Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][C:12]([C:15](=[O:19])[CH:16](Br)[Br:17])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:20](=[O:24])[CH:21](Br)[Br:22].CCN(CC)CC.P([O-])(OCC)OCC>C1COCC1>[S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][C:12]([C:15](=[O:19])[CH2:16][Br:17])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:20](=[O:24])[CH2:21][Br:22]
Reactant: O=C(c1ccc2c(c1)OCCc1cc(C(=O)C(Br)Br)sc1-2)C(Br)Br
Agent: CCOP([O-])OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CBr)c1ccc2c(c1)OCCc1cc(C(=O)CBr)sc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,1′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(2,2-dibromoethanone) (2d) (0.65 g, 1.08 mmol) in 20 ml THF at 0° C. was added Et3N (0.45 ml, 3.24 mmol) and diethyl phosphite (0.42 ml, 3.24 mmol). The reaction mixture was gradually warmed to room temperature and the mixture was stirred for 1 hr. The volatiles were removed under reduced pressure and the crude residue was washed with n-pentane to yield an yellow solid (2e) that was used in the next step without purification (0.42 g, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:17]C(=O)OC(C)(C)C)=[N:9]3)=[CH:4][C:3]=1[O:25][CH3:26].C(O)(C(F)(F)F)=O>C(Cl)Cl.O.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH2:17])=[N:9]3)=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc(C23CCCC2CSC(NC(=O)OC(C)(C)C)=N3)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cc([C@]23CCCC2CSC(N)=N3)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution tert-butyl 7a-(4-fluoro-3-methoxyphenyl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-ylcarbamate (1.04 g, 2.73 mmol) in CH2Cl2 (20 mL) is added TFA (5 mL) and the reaction is stirred at room temperature for 16 hr. The solvent is removed under reduced pressure to give a residue that is diluted with water and 5N NaOH. The aqueous layer is extracted four times with EtOAc. The organic layer is dried over Na2SO4 and the solvent is removed under reduced pressure. The crude product is purified with a 10 g SCX column using 4:1 CH2Cl2:MeOH and then 2:1 CH2Cl2: 7 N NH3 in MeOH to elute the product and give the title compound (0.756 g, 99%). ES/MS m/e: 281 (M+1).
Reaction SMILES: [OH2:1].O.P([O-])(O)(O)=O.[Na+].CC(=CC)C.Cl([O-])=O.[Na+].[F:18][C:19]([F:28])([F:27])[C:20]1[N:21]=[C:22]([CH:25]=[O:26])[NH:23][CH:24]=1>C(O)(C)(C)C>[F:28][C:19]([F:18])([F:27])[C:20]1[N:21]=[C:22]([C:25]([OH:1])=[O:26])[NH:23][CH:24]=1
Reactant: O
Reactant: O=Cc1nc(C(F)(F)F)c[nH]1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)c1nc(C(F)(F)F)c[nH]1
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
Sodium dihydrogenphosphate dihydrate (720 mg, 4.62 mmol), 2-methyl-2-butene (1.2 ml, 11.4 mmol) and sodium chlorite (420 mg, 4.64 mmol) were added under ice-cooling to a solution of 4-(trifluoromethyl)-1H-imidazole-2-carbaldehyde obtained in Example (33b) (375 mg, 2.29 mmol) in t-butyl alcohol (12 ml)/distilled water (5 ml), followed by stirring for 1.5 hours. The reaction solution was concentrated under reduced pressure, and then the residue was purified by reverse phase silica gel column chromatography (elution solvent: distilled water) to obtain 0.402 g of the title compound as a white solid (98%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)[CH:5]=[CH:4][C:3]=1[C:34]1([CH2:37]O)[CH2:36][CH2:35]1.[F:39][C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[CH:42]=[C:43](B1OC(C)(C)C(C)(C)O1)[NH:44]2.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1.O>[F:39][C:40]1[C:41]2[CH:42]=[C:43]3[C:2]4[N:7]=[C:6]([C:8]5[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:30])=[O:31])=[CH:10][C:11]6[O:15][C:14]([C:16]7[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=7)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=6[CH:27]=5)[CH:5]=[CH:4][C:3]=4[C:34]4([CH2:35][CH2:36]4)[CH2:37][N:44]3[C:45]=2[CH:46]=[CH:47][CH:48]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C4(CO)CC4)c(Cl)n3)cc12
Reactant: CC1(C)OB(c2cc3c(F)cccc3[nH]2)OC1(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC43CC3)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
To a solution of 5-(6-chloro-5-(1-(hydroxymethyl)cyclopropyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (80 mg, 0.143 mmol) and 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (56.1 mg, 0.215 mmol) in 1,4-Dioxane (2 mL) and water (20 μL) was added Cs2CO3 (93 mg, 0.287 mmol) and DTBPF PdCl2 (21 mg, 0.032 mmol). The mixture was heated to 80° C., stirred overnight, concentrated in vacuo and dried. The residue was dissolved in DCM (2.00 mL), followed by addition of triphenylphosphine (94 mg, 0.358 mmol) and DIAD (0.070 mL, 0.358 mmol). The mixture was stirred at RT for 4 h. Preparative TLC (eluted with 20% ethyl acetate in DCM) gave 5-(11′-fluoro-6′H-spiro[cyclopropane-1,5′-indolo[1,2-h][1,7]naphthyridin]-2′-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (4.5 mg, yield: 5%) MS (M+H)+: 639.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:14]1[N:15]=[CH:16][C:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])=[N:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C(OCC)C.O.CS(C)=O>[CH3:23][N:22]([CH3:24])[C:20]([C:17]1[N:18]=[CH:19][C:14]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:15][CH:16]=1)=[O:21]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(=O)c1cc(O)cc(Oc2cnc(C(=O)N(C)C)cn2)c1
Temperature: 50 °C

Procedure:
To methyl 3,5-dihydroxybenzoate (CAS no. 2150-44-9) (85 g, 0.49 mol) was added 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (88.9 g, 0.48 mol), DMSO (1000 mL,) and cesium carbonate (418 g, 1.2 mol) and the mixture was heated to 50° C. for 3 hours. Water (1577 mL,) was charged followed by diethyl ether (540 mL). To the aqueous layer was charged 5M hydrochloric acid solution (395 mL, 1.97 mol) and the resulting white solid was filtered washed with water (2×311 mL) and dried under vacuum at 40° C. over P2O5 overnight to give the desired compound (143 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH2:7]([O:9][C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:12]([CH3:14])([CH3:13])[CH2:11][C:10]([O:9][CH2:7][CH3:8])=[O:15])[CH:6]=1
Reactant: CCOC(=O)C=C(C)C
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)(C)n1cc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-bromo-1H-pyrazole (3.42 g, 23.43) and 3-methyl-2-butenoic acid ethyl ester (1 g, 7.81 mmol) in DMF (50 mL) was treated with cesium carbonate (10.1 g, 31.07) and allowed to stir for 3 hours at room temperature. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined extracts were dried over sodium sulfate and concentrated to afford the desired product, 1.1 g (51%) yield. 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.45 (s, 1H), 3.98-4.05 (m, 2H), 2.82 (s, 2H), 1.62 (s, 6H), 1.18-1.10 (t, 3H).
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1.Br[CH2:37]C1C=CC=CC=1C.C(OC(=O)C(C)(C)CSC1SC(N)=NC=1)C>>[CH3:22][C:18]([CH3:23])([CH2:17][S:16][C:13]1[S:12][C:11]([NH:10][C:9]([N:8]([CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]=2[CH3:37])[C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[N:15][CH:14]=1)[C:19]([OH:21])=[O:20]
Reactant: Cc1ccccc1CBr
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Product: Cc1ccccc1COCCN(C(=O)Nc1ncc(SCC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-bromomethyl-2-methyl-benzene and 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@H:7]3[C:6]=2[CH:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[CH:31]([Zn]C(C)C)([CH3:33])[CH3:32]>C1(C)C=CC=CC=1.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH:31]([C:4]1[CH:3]=[C:2]([CH3:1])[C:11]2[C:10](=[O:12])[NH:9][C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@H:7]3[C:6]=2[CH:5]=1)([CH3:33])[CH3:32]
Reactant: CC(C)[Zn]C(C)C
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc2c1C(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)C)cc2c1C(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-trans tert-butyl 6-methyl-5-oxo-8-(trifluoromethylsulfonyloxy)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 91, Part A (265 mg, 0.59 mmol) was added diisopropylzinc (1.76 mL of a 1.0 M solution in toluene, 1.76 mmol). The reaction mixture was degassed with a stream of argon and then there was added bis(diphenylphosphino)ferrocene]-dichloropalladium (II) (22 mg, 0.029 mmol). The reaction mixture was allowed to stir at 65° C. for 18 h. The reaction was allowed to cool to ambient temperature and was quenched with 1N HCl. The mixture was diluted with ethyl acetate and the organics were washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 0.22 g of the title compound as an off-white solid, which was sufficiently pure to be employed directly in Part B. LRMS (ESI): 345.2 (M+H)+.
Reaction SMILES: IC1C=CC(C)=CC=1C(O)=O.OOS([O-])=O.[K+].[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:27])[CH2:23][CH2:24][CH2:25][CH3:26]>C(OCC)(=O)C>[CH3:18][CH2:19][CH2:20][CH2:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(O)CCCC
Agent: Cc1ccc(I)c(C(=O)O)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCC(=O)CCCC
Temperature: 70 °C
Reaction time: 12 h

Procedure:
7.86 mg (0.03 mmol) of 2-iodo-5-methylbenzoic acid prepared by Preparation Example 3, 1.48 g (2.4 mmol) of Oxone (registered trademark) and 433 mg (3 mmol) of 5-nonanol were added to 3.75 ml of ethyl acetate, and the mixture was heated at 70° C. while being stirred for 12 hours. After being heated, the mixture was cooled to room temperature, and the insoluble substance was removed by means of filtering. Water was added to the filtrate, extraction was carried out using diethyl ether. The organic phase was dried by using sodium sulfate, and then 5-nonanone was obtained by the means of vacuum-concentration. The yield of the obtained 5-nonanone was determined and the result is shown in Table 1.
Reaction SMILES: C(O[C:4]([C:6]1[N:14]([CH2:15][C:16]#[CH:17])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:5])C.[OH-].[Na+].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:50]([O:52][CH2:53][CH2:54][O:55][NH2:56])=[CH2:51].CCN(C(C)C)C(C)C>C1COCC1.CO>[CH:50]([O:52][CH2:53][CH2:54][O:55][NH:56][C:4]([C:6]1[N:14]([CH2:15][C:16]#[CH:17])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:5])=[CH2:51]
Reactant: C#CCn1c(C(=O)OCC)c(Nc2ccc(I)cc2F)c2cnccc21
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: C#CCn1c(C(=O)NOCCOC=C)c(Nc2ccc(I)cc2F)c2cnccc21
Temperature: 65 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a stirred solution of 3-(2-fluoro-4-iodo-phenylamino)-1-prop-2-ynyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (55.0 mg, 0.12 mmol) in anhydrous THF (1.0 mL) and MeOH (0.5 mL) under N2 was added freshly prepared 1N aqueous sodium hydroxide (0.24 ml, 2.0 eq). The reaction mixture was stirred at 65° C. for 1 h. The resultant reaction mixture was evaporated in vacuo and azeotroped with toluene (3×5 ml) to give a tan solid. The tan solid was redissolved in anhydrous THF (2.4 ml). EDCI (45.2 mg, 0.24 mmol, 2.0 eq) and HOBT (35.0 mg, 0.26 mmol, 2.2 eq) were added. The reaction mixture was stirred at room temperature. After 5 minutes O-(2-vinyloxy-ethyl)-hydroxylamine (14.6 mg, 0.14 mmol, 1.2 eq) and DIPEA (82.2 μL, 0.47 mmol, 4.0 eq) were added, and the reaction mixture was stirred at ambient temperature under N2 for 24 h. The reaction mixture was absorbed onto silica and purified by flash column chromatography (silica, ISCO, 45 mL/min, EtOAc:MeOH, gradient 100:1 to 50:50) to give the desired product as a yellow solid (34.4 mg, 56.0%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.72 (s, 1H), 8.60 (s, 1H), 8.37 (d, J=6.4 Hz, 1H), 7.79-7.47 (m, 3H), 7.24 (d, J=10.0 Hz, 1H), 6.50 (dd, J=14.0 Hz, 8.0 Hz, 1H), 6.35-6.15 (m, 1H), 5.31 (s, 2H), 4.27-4.11 (m, 1H), 4.11-3.90 (m, 4H), 3.92-3.70 (m, 2H); LC-MS (method D): [M+H]+=521.0, RT=2.18 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[N+:8]([C:5]1[CH:4]=[CH:3][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:7][N:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])nc1
Temperature: 65 °C
Reaction time: 4 h
Yield: 45.1 %

Procedure:
To a solution of 5-bromo-2-nitropyridine (1.00 g, 4.93 mmol) in N-methylpyrrolidinone (20 mL) were added trimethylsilyl acetylene (1.39 mL, 9.85 mmol), tetrakis(triphenylphosphine)palladium (0) (114 mg, 985 μmol), copper (I) iodide (37.5 mg, 197 μmol) and N,N-diisopropylethylamine (1.72 mL, 9.85 mmol) at room temperature, which was stirred under nitrogen atmosphere for 4 hours at 65° C. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (490 mg, 45%).
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: ClCCl
Solvent: C1CCOC1
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: C(C1C2C(=CC(OC)=C(OC)C=2)C=C(O)N=1)C.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C:26]([CH2:32][CH2:33][CH3:34])=[N:25][C:24]([OH:35])=[CH:23]2.[OH-].[K+].Cl.Cl[CH2:40][C:41]1[CH:42]=[N:43][C:44]2[C:49]([CH:50]=1)=[CH:48][CH:47]=[C:46]([O:51][CH3:52])[CH:45]=2>C1(C)C=CC=CC=1.C(Cl)Cl.O>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C:26]([CH2:32][CH2:33][CH3:34])=[N:25][C:24]([OH:35])=[C:23]2[CH2:40][C:41]1[CH:42]=[N:43][C:44]2[C:49]([CH:50]=1)=[CH:48][CH:47]=[C:46]([O:51][CH3:52])[CH:45]=2
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COc1ccc2cc(CCl)cnc2c1
Agent: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cnc3cc(OC)ccc3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol RBO 35142 (117 mg, 473 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.52 mL, 1.04 mmol) at RT followed by 3-(chloromethyl)-7-methoxyquinoline hydrochloride MDE 32012 (124 mg, 508 μmol) and the mixture was stirred at 150° C. for 2 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2 (50 mL) and H2O (10 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave 26 mg of 6,7-dimethoxy-4-((7-methoxyquinolin-3-yl)methyl)-1-propylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((7-methoxyquinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 32 as a brown solid (30 mg, 13% yield).
Reaction SMILES: C(OC([CH:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[N:13][C:12]([S:15][CH2:16][C:17]([NH:19][CH2:20][C@@H:21]2[O:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)[CH2:22]2)=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[Na+]>FC(F)(F)C(O)=O.[Cl-].[Na+].O>[Cl:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[Cl:34])[CH2:27][N:23]1[CH2:24][CH2:25][O:26][C@@H:21]([CH2:20][NH:19][C:17](=[O:18])[CH2:16][S:15][C:12]2[N:13]=[N:14][C:9]([CH3:8])=[CH:10][CH:11]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)nn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The resultant product (940 mg) of (217-3) was dissolved in trifluoroacetic acid (6 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH=4 with a 1 mol/L aqueous sodium hydroxide solution. Saturated brine was added to the obtained solution, and the mixture was extracted with a mixed solvent of chloroform-methanol. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (265 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C:3]=1[CH:23]([CH2:28][CH2:29][CH3:30])[C:24]([O:26]C)=[O:25].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C:3]=1[CH:23]([CH2:28][CH2:29][CH3:30])[C:24]([OH:26])=[O:25]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)c(Cl)c1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)c(Cl)c1)CCCC3
Temperature: 60 °C
Yield: 72.9 %

Procedure:
To a solution of methyl [2-methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.172 g; 0.37 mmol) in methanol (3.7 mL) was added a solution of sodium hydroxide 5 N (0.74 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.121 g (73%) of the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]#[N:19])[CH2:14][CH2:13]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]#[N:19])[CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: N#CC1CCNCC1
Reactant: Clc1nc(Cl)c2occc2n1
Solvent: C1COCCO1
Product: N#CC1CCN(c2nc(Cl)nc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.6 %

Procedure:
A mixture of 2,4-dichlorofuro[3,2-d]pyrimidine (0.40 g, 2.1 mmol, ArkPharm), piperidine-4-carbonitrile (0.23 g, 2.1 mmol, Oakwood) and TEA (0.59 mL, 4.2 mmol) in 1,4-dioxane (10 mL) was stirred at about 25° C. for about 12 h. The solvent was removed under reduced pressure and water (5 mL) and DCM (10 mL) were added to the residue. The layers were separated and the organic solution was concentrated under reduced pressure to give 1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)piperidine-4-carbonitrile (0.50 g, 90%): LC/MS (Table 2, Method 1) Rt=0.76 min; MS m/z: 263 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: ClCCCCCSc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCSc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using [(5-chloropentyl)sulfanyl]benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.1 (M+H)+.