Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:19])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=2[C:9]=1[CH3:10].[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C.CC(OC)(C)C>[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][C:4]2[C:5](=[O:19])[O:6][C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=3[C:9]=2[CH3:10])[CH2:29][CH2:28]1
Reactant: COc1cc(OC)c2c(C)c(CCCl)c(=O)oc2c1
Reactant: Oc1ccccc1N1CCNCC1
Solvent: CCO
Solvent: COC(C)(C)C
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4ccccc4O)CC3)c(=O)oc2c1
Yield: 22 %

Procedure:
Process B; starting materials: 3-(2-chloroethyl)-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 39) and 1-(2-hydroxyphenyl)piperazine; yield 22%; m.p. 164°-165° C. (from ethanol/TBME).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:26][N:27]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][CH2:12][N:11]([C:14]3[C:19](C(O)=O)=[CH:18][N:17]=[C:16]4[NH:23][CH:24]=[CH:25][C:15]=34)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:26][NH2:27])[CH2:9][CH2:10][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]4[NH:23][CH:24]=[CH:25][C:15]=34)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc2[nH]ccc2c1N1CCC(CN2C(=O)c3ccccc3C2=O)(c2ccc(Cl)cc2)CC1
Solvent: O
Product: NCC1(c2ccc(Cl)cc2)CCN(c2ccnc3[nH]ccc23)CC1
Yield: 46.9 %

Procedure:
A mixture of crude 4-[4-(4-chlorophenyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (12.8 mg, 0.025 mmol) and water (1 mL) was irradiated in a microwave reactor (250 W) for 2 hrs at 180° C. The resulting suspension was filtered and the filtrate was concentrated. Preparative TLC gave the product (4 mg, 47%). LC-MS (LCT2) m/z 342 [M+H+], Rt 2.19 min.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:36]2[CH2:41][C@H:40]([CH3:42])[O:39][C@H:38]([CH3:43])[CH2:37]2)=[C:22]([F:35])[C:23]([F:34])=[C:24]([CH:26]([C:28]2[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=2)[OH:27])[CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:36]2[CH2:37][C@H:38]([CH3:43])[O:39][C@H:40]([CH3:42])[CH2:41]2)=[C:22]([F:35])[C:23]([F:34])=[C:24]([C:26]([C:28]2[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=2)=[O:27])[CH:25]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3cncn3C)c(F)c2F)C[C@H](C)O1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3cncn3C)c(F)c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of {5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorophenyl}(1-methyl-1H-imidazol-5-yl)methanol (Intermediate 69, 50 mg, 0.08 mmol) in anhydrous DCM (5 mL), MnO2 (143 mg, 1.65 mmol) was added at 0° C. and allowed to stir for 1 hour at room temperature. The reaction mixture was filtered and the solvents were removed under vacuum and the residue was purified over silica gel chromatography column using ethyl acetate-pet. ether gradient to give solid. Yield: 37 mg, (75%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:11]([Cl:14])[CH2:12][CH3:13].C([O-])(O)=O.[Na+]>C(#N)C>[Cl:14][CH2:11][CH2:12][CH2:13][NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: CCC(Cl)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: ClCCCNCCc1ccccc1
Reaction time: 16 h
Yield: 26.5 %

Procedure:
A mixture of phenethylamine (7.1 g, 7.38 ml, 58.5 mmol) and bromochloropropane (3.07 g, 1.93 ml, 19.5 mmol) in acetonitrile (15 ml) is stirred for 16 h. In the course of the reaction a white crystalline solid forms. Saturated aqueous NaHCO3 solution is added to adjust the pH to 9-10. The free amine is extracted three times with AcOEt. The combined organic phases are dried over Na2SO4. Evaporation of the solvent in vacuo yields a yellow oil. It is purified by chromatography on silica-gel (dichloromethane/MeOH, 95:5), yielding the title compound (1.02 g) in 26% as a slightly yellow oil which crystallizes on standing: 1H-NMR (CDCl3): δ (ppm) 1.91 (quint., 2H, CH2CH2N), 2.75 (m, 4H), 2.81-2.89 (m, 2H), 3.59 (t, 2H, CH2Cl), 7.20 (m, 3Harom), 7.24-7.32 (m, 2Harom).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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(C)C=CC=CC=1.O>[CH2:5]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[C:19]=2[F:20])=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH3:2]
Reactant: BrCCCCOc1ccccc1
Reactant: OB(O)c1cccc(F)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccc(-c2cccc(F)c2F)cc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
4-Bromobutoxybenzene (16) (50.0 g), 2,3-difluorophenylboronic acid (17) (37.9 g), potassium carbonate (90.5 g), Pd(Ph3P)2Cl2 (4.6 g), toluene (200 ml), Solmix A-11 (200 ml) and water (200 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25° C., and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by means of recrystallization from Solmix A-11 and dried, giving 44.7 g of 4′-butoxy-2,3-difluoro-1,1′-biphenyl (18). The yield based on the compound (16) was 78.1%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13]CC)=[O:12])[N:8]([CH2:16][C:17](=[O:26])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)[N:7]=1)=[O:5])[CH3:2].Cl>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[N:8]([CH2:16][C:17](=[O:26])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)Nc2ccc(Cl)cn2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(C(=O)O)n(CC(=O)Nc2ccc(Cl)cn2)n1
Reaction time: 16 h

Procedure:
To a solution of 8 g 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-pyrazole-3,5-dicarboxylic acid diethyl ester in 200 ml THF and 50 ml H2O 17.2 ml 1N NaOH is added. After standing for 16 h, the solution was acidified using 1 N HCl. THF was removed in vacuo and water was removed by lyophilization. The residue was purified by chromatography on silica gel using ethyl acetate followed by CH2Cl2/MeOH/HOAC/H2O=9/1/0.1/0.1. The fractions containing the product were evaporated and lyophilized to give a white solid.
Reaction SMILES: CN.O1CCCC1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1.COC1C=CC([CH2:30][NH:31]C2C3C(=CC=C(C(O)=O)C=3)C=CN=2)=CC=1>>[CH3:30][NH:31][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)c1ccc2ccnc(Cl)c2c1
Reactant: COc1ccc(CNc2nccc3ccc(C(=O)O)cc23)cc1
Agent: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2ccnc(NC)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of methylamine in tetrahydrofuran (30 mL, 60 mmol, 2 M) was added to ethyl 1-chloroisoquinoline-7-carboxylate (formed in Step 3 of Intermediate 27) (705 mg, 2.99 mmol) in a sealed tube. The reaction was heated to 60° C. and stirred overnight. LCMS indicated the reaction was not complete. Additional methylamine (10 mL, 20 mmol, 2 M in THF) was added and the reaction was heated to 60° C. for another 18 hours. The reaction was cooled to room temperature and concentrated. The residue was partitioned between water and dichloromethane. The organic layer was dried over magnesium sulphate, filtered, and concentrated. Purification by flash column chromatography (25-65% ethyl acetate/heptanes) gave the title compound (584 mg, 85%) as a yellow oil that solidified upon standing. +ESI (M+H) 231.1; 1H NMR (400 MHz, DMSO-d6, δ): 8.83-8.94 (m, 1H), 8.07 (dd, J=8.58, 1.56 Hz, 1H), 7.99 (d, J=5.85 Hz, 1H), 7.89 (d, J=4.49 Hz, 1H), 7.77 (d, J=8.58 Hz, 1H), 6.92 (d, J=5.07 Hz, 1H), 4.38 (q, J=7.02 Hz, 2H), 2.97 (d, J=4.49 Hz, 3H), 1.38 (t, J=7.12 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.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>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:17]1
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1-c1ccsc1
Temperature: 25 °C

Procedure:
To a mixture of 2-bromobenzaldehyde (0.32 mL, 2.70 mmol) and 3 mL of 2 M aqueous sodium carbonate in 15 mL of toluene was added thiophene-3-boronic acid (384 mg, 3.00 mmol) in ethanol (3 mL). The mixture was stirred and then treated with tetrakis(triphenylphosphine)palladium (0) (93.0 mg, 3 mole %) and heated to reflux under nitrogen atmosphere for 4.5 hr. The resulting solution was cooled to room temperature, the dark brown reaction mixture was diluted with ethyl acetate (75 mL) and washed with water (2×75 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to yield 2-(3-thienyl)benzaldehyde as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)N)=[CH:4][CH:3]=1.CO[CH:20](OC)[CH2:21][CH2:22][CH2:23][NH:24][CH3:25]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:20]=[C:21]2[CH2:22][CH2:23][NH:24][CH3:25]
Reactant: NN(CCN1CCCCC1)c1ccc(Cl)cc1
Reactant: CNCCCC(OC)OC
Product: CNCCc1cn(CCN2CCCCC2)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 10 using 1-(4-chlorophenyl)-1-(2-(piperidin-1-yl)ethyl)hydrazine (Example 3) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([CH3:13])[C:10]([NH:14][C:15](=[O:17])[CH3:16])=[C:9]([CH3:18])[C:3]=1[C:4](OCC)=[O:5].O.[NH2:20][NH2:21]>O.CO>[NH2:1][C:2]1[N:12]=[C:11]([CH3:13])[C:10]([NH:14][C:15](=[O:17])[CH3:16])=[C:9]([CH3:18])[C:3]=1[C:4]([NH:20][NH2:21])=[O:5]
Reactant: NN
Reactant: CCOC(=O)c1c(N)nc(C)c(NC(C)=O)c1C
Solvent: CO
Solvent: O
Product: CC(=O)Nc1c(C)nc(N)c(C(=O)NN)c1C
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-amino-5-acetamido-4,6-dimethylnicotinate (45.3 g., 0.18 mole) and hydrazine hydrate (100 ml.) is heated in an oil bath with stirring at 120° C. for two hours. The mixture is cooled, the solid collected, and a second crop of solid obtained by evaporating the mother liquor to about half its initial volume. The combined solids melt at 293° C. (dec.), yield 38.1 g. (89%). Analytically pure compound is obtained by dissolving the solid in about six and one-half parts (volume by weight) of hot water and diluting the filtered solution with methanol. The purified product decomposed at about 309° C. with only partial melting.
Reaction SMILES: B#B.[O:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[O:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)CCCCCCCCCCOc1ccccc1
Agent: B#B
Solvent: C1CCOC1
Product: OCCCCCCCCCCCOc1ccccc1
Reaction time: 19 h

Procedure:
To 100 ml of 1M diborane in tetrahydrofuran under nitrogen chilled in an ice bath is added dropwise 13.92 g of 11-phenoxyundecanoic acid in 50 ml of tetrahydrofuran over 30 minutes. The solution is allowed to stand at room temperature for 19 hours and is poured onto ice. After standing, the mixture is filtered and the solid washed with water to give white crystals, mp 56°-58° C. A sample on recrystallization from ethanol gives white crystals, mp 56.5°-57.5° C.
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[CH:21][C:22]([O:30][CH3:31])=[C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=4)[CH:17]=3)[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH:11]=2)[CH:7]=[N:6]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[CH:21][C:22]([O:30][CH3:31])=[C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)ccc4F)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)ccc5F)c4)c3c2)cc1NS(C)(=O)=O
Yield: 22.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)methanesulfonamide (120 mg, 0.180 mmol) was hydrolyzed by lithium hydroxide 38 mg, 0.904 mmol) in THF/methanol/water (15/7.5/4 ml) to yield 21 mg of the titled compound. 1H NMR (CDCl3, 400 MHz): δ 10.3 (s, 1H), 8.49-8.48 (d, 1H), 8.256-8.252 (d, 1H), 7.85 (s, 1H), 7.81-7.80 (d, 1H), 7.77 (s, 1H), 7.48-7.47 (d, 1H), 7.39-7.37 (dd, 1H), 7.26-6.91 (m, 5H), 5.42 (s, 2H), 3.96 (s, 3H), 3.01 (s, 3H). MS: m/z=510.1 (M+1), HPLC: 96.37% in method B.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=1.[CH2:17]1[O:19][CH2:18]1.Cl>O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([CH2:17][CH2:18][OH:19])[S:13][C:12]=2[CH:16]=1
Reactant: C1CO1
Reactant: COc1ccc2ccsc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(CCO)sc2c1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
Butyl lithium (0.27 mol of a 2.5 M solution) was added dropwise to 6-methoxy-benzo[b]thiophene [prepared analogous to the procedure described in J. Med. Chem. 1989, 32(12), 2548-2554] (0.25 mol) in tetrahydrofuran (1000 ml), stirred at −30° C. The mixture was stirred for 10 minutes at −30° C. Ethylene oxide (0.38 mol in 100 ml tetrahydrofuran) was added dropwise at −30° C. The mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was acidified with dilute HCl solution. The solvent was evaporated. The residue was diluted with water and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. The residue was stirred in hexane, filtered off and dried, yielding 41.3 g 6-methoxybenzo[b]thiophene-2-ethanol (interm. 5).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18]2[O:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[C:19]3[CH2:25][CH:24]4[N:26]([C:27](=[O:32])C(F)(F)F)[CH:21]([CH2:22][CH2:23]4)[CH2:20]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-:33].[Na+]>O1CCOCC1>[C:5]([O:32][C:27]([N:26]1[CH:21]2[CH2:22][CH2:23][CH:24]1[CH2:25][C:19](=[C:10]1[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:2])=[O:4])[C:18]=3[O:17][C:16]3[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:20]2)=[O:33])([CH3:18])([CH3:6])[CH3:3]
Reactant: COC(=O)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(=C1c3ccccc3Oc3c(C(=O)O)cccc31)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of compound 7 (2.2 g, 4.96 mmol) in dioxane (25 mL) was added a 3N sodium hydroxide solution (3.5 mL) and the mixture was heated to reflux for 3 h. Additional 3N sodium hydroxide solution (3.5 mL) was added and the mixture was heated to reflux for 16 h. The mixture was allowed to cool to rt and Boc-anhydride (3.24 g, 14.9 mmol) was added. The mixture was stirred for 24 h at rt, the solvent was evaporated, and the residue was partitioned between water and ethyl acetate. The organic phase was separated, dried over sodium sulfate, filtered, and evaporated. The residue was used without further purification.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]([NH:17][C@H:18]([C:28]([O:30]C)=[O:29])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+]>CO>[F:1][C:2]([F:32])([F:33])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]([NH:17][C@H:18]([C:28]([OH:30])=[O:29])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:16])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)O)cc1
Yield: 69.7 %

Procedure:
The same procedures as in Example 90 were carried out from the compound obtained in Example 49 (3.4 g), 1 mol/L of an aqueous sodium hydroxide solution (11 mL), and methanol (110 mL), to give the captioned compound (2.3 g, 71%) as crystals.
Reaction SMILES: [CH3:1][Mg]Cl.[Cl:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14](N(OC)C)=[O:15])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.O.Cl>O1CCCC1>[Cl:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14](=[O:15])[CH3:1])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1cc2c(Cl)cccc2s1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc2c(Cl)cccc2s1
Reaction time: 0.5 h

Procedure:
Methylmagnesium chloride (3M solution in tetrahydrofuran; 5.7 ml) was added under nitrogen to a stirred solution of 4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (4 g; prepared in a manner similar to that described in Example 18) in tetrahydrofuran (120 ml) then the mixture was allowed to stand at ambient temperature for 30 minutes, heated under reflux for 30 minutes and allowed to stand at ambient temperature for 30 minutes. Further methylmagnesium chloride (3M solution in tetrahydrofuran; 2.0 ml) was added and the mixture was allowed to stand at ambient temperature for 2 hours. Further methylmagnesium chloride (3M solution in tetrahydrofuran; 2.0 ml) was added and the mixture was allowed to stand at ambient temperature for 30 minutes. Water (200 ml) and 5M hydrochloric acid (15 ml) were added and the product was extracted into dichloromethane (3×80 ml). The combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 1-(4-chloro-benzo[b]thiophen-2-yl]ethan-1-one (1.8 g) as an off-white solid, m.p. 113-115° C.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[CH:11][CH:10]=1.[CH2:30]([O:37][C:38](=[O:44])[NH:39][CH2:40][CH2:41][C:42]#[CH:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:30]([O:37][C:38](=[O:44])[NH:39][CH2:40][CH2:41][C:42]#[C:43][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[CH:11][CH:10]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C#CCCNC(=O)OCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCC#Cc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCC#Cc1ccc(C#CCCN2C(=O)c3ccccc3C2=O)cc1)OCc1ccccc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution containing triethylamine (100 mL), copper (I) iodide (0.50 g, 2.60 mmol) and 57 (7.00 g, 17.40 mmol) dissolved in anhydrous tetrahydrofuran (100 mL) was stirred at room temperature. The reaction flask was vacuumed and then purged with nitrogen three times. The solution was treated with bis(triphenylphosphine) palladium(II) dichloride (1.20 g, 1.70 mmol) and continued to stir at room temperature for 30 min. The reaction mixture was then treated with but-3-ynylcarbamic acid benzyl ester (4.25 g, 20.90 mmol). The reaction was allowed to stir at room temperature for 16 h. The solution was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the desired product 58 (6.0 g, 72%) as a brown solid: 1H NMR (500 MHz, CD2Cl2) δ 7.85 (dd, 2H), 7.74 (dd, 2H), 7.35-7.32 (m, 5H), 7.27 (d, 2H), 7.22 (d, 2H), 5.08 (s, 2H), 3.93 (t, 2H), 3.39 (t, 2H), 2.81 (t, 2H), 2.62 (t, 2H); m/z (ESI) 477 [C30H24N2O4+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.[BH4-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(Cl)nc1
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a mixture of 3.0 g (0.0175 mole) of methyl 6-chloronicotinate, 2.0 g of sodium borohydride and 60 ml of THF on reflux, 8.0 ml of MeOH was added with stirring over a period of 1 hour. After completion of the dropwise addition, the mixture was further refluxed for 30 minutes and when cold, the solvent was distilled off. The residue was diluted with 30 ml of water, saturated with NaCl and extracted with CH2Cl2 (20 ml×3). The CH2Cl2 layer was dried over MgSO4 and the CH2Cl2 was distilled off to give 2.3 g of 6-chloro-3-pyridylmethanol as a yellow oil. When left standing at room temperature, this product was thoroughly crystallized.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1.[NH:12]1[C:19](=O)[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].CS(O)(=O)=O>C(O)CCC>[CH2:2]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:19]3[NH:12][C:13](=[S:14])[NH:15][C:16](=[O:17])[C:18]=3[CH2:8][C:7]=2[CH:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=Cc1cc(CO)ccc1O
Reactant: O=C1CC(=O)NC(=S)N1
Agent: CS(=O)(=O)O
Solvent: CCCCO
Product: CCCCOCc1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxymethyl-salicylaldehyde (5.8 g.) and 2-thiobarbituric acid (6 g.) in n-butanol (100 ml.) add methanesulfonic acid (10 ml.) and heat to reflux, with stirring, for 1 hour. Cool, filter and wash the solid with ethanol and ether to yield 7-n-butyloxymethyl-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione.