Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].[Cl-].[CH3:14][NH2+:15][CH3:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[CH3:14][N:15]([CH3:16])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: C[NH2+]C
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(C)C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 2.0 g 2-nitrobenzoic acid and 0.98 g dimethylammonium chloride in dichloromethane at 0° C. were added 2.29 g 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1.62 g N-hydroxy-benzotriazol and 6.05 g N-methyl-morpholine. The resulting mixture was stirred at room temperature overnight. The reaction mixture was then washed sequentially, with saturated sodium hydrogen carbonate, a 5% aqueous solution of citric acid and brine. The organic phase was dried over sodium sulfate. After filteration the solvent was removed in vacuo yielding N,N-dimethyl-2-nitrobenzamide (2.13 g).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH3:4]>C(O)C.[OH-].[Na+]>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([OH:16])[CH2:10][CH2:9]2)[CH3:4]
Reactant: CCOc1ccc2c(c1)CCC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc2c(c1)CCC(O)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.97 g (52 mmol) of sodium borohydride were added in portions of 0° C. to 9.8 g (51.4 mmol) of 6-ethoxy-2-tetralone in 150 ml of ethanol. The mixture was stirred for 1 hour at 0° C. and diluted with 200 ml of 2N sodium hydroxide solution, and the solution was extracted with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried and concentrated. This gave 9.8 g of an oil which was further reacted without purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:11]O>C(O)(=O)C>[F:1][C:2]1[CH:10]=[N+:9]([O-:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: OO
Reactant: O=C(O)c1ccncc1F
Solvent: CC(=O)O
Product: O=C(O)c1cc[n+]([O-])cc1F
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoroisonicotinic acid (5.0 g, 35.33 mmol) in acetic acid (25 ml) was added hydrogen peroxide (6 ml). The reaction mixture was stirred at 70-80° C. overnight. The solvent was removed to obtain 5.5 g of 3-fluoroisonicotinic acid 1-oxide in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[N:13][NH:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cccc(C=O)c1
Solvent: C1CCOC1
Product: COc1cccc(C=NNC(=O)OC(C)(C)C)c1
Yield: 103.1 %

Procedure:
A solution of 3-methoxybenzaldehyde (27.0 g) and t-butyl carbazate (25.0 g) in tetrahydrofuran (350 ml) was refluxed for 4 hours. The reaction mixture was concentrated to dryness giving t-butyl 3-methoxybenzylidenecarbazate (48.8 g) as an oil, which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1)=[O:2].[BH4-].[Na+].CO.Cl>C1COCC1.[Cl-].[Na+].O>[OH:2][CH2:1][C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1
Reactant: COC(=O)c1cnc(C=O)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cnc(CO)cn1
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a solution of methyl 5-formylpyrazine-2-carboxylate (2.47 g) in THF (20 mL) was added sodium borohydride (170 mg) portionwise over 10 mins. After stirring for 1 h, methanol (10 mL) was added. The reaction mixture was stirred for a further 20 mins, and then HCl (1 N, aq., 20 mL) and brine (20 mL) were added. The mixture was extracted with EtOAc (3×40 mL) and the combined organic portions dried over MgSO4 and evaporated to afford the title compound (1.31 g). 1H NMR (400 MHz, CDCl3) δ ppm 4.07 (s, 3H), 4.98 (br. s., 2H), 8.80 (s, 1H), 9.27 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>[Ni].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CN2CCCCC2)cc1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: O=C(CCc1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
A suspension of 0.200 g (0.464 mmol) (E)-3-(4′-chloro-biphenyl-4-yl)-N-(4-piperidin-1-ylmethyl-phenyl)-acrylamide (Example 172) and 100 mg Raney nickel in 50 mL EtOAc was hydrogenated at RT and 50 psi. The catalyst was filtered off, the filtrate was evaporated down i. vac. and the residue was triturated with ether. The precipitate was filtered off, washed with ether and dried at 50° C. i. vac.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](Cl)=[N:20][N:19]=2)=[C:9]1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[OH-:31].[Na+]>CC(O)=O>[C:1]([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:31])[NH:20][N:19]=2)=[C:9]1[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: Cc1c(-c2nnc(Cl)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2n[nH]c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
The product of step b) (300 mg) was treated with 10 mL HOAc and 2 mL of 1 M NaOH. The suspension was heated to 70° C. for 4 h. The reaction was cooled and partitioned between EtOAc and water. The organic layer was dried over MgSO4 and concentrated to give 300 mg of the sub-title compound as a yellow oil. MS: ESI (negative): 422, 424 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(I)ccc1O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(I)ccc1Oc1ccc(C(F)(F)F)cn1
Yield: 93.8 %

Procedure:
To a solution of 2-hydroxy-5-iodo-benzonitrile (80.0 g, 0.328 mol) and 2-chloro-5-tri fluoromethylpyridine (60.0 g, 0.328 mol) in DMF (500 ml) was added K2CO3 (91.0 g, 0.656 mol). The reaction mixture was refluxed overnight, then filtered and concentrated. Purification via column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) afforded the title product (120 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][C:14]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)=[CH:13]2)=[O:6].O1CCCC1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:1][CH:2]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][C:14]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)=[CH:13]2)=[O:6]
Reactant: O=C(CCC(=O)c1cccs1)Nc1cccc2cc(-c3nccs3)[nH]c12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCC(O)c1cccs1)Nc1cccc2cc(-c3nccs3)[nH]c12
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a mixture of 4-oxo-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]-4-(2-thienyl)butanamide (1.43 g), tetrahydrofuran (10 ml) and methanol (10 ml) was added sodium borohydride (0.16 g) at 0° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (1.21 g, yield 84%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. melting point 155-157° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17]=[C:18]([CH3:20])[CH3:19]>C(Cl)Cl.O1CCOCC1>[C:18]([O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C(C)C
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1cc(F)cc(F)c1
Reaction time: 120 h
Yield: 81 %

Procedure:
3,5-Difluorobenzoic acid (25 g, 0.158 mol) was dissolved in DCM (150 mL) and dioxane (50 mL). The mixture was transferred into a stainless steel autoclave. Concentrated sulfuric acid (3.6 mL) was added, followed by isobutene (100 mL). The mixture was kept in the autoclave for 5 days. Excess isobutene and the solvents were removed under reduced pressure, the mixture diluted with EtOAc and washed with water, saturated aqueous sodium hydrogen carbonate and brine. Drying and evaporation gave a dark-yellow oil, which was purified by kugelrohr distillation (80–100° C., 1.0 mbar) to give tert-butyl-3,5-difluorobenzoate (27.51, g, 81% ) as a colorless solid.
Reaction SMILES: [C:1]12([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]1)[C:9]1[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:3][CH2:2]2.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[Br:31]Br>C(Cl)(Cl)Cl>[Br:31][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]2([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]2)[CH2:2]1
Reactant: BrBr
Reactant: O=C1NC(=O)C2(CCc3ccccc32)N1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)C2(CC(Br)c3ccccc32)N1
Temperature: 25 °C
Yield: 29 %

Procedure:
Spiro[imidazolidine-4,1'-indan]2,5-dione, (C.A. reg. no. 6252-98-8) (6.06 g, 30 mmol) was combined with 7.95 ml (30 mmol) bis(trimethylsilyl)trifluoroacetamide and 4.8 g (30 mmol) bromine in 50 ml chloroform and heated to reflux. Decolorization occurred during the 18 hour reaction. The reaction mixture was cooled to 25° C. and after 45 minutes stirring a solid which had crystallized was collected by filtration to give 2.45 g (29%) of crude 3'-bromo-spiro[imidazolidine-4,1'-indan]2,5-dione. The chloroform mother liquors deposited an additional 2.18 g (26% yield), mp 58°-65° C. Two grams (7.1 mmol) of material, mp 58°-65° C., was combined with 25 ml water to give a slurry. Following stirring for 22 hours the resultant solid was collected by filtration and dried to give 0.52 g (33% yield) of the title compound: mp 260°-263° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:21])([C:14]([NH:16][CH2:17][CH:18]([OH:20])[CH3:19])=[O:15])[CH2:6][CH2:5]2.[O:23]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:23][C:7]([CH3:21])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:22])[C:14]([NH:16][CH2:17][CH:18]([OH:20])[CH3:19])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCC(C)O)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCC(C)O)=C(C)C1=O
Yield: 93.5 %

Procedure:
Oxidation as described in protocol B, using 505 mg (1.64 mmol) of 6-hydroxy-N-(2-hydroxypropyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 1.99 mg CAN (3.62 mmol) yielded 496 mg of 2-hydroxy-N-(2-hydroxypropyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([O:23][CH3:24])=[O:22])[C:6]=1[OH:25])(=[O:3])[CH3:2].[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.CO>C1COCC1.CCOC(C)=O.C1CCCCC1>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([O:23][CH3:24])=[O:22])[C:6]=1[O:25][CH3:26])(=[O:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1OC
Reaction time: 24 h
Yield: 43.3 %

Procedure:
Methyl 4-acetamido-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-hydroxypicolinate (568 mg, 1.54 mmol), triphenylphosphine (404 mg, 1.54 mmol), diethyl azodicarboxylate (243 μL, 1.54 mmol), and CH3OH (94 μL, 2.31 mmol) were combined in THF and allowed to stir for 24 h. Flash chromatography (SiO2; 0-50% EtOAc/cyclohexane gradient) afforded the title compound as a yellow oil (255 mg, 43%): 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=1.6 Hz, 1H), 8.06 (s, 1H), 7.56 (dd, J=8.5, 7.7 Hz, 1H), 7.23 (dd, J=8.6, 1.7 Hz, 1H), 4.01 (s, 3H), 3.99 (d, J=1.0 Hz, 3H), 3.98 (s, 3H), 2.29 (s, 3H); ESIMS m/z 383 ([M+H]+).
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][NH2:14])=[CH:8][CH:7]=2.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[F:16][C:3]([F:2])([F:15])[C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][NH:14][C:23]([C:22]1[CH:21]=[N:20][C:19]([C:18]([F:29])([F:17])[F:28])=[CH:27][CH:26]=1)=[O:24])=[CH:8][CH:7]=2
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)nc1
Temperature: 5 °C
Reaction time: 0.21 h
Yield: 60.7 %

Procedure:
{[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine hydrochloride (Intermediate 5A, 646 g, 71% free amine equivalent), 6-trifluormethylnicotinic acid (429.7 g), diisopropylethylamine (1500 mL) and tetrahydrofuran (5.1 L) were placed in a flask equipped with an addition funnel, thermometer, and nitrogen inlet. The mixture was stirred vigorously for 10-15 min. The mixture was cooled to ˜5° C. and propylphosphonic anhydride (3.2 L of 50 wt % solution) added slowly. The mixture was stirred at ˜15° C. for 2 hrs. The mixture was cooled to ˜5° C. and quenched by the addition of water (505 mL) slowly. The pH was adjusted to 5-6 by adding 20 wt % K3PO4 (2.9 L). The mixture was diluted with EtOAc (3.2 L) and the temperature adjusted to 15-20° C. The phases were separated and the organic mixture was washed sequentially with water (1.5 L) and then 5 wt % sodium bicarbonate solution (2.6 L). The mixture was filtered and the solvent removed to minimum volume under vacuum. Isopropyl alcohol (2.0 L) was added and the mixture filtered, and the solvent removed under vacuum two times. Isopropyl alcohol (980 mL) was added and the mixture heated to 70-80° C. Water (1.5 L) was added while maintaining temperature above 65° C. and monitoring turbidity. The temperature was adjusted to 65° C., seeded with product (4.5 g) and the mixture held at 65° C. for 30 min. The mixture was cooled to ˜5° C. overnight and the product was isolated by filtration, washing the solids with cold 10% IPA in water (1 L), then dried in a vacuum oven to give the title compound (529 g);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:29](Br)[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:29]/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:6][CH:5]=1
Reactant: BrCC=Cc1ccccc1
Reactant: COC(=O)c1ccc(OCCNS(C)(=O)=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN(C/C=C/c2ccccc2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.1 %

Procedure:
To a solution of 4-(2-methanesulfonylamino-ethoxy)-benzoic acid methyl ester (62 mg, 0.23 mmol) in DMF (10 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1.0M in THF, 0.24 mL, 0.24 mmol) dropwise. After 20 minutes, cinnamyl bromide (51 mg, 0.26 mmol) was added and the reaction was stirred at room temperature for 2 h. Aqueous 1N HCl was added and the product was extracted into EtOAc. The organic solution was washed with 1N HCl (3×) followed by brine. The organic solution was dried (Na2SO4), filtered, and concentrated. Radial chromatography (20% EtOAc in hexanes) provided trans4-{2-[methanesulfonyl-(3-phenyl-allyl)-amino]-ethoxy}-benzoic acid methyl ester (70 mg). 1NMR (400 MHz, CDCl3) δ 7.97 (d, 2H), 7.35-7.23 (m, 5H), 6.88 (d, 2H), 6.58 (d, 1H), 6.18 (m, 1H), 4.20 (t, 2H), 4.12 (d, 2H), 3.88 (s, 3H), 3.68 (t, 2H), 2.95 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C1COCC1.C([Li])CCC.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCCCCC.O>[CH2:17]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: c1ccsc1
Reactant: CCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCc1cccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Thiophene (67.4 g, 0.801 mol) and THF (200 ml) were placed in a 1000-ml three-necked flask equipped with a 200-ml dropping funnel and a reflux tube. The solution was cooled to −78° C., and a solution (200 ml) of n-butyllithium (2.6 M) in n-hexane was added dropwise to the cooled solution over a period of about one hr. After the completion of the dropwise addition, the mixture was stirred at −78° C. for about one hr. Thereafter, the reaction temperature was raised to room temperature. At that temperature, the mixture was again stirred for one hr, and 1-bromodecane (118.0 g, 0.534 mol) was added dropwise thereto at 0° C. over a period of about one hr. After the completion of the dropwise addition, the reaction temperature was raised to room temperature, and, at that temperature, the mixture was stirred overnight. After the completion of the reaction, water (200 ml) was added, and the organic layer was extracted with diethyl ether, was dried over sodium sulfate, and was applied to column chromatography (n-hexane) to give an objective compound 2-decylthiophene as a yellow liquid (112.8 g, yield 96.60%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.29 (m, 14H), 1.67 (m, 2H), 2.81 (t, 2H, J=7.32 Hz), 6.76 (d, 1H, J=3.91 Hz). 6.90 (dd, 1H, J=3.91 Hz, J=4.88 Hz), 7.09 (d, 1H, J=4.88 Hz.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.Cl[C:15]1[C:16]2[CH:23]=[CH:22][N:21]([CH3:24])[C:17]=2[N:18]=[CH:19][N:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[CH3:24][N:21]1[C:17]2[N:18]=[CH:19][N:20]=[C:15]([N:1]3[C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:4]4[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]3)[C:16]=2[CH:23]=[CH:22]1
Reactant: Cn1ccc2c(Cl)ncnc21
Reactant: COC(=O)c1c[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cn(-c2ncnc3c2ccn3C)c2ncccc12
Temperature: 120 °C
Yield: 44.2 %

Procedure:
To 1.9 g (9.2 mmol) of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate in 50 cm3 of dimethylsulfoxyde under argon atmosphere, were added 1.85 g (11.0 mmol) of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, followed by 3.2 g (23.0 mmol) of potassium carbonate. The reaction mixture was heated at about 120° C. for 24 hours, upon which it was cooled to about 20° C. and treated with 200 cm3 of distilled water. The mixture was then treated with 300 cm3 and 150 cm3 of ethyl acetate and filtered on Celite®. The aqueous phase was extracted with 150 cm3 of ethyl acetate. The combined organic extracts were dried on magnesium sulfate and concentrated to dryness in vacuo (2.7 kPa). The residue was purified via column chromatography on silica gel (0,04–0,06 mm), with dichloromethane/methanol 99:1 v/v as eluting solvent. Thus, 1.25 g of methyl 1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate were obtained as a light-yellow crystalline powder. mp: 207° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: CO
Reactant: O=C(O)Cc1cc(Cl)ccc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(Cl)ccc1Br
Temperature: 25 °C

Procedure:
A solution of (2-bromo-5-chlorophenyl)acetic acid (1-1) (15.0 g, 60.1 mmol) and concentrated sulfuric acid (0.150 mL of a 36N solution) in methanol (120 mL) was heated at reflux for approximately 15 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous phase re-extracted twice with methylene chloride. The combined organic extracts were washed with water, brine, dried (MgSO4) and the volatiles evaporated. The residual colorless liquid (15.9 g) was used without further purification in the Step C below.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])[O:6][CH:7]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[C:18]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])[O:6][CH:7]=1)(=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C[Si](C)(C)c1cc(CO)co1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCc1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-hydroxymethyl-2-trimethylsilylfuran (0.288 g., 1.70 mmol) and pyridine (0.214 g., 2.55 mmol) in 30 ml dry tetrahydrofuran at 0 degrees was added lauroyl chloride (0.408 g., 1.86 mmol). This solution was allowed to warm to room temperature, stirred 30 minutes, and partitioned between ethyl ether and 5% sodium bicarbonate solution. The organic portion was washed with aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to a colorless oil. This material was purified by flash chromatography (silica, 5% ethyl ether/petroleum ether) to give the desired ester.