Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37](O)=[O:38])[C:32]2=[O:40])=[CH:27][CH:26]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O.O>[O:17]=[C:11]1[C:10]2[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=2[C:8]2[C:13](=[N:14][CH:15]=[CH:16][C:7]=2[O:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:33]3[C:32](=[O:40])[N:31]([C:28]4[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=4)[CH:36]=[CH:35][CH:34]=3)=[O:38])=[CH:3][CH:4]=2)[NH:12]1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Compound 137 (40 mg, 0.13 mmol), 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (37 mg, 0.16 mmol), BOP-Cl (50 mg, 0.20 mmol), and DIEA (0.07 mL, 0.40 mmol) were suspended in dioxane (2 mL), and stirred overnight at room temperature. The reaction mixture was diluted with EtOAc/H2O. The resulting precipitate was filtered, washed with EtOAc/H2O, and dried under vacuum to provide 181 (42 mg, 61% yield) as a white solid. LC-MS (M+H=519, obsd.=519).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]([CH2:33][C:34]#[C:35][CH3:36])[C:17](=[O:32])[N:18]3COC(=O)C(C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]([CH2:33][C:34]#[C:35][CH3:36])[C:17](=[O:32])[NH:18]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCn1c(=O)n(COC(=O)C(C)(C)C)c2nc(Cl)nc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCn1c(=O)[nH]c2nc(Cl)nc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
4-[7-(2-Butynyl)-2-chloro-9-(2,2-dimethylpropionyloxymethyl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazine-1-carboxylic acid t-butyl ester (665 mg) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (3 mL), and then sodium hydride (60-72% in oil) (61 mg) was added to this solution. The reaction solution was stirred at room temperature for three hours. 1 N aqueous hydrochloric acid (3 mL) was then added to the reaction solution, which was extracted using ethyl acetate. The obtained organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (294 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH:16]=[C:17]3C(=O)OC(C)(C)[O:19][C:18]3=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[C:9]2[CH:14]=[C:13]3[C:12](=[CH:11][CH:10]=2)[N:15]=[CH:16][CH:17]=[C:18]3[OH:19])=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(=CNc2ccc(C(c3ccc(Cl)cc3)c3nccs3)cc2)C(=O)O1
Solvent: CCCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Oc1ccnc2ccc(C(c3ccc(Cl)cc3)c3nccs3)cc12
Temperature: 25 °C

Procedure:
5-(((4-((4-Chlorophenyl)(thiazol-2-yl)methyl)phenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.8 g, 3.957 mmol) was added as a solid portionwise over 3-4 minutes to DOWTHERM (75 mL) at 220° C. The resulting mixture was heated for 20 minutes, cooled to room temperature, and treated with excess heptane (30 mL) with stirring. After allowing the solid to settle, the supernatant was decanted and the process repeated 3 times. After concentrating to remove heptane, the residue was purified by MPLC using a dichloromethane-methanol gradient to yield 6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-4-ol. (ES, m/z) 352, 354 [M+H]+
Reaction SMILES: CC(C)(C)[C@H](NC(=O)[C@@H](NC)C)C(N1[C@H](C(N[C@H]2C3C(=CC=CC=3)CCC2)=O)CC2C(=CC([C@H]3C[C@@H](C(=O)N[C@H]4C5C(=CC=CC=5)CCC4)N(C(=O)[C@@H](NC(=O)[C@@H](NC)C)C(C)(C)C)C3)=CC=2)C1)=O.[C:70]([O:74][C:75]([N:77]1[C@H:81]([C:82](=[O:94])[NH:83][C@H:84]2[C:93]3[C:88](=[CH:89][CH:90]=[CH:91][CH:92]=3)[CH2:87][CH2:86][CH2:85]2)[CH:80]=[C:79]([C:95]2[CH:104]=[C:103]3[C:98]([CH2:99][C@@H:100]([C:112]([O:114][CH3:115])=[O:113])[N:101]([C:105]([O:107][C:108]([CH3:111])([CH3:110])[CH3:109])=[O:106])[CH2:102]3)=[CH:97][CH:96]=2)[CH2:78]1)=[O:76])([CH3:73])([CH3:72])[CH3:71]>>[C:70]([O:74][C:75]([N:77]1[C@H:81]([C:82](=[O:94])[NH:83][C@H:84]2[C:93]3[C:88](=[CH:89][CH:90]=[CH:91][CH:92]=3)[CH2:87][CH2:86][CH2:85]2)[CH2:80][C@H:79]([C:95]2[CH:104]=[C:103]3[C:98]([CH2:99][C@@H:100]([C:112]([O:114][CH3:115])=[O:113])[N:101]([C:105]([O:107][C:108]([CH3:110])([CH3:109])[CH3:111])=[O:106])[CH2:102]3)=[CH:97][CH:96]=2)[CH2:78]1)=[O:76])([CH3:73])([CH3:71])[CH3:72]
Reactant: COC(=O)[C@@H]1Cc2ccc(C3=C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)OC(C)(C)C)C3)cc2CN1C(=O)OC(C)(C)C
Agent: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Product: COC(=O)[C@@H]1Cc2ccc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)OC(C)(C)C)C3)cc2CN1C(=O)OC(C)(C)C
Yield: 88.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound E of Example 22, (S)-2-tert-butyl 3-methyl 7-((S)-1-(tert-butoxycarbonyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-2,5-dihydro-1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (730 mg, 1.16 mmol) was converted to the title compound (650 mg, 89%). MS (ESI+) m/z 634.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH:17]1([C:20](=O)[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:19][CH2:18]1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>CCO>[CH3:25][O:24][C:22]([C:21]1[C:20]([CH:17]2[CH2:19][CH2:18]2)=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:4][C:5]([Cl:8])=[CH:6][CH:7]=2)=[O:23]
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: COC(=O)c1c(C2CC2)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
In a 5 ml round-bottomed flask, (2-amino-5-chlorophenyl)(phenyl)methanone (100 mg, 432 μmol, Eq: 1.00) and methyl 3-cyclopropyl-3-oxopropanoate (79.8 mg, 561 μmol, Eq: 1.3) were combined with EtOH (1.5 ml) to give a light yellow solution. Ytterbium triflate (26.9 mg, 43.2 μmol, Eq: 0.1) was added. The mixture was stirred at room temperature overnight, upon which a white precipitate formed. The precipitate was filtered and washed with ethanol to provide the title compound (67 mg, 46%) as a white powder.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C@H:21]([CH3:25])[C:22](O)=[O:23])[CH:15]=[CH:14]2.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C@H:21]([CH3:25])[C:22]([O:1][CH2:2][C:3]([CH2:7][OH:8])([CH3:4])[CH2:5][OH:6])=[O:23])[CH:15]=[CH:14]2
Reactant: CC(CO)(CO)CO
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2cc([C@H](C)C(=O)OCC(C)(CO)CO)ccc2c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 65.4 %

Procedure:
To a stirred solution of 1,1,1-tris(hydroxymethyl)ethane (13.1 g, 109 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 5.00 g, 21.7 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (4.80 g, 25 mmol), and N,N-dimethylaminopyridine (DMAP, 20 mg, catalytic amount) in acetonitrile (200 mL) was added triethylamine (4.2 mL, 30 mmol). The reaction mixture was stirred at ambient temperature for 25 hours, filtered, and the filtrate was concentrated to dryness. The residue was diluted with EtOAc, washed with 1N HCl (2×), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The resulting material was purified by crystallization (2×) from EtOAc/Hexanes (1:3 v:v) to give the title compound (4.72 g, 66% yield) as white flakes. Mp 105° C. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=2.0 Hz, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.66 (s, 1H), 7.39 (dd, J=8.5, 1.7 Hz, 1H), 7.17-7.10 (m, 2H), 4.25 (d, J=11.3 Hz, 1H), 4.09 (d, J=11.3 Hz, 1H), 3.90 (s, 3H), 3.88 (q, J=7.1 Hz, 1H), 3.46-3.25 (m, 4H), 2.65-2.55 (m, 2H), 1.60 (d, J=7.1 Hz, 3H), 0.67 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 175.8, 157.7, 135.3, 133.8, 129.2, 128.9, 127.3, 126.0, 119.2, 105.6, 67.7, 67.5, 66.8, 55.3, 45.6, 40.9, 18.1, 16.7. LRMS (API-TIS) m/z 350.2 ((M+NH4)+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1O)[C:5]([OH:7])=[O:6].[CH3:13][Si](C=[N+]=[N-])(C)C.S([O-])([O-])(=O)=O.[Mg+2]>CCOCC.CO>[CH3:13][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:12])[CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,5-dimethyl-4-hydroxybenzoic acid (1.0 g) in ether (5 mL) and methanol(5 mL) was treated with excess trimethylsilyldiazomethane. After stirring 30 min at room temperature the reaction was treated with magnesium sulfate, filtered and concentrated to a brown solid. The title compound was obtained by purification on silica gel to give a colorless solid (670 mg). NMR (CDCl3); δ 7.75 (s,2H), 3.85 (s,3H), 2.30 (s,6H).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13]O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:13][CH2:12][CH2:11][CH2:10][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCCCCn1cnc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCCCCn1cnc2ccccc21
Reaction time: 3 h
Yield: 45 %

Procedure:
To a stirred mixture of 50 parts of 1H-benzimidazole-1-butanol and 375 parts of trichloromethane are added dropwise 35.2 parts of sulfinyl chloride. Upon completion, stirring is continued for 3 hours at reflux temperature. The reaction mixture is evaporated. The residue is taken up in trichloromethane. The whole is washed with ammonium hydroxide and the solvent is evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 22 parts (45%) of 1-(4-chlorobutyl)-1H-benzimidazole as an oily residue.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14](I)[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.[Cu][C:35]#[N:36]>CN(C=O)C.CCOCC>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14]([C:35]#[N:36])[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCOc3cc(I)ccc3-4)CC21
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCOc3cc(C#N)ccc3-4)CC21
Temperature: 110 °C

Procedure:
The product from Example 102A (24.7 mg, 0.044 mmol) was treated with copper(I) cyanide (27.5 mg, 0.307 mmol) in DMF (0.5 mL) heated at 110° C. overnight, cooled, diluted with Et2O (25 mL), washed with water (2×20 mL), washed with brine, dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel eluting with hexane:EtOAc (2:1, 1:1, 4:1) to provide the title compound. MS (M+H)+ m/z 463.
Reaction SMILES: [CH2:1]([NH:8][C:9](SC)=[C:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH:22]1[O:27][CH2:26][CH2:25][N:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:23]1>C(#N)C>[CH2:1]([NH:8][C:9]([NH:20][CH2:21][CH:22]1[O:27][CH2:26][CH2:25][N:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:23]1)=[C:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Reactant: CCOC(=O)C(C#N)=C(NCc1ccccc1)SC
Solvent: CC#N
Product: CCOC(=O)C(C#N)=C(NCc1ccccc1)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: 25 °C
Reaction time: 10 h
Yield: 40 %

Procedure:
To a solution of ethyl 3-benzylamino-3-methylthio-2-cyanoacrylate (1.07 g, 3.87 mmol) in acetonitrile (10 ml) was added 2-aminomethyl-4-(p-fluorobenzyl)morpholine (0.90 g, 4.02 mmol) and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as white crystals (0.70 g) from the fraction from hexane-ethyl acetate (1/1). Yield=40%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][CH2:16][CH2:17][CH2:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH2:18][CH2:17][CH2:16][OH:15])(=[O:21])=[O:20])=[CH:30][CH:29]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)CCCO)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCCO)cc1

Procedure:
5 g of 4-fluorobenzonitrile was used in Procedure Q with 3-mercapto-1-propanol to afford 4-(3-hydroxypropylthio)benzonitrile. 1.8 g of 4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure T to give 4-(3-hydroxypropylthio)benzoic acid. 1.2 g of 4-(3-hydroxypropylthio)benzoic acid was reacted via Procedure R to give 4-(3-hydroxypropylsulfonyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(3-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.3 (M)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:7][C:6]=1[C:31]([F:34])([F:33])[F:32])[NH2:4].[CH:35]1([C:38](Cl)=O)[CH2:37][CH2:36]1>N1C=CC=CC=1>[CH:35]1([C:38]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH:16]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)[C:17]([F:19])([F:20])[F:18])=[O:14])=[CH:7][C:6]=3[C:31]([F:32])([F:33])[F:34])[N:4]=2)[CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CC1
Reactant: NC(=NO)c1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccc(-c2noc(C3CC3)n2)c(C(F)(F)F)c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F

Procedure:
80 mg (0.16 mmol) of (2E)-3-[4-(N′-hydroxycarbamimidoyl)-3-(trifluoromethyl)phenyl]-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}acrylamide from Stage 1 were initially charged in 2 ml of pyridine, admixed at room temperature with 16.7 mg (0.16 mmol) of cyclopropanecarbonyl chloride and heated under reflux for 18 hours. The pyridine was for the most part distilled off under reduced pressure, and the residue was admixed with water and extracted with ethyl acetate. After drying over magnesium sulphate, the solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 0% ethyl acetate to 100% ethyl acetate).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30].O1CCCC1.C>O>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=CC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Solvent: O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 0.5 h

Procedure:
3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylic acid, (XIII, Example 89, 1.934 kg), tetrahydrofuran (11.875 l), water (0.625 l) and activated charcoal (0.100 kg) are mixed and stirred at 16 to 25° for 30 minutes and then filtered. The filter cake is washed with THF (0.500 l). A separate flask is charged with palladium on carbon (10%, 0.130 kg) and the filtered tetrahydrofuran/water mixture of the starting material. The flask is placed under reduced pressure and purged with nitrogen. The reduced pressure/nitrogen purge is repeated twice. The flask and contents are placed under reduced pressure and purged twice with hydrogen. The mixture is vigorously stirred under an atmosphere of hydrogen at 20° C. for 3 hours. The reaction vessel is evacuated and purged with nitrogen three times. The contents are filtered through celite (0.500 kg) and the filter cake washed with tetrahydrofuran (2×0.500 l). The solvent is removed under reduced pressure at 40 to 45°. Aqueous acetonitrile (50%, 7.540 l) is added to the residue and the slurry is aged at 15 to 25°, with stirring, for 3 hours. The slurry is cooled to between 0 and 5° and filtered. The filter cake is washed with aqueous acetonitrile (50%, 1.93 l), transferred to drying trays and dried at 50 to 60° under reduced pressure for 24 hours to give the title compound.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=[C:20]([C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.O>[F:17][C:18]1[CH:19]=[C:20]([C:24]2[N:29]=[CH:28][C:27]([NH:30][C:14](=[O:16])[CH2:13][C:10]3[CH:11]=[N:12][C:7]([N:4]4[CH2:3][CH2:2][S:1][CH2:6][CH2:5]4)=[CH:8][CH:9]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc(-c2cccc(F)c2)nc1
Reactant: O=C(O)Cc1ccc(N2CCSCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(N2CCSCC2)nc1)Nc1ccc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(6-thiomorpholinopyridin-3-yl)acetic acid 219-4 (92 mg, 0.39 mmol), 6-(3-fluorophenyl)pyridin-3-amine 219-1 (73 mg, 0.39 mmol), HATU (162 mg, 0.43 mmol) and DIEA (104 μl, 0.6 mmol) in DMF (1.0 ml) was stirred at room temperature overnight. Then it was redistributed between water (30 ml) and ethyl acetate (40 ml). The organic phase was dried over Na2SO4 and concentrated by rotary evaporation. Silica gel column chromatography (with ethyl acetate/hexanes from 1:10 to 2:1 as eluent) gave N-(6-(3-fluorophenyl)pyridin-3-yl)-2-(6-thiomorpholinopyridin-3-yl)acetamide 219-5 as solid. Step 7. N-(6-(3-fluorophenyl)pyridin-3-yl)-2-(6-thiomorpholinopyridin-3-yl)acetamide 219-5 (114 mg, 0.28 mmol) was treated with mCPBA in DCM (2 ml) at 0° C. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (30 mL), washed with 5% Na2CO3 solution, dried over Na2SO4 and concentrated by rotary evaporation. The residue was subjected to reverse phase HPLC purification and gave N-(6-(3-fluorophenyl)pyridin-3-yl)-2-(S,S-dioxo-6-thiomorpholinopyridin-3-yl)acetamide 219 as solid. MS m/z 396.3 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 10.53 (s, 1 H), 8.82 (d, 1 H), 8.16 (dd, 1 H), 8.11 (d, 1 H), 7.99 (d, 1 H), 7.92-7.80 (m, 2 H), 7.60 (dd, 1 H), 7.50 (m, 1 H), 7.22 (m, 1 H), 7.02 (d, 1 H), 4.06-4.01 (m, 4 H), 3.61 (s, 2 H), 3.10-3.05 (m, 4 H).
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl[C:10]1[CH:11]=[C:12]2[C:17](=[O:18])[N:16]([CH3:19])[C:14](=[O:15])[C:13]2=[CH:20][CH:21]=1>>[O:1]([C:10]1[CH:11]=[C:12]2[C:17](=[O:18])[N:16]([CH3:19])[C:14](=[O:15])[C:13]2=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-]c1ccccc1
Reactant: CN1C(=O)c2ccc(Cl)cc2C1=O
Agent: [Na+]
Product: CN1C(=O)c2ccc(Oc3ccccc3)cc2C1=O
Temperature: 250 °C
Yield: 45.6 %

Procedure:
A mixture of 0.440 g (3.80 mmol) of anhydrous sodium phenoxide and 1.50 g (76.7 mmol) of 4-chloro-N-methyl phthalimide is heated to 250° C. for 4 hours under a nitrogen gas atmosphere in an autoclave. There was obtained a 45.6% yield of 4-phenoxy-N-methyl phthalimide based on the phenoxide as determined by gas or liquid chromatographic analysis using o-terphenyl as an internal standard. The product was identified by a comparison of its retention time with that of an authentic sample of the desired material in a conventional matter.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[CH:15](SC1C=CC=CC=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Ni].C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1oc(-c2ccccc2)cc(O)c1C(Cc1ccccc1)Sc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: O=c1oc(-c2ccccc2)cc(O)c1CCc1ccccc1

Procedure:
The title compound was prepared by Method F using Raney-Nickel (Grace 3100), ethanol (20 mL), 4-hydroxy-6-phenyl-3-[2-phenyl-1-(phenylthio)ethyl]-2H-pyran-2-one (0.425 g, 1.06 mmol). m.p. dec. >255° C.; 1H NMR (400 MHz, DMSO-d6) δ2.65 (dd, 2 H), 2.71 (dd, 2 H), 6.68 (s, 1 H), 7.23 (m, 3 H), 7.52 (m, 3 H), 7.76 (m, 2 H), 11.85 (bs, 1 H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:5][N:6]=1.[CH2:21]([C:23]1[C:28](/[CH:29]=[CH:30]/[O:31][CH3:32])=[CH:27][CH:26]=[CH:25][C:24]=1B1OC(C)(C)C(C)(C)O1)[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([C:23]1[C:28](/[CH:29]=[CH:30]/[O:31][CH3:32])=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:5][N:6]=1)[CH3:22]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 120 °C
Yield: 64 %

Procedure:
To a suspension of 2-bromo-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D4) (55 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (64.8 mg) and tripotassium phosphate (79 mg) in N,N-dimethylformamide (DMF) (4 mL) and water (1 mL) under nitrogen was added Pd(Ph3P)4 (17.31 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. After cooling the reaction, water was added. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, the residue was purified by column chromatography to afford 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D18) (43 mg) as a yellow oil. MS (ES): C23H23F3N2O2S requires 448. found 449.1 (M+H+).