Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Cl)=[CH:7][CH:8]=1)(=O)[CH3:2].[Cl:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.C1(=O)CCCCC1.N1CCOCC1.[S]>>[NH2:20][C:19]1[S:5][C:6]2[CH2:2][CH2:1][CH2:4][CH2:8][C:7]=2[C:18]=1[C:16]([C:14]1[S:15][C:11]([Cl:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: N#CCC(=O)c1ccc(Cl)s1
Reactant: CC(=O)c1ccc(Cl)s1
Agent: [S]
Solvent: O=C1CCCCC1
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1ccc(Cl)s1)CCCC2
Yield: 76 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-chlorothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-chlorothiophene-2-carbonyl)acetonitrile (Steps A and B). Cyclohexanone (Aldrich), 2-(5-chlorothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 76%; IR (KBr) cm−1: 3349, 3237, 3131, 2911, 1577, 1547, 1430, 1281, 1006, 765; 1H NMR (CDCl3):δ 1.59 (m, 2H), 1.65 (m, 2H), 2.35 (t, 2H, J=5.8 Hz), 2.55 (t, 2H, J=5.8 Hz), 6.07 (bs, 2H), 6.88 (d, 1H, J=4 Hz), 7.16 (d, 1H, J=4 Hz); yellow solid, mp: 173–175° C. (petroleum ether).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:20]2[CH:25]=[N:24][N:23]([CH:26]([CH3:28])[CH3:27])[C:21]=2[N:22]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:26]([N:23]1[C:21]2[N:22]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:18]=[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:20]=2[CH:25]=[N:24]1)([CH3:28])[CH3:27]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc(O)nc2c1cnn2C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
Trifluoromethanesulfonic anhydride (5.23 g, 18.5 mmol) was added to a cooled solution of ethyl 6-hydroxy-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (4.2 g, 16.9 mmol) and pyridine (1.46 g, 18.5 mmol) in DCM (60 mL); and it was allowed to stirred at room temperature for 2 h. After completion of the reaction, saturated NaHCO3 solution (60 mL) was added to it and extraction was carried out using DCM (30 mL×3). The combined organic layers were washed with water (100 mL); brine (100 mL); dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was finally purified by silica gel column chromatography to provide pure the desired intermediate (5 g, 77.8% yield).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[C:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][CH:9]=1)=[O:6])[CH2:2][CH3:3].[H-].[Na+].[CH3:24]I>CN(C)C=O.C(OCC)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:24])[CH:9]=1)=[O:6])[CH2:20][CH3:21]
Reactant: CI
Reactant: CCCN(CCC)C(=O)Cc1c[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)Cc1cn(C)c2ccc(OC)cc12
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 3-(di-n-propylaminocarbonylmethyl)-5-methoxyindole (180 mg, 0.62 mmol) in 1.8 mL of N,N-dimethylformamide was added sodium hydride (55%, 40 mg, 0.93 mmol) at 0° C. After the reaction mixture was stirred at the same temperature for 30 min, methyl iodide (0.10 mL, 1.2 mmol) was added with additional stirring at room temperature for 12 h. After the reaction mixture was diluted with diethyl ether, and washed with water and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound (126 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.[Si:29](OS(C(F)(F)F)(=O)=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].[Cl-].[NH4+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]([O:8][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[O:7]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
To a methylene chloride solution (1.0 ml) of N-t-butoxycarbonyl-L-phenylalanine methyl ester (139.5 mg, 0.5 mmol) and 2,6-lutidine (0.116 ml, 1.0 mmol), t-butyldimethylsilyltrifluoromethane sulfonate (TBDMSOTf) (0.172 ml, 0.75 mmol) was added dropwise at room temperature in a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a saturated aqueous solution of ammonium chloride (2 ml) was added to quench the reaction and extraction with ether was conducted. The organic layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent, the titled compound was obtained in an amount of 186.8 mg.
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.[C:8]([NH:15][C@H:16]([C:21]([OH:23])=O)[CH2:17][CH:18]([CH3:20])[CH3:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>ClCCl>[CH3:24][O:25][N:3]([CH3:6])[C:21](=[O:23])[C@H:16]([CH2:17][CH:18]([CH3:19])[CH3:20])[NH:15][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(CC)CC
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C

Procedure:
Triethylamine (10 ml) is added to a stirred solution of Boc-Leucine in dichloromethane. Then sequentially, carbonyl-diimidazole (10 mmol) are added followed by, N-dimethylhydroxyamine hydrochloride (11 mmol), and triethylamine (11 mmol). The reaction is monitored by TLC, was found to be completely within an hour. The mixture is diluted with dicloromethane (250 ml) and washed successively with 1N HCl, and a saturated sodium chloride solution. The organic solution was dried with magnesium sulfate, and the solvent evaporated to give the desired product (9.0 mmol yield).
Reaction SMILES: CN1CCCC1=O.F[C:9]1[C:14]([F:15])=[C:13]([CH3:16])[C:12]([F:17])=[C:11]([F:18])[N:10]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH2:19]([NH:26][C:9]1[C:14]([F:15])=[C:13]([CH3:16])[C:12]([F:17])=[C:11]([F:18])[N:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1c(F)c(F)nc(F)c1F
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: Cc1c(F)c(F)nc(NCc2ccccc2)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 2 ml of N-methylpyrrolidone were added 1.65 g of 2,3,5,6-tetrafluoro-4-methylpyridine and 2.30 g of benzylamine, and the mixture was stirred at 80° C. for 2 hours and allowed to cool. After adding 25 ml of chloroform, the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound in crude form.
Reaction SMILES: [N:1]1([C:7]2[O:11][C:10]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[N:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1([C:7]2[O:11][C:10]([NH:12][C:13]([N:35]3[CH2:36][CH2:37][N:32]([C:30]4[S:29][N:28]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:31]=4)[CH2:33][CH2:34]3)=[O:20])=[N:9][N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1nnc(N2CCOCC2)o1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1nnc(N2CCOCC2)o1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 9 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (5-morpholin-4-yl-1,3,4-oxadiazol-2-yl)carbamate (269 mg, 0.777 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (211 mg, 0.854 mmol) and diisopropylethylamine (0.149 ml, 0.854 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 31 mg (9.0%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:6]=[C:5]([O:13][CH2:14][O:15][CH3:16])[CH:4]=1.[Li][CH2:18]CCC.CI>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([CH3:18])=[C:5]([O:13][CH2:14][O:15][CH3:16])[CH:4]=1
Reactant: COCOc1cc(OC)cc(OCOC)c1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COCOc1cc(OC)cc(OCOC)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
A solution of 8 (441 mg, 1.93 mmol) in anhydrous THF (1.55 mL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 1.16 mL, 2.90 mmol) in anhydrous THF (1.26 mL) at room temperature. After 1 hour, the solution was cooled to −78° C. and methyl iodide (480 μL, 7.73 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1→4:1; Hexane:EtOAc) to afford 9 as a yellow oil (314 mg, 67%): 1H NMR (CDCl3, 500 MHz) 6.38 (d, J=2.2 Hz, 1H), 6.24 (d, J=2.1 Hz, 1H), 5.08 (d, J=3.6 Hz, 2H), 5.06 (d, J=2.6 Hz, 2H), 3.72 (s, 3H), 3.40 (s, 6H), 1.97 (s, 3H); 13C NMR (CDCl3, 125 MHz) 160.3, 157.8, 155.4, 108.2, 93.9, 93.8, 93.7, 92.9, 55.0, 55.0, 54.6, 7.0; IR (film) νmax 2953, 2934, 2905, 1597, 1497, 1396, 1215, 1144, 1126, 1074, 1059, 1028, 922, 822 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C12H18O5, 243.1233. found, 243.1223.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=1.[CH3:29][C:30]1([CH3:47])[CH2:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]([CH3:46])([CH3:45])[NH:31]1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.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>[CH3:26][C:25]1[CH:24]=[C:23]([CH3:27])[NH:22][C:21](=[O:28])[C:20]=1[CH2:19][NH:18][C:16]([C:4]1[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=[C:2]([C:34]2[CH2:33][C:32]([CH3:46])([CH3:45])[NH:31][C:30]([CH3:47])([CH3:29])[CH:35]=2)[CH:3]=1)=[O:17]
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Reactant: CCc1nn(C(C)C)c2nc(Br)cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CCc1nn(C(C)C)c2nc(C3=CC(C)(C)NC(C)(C)C3)cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-ethyl-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.15 g, 0.336 mmol), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.106 g, 0.403 mmol) and Pd(PPh3)4 (0.020 g, 0.017 mmol) in 1,4-dioxane (3 mL) was purged with argon for 10 min. Then, 2M Na2CO3 solution (0.128 g, 1.21 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (59% yield). LCMS: 505.30 (M+1)+; HPLC: 99.84% (@ 254 nm) (Rt; 5.386); 1H NMR (DMSO-d6, 400 MHz) δ 11.49 (s, 1H), 8.68 (t, 1H), 7.32 (s, 1H), 6.72 (s, 1H), 5.88 (s, 1H), 5.17-5.10 (m, 1H), 4.33 (d, 2H, J=4.4 Hz), 2.84-2.79 (q, 2H, J=7.6 Hz), 2.39 (s, 2H), 2.25 (s, 3H), 2.11 (s, 3H), 1.46 (d, 6H, J=6.8 Hz), 1.22 (s, 6H), 1.13 (s, 6H), 1.06 (t, 3H, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=O.[Cl-].[OH:18][NH3+:19].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=[N:19][OH:18]
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1OC
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=NO)C(F)(F)F)cc1OC
Temperature: 0 °C
Yield: 95.2 %

Procedure:
2.9 g (9.7 mmol) of 2,2,2-trifluoro-1-(3,4-dimethoxyphenyl)-ethanone are dissolved in 12 ml of ethanol at 80° C. To the solution are added dropwise 0.83 g (12.0 mmol) of hydroxylammonium chloride and 1.2 g (15.0 mmol) of sodium acetate dissolved in 6 ml of water. The reaction mixture is refluxed for 7.5 hours, poured into ice water, and extracted with ether. The organic phase is washed with water and brine, dried over MgSO4, and concentrated, yielding 2.3 g of 2,2,2-trifluoro-1-(3,4-dimethoxyphenyl)-ethanone oxime. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]=O)=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.[CH3:14][O:15][C:16](=[O:37])[CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8](/[CH:12]=[CH:17]/[C:16]([O:15][CH3:14])=[O:37])[CH:7]=2)[C:3](/[CH:1]=[CH:17]/[C:16]([O:15][CH3:14])=[O:37])=[CH:4]1
Reactant: O=Cc1ccc2c(C=O)c[nH]c2c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc2c(/C=C/C(=O)OC)c[nH]c2c1
Yield: 72.8 %

Procedure:
A mixture of 3,6-diformylindole (1 g), methyl(triphenylphosphoranylidene)acetate (7.76 g) and dry dioxane (50 ml) was stirred and heated under reflux for 6 hr under an atmosphere of nitrogen. The solvent was evaporated, the residue extracted with several portions of ether, the ether extracts evaporated and the crude product purified by flash chromatography, eluting with 2:3 ethyl acetate:hexane, to give dimethyl E,E-indole-3,6-diacrylate (1.2 g, 73%) as a yellow solid; partial NMR (250 MHz, DMSO-d6): 3.71(s, 3H, OCH3), 3.73(s, 3H, OCH3), 6.40(d, J=16.0 Hz, 1H, olefinic H); 6.60(d, J=16.0 Hz, 1H, olefinic H); 12.02(br s, 1H, NH).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][C:10]2[C:12]([OH:28])=[CH:13][C:14]([O:16][CH:17]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:18])=[CH:15][C:9]=2[O:8][C:7]1([CH3:30])[CH3:29])#N.[OH-:31].[Na+].C[OH:34]>>[OH:28][C:12]1[C:10]2[CH2:11][CH:6]([CH2:5][CH2:4][CH2:3][C:1]([OH:34])=[O:31])[C:7]([CH3:30])([CH3:29])[O:8][C:9]=2[CH:15]=[C:14]([O:16][CH:17]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:18])[CH:13]=1
Reactant: CO
Reactant: [OH-]
Reactant: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)OC(C)(C)C(CCCC#N)C2
Agent: [Na+]
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)OC(C)(C)C(CCCC(=O)O)C2

Procedure:
A mixture of 1.407 g (3.45 mmole) dl-3-(3-cyanopropyl)-5-hydroxy-2,2-dimethyl-7-(5-phenyl-2-pentyloxy)-3,4-dihydro-2H-benzopyran, 50 ml methanol and 26 ml 1N sodium hydroxide was heated at reflux overnight. The methanol was evaporated and the aqueous residue washed with methylene chloride. The methylene chloride washings were extracted with 10 ml 1N sodium hydroxide, the combined aqueous layers acidified with hydrochloric acid, extracted with methylene chloride and the organic extracts dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to obtain 1.189 g of the title acid as a foam. Mass spectrum (m/e): 426 (M+) 280 (M-146), 139 (base).
Reaction SMILES: CN(C=O)C.[C:6]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O:8][CH2:9][CH3:10])=[O:7].[CH:18]([S:20]([F:23])(=[O:22])=[O:21])=[CH2:19]>O>[C:6]([C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH:19]=[CH:18][S:20]([F:23])(=[O:22])=[O:21])=[CH:16][CH:17]=1)([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: C=CS(=O)(=O)F
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(NC=CS(=O)(=O)F)cc1
Temperature: 110 °C
Yield: 49.8 %

Procedure:
To a 75 mL DMF solution of 4-carboethoxyaniline (3.88 g, 23.5 mmol) was added ethenesulfonyl fluoride (3.3 mL, 30 mmol) under nitrogen. The solution was warmed to 100-120° C. for 6 hours. The cooled solution was slowly Poured into water and chilled in ice. The yellow solid precipitate was collected, dissolved in methylene chloride, washed with brine and dried (Na2SO4). After the solvent had been removed by distillation, the brown solid (5.4 g) was crystallized from methylene chloride/ether/hexane. The title compound (3.2 g, 49% yield) was obtained as a tan solid, mp 109.5°-111.5° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].C([O-])(O)=O.[Na+]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[F:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]3[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]3)[CH2:17][CH2:18]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.155 g (0.368 mmol) of trans-(4-{2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester was solved in dichloromethane (2 mL) and trifluoroacetic acid was added at 0° C. (0.230 mL, 3 mmol) and the mixture was stirred at room temperature overnight. NaHCO3 was slowly added until pH 9 and the mixture extracted 3 times with dichloromethane and ethyl acetate. The solvent was evaporated to yield 0.160 g (0.368 mmol, 100%) of a white solid that was used without purification on the next steps. MS (m/e): 321.4 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=2)=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1)CCC.C1(C)C=CC=CC=1>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>[CH3:25][C:22]1[N:21]=[CH:20][C:19]([CH2:18][NH:17][C:15]([C:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[CH:7]=[C:2]([C:31]3[N:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[CH:3]=2)=[O:16])=[CH:24][N:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(-c3ncccn3)c2)cc1
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-4′-methyl-N-((2-methylpyrimidin-5-yl)methyl)biphenyl-3-carboxamide (100 mg, 0.0002 mol), 2-(tributylstannyl)pyrimidine (0.1 g, 0.0003 mol), tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.000005 mol) and toluene (1 mL, 0.009 mol) was heated in the microwave at 120° C. for 1 hour. LC/MS showed the desired product, LC/MS m/e=396.3. The mixture was cooled to room temperature and the reaction mixture filtered over celite and solvent removed under reduced pressure. The residue was purified by reverse phase prep HPLC to get the product as white solid.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22](O)[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1.[CH3:25][O:26][CH2:27]Cl>C(N(CC)CC)C>[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([CH2:25][O:26][CH3:27])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1
Reactant: Oc1ccc2nc(-c3ccc(I)cc3)sc2c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1ccc2nc(-c3ccc(I)cc3)sc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 30 mg, 0.76 mmol) was added to a DMF (2 mL) solution of 5 (225 mg, 0.64 mmol), cooled in an ice bath. After stirring at 0° C. for 1 h, chloromethyl methyl ether (100 μL, 1.33 mmol) and triethylamine (0.2 mL) were added. The reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with pH 7 buffer solution (10 mL). The organic phase was dried with anhydrous Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash chromatography on silica gel (CH2Cl2), to give 2-(4-iodophenyl)-6-(methoxymethyl)-1,3-benzothiazole (6) (237 mg, 93.7%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:28][CH:27]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenylcarbamate (6) (404 mg, 0.8 mmol) in 8 mL DCM was added 2 mL TFA dropwise. The reaction mixture was stirred at rt for 1 hr, then concentrated to dryness. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in DCM (0.3% Et3N)) to give 6-amino-9-(3-aminophenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (7) (325 mg, 100%) as a yellow solid. LC-MS (ESI): m/z (M+1) 411.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:10])[CH:4]=[CH:5][C:6](=[O:9])[C:7]=1[F:8].[CH:11]1[CH2:16][CH2:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[F:1][C:2]1[C:3](=[O:10])[CH:4]2[CH:5]([C:6](=[O:9])[C:7]=1[F:8])[CH:13]1[CH2:14][CH2:15][CH:16]2[CH:11]=[CH:12]1
Reactant: O=C1C=CC(=O)C(F)=C1F
Reactant: C1=CCCC=C1
Solvent: CCOCC
Product: O=C1C(F)=C(F)C(=O)C2C3C=CC(CC3)C12
Temperature: 25 °C

Procedure:
A solution of 1.7 g of 2,3-difluoro-1,4-benzoquinone (G. Haufe, Perkin Transactions 1 (2002), (23), 2719-2728), 2.2 mL of 1,3 cyclohexadiene in 25 mL of Et2O was heated in a closed vessel at 50° C. for 2 h. After cooling to rt the mixture was concentrated in vacuo to obtain 1.4 g of the desired compound as mixture of stereoisomers as yellow solid.