Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]3[N:23]=[CH:24][CH:25]=[CH:26][C:14]=3[N:13]2[C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]2([NH:38]C(=O)OC(C)(C)C)[CH2:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.[ClH:46].O1CCOCC1>C(Cl)Cl>[ClH:46].[ClH:46].[ClH:46].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]3[N:23]=[CH:24][CH:25]=[CH:26][C:14]=3[N:13]2[C:27]=1[C:28]1[CH:29]=[CH:30][C:31]([C:34]2([NH2:38])[CH2:37][CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nc5ccccc5o4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4nc5ccccc5o4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 92.7 %

Procedure:
tert-Butyl (1-{4-[2-(1,3-benzoxazol-2-yl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (11.3 mg, 0.0189 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 17.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (10.6 mg, 92.7%) as pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.73 (s, 1H), 8.67 (br s, 3H), 8.16 (dd, J=4.8, 1.6 Hz, 1H), 8.00 (dd, J=7.9, 1.6 Hz, 1H), 7.75-7.71 (m, 1H), 7.68-7.64 (m, 1H), 7.63-7.49 (m, 4H), 7.46-7.31 (m, 4H), 7.21-7.13 (m, 1H), 6.95 (dd, J=7.9, 1.6 Hz, 1H), 6.77 (dd, J=7.9, 4.8 Hz, 1H), 2.70-2.43 (m, 4H), 2.27-2.13 (m, 1H), 1.93-1.78 (m, 1H); LCMS: 497 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[C:6]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:5]2[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21].Cl.[CH3:27][O:28][NH2:29]>C(O)C>[CH3:27][O:28][N:29]=[C:7]1[C:6]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:5]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[NH:8]1
Reactant: CC(C)OC(=O)c1c(-c2ccc(Cl)cc2)c(=S)[nH]c2ccc(Cl)cc12
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CON=c1[nH]c2ccc(Cl)cc2c(C(=O)OC(C)C)c1-c1ccc(Cl)cc1

Procedure:
0.42 g (1.07 mol) of 6-chloro-3-(p-chlorophenyl)-4-isopropoxycarbonylquinoline-2(1H)-thione (prepared according to methods from Examples 6, 7 and 8 described above, but using 5-chloroisatin and p-chlorophenyl acetic acid as starting materials) is dissolved in 10 ml of abs. ethanol and treated with 0.5 g of O-methylhydroxylamine hydrochloride. The reaction mixture is heated at reflux temperature for 3 hours. It is then concentrated under reduced pressure on a rotary evaporator, the residue is taken up in ethyl acetate, the organic phase is washed twice with water and, after drying by means of sodium sulfate, concentrated under reduced pressure on a rotary evaporator. The crude product obtained is purified by means of chromatography on silica gel (mobile phase: ethyl acetate/n-heptane=1/4). For fine purification, chromatography on ®Sephadex type LH-20 using methanol as the mobile phase is suitable.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([CH3:12])[C:5]([I:13])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].[H][H]>C(OCC)C>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([CH3:12])[C:5]([I:13])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)c1c(F)ccc(I)c1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: Cc1c(I)ccc(F)c1CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Step B (5.5 g, 18.7 mmol) in diethyl ether (20 ml) was carefully added lithium aluminum hydride (0.8 g, 18.7 mmol). The mixture was stirred at room temperature for 16 h. Saturated aqueous ammonium chloride solution was added dropwise until no hydrogen gas was being generated. A few more drops of saturated aqueous ammonium chloride solution were added and the mixture was stirred at room temperature for 30 min and filtered. The filtrated was dried over magnesium sulfate and concentrated to dryness to give the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O1CCO[CH2:19][CH2:18]1>O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:18]([C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1)=[CH2:19]
Reactant: COC(=O)c1ccc(Br)o1
Reactant: C1COCCO1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ccc(C(=O)OC)o1
Yield: 58 %

Procedure:
A solution of methyl 5-bromo-2-furancarboxylate (2.5 g, 12.19 mmol), potassium carbonate (8.43 g, 61.0 mmol), bis(tri-t-butylphosphine)palladium(0) (0.312 g, 0.61 mmol) and 2,4,6-trivinylcycloboroxane-pyridine complex (1.47 g, 6.10 mmol) in 1,4-dioxane (50 ml) and water (10 ml) was stirred at 80° C. in a sealed tube for 2 h. The reaction contents were partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-ethenyl-2-furancarboxylate (1.3 g, 7.09 mmol, 58% yield) as a yellow oil: LCMS (ES) m/z=153 (M+H)+.
Reaction SMILES: CN(C=O)C.[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:37]([OH:39])=O)=[CH:25][C:24]=3[CH:40]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O.[CH3:45][N:46]([CH2:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1)[CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>O1CCCC1.O.C(N(CC)CC)C>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:37]([NH:58][C:57]4[CH:59]=[CH:60][C:54]([CH2:53][N:46]([CH3:45])[CH:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)=[CH:55][CH:56]=4)=[O:39])=[CH:25][C:24]=3[CH:40]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccnn2C)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Solvent: C1CCOC1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccnn2C)cc1
Reaction time: 1 h
Yield: 21 %

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-[(1-methylpyrazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (150 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. Then, this mixture was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (111 mg) and triethylamine (1.0 g) in tetrahydrofuran (25 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with basic silica gel column chromatography (methanol:ethyl acetate=1:3) to give 7-(4-butoxyethoxyphenyl)-1-[(1-methylpyrazol-5-yl)methyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 70) (60 mg) as yellow amorphous.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24](Cl)=[O:25])[CH2:19][CH2:18]1.[K].CN1CCC(CC(O)=O)CC1.S(Cl)(Cl)=O>O1CCOCC1.N1C=CC=CC=1.O>[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9](=[O:11])[C:10]3=[CH:1][S:2][CH:3]=[C:4]23)=[O:25])[CH2:19][CH2:18]1
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: CN1CCC(CC(=O)Cl)CC1
Agent: CN1CCC(CC(=O)O)CC1
Agent: [K]
Solvent: C1COCCO1
Solvent: O
Solvent: c1ccncc1
Product: CN1CCC(CC(=O)N2c3ccccc3NC(=O)c3cscc32)CC1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 2.2 gm (0.01 mol) of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 50 ml of dioxane and 10 ml of pyridine was mixed at ambient temperature with a solution of 0.02 mol of (1-methyl-4-piperidinyl)acetyl chloride (prepared from the potassium salt of 1-methyl-4-piperidinylacetic acid by reaction with thionyl chloride) in 100 ml of dioxane. The mixture was heated at 40° C. for three hours, with stirring, and then at 80° C. for two hours. After the dioxane solution was poured off, the viscous residue was taken up in water, the resulting mixture was filtered, and the filtrate was rendered alkaline and extracted with methylene chloride. The extraction residue was purified by column chromatography [silica gel, eluant: ethyl acetate/methylene chloride (1:1); then with methylene chloride/cyclohexane/methanol/ammonia (102:23:23:3) as eluant]. The desired fraction was concentrated by evaporation in vacuo and the residue was recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:19])[O:8][C:9]2([CH2:18][S:17][CH2:16][CH2:15][S:14][CH2:13]2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:21]([O:23][NH2:24])[CH3:22]>CO>[CH2:21]([O:23][N:24]=[C:1]([C:6]1[C:7](=[O:19])[O:8][C:9]2([CH2:18][S:17][CH2:16][CH2:15][S:14][CH2:13]2)[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH3:22]
Reactant: CCCC(=O)C1=C(O)CC2(CSCCSC2)OC1=O
Reactant: CCON
Agent: Cl
Solvent: CO
Product: CCCC(=NOCC)C1=C(O)CC2(CSCCSC2)OC1=O
Yield: 32.8 %

Procedure:
The acylated compound (8.52) (0.453 g, 1.50 mmol) was oximated with ethoxyamine hydrochloride (0.195 g, 2.00 mmol) in methanol (10 ml) as described in Part (c) of the general procedure above to afford a product which was recrystallized from ether to give the title compound (6.25) (0.170 g, 33%) as white microcrystals m.p. 108°-110° C. Mass spectrum m/z 346 (M+1). 1H n.m.r. δ (CDCl3) 4.11, q, J 7 Hz, OCH2CH3 ; 3.95-1.1, complex, 14H; 1.33, t, J 7 Hz, OCH2CH3 ; 1.00, t, J 7 Hz CH2CH2CH3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10](=[N:12][OH:13])[CH3:11])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[I-].[K+].II.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:13][N:12]=[C:10]([CH3:11])[C:9]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: CC(=NO)C(=Cc1ccc(Br)cc1)c1ccccc1
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1-c1ccccc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To a stirred mixture of 4-(4-bromophenyl)-3-phenyl-3-buten-2-one oxime (2.06 g, 6.52 mmol) and sodium bicarbonate (2.46 g, 29.3 mmol) in a mixture of tetrahydrofuran (30 ml) and water (20 ml) was added a solution of potassium iodide (4.09 g, 24.7 mmol) and iodine (1.98 g, 7.82 mmol) in water (30 ml) at room temperature. Then, the resulting mixture was refluxed for 5 hours in the dark. After cooling down to room temperature, 50 ml of saturated aqueous sodium sulfite was added. The organic layer was separated and the water layer was extracted, with ethyl acetate (100 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate and evaporated. The obtained residue was chromatographed on a column of silica gel (120 g) as eluting with ethyl acetate/hexane (1:15) to afford 1.64 g (80%) of the title compound as a pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[H-].[Na+].C1(C)C=CC(S(O[CH2:40][C@H:41]2[O:45][C:44](=[O:46])[CH2:43][CH2:42]2)(=O)=O)=CC=1>CO.CCOC(C)=O.[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:40][C@@H:41]3[CH2:42][CH2:43][C:44](=[O:46])[O:45]3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)O2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SC[C@@H]3CCC(=O)O3)c2CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepine (137 mg, 0.356 mmol) in methanol (2 mL) add potassium hydroxide pellets (640 mg, 11.4 mmol) and heat for 3 h at 50° C. Cool to ambient temperature, add saturated aqueous NH4Cl, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Dissolve the crude thiophenol thus obtained in dry DMF (2 mL), and add with stirring sodium hydride (18 mg, 0.713 mmol, 95% dispersion), followed by (S)-(+)-dihydro-5-(p-tolylsulfonyloxymethyl)-2-(3H)-furanone (144 mg, 0.533 mmol). Continue stirring overnight at ambient temperature, then dilute cautiously with EtOAc and cold saturated aqueous NH4Cl. Extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (7:3) to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([CH2:12]SC)[C:8]([NH2:9])=[C:7]([Cl:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[CH:11]=[C:10]([CH3:12])[C:8]([NH2:9])=[C:7]([Cl:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCc1cc(C(C)(C)C)cc(Cl)c1N
Agent: [Ni]
Solvent: CO
Product: Cc1cc(C(C)(C)C)cc(Cl)c1N

Procedure:
4-t-Butyl-2-chloro-6-(methylthiomethyl)aniline (1.3 g) was dissolved in methanol (50 ml) and Raney-nickel (prewashed to pH 7) was added portionwise until t.l.c. indicated all starting material had reacted (ether-hexane, 1:10). The Raney-nickel was removed by filtration through Celite and the filtrate was evaporated. The residue was dissolved in ether and washed with brine, dried (MgSO4) and evaporated. The residue was purified on silica using hexane and 5% ether in hexane as eluent to afford 4-t-butyl-2-chloro-6-methylaniline as a yellow liquid. 1H NMR (360 MHz, CDCl3) δ1.26 (9H, s, (CH3)3), 2.19 (3H, s, CH3), 3.97 (2H, s, NH2), 6.97 (1H, d, J=2.0 Hz, ArH), 7.14 (1H, d, J=2.0 Hz, ArH).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1([C:15]([O:17]CC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:4].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[O:17]=[C:15]1[N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:2][C:3](=[O:4])[N:5]2[CH2:9][CH2:8][CH2:7][C:6]12[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1C(=O)CBr
Reactant: NCc1ccccc1
Solvent: CC#N
Product: CCOC(=O)C12CCCN1C(=O)CN(Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of diethyl 1-(bromoacetyl)-2,2-pyrrolidinedicarboxylate (D64, 950 mg) in acetonitrile (10 mL) at r.t, benzylamine (340 microL) was added. The resulting mixture was stirred at r.t. for 3.5 hours: the formation of a white solid was observed. The suspension was then filtered over a Gooch funnel. The organic filtrate was diluted with ethyl acetate (15 mL) and washed with water (2×10 mL). The organic phase was dried and concentrated in vacuo to a residue which was purified by flash chromatography (Cycl/EtOAc from 50/50 to 35:65) to give the desired compound (200 mg) as colourless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7](O)[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc(C(F)(F)F)n1
Product: FC(F)(F)c1nccc(Cl)n1

Procedure:
To 2-(trifluoromethyl)pyrimidin-4-ol (2 g, 12 mmol) was added POCl3 (15 mL). It was refluxed overnight. The solvent was removed. 1N NaOH was added to the reaction mixture slowly until pH=10. The mixture was extracted with DCM (3×80 mL). Combined DCM layer dried over Na2SO4 and taken to dryness. The crude product was vacuum distilled. 4-chloro-2(trifluromethyl)pyrimidine was obtained as a clear oil. (94%). 1H NMR (400 MHz, DCM) δ: 7.60 (d, J=3 Hz, 1H), 8.80 (d, J=3 Hz, 1H), To a mixture of compound 30a (137 mg, 0.75 mmol) and compound 4b (235 mg, 0.75 mmol) in IPA (1 mL), was added TEA (210 mL, 1.5 mmol). The reaction was heated in microwave oven at 140° C. for 20 min. HPLC yielded the desired product as a white powder (28 mg, 6.4%). 1H NMR (400 MHz, DMSO) δ: 1.04 (m, 2 H), 1.62 (m, 6 H), 1.88 (m, 1 H), 2.73 (m,1 H), 4.34 (m, 2 H), 7.09-7.37 (m, 6 H), 8.41 (s, 1 H). Anal. (C22H22N7OF3.0.52TFA.0.54H2O) C, H, N. APCI-MS:[M+H] 458.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[C:9]([Cl:15])=[C:10]([Cl:14])[C:11]([OH:13])=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:13][C:11]1[C:10]([Cl:14])=[C:9]([Cl:15])[C:7]2[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=2[CH:12]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(C(C)=O)sc2c(Cl)c1Cl
Yield: 42.6 %

Procedure:
To a solution of 9.0 g of 2-acetyl-6,7-dichloro-5-hydroxybenzo[b]thiophene and 200 ml of 2-butanone is added a solution of 6.62 g of ethyl bromoacetate in 50 ml of 2-butanone, 5.2 g of potassium carbonate and 2.2 ml of dimethylformamide. The reaction mixture is heated under reflux for 2 hrs, allowed to cool and filtered. The filtrate is extracted with ether (3 times). The layers are separated and the organic phase is washed with water, saturated sodium chloride solution, dried and filtered. The filtrate is evaporated. The residue is dissolved in dichloromethane and chromatographed on alumina, using dichloromethane as the eluant. Evaporation of the eluant gives 5.1 g of ethyl[(6,7-dichloro-2-acetylbenzo[b]thien-5-yl)oxy]acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.O.[Cu]I>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:13])[CH2:16][CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(C#C[Si](C)(C)C)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (25) (200 mg, 0.58 mmol), PdCl2(Ph3P)2 (16 mg, 0.03 mol %) and CuI (6 mg, 0.05 mol %) in triethylamine (1.2 mL) was heated to reflux. (Trimethylsilyl)acetylene (100 μL, 0.7 mmol) was added, and the bright yellow solution quickly turned orange then went brown within a minute. The reaction mixture was stirred for 3 h, cooled to room temperature, diluted with H2O (20 mL), and extracted with CHCl3 (3×15 mL). The combined organics were washed with saturated NaCl (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-[(trimethylsilyl)ethynyl]benzoate 26 (185.5 mg): 1H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), 7.75 (s, 1H), 7.43 (s, 1H), 3.74 (s, 3H), 3.25 (br s, 2H), 2.95 (br s, 2H), 1.49 (br s, 2H), 1.34 (br s, 2H), 0.79 (br s, 3H), 0.56 (br s, 3H), 0.06 (s, 9H).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[H-].[Na+].C([Li])CCC.[C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>CCCCCC.O1CCCC1>[CH3:20][CH:19]([CH3:21])[CH2:18][CH2:17][C:16]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:22][C:1](=[O:6])[CH:2]=[CH:3][CH2:5]1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)CCC(=O)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)CCC1(c2ccccc2)CC=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane, 25 mmol of isohexanophenone and 70 mL of tetrahydrofuran. Upon concentrating the reaction a solid precipitated out which was triturated with ether and filtered (m.p. 134°-136° C.). 1H NMR (CDCl3) δ 0.83 (dd, 6 H), 1.1-1.3 (m, 2 H), 1.4-1.6 (m, 1 H), 1.9-2.1 (m, 2 H), 2.90 (d, 1 H), 2.92 (d, 1 H), 3.25 (d, 1 H), 3.35 (d, 1 H), 7.2-7.5 (m, 5 H).
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:5]=2[S:6][C:7]=1[C:8]([O:10]CC)=[O:9])#[N:2].[OH-].[Na+]>CO.C1COCC1.O>[C:1]([C:3]1[C:4]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:5]=2[S:6][C:7]=1[C:8]([OH:10])=[O:9])#[N:2]
Reactant: CCOC(=O)c1sc2cccc(C)c2c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2sc(C(=O)O)c(C#N)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
15.59 g (63.6 mmol) of the 3-cyano-2-ethoxycarbonyl-4-methylbenzo[b]thiophene obtained in Step 3 were dissolved in a mixture of methanol (150 ml), THF (150 ml) and water (150 ml) followed by the addition of 30 ml of 5 M aqueous sodium hydroxide solution and stirring for 2 hours at room temperature. After concentrating the solvent under reduced pressure, the pH was lowered to 4 by addition of 1 M hydrochloric acid and, after extracting with ethyl acetate and washing the organic phase with water, it was dried with magnesium sulfate. The solvent was then concentrated under reduced pressure to obtain 3-cyano-2-carboxy-4-methylbenzo[b]thiophene. This and 1.27 g (20 mmol) of copper powder were added to 18 ml of quinoline followed by stirring for 2 hours at 150° C. After cooling the reaction solution, it was filtered with Celite and the pH of the filtrate was lowered to 3 by addition of hydrochloric acid to transfer the quinoline as the solvent to the aqueous phase followed by extraction with ethyl acetate. After washing the organic phase with water, it was dried with magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 9.10 g (52.6 mmol) of the target compound (yield of the two steps: 83%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH2:10])[N:3]=1.C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])(=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH:10][C:24](=[O:23])[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: COc1ccc(N)nc1Br
Reactant: CC(=O)OC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)C(F)(F)F)nc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
2-Bromo-3-methoxy-6-aminopyridine (Desc. 6; 1.0 g, 4.9 mmol) in dichloromethane (25 ml) was treated with N,N-diisopropylethylamine (2.2 ml, 12.3 mmol) and the solution cooled to 0° C. Trifluoroacetic acetic anhydride (770 μl, 5.4 mmol) was then added dropwise and the solution stirred to 22° C. over 2 hours. The mixture was then poured into saturated sodium bicarbonate solution (25 ml) and extracted with dichloromethane (25 ml). The extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash silica chromatography to give the product as a white solid (890 mg, 3.0 mmol, 61% yield).