Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C@@:6]12[O:13][C@@H:10]([CH2:11][CH2:12]1)[C:9](=[O:14])[CH2:8][C:7]2=[O:15].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([Pb+3])[CH:36]=2)=[CH:31][CH:30]=1.Cl>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH:8]3[C:9](=[O:14])[C@H:10]4[O:13][C@:6]([CH3:5])([CH2:12][CH2:11]4)[C:7]3=[O:15])[CH:36]=2)=[CH:33][CH:34]=1
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 25 °C
Yield: 41.8 %

Procedure:
To a mixture of chloroform (3.5 ml) and toluene (0.75 ml) is added (1R*,5S*)-1-methyl-8-oxa-bicyclo[3.2.1]octane-2,4-dione (0.25 g, 1.62 mmol) and N,N-dimethylaminopyridine (0.99 g, 8.11 mmol) under a nitrogen atmosphere with stirring. To this reaction mixture is then added 4′-chloro-4-methylbiphenyl-3-yllead triacetate (1.05 g, 1.78 mmol) in one portion, then the mixture heated at 80° C. for 1-2 hours. The reaction mixture is cooled to room temperature, acidified with dilute aqueous hydrochloric acid then filtered through diatomaceous earth to remove inorganic residues (subsequent washing with dichloromethane). Aqueous fractions are extracted with dichloromethane (2×10 ml), then all organic fractions are combined, dried over sodium sulfate and concentrated under vacuum to give crude product which is purified by flash chromatography (hexane/ethyl acetate) to give (1R*,5S*)-3-(4′-chloro-4-methylbiphenyl-3-yl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.240 g) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>CO.CCOCC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:16][C:17]=1[O:22][CH3:23].[ClH:24]
Reactant: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1cc(C2(O)CCNCC2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-Chloro-3-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (502 mg) in MeOH (5 mL) was added a solution of HCl in ether (2 M, 9.5 mL). The resultant mixture was stirred at room temperature for 1 h followed by the addition of ether (50 mL). The reaction mixture was stirred at 0° C. for an additional 30 min, then filtered and concentrated to provide 4-(4-Chloro-3-methoxy-phenyl)-piperidin-4-ol in the form of HCl salt as a white solid.
Reaction SMILES: [C:1]([CH2:14]I)(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[Na].[K].[C:18]([OH:31])(=[O:30])/[CH:19]=[CH:20]/[C:21]1[CH:29]=[CH:28][C:26]([OH:27])=[C:23]([O:24][CH3:25])[CH:22]=1>>[CH3:8][O:7][C:6]1[CH:5]=[C:4](/[CH:3]=[CH:2]/[C:1]([CH2:14][O:31][C:18](/[CH:19]=[CH:20]/[C:21]2[CH:29]=[CH:28][C:26]([OH:27])=[C:23]([O:24][CH3:25])[CH:22]=2)=[O:30])=[O:13])[CH:12]=[CH:11][C:9]=1[OH:10]
Reactant: COc1cc(/C=C/C(=O)CI)ccc1O
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: [K]
Agent: [Na]
Product: COc1cc(/C=C/C(=O)COC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O

Procedure:
Calebin-A (10a) was prepared by reacting feruloyliodomethane with sodium or potassium salt of ferulic acid with reaction steps and conditions maintained as mentioned in the general synthetic scheme discussed herein above in Para 0010. The yield of the product was 60%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[O:17])=[C:5]([CH3:18])[O:4][N:3]=1.[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([OH:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(=O)C(=O)N2
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccccc1)C(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
5-(3,5-Dimethylisoxazol-4-yl)indoline-2,3-dione (24.2 g, 0.1 mol) was dissolved in anhydrous THF (400 mL) and cooled to 0° C. followed by dropwise addition of a 2.0 M solution of PhMgBr in THF (110 mL, 220.0 mmol). The ice-bath was removed, and the reaction was stirred under N2 for 30 min at which point TLC analysis indicated complete consumption of the starting material. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL), and extracted with EtOAc (3×100 ml). The combined organic layers were washed with saturated aqueous NaHCO3 (100 ml), brine (100 ml), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was evacuated under high vacuum to give the crude alcohol (30 g, 94%). 1H NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 7.22-7.32 (m, 6H), 7.09 (d, J=1.2 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.71 (brs, 1H), 2.32 (s, 3H), 2.15 (s, 3H) MS (ESI) m/e [M+1]+ 321.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[N:23]([CH2:24][C:25](O)=[O:26])[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:30][CH:31]1[O:36][CH:35]([CH3:37])[CH2:34][NH:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:19][O:20][C:21]([CH3:29])([CH3:28])[CH2:22][N:23]3[CH2:24][C:25]([N:33]3[CH2:32][CH:31]([CH3:30])[O:36][CH:35]([CH3:37])[CH2:34]3)=[O:26])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1CNCC(C)O1
Reactant: CC1(C)CN(CC(=O)O)C(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Product: CC1CN(C(=O)CN2CC(C)(C)OCC2C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CC(C)O1

Procedure:
The desired compound was prepared using [5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and 2,6-dimethyl morpholine following Method F. Chromatographic purification gave the desired product in 70-80% yield. 1H-NMR (300 MHz, CDCl3): δ 9.31 (s, 1H), 8.75 (d, 1H), 8.55 (d, 1H), 8.37 (d, 1H), 8.14 (m, 1H), 4.73 (m, 2H), 4.96 (m, 1H), 4.37 (m, 2H), 3.69 (m, 2H), 3.57 (m, 4H), 2.82 (t, 1H), 2.47 (t, 1H), 1.50 (d, 3H), 1.42 (d, 3H), 1.18 (m, 6H). Retention Time (LC, method: formic acid standard): 1.14 min (Diode Array).
Reaction SMILES: [O:1]=[C:2]1[NH:16][CH2:15][CH2:14][C:5]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6]2)[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:20]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][N:16]1[C:2](=[O:1])[CH2:3][CH2:4][C:5]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6]2)[CH2:14][CH2:15]1
Reactant: CI
Reactant: O=C1CCC2(CCN1)COc1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC2(CCC1=O)COc1ccccc12
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
1,2,3,5,6,7-Hexahydro-7-oxospiro[4H-azepine-4,3'(2H)-benzofuran] (D25, 0.42 g, 1.9 mmol) was dissolved in dry DMF (10 ml) and added under Ar to sodium hydride (80% in mineral oil, 0.09 g, 3 mmol) in dry DMF (1 ml). After stirring for 5 min, iodomethane (0.24 ml, 3.8 mmol) was added. The mixture was stirred for 1 h, diluted with ethyl acetate (150 ml), washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (0.36 g, 79%) as yellow semi-solid.
Reaction SMILES: [C:1](#[N:16])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.[NH2:18][OH:19].[OH-].[Na+]>C(O)C>[NH2:16][C:1]1[O:19][N:18]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:2]=1
Reactant: CCCCCCCCCCCCC#CC#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCc1cc(N)on1
Temperature: 25 °C
Reaction time: 22 h
Yield: 71.2 %

Procedure:
A solution of 2-pentadecynenitrile (10.0 g, 45.6 mmol) in ethanol (50 mL) was added to a stirred solution of hydroxylamine hydrochloride (3.8 g, 54.6 mmol) in 2.5 N NaOH (20.0 mL, 50.1 mmol). The resulting mixture was diluted with ethanol (100 mL) and stirred (22 hours, 25° C.). The obtained slurry was concentrated, then partitioned between ethyl acetate (300 mL) and brine (100 mL). The organic layer was dried (MgSO4), concentrated in vacuo, and chromatographed on silica (95:5 to 70:30 hexane:ethyl acetate) to yield 8.2 g (71.2%) of 5-amino-3-dodecyl-isoxazole as a waxy solid, m.p. 48.5°-49.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1([C:31](Cl)=[O:32])[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:31]([C:18]1([CH2:17][CH2:16][CH2:15][CH2:14][Br:13])[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:32]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)c(OC)c1

Procedure:
Prepared analogously to Example 1 from 2,4-dimethoxybenzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]([I:21])[C:12]2[O:16][C:15]([N:17]([CH3:19])[CH3:18])=[N:14][C:13]=2[CH:20]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:18][N:17]([CH3:19])[C:15]1[O:16][C:12]2[C:11]([I:21])=[CH:10][C:9]([CH2:8][NH2:7])=[CH:20][C:13]=2[N:14]=1
Reactant: CN(C)c1nc2cc(CNC(=O)OC(C)(C)C)cc(I)c2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1nc2cc(CN)cc(I)c2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of tert-butylN-{[2-(dimethylamino)-7-iodo-1,3-benzoxazol-5-yl]methyl}carbamate (120 mg, 0.29 mmol) in 4 ml of CH2Cl2 was added slowly 0.5 mL of trifluoroacetic acid and it was stirred at room temperature for 30 min. The excess of TFA was removed under vacuum. The product was purified by column chromatography (CH2Cl2/MeOH 9:1) yielding 64 mg (70%) of N2,N2-dimethyl-5-(aminomethyl)-7-iodo-1,3-benzoxazol-2-amine as a white solid. 1H NMR (CD3OD) δ 7.46 (d, 1H, J=1.5 Hz, H-6); 7.30 (d, 1H, J=1.5 Hz, H-4); 4.12 (s, 2H, CH2); 3.23, 3.24 (s, 6H, CH3×2); 13C NMR (CD3OD) δ 164.5 (C-2), 152.7 (C-7a), 144.6 (C-3a), 132.9 (C-5), 131.6 (C-6), 117.3 (C-4), 72.0 (C-7), 44.2 (CH2), 38.3 (CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:14]=[N:13]2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:14]=[N:13]2)[CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Reaction time: 24 h

Procedure:
To a solution of 3.2 g (8.2 mmoles) of 3,3-bis(4-fluorophenyl)-2-(5-phenyl-1H-tetrazol-1-yl)-2-propenol in 200 mL of dry methylene chloride at room temperature was added 1.9 g (8.8 mmoles) of pulverized pyridinium chlorochromate in a single portion. The oxidation was allowed to proceed at room temperature for 24 hours. The crude reaction suspension was diluted with 200 mL of hexanes and the resulting dark brownish suspension was filtered through a bed (1 cm thick) of fine silica gel. The pale filtrate was collected and evaporated under reduced pressure to give the desired product. The solid was recrystallized from an ethyl acetate-hexanes mixture to yield 2.9 g (91.1%) of the title compound; m.p.=193.0°-194.5° C.
Reaction SMILES: O1CCCC1.[CH:6]1([O:9][C:10]2[CH:11]=[C:12]([C:20]3[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]4[CH:24]=[N:25][NH:26][C:27](=[O:28])[C:22]=4[C:21]=3[CH:38]=[O:39])[CH:13]=[CH:14][C:15]=2[O:16][CH:17]([F:19])[F:18])[CH2:8][CH2:7]1.[BH4-].[Na+]>O>[CH:6]1([O:9][C:10]2[CH:11]=[C:12]([C:20]3[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])[C:23]4[CH:24]=[N:25][NH:26][C:27](=[O:28])[C:22]=4[C:21]=3[CH2:38][OH:39])[CH:13]=[CH:14][C:15]=2[O:16][CH:17]([F:19])[F:18])[CH2:8][CH2:7]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(C=O)c2c(=O)[nH]ncc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(CO)c2c(=O)[nH]ncc21
Temperature: 25 °C
Yield: 69.8 %

Procedure:
To 3 ml of tetrahydrofuran solution containing 221 mg (0.450 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 10-(a) was added 58 mg (1.53 mmol) of sodium borohydride under ice-cooling, and the reaction mixture was raised to room temperature. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 155 mg of the title compound as a pale yellowish foam. (Yield: 70%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][NH:10][C:9](=[O:19])[CH2:8][C:7]=2[CH:20]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([N:10]1[C:9](=[O:19])[CH2:8][C:7]2[CH:20]=[C:3]([O:2][CH3:1])[C:4]([O:21][CH3:22])=[CH:5][C:6]=2[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NNC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(c1ccccc1)=NN(Cc1ccccc1)C(=O)C2
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 7,8-dimethoxy-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIaa (100 mg, 0.34 mmol) in DMF (5 ml), under an inert atmosphere, add NaH in oil (12 mg, 0.30 mmol). Then add dropwise benzyl bromide (40 μl, 0.34 mmol). After 2 hours at room temperature, evaporate the DMF. Take up the residue in CH2Cl2, wash twice with water. Dry the organic phases on Na2SO4. Purify by silica gel column chromatography (AcOEt/hexane, 4:1). Yield: 71%. M: 114–116° C. 1H-NMR (200 MHz, CDCl3): d 3.53–3.64 (m, 2H, CH2), 3.73 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 4.93–5.32 (d, 2H, NCH2Ph), 6.63 (s, 1H, Ar), 6.92 (s, 1H, Ar), 7.20–7.59 (m, 10H, Ar).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1>C1COCC1.O>[CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
A solution of 33.9 mg (0.08 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67) and 8.5 mg (0.20 mmol) of LiOH--H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of sat. aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid.
Reaction SMILES: ClC1C=C(C=CC=1)C[N:6]1[C:14]2[N:13]=[C:12](C(C)C)[NH:11][C:10]=2[C:9](=[O:18])[NH:8][C:7]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24].[OH-].[Na+]>N1C=CC=CC=1>[NH:8]1[C:9](=[O:18])[C:10]2[NH:11][CH:12]=[N:13][C:14]=2[NH:6][C:7]1=[S:24]
Reactant: CC(C)c1nc2c([nH]1)c(=O)[nH]c(=O)n2Cc1cccc(Cl)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=c1[nH]c(=S)[nH]c2nc[nH]c12
Temperature: -5 °C
Yield: 226.7 %

Procedure:
3.19 g of 3-(3-chlorobenzyl)-8-isopropyl-xanthine and 2.67 g of phosphorus pentasulfide were heated under reflux in 35 ml of pyridine for 5 hours. After cooling to -5° C., 13.2 ml (26.4 mM) of 2N NaOH were added over 15 minutes. The reaction mixture was evaporated to dryness, the residue suspended in water, the pH adjusted to 7.5 and the solid collected. The product was redissolved in 100 ml of 1N NaOH, treated with charcoal (5%), filtered and neutralized to pH 7.5. The solid was collected, washed and dried to give 2.29 g of crude thioxanthine. The product was dissolved in 250 ml of chloroform and filtered through 15 g of silica gel. The collected material was reprecipitated from NaOH by neutralization with HCl to give the title compound (2.38 g) as an off-white solid mp 218-20° C.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:14]1[CH2:19][C@@H:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:17][CH2:16][C@@H:15]1[CH3:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[CH2:20]([C@H:18]1[CH2:19][N:14]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:15]([CH3:27])[CH2:16][N:17]1[C:29]([O:31][CH3:32])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cl
Reactant: C[C@H]1CN[C@H](Cc2ccccc2)CN1Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1C[C@@H](C)N(Cc2ccccc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Pyridine (0.57 ml, 7.0 mmol) was added to a stirring solution of (2S,5R)-1,5-dibenzyl-2-methylpiperazine (0.40 g, 1.2 mmol) and methyl chloroformate (0.20 ml, 2.5 mmol) in CH2Cl2 (14 ml). After stirring at ambient temperature for 2 h, the reaction was evaporated in vacuo and the residue purified by flash chromatography (SiO2, 3% MeOH in CH2Cl2) to afford pure product (0.28 g, 68% yield over the two steps). MS (ESI) 339 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:12][N:11]=1.C(N[C:24](=O)[O-:25])C>O>[Cl:8][C:7]1[C:2]2[NH:1][C:24](=[O:25])[N:11]3[N:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:10]3[C:3]=2[CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1c(Cl)cc(Cl)cc1-c1n[nH]c(-c2ccccc2)n1
Reactant: CCNC(=O)[O-]
Solvent: O
Product: O=c1[nH]c2c(Cl)cc(Cl)cc2c2nc(-c3ccccc3)nn12
Reaction time: 16 h

Procedure:
A mixture of 3-(2-amino-3,5-dichlorophenyl)-5-phenyl-1H-1,2,4-triazole (6 g) and ethylcarbamate (50 g) is heated under nitrogen at 195° for 6 hours after which it is cooled to 80°, poured into water (1000 ml) and stirred 16 hours. The product is collected, washed with water, then methanol (300 ml) and air dried. The crude material is recrystallized from 12:1 2-methoxyethanol-water to afford pure 7,9-dichloro-2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)one, mp 309°-311°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cccc2c1CCCC2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc4c3CCCC4)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 176.7 mg (1.2 mmol) of 1-amino-5,6,7,8-tetrahydronaphthalene and 115.6 mg (1 mmol) of pyridine hydrochloride in 12 mL of 2-ethoxyethanol was refluxed for 2 hr. The work up gave 195.1 mg (54.3%) of the product as a yellow solid, m.p. 248° C. (dec.), mass (electrospray, m/e): M+H 360.1. HRCIMS: calcd 359.163 for C22H16N3O2Cl(M+), obsd 359.1632.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.[NH:35]1[C:43]2[C:38](=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1.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.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:39]4[CH:40]=[CH:41][CH:42]=[C:43]5[C:38]=4[CH:37]=[CH:36][NH:35]5)=[CH:32][C:17]=3[C:18]=2[C:28]([NH:29][CH3:30])=[O:31])=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc4[nH]ccc34)cc12
Temperature: 90 °C
Yield: 47.8 %

Procedure:
Cesium carbonate (176 mg, 0.539 mmol) was added to Pd(Ph3P)4 (20.77 mg, 0.018 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (150 mg, 0.359 mmol), 1H-indol-4-ylboronic acid (87 mg, 0.539 mmol). Dioxane (3 mL) and water (600 μL) was added at rt. The reaction was degassed 3× and then heated to 90° C. overnight. It was allowed to cool. The mixture was diluted with ethyl acetate and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (66 mg, 46%). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.28 (1H, br. s.), 8.48-8.57 (1H, m), 7.98-8.07 (2H, m), 7.86 (1H, br. s.), 7.79 (1H, d, J=8.24 Hz), 7.69 (1H, d, J=7.93 Hz), 7.37-7.47 (4H, m), 7.21 (1H, t, J=7.63 Hz), 7.14 (1H, d, J=7.02 Hz), 6.60 (1H, br. s.), 2.84 (3H, d, J=4.27 Hz). LC-MS retention time: 1.53 min; m/z (MH+): 385. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=13.46 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=12.27 min, purity=97%.