Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:8][CH:9]=1)[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH:3]=1)[O:10][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=Cc1ccc(Cl)cc1O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(Cl)ccc1C=O
Temperature: 80 °C
Yield: 18.2 %

Procedure:
A mixture of 22.0 g (0.141 mole) of 4-chlorosalicylaldehyde, 30 g (0.22 mole) of anhydrous potassium carbonate, and 30.0 g (0.184 mole) of methyl 2-bromopropionate in 120 mL of N,N-dimethylformamide was heated at 80° C. for approximately 17 hours. At the end of that period, the reaction mixture was poured over ice and extracted successively with diethyl ether and ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate, and filtered. The solvents were then evaporated under reduced pressure, leaving a residue weighing 20 g. This residue was purified by placing it on a silica gel column and eluting with diethyl ether/petroleum ether (25/75). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 6.23 g of methyl 2-(5-chloro-2-formylphenoxy)propionate was isolated as a yellow liquid. Similarly, other fractions were combined and evaporated, yielding 1.69 g of methyl 2-(3-chloro-2-formylphenoxy)propionate as a yellow liquid. The NMR spectra of both compounds were consistent with proposed structure of each. This reaction was repeated several times.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C:8]1=[O:20].C(NC(C)C)(C)C.Br[CH2:29][CH:30]([CH3:32])[CH3:31]>C1COCC1.C(OCC)(=O)C.CN(P(N(C)C)(N(C)C)=O)C>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:9]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:8]1=[O:20]
Reactant: CN1CCN(Cc2ccccc2)CC1=O
Reactant: CC(C)CBr
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)CC1C(=O)N(C)CCN1Cc1ccccc1

Procedure:
Butyl lithium (8.0 ml. of 1.6M in hexane, 0.012 mole) is added at -60° to a stirred solution of 1-methyl-4-(phenylmethyl)piperazinone (Example 46, 2.04 g., 0.010 mole), diisopropylamine (1.1 g., 0.011 mole) and hexamethylphosphorotriamide (2.0 ml.) in THF (25 ml.). The solution is allowed to warm to 20°-25°, 1-bromo-2-methylpropane (4.1 g., 0.030 mole) is added and the solution is refluxed for 3 hours. The THF is removed under reduced pressure and the residual ol is partitioned between chloroform and water. Evaporation of the chloroform gives an oil which is dissolved in ethyl acetate and chromatographed on silica gel. Elution of the column with ethyl acetate and pooling of the appropriate fractions gives the title compound.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16])=[CH:9][CH:8]=1.Cl[C:20](=[N:26]O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[CH2:24]([O:23][C:21]([C:20]1[C:14]([C:13](=[O:18])[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:12][CH:11]=2)=[C:15]([CH3:16])[O:17][N:26]=1)=[O:22])[CH3:25]
Reactant: COc1ccc(C(=O)CC(C)=O)cc1
Reactant: CCOC(=O)C(Cl)=NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1noc(C)c1C(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
To 7.04 mL of 21% sodium ethoxide in ethanol (18.8 mmol) in 60 mL ethanol at 0° C. was added 4.70 g of 1-(4-methoxyphenyl)butane-1,3-dione (17.1 mmol) in 60 mL ethanol dropwise over 24 minutes. After 30 min a solution of 2.59 g of ethyl chloro-(hydroximino)acetate (17.1 mmol) in 30 mL ethanol was added dropwise over 6 minutes. The reaction was warmed to room temperature slowly. When TLC indicated the reaction was complete, the reaction was concentrated in vacuo. Water and saturated NaHCO3 was added and the product extracted with ethyl acetate. The ethyl acetate extracts were dried with Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel chromatography eluting with 8:1 hexane:ethyl acetate to give 4-(4-methoxybenzoyl)-5-methylisoxazole-3-carboxylic acid ethyl ester which was dried overnight under high vacuum to give 3.74 g (71.8%).
Reaction SMILES: [CH3:1][CH:2]1[CH:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][N:3]1[C:17](Cl)=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:29])[CH:27]=[CH2:28]>O1CCCC1.O>[CH3:1][C@H:2]1[C@@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][N:3]1[C:17]([NH:29][CH2:26][CH:27]=[CH2:28])=[O:18]
Reactant: CC1C(Oc2cccc(C(F)(F)F)c2)CN1C(=O)Cl
Reactant: C=CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(=O)N1C[C@H](Oc2cccc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
A stirred mixture of 4.02 g (0.01 mole) of crude (73%) 2-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride cis isomer and 1.4 g (0.01 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 0.57 g (0.01 mole) of 2-propenylamine. After stirring for 15 minutes, a small piece of ice was added and stirring continued for 3 hr. The reaction mixture was diluted with water and the oil which separated was extracted with methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo (5.2 g). The crude product was chromatographed on a 125 g silica gel column. Elution with chloroform washed impurities from the column and the product was removed by eluting with an ethyl acetate/chloroform gradient (1-20%). The combined product fractions gave a pale yellow oil which solodified on standing and was recrystallized from isopropyl ether/hexane to give an oil which slowly crystallized, yielding 2.1 g (67.8%) of white product, m.p. 74°-77° C.
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(OC)nc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2nc3ccc(C(=O)O)cc3nc2N(C)C(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(6-methoxypyridin-3-yl)quinoxaline-6-carboxylate (140 mg, 0.38 mmol) in methanol (25 mL) was added sodium hydroxide (45.9 mg, 1.15 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 6 with HCl (3N). The product were collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(6-methoxypyridin-3-yl)quinoxaline-6-carboxylic acid as a light yellow solid (105 mg, 78%). LC/MS (ES, m/z): [M+H]+ 352.0
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([S:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH:16]([CH3:18])[CH3:17])[CH:6]=1)=[O:4].[OH-:21].[Na+]>O1CCCC1>[CH:16]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([S:14][CH3:15])[CH:9]=2)[C:5]([C:3]([OH:4])=[O:21])=[CH:6]1)([CH3:18])[CH3:17]
Reactant: [OH-]
Reactant: CSc1ccc2c(C(=O)C(F)(F)F)cn(C(C)C)c2c1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Temperature: 100 °C
Yield: 77 %

Procedure:
A solution of 2,2,2-trifluoro-1-(1-isopropyl-6-methylsulfanyl-1H-indol-3-yl)-ethanone (200 mg, 0.77 mmol) in tetrahydrofuran (1 mL) at 25° C. was treated with a 20% aqueous sodium hydroxide solution (2 mL). The mixture was heated at 100° C. for 24 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (40 mL) and ethyl acetate (40 mL). The solution was treated with a 1N aqueous hydrochloric acid solution. The layers were then shaken and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-methylsulfanyl-1H-indole-3-carboxylic acid (126 mg, 77%) as a white solid: mp 132-133° C.; EI-HRMS m/e calcd for C13H15NO2S (M+) 249.0823, found 249.0819.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CC(=O)OCC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:13][CH2:14][O:15][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][O:16]2)(=[O:11])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(S(=O)(=O)CCO)cc1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)CCOC2CCCCO2)cc1Br
Temperature: 25 °C
Yield: 85.3 %

Procedure:
To the title compound of step 3 (1.0 g, 3.4 mmol) in CH2Cl2 (10 mL) was added 3,4-dihydro-2H-pyran (1.4 g, 17.0 mmol) followed by pyridinium p-toluensulfonate (64.6 mg, 0.34 mmol). After stirring at r.t. 12 h, the mixture was subjected to CH2Cl2 extractive work up & silica gel chromatography (PE:EA=1:0˜5:1) to give the title compound (1.1 g, 85.6%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.11 (d, J=2.4 Hz, 1H), 7.86 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 4.51 (dd, J1=4.0 Hz, J2=2.4 Hz, 1H), 4.09-4.03 (m, 1H), 3.98 (s, 3H), 3.84-3.79 (m, 1H), 3.79-3.74 (m, 1H), 3.50-3.46 (m, 1H), 3.45-3.42 (m, 2H), 1.58-1.37 (m, 6H). LCMS: 401.0, 403.0 (M+Na)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:23]([C:24]([O:26]C)=[O:25])=[C:22]2[O:28][CH2:29][C:30]3[CH:31]=[N:32][S:33][C:34]=3[C:21]2=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.C(Cl)Cl>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:23]([C:24]([OH:26])=[O:25])=[C:22]2[O:28][CH2:29][C:30]3[CH:31]=[N:32][S:33][C:34]=3[C:21]2=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1cnsc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=CO
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCc1cnsc1-2
Temperature: 85 °C
Yield: 47.8 %

Procedure:
Methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-chromeno[3,4-d]isothiazole-6-carboxylate (Intermediate 72, 0.058 g) was dissolved in dioxane (1.5 mL) and water (0.6 mL). Lithium hydroxide monohydrate (0.018 g) was added and the resultant mixture was heated at 85° C., under nitrogen for 3 hours. The mixture was left to cool overnight. A further amount of lithium hydroxide monohydrate (0.010 g) was added and the mixture was heated at 85° C. for a further 1 hour. The mixture was cooled, diluted with DCM and acidified to pH4 with aqueous formic acid (10%), to give an emulsion. The emulsion was concentrated in vacuo to give a gum, which was triturated with a solution of 2M methanol in DCM and the solid was removed by filtration. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-8%. The resultant product was dissolved in acetonitrile and water and freeze-dried overnight to give 7-[2((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-chromeno[3,4-d]isothiazole-6-carboxylic acid (0.027 g) as a white solid.
Reaction SMILES: C(N1C2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC=CC=4)=[S:26])=CC=3F)C=2C=C1)C1C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41]([NH:55][C:56]([NH:58][C:59](=[O:67])[CH2:60][C:61]2C=C[CH:64]=[CH:63][CH:62]=2)=[S:57])[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12.S1C=CC=C1CC(N=C=S)=O>>[F:38][C:39]1[CH:40]=[C:41]([NH:55][C:56]([NH:58][C:59](=[O:67])[CH2:60][C:61]2[S:26][CH:64]=[CH:63][CH:62]=2)=[S:57])[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ccn3Cc2ccccc2)c(F)c1
Agent: O=C(Cc1cccs1)N=C=S
Product: O=C(Cc1cccs1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Yield: 9 %

Procedure:
Starting from the amine 169 (scheme 33), following the procedures described above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl isothiocyanate with 2-(thiophen-2-yl)acetyl isothiocyanate, title compound 192b was obtained in 9% yield. Characterization of 192b is provided in table 18.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:36]([F:37])=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=2)[CH2:24][CH:23]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:44].O1CCOCC1>>[ClH:44].[F:37][C:36]1[C:28]([N:25]2[CH2:26][CH2:27][CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:23]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:24]2)=[N:29][CH:30]=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2ncc(C(=O)O)cc2F)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(c2ncc(C(=O)O)cc2F)CC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 187 mg of the crude product of 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-fluoronicotinic acid was added 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and to the obtained residue were added isopropanol and ethyl acetate, followed by heating under reflux, and then being left to be cooled to room temperature. The precipitate was collected by filtration, and dried under reduced pressure to obtain 106 mg of 5-fluoro-6-[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]nicotinic acid hydrochloride as a white solid.
Reaction SMILES: C([O:3][P:4]([C:9]([F:25])([F:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:8])[O:5]CC)C.C(Cl)Cl>>[F:25][C:9]([P:4](=[O:3])([OH:5])[OH:8])([F:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCC(F)(F)P(=O)(OCC)OCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC(F)(F)P(=O)(O)O
Temperature: 25 °C
Yield: 78.1 %

Procedure:
To a solution of vacuum dried 10 (225 mg, 0.585 mmol) in methylene chloride (5 mL) bromotrimethyl silane (895 mg, 5.85 mmol) was added and the mixture was stirred at room temperature. TLC showed completion of the reaction after 6 h. Solvents were removed under reduced pressure, and the residue was stirred in 95% methanol (3 mL) for 1 h. The mixture was concentrated under reduced pressure, dried under vacuum to give 150 mg (78%) of 11 as light yellow solid. mp 66-69° C.; 1H NMR (CD3OD): δ2.03 (m, 2H), 1.59 (m, 2H), 1.24 (br s, 22H), 0.90 (t, J=6.6 Hz, 3H); MS: [M−H]− at m/z 327.3. Anal. (C15H3]F2O3P.0.2H2O)C, H.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15]COCC[Si](C)(C)C)=[C:11]([O:24][CH3:25])[CH:10]=2)[C:5](=[O:26])[CH:4]=1.CO.Cl.O1CCOCC1>C(Cl)Cl>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([N:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][C:5]2=[O:26])=[CH:10][C:11]=1[O:24][CH3:25]
Reactant: COc1cc(-n2ccc(CO)cc2=O)ccc1OCOCC[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(-n2ccc(CO)cc2=O)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(hydroxymethyl)-1-(3-methoxy-4-((2-(trimethylsilyl)ethoxy)-methoxy)phenyl)pyridin-2(1H)-one Part E of Procedure 1 (900 mg, 2.38 mmol) in CH2Cl2 (10 mL) and MeOH (10 mL) was added 4M HCl/Dioxane (10.7 mL, 43 mmol). After stirring at RT for 1 h, concentration under vacuum provided the crude phenol as a white solid. LC-MS, [M+H]+=428.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[S:23][C:24]([CH3:27])=[N:25][N:26]=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:29][CH3:30].[OH-].[Na+].CN(C)C=O>O>[CH2:29]([N:26]1[N:25]=[C:24]([CH3:27])[S:23][C:22]1=[N:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH3:30]
Reactant: CCBr
Reactant: COc1ccc(N2CCN(c3ccc(Nc4nnc(C)s4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(C)sc1=Nc1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1
Reaction time: 4 h
Yield: 25.3 %

Procedure:
A mixture of 10.6 parts of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5-methyl-1,3,4-thiadiazol-2-amine, 0.5 parts of bromoethane, 4 parts of sodium hydroxide pellets and 188 parts of N,N-dimethylformamide was stirred for 4 hours at 40°-50° C. After the addition of water, the crystallized product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane, methanol, ethyl acetate and hexane (48:2:30:20 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 2.9 parts (25.3%) of N-(3-ethyl-5-methyl-1,3,4-thiadiazol-2(3H)-ylidene)-4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine; mp. 175.4° C. (int. 14). The second fraction was collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 6.5 parts (56.7%) of N-ethyl-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5-methyl-1,3,4-thiadiazol-2-amine; mp. 186.8° C. (int. 15).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11]#[N:12])[CH:2]=1.B1([O-])O[O:14]1.O.O.O.O.[Na+]>C(O)(=O)C>[C:11]([C:3]1[CH:2]=[N+:1]([O-:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)#[N:12]
Reactant: N#Cc1cnc2c(c1)CCCC2
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc2c([n+]([O-])c1)CCCC2
Temperature: 40 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a solution of 5,6,7,8-tetrahydroquinoline-3-carbonitrile (633 mg, 4.00 mmol) in acetic acid (5 ml) at 40° C. was portionwise added sodium perborate tetrahydrate (677 mg, 4.4 mmol) and the mixture was stirred at 40° C. for 16 hours. The acetic acid was removed by evaporation at reduced pressure, the residue was basified with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture extracted thrice with ethyl acetate. The combined extracts were dried over sodium sulphate and the solvent removed in vacuum to give the 3-cyano-5,6,7,8-tetrahydroquinoline 1-oxide (645 mg, 93% yield) as a white solid. MS (ISP): m/z=175.1 [M+H]+.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]([CH:10]=[CH:11][CH3:12])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](=[O:16])[CH2:14][CH3:15].C(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O)C.O>[OH:3][C:4]1[C:9]([CH:10]=[CH:11][CH3:12])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](=[O:16])[CH:14]=[CH:15][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC=Cc1cccc(C(=O)CC)c1O
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC=Cc1cccc(C(=O)C=Cc2ccccc2)c1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
60 ml of 50% (w/v) sodium hydroxide was added dropwise during 30 minutes to a solution of 17.6 g of a 7:3 E-Z mixture of 2'-hydroxy-3'-(1-propenyl)propiophenone (prepared as described in R. E. Ford. et al., J. Med. Chem., 29,538, (1986)) and 10.82 g of benzaldehyde in 73 ml of ethanol stirred at 0° C. The temperature of the reaction mixture was raised to 25° C. and stirring was continued for 4 hours. After standing at room temperature overnight, 150 ml of water was added, followed by dropwise addition of 95 ml of 37% hydrochloric acid under stirring at O° C. The precipitated solid was filtered by suction, washed with water and desiccated, yielding 26.8 g of 1-[2-hydroxy-3-(1-propenyl)phenyl]-3-phenyl-2-propen-1-one. This material was used without further purification in the next step.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC(Cl)=O)(C)C.C(N(CC)CC)C.[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48]([O:49][CH:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)=[C:43]3[CH:42]=[N:41]2)=[CH:36][CH:35]=1)(=[O:33])=[O:32]>CS(C)=O>[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48]([O:49][CH:50]4[CH2:55][CH2:54][N:53]([C:13]([C:11]5[O:12][C:8]([CH2:7][N:1]6[CH2:2][CH2:3][O:4][CH2:5][CH2:6]6)=[CH:9][CH:10]=5)=[O:15])[CH2:52][CH2:51]4)=[C:43]3[CH:42]=[N:41]2)=[CH:36][CH:35]=1)(=[O:32])=[O:33]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Reactant: O=C(O)c1ccc(CN2CCOCC2)o1
Agent: CC(C)OC(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)c5ccc(CN6CCOCC6)o5)CC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Morpholin-4-ylmethyl-furan-2-carboxylic acid (0.12 mmol, 25 mg), and isopropylchloroformate (0.12 mmol, 17 μL) and triethylamine (0.12 mmol, 17 μL) were dissolved in DMSO (2 mL) and stirred for 30 minutes at room temperature. Then, 1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (0.12 mmol, 50 mg) and excess triethylamine were added. The mixture was heated in a microwave for 5 minutes at 120° C. The progress of the reaction was monitored by thin layer chromatography and LCMS. Purification by HPLC provided compound A116 as a white solid. LCMS (ESI), m/z 567.3 (MH+, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:25]([O:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
The mixture of 2-(2-isopropoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (6) (265 mg, 0.69 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (6 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and the solution acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (7) as white solid (244 mg, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([SH:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1>C(N(CC)CC)C>[CH3:22][O:21][C:17](=[O:20])[CH2:18][CH2:19][S:15][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=1[OH:16]
Reactant: CC(C)(C)c1cc(S)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCSc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
In a 50 ml flask under nitrogen, a mixture of 5.00 grams of 2,4-di-tert-butyl-6-mercaptophenol, 1.80 grams of methyl acrylate and 20 mls toluene was treated with 0.50 mls of triethylamine. After stirring for three hours at ambient temperature, the solvent was removed in vacuo. The residue was purified by chromatography on silica gel using toluene/heptane eluent to give 3.90 g (57% yield) of a colorless oil.