Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:50]1([N:55]2[CH2:59][CH:58]([C:60]3[C:68]4[C:63](=[CH:64][C:65]([F:69])=[CH:66][CH:67]=4)[NH:62][CH:61]=3)[CH:57]3[NH:70][CH2:71][CH2:72][CH:56]23)[CH2:54][CH2:53][CH2:52][CH2:51]1>CN1C(=O)CCC1.CCOC(C)=O>[C:13]([O:12][C:10](=[O:11])[NH:1][CH:2]([C:7]([N:70]1[CH2:71][CH2:72][CH:56]2[N:55]([CH:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)[CH2:59][CH:58]([C:60]3[C:68]4[C:63](=[CH:64][C:65]([F:69])=[CH:66][CH:67]=4)[NH:62][CH:61]=3)[CH:57]12)=[O:9])[C:3]([CH3:4])([CH3:5])[CH3:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: Fc1ccc2c(C3CN(C4CCCC4)C4CCNC34)c[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C1CCCC1)C(C)(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution containing Boc-L-Tle-OH (160 mg, 0.7 mmol) in anhydrous NMP (4 mL) was cooled to 0° C. HATU (264 mg, 0.7 mmol) and DIPEA (148 mg, 0.7 mmol) were added followed by the addition of crude 37 (220 mg, 0.7 mmol) in anhydrous NMP (5 mL). The reaction mixture was slowly warmed to ambient temperature. After 4 h, the reaction mixture was diluted with EtOAc and washed successively with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel HPLC (2″ Dynamax SiO2, 20-100% EtOAc/hexanes over 30 min; Flow: 40 mL/min) to afford 280 mg (66%, 2 steps) of 38. 1H NMR (CDCl3, 300 MHz): δ8.37 (s, 1H), 7.58 (dd, J=5.7, 8.4 Hz, 1H), 7.12 (s, 1H), 6.73 (dd, J=1.8, 9.6 Hz, 1H), 6.65-6.58 (m, 1H), 5.07 (d, J=9.3 Hz, 1H), 4.76 (app t, J=8.4 Hz, 1H), 3.76 (d, J=9.3 Hz, 1H), 3.69 (app t, J=7.2 Hz, 1H), 3.41 (app t, J=8.7 Hz, 1H), 3.09 (app t, J=6.9 Hz, 1H), 3.00-2.94 (m, 2H), 2.66-2.50 (m, 2H), 1.69-1.51 (m, 5H), 1.39 (m, 3H), 1.18 (s, 9H), 0.01 (s, 9H) ppm. Mass spectrum, m/z [527.4] (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:7][C:8]([O:10]C(C)(C)C)=[O:9].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:7][C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(C=CC(=O)OC(C)(C)C)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C=CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of t-butyl 3-methoxy-4-methoxycarbonylcinnamate (23.5 g) in anhydrous dichloromethane (100 ml) is added trifluoroacetic acid (50 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure to remove the solvent, and the residue is crystallized from ethanol to give 3-methoxy-4-methoxycarbonylcinnamic acid (8.35 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C1C(=O)N([Br:23])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1.CC(=O)OCC>[Br:23][CH2:15][C:12]1[CH:13]=[CH:14][C:3]2[C:2]([Cl:1])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[S:5][C:4]=2[CH:11]=1
Reactant: COC(=O)c1sc2cc(C)ccc2c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2cc(CBr)ccc2c1Cl
Yield: 68.6 %

Procedure:
2.5 g (10.4 mmol) of 3-chloro-2-methoxycarbonyl-6-methylbenzo[b]thiophene (prepared according to J. Org. Chem. 41, 3399 (1976)) are boiled under reflux in 150 ml of chlorobenzene with 1.87 g of NBS and 420 mg of dibenzoyl peroxide for 5 h. After distilling off the chlorobenzene in a rotary evaporator, the residue obtained is taken up in EA, and the EA solution is washed with satd. NaHCO3 solution, 10% strength Na2SO3 solution and satd. NaCl solution, dried over Na2SO4 and concentrated. Chromatography on SiO2 using EA/Hep 1:20 yields 2.28 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([F:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N+:21]([C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]([O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)[C:5]2[C:10]([F:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(F)c2c(Cl)nc(Cl)nc21
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(F)c2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Temperature: 60 °C
Yield: 95.9 %

Procedure:
To a vial containing 2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (389.5 mg, 1.2 mmol) was added m-nitrophenol (161 mg, 1.2 mmol), DMF (5 mL) and K2CO3 (320 mg, 2.3 mmol). The reaction mixture was heated at 60° C. for 1 hr. The reaction was diluted with EtOAc (120 mL) and water (30 mL). The organic layer was separated, washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and evaporated to give an oil. The oil was purified via flash chromatography eluting with 100% heptanes. The solvent was removed to afford the title compound (505 mg, 99% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (t, J=2.27 Hz, 1H) 8.22-8.28 (m, 1H) 7.90-7.96 (m, 1H) 7.86 (d, J=8.31 Hz, 1H) 7.78-7.84 (m, 1H) 5.59 (s, 2H) 3.54-3.66 (m, 2H) 0.84-0.99 (m, 2H) 0.00 (s, 9H). m/z (APCI+) for C18H20ClFN4O4Si 439.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10][OH:11].[N+]([O-])(O)=O>O>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][CH:10]([O:11][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])[CH:9]=[C:8]([CH3:12])[CH3:7]
Reactant: CC(C)=CC=O
Reactant: CC(C)=CCO
Solvent: O
Solvent: O=[N+]([O-])O
Product: CC(C)=CCOC(C=C(C)C)OCC=C(C)C
Reaction time: 4.5 h

Procedure:
690 g (8.2 moles) of 3-methyl-but-2-en-1-al, 1730 g (20 moles) of 3-methyl-but-2-en-1-ol and 23 mg of 65% strength nitric acid (corresponding to 0.62 × 10-4 % by weight of 100% strength HNO3, based on 2,420 g of starting compounds) are boiled under 60 mm Hg in a 4 liter flask surmounted by a packed column (filled with 5 mm Raschig rings). The bottom temperature assumes a value of 76-88° C. The packed column has a diameter of 45 mm and has 30 theoretical plates. The water formed in the reaction is taken off at the top of the column and the organic material which separates from the water is returned continuously into the top of the column. With a reflux of 600 g/hour, quantitative conversion of the aldehyde is achieved after 4.5 hours. 1,1-Bis-(3-methyl-but-2-en-1-yl-oxy)-3-methyl-but-2-ene is obtained about 99% pure after distilling off the excess alcohol, the yield being 98.6% based on 3-methyl-but-2-en-1-al and 98.2% based on 3-methyl-but-2-en-1-ol.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 82.9 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (366 mg, 3 mmol) in anhydrous DMF (7 ml), under nitrogen atmosphere, K2CO3 (829 mg, 6 mmol), and, after 10 minutes, 4-bromonitrobenzene (726 mg, 3.6 mmol) were added. The mixture was heated to reflux for 3 hours, then water was added and the product was extracted with CH2Cl2. The organic layers were washed with water and with NaCl saturated solution and dried with Na2SO4. After evaporation of the solvent the crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate 5/1); 605 mg (yield 82%) of pure title product were obtained.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C@@H:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9].[CH3:17]O>>[NH2:6][C@@H:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([O:10][CH3:17])=[O:9]
Reactant: N[C@H](C(=O)O)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H](N)c1ccccc1
Temperature: 65 °C
Yield: 74 %

Procedure:
A catalytic amount of concentrated sulfuric acid (0.1 mL) was added to a 50 mL round bottom flask containing a solution of (S)-2-amino-2-phenylacetic acid (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (1.0 g, 6.6 mmol) in MeOH (10 mL). The resulting mixture was heated at 65° C. for 6 hours. The solvent was removed under reduced pressure, and the mixture was quenched with aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to afford (S)-methyl 2-amino-2-phenylacetate (0.8 g, 74.0%) as a white solid. 1H NMR (300 MHz, CDCl3) δ: 7.37-7.32 (m, 5H), 4.62 (s, 1H), 3.70 (s, 3H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]3[CH:14]=[N:15][C:16]([NH:18][C:19]4[CH:34]=[CH:33][C:22](C(NC5CCN(C)CC5)=O)=[CH:21][C:20]=4[O:35][CH3:36])=[N:17][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.Cl>O.CO.C(#N)C>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]3[CH:14]=[N:15][C:16]([NH:18][C:19]4[CH:34]=[CH:33][CH:22]=[CH:21][C:20]=4[O:35][CH3:36])=[N:17][C:6]2=3)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CCC(=O)N2C
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: O
Product: COc1ccccc1Nc1ncc2c(n1)N(C1CCC1)CCC(=O)N2C
Reaction time: 0.25 h
Yield: 12.3 %

Procedure:
A mixture of 0.23 g (0.00085 mole) of 4-(9-cyclobutyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-24) and 3 mL of 1M hydrochloric acid was heated at 180 degree for 45 minutes in a microwave reactor. The cooled mixture was diluted with 2 mL of water, 3 mL of methanol and 2 mL of acetonitrile and then stirred for 15 minutes. The solids were removed by filtration and the aqueous solution was made basic (pH>10). The solid which formed was collected, washed with water, and then purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (10:90-100:0) to give 0.037 g of 9-cyclobutyl-2-(2-methoxy-phenylamino)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (I-25)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][CH2:24][CH2:25][CH2:26][OH:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NCCCO
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Product: N#Cc1cnc2cnc(NCCCO)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 55 %

Procedure:
Following the procedure described above in Example 34, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile was reacted with 3-aminopropan-1-ol. The crude product was purified by flash column chromatography (1% methanol in methylene chloride) to give a yellow solid (0.048 g, 55%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (m, 2 H) 3.3 (d, J=6.3 Hz, 4 H) 3.5 (m, 2 H) 6.9 (m, 1 H) 7.0 (s, 1 H) 7.4 (m, 1 H) 7.5 (t, J=9.2 Hz, 1 H) 7.6 (m, 1 H) 8.3 (s, 1 H) 8.8 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[CH:12][C:13]=1[C:14]#[N:15].C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29].O>CN(C)C=O>[NH2:29][C:28]1[N:30]=[C:16]([C:11]2[NH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:13]([C:14]#[N:15])[CH:12]=2)[CH:17]=[CH:18][N:27]=1
Reactant: N=C(N)N
Reactant: CN(C)/C=C/C(=O)c1cc(C#N)c(-c2ccc(Cl)cc2Cl)[nH]1
Agent: O=C(O)O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(-c2ccnc(N)n2)[nH]c1-c1ccc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 22 h
Yield: 83 %

Procedure:
To a suspension of 2-(2,4-dichloro-phenyl)-5-((E)-3-dimethylamino-acryloyl)-1H-pyrrole-3-carbonitrile (6.80 g, 20.35 mmol) in 82 mL of N,N-dimethylformamide was added guanidine carbonate (9.17 g, 101.75 mmol). The mixture was heated to 110° C. for 18 hours under efficient stirring. Then, a further amount of guanidine carbonate (1.83 g; 20.35 mmol) was added to the mixture and heating to 115° C. was prolonged for additional 22 hours. The resulting mixture was diluted by dropwise addition of 325 mL of water over 30 minutes. The solid was isolated by filtration, washed with 100 mL of water, dried in the air and, finally, in a vacuum oven at 60° C. affording 5.58 g of product as a light brown powder. Yield=83%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:19][O:20][CH3:21])[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[C:27]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]([CH2:19][O:20][CH3:21])[C:10]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCn1c(-c2ccncc2)cnc1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1c(-c2ccc(Cl)cc2)nc(C(=O)c2ccccc2)c1-c1ccncc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 26.7 %

Procedure:
To a cooled solution of 2-(4-chlorophenyl)-1-methoxymethyl-5-(4-pyridyl)imidazole from Step B (40 mg, 0.13 mmol) in THF (0.5 mL) at -30° C. was added dropwise a solution of n-butyllithium in hexanes (93 μL of a 2.5 M solution, 0.23 mmol). The reaction was stirred at -30 to -10° C. for 90 min. After cooling to -30° C., benzoyl chloride (47 μL, 0.40 mmol) was added. The reaction was stirred overnight at room temperature. The reaction was quenched by the addition of saturated ammonium chloride solution and the mixture was extracted with ethyl acetate (2 times). The combined extracts were successively washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The solution was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-4% methanol in methylene chloride to yield the title compound as a red-brown glass (14 mg, 26% yield), mass spectrum (CI) m/e=404 (M+1)+.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([NH2:26])=[N:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2.[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46](Cl)=[O:47])=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[S:1]1[C:5]([C:6]2[C:7]([NH:26][C:46](=[O:47])[CH2:45][C:42]3[CH:41]=[CH:40][C:39]([O:38][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])=[CH:44][CH:43]=3)=[N:8][CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[N:11]=2)=[CH:4][C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cc4ccccc4s3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cc3ccccc3s2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
Under an argon atmosphere, to a mixture of 3-(benzo[b]thiophen-2-yl)-5-[4-(tert-butyldimethylsilyloxy)phenyl]pyrazin-2-amine (7h) (505 mg, 1.16 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyl dimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1). The resulting solid was recrystallized (n-hexane/ethanol) to give Compound 11h (294 mg, 431 μmol, 37.0%) as a colorless solid. Rf=0.19 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.19 (s, 6H), 0.25 (s, 6H), 0.96 (s, 9H), 0.97 (s, 9H), 3.71 (s, 2H), 6.82-6.89 (AA′BB′, 2H), 7.01-7.08 (AA′BB′, 2H), 7.26-7.42 (m, 4H, includes AA′BB′), 7.60-7.65 (m, 2H), 7.96 (d, 1H, J=7.9 Hz), 8.10-8.18 (AA′BB′, 2H), 9.02 (s, 1H), 10.82 (s, 1H), IR (KBr, cm−1) 525, 677, 692, 710, 727, 743, 779, 797, 808, 835, 922, 972, 1011, 1074, 1171, 1256, 1327, 1362, 1391, 1416, 1445, 1503, 1603, 1657, 859, 2886, 2930, 2957, 3059, 3161, 3211; HRMS (ESI+) m/z 704.2758 ([M+Na]+, C38H47N3NaO3SSi2+ requires 704.2769).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([O:16][CH2:17]C)[C:8]([O:13][CH2:14]C)=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4].[Se](=O)=[O:20].[CH2:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[C:10]([C:9]1[CH:12]=[C:5]([C:3](=[O:4])[C:2]([O:28][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:13][CH3:14])#[N:11]
Reactant: CCCCCCO
Reactant: CCOc1cc(C(=O)CBr)cc(C#N)c1OCC
Reactant: O=[Se]=O
Solvent: ClCCl
Product: CCCCCCOC(=O)C(=O)c1cc(C#N)c(OC)c(OC)c1
Temperature: 25 °C

Procedure:
1.45 g of 5-(bromoacetyl)-2,3-diethoxybenzonitrile and 1.12 g of selenium dioxide are stirred at 120° for 18 hours in 10 ml of n-hexanol. After cooling to room temperature the mixture is diluted with 20 ml of methylene chloride and filtered. The filtrate is washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 70 g of silica gel with hexane/ether (2:1). there is obtained hexyl (3-cyano-4,5-dimethoxyphenyl)glyoxylate as an oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([Si:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][CH2:16]I)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23].[H][H]>CN(C)C=O.O.C(O)(=O)C>[CH3:25][O:24][C:22](=[O:23])[CH:21]([C:20]([O:27][CH3:28])=[O:26])[CH2:16][CH2:15][CH2:14][Si:13]([CH3:19])([CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCCCCCCCCC[Si](C)(C)CCCI
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCCCC[Si](C)(C)CCCC(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a reaction vessel system filled with nitrogen, 964 mg (24.5 mmole) of 61.1% sodium hydride in mineral oil is added, which is washed free of the oil by employing 3 portions of petroleum ether/hexane (1:1). The thus-washed sodium hydride is then suspended in 20 ml of fresh hexane and added in several portions to 8.1 g (22.0 mmoles) of n-decyl-dimethyl-(3-iodopropyl)-silane plus 3.6 g (27.3 mmole) of dimethyl malonate in 25 ml of dry dimethylformamide plus 25 ml of dry petroleum ether, with stirring and cooling at such a rate that hydrogen gas evolution is controlled, and the temperature is at 0° to 10° (new solids form). The reaction mixture is then stirred in a bath at 55° for 2 hrs. and then at 65° for 1 hr. After cooling to room temperature, 2 ml of acetic acid (85%) is added, followed by an excess of water and petroleum ether. The organic layer is separated, washed thrice with water, dried and then concentrated to obtain the crude title product of this step as an oily residue, which is distilled through a Vigreux column to obtain refined title product of this step at 135°-139° at 0.105 mm Hg.
Reaction SMILES: I[C:2]1[C:10](=[O:11])[N:9]2[C:5]([N:6]([CH3:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=32)=[N:4][C:3]=1[CH3:17].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].FC1C=C(C2C(=O)N3C=CSC3=NC=2C)C=C(F)C=1>C1(C)C=CC=CC=1.O.C(O)C>[CH3:17][C:3]1[N:4]=[C:5]2[N:9]([C:10](=[O:11])[C:2]=1[C:24]1[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=1)[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[N:6]2[CH3:16]
Reactant: Cc1nc2n(C)c3ccccc3n2c(=O)c1I
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc2n(C)c3ccccc3n2c(=O)c1-c1ccc(OC(F)(F)F)cc1

Procedure:
A solution of Step 3 intermediate (1.2 g, 3.512 mmol), 4-trifluoromethoxyphenyl boronic acid (0.864 g, 4.212 mmol), Pd[(C6H5)3P]4 (0.161 g, 1.420 mmol), Na2CO3 (2.32 g) was reacted together in a mixture of toluene (20 ml), ethanol (5 ml) and water (5 ml) according to the procedure outlined in Step 3, Intermediate 3 to afford the desired compound: 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 3.78 (s, 3H), 7.33-7.46 (m, 4H), 7.52-7.57 (m, 1H), 7.68-7.71 (m, 1H), 8.40-8.43 (s, 1H); ESI-MS (m/z) 374.62 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O>[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[O:20][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCN2CCCC2)c(F)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
1-(2-Chloro-ethyl)-pyrrolidine hydrochloride (1.2 g, 7.0 mmol, 1.1 equiv) is added to a suspension of 2-fluoro-4-nitrophenol (1 g, 6.4 mmol) and cesium carbonate (5.2 g, 15.9 mmol, 2.5 equiv) in DMF (20 mL). The resulting mixture is heated to 80° C. and stirred for 18 h. Additional 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1 g) is added and the mixture is stirred for 3 h at 80° C. The reaction mixture is cooled to RT, diluted with EtOAc and H2O. The layers are separated and the aqueous layer is extracted with EtOAc. The organic phase is washed with H2O, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) to provide the title compound as a yellow solid. ESI-MS: 255.1 [MH]+; tR=2.57 min (system 1); TLC: Rf=0.55 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[S:7][C:8]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[O:15])=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.O[Li].O>CO.O>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[S:7][C:8]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:15])=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1
Reactant: COC(=O)CCCCNC(=O)c1sc2ccc(OC)cc2c1OC(C)C
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COc1ccc2sc(C(=O)NCCCCC(=O)O)c(OC(C)C)c2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 85 %

Procedure:
Methyl 5-[[5-methoxy-3-(1-methylethoxy)benzo[b]thien-2-yl]carbonyl]aminovalerate (250 mg, 0.66 mmol) and 83 mg of LiOH-H2O in a mixture of 5 mL of methanol and 2 mL of water are stirred at room temperature for 7 hours. The reaction mixture is partitioned between ethyl acetate and aqueous HCl. The organic layer is washed with water, then brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from ethyl acetate:hexane gives 205 mg of product (85%); mp 135°-137° C.