1.752 mmol, 0.2 g) was stirred in dichloromethane at 0° C. Oxalyl chloride (8.76 mmol, 0.752 mL, 1.112 g) was added and the reaction stirred overnight. The reaction mixture was concentrated under vacuum to give the intermediate 3-(1-methylcyclopropyl)propanoyl chloride. A mixture of 3-(1-methyl-cyclopropyl)propanoyl chloride (0.813 mmol, 0.119 g), (4-aminophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.542 mmol, 0.25 g) and triethylamine (1.084 mmol, 0.151 mL, 0.110 g) were stirred in dichloromethane at 0° C. for 1 hour. The reaction mixture was allowed to warm to room temperature. The reaction mixture was washed with water, concentrated under vacuum and purified by acidic prep HPLC to afford the title compound (67 mg). MS (ESI) m/z 572.3 [M+H]+
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]=[O:11].[CH2:12](O)[CH:13]=[CH:14][CH3:15].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>>[CH2:12]([O:11][CH2:10][C:3]1[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=1[I:1])[CH:13]=[CH:14][CH3:15]
Reactant: CC=CCO
Reactant: COc1nccc(I)c1C=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC=CCOCc1c(I)ccnc1OC
Temperature: 22 °C
Reaction time: 12 h

Procedure:
A 500 mL 3-necked round-bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with 4-iodo-2-methoxy-pyridine-3-carbaldehyde (Intermediate 1, 75.0 g, 0.29 mol), crotyl alcohol (75 mL, 0.88 mol), and triethylsilane (70 mL, 0.44 mol). To the stirred suspension at 0° C. is added trifluoroacetic acid (175 mL, 2.27 mol) dropwise via an addition funnel. The resulting solution is stirred at about 22° C. for approximately 12 hours. The reaction mixture is slowly poured into a rapidly stirring saturated sodium bicarbonate solution (2 L). The mixture is extracted with 3×500 mL of hexane. The combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo to give an oil. Purification of this oil by vacuum distillation (about 0.4 mm Hg, about 120-130° C.) yields 3-(but-2-enyloxymethyl)-4-iodo-2-methoxypyridine as a pale yellow oil: 1H-NMR (400 MHz, CDCl3) d 7.69 (d, J=5 Hz, 1H), 7.34 (d, J=5 Hz, 1H), 5.71 (m, 2H), 4.58 (s, 2H), 4.02 (d, J=1 Hz, 2H), 3.94 (s, 3H), 1.72 (d, J=6 Hz, 3H); IR (neat) 2948, 2859, 1561, 1459, 1381, 1361, 1301, 1233, 1169, 1094, 1052 cm-1 ; Elemental analysis: calculated for C11H14NO2I: C 41.40, H 4.42, N 4.39, I 39.76; Found: C 41.31, H 4.45, N 4.37, I 39.71.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[C:24](O)=[O:25])=[CH:18][CH:17]=1>>[OH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]2[C:24](=[O:25])[N:4]3[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:7][C:2]([CH3:1])=[C:3]3[N:14]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Reactant: Cc1nc(-c2ccccc2)cnc1N
Product: Cc1[nH]c(-c2ccccc2)cn2c(=O)c(Cc3ccc(O)cc3)nc1-2

Procedure:
Synthesized using method A with 3-methyl-5-phenylpyrazin-2-amine and 3-(4-hydroxyphenyl)-2-oxopropanoic acid as starting materials. 1H NMR (300 MHz, dmso) δ 8.84 (s, 1H), 8.00 (d, J=7.6, 2H), 7.47 (dd, J=8.6, 16.2, 3H), 7.17 (d, J=7.3, 2H), 6.69 (d, J=8.4, 2H), 6.26 (s, 4H), 4.17 (s, 2H), 2.86 (s, 3H), 2.48 (s, 1H).