Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH2:21](Br)[C:22]1[CH:30]=[CH:29][C:28]2[O:27][CH2:26][O:25][C:24]=2[CH:23]=1.S(=O)(=O)(O)O.N1C=CC=CC=1>COCCOC.CCOCC>[CH2:3]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:30]=[CH:29][C:28]2[O:27][CH2:26][O:25][C:24]=2[CH:23]=1)[CH2:4][CH:5]([CH3:6])[CH3:7]
Reactant: BrCc1ccc2c(c1)OCO2
Reactant: CC(C)CCOCCCCOCCCCCCO
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)CCOCCCCOCCCCCCOCc1ccc2c(c1)OCO2
Reaction time: 2 h

Procedure:
0.60 g (0.020 mol) of 80% sodium hydride dispersion are added by portions, at 20°, under nitrogen and while stirring, to 4.02 g (0.0155 mol) of 6-(4-Isopentyloxy-butyloxy)-hexanol in 60 cc of absolute 1,2-dimethoxy-ethane. The mixture is stirred at 60° over the course of 2 hours, cooled to 0° and a solution of 3.65 g (0.017 mol) of piperonyl bromide in 40 cc of absolute 1,2-dimethoxy ethane is added dropwise over the course of 10 minutes. The mixture is stirred at 20° for 3 hours and then at 40° for 20 hours, neutralized with 6N sulphuric acid and together with 1.35 g (0.017 mol) of pyridine heated to 60° over the course of 2 further hours. The reaction product is taken up in ether, washed with water, 6N sulphuric acid, water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated. After chromatography of the residue on silica gel with hexane/acetone (98:2) and (96:4), [6-(4-Isopentyloxybutyloxy)-hexyl]-piperonyl ether is obtained as a colourless oil.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][OH:6].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]([C:21]1[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[C:41]5[C:36](=[N:37][CH:38]=[CH:39][CH:40]=5)[NH:35][C:34]4=[O:42])[CH2:29][CH2:28]3)[C:24](I)=[CH:23][N:22]=1)=[O:20])[CH2:14][CH2:13]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCOCC1.C1COCC1.[Cu]I>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]([C:21]1[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[C:41]5[C:36](=[N:37][CH:38]=[CH:39][CH:40]=5)[NH:35][C:34]4=[O:42])[CH2:29][CH2:28]3)[C:24]([C:3]#[C:4][CH2:5][OH:6])=[CH:23][N:22]=1)=[O:20])[CH2:14][CH2:13]2
Reactant: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c(I)cn1)N1CCc2cc(F)ccc21
Reactant: C[Si](C)(C)C#CCO
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c(C#CCO)cn1)N1CCc2cc(F)ccc21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Under an argon atmosphere 44 mg (0.34 mmol) 3-trimethylsilanyl-prop-2-yn-1-ol, 50 μL TEA, 13 mg 1,1′-bis(diphenylphosphine)ferrocene dichloropalladium (II) and 3 mg (20 μmol) copper(I) iodide were added to 0.10 g (0.17 mmol) 1-[2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-5′-iodo-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one in 4.0 mL 1,4-dioxane. Then 0.36 mL (0.36 mmol) of a 1 molar tetrabutylammonium fluoride solution in THF were added dropwise and the mixture was then stirred for 4 h at 80° C. The reaction mixture was mixed with water and the precipitate formed was suction filtered. The precipitate was stirred in 6 mL DMF and suction filtered. The filtrate was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=CC=C[CH:2]=1.[N:11]1[CH:12]=[CH:13][N:14]2[CH:19]=[C:18]([CH2:20][NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:17]=[CH:16][C:15]=12.N1C=CN2C=CC(CNC(=O)C3C=CC(C4CCNCC4)=CC=3)=CC=12>>[N:11]1[CH:12]=[CH:13][N:14]2[CH:19]=[C:18]([CH2:20][NH:21][C:22](=[O:35])[C:23]3[CH:24]=[CH:25][C:26]([CH:29]4[CH2:30][CH2:31][N:32]([S:7]([CH:1]([CH3:6])[CH3:2])(=[O:9])=[O:8])[CH2:33][CH2:34]4)=[CH:27][CH:28]=3)[N:17]=[CH:16][C:15]=12
Reactant: O=C(NCc1cn2ccnc2cn1)c1ccc(C2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)cc1
Product: CC(C)S(=O)(=O)N1CCC(c2ccc(C(=O)NCc3cn4ccnc4cn3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 682, substituting propane-2-sulfonyl chloride for benzenesulfonyl chloride and N-(imidazo[1,2-a]pyrazin-6-ylmethyl)-4-(piperidin-4-yl)benzamide for N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(piperidin-4-yl)benzamide. 1H NMR (500 MHz, methanol-d4) δ ppm 9.21 (d, J=1.4 Hz, 1H), 8.67 (d, J=1.4 Hz, 1H), 8.22 (d, J=1.6 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.89-7.82 (m, 2H), 7.40-7.35 (m, 2H), 4.85-4.79 (m, 1H), 4.75 (s, 2H), 3.96-3.85 (m, 2H), 3.12-3.00 (m, 2H), 2.88-2.74 (m, 1H), 1.95-1.85 (m, 2H), 1.84-1.65 (m, 2H), 1.33 (d, J=6.8 Hz, 6H); MS (ESI(+)) m/e 442 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]([C:17]1([C:20](=[O:46])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36](OC4C=CC=CC=4)=[O:37])[CH:30]=3)=[CH:24][C:23]=2[F:45])[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:47][N:48]1[CH2:53][CH2:52][N:51]([CH:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:50][CH2:49]1>CN(C)C=O>[CH2:7]([O:14][C:15]([C:17]1([C:20](=[O:46])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]3[CH2:34][CH2:33][NH:32][CH:31]([NH:35][C:36]([N:57]4[CH2:58][CH2:59][CH:54]([N:51]5[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]5)[CH2:55][CH2:56]4)=[O:37])[CH2:30]3)=[CH:24][C:23]=2[F:45])[CH2:18][CH2:19]1)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1)Oc1ccccc1
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)NC3CC(Oc4ccc(NC(=O)C5(C(=O)OCc6ccccc6)CC5)c(F)c4)CCN3)CC2)CC1
Yield: 49.8 %

Procedure:
Potassium carbonate (772 mg) was added to a mixture of 1-[2-fluoro-4-(2-phenoxycarbonylaminopyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (2.75 g) and N,N-dimethylformamide (13.8 ml) was added, followed by stirring. 1-Methyl-4-(piperidin-4-yl)piperazine (1.02 g) was added, followed by stirring for 6 hours. The reaction mixture was partitioned after the addition of ethyl acetate (41 ml) and water (27.5 ml). The resultant organic layer was washed with water (13.8 ml, three times), dried over sodium sulfate, and filtered, and the filtrate was concentrated. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=30:1). The eluate was concentrated under reduced pressure, and the precipitate appeared by the addition of tert-butyl methyl ether (3 ml) and the application of a stimulus. tert-Butyl methyl ether (40 ml) was further added, followed by stirring overnight. The resultant precipitate was collected by filtration, washed with tert-butyl methyl ether (3 ml), and dried under aeration to give the target title compound (1.61 g).
Reaction SMILES: C(OC([N:8]1[CH2:29][CH2:28][C:11]2[N:12]=[C:13]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:23]1([C:13]2[N:14]=[C:15]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:10]3[CH2:9][NH:8][CH2:29][CH2:28][C:11]=3[N:12]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Cc1ccc(-c2nc(N3CCCC3)nc3c2CN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(N3CCCC3)nc3c2CNCC3)cc1
Reaction time: 16 h
Yield: 78.7 %

Procedure:
To a solution of 2-Pyrrolidin-1-yl-4-p-tolyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester (0.075 g, 0.19 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). After 16 h, the mixture was concentrated, diluted with saturated (satd.) aqueous (aq.) NaHCO3, and extracted with CH2Cl2. The combined organic layers were dried and concentrated. Purification by FCC (2 M NH3 in MeOH/CH2Cl2) provided the title compound (0.044 g, 79%). HPLC: Rt=7.7 min. MS (ESI): mass calcd. for C18H22N4, 294.4; m/z found, 295.4 [M+H]+. 1H NMR (CDCl3): 7.42-7.34 (m, 2H), 7.28-7.22 (m, 2H), 3.87 (s, 2H), 3.61-3.58 (m, 4H), 3.20 (t, J=6.2, 2H), 2.82 (t, J=6.2, 2H), 2.39 (s, 3H), 1.97-1.94 (m, 4H).
Reaction SMILES: [BH4-].[Na+].[C:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:21])[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].O>CO>[C:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]([OH:21])[CH2:16][CH2:17][N:18]([CH3:19])[CH3:20])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCc2cc(C(=O)CCN(C)C)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)N1CCc2cc(C(O)CCN(C)C)ccc21
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Sodium borohydride (0.75 g) was added to a solution of 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-3-(dimethylamino)-1-propanone (4.3 g) obtained in Reference Example 12 in methanol (40 ml) under cooling with ice-bath, and the mixture was stirred at 0 to 5° C. for 30 minutes. After iced water was added to the reaction solution, the solvent was distilled away under reduced pressure, and the residues were extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residues were purified by alumina column chromatography (developing solvent; ethyl acetate), whereby 3-[1-acetyl-2,3-dihydro-1H-indol-5-yl]-3-hydroxy-N,N-dimethyl-1-propanamine (3.3 g) was obtained as colorless powder.
Reaction SMILES: C(O[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=[O:15])C1C=CC=CC=1.Br[C:17]1[CH:22]=[C:21]2[N:23]([CH3:34])[C:24]3[CH:33]4[N:28]([CH2:29][CH2:30][CH2:31][CH2:32]4)[CH2:27][CH2:26][C:25]=3[C:20]2=[CH:19][CH:18]=1.BrC1C=C2C([C:40]3[CH2:52][CH2:51][N:50]4[CH:46](CCC4)[C:41]=3N2C)=CC=1.[ClH:53]>CO.CCOCC>[ClH:53].[Cl:53][C:41]1[CH:40]=[CH:52][C:51]([C:12]2[CH:13]=[CH:14][N:9]([C:17]3[CH:22]=[C:21]4[N:23]([CH3:34])[C:24]5[CH:33]6[N:28]([CH2:29][CH2:30][CH2:31][CH2:32]6)[CH2:27][CH2:26][C:25]=5[C:20]4=[CH:19][CH:18]=3)[C:10](=[O:15])[CH:11]=2)=[N:50][CH:46]=1
Reactant: O=c1ccccn1OCc1ccccc1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN1CCCCC21
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN1CCCC21
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cn5)cc4=O)cc31)CCN1CCCCC21
Yield: 84 %

Procedure:
According to the procedure of Example 2 (step b), except substituting 4-(5-chloropyridin-2-yl)pyridin-2(1H)-one for 4-(benzyloxypyridin-2(1H)-one and substituting 10-Bromo-12-methyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine for 9-bromo-11-methyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole, a yellow oil was obtained in 30% (56 mg). The yellow oil was dissolved in CH3OH (1 mL) and was treated with 2 N HCl in Et2O (1 mL). The resulting solid was isolated by filtration and dried under vacuum to give the title compound (51 mg, 84%) as a yellow solid: mp 210-213° C.; 1H NMR (500 MHz, CD3OD) δ 8.73 (d, J=2.5 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 8.00 (dd, J=8.5, 2.0 Hz, 1H), 7.79 (d, J=7.0 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.31 (d, J=1.5 Hz, 1H), 7.20 (dd, J=7.5, 2.0 Hz, 1H), 7.16 (dd, J=8.5, 2.0 Hz, 1H), 4.93 (dd, J=12, 4.0 Hz, 1H), 4.17-4.11 (m, 1H), 3.76 (s, 3H), 3.67-3.60 (m, 3H), 3.24-3.21 (m, 2H), 2.35-2.33 (m, 1H), 2.12-1.99 (m, 3H), 1.94-1.88 (m, 2H); ESI MS m/z 445 [M+H]+; HPLC (Method A) 97.3% (AUC), tR=12.9 min.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:26])[CH:10]2[NH:14][C:15](=[O:25])[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[S:22]([CH3:24])=[O:23])[C:7]=1[C:27]([OH:29])=[O:28])(=O)C.C(=O)(O)[O-].[Na+].[CH3:35][C:36]1[S:37][C:38](=[S:41])[NH:39][N:40]=1.Cl>O>[C:27]([C:7]1[N:8]2[CH:11]([S:12][CH2:13][C:6]=1[CH2:5][S:41][C:38]1[S:37][C:36]([CH3:35])=[N:40][N:39]=1)[CH:10]([NH:14][C:15](=[O:25])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[S:22]([CH3:24])=[O:23])[C:9]2=[O:26])([OH:29])=[O:28]
Reactant: Cc1n[nH]c(=S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3ccnc3S(C)=O)C2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cn4ccnc4S(C)=O)C3SC2)s1
Temperature: 60 °C
Yield: 27.3 %

Procedure:
3-Acetoxymethyl-2-carboxy-7-[(2-methylsulphinylimidazol-1-yl)-acetamido]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]-oct-2-ene (8.5 g.) and sodium bicarbonate (1.62 g.) are dissolved in water (75 cc.). A solution of 2-methyl-5-thioxo-1,3,4-thiadiazoline (2.54 g.) and sodium bicarbonate (1.62 g.) in water (75 cc.) is added and the mixture is heated at 60° C. for 6 hours. After cooling, the pH is adjusted to 6 by adding hydrochloric acid (4 N) and the mixture is washed twice with ethyl acetate (a total of 200 cc.). The mixture is acidified to pH 2 by adding hydrochloric acid (4 N); a product precipitates and is filtered off and dried under reduced pressure (1 mm.Hg) to give 7.9 g. of product. Recrystallisation from methanol (25 cc.), filtration and drying under reduced pressure (0.1 mm.Hg) gives 2-carboxy-3-[(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl]-7-[(2-methylsulphinyl-imidazol-1-yl)-acetamido]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (2.7 g.), m.p. 227° C. (with decomposition), [α]D20 = -35° ± 1° (c= 1, dimethylformamide).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:24][CH2:25][CH2:26]Br>C(OCC)(=O)C>[Br:24][CH2:25][CH2:26][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(-c2noc3cc(F)ccc23)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Fc1ccc2c(-c3ccc(OCCBr)cc3)noc2c1
Yield: 41 %

Procedure:
Combine 4-(6-fluoro-benzo[d]isoxazol-3-yl)-phenol (2.00 g, 8.726 mmol) and potassium carbonate (1.81 g, 13.088 mmol) in 1,2-dibromoethane (9.70 mL) and heat at reflux for 6 hours. Cool reaction mixture to room temperature and dilute with ethyl acetate (150 mL) and wash with water (50 mL), 10% HCl (50 mL), water (50 mL), saturated sodium chloride (50 mL), dry (MgSO4), filter and evaporate. Purify the residue by column chromatography (5% ethyl acetate in heptane) to obtain the title compound as a white solid (1.21 g, 41% Yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][CH2:22][NH:23][OH:24])[CH:16]=3)[C:11]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][N:27]=[C:28]=[O:29]>O1CCOCC1.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][CH2:22][N:23]([C:28]([NH:27][CH3:26])=[O:29])[OH:24])[CH:16]=3)[C:11]2=[O:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccc(OCCNO)cc2CCN1CCCc1ccccc1
Reactant: CN=C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)N(O)CCOc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O
Reaction time: 12 h

Procedure:
2-(3-Phenylpropyl)-6-[2-(N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (498 mg, 1.5 mmol) is dissolved in dioxane t 15 mL) and methyl isocyanate (0.22 mL, 3.7 mmol) is added. After 12 hours, the reaction mixture is diluted with EtOAc (150 mL) and the organic phase washed with 2N HCl (2×200 mL), H2O (4×200 mL), saturated NaHCO3 solution (2×200 mL), saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The resulting material is triturated with hexanes and recrystallized from CH2C2 /hexanes to give 2-(3-phenylpropyl)-6-{2-[N-(methylaminocarbonyl)-N-hydroxyamino]-ethoxy}-1-oxo-1,2,3,4-tetrahydroisoquinoline, m.p. 138°-139°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][OH:15])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of 4-bromobenzotrifluoride (6.5 g, 28.89 mmol), propargyl alcohol (2.35 ml, 40.45 mmol), triethylamine (5.64 ml, 40.45 mmol), triphenylphosphine (230 mg, 0.87 mmol), cuprous iodide (110 mg, 0.58 mmol), and dichlorobis(triphenylphosphine)palladium (210 mg, 0.29 mmol) in toluene (100 ml) was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was allowed to return to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate =9/1) to afford 3-(4-trifluoromethylphenyl)-2-propyn-1-ol (3.47 g, yield 60%) as a pale brown oil.
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[C:16]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[S:18][C:12]=2[N:11]([CH3:35])[C:10]1=[O:36])=O.O[Li].O>C1COCC1.O.C(Cl)Cl>[OH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[C:16]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[S:18][C:12]=2[N:11]([CH3:35])[C:10]1=[O:36]
Reactant: CC(C)CCc1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)n2C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)CCc1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.4 %

Procedure:
To a solution of 3-(5-isopentyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydro thieno[2,3-d]pyrimidin-3(4H)-yl)propyl 2,2,2-trifluoroacetate (35 mg, 0.062 mmol) in THF (4 mL) and water (4 mL) was added LiOH.H2O (5.19 mg, 0.123 mmol). The reaction was stirred at RT for 15 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-5-isopentyl-1-methyl-6-(3-(trifluoromethoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 51.6% yield) as a white solid. 1H NMR (DMSO-d6) δ: 7.65 (t, J=8.0 Hz, 1H), 7.47 (dd, J=12.5, 8.3 Hz, 2H), 7.41 (s, 1H), 4.49 (s, 1H), 4.02-3.89 (m, 2H), 3.47 (s, 5H), 2.91-2.78 (m, 2H), 1.78-1.63 (m, 2H), 1.51 (dd, J=12.4 and 6.0 Hz, 1H), 1.48-1.37 (m, 2H), 0.81 (d, J=6.4 Hz, 6H). LCMS: MH+ 471 and TR=3.347 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:26][C:27]1[C:32]([C:2]2[CH:3]=[C:4]([C:8]3([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:17])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)ccn1
Reactant: OB(O)c1cccnc1F
Product: COc1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)c3ccccc32)ccn1
Yield: 23 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine (Example 118) as described in Example 67 Scheme #10, D in 23% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.20-8.26 (m, 1 H), 7.97-8.09 (m, 2 H), 7.75-7.92 (m, 2 H), 7.37-7.58 (m, 7 H), 6.78-7.10 (m, 3 H), 6.67 (s, 1 H), 3.79 (s, 3 H); MS (ESI) m/z 411 [M+1]+.
Reaction SMILES: N[C@H]([C:5](O)=[O:6])C[SeH].[Li]CCCC.[Si]([O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1)(C(C)(C)C)(C)C.CN(CCN(C)C)C.CN(C=O)C.Cl>C1COCC1>[OH:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([CH:5]=[O:6])=[C:23]([Cl:28])[CH:22]=1
Reactant: N[C@@H](C[SeH])C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(Cl)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1c(F)cc(O)cc1Cl
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Sec-BuLi (1.3M solution in cyclohexane, 42.3 mL, 55 mmol) was added slowly at −78° C. to a solution of intermediate 16, 1-(tert-Butyldimethylsilyl)oxy-3-chloro-5-fluorobenzene (13.1 g, 50 mmol) and TMEDA (8.3 mL, 55 mmol) in THF (200 mL) and the mixture was stirred at the same temperature for 30 min. DMF (4.23 mL, 55 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for 1.5 h. Then 10% aqueous HCl was added to attain pH˜4-5 (200 mL), and the reaction mixture was stirred at RT for 12 h. Aqueous layer was extracted with EtOAc (200 mL). The organic layer was separated. The organic layer was washed with sat. NaHCO3, then H2O was added, HCl was added to attain pH˜3-4, the organic layer was separated, washed with brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (7.53 g, 86%, 43 mmol) as a white solid. 1H NMR data (dmso-d6): 11.51 (br.s, 1H, OH), 10.15 (s, 1H, CHO), 6.78-6.83 (m, 1H, H—Ar), 6.68 (dd, 1H, J1=2.2 Hz, J2=12.7 Hz, H—Ar).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=[O:20])[CH3:19])=[C:13]([CH3:21])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.[Cu]>[CH3:9][O:8][C:5]1[CH:4]=[N:3][C:2]([O:10][C:11]2[CH:12]=[C:13]([CH3:21])[C:14]([C:18](=[O:20])[CH3:19])=[C:15]([CH3:17])[CH:16]=2)=[N:7][CH:6]=1
Reactant: COc1cnc(Cl)nc1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cnc(Oc2cc(C)c(C(C)=O)c(C)c2)nc1
Temperature: 120 °C
Yield: 24 %

Procedure:
2-Chloro-5-methoxypyrimidine (8-1, 5.13 g, 35.6 mmol) and 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 6.10 g, 37.2 mmol) were suspended in DMF (80.0 ml) and added with copper powder (0.78 g, 7.8 mmol) and potassium carbonate (15.31 g, 0.11 mol). The reaction was heated at 120° C. for 16 h. The reaction was cooled to room temperature and diluted with EtOAc (90 mL). The organic phase was washed with 15% NaOH and water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40% EtOAc in hexanes as eluant) to give 1-{4-((5-methoxypyrimidin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (8-2, 2.33 g) as light yellow solids in 24% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.41 (s, 2 H), 6.86 (s, 2 H), 3.86 (s, 3 H), 2.47 (s, 3 H), 2.18 (s, 6 H).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C@:21]2([CH3:27])[CH2:25][O:24]C(=O)[NH:22]2)[CH:15]=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:22][C@@:21]([C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH:7]3[CH2:6][CH2:5][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)[CH:12]=2)[CH:17]=1)([CH3:27])[CH2:25][OH:24]
Reactant: CC(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Yield: 32.8 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(4-isopropyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol), 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 56 mg of the desired compound as a yellow brown solid (30%). ESI-MS: 325 (M−16)+. 1H NMR (400 MHz, CDCl3) δ=7.94-7.61 (m, 3H), 7.50 (d, J=8.5 Hz, 1H), 7.23-7.05 (m, 2H), 4.67 (br. s., 1H), 4.33-4.17 (m, 1H), 3.84-3.51 (m, 2H), 2.35-1.75 (m, 4H), 1.68-1.08 (m, 10H), 1.01-0.68 (m, 6H).