Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[Na].C(NC1C=CC=CC=1)=O.[C]=O>C1(C)C(C)=CC=CC=1>[CH:17]1[CH:18]=[CH:19][C:14]([NH:13][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:16]=1
Reactant: O=CNc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [C]=O
Agent: [Na]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 10 °C

Procedure:
Into a suitable reactor is charged 78.5 parts by weight (0.5 mole) of p-nitrochlorobenzene, 93.8 parts by weight (0.65 mole) of sodium formanilide, 96 parts by weight (0.8 mole) of formanilide. The mixture is gradually heated and stirred; and, at about 134° C., evolution of carbon monoxide begins. Heating is continued until the temperature reaches 180°, at which temperature the reaction mixture becomes self-heating. Stirring is continued at 180°. After about two and one-half hours, 18 parts by weight of carbon monoxide are evolved; and reaction is stopped, xylene added, and the xylene solution washed with 250 parts by weight of water, separated from the water and cooled to 10° C. The crystals of 4-nitrodiphenylamine which form are separated by filtration and washed with a little xylene. From the mother liquor a second crop of 4-nitrodiphenylamine is recovered. The yield of 4-nitrodiphenylamine is 86% and conversion of p-nitrochlorobenzene is 96%. The presence of the formanilide reduces tertiary amine byproduct which becomes excessive in the case of reaction in dimethylformamide, for example.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]Cl)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=1>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[S:20][C:21]([S:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:22][CH:23]=2)=[CH:17][CH:18]=1
Reactant: Brc1ccc(-c2cccs2)cc1
Reactant: O=[N+]([O-])c1cccc(SCl)c1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Sc2ccc(-c3ccc(Br)cc3)s2)c1
Yield: 43.6 %

Procedure:
To a solution of 21.2 g (0.112 mole) of m-nitrobenzenesulfenyl chloride in 160 ml of carbon tetrachioride were added 24.5 g (0.103 mole) of 2-(p-bromophenyl)thiophene and 0.1 g of iron powder. The reaction mixture was allowed to stand one week at room temperature. Evaporation of the solvent and recrystallization of the residue from 140 ml of ethyl acetate gave 17.6 g (44%) of 2-(p-bromophenyl)-5-(m-nitrophenylthio)thiophene, m.p. 120°-122° C.
Reaction SMILES: C[N:2](C)[C:3]([CH3:24])=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[C:26]1([NH:32]N)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:24][C:3]1[CH:4]=[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)[N:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:2]=1
Reactant: NNc1ccccc1
Reactant: CC(=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O)N(C)C
Solvent: CC(=O)O
Product: Cc1cc(-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)n(-c2ccccc2)n1
Temperature: 25 °C
Yield: 15.7 %

Procedure:
A solution of 3-[3-(dimethylamino)but-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.270 g, 0.77 mmol) and phenyl hydrazine (0.200 mL, 2.0 mmol) in acetic acid (5.0 mL) was heated under microwave conditions at 120° C. for 10 min. After this time, the reaction was cooled to room temperature and concentrated onto silica gel. The crude product purified by column chromatography (silica gel, 50:50 ethyl acetate/hexanes to ethyl acetate) to separate the two isomers, followed by preparative reverse phase HPLC and crystallization from diethyl ether to give 3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.048 g, 16%) as a white solid. 1H NMR (300 MHz, CDCl3). δ ppm 2.42 (s, 3H), 6.73 (d, J=7.9 Hz, 1H), 6.99 (dd, J=1.7, 8.1 Hz, 1H), 7.18 (br s, 1H), 7.21 (s, 1H), 7.30-7.49 (m, 6H), 7.55 (d, J=7.8 Hz, 1H), 8.19 (d, J=7.9 Hz, 1H); APCI MS m/z 397 [M+H]+; mp 167-168° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.Cl.[CH3:15][N:16]([CH3:21])[C:17](=[O:20])[CH2:18][NH2:19]>C(N(CC)CC)C>[CH3:15][N:16]([CH3:21])[C:17]([CH2:18][NH:19][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=[O:20]
Reactant: CN(C)C(=O)CN
Reactant: CCOC(=O)c1ccnc(C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccnc(CNCC(=O)N(C)C)c1

Procedure:
By General Procedure A from Ethyl 2-formylpyridine-4-carboxylate, N,N-dimethylglycineamide hydrochloride, and triethylamine. Purification by column chromatography with a gradient of 0-10% MeOH in DCM gave the title product as yellow oil. 1H NMR (300 MHz, chloroform-d): δ ppm 8.69 (s, 1H), 7.94 (s, 1H), 7.72 (d, 1H), 4.40 (q, 2H), 4.03 (s, 2H), 3.48 (s, 2H), 2.95 (d, 6H), 1.40 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][NH:20][CH3:21])[C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=3[S:10]2)=[CH:5][CH:4]=1.C(Cl)Cl.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[CH2:34][CH2:35]Cl.[I-].[Na+]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:21])[CH2:35][CH2:34][C:33]3[CH:37]=[CH:38][CH:39]=[C:31]([O:30][CH3:29])[CH:32]=3)[C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1cccc(CCCl)c1
Reactant: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)CCc3cccc(OC)c3)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.3 %

Procedure:
A mixture of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (1.07 g), methylene chloride (20 ml), 3-methoxyphenethyl chloride (500 mg), triethylamine (313 mg) and sodium iodide (30 mg) is stirred at room temperature for 48 hours. After the completion of the reaction, the solvent is distilled off, and the resulting residue is purified by silica gel column chromatography (eluent; chloroform: ethanol=15:1) to give (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-{2-[N-methyl-N-(3-methoxyphenethyl)amino]ethyl}-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (625 mg) as oily product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>O1CCCC1>[C:21]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 1-benzylpiperazine (1 g) and triethylamine (1.19 mL) in tetrahydrofuran (20 mL) was stirred at room temperature under argon. Acetyl chloride (0.424 mL) was added and the mixture was stirred for 10 minutes. The reaction was filtered and the white solid washed with ether. The filtrate was concentrated at reduced pressure to give the title compound as a colourless oil (1.2 g).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O1CCO[CH2:26][CH2:25]1>O.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>[Cl:8][C:7]1[C:2]([CH:25]=[CH2:26])=[N:3][CH:4]=[C:5]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:6]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(Cl)c(Cl)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: [K+]
Solvent: O
Product: C=Cc1ncc(CO[Si](C)(C)C(C)(C)C)cc1Cl
Yield: 49 %

Procedure:
In a sealed tube charged with a solution of 2,3-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)pyridine (1500 mg, 5.13 mmol) in 1,4-dioxane (20 ml) was added K2CO3 (2128 mg, 15.40 mmol). The mixture was degassed with N2, then vinylboronic anhydride pyridine complex (1235 mg, 5.13 mmol) and tetrakis(triphenylphosphine)palladium (0) (178 mg, 0.154 mmol) were added. The reaction mixture was stirred at reflux temperature overnight. The crude was diluted with water and extracted twice with EtOAc. The combined organic phases were washed with water and with sat. NaCl, dried over anhydrous MgSO4 and concentrated under vacuum. Purification by flash chromatography using Flashmaster II, a 50 g Merck silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded 3-chloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-ethenylpyridine (754 mg, 49%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Na+].[I-].Br[CH:35]([CH2:41][CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH4+].[Cl-]>CC(C)=O.O>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][CH2:41][CH2:42][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:20]=[CH:21][C:22]([CH2:24][CH3:25])=[CH:23][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:19])[CH:14]=1)[CH3:40]
Reactant: CCc1ccc(Oc2ccc(O)cc2F)c(OCc2ccccc2)c1
Reactant: CCOC(=O)C(Br)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(Oc2ccc(CC)cc2OCc2ccccc2)c(F)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 73.3 %

Procedure:
To a solution of 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenol (0.30 mmol; 100 mg) in dry acetone (2 mL), under argon, were added potassium carbonate (0.35 mmol; 49 mg), NaI (0.06 mmol; 9 mg) and ethyl bromobutyrate (0.35 mmol; 51 μL). The reaction was stirred 14 hours at 60° C. Water (100 μL) and tetrabutylammonium hydroxide (0.03 mmol; 8 mg) were added and the mixture was stirred 16 hours at 60° C. The reaction was hydrolysed with NH4Cl sat. (5 mL) and extracted with ethyl acetate (3*3 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo. The title compound (100 mg; 0.22 mmol; 75%) was obtained as a yellow oil, after purification by preparative TLC (cyclohexane/ethyl acetate: 7/3).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[N:20][NH:21][CH:22]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO.O>[CH3:9][S:8][C:4]1[N:3]=[C:2]([C:18]2[CH:19]=[N:20][NH:21][CH:22]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccc(Cl)n1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1nccc(-c2cn[nH]c2)n1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
4-Chloro-2-methylsulfanyl-pyrimidine (1.4 g, 8.8 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 10.3 mmol), Na2CO3 (2.8 g, 26.4) and Pd(PPh3)4 (500 mg, 0.43 mmol) were combined in a solvent comprised of toluene/EtOH/H2O (4/4/1, 20 mL). The mixture was degassed by applying a vacuum and backfilling the headspace with argon. The reaction mixture was heated overnight at 100° C. The insoluble portion was filtered and the filtrate was concentrated and purified by silica gel chromatography to provide 2-(methylthio)-4-(1H-pyrazol-4-yl)pyrimidine (1.2 g, 71% yield). 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=6.4 Hz, 1H), 8.24 (s, 1H), 7.23 (s, 1H), 7.05 (d, J=6.4 Hz, 1H), 2.51 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[N:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([Br:24])[C:21]=1[O:22][CH3:23])[C:16](Cl)=[O:17].C(N(CC)CC)C.O>ClCCl>[Br:1][C:2]1[CH:11]=[N:10][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:16]([C:15]3[CH:19]=[C:20]([Br:24])[C:21]([O:22][CH3:23])=[C:13]([Br:12])[CH:14]=3)=[O:17])[C:4]=2[CH:3]=1
Reactant: Brc1cnc2c(c1)NCCO2
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(Br)cc32)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a 10 ml flask, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (37 mg, 0.172 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (113 mg, 0.344 mmol) were dissolved in dichloromethane (0.5 ml). Triethylamine (0.120 ml, 0.860 mmol) was added thereto and then stirred at room temperature for 1 hour. After completion of the reaction by adding water to the reaction mixture, the organic layer was extracted with dichloromethane and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:ethyl acetate:n-hexane=1:2:5. The fractions containing the product were collected and evaporated to obtain white solid (55 mg, 63%).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH2:19][N:20]=[C:12]3[C:11]3(OCCC[O:21]3)[C:10]=2[CH:9]=1.[NH4+].[OH-]>>[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH2:19][N:20]=[C:12]3[C:11](=[O:21])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccc2c(c1)C(=O)C1=NCCCN12
Reaction time: 0.58 h

Procedure:
To cold concentrated H2SO4 (4 mL) was added 8′-methoxy-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole] (0.204 g, 0.744 mmol) portion-wise over a period of 15 minutes with cooling in an ice bath. After stirring for 35 min., the reaction was poured onto ice and basified with concentrated NH4OH keeping the reaction cold with ice. The reaction mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, and filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (98.5/1/0.5) to give the title compound as a bright red solid. Anal: Calc'd for C12H12N2O2 0.1H2O: C, 66.10; H, 5.64; N, 12.85. Found: C, 65.81; H, 5.28; N, 12.78. NMR (300 Mz, DMSO-d6): consistent. MS: (APCI+) m/z 217[M+H]. m.p.: 152° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:13][CH:12]=3)=[N:9][N:8]=2)[CH:7]=1
Reactant: O=C(NNc1ccc(F)cn1)c1ccc(CN2CCOCC2)cc1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc2nnc(-c3ccc(CN4CCOCC4)cc3)n2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
To an ice cold solution of Intermediate 18a (980 mg, 2.97 mmol) in THF (15 mL) was added triphenylphosphine (1.56 g, 5.94 mmol), triethylamine (1.65 mL, 11.9 mmol) and hexachloroethane (1.40 g, 5.94 mmol). The reaction was stirred for 90 min then partitioned between EtOAc (75 mL) and water (75 mL) and the aqueous layer extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo then purified by SCX-2, washing with MeOH and eluting with 2M NH3 in MeOH to give the title compound (640 mg, 2.05 mmol, 69%). LCMS (Method 2): Rt 0.28, 1.32, m/z 313 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][C@@H:27]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38](Br)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=1)=[O:31])[CH3:28].CN(C=O)C>C(OCC)C.[Cu]I.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>[CH3:24][O:25][CH2:26][C@@H:27]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[CH:33]=1)=[O:31])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
6-Fluoro-3-tributylstannyl-1H-indazole (1.10 g, 2.59 mmol), copper(I) iodide (24 mg, 0.13 mmol,) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (560 mg, 1.26 mmol) were combined with DMF (6 mL) to give a yellow solution. The mixture was degassed with bubbling nitrogen for 10 min, then tetrakis(triphenylphosphine)palladium (0) (73 mg, 0.06 mmol) was added and the reaction was stirred under nitrogen at 80° C. for 2 h. The reaction mixture was cooled, diluted with diethyl ether (60 mL) and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane with 0.5% ammonium hydroxide) to obtain 580 mg (92%) of 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. MS: (M+H)+=499.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:22][C:21]2[CH:23]=[CH:24][C:18]([CH3:17])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccc(C)cc2)c1
Yield: 79.3 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) (2.0 g, 7.23 mmol) in dioxane (10 ml) was added to a mixture of 4methylaniline (0.77 g, 7.23 mmol) in dioxane (20 ml) and NaHCO3 (1.2 g, 14.5 mmol) in water (20 ml), and the resultant solution was stirred at room temperature for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with dichloromethane-ethyl acetate (20:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (1.9 g, 79%). 1H NMR (DMSO-d6, HMDSO), δ: 2.16 (3H, s); 3.69 (3H, s); 6.65 (1H, d, J=16.0 Hz); 7.00 (4H, s); 7.49-8.11 (5H, m); 10.14 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([OH:19])[C:11]=1[CH2:20][CH2:21][CH3:22].[S:24]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33]OS(=O)(=O)C)(=[O:27])(=[O:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([O:19][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][S:24]([CH3:25])(=[O:27])=[O:26])[C:11]=1[CH2:20][CH2:21][CH3:22]
Reactant: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1O
Reactant: CS(=O)(=O)OCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Yield: 81.9 %

Procedure:
A mixture of 4.0 g (0.012 mole) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester, 16.3 g (0.062 mole) of diethyleneglycol dimesylate and 3.4 g (0.024 mole) of anhydrous potassium carbonate in 90 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 22 hours. The solvents were removed in vacuo and the residue was treated with 100 ml of 50% ethyl acetate-hexane. Some of the residual starting dimesylate was insoluble and was removed by filtration. The filtrate was concentrated in vacuo and the residual oil was purified by HPLC to give 4.8 g (80% yield) of 6-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]hexanoic acid methyl ester as an oil.
Reaction SMILES: Cl.N[C@@H]1CC[C@H](NC(=O)C[NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)CC1.OC1(C2C=CC=CN=2)CCC(=O)CC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(Cl)Cl>[F:21][C:20]([F:22])([F:23])[C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH2:12])=[O:24]
Reactant: N[C@H]1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 140.2 %

Procedure:
N-(2-(cis-4-Amino-cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide hydrochloride (50 mg, 0.132 mmol, 1 eq), 4-hydroxy-4-(pyridin-2-yl)cyclohexanone (25 mg, 0.132 mmol, 1 eq) and sodium triacetoxyborohydride (56 mg, 0.263 mmol, 2 eq) were stirred in 2% acetic acid/methylene chloride (10 mL) at room temperature for 20 hours. Worked up by adding saturated sodium bicarbonate (10 mL). Stirred 10 minutes then extracted 3 times with methylene chloride (10 mL). The organic layers were combined, dried (sodium sulfate) and stripped to give an oil. Purified over silica gel in 100% ethyl acetate to 4:1 methylene chloride/methanol to give N-(2-(cis-4-(cis- and trans-4-hydroxy-4-(pyridin-2-yl)cyclohexylamino)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide (35 mg) as a white solid. MS found: (M+H)+=519.27.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C([Mg]Cl)(C)C.[O:19]=[C:20]1[CH2:26][CH:25]2[CH2:27][CH:21]1[CH2:22][N:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24]2>C1COCC1>[OH:19][C:20]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)[CH2:26][CH:25]2[CH2:27][CH:21]1[CH2:22][N:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24]2
Reactant: Brc1cncc(-c2ccccc2)c1
Reactant: CCOC(=O)N1CC2CC(=O)C(C2)C1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)N1CC2CC(C1)C(O)(c1cncc(-c3ccccc3)c1)C2
Yield: 14.2 %

Procedure:
To a solution of 3-bromo-5-phenylpyridine (0.23 g, 1.0 mmol) in THF (5 mL) at ambient temperature was added 2.0 M isopropylmagnesium chloride in THF (0.5 mL). The reaction was stirred for an hour under nitrogen. Then a solution of ethyl 6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (0.21 g, 1.0 mmol) in THF (2 mL) was added. The mixture was stirred at ambient temperature overnight, concentrated and quenched with water (1 mL). The mixture was extracted with chloroform (2×10 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. The compound was purified by silica gel column chromatography (1:1 ethyl acetate/hexane) to yield 50 mg of product (13%).