Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:30])[CH2:10][C@@:11]1([C:24]2[S:25][C:26](Br)=[CH:27][CH:28]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1.[CH3:31][NH:32][C:33]([NH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:34]>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[OH:7][NH:8][C:9](=[O:30])[CH2:10][C@@:11]1([C:24]2[S:25][C:26]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([NH:35][C:33]([NH:32][CH3:31])=[O:34])[CH:37]=3)=[CH:27][CH:28]=2)[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)N1CC[C@](CC(=O)NOC2CCCCO2)(c2ccc(Br)s2)S(=O)(=O)CC1
Reactant: CNC(=O)Nc1cccc(B(O)O)c1
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: CCOC(C)=O
Solvent: COCCOC
Product: CNC(=O)Nc1cccc(-c2ccc([C@@]3(CC(=O)NO)CCN(S(C)(=O)=O)CCS3(=O)=O)s2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 13.4 %

Procedure:
A mixture of N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-bromo-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (230 mg), 3-(methylaminocarbonylamino)phenylboronic acid (123 mg) and tetrakis(triphenylphosphine)palladium(0) (24.4 mg) in a mixture of 1,2-dimethoxyethane (2 ml) and 2M aqueous sodium carbonate solution (0.85 ml) was stirred for 4 hours at 80° C. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was dissolved in methanol (2 ml) and 10% hydrogen chloride in methanol (0.5 ml) was added thereto. After being stirred for 30 minutes at room temperature, the solution was concentrated in vacuo. The residue was purified with silica gel column chromatography (eluent; 0.5-5% methanol in chloroform) to give N-hydroxy-2-[(S)-7-(5-(3-(methylaminocarbonylamino)-phenyl)-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (30 mg).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:27]=[CH:26][C:18](/[CH:19]=[N:20]/[NH:21][C:22](SC)=[S:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:30][N:31]([CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH2:38])[CH:33]=1>CN(C=O)C>[CH3:30][N:31]([CH3:39])[C:32]1[CH:33]=[C:34]([NH:38][C:22]([NH:21][N:20]=[CH:19][C:18]2[CH:17]=[CH:16][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:28])([F:1])[F:29])=[CH:9][CH:8]=4)[N:11]=3)=[CH:27][CH:26]=2)=[S:23])[CH:35]=[CH:36][CH:37]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: CSC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CN(C)C=O
Product: CN(C)c1cccc(NC(=S)NN=Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 150 °C
Reaction time: 5 h
Yield: 78.3 %

Procedure:
To a 50 mL round-bottomed flask containing (E)-methyl 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbodithioate (250 mg, 0.571 mmol) in DMF (3 mL) was added N1,N1-dimethylbenzene-1,3-diamine (195 mg, 1.43 mmol). The contents were heated at 150° C. with stirring for 5 h before the solution was allowed to cool overnight. The mixture was filtered, and the filtrate was purified via RP-HPLC to afford the desired material (235 mg, 78%) as an off-white solid: mp 192-194° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.04 (s, 1H), 9.41 (s, 1H), 8.19 (s, 1H), 8.16-7.99 (m, 6H), 7.61 (d, J=8.3 Hz, 2H), 7.16 (t, J=7.2 Hz, 1H), 7.01 (m, 1H), 6.87 (m, 1H), 6.58 (m, 1H), 2.88 (s, 6H); ESIMS m/z 526 ([M+1-1]+).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)#[N:20]>>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C1=Cc2cc(C(=O)c3ccc(C#N)cc3)c(O)cc21

Procedure:
In a manner analogous to that described in Example 5, starting from 26.6 g of aluminium trichloride, 9.61 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester and 17.56 g of p-cyanobenzoyl chloride there is obtained 4-(p-cyanobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester having a melting point of 113°-114°.
Reaction SMILES: FC(F)(F)[C:3]([N:5]([C:7]1[C:8](=[O:33])[N:9]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)C)=O.C(OCC)(=O)C>[Cl-].[Na+].O>[CH3:3][NH:5][C:7]1[C:8](=[O:33])[N:9]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:31])[CH3:32])[C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])=[O:21])[C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N(C)C(=O)C(F)(F)F)c1=O)C(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1ccc(-c2ccccc2)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1=O

Procedure:
Using a procedure similar to that described above under Example 49.j. for the basic hydrolysis of the analogous 3-(N-trifluoroacetylamino) compound to the 3-amino-compound, but using the following extractive work-up, the title compound was prepared from 2-[3-(N-trifluoroacetyl-N-methylamino)-2-oxo-6-phenyl -1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl -2-oxopropyl)acetamide. On completion of hydrolysis, ethyl acetate and brine were added. The organic phase was separated, washed (brine), dried (MgSO4), and evaporated. The resultant solid was triturated with diethyl ether, chromatographed, eluting with dichloromethane:methanol (96:4), and dried overnight under vacuum to give the title product as a white solid; TLC: Rf =0.20, dichloromethane:methanol (96:4); MS: m/z=410(M+1).
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=2[C:18]#[C:19][Si](C)(C)C)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl>CO.O>[C:18]([C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[C:6]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:7])[C:12]([OH:14])=[O:13])#[CH:19]
Reactant: COC(=O)c1ccc(C(=O)N2CCCC2)c(C#C[Si](C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1

Procedure:
7.70 g (23.4 mmol) of methyl 4-(pyrrolidin-1-ylcarbonyl)-3-(2-trimethylsilylethynyl)benzoate is dissolved in 30 mL of methanol, combined with 46.7 mL (93.4 mmol) 2 molar potassium hydroxide solution, and refluxed for 2 hours. After the elimination of volatile constituents in vacuo, the residue is diluted with demineralized water and acidified with 2 molar hydrochloric acid solution. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulfate, and then the solvent is eliminated in vacuo. Yield: 3.14 g (55%); Rf value: 0.59 (silica gel; dichloromethane/ethanol=4:1); C14H13NO3 (243.27); mass spectrum: (M+H)+=244.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:12][CH2:11][C:10]2=[O:21].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[O:21]=[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=2)[N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:12][CH2:11]1
Reactant: CCC(=O)Cl
Reactant: CCC(=O)N1CCC(=O)c2cc(O)ccc21
Agent: CN(C)c1ccncc1
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCC(=O)Oc1ccc2c(c1)C(=O)CCN2C(=O)CC
Yield: 110.3 %

Procedure:
A solution of propionyl chloride (1.018 g) in chloroform (5 ml) was added dropwise to a solution of 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.09 g), N,N-dimethylaniline (1.513 g), and 4-dimethylaminopyridine (0.061 g) in chloroform (20 ml) with stirring and ice cooling over a period of 10 minutes After being stirred overnight at ambient temperature, the mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed successively with 5% hydrochloric acid, water, aqueous sodium bicarbonate, and water, dried over magnesium sulfate, and evaporated in vacuo to give an oil of 4-oxo-1-propionyl-6-propionyloxy-1,2,3,4-tetrahydroquinoline (1.51 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](I)[CH3:33]>CN(C)C=O>[CH2:23]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:32][CH3:33])[C:10]1=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCI
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1N(Cc1ccccc1)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(N(Cc2ccccc2)Cc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
A solution of 3-dibenzylamino-6,7-difluoro-1H-quinazoline-2,4-dione (Example 16) (0.43 g, 1.1 mmol) in 10 mL of N,N-dimethylformamide is added to a suspension of sodium hydride (0.05 g, 1.3 mmol) in 10 mL of N,N-dimethylformamide and stirred for 30 minutes. Ethyl iodide (0.13 mL, 1.6 mmol) is added, and the mixture is stirred at 25° C. for 18 hours. The reaction is quenched with 1 mL of water and concentrated in vacuo. The residue is dissolved in chloroform, washed with water, brine, and dried over magnesium sulfate. The solution is concentrated and purified via chromatography (SiO2, CHCl3) to give 0.34 g of the title compound as a solid, mp 133–135° C., MS CI, m/z 422 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:6]([NH2:8])[CH:7]=1.Cl[C:17]1[CH:26]=[CH:25][N:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]2>>[CH3:27][C:21]1[N:22]=[C:23]2[C:18]([C:17]([NH:8][C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[CH:26][CH:25]=[N:24]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccccn2)c(N)c1
Product: Cc1ccc(Sc2ccccn2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product of Example 227b (60 mg, 0.278 mmol) was reacted with the product from Example 1d (50 mg, 0.278 mmol) for 16 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (24 mg, 28%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.44 (s, 3 H), 2.73 (s, 3 H), 6.45 (d, J=6.99 Hz, 1 H), 7.02-7.12 (m, J=7.72, 1.10 Hz, 2 H), 7.40-7.49 (m, 2 H), 7.50-7.58 (m, J=1.84 Hz, 1 H), 7.72 (dd, J=8.46, 3.31 Hz, 2 H), 8.21-8.27 (m, J=2.94, 0.74 Hz, 1 H), 8.38 (d, J=6.99 Hz, 1 H), 8.85 (d, J=8.82 Hz, 1 H), 10.99 (s, 1 H); MS (ESI+) m/z 359 (M+H−TFA)+; (ESI−) m/z 357 (M−H−TFA)−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CC(OC)(C)C>[F:11][C:5]1[CH:4]=[CH:3][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: OB(O)c1ccccc1
Solvent: COC(C)(C)C
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)ccc1F

Procedure:
5-Bromo-2-fluoro-benzoic acid (49) (2.0 g, 9.00 mmol) was coupled to phenyl boronic acid (1.23 g, 10.00 mmol) using method F, except that after the 2 hour reaction, water (50 mL) and TBME (50 mL) were added. The mixture was filtered and the aqueous layer was washed with TBME. The aqueous layer was then acidified with 1N HCl and the precipitated solid was collected and dried. Yield: 1.6 g, 82%
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11](#[N:15])[C:12]([CH3:14])=[CH2:13].OS(O)(=O)=O>CCOCC>[CH2:1]([O:8][CH2:13][CH:12]([CH3:14])[C:11]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C#N
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C#N)COCc1ccccc1

Procedure:
Benzyl alcohol (108 g.; 1 mole) was stirred and treated with 0.3 g. of 50% by weight sodium hydride in a mineral oil dispersion. To the resulting solution was added dropwise 415 ml. (335 g.; 5moles) of methacrylonitrile over a 40 minute period, at room temperature. The reaction mixture was heated at 60°-65° C. for 5 hours then cooled, acidified with 1 N aqueous H2SO4 and diluted with ether. The ether solution was washed twice with saturated brine then dried, filtered and concentrated in vacuo. Distillation of the residue gave, after removal of low boiling materials, 149.3 g. (85%) of rac. 3-benzyloxy-2-methylpropionitrile as a colorless liquid, b.p. 90°-93° C. (0.02 mm Hg.).
Reaction SMILES: [CH2:1]([C:3]1([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([C:34]#[C:35][CH2:36][OH:37])[C:18]4[S:22][C:21]([N:23]5[CH2:28][N:27]([CH3:29])[CH2:26][N:25]([CH2:30][CH3:31])[C:24]5=[O:32])=[N:20][C:19]=4[CH:33]=3)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl.O>[CH2:1]([C:3]1([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:4][CH2:5][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([C:34]#[C:35][CH2:36][O:37][S:51]([CH3:50])(=[O:53])=[O:52])[C:18]4[S:22][C:21]([N:23]5[CH2:28][N:27]([CH3:29])[CH2:26][N:25]([CH2:30][CH3:31])[C:24]5=[O:32])=[N:20][C:19]=4[CH:33]=3)=[CH:11][N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C#CCO)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C#CCOS(C)(=O)=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Ethyl 4-ethyl-1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-(3-hydroxyprop-1-ynyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (325 mg, 0.55 mmol) was dissolved in anhydrous DCM (32 mL) under argon and the solution cooled to 0° C. Triethylamine (0.19 mL, 1.40 mmol) was added followed by methanesulfonyl chloride (0.064 mL, 0.82 mmol) and the mixture allowed to warm to rt and stirred for 45 minutes. The mixture was diluted with water, extracted into DCM (3×20 mL) and the combined organic layer washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure. The desired compound was obtained as a yellow oil which was used without further purification in the next step. MS: 670.09 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[CH2:2].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:21])=[C:18]([CH:20]=1)[NH2:19]>N1C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:21])=[C:18]([NH:19][S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH:20]=1
Reactant: Nc1cc(Cl)ccc1F
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: C=Cc1ccc(S(=O)(=O)Nc2cc(Cl)ccc2F)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-vinylbenzene-1-sulfonyl chloride (950 mg, 4.69 mmol) in pyridine (8 mL) at 20° C. was added 5-chloro-2-fluoroaniline (682 mg, 4.69 mmol). The reaction mixture was stirred at 20° C. for 2 hours then evaporated in vacuo and redissolved in ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate (25 mL), dried using a hydrophobic frit and evaporated in vacuo to give the crude product as a yellow oil. The crude was purified by silica (Si) chromatography using a 0-25% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product, 822.7 mg as a white solid. LCMS [LCMS2] Rt 0.86 min, m/z (ES+) 312 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Si:20](OS(C(F)(F)F)(=O)=O)([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2n1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)nc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
6-bromo-1H-pyrrolo[2,3-b]pyridine (587, 275 mg, 1.39 mmol) was dissolved in 4 mL of dry dioxane. DIEA (3 equiv) and TIPS-OTf (2.5 equiv) were added and the reaction was stirred at 50° C. overnight. The reaction was then diluted with 20 mL of ethyl acetate and washed 2 times with 10 mL NaHCO3 (aq., 5%) and once with 10 mL brine. The organic fraction was dried over MgSO4, evaporated and diluted with 5.5 mL of dry toluene 10 mg bromide per 0.2 mL of solution) to use directly in the next reaction step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.[CH2:13](O)[CH2:14][OH:15]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7]3([O:15][CH2:14][CH2:13][O:11]3)[C:6]=2[CH:12]=1
Reactant: OCCO
Reactant: O=C1CCSc2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)C1(CCS2)OCCO1
Yield: 78.8 %

Procedure:
14.7 g (0.060 mol) of the title compound of Step B, 11 mL (0.19 mol) of ethylene glycol (purchased from Aldrich Chemical Company), and 0.4 g (2.10 mmol) of p-toluenesulfonic acid monohydrate (purchased from Aldrich Chemical Company) were added to 125 mL of toluene. The solution was stirred at reflux under nitrogen overnight, and was then washed with 1M sodium carbonate (2×250 mL), followed by water (2×250 mL). The organic layer was dried (Na2SO4), filtered, and evaporated to dryness to yield 13.58 g of the title compound of Step C as an oil. 1H NMR (CDCl3): δ2.2 (m,2H), 3.16 (m,2H), 4.1 (m,2H), 4.2 (m,2H), 7.0-7.6 (3H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[NH:17][C:18]4[C:23]([C:24]=3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=2)[C:7]=1[Br:30].[CH3:32]C([O-])(C)C.[K+].[H-].[Na+]>C1COCC1>[Br:30][C:7]1[C:8]2[C:13](=[CH:12][C:11]([C:16]3[N:17]([CH3:32])[C:18]4[C:23]([C:24]=3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[O:5][CH2:4][C:3]([OH:2])=[O:31]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)OC)ccc3c2)[nH]c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a stirred solution of {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetic acid methyl ester (0.410 g, 0.853 mmol) in THF (20 mL) at 0° C. was added KOt-Bu (0.105 g, 0.938 mmol) followed by Mel (0.064 mL, 1.02 mmol). The reaction was warmed to rt and let stir for 1 h. It appeared by TLC and MS that all the starting material was gone; however, two polar acids (one N-Me and one N—H) had been generated due to hydrolysis in these basic conditions. After concentration, the residue was taken up in DMF (20 mL). Added NaH (0.075 g, 60% by wt., 1.88 mmol) followed by excess Mel to convert all intermediate to one acid (N-Me). After 1 h, the reaction mixture was concentrated and then diluted with EtOAc (200 mL) and 1 N HCl (20 mL). The organic layer was washed with H2O (20 mL) and brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified by preparatory plate chromatography (10% MeOH:CHCl3) to afford the product (0.232 g, 57%) as a yellowish-orange foamy solid, mp>73° C. (decomp.); 1H NMR (DMSO-d6) δ 0.73 (t, J=7.0 Hz, 3H), 1.11-1.20 (m, 4H), 1.50-1.58 (m, 2H), 2.66 (t, J=7.3 Hz, 2H), 3H), 4.93 (s, 2H), 7.07 (t, J=7.6 Hz, 1H), 7.19 (t, J=7.1 Hz, 1H), 7.42-7.48 (m, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.68 (dd, J=1.7, 8.7 Hz, 1H), 7.99 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 11.95-14.75 (bs, 1H); IR (neat) 3050, 2955, 2925, 2850, 1725, 1670, 1600, 1480, 1470, 1430, 1370, 1325, 1275, 1220, 1190, 1145, 1095, 1015, 980, 925, 895, 830, 800, 765, 735, 700, and 665 cm−1; mass spectrum [(+) ESI], m/z 480/482 (M+H)+;
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][CH:12]3[CH:8]([C:9](=[O:17])[NH:10][C:11]3=[O:16])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:18][CH3:19].[CH2:20](O)[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:20]([N:10]1[C:9](=[O:17])[CH:8]2[CH:12]([CH2:13][CH2:14][C:15]3[C:3]([O:2][CH3:1])=[C:4]([O:18][CH3:19])[CH:5]=[CH:6][C:7]=32)[C:11]1=[O:16])[CH3:21]
Reactant: COc1ccc2c(c1OC)CCC1C(=O)NC(=O)C21
Reactant: CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1C(=O)C2CCc3c(ccc(OC)c3OC)C2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
A solution of thee compound of example 3 (1.5 g, 5.8 mmole), absolute ethanol (0.42 mL, 7.3 mmole), triphenylphosphine (1.5 g, 5.8 mmole), and dry THF (9.8 mL) was stirred under N2 at 15° C. as diethyl azodicarboxylate (0.92 mL, 5.8 mmole) was added dropwise. The reaction mixture was stirred at room temperature for 18 hrs., then the crude reaction mixture was chromatographed on silica gel, eluting with CH2Cl2 containing 0.5% EtOH to obtain 0.96 g yellow solid (57%); M+ 289.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[Si:9](Cl)([C:12]([CH3:15])(C)C)([CH3:11])[CH3:10].N1[CH:21]=[CH:20]N=C1>CN(C)C=O>[CH2:12]([Si:9]([CH3:11])([CH3:10])[O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:15][CH2:20][CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: c1c[nH]cn1
Reactant: OCCc1cccs1
Solvent: CN(C)C=O
Product: CCCC[Si](C)(C)OCCc1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2-(2-Thienyl)ethanol (2.6 g) was dissolved in N,N-dimethylformamide (20 ml), followed by the addition of t-butyldimethylsilyl chloride (3.667 g) and imidazole (1.634 g) and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a colorless oil (4.87 g, yield; 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])/[CH:7]=[CH:8]/[CH2:9]I)([CH3:4])([CH3:3])[CH3:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1>[O:15]1[CH2:16][CH2:17][N:12]([CH2:9]/[CH:8]=[CH:7]/[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)/C=C/CI
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/C=C/CN1CCOCC1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 4-iodocrotonic acid tert-butyl ester (310 mg) synthesized according to the method described in Journal of Medicinal Chemistry, 2005, vol. 48, pp. 1107-1131 in tetrahydrofuran (3 mL), morpholine (200 μL) was added under ice cooling, and the mixture was stirred at room temperature for 13 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain (E)-tert-butyl 4-morpholino-2-butenoate (B14, 180 mg).