Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:30]([CH3:31])=[C:29]([F:32])[C:28]([F:33])=[CH:27][C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:23]([NH:22][C:16]1[N:15]=[C:14]([N:13]2[C:2]3[C:3](=[CH:27][C:28]([F:33])=[C:29]([F:32])[C:30]=3[CH3:31])[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)[C:19]([F:20])=[CH:18][C:17]=1[F:21])([CH3:25])([CH3:26])[CH3:24]
Reactant: CCOC(=O)C(=CNc1nc(NC(C)(C)C)c(F)cc1F)C(=O)c1cc(F)c(F)c(C)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(C)c(F)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
To the solution of 4.6 g of the thus obtained ethyl 2-(2,4,5-trifluoro-3-methylbenzoyl)-3-[6-(t-butylamino)-3,5-difluoropyridine-2-yl]aminoacrylate in 10 ml dimethylformamide was added 1.35 g of potassium carbonate, and the mixture was stirred at 100° C. for 50 minutes. The reaction solution was extracted by adding water and acetic acid, and the organic layer was collected and dried over magnesium sulfate. The solvent was distilled off, and the residue was collected by filtration with ethanol and washed with diethylether to obtain 2.6 g of the title compound as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1)=[O:10].C([O-])([O-])=O.[K+].[K+].[CH3:25][S:26][CH2:27][CH2:28][CH2:29][CH2:30]S(C1C=CC(C)=CC=1)(=O)=O>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:30][CH2:29][CH2:28][CH2:27][S:26][CH3:25])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1)=[O:10]
Reactant: CSCCCCS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1nccc(C(=O)c2ccc(O)cc2F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CSCCCCOc1ccc(C(=O)c2ccnc(SC)n2)c(F)c1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
(2-Fluoro-4-hydroxyphenyl)-(2-methylsulfanyl-pyrimidin-4-yl)-methanone (2.26 g, 12.7 mmol), K2CO3 (3.5 g, 25.4 mmol) and 1-methylthio-4-tosylbutane (8.5 g, 44.5 mmol) were stirred in NMP for 1 h at 100° C., cooled to RT, filtered, diluted with water, and extracted into EtOAc. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography on a silica column eluting with hexane:ethyl acetate 9:1 to 3:2 to yield [2-fluoro-4-(4-methylsulfanyl-butoxy)-phenyl]-(2-methylsulfanyl-pyrimidin-4-yl)-methanone (3.42 g).
Reaction SMILES: [S:1]1[C:5]([C:6]2(C#N)[CH2:9][CH2:8][CH2:7]2)=[CH:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]1=2.C[Mg]I.CC[O:21][CH2:22][CH3:23]>>[S:1]1[C:5]([C:6]2([C:22](=[O:21])[CH3:23])[CH2:7][CH2:8][CH2:9]2)=[CH:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]1=2
Reactant: CCOCC
Reactant: N#CC1(c2cc3ccccc3s2)CCC1
Agent: C[Mg]I
Product: CC(=O)C1(c2cc3ccccc3s2)CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(benzo[b]thiophen-2-yl)cyclobutanecarbonitrile (7.7 g) in ether (50 ml) was added dropwise at ambient temperature under nitrogen to stirred ethereal methylmagnesium iodide solution (3M; 18 ml). When the addition was complete, the mixture was stirred at reflux temperature for 3.5 hours, then it was cooled to ambient temperature. The resulting solid was collected by filtration, washed well with ether, and added in portions to 5M hydrochloric acid (143 ml). The resulting mixture was heated at 95° C. with occasional stirring for 1.5 hours, then allowed to stand at ambient temperature for 18 h. The product was extracted into dichloromethane (3×200 ml), then the combined extracts were washed with water (2×400 ml) and saturated aqueous sodium hydrogen carbonate solution (400 ml), dried (Na2SO4), and the solvent removed in vacuo to give 1-[1-(benzo[b]thiophen-2 yl)cyclobutyl]ethanone as a brown oil (5 g) which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16]Cl)[C:10]=3[OH:18])[N:8]=[C:4]2[CH:3]=1.[CH2:21]([OH:26])[CH2:22][CH:23]([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][O:26][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]=3[OH:18])[N:8]=[C:4]2[CH:3]=1
Reactant: CC(C)CCO
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cc(COCCC(C)C)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
2-(5-Chloro-2H-benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (5.0 g, 16 mmol) is suspended in a mixture of isoamyl alcohol (20.0 g, 227 mmol) and acetone (5 g) and stirred at 80° C. for 15 minutes. Sodium carbonate (2.1 g, 20 mmol) is added. The slightly yellow reaction mixture is stirred at 80° C. for 2 hours and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with aqueous citric acid (5%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 4.7 g of 2-(5-Chloro-2H-benzotriazol-2-yl)-4-methyl-6-(3-methyl-butoxymethyl)-phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH2:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:15]([Cl:14])[CH:16]=2)=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 91.7 %

Procedure:
Following the procedure of Example 1, 5.04 g of 4-chlorobenzenesulfonyl isocyanate and 3.85 g of 3,4-dichloroaniline were allowed to react providing 8.06 g of the desired title product, m.p. 195°-196° C.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:20][CH3:21])=[C:10]([S:12]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13])[CH:11]=1>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:20][CH3:21])=[C:10]([S:12]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13])[CH:11]=1)#[N:2]
Reactant: COc1ccc(CBr)cc1S(=O)(=O)NC(C)(C)C
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CC#N)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A mixture of 1.63 g potassium cyanide and 8 g of the compound from Example 1 in 50 ml of DMSO was stirred at room temperature overnight. The solution became darker in color with time, going from orange to purple to black. After being stirred overnight the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and the solvent evaporated. The residual red oil was eluted through a dry silica column with 20% ethyl acetate-80% dichloromethane. The product band was isolated to give 3.0 g solid m.p. 146°-147° C.
Reaction SMILES: [CH2:1]([C:3]1[S:14][C:6]2=[N:7][C:8]([CH2:12][OH:13])=[CH:9][C:10](=[O:11])[N:5]2[N:4]=1)[CH3:2]>CC(C)=O.O=[Mn]=O>[CH2:1]([C:3]1[S:14][C:6]2=[N:7][C:8]([CH:12]=[O:13])=[CH:9][C:10](=[O:11])[N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2c(=O)cc(CO)nc2s1
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: CCc1nn2c(=O)cc(C=O)nc2s1

Procedure:
A mixture of 7-Chloromethyl-2-ethyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (11.48 g, 50 mmol), sodium iodide (15 g, 100 mmol, 2 equiv), sodium bicarbonate (12.6 g, 150 mmol, 3 equiv), water (25 mL) and DMSO (250 mL) was stirred and heated at 80° C. for 18 h. The volatiles were mostly removed on the rotary evaporator, then the residue treated with ethyl acetate to precipitate the salts, and the mixture filtered. The filtrate was lyophilized and chromatographed on silica gel using a gradient of ethyl acetate to 3% methanol in ethyl acetate, affording 2-ethyl-7-hydroxymethyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (4.24 g, 40%). This alcohol was dissolved in acetone (150 mL) and refluxed for 3 days with a total of 15 equivalents of MnO2, added in 3-equiv portions over this time, affording complete conversion to the corresponding aldehyde. The reaction mixture was filtered through celite, the cake washed with acetone (3×100 mL), and the filtrate concentrated in vacuo, affording the title product (2.84 g, 67%). 1H NMR (300 MHz, CDCl3): δ 1.55 (t, 3H), 3.10 (q, 2H), 6.98 (s, 1H), 9.90 (s, 1H). MS (APCI) calcd for C8H7ClN3O2S: 209.03, found (M+H+): 210.2.
Reaction SMILES: [N:1]1([CH2:7][C:8](=[CH2:11])[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]CC.[Na+].Cl>C(O)C>[N:1]1([CH2:7][CH:8]2[CH2:11][N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:19][C:9]2=[NH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNc1ccccc1
Reactant: C=C(C#N)CN1CCCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N=C1NN(c2ccccc2)CC1CN1CCCCC1

Procedure:
α-Piperidinomethylacrylonitrile (17g) and phenylhydrazine (10.8g) were added to a solution of sodium ethoxide (2.3g sodium) in ethanol (200 ml). The resulting solution was boiled under reflux for 2 hours and a solid precipitate formed during the reaction. Dilute hydrochloric acid (50 ml of 2N) was added to the reaction mixture and the solution was evaporated to dryness. The solid residue was extracted with dry ethanol and the product crystallised from the ethanol as colourless plates (melting point 186-7° C).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:38])=[CH:40][CH:41]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CC(C)(C)Oc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)cc1

Procedure:
The title compound, white solid (113 mg, 89%), MS (ISP) m/z=507.4 [(M+H)+], mp 168.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-tert-butoxy-benzoic acid.
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[N:15]=1)=[CH2:2].[CH3:17][NH:18][CH3:19]>C(Cl)Cl.CO>[CH3:17][N:18]([CH3:19])[CH2:2][CH2:1][C:3]1[S:4][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[N:15]=1
Reactant: C=Cc1nc2c([nH]c(=O)c3ccccc32)s1
Reactant: CNC
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCc1nc2c([nH]c(=O)c3ccccc32)s1
Temperature: 65 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
To a suspension of 2-vinyl-4H-1,3-thiazolo[5,4-c]isoquinolin-5-one (0.05 g, 0.22 mmol) and CH2Cl2/methanol (6 ml; 1/1) was added dimethylamine (0.33 ml of 2M solution in THF, 0.66 mmol). After stirring at 65° C. for 48 hours, the reaction mixture was concentrated under reduced pressure and purified by flash-chromatography (CH2Cl2/methanol, 90/10). Recrystallization from methanol/diethyl ether yielded 0.038 g (a 63% yield) of the title compound as a white solid. m.p. 236-240° C. (dec.); 1H NMR (400 MHz, DMSO) δ 2.85 (s, 6H, (CH2)2N(CH3)2), 3.52-3.56 (m, 4H, (CH2)2N(CH3)2), 7.56-7.59 (m, 1H, Ar), 7.84-7.87 (m, 1H, Ar), 8.19-8.26 (m, 2H, Ar), 12.37 (bs, NH); 13C NMR (100.6 MHz, DMSO) δ 29.71, 44.26, 56.79, 124.03, 125.74, 128.69, 129.79, 133.45, 134.44, 135.15, 158.51, 162.72.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][S:12](=[S:21])([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19]Br)=[O:13].[Cl-].[Cs+]>>[CH3:11][S:12](=[S:21])([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:8])=[O:13]
Reactant: CS(=O)(=S)OCCOCCBr
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Cl-]
Agent: [Cs+]
Product: CS(=O)(=S)OCCOCCOC(=O)c1ccc(N)cc1
Yield: 14.7 %

Procedure:
In a manner analogous to that above, the reaction of p-aminobenzoic acid (671 mg; 4.90 mmol), 1-(5-bromo-3-oxapentyl) methanethiosulfonate (1.29 g, 4.9 mmol) and CsCl (1.63 g, 5 mmol) yielded 7-(4-aminophenyl)-7-oxo-3,6-dioxaheptyl methanethiosulfonate (230 mg). 1H NMR (500 MHz, (CD3)2SO) δ 7.62 (d, J=8.7 Hz, 2H), 6.55 (d, J=8.7 Hz, 2H), 5.95 (s, br., 2H), 4.27 (t, J=4.7 Hz, 2H), 3.77 (t, J=6.0 Hz, 2H), 3.73 (t, J=4.7 Hz, 2H), 3.50 (s, 3H), 3.39 (t, J=6.0 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].C(Cl)(=O)C(C)(C)C.C(NCC)C>O1CCCC1>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Temperature: -4 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
To a 12 L flask equipped with mechanical stirrer and cold bath was charged 300 g (2 mol) of 4-carboxybenzaldehyde, 4.5 L of tetrahydrofuran and 245 g (2.4 mol) of triethylamine. This solution was cooled to −4° C. with methanol/ice bath. To the reaction was charged 236 g (1.9 mol) of pivaloyl chloride at a rate that maintained the temperature below 5° C. After stirring for 2 h the resulting slurry was filtered and the filter cake was washed with 1 L of THF. The filtrates were returned to the reactor and cooled below −5° C. Diethylamine (438 g, 6 mol) was slowly added maintaining the temperature below 0° C. The reaction was stirred for several hours and allowed to warm. The solvent was then removed under vacuum and the resulting residue was dissolved in 2 L of ethyl acetate. The resulting solution was washed with 1 L of water and the aqueous layer was back-extracted with 2×500 mL ethyl acetate. The combined organic layer was washed with 3×500 mL of 1 N HCl and 3×500 mL of NaHCO3 (aq, sat). This solution was dried with Na2SO4 and the solvent was removed under vacuum to give a golden brown oil (172 g, 85%) containing ˜13% impurity by NMR. The aldehyde was used with out further purification.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.S(=O)(=O)(O)[OH:15].N([O-])=O.[Na+]>C(Cl)Cl>[OH:15][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(O)cc1OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
To a 250 mL Erlenmeyer flask was added methyl 4-amino-2-methoxybenzoate (7.5 g, 41.4 mmol) and a 25% solution of sulfuric acid (40 mL, 188 mmol). The solution was cooled to 0° C. and a saturated solution of sodium nitrite (4.29 g, 62.2 mmol) was added drop wise. The orange mixture was stirred for 15 minutes. The resulting diazonium solution was then very slowly poured into a 1 L flask containing 500 mL of 3% sulfuric acid. The solution was stirred for 5 minutes then transferred to a separatory funnel. The reaction mixture was diluted with 150 mL of DCM, extracted, dried over magnesium sulfate and concentrated. to a red solid. The resulting solid was triturated with hexane to give 5.71 grams of the desired phenol as a red powder (73% yield). The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 1 minute hold at a rate of 4 mL/minute. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.67-3.72 (m, 3 H), 3.74 (s, 3 H), 6.39 (dd, J=8.66, 2.13 Hz, 1 H), 6.45 (d, J=2.13 Hz, 1 H), 7.59 (d, J=8.66 Hz, 2 H). LCMS Rt=1.070 min., m/z 183.09 (M+H), 96% purity.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=4[C:30]([O:32][CH3:33])=[O:31])[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:42]([P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:56]([O:55][P:51](/[CH:42]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=4[C:30]([O:32][CH3:33])=[O:31])[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:52][CH2:53][CH3:54])=[O:58])[CH3:57]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COC(=O)c1ccccc1-c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3C=O)cc2OC)c(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3C(=O)OC)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 50.8 %

Procedure:
To a mixture of methyl 2-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (0.65 g), tetraethyl methylenediphosphonate (0.37 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.060 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate as a colorless oil (0.41 g, yield 49%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v).
Reaction SMILES: [CH2:1]([N:4]([C:6]([CH3:13])([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH2:5])[CH:2]=[CH2:3].[CH2:14]([N:21]=[C:22]=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:4]([C:6]([CH3:12])([CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:5][C:22](=[O:23])[NH:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:2]=[CH2:3]
Reactant: O=C=NCc1ccccc1
Reactant: C=CCN(N)C(C)(C)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCN(NC(=O)NCc1ccccc1)C(C)(C)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of ethyl 2-(1-allylhydrazinyl)-2-methylpropanoate (Compound XIV-1) (4.33 g, 23.25 mmol) in THF was added benzyl isocyanate (2.87 ml, 23.25 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with water (100 ml) and brine (100 ml). Then the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was subjected to silica gel column chromatography (eluent: n-hexane:ethylacetate=1:1 to 1:2) to obtain the title compound (2.55 g, 35%).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=O)[O:8][C:4]=2[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([CH:29]3[C:33]4[NH:34][C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=5[C:41](=[O:42])[C:32]=4[CH2:31][NH:30]3)=[CH:23][C:22]=2[O:21]1.C(N(CC)CC)C>O1CCCC1.CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([CH:29]3[C:33]4[NH:34][C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=5[C:41](=[O:42])[C:32]=4[CH2:31][N:30]3[C:9]([C:7]3[O:8][C:4]4[CH:3]=[C:2]([OH:1])[CH:13]=[CH:12][C:5]=4[CH:6]=3)=[O:11])=[CH:23][C:22]=2[O:21]1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)NC2
Reactant: O=C(O)c1cc2ccc(O)cc2o1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc2ccc(O)cc2o1)N1Cc2c([nH]c3ccccc3c2=O)C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-hydroxy-2-benzofuranoic acid (0.054 g, 0.3 mmol) in tetrahydrofuran (5 mL) at 0° C. was added dropwise oxalyl chloride (0.046 g, 0.36 mmol) followed by DMF (2 drops). The solution was warmed to 25° C. and stirred for 30 min, then concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL), and added to a solution of 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (0.092 g, 0.3 mmol) (prepared as in Example 5) in THF (5 ml), triethylamine (0.045 g, 0.45 mmol) and 4-dimethylaminopyridine (0.01 g, cat.). The solution was stirred for 20 h at 25° C., and then concentrated in vacuo. The resulting crude residue was purified by silica gel column chromatography, eluting with 3% methanol in dichloromethane, to yield the product as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:13]>O1CCOCC1>[Cl:13][C:3]1[C:2]([CH3:1])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(C)c(=O)[nH]1
Solvent: C1COCCO1
Product: CSc1ncc(C)c(Cl)n1
Yield: 89 %

Procedure:
A mixture of 5-methyl-2-methylsulfanyl-3H-pyrimidin-4-one (6.86 g, 44 mmol) and POCl3 (14 ml) in dioxane (60 ml) was refluxed for 2 hours. The solvent was removed under vacuum and the residue was quenched with ice and extracted with diethylether. The organic phase was dried (Na2SO4) and evaporated to give 6.8 g of the title compound as oil that was used in the next step without further purification. (89% yield)
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.1 %

Procedure:
To a cooled and stirred solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (example 155) (0.38 g, 0.65 mmol) in dichloromethane (5 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.31 g, 90%). MS (ISN) 522.3 [(M−H)−]; mp 267° C.