Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[NH:26][CH:27]([CH:31]([CH3:33])[CH3:32])[C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C)C=O>[CH3:15][C:16]1[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][C:17]=1[NH:26][CH:27]([CH:31]([CH3:33])[CH3:32])[C:28]([O:14][CH2:13][C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:29]
Reactant: Cc1cc(C(F)(F)F)ccc1NC(C(=O)O)C(C)C
Reactant: OCc1[nH]ccc1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)ccc1NC(C(=O)OCc1[nH]ccc1Cc1ccccc1)C(C)C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-benzylpyrrolylmethyl alcohol (1.8 mmol), 2-(2-methyl-4-trifluoromethylphenylamino)-3-methylbutanoic acid (2.0 mmol) and 4-dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of dimethylformamide is added N,N'-dicyclohexylcarbodiimide (2.0 mml). The reaction mixture is stirred, under nitrogen, for two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a rotary chromatograph eluting with 25% ether/hexane to yield 3-benzylpyrrolylmethyl 2-(2-methyl-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:16]([CH3:24])([CH2:17][CH2:18][C:19]=32)[C@@H:11]([C@H:12]([CH3:15])[CH:13]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:26])[CH3:25].[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:27]1([N:33]2[CH2:38][CH2:37][N:36]([CH2:15][C@H:12]([C@@H:11]3[C@:16]4([CH3:24])[C:8]([C:7]5[CH2:6][CH2:5][C@@H:4]6[C@:20]([C:19]=5[CH2:18][CH2:17]4)([CH3:23])[CH2:21][CH2:22][C@H:2]([OH:1])[C:3]6([CH3:26])[CH3:25])=[CH:9][CH2:10]3)[CH3:13])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@H](CN1CCN(c2ccccc2)CC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-al was treated with N-phenyl-piperazine and sodium tris(acetoxy)borohydride as described in Example 1h). (20S)-20-[(4-phenylpiperazin-1-yl)methyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[NH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27]([NH:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NN1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NN4CCCCC4)cc3)c2cc1OC
Yield: 56.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (40 mg, yield 56%).
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][CH:7]([F:33])[C:8]1[N:9]=[C:10]([CH2:30][CH2:31][CH3:32])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:12](=[O:14])[CH:13]=1.[Br:34]Br>C(O)(=O)C>[Br:34][C:13]1[C:12](=[O:14])[N:11]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:10]([CH2:30][CH2:31][CH3:32])=[N:9][C:8]=1[CH:7]([F:6])[F:33]
Reactant: CCCc1nc(C(F)F)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(C(F)F)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 4 h
Yield: 61 %

Procedure:
To a solution of sodium acetate (1 g) and 4′-{[4-(difluoromethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (4.4 g) in acetic acid (44 mL) was added bromine (0.62 mL), and the mixture was stirred for 4 hr. Acetic acid was removed in vacuo, and the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (2.7 g, 61%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)[C:3]=1[C:4]([OH:6])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1[C:33](=O)C2C(=CC=CC=2)C1=O.ClC1[N:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)[C:3]=1[C:4]([N:20]1[CH2:21][CH2:22][CH2:23][C@@H:18]([CH3:17])[C@H:19]1[CH2:24][NH:25][C:33]1[N:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1)=[O:6]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: O=C(O)c1c(-n2nccn2)ccc(F)c1F
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Product: C[C@@H]1CCCN(C(=O)c2c(-n3nccn3)ccc(F)c2F)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 2,3-difluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 482 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.75-7.05 (m, 7H), 5.05-2.70 (m, 5H), 1.95-0.65 (m, 8H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]([O:16]CC)=O)=[O:5])[CH3:2].[O-:27][C:28]#[N:29].[K+].Cl>>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14](=[O:16])[NH:29][C:28]1=[O:27])=[O:5])[CH3:2]
Reactant: CCCCCCCCC(NCCCCCCC(=O)OCC)C(=O)OCC
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Product: CCCCCCCCC1C(=O)NC(=O)N1CCCCCCC(=O)OCC

Procedure:
Ethyl 2-(6-ethoxycarbonylhexylamino)decanoate (7.4 g) was reacted with potassium cyanate and hydrochloric acid to give 1-(6-ethoxycarbonylhexyl)-5-octylhydantoin which formed colourless crystals, m.p. 68°-70° C., from light petroleum (b.p. 60°-80° C.).
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH:14]1([C:12](=[O:13])[CH:11]([N:8]2[CH2:9][CH2:10][CH:5]([SH:4])/[C:6](=[CH:24]/[C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)/[CH2:7]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:16][CH2:15]1
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(C1CC1)C(c1ccccc1F)N1CCC(S)/C(=C/c2ccco2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-[(furan-2-yl)methylidene]piperidine (100 mg) in methanol (2.5 ml) was added potassium carbonate (50 mg) under ice-cooling, and the resulting mixture was stirred at room temperature for 15 minutes. After stirring, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified using a preparative HPLC [YMC-Pack ODS-A; YMC, mobile phase: a mixture of 70% methanol/water containing acetic acid (0.20%) and triethylamine (0.45%) (70:30, v/v)]. The eluted fraction containing the reaction product was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to afford the title compound (40 mg, yield: 45%) as pale brown crystals.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[CH:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].O.S(=O)(=O)(O)[OH:20]>C(O)(=O)C>[C:16]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:14][C:13]2=[O:15])(=[O:20])[CH3:17]
Reactant: C#Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1.20 g of 2-butyl-6-ethynyl-4(1H)-quinazolinone in 90 ml of acetic acid is added 0.45 g of mercuric sulfate, 0.9 ml of water and 0.3 ml of sulfuric acid. The reaction mixture is heated at reflux for 5 hours, cooled to room temperature and quenched with 150 ml of water. The resulting mixture is concentrated in vacuo, diluted with 150 ml of water and extracted with 6:1 chloroform-methanol. The combined organics are dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate-hexanes to give 0.67 g of the desired product as a white solid. CI MASS SPEC 245(M+).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)=[CH:12][C:7]=2[C:6](=[O:24])[NH:5][CH2:4][C:3]1=[O:25].[H-].[Na+].[H][H].Br[CH2:31][CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([O:33][CH2:32][CH2:31][N:5]1[C:6](=[O:24])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=3)[CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:25])[CH2:4]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: [H][H]
Reactant: BrCCOCc1ccccc1
Reactant: CN1C(=O)CNC(=O)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN(CCOCc2ccccc2)C(=O)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc21
Reaction time: 0.83 h
Yield: 61.6 %

Procedure:
1-Methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (50.0 mg, 0.143 mmol) and NaH (17 mg, 0.428 mmol, 3.0 equiv.) were placed in a 2-5 mL Smith process vial under a nitrogen atmosphere. To the vial was added DMF (5 mL) to observe hydrogen extlusion. And then ((2-bromoethoxy)methyl)benzene (45 μL, 0.285 mmol, d=0.135, 2 equiv.) was added at room temperature. After stirring for 50 min, the reaction was quenched with AcOH. Resulting mixture was directly injected to a preparative HPLC to give the desired product (4-(2-(benzyloxy)ethyl)-1-methyl-7-(4-(trifluoromethoxy)-phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione, 42.7 mg) as a light yellow film.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[C:15]([C:24]#[N:25])=[N:14]1.ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19]([C:20]([F:23])([F:21])[F:22])=[O:34])[C:15]([C:24]#[N:25])=[N:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1S(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 15 g (35.5 mmol) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole in 125 ml of dichloromethane at room temperature was added a solution of m-chloroperbenzoic acid (8.76 g, 70%, 35.5 mmol) in 375 ml of dichloromehane. The resulting solution was stirred at room temperature for 17 hr. It was then concentrated and triturated with ethyl acetate and heptane (1:2). Upon filtration a solid was obtained. This solid was dissolved in ethyl acetate and stirred with saturated sodium bicarbonate solution. Ther layers were separated and the aqueous layer was extracted with three times of ethyl acetate. The combined organic layer was dried (magnesium sulfate) and concentrated. Upon chromatographic purification via silica gel column, a solid (5.7 g, 13.01 mol, 37%) was obtained as the desired product, mp 185-187d.
Reaction SMILES: [NH2:1][C:2](=[N:35][N+]([O-])=O)[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1)=[O:25])[NH:8][C:9]([CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10].[C:39]([OH:42])(=[O:41])[CH3:40]>[Pd]>[CH:13]1[C:12]2[CH:11]([C:9]([NH:8][C@@H:7]([C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:41])=[O:25])[CH2:6][CH2:5][CH2:4][NH:3][C:2](=[NH:35])[NH2:1])=[O:10])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1.[C:39]([O-:42])(=[O:41])[CH3:40]
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C1c2ccccc2-c2ccccc21)C(=O)NCc1ccc(O)cc1
Reactant: CC(=O)O
Agent: [Pd]
Product: CC(=O)[O-]
Product: N=C(N)NCCC[C@@H](NC(=O)C1c2ccccc2-c2ccccc21)C(=O)NCc1ccccc1O
Yield: 40 %

Procedure:
Prepared analogously to Example 1c) from (R)-N5 -[amino(nitroimino)methyl]-N2 -[(9-fluorenyl)carbonyl]-N-[(4-hydroxyphenyl)methyl]-ornithinamide by catalytic hydrogenation in the presence of palladium black and 80% aqueous acetic acid in a yield of 40% of theory.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[H-].[Na+].[OH2:23]>>[Cl:11][C:4]1[C:3]([S:12]([N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[C:2]([OH:23])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1O
Yield: 33.5 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, 2,6-dichloro-3-nitro-1-(4-thiomorpholinylsufonyl)benzene (1.04 g, 2.91 mmol), 60% NaH (349 mg, 8.73 mmol) and water (63 μL, 3.50 mmol) were reacted to form the desired product (330 mg, 33%). EI-MS (m/z) 336.89, 338.93 (M−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14](SC)=[N:15][CH2:16][Si](C)(C)C)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:2].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[N:25]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:23][C:24]1[CH:29]=[C:28]([C:30]2([C:32]([F:33])([F:34])[F:35])[CH2:31][C:14]([C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[N:12][CH:11]=[N:10]4)=[C:3]([CH:4]=3)[C:1]#[N:2])=[N:15][CH2:16]2)[CH:27]=[C:26]([Cl:36])[N:25]=1
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(-n2cncn2)c(C#N)c1
Reactant: C=C(c1cc(Cl)nc(Cl)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C2=NCC(c3cc(Cl)nc(Cl)c3)(C(F)(F)F)C2)ccc1-n1cncn1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To the crude solution of methyl 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzenecarbimidothioate (Japanese patent application JP2008-143120) was added 2,6-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (0.15 g) and the resultant mixture was cooled to −10° C. Additionally, a solution of tetrabutylammonium fluoride (0.70 mL of 1.0 M in THF) in THF was added over 10 minutes under argon atmosphere. The reaction mixture was stirred for 30 minutes at the same temperature and returned to room temperature gradually, and then stirred 3 hours. Water was added to the reaction liquor, and aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous brine, and subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 5-[3-(2,6-dichloropyridin-4-yl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.14 g) at a yield of 46%.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9](Br)[CH:10]=[CH2:11].C1(=O)OCC1.BrCCCCCCCCC=C>>[CH2:11]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:1]1=[O:8])[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: O=C1CCCCCO1
Agent: C=CCCCCCCCCBr
Agent: O=C1CCO1
Product: C=CCC1CCCCOC1=O
Yield: 65 %

Procedure:
10.02 g of 3-(2-propenyl)-2-oxepanone of interest were prepared in the same manner as in Preparation Example 2Z-3 except that 11.41 g (100.0 mmol) of ε-caprolactone and 14.52 g (110.0 mmol) of allyl bromide were used instead of β-propiolactone and 10-bromo-1-decene described in Preparation Example 2Z-0.3, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][N:30]([CH2:38][CH3:39])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:28][CH2:29][N:30]([CH2:38][CH3:39])[C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=5)=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: CCN(CCCl)c1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CCOc1ccc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1OC)c1cccc(C)c1
Temperature: 75 °C
Yield: 42 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (96 mg, 0.25 mmol, the preparation of which can be found in the section detailing the preparation of Example K1) in DMF was added N-(2-chloroethyl)-N-ethyl-3-methylaniline (99 mg, 0.50 mmol) and cesium carbonate (0.24 g, 0.75 mmol) and the mixture was stirred with heating at 75° C. for 12 h. The reaction was allowed to cool and 10 mL solution of 20% water/ethanol was added. The resulting precipitate was filtered and dried in a vacuum oven to give the title compound (58 mg, 42%). 1H NMR (DMSO-D6) δ 1.13 (3H, t, J=7.0 Hz), 2.24 (3H, s), 3.45 (2H, q, J=7.0 Hz), 3.70 (2H, d, J=5.8 Hz), 3.79 (3H, s), 4.16 (2H, d, J=5.8 Hz), 6.43 (1H, t, J=7.3 Hz), 6.57 (2H, m), 7.02-7.20 (4H, m), 7.60 (2H, d, J=8.6 Hz), 7.96 (3H, m), 8.39 (1H, s). LCMS m/z=546 (m+H+).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:9]1)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:9]1
Reactant: O=[O+][O-]
Reactant: CC=CCC1CC(=O)c2ccccc2S1
Solvent: ClCCl
Solvent: CO
Product: O=CCC1CC(=O)c2ccccc2S1
Reaction time: 0.25 h
Yield: 99 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted while stirring for 15 minutes through a solution, cooled to -70°, of 3 g of (RS)-2-(2-buten-1-yl)-4-thiochromanone in 100 ml of anhydrous dichloro-methane and 30 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was subsequently evaporated in a vacuum. The residue was treated with 50 ml of dichloromethane and, after the addition of 5 ml of water and 5 ml of trifluoroacetic acid, stirred at room temperature for 1 hour. The mixture was subsequently poured into 50 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 80 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. There were obtained 2.8 g (99%) of 2-(2-oxoethyl)-4-thiochromanone as a yellow oil which was used in the next reaction without further recrystallization.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[C:13]([C:16]1[S:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:9]([O:8][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([C:19]2[S:20][C:16]([C:13](=[O:15])[CH3:14])=[CH:17][CH:18]=2)[CH:7]=1)[CH3:10]
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: CCOc1cc(Cl)nc(SC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccc(C(C)=O)s2)nc(SC)n1
Temperature: 80 °C
Yield: 27.9 %

Procedure:
The crude product of Preparation 27, 4-chloro-6-ethoxy-2-methylsulfanylpyrimidine, (525 mg, 2.56 mmol) was dissolved in DMF (4 mL). To this solution was added 5-acetyl-2-thiopheneboronic acid (523 mg, 3.08 mmol), PdCl2dppf (209 mg, 0.26 mmol), potassium carbonate (1.06 g, 7.69 mmol) and water (0.4 mL). The reaction mixture was heated at 80° C. under nitrogen atmosphere for overnight. The reaction mixture was cooled and poured into 30 mL of water and was then extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo. The resulting crude product was purified by flash silica column chromatography (20% ethyl acetate in hexane) to give product 1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone (210 mg, 28% yield over two steps). 1H-NMR (CDCl3): δ 7.67 (m, 2H), 6.68 (s, 1H), 4.46 (q, J=7.1 Hz, 2H), 2.60 (s, 3H), 2.59 (s, 3H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[CH:11]1[C:24]2[CH:23]([C:25](Cl)=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>>[C:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:25]([CH:23]2[C:24]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[O:16][C:17]3[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:26])=[N:6]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)n1nnc(N)n1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: CC(C)(C)n1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid, m.p. 230-231° and MS: (neg. ions): m/e=348.2 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-tert-butyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.