Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[C:15]2[CH:16]=[CH:17][CH2:18][O:19][C:14]=2[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[C:1]([CH:3]([CH2:9][C:10]1[C:15]2[CH:16]=[CH:17][CH2:18][O:19][C:14]=2[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=Cc1cc(OC)c(OC)c2c1C=CCO2
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)Cc1cc(OC)c(OC)c2c1C=CCO2
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-cyano-3-(7,8-dimethoxy-2H-1-benzopyran-5-yl)-propenoate (19.8 g, 0.63 mole) in ethanol (500 mL) under nitrogen was treated with acidic acid (4 mL) and a trace of bromocresol green and heated to reflux. Heating was discontinued and sodium cyanoborohydride (4.4 g, 0.07 mole) in ethanol (100 mL) was co-added with additional acetic acid (11 mL). The mixture was stirred under nitrogen for 2 hr, acetic acid (10 mL) added and the ethanol removed under reduced pressure. The resultant yellow solid was taken up in ethyl acetate (250 mL) and successively extracted with water (125 mL), saturated sodium bicarbonate (3×100 mL) and water (100 mL), then dried over magnesium sulfate. The volatiles were removed under reduced pressure to leave an amber oil, 18.22 g (91.4%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Na+].[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:1][C:2]1[C:3]([CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(Cl)c(COC2CCCCO2)c2cc[nH]c12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(Cl)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-indole (8.95 g, 32 mmol) in CH2Cl2 (150 mL), at 0° C. was added NaOH (2.56 g, 64.0 mmol), followed by triethylbenzylammonium chloride (0.729 g, 3.20 mmol) and TsCl (12.20 g, 64.0 mmol). The mixture was then stirred at room temperature. After 17 h, additional NaOH (1.28 g, 32.0 mmol), and TsCl (6.10 g, 32.0 mmol) were added. The mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with H2O, and was vigorously stirred for 1 h. The mixture was diluted with CH2Cl2 and the organic layer was successively washed with H2O and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave the crude product, which was purified by FCC [heptane/(30% EtOAc in CH2Cl2)=82/18 then 79/21] to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 7.84 (d, J=3.79 Hz, 1H), 7.67 (d, J=8.20 Hz, 1H), 7.59 (d, J=8.59 Hz, 1H), 7.48 (d, J=8.20 Hz, 1H), 7.33 (d, J=8.50 Hz, 1H), 7.13 (s, 1H), 6.97 (d, J=3.79 Hz, 1H), 4.97 (d, J=11.37 Hz, 1H), 4.76 (d, J=11.37 Hz, 1H), 4.61-4.70 (m, 1H), 3.79-3.91 (m, 1H), 3.40-3.52 (m, 1H), 2.53 (s, 3H), 2.36 (s, 3H), 1.58-1.75 (m, 2H), 1.38-1.58 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33](OC)=[O:34])=[CH:31][CH:30]=3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[OH-].[Na+].O1CCCC1.Cl>CO>[OH:34][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:18]2[C:17](=[O:39])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)=[CH:38][CH:37]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C(=O)OC)cc2)c2ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(CO)cc2)c2ncnn12
Temperature: 50 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A mixture of methyl 4-({6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}methyl)benzoate (2.8 g), 1N aqueous sodium hydroxide solution (30 mL), tetrahydrofuran (30 mL) and methanol (30 mL) was stirred at 50° C. for 3 hr. 1 N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (50 mL), N-methylmorpholine (0.67 mL) and ethyl chlorocarbonate (0.58 mL) was added at 0° C., and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was cooled to −15° C., sodium borohydride (0.57 g) and methanol (10 mL) were added, and the mixture was allowed to gradually warm to room temperature. The reaction mixture was extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.86 g, 70%).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.[CH:12](O)=O.Cl.Br>O>[OH:3][C:4]1[CH:9]=[CH:8][C:7]2[NH:10][CH:12]=[N:11][C:6]=2[CH:5]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: O=CO
Agent: Br
Agent: Cl
Solvent: O
Product: Oc1ccc2[nH]cnc2c1
Yield: 88 %

Procedure:
Twenty grams (0.114 mole) of 4-methoxy-1,2-phenylenediamine hydrochloride was refluxed with 30 ml of 88% formic acid, 15 ml of concentrated HCl and 90 ml of water for eight hours. The solvent was then removed in vacuo and the residue was treated with 100 ml of concentrated NH4OH, extracted with dichloromethane (2×200 ml), dried over MgSO4 and concentrated to leave a thick oil which was converted to its HCl salt, mp 212°-5° C. (12.8 g, 60%). This compound (12.0 g, 65 mmole) was refluxed with 125 ml of concentrated HBr, under argon, for three hours. After evaporation in vacuo, the residue was dissolved in water, neutralized with solid NaHCO3. The product deposited was recrystallized from water, yielding 7.7 g (88%) of 5-hydroxy-1H-benzimidazole, mp 216°-8° C.
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]4[NH:21][C:20]([NH:22]C(=O)OC)=[N:19][C:16]4=[N:17][CH:18]=3)=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:28]1[C:37]2[CH2:36][CH2:35][C@H:34]([CH2:38][CH3:39])[CH2:33][C:32]=2[N:31]=[CH:30][N:29]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.CO>[CH2:38]([C@@H:34]1[CH2:33][C:32]2[N:31]=[CH:30][N:29]=[C:28]([N:5]3[CH2:6][C:7]4[CH:12]=[C:11]([C:13]5[CH:14]=[C:15]6[NH:21][C:20]([NH2:22])=[N:19][C:16]6=[N:17][CH:18]=5)[CH:10]=[CH:9][C:8]=4[O:2][CH2:3][CH2:4]3)[C:37]=2[CH2:36][CH2:35]1)[CH3:39]
Reactant: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Reactant: CC[C@H]1CCc2c(Cl)ncnc2C1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(-c4cnc5nc(N)[nH]c5c4)cc3C2)C1
Temperature: 25 °C

Procedure:
A mixture of methyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate hydrochloride (84 mg, 0.23 mmol, (7S)-4-chloro-7-ethyl-5,6,7,8-tetrahydroquinazoline (reagent preparation 3) (35 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.90 mmol) in N-methyl-2-pyrrolidone (2.0 mL) was reacted in a microwave apparatus (250 W) for 5 min. at 110° C. After cooling to room temperature the reaction mixture was diluted with methanol (2 mL) and purified by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) to give 6-{4-[(7S)-7-ethyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-imidazo[4,5-b]pyridin-2-amine. 1H NMR (400 MHz, Methanol-d4): 8.33 (s, 1H), 8.13 (brs, 1H), 7.63 (s, 1H), 7.50 (brs, 1H), 7.31 (d, 1H), 7.04 (d, 1H), 4.75 (b, 2H), 4.44 (m, 1H), 4.24 (m, 1H), 3.99 to 3.86 (m, 2H), 2.94 to 2.86 (m, 2H), 2.60 (m, 1H), 2.28 (m, 1H), 1.97 (m, 1H), 1.75 (m, 1H), 1.36 (m, 2H), 1.14 (m, 1H), 0.97 (t, 3H); MS (EI) for C25H27N7O: 442 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)=O.C(OP([CH2:31][C:32]#[N:33])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)=[CH:31][C:32]#[N:33]
Reactant: COc1cc(OC)cc(C(=O)c2cc(OC)ccc2OC)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2cc(OC)ccc2OC)c1
Yield: 89 %

Procedure:
(2,5-dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (0.92 g, 3.04 mmol), cyanomethylphosphonic acid diethyl ester (0.96 ml, 6.09 mmol) in anhydrous THF (15 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 6.09 ml, 6.09 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 25% EtOAc in hexane in about 20 min.) to give a brown oil, which was lyophilized to give 3-(2,5-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as a light yellow solid (0.88 g, 89%): δ 1HNMR (CDCl3) δ 6.94-6.43 (m, 12H, Ar), 5.89 (s, 0.65H, double proton of one isomer), 5.87 (s, 0.84H, double proton of the other isomer), 3.83-3.67 (multiple singlets, 24H, 8OCH3). The product was a mixture of two isomers with the ratio of 43.6%:56.4%; 13C NMR (CDCl3) δ 161.0, 160.7, 159.9, 159.8, 153.6, 153.5, 151.9, 151.2, 140.3, 140.0, 128.9, 126.9, 117.9, 117.5, 117.3, 116.3, 116.2, 115.8, 113.2, 107.0, 105.8, 102.0, 102.0, 98.3, 97.4, 56.5, 56.0, 56.0, 55.6, 55.6; Anal. Calcd. For C19H19NO4: C, 70.14; H, 5.89; N, 4.30. Found: C, 69.78; H, 5.77; N, 4.20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=2)[N:12]=[CH:11]1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)Cl>[Br:30][C:14]1[N:10]([CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:11]=[N:12][C:13]=1[C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=1
Reactant: N#Cc1ccnc(-c2cn(CCc3ccccc3Cl)cn2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#Cc1ccnc(-c2ncn(CCc3ccccc3Cl)c2Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 2-[1-[2-(2-chlorophenyl)ethyl]imidazol-4-yl]pyridine-4-carbonitrile (1 eq) in DCM (10 mL) was added NBS (1.05 eq) at rt and stirred for 3 hr at rt. Washed by H2O, dried and concentrated to afford the title compound (95%). [M+H] Calc'd for C17H12BrClN4, 387. Found, 387.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]3[C:15]([NH:16][C@H:17]4[C@@H:21]([CH2:22][F:23])[CH2:20][NH:19][CH2:18]4)=[C:14]([C:24]([NH2:26])=[O:25])[CH:13]=[N:12][N:11]3[CH:27]=2)[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O.[C:35]([C:37]1([C:40](O)=[O:41])[CH2:39][CH2:38]1)#[N:36].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>CN(C=O)C>[C:35]([C:37]1([C:40]([N:19]2[CH2:20][C@H:21]([CH2:22][F:23])[C@H:17]([NH:16][C:15]3[C:10]4[N:11]([CH:27]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=5)[N:9]=4)[N:12]=[CH:13][C:14]=3[C:24]([NH2:26])=[O:25])[CH2:18]2)=[O:41])[CH2:39][CH2:38]1)#[N:36]
Reactant: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CNC[C@@H]4CF)c3n2)cn1
Reactant: N#CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CN(C(=O)C5(C#N)CC5)C[C@@H]4CF)c3n2)cn1
Yield: 59.2 %

Procedure:
A solution of 2-(1-ethyl-1H-pyrazol-4-yl)-8-(((3S,4S)-4-(fluoromethyl)pyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, TFA (15 mg, 0.031 mmol), 1-cyanocyclopropanecarboxylic acid (6.85 mg, 0.062 mmol), HATU (17.59 mg, 0.046 mmol) and DIPEA (0.027 ml, 0.154 mmol) in DMF (0.4 ml) in a reaction vial was stirred at room temperature for 135 min. The crude material was purified via preparative LC/MS (Method A). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound of Example 56 (8.5 mg, 59.2% yield). 1H NMR (500 MHz, DMSO-d6, two rotamers) δ 10.74 (d, J=8.9 Hz, 1H), 10.70 (d, J=8.4 Hz, 1H), 8.49 (br. s., 1H), 8.47 (br. s., 1H), 8.29 (br. s., 1H), 8.28 (br. s., 1H), 8.17 (s, 2H), 8.02 (br. s., 2H), 7.90 (s, 2H), 7.43 (br. s., 2H), 6.14 (br. s., 1H), 6.06 (br. s., 1H), 4.75 (d, J=5.4 Hz, 1H), 4.69 (d, J=6.4 Hz, 2H), 4.59 (d, J=6.9 Hz, 2H), 4.29 (dd, J=9.9, 5.9 Hz, 1H), 4.17 (q, J=7.4 Hz, 4H), 3.91-3.80 (m, 3H), 3.76 (dd, J=12.4, 8.9 Hz, 1H), 3.55 (d, J=10.9 Hz, 1H), 3.47 (dd, J=12.4, 7.4 Hz, 1H), 3.15 (dd, J=13.1, 6.2 Hz, 1H), 3.10-2.99 (m, 1H), 1.63 (br. s., 2H), 1.60-1.49 (m, 6H), 1.40 (t, J=7.2 Hz, 6H). HPLC/LCMS (Method F): m/z 466.21 ([M+H]+), Rt. 1.118 min.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](N)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(O)(=[O:24])C>O>[O:1]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:24])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CC(Oc1ccc(COc2ccccc2)cc1)C(N)=O
Agent: Cl
Solvent: O
Product: CC(Oc1ccc(COc2ccccc2)cc1)C(=O)O

Procedure:
A mixture of 1 g. of 2-(4-phenoxymethylphenoxy)-propionamide, 2 ml. of concentrated hydrochlorid acid, and 2 ml. of acetic acid is refluxed for 48 hours and, after adding water, worked up as usual, yielding 2-(4-phenoxymethylphenoxy)-propionic acid.
Reaction SMILES: [Mg].CN(C)P(N(C)C)(N(C)C)=O.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1Cl.II.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25].C([O-])(O)=O.[Na+]>>[CH3:25][Si:24]([CH3:27])([CH3:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Si:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)Cl
Reactant: Clc1ccccc1Cl
Agent: II
Agent: O=C([O-])O
Agent: [Mg]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C[Si](C)(C)c1ccccc1[Si](C)(C)C
Temperature: 70 °C
Yield: 54.13 %

Procedure:
Magnesium (9.72 g, 400 mmol), hexamethylphosphoramide (HMPA) (80 mL, 460 mmol), 1,2-dichlorobenzene (14.76 g, 100 mmol), and a catalytic amount of I2 were combined in a 500 mL round bottomed flask and heated to 70° C. with stirring. Chlorotrimethylsilane was added dropwise to the solution at 70° C. The solution was stirred for an additional 30 minutes and then heated to 100° C. for 48 h. After cooling, the reaction mixture was poured over ice and NaHCO3. The Mg and precipitate were filtered off and the filtrate was extracted with ether (3×, 200 mL). The organic phase was washed with water (2×, 400 mL) and brine (1×, 400 mL) and dried with Na2SO4 and concentrated. The product was distilled under reduced pressure at 128-133° C. to yield a light yellow oil (12.0426 g, 54.13%). 1H NMR (300 MHz, CDCl3) δ 7.85 (dd, 2H, J=3.4 Hz, J=5.5 Hz, ArH), 7.49 (dd, 2H, J=3.4 Hz, J=5.5 Hz, ArH), 0.55 (s, 18H, CH3); 13C NMR (300 MHz, CDCl3) δ 145.98, 135.17, 127.76, 1.96
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].[CH:21]1(C(OC)=O)CCC[CH2:22]1>>[CH2:16]([C:2]1([CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:10])([CH3:11])[CH3:12])=[O:6])[CH2:20][CH2:22][CH2:21][CH2:1]1)[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)C1CCCC1
Product: C=CCCC1(COC(=O)N[C@H](C(=O)O)C(C)(C)C)CCCC1

Procedure:
N-{[(1-But-3-en-1-ylcyclopentyl)methoxy]carbonyl}-3-methyl-L-valine was prepared according to the procedure for N-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine by using methyl cyclopentanecarboxylate instead of ethyl isobutyrate in Step 1. LRMS (ESI) m/z 312.3 [(M+H)+; calcd for C17H30NO4: 312.2].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:12]3=[CH:13][N:14]=[C:15]([C:17]([O:19]CC)=O)[CH:16]=[C:11]3[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.N1C2=CN=C(C(OCC)=O)C=C2C=C1.ClC1SC(CCl)=CC=1.ClC1C(F)=C(C(F)=CC=1)CN1C2=CN=C(C(O)=O)C=C2C=C1.ClC1C(F)=C(C(F)=CC=1)CN1C2=CN=C(C([NH:82][OH:83])=O)C=C2C=C1.ClC1SC(CN2C3=CN=C(C(O)=O)C=C3C=C2)=CC=1.Cl.NO>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:12]3=[CH:13][N:14]=[C:15]([C:17]([NH:82][OH:83])=[O:19])[CH:16]=[C:11]3[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccn(Cc3ccc(Cl)s3)c2cn1
Reactant: O=C(NO)c1cc2ccn(Cc3c(F)ccc(Cl)c3F)c2cn1
Agent: CCOC(=O)c1cc2cc[nH]c2cn1
Agent: Cl
Agent: ClCc1ccc(Cl)s1
Product: O=C(NO)c1cc2ccn(Cc3ccc(Cl)s3)c2cn1

Procedure:
Ethyl 1-(5-chloro-thiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate. The title compound was prepared by alkylation of ethyl 1H-pyrrolo[2,3-c]pyridine-5-carboxylate with 2-chloro-5-(chloromethyl)-thiophene in a manner similar to step (a) of example 1. 1H NMR (CD3O D) δ: 8.89 (s, 1H), 8.48 (s, 1H), 7.72 (d, 1H, J=3.2 Hz), 6.99 (d, 1H, J=3.8 Hz)), 6.87 (d, 1H, J=4.8 Hz), 6.75(d, 1H, J=3.2 Hz), 5.73 (s, 2H), 4.46 (q, 2H, J=7.2 Hz), 1.46 (t, 3H, J=7.2 Hz). LCMS (API-ES, M+H+): 321.0. (b) 1-(5-Chloro-thiophen-2-yl methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound was prepared by hydrolysis of ethyl 1-(5-chloro-thiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate in a manner similar to step (b) of example 1. 1H NMR (DMSO-d6): δ: 9.05 (s, 1H), 8.34 (s, 1H), 7.88 (d, 1H, J=3.0 Hz), 7.12 (d, 1H, J=3.8 Hz), 7.01 (d, 1H, J=4.0 Hz), 6.75 (d, 1H, J=3.2 Hz), 5.78 (s, 2H). LCMS (API-ES, M+H+): 293.0. (c) 1-(5-Chloro-thiophen-2-yl methyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. The title compound was prepared by coupling of 1-(1-(5-Chloro-thiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (DMSO-d6) δ: 11.15 (s, 1H), 8.93 (s, 2H), 8.21 (s, 1H), 7.81 (d, 1H, J=2.1 Hz), 7.10 (d, 1H, J=3.6 Hz), 6.99 (d, 1H, J=2.8 Hz), 6.70 (d, 1H, J=3.0 Hz), 5.76 (s, 2H). LCMS (API-ES, M+H+): 308.0. HRMS calcd for C13H11N3O2SCI (M+H) 308.0261, found 308.0265. Anal. (C13H10CIN3O2S) C, H, N. HPLC: 100% purity.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:11]=[CH:10][NH:9][CH:8]=1)=[O:6].I[CH:13]([CH3:15])[CH3:14]>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[CH:11]=[CH:10][N:9]([CH:13]([CH3:15])[CH3:14])[CH:8]=1)=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(C(C)C)c1
Reaction time: 1.5 h

Procedure:
NaH (58.1 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid methyl ester [2703-17-5] (38.8 mmol) in DMF (80 mL) at 0° C. and the mixture was stirred for 1.5 h. 2-Iodo-propane (78 mmol) was added and the mixture was stirred at rt for 4 h. The reaction mixture was quenched with 1N aqueous KHSO4 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as an orange-brown oil. tR: 3.80 min (HPLC 1); ESI-MS: tR=0.92 min, [M+H]+ 168 (LC-MS 1); TLC: Rf=0.22 (1:6 EtOAc/heptanes).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([OH:19])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][C:17](=[O:19])[C:20]=2[CH:21]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2ccccc2CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc2c(c1)C(=O)Cc1ccccc1O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1.0 g of 2-(4-methylsulfonylphenoxy)phenylacetic acid and 10 ml of polyphosphoric acid under nitrogen is stirred at 90°-100° C. for 2 hours. The reaction mixture is permitted to cool and then poured into 100 ml of an ice-water slurry. The aqueous solution is basified with 20% sodium hydroxide before being extracted with methylene chloride. The combined extracts are dried and then evaporated to dryness leaving an oil. The oil is chromatographed through a silica gel/methylene chloride column with 2% methanol in methylene chloride. The chromatographed solution is evaporated to dryness leaving an oil which solidifies on standing. The solid is triturated with pentane to provide 10,11-dihydro-2-methylsulfonyl-11-oxodibenz[b,f]oxepin, mp 105°-106° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[OH:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=1>>[OH:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc(O)c1
Product: O=C(Cc1cccc(O)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3-hydroxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.31-8.30 (s, 1H), 8.05-8.01 (m, 1H), 8.01-7.96 (m, 1H), 7.93-7.89 (s, 1H), 7.17-7.13 (m, 1H), 6.86-6.77 (m, 2H), 6.68 (dd, J=7.8, 2.0, 1H), 3.87-3.78 (m, 4H), 3.57 (s, 2H), 3.14-3.03 (m, 4H); MS (ESI+) M/Z 381 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:8][CH2:7]2.[Cl-].[Li+].[CH2:35]([Sn](CC)(CC)CC)[CH3:36]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:35]([C:2]1[C:3]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12](=[O:17])[C:13]([F:15])([F:14])[F:16])[CH2:8][CH2:7]2)[CH3:36]
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2Br)CN(C(=O)C(F)(F)F)CC3)cc1C(F)(F)F
Reactant: CC[Sn](CC)(CC)CC
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCc1c(NC(=O)c2ccc(OC)c(C(F)(F)F)c2)ccc2c1CN(C(=O)C(F)(F)F)CC2
Temperature: 120 °C
Reaction time: 20 h
Yield: 38 %

Procedure:
N-(8-Bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.525 g), lithium chloride (0.127 g), tetraethyltin (0.47 g) and bis(triphenylphosphine)palladium(II)chloride (0.04 g) were combined in dimethylformamide (10 ml) and the mixture stirred under argon at 120° C. for 20 h. Solvent as removed at reduced pressure, the residue dissolved in dichloromethane and filtered through Celite. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, ethyl acetate/hexane mixtures) to give the title compound (0.18 g) as an oil.