Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Cl:5][C:6]([Cl:13])([Cl:12])[CH2:7][CH2:8][C:9](Cl)=[O:10].C(N(CC)CC)C>C1CCCCC1>[Cl:5][C:6]([Cl:13])([Cl:12])[CH2:7][CH:8]1[C:2]([CH3:4])([CH3:3])[CH2:1][C:9]1=[O:10]
Reactant: O=C(Cl)CCC(Cl)(Cl)Cl
Reactant: C=C(C)C
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)C1CC(Cl)(Cl)Cl
Reaction time: 4 h

Procedure:
261 g of isobutylene is injected into a 1 liter autoclave containing 49 g (0.23 mol) of 4,4,4-trichlorobutyric acid chloride in 280 ml of cyclohexane. A solution of 28.3 g (0.28 mol) of triethylamine in 233 ml of cyclohexane is pumped in at 70° C. in the course of 4 hours. The reaction mixture is afterwards held at 70° C. for a further 4 hours. The precipitated hydrochloride of the triethylamine is filtered off; the filtrate obtained is washed with dilute hydrochloric acid and then with water, dried over sodium sulphate and concentration by evaporation. Distillation of the residue yields 2-(2',2',2'-trichloroethyl)-3,3-dimethylcyclobutanone as a clear liquid, b.p. 118°-122° C./14 mm Hg.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:36])=[C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:28]3[CH:29]=[C:24]([O:23][CH3:22])[CH:25]=[CH:26][C:27]=3[CH3:36])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccc(C)c(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(OC)ccc3C)CC2)c(OC)nc1C
Yield: 66 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(5-methoxy-2-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl[N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[CH3:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH3:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH:21][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1
Reactant: CN(C)CCCN
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(Cl)S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CN(C)CCCNN1NC=C(c2ncc([N+](=O)[O-])n2C)S1
Temperature: 25 °C

Procedure:
A mixture consisting of 3.8 gm., 0.0l55 mole of 2-(2-chloro- 5-thiadiazolyl)-1-methyl-5-nitroimidazole, prepared as in Example 16 2.5 gm., 0.029 mole of 3-dimethylaminopropylamine, 2.1 gm. 0.025 mole, of sodium bicarbonate and 100 ml. of benzene is refluxed for twenty-two hours. The reaction mixture is cooled to room temperature, washed with aqueous sodium bicarbonate and sodium chloride solutions. Cooling to 5° C. gives a crystalline precipitate which is collected and recrystallized from benzene to give the pure compound melting at 153°-154° C. More product is obtained from the mother liquors to give an overall yield of 3.0 gm.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([O:19][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[C:10]([C:29]#[N:30])=[N:9][C:8]([C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])=[C:17]4[OH:18])=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4c(c3)OCO4)cc2c1O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Oc3ccc4c(c3)OCO4)ccc12

Procedure:
Prepared in analogy to example 31h from 6-(benzo[1,3]dioxol-5-yloxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine. ESI MS (m/z): 408 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[C:17]([NH2:19])=[NH:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[C:25]([O-:28])([O-])=[O:26].[Cs+].[Cs+].[OH:31]/[CH:32]=[C:33](/[CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[N:43][CH:44]=1)\[C:34](OC)=O>CN1C(=O)CCC1>[F:22][C:21]([F:24])([F:23])[C:25]([OH:28])=[O:26].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[C:17]3[NH:19][CH:34]=[C:33]([CH2:38][C:39]4[CH:44]=[N:43][CH:42]=[N:41][CH:40]=4)[C:32](=[O:31])[N:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: COC(=O)/C(=C\O)Cc1cncnc1
Reactant: CN(Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=N)N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN(Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)c1nc(=O)c(Cc2cncnc2)c[nH]1
Product: O=C(O)C(F)(F)F
Temperature: 130 °C
Yield: 15.3 %

Procedure:
To the mixture of N-[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]-N-methylguanidine (50 mg, 0.106 mmol) and Cs2CO3 (138 mg, 0.425 mmol) in NMP (1 mL) was added methyl (2Z)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (25 mg, 0.129 mmol). It was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound as a white solid (5 mg, 7.6%, yield). LCMS: rt=3.12 min, [M+H+]=502
Reaction SMILES: C[C:2]([N:5]([CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)C(=O)[O-])([CH3:4])C.CC(N(CCN1CCNCC1)C(=O)[O-])(C)C.Br[C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][C:35]=1[F:46].BrC1C(F)=CN=C2C=1N=C(OC)C=C2.[O:61]=[C:62]1[CH2:67][O:66][C:65]2[CH:68]=[CH:69]C(C=O)=[N:71][C:64]=2[NH:63]1.O=C1CSC2C=CC(C=O)=NC=2N1>>[F:46][C:35]1[CH:36]=[N:37][C:38]2[C:43]([C:34]=1[N:14]1[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][NH:5][CH2:2][C:4]3[CH:69]=[CH:68][C:65]4[O:66][CH2:67][C:62](=[O:61])[NH:63][C:64]=4[N:71]=3)[CH2:16][CH2:15]1)=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2
Reactant: CC(C)(C)N(CCC1CCNCC1)C(=O)[O-]
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2ncc(F)c(Br)c2c1
Agent: CC(C)(C)N(CCN1CCNCC1)C(=O)[O-]
Agent: COc1ccc2ncc(F)c(Br)c2n1
Agent: O=Cc1ccc2c(n1)NC(=O)CS2
Product: COc1ccc2ncc(F)c(N3CCC(CCNCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Yield: 32.7 %

Procedure:
The title compound (100 mg, 33%) was prepared as a yellow solid according to Example 1, except substituting the following three reagents: 1,1-dimethylethyl[2-(4-piperidinyl)ethyl]carbamate (1 g, 4.38 mmol) [prepared according to Ambler, J.; et. al. Bioorg. Med. Chem. Lett. 1999, 9, 9, 1317.] for 1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate, 4-bromo-3-fluoro-6-(methyloxy)quinoline (2.25 g, 8.77 mmol) for 8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (117 mg, 0.657 mmol) for 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS (ES) m/e 482 (M+H)+; 1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=4.5 Hz, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.34 (dd, J=2.7, 6.3 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 4.66 (s, 2H), 3.97 (s, 3H), 3.79 (s, 2H), 3.35-3.50 (m, 2H), 3.26-3.30 (m, 2H), 2.71-2.75 (m, 2H), 1.87-1.90 (m, 2H), 1.62-1.66 (m, 3H), 1.52-1.55 (m, 2H).
Reaction SMILES: [C:1]([O-])(=[O:12])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11].[Li].[H-].O>CCOCC>[CH2:1]([OH:12])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC=CC=C/C=C/C(=O)[O-]
Agent: [H-]
Agent: [Li]
Solvent: O
Solvent: CCOCC
Product: CCCCC=CC=C/C=C/CO
Yield: 64.7 %

Procedure:
To a solution of ethyl trans, trans, trans-2,4,6-undecatrienoate (12 g) in dry ether (300 ml) was added little by little, lithium alminum hydride (1.6 g) with stirring under ice-cooling in the course of 30 minutes and then the mixture was stirred for 30 minutes at ambient temperature. To the resultant mixture was added ether containing water and then insoluble materials was removed by filtration. The filtrate was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give oily trans, trans, trans-2,4,6-undecatrien-1-ol (7.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:30])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([O:19][CH3:20])[C:12]=1[O:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:10].N1CCCCC1>O>[Cl:30][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:19][CH3:20])[C:12]=1[O:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:10]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c(OCCc2ccccc2)c1OC
Solvent: O
Solvent: C1CCNCC1
Product: COc1c(O)ccc(C(=O)Cc2c(Cl)cncc2Cl)c1OCCc1ccccc1
Temperature: 90 °C

Procedure:
2-(3,5-Dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-2-phenethyloxy-phenyl)-ethanone obtained from example 112 (89.3 mg, 0.1 mmol) was treated with piperidine (0.8 mL) and water (0.32 mL). The yellow suspension was heated to 90° C. for 54 hours. The solvent was evaporated in vacuo. The crude mixture was treated with NH4Cl (sat., 1 mL) and the organic products were extracted with EtOAc (3×2 mL). The combined organic phases was dried over Na2SO4 and evaporated in vacuo. Purification by flash chromatography using a gradient of EtOAc in toluene as eluent provided 2-(3,5-dichloro-pyridin-4-yl)-1-(4-hydroxy-3-methoxy-2-phenethyloxy-phenyl)-ethanone as a white solid. Yield 8.6 mg (20%). 2-(3,5-Dichloro-pyridin-4-yl)-1-(4-hydroxy-3-methoxy-2-phenethyloxy-phenyl)-ethanone (5.5 mg, 0.013 mmol) was dissolved in DMSO (0.45 mL) and treated with K2CO3 (0.019 mL of a 1M aq. solution) followed by ethyliodide (0.019 mL of a 1M solution in DMSO). The reaction mixture was left at rt for 48 hours and purified by standard HPLC purification. 2-(3,5-Dichloro-pyridin-4-yl)-1-(4-ethoxy-3-methoxy-2-phenethyloxy-phenyl)-ethanone was obtained as a colourless solid. Yield 3.2 mg (36%).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[C:10]([NH:17][CH3:18])=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC([O:29][C:30](Cl)(Cl)Cl)=O>O1CCOCC1>[C:1]1([N:7]2[CH2:8][C:9]3[C:10](=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=3)[N:17]([CH3:18])[C:30]2=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNc1nc(SC)ncc1CNc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1ccccc1)C2
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A mixture of 200 mg (0.77 mmol) of 5-phenylaminomethyl-4-methylamino-2-methylthiopyrimidine and 0.2 ml (1.4 mmol) of triethylamine in 15 ml of dioxan was added dropwise to a solution, cooled in ice, of 150 mg (0.79 mmol) of trichloromethyl chloroformate in 10 ml of dioxan. The mixture was then left to warm to room temperature. After a further 10 minutes the mixture was evaporated. 40 ml of dichloromethane and 40 ml of saturated aqueous sodium bicarbonate solution were added to the residue. The phases were separated and the dichloromethane phase was dried over magnesium sulfate, filtered and evaporated to give 162 mg (74%) of 3-phenyl-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[O:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[Li])[CH3:18]>O1CCCC1>[NH2:15][C:7]1[C:6]([C:4]([C:24]2[CH:23]=[C:22]([F:25])[CH:21]=[CH:20][C:19]=2[O:17][CH3:18])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: [Li]c1cc(F)ccc1OC
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methylamide (400 mg, 1.65 mmol, Example 1) was dissolved in anhydrous tetrahydrofuran (6 mL) and cooled to −78° C. A solution of the freshly prepared 2-methoxyl-5-fluorophenyl lithium (˜5 equiv, prepared following the same procedure as described in Step A of Example 2) was added over 10-30 minutes and the orange colored reaction mixture was stirred at −78 to 0° C. for 1-3 hours until the complete consumption of the starting material. The resulting mixture was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate (3×20 mL), washed with brine (2×10 mL), dried over sodium sulfate and evaporated in vacuo. The residue was purified on silica gel with 80/20→60/40 of hexane/ethyl acetate to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid (277 mg). MS (M+H)+, 308.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.C([O:14][C:15]([C:17]1[C:21]2=[N:22][C:23]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:24][CH:25]=[C:20]2[NH:19][CH:18]=1)=O)C.CO>C1(C)C=CC=CC=1.ClCCCl>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:15]([C:17]1[C:21]2=[N:22][C:23]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:24][CH:25]=[C:20]2[NH:19][CH:18]=1)=[O:14]
Reactant: CCOC(=O)c1c[nH]c2ccc(OC3CCN(C)CC3)nc12
Reactant: Nc1ccccn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCCl
Product: CN1CCC(Oc2ccc3[nH]cc(C(=O)Nc4ccccn4)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
AlMe3 (0.3 mL, 0.59 mmol, 2 M in PhCH3) is added to a solution of 2-aminopyridine (56 mg, 0.59 mmol) in toluene (1.0 mL) and 1,2-dichloroethane (1.0 mL) at room temperature. The resulting solution is stirred for 30 minutes at room temperature, 5-(1-methyl-piperidin-4-yloxy)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid ethyl ester (60 mg, 0.20 mmol) is then added. The resulting mixture is heated at 100° C. for a period of 3 h. The mixture is cooled to room temperature and Na2SO4.10H2O (285 mg, 0.89 mmol) is added. The mixture is stirred for 30 minutes and MeOH (5 mL) is added. The resulting mixture is filtered through a pad of celite and washed with MeOH (3×5 mL) and CHCl3 (3×5 mL). The filtrate is concentrated and purified by chromatography on silica (gradient elution with 5% MeOH/CHCl3 with 0.1% NH4OH to 8% MeOH/CHCl3 with 0.1% NH4OH to 10% MeOH/CHCl3 with 0.1% NH4OH) to give the title compound as a light yellow solid: (Cmp. #1) 1H NMR (400 MHz, CD3OD) δ 8.29-8.27 (m, 2H), 8.01 (s, 1H), 7.73-7.69 (m, 2H), 7.03 (dd, 1H, J=7.1, 5.4 Hz), 6.63 (d, 1H, J=8.7 Hz), 5.40-5.34 (m, 1H), 2.86-2.80 (m, 2H), 2.57-2.52 (m, 2H), 2.35 (s, 3H), 2.30-2.26 (m, 2H), 1.91-1.86 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 163.9, 159.5, 152.4, 148.1, 139.1, 138.2, 131.6, 125.1, 124.1, 119.5, 114.2, 109.3, 107.2, 70.8, 53.6, 45.7, 30.8; MS (CI) m/z 352.3 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[O:19])[CH:14]=[CH:13][N:12]=1.O>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[C:1]([NH:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=2)=[O:19])[CH:14]=[CH:13][N:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C)cc(C(=O)Cc2ccnc(N)c2)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)cc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
Benzoyl chloride (7.5 g, 53 mmol) and 4-dimethylaminopyridine (1.0 g, 8.3 mmol) were added to a solution of 2-(2-amino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone (6.4 g, 27 mmol) in N,N-dimethylacetamide (100 mL) and the mixture was stirred at 70° C. for 12 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in a mixed solvent of tetrahydrofuran (150 mL) and methanol (40 mL) and 1N aqueous solution of sodium hydroxide (50 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, water (100 mL) was added and neutralized with 2N-hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 2:1) to obtain 6.4 g of the title compound (19 mmol, yield 70%).
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1([CH3:23])[CH:16]=[CH:15][C:14]([S:17]([O:20]CC)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[CH2:24](O)[CH3:25]>>[CH2:11]([S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N+:6]=1[CH2:24][CH3:25])[CH3:12].[CH3:23][C:11]1[CH:16]=[CH:15][C:14]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Sc1nc2ccccc2o1
Reactant: CCO
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Product: CCSc1oc2ccccc2[n+]1CC
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 150 °C

Procedure:
A mixture of 3.0 g of 2-mercaptobenzoxazole and 12.0 g of ethyl p-toluenesulfonate was heated to 150° C. to react them for 6 hours. The reaction product was cooled to 80° C., and 25 ml of ethanol was added to it, thereby producing an ethanol solution of 2-ethylmercapto-3-ethylbenzoxazolium-p-toluenesulfonate.
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:26]([OH:33])[C@@H:27]([C@@H:29](CO)[OH:30])[OH:28].C(=O)([O-])[O-].[K+].[K+].C(O)=O>CN(C)C=O>[CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C@@H:26]([C@@H:27]([CH2:29][OH:30])[OH:28])[OH:33])=[O:7]
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Reactant: OC[C@@H](O)[C@@H](O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC(=CCCC(=O)OC[C@H](O)[C@H](O)CO)CCCC(C)CCCC(C)CCCC(C)C
Reaction time: 10 h

Procedure:
Under reduced pressure of 60-70 mmHg and nitrogen gas stream, 199 g (0.564 mol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise to a solution of 191 g (1.56 mol) of erythritol and 1.58 g (1.15 mmol) of potassium carbonate in dry N,N-dimethylformamide (700 mL) at 78-83° C. After the reaction mixture was stirred at the same temperature for 10 hours, formic acid was added at 75° C. to adjust the pH to 4. After the resulting solution was subjected to vacuum concentration, the residue was diluted with t-butylmethylether (1.5 L), and the insoluble matter generated was separated by filtration. The filtrate was washed with 10% sodium bicarbonate aqueous solution twice, and decolorized with activated carbon (8 g). After filtration, the filtrate was concentrated, and the residue was dissolved in ethanol, followed by filtration through cellulose powder. After the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate mixture) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2]C(=O)C1C=CC(N)=C(C=O)C=1.[OH-].[K+].[Cl:16][C:17]1[CH:48]=[CH:47][C:20]([C:21]2[C:26]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:37]([OH:39])=[O:38])[CH:33]=4)[N:28]=3)=[CH:25][C:24](C(N3CCCC3)=O)=[CH:23][CH:22]=2)=[CH:19][CH:18]=1>CCO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[C:26]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:37]([OH:39])=[O:38])[CH:33]=4)[N:28]=3)=[CH:25][C:24]([O:2][CH3:1])=[CH:23][CH:22]=2)=[CH:47][CH:48]=1
Reactant: COC(=O)c1ccc(N)c(C=O)c1
Reactant: O=C(O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3-c3ccc(Cl)cc3)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(C(=O)O)ccc3n2)c1
Yield: 91 %

Procedure:
Compound 7 (3.06 g. 11.72 mmol) was reacted with compound 525a (2.1 g, 11.72 mmol) and KOH (2.32 g, 35.16 mmol) in EtOH (150 mL) according to the procedure in the preparation of Compound 259e. Purification by chromatography using CHCl3-MeOH (7:1) as the eluent gave the title intermediate (3.1 g, 91%). MS: 388.07 (M+H+).
Reaction SMILES: [F:1][C:2]([F:8])(F)[S:3]([O-:6])(=[O:5])=[O:4].[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([S+:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.[F:30][C:31]([F:37])(F)S([O-])(=O)=O.ClCl.[CH3:40]O>>[CH:24]12[CH2:40][CH:27]([CH2:26][CH2:25]1)[CH2:28][CH:29]2[C:31]([F:37])([F:30])[C:2]([F:8])([F:1])[S:3]([O-:6])(=[O:5])=[O:4].[CH:9]1([S:10][C:11]2[CH:12]=[CH:13][C:14]([S+:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH2:15][CH2:16][CH2:11][CH2:12][CH2:13]1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CSc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reactant: CO
Agent: ClCl
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C1CC2CCC1C2
Product: c1ccc([S+](c2ccccc2)c2ccc(SC3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
19.2 g of the resulting 4-methanethiophenyl diphenylsulfonium trifluoromethane sulfonate was dissolved in 100 g of methanol in a reaction flask. The mixture was fed into an ion-exchange chromatography (an ion-exchange resin: Shephadex R-QAE A25, packing amount: 60 g, manufactured by Aldrich Corporation) to replace trifluoromethanesulfonate anions with chlorine ions. After evaporating methanol using an evaporator, the resulting residue was dissolved in 100 g of dichloromethane. 15 g of 30 wt % 2-(bicyclo[2.2.1]heptan-2-yl)-1,1,2,2-tetrafluoroethane sodium sulfonate aqueous solution was added. The mixture was stirred for one hour at room temperature and transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. 100 ml of distilled water was added and the mixture was shaken again and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried with anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 20.1 g of 4-cyclohexylthiophenyl diphenylsulfonium 2-(bicyclo[2.2.1]heptan-2-yl)-1,1,2,2-tetrafluoroethanesulfonate. 20.1 g of the resulting 4-methanethiophenyl diphenylsulfonium 2-(bicyclo[2.2.1]heptan-2-yl)-1,1,2,2-tetrafluoroethanesulfonate was dissolved in 300 ml of methanol in a reaction flask. 18 g of 30 wt % hydrogen peroxide solution and 10.5 g of sodium tangstate dihydride were added. The mixture was stirred for 30 minutes at room temperature. The resulting methanol solution was condensed under reduced pressure and the residue was dissolved in 300 g of dichloromethane. The mixture was transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. 100 ml of distilled water was added and the mixture was shaken again and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried with anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 15.5 g of 4-methanesulfonylphenyl diphenylsulfonium 2-(bicyclo[2.2.1]heptan-2-yl)-1,1,2,2-tetrafluoroethanesulfonate. This compound is indicated as “acid generator (A-17)”.