Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:19]([CH:20]([CH3:23])[CH:21]=[CH2:22])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:24])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[C:19]([CH:20]([CH3:23])[CH2:21][CH3:22])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:24])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: C=CC(C)c1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Pd]
Solvent: CCO
Product: CCC(C)c1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 65.9 %

Procedure:
To a solution of the known 3-hydroxy-2-(1-methyl-2-propenyl)estra-1,3,5(10)-trien-17-one (ref. Patton, 1962; Chemical Abstracts Registry Number [98543-85-2], 30 mg, 0.093 mmol) dissolved in 10 mL of anhydrous ethanol was added 20 mg of 5% Pd/C. The reaction flask was shaken under 2.7 atm. of hydrogen for 3 h. The reaction mixture was then filtered and the catalyst was washed with ethanol. After solvent removal, the crude product was purified by chromatography (silica gel eluted with 12.5% ethyl acetate in hexanes) and then recrystallized from methylene chloride-hexanes to give 20 mg of pure product: m.p. 186-187° C.; 1H NMR(CDCl3) δ 0.85-0.90 (m, 3H, CH3), 0.91 (s, 3H, CH3), 1.20-1.24 (m, 3H, CH3), 2.81-2.89 (m, 2H, CH2), 6.51 (s, 1H, Ar—H), 7.06 (s, 1H, Ar—H); 13C NMR(CDCl3) δ 12.17, 13.75, 20.44, 21.46, 25.93, 28.91, 29.83, 31.49, 33.87, 35.81, 38.33, 44.05, 48.01, 50.24, 115.37, 123.99, 124.17, 130.86, 131.88, 134.78, 157.267, 221.79.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[O-][Si]([O-])=O.[Mg+2]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccccc1Cl
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOC(=O)Cn1c(-c2ccccc2Cl)nc2cccnc21
Yield: 11 %

Procedure:
Solid N-[3-[(2-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester, 15.0 g (0.045 mole) was heated in a Wood's metal bath at 210°-20° C. for 9 minutes. The residue was dissolved in methylene chloride, treated with Florisil® (90 g), and filtered. The filtrate was treated with decolorizing charcoal and filtered through a Celite pad to give a yellow filtrate. The filtrate was evaporated to an oil, which crystallized upon standing. The solid (3.0 g) was recrystallized from petroleum ether-tetrahydrofuran (minimum) by cooling in a freezer overnight. The solid was collected, washed with petroleum ether-tetrahydrofuran and dried under high vacuum at room temperature to give 1.62 g (11%) of title compound, mp 64°-66° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[NH:20][C:19](=[O:21])[C:18]([N+:22]([O-])=O)=[CH:17][N:16]=2)=[CH:7][CH:6]=1)[CH3:3].COCCO.Cl>[Ni]>[NH2:22][C:18]1[C:19](=[O:21])[NH:20][C:15]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]2[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=2)=[N:16][CH:17]=1
Reactant: CN(C)Cc1ccc(CSCCNc2ncc([N+](=O)[O-])c(=O)[nH]2)o1
Agent: [Ni]
Agent: Cl
Solvent: COCCO
Product: CN(C)Cc1ccc(CSCCNc2ncc(N)c(=O)[nH]2)o1
Yield: 90.6 %

Procedure:
To a solution of 2-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-5-nitro-4(3H)-pyrimidone (4.26 g; 12.05 mmoles) in 50 ml of 2-methoxyethanol containing 1.55N methanolic HCl (7.75 ml; 12.01 meq.) was added a catalytic amount of Raney nickel No. 28 (approximately 2.8 cm3), and the mixture was hydrogenated in a Parr apparatus at 50 psi for 1.25 hours. The reaction mixture was filtered, treated with 20 ml of 1.55N methanolic HCl and evaporated under reduced pressure. The residue was placed on 190 g of silica gel and chromatographed by flash chromatography using CH3OH:CH3CN:NH4OH (20:80:1) as eluent. The appropriate fractions were combined and evaporated to dryness. The residue was dissolved in 25 ml (38.8 meq.) of 1.55N methanolic HCl, evaporated under reduced pressure and dried under high vacuum at 56° C. to give 3.53 g of the title compound as a trihydrochloride, mp 127°-132° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[OH-].[K+].[CH2:20](Br)[CH2:21][CH2:22][CH3:23]>CS(C)=O.O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH2:21][CH2:22][CH3:23]
Reactant: Cc1ccccc1C(=O)Nc1cccc(O)c1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCOc1cccc(NC(=O)c2ccccc2C)c1
Reaction time: 3 h
Yield: 92.9 %

Procedure:
A 22.7 g (0.1 mol) portion of 3'-hydroxy-2-methylbenzanilide was dissolved in 80 ml of dimethyl sulfoxide and to this solution was added a solution of 5.6 g (0.1 mol) of potassium hydroxide in 40 ml of water. The white mixture was cooled with water, and 30 ml of dimethyl sulfoxide containing 13.7 g (0.1 mol) of n-butylbromide was added dropwise to the solution with stirring. After the addition, the mixture was warmed and kept at 40° to 50° C for 3 hours. The reaction mixture was poured into 700 ml of water and the oily material formed was extracted with benzene. The benzene layer was washed with water, dehydrated over anhydrous sodium sulfate and the benzene was removed to obtain the product, which was recrystallized from a mixture of benzene and n-hexane (1 : 2) to obtain 26.3 g (92.9%) of greyish needle-like crystals having a melting point of 87° C.
Reaction SMILES: C(OCC)(=O)C.[OH:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[NH:11][C:12](=[O:15])[CH:13]=[CH2:14].[CH2:19]([N:37]=[C:38]=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(N(CC)CC)C>[CH2:19]([NH:37][C:38]([O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[NH:11][C:12](=[O:15])[CH:13]=[CH2:14])=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: C=CC(=O)Nc1cccc(O)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cccc(OC(=O)NCCCCCCCCCCCCCCCCCC)c1
Temperature: 20 °C

Procedure:
A reaction vessel is charged with 100 parts of ethyl acetate, 16.3 parts of 3'-hydroxyacrylanilide, 29.5 parts of octadecyl isocyanate and one part of triethylamine. The reaction mixture is heated at reflux for about 1 hour, cooled to 20°C and filtered. The solids are washed with ethyl acetate and air dried to give 40.5 parts of 3'-(octadecylcarbamoyloxy)acrylanilide, m.p. 124°-126°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[H-].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH4+].[Cl-]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:12]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:11](=[O:27])[C:10]=2[CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)N(Cc1ccccc1)C1(CCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 58.7 %

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (1.8 g, 4.5 mmol, Example 25, Step A) was dissolved in dry DMF (25 ml) under N2, and NaH (268.6 mg, 6.71 mmol, 60% suspension in mineral oil) was added. After 10 min stirring, benzyl bromide (1.07 ml, 8.95 mmol) was added dropwise and the mixture was heated for 3 h at 80° C. The mixture was poured into water and a saturated NH4Cl solution was added. The aqueous phase was extracted with DCM, and the combined organic phases were dried and concentrated. The crude residue was purified by column chromatography (eluent:petroleum ether/AcOEt 90:10 to 70:30) to give (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (1.3 g, 59%) as a white solid.
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: O=c1c2cccnc2sc(=Nc2ccccc2)n1Cc1ccccc1

Procedure:
The reaction procedure of Example 11 was followed except that 150 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 6 mg of lithium hydride and 0.070 ml of benzyl bromide were used. As a result, 130 mg of 3-benzyl-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14](C(OC)=O)[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C(=O)OC)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1

Procedure:
To a solution of dimethyl [4-(tert-butoxycarbonyl)phenyl]malonate (4.00 g, 13.0 mmol) in THF (30 mL) and MeOH (10 mL) was added NaOH (2N, 19.5 mL, 38.9 mmol). After stirring the reaction for 45 minutes at room temperature, it was diluted with 1 M citric acid and extracted with EtOAc. The organic layer was washed (water, brine), dried (MgSO4), and concentrated to a yellow residue. The residue was redissolved in EtOAc (50 mL) and H2O (50 mL) and stirred for 2 h at 80° C. The mixture was extracted with EtOAc, washed with water and brine, dried (MgSO4), and concentrated to give [4-tert-butoxycarbonyl)phenyl]acetic acid as an off-white solid. MS (ESI) calcd [M+Na]+ 259.1, found 259.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]([CH3:24])([CH3:23])[C:12]([N:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][C:2]1[CH:3]=[C:4]([C:11]([CH3:24])([CH3:23])[C:12]([N:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C)CCCN
Reactant: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(NCCCN(C)C)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 2-(3-chloro-4-nitrophenyl)-N,N-diisobutyl-2-methylpropanamide (78 mg, 1 eq), 3-dimethylaminopropylamine (45 mg, 2 eq) and potassium carbonate (62 mg, 2 eq) in DMF (2 ml) is heated under reflux for 3 hours then cooled down to ambient temperature. The residue is taken up in ethyl acetate (20 ml) and water (8 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent:100% dichloromethane to dichloromethane/methanol 8:2) produces the expected compound in the form of a yellow oil (44 mg; 48% yield).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7](Cl)=[CH:6][N:5]=1.[CH3:15][Zn]C.O>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][O:10][C:9]1[C:4]([CH:3]=[O:2])=[N:5][CH:6]=[C:7]([CH3:15])[N:8]=1
Reactant: C[Zn]C
Reactant: COc1nc(Cl)cnc1C(OC)OC
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C)cnc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
After dissolving 3.34 g of 5-chloro-3-methoxypyrazine-2-carboxaldehyde dimethylacetal in 50 ml of tetrahydrofuran, 400 mg of [1,3-bis(diphenylphosphino)propane]dichloronickel(II) was added, 9.17 ml of dimethyl zinc (2.0 M, toluene solution) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours and then at 50° C. for 1.5 hours. The reaction solution was cooled on ice, water was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 16 ml of acetone, 4 ml of 5N hydrochloric acid was added and the mixture was all owed to stand at room temperature for 15 minutes. A sodium bicarbonate solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.43 g, 61% yield).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH2:39][CH2:40][OH:41])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[C:43]1[C:44]([I:53])=[N:45][CH:46]=[C:47]([CH:52]=1)[C:48]([O:50][CH3:51])=[O:49].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[I:53][C:44]1[C:43]([O:41][CH2:40][CH2:39][C:35]2[N:34]([C:15]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:38]=[CH:37][N:36]=2)=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][N:45]=1
Reactant: OCCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cnc(I)c(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(I)c(OCCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 3 h
Yield: 43.6 %

Procedure:
Diisopropyl azodicarboxylate (1160 uL, 5.90 mmol) was added dropwise to a mixture of 2-(1-trityl-1H-imidazol-2-yl)ethanol (1900 mg, 5.4 mmol), methyl 5-hydroxy-6-iodonicotinate (1570 mg, 5.63 mmol) and Triphenylphosphine (1550 mg, 5.90 mmol) in Tetrahydrofuran (45.0 mL, 555 mmol) at 00 C. After stirring for 3 hours the mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuum. The residue was purified on 40 g silica column eluting with 50% ethyl acetate in DCM to give 1.45 g (44%) of methyl 6-iodo-5-(2-(1-trityl-1H-imidazol-2-yl)ethoxy)nicotinate. MS (ESI+): 616.0. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=1.9, 1H), 7.40-7.28 (m, 10H), 7.20-7.16 (m, 6H), 6.99 (d, J=1.5, 1H), 6.81 (d, J=1.5, 1H), 3.98-3.91 (m, 5H), 2.46 (t, J=7.3, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]2[N:8](O)[CH:7]=1)=[O:5])[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(O)c2cc(C)cnc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2cc(C)cnc12
Reaction time: 24 h
Yield: 53.9 %

Procedure:
Pd(OH)2 (200 mg) is added to a solution of 1-Hydroxy-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid ethyl ester (1.2 g, 0.005 mole) in ethanol (20 mL) and is hydrogenated at 50 psi for 24 h. The catalyst is removed by filtration through a pad of celite and the solvent evaporated under vacuum. The residue is chromatographed over silica gel eluting with 5% MeOH-DCM containing few drops of NH4OH to afford 6-Methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid ethyl ester (550 mg, 50%); 1H NMR (300 MHz, DMSO-d6) δ 1.28 (t, J=6 Hz, 3H), 2.38 (s, 3H), 4.24 (q, J=6.6 Hz, 2H), 7.62 (s, 1H); 8.17 (s, 1H), 8.31 (s, 1H); LRMS Calcd 204.23; found 205.15.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Temperature: 40 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A mixture of (R)-5-dibenzylamino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (1.08 g, 2.64 mmol) and 20% palladium hydroxide on carbon (0.6 g) in absolute ethanol (25 mL) was shaken under a hydrogen atmosphere (3 atm) at 40 °C. for 4 hours. The resulting mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure to afford the title compound (0.60 g, 2.62 mmol, 99%) as a white foam: 1H NMR (DMSO-d6) δ 10.65 (br s, NH), 7.14 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 6.60 (dd, J=2.0 and 8.6 Hz, 1H), 3.63-2.83 (m, 7H), 2.78 (s, 3H), 2.05-1.67 (m, 4H); [α]25 =+9° (MeOH, c=1.0); HRMS calculated for C14H19N3: 229.1575; found: 229.1593.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH:15]=O)[CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=1.S(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]2[N:24]=[C:15]([C:4]3[CH:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=4)[N:5]=3)[NH:25][C:20]=2[CH:19]=1
Reactant: Cc1ccc(Cn2nc(C=O)cc2C)cc1
Reactant: Nc1ccc(Br)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2nc(-c3nc4ccc(Br)cc4[nH]3)cc2C)cc1
Temperature: 110 °C

Procedure:
To a solution of 5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carbaldehyde (Step 2, 700 mg, 3.27 mmol) in DMF (25 mL) was added 4-bromo-o-phenylenediamine (1.2 g, 6.53 mmol) followed by sodium bisulfite (679 mg, 6.53 mmol), and the resulting mixture was heated at 110° C. for 5 h. After being cooled to rt, the reaction mixture was diluted with water. The aqueous phase was extracted with ethyl acetate (3×50 mL), and the combined organics were washed with water (1×50 mL) and brine (1×50 mL), dried (Na2SO4), filtered, and concentrated to dryness. The crude material was then purified with an ISCO CombiFlash Companion using gradient elution from 0% to 50% EtOAc in hexanes to afford the title compound as a mixture of regioisomers as a light yellow solid (600 mg, 48%): 1H NMR (300 MHz, DMSO-d6) δ 11.76 (m, 1H), 11.60 (s, 1H), 7.35-7.77 (m, 2H), 7.27-7.30 (m, 1H), 7.13 (d, 2H), 7.04 (d, 2H), 6.69 (s, 1H), 5.36 (s, 2H), 2.27 (s, 3H), 2.24 (s, 3H); ES-MS m/z 381.20, HPLC RT (Method B) 3.20 min.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([CH2:31][NH:32][CH2:33][C:34]2[S:38][C:37]([S:39](Cl)(=[O:41])=[O:40])=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][N:22]([S:39]([C:37]3[S:38][C:34]([CH2:33][NH:32][CH2:31][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:35][CH:36]=3)(=[O:40])=[O:41])[CH2:21][CH2:20]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)c1ccc(CNCc2ccccc2)s1
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4ccc(CNCc5ccccc5)s4)CC3)c[nH]c12

Procedure:
Following the general procedure in example 267, 5-(phenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 5-{[(phenylmethyl)amino]methyl}-2-thiophenesulfonyl chloride (45.3 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (20 mg, 34%).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].[C:13]([O:17][C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.C(=O)=O.C(O)C.ClC(OCC(C)C)=O>CO.O1CCCC1>[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NOCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(=O)NOCc1ccccc1
Reaction time: 0.03 h

Procedure:
O-Benzylhydroxylamine hydrochloride (15.0 g, 93.8 mMol) was dissolved in methanol (150 ml) and added to a solution of potassium hydroxide (5.27 g, 93.8 mMol) in methanol (50 ml). The resulting mixture was cooled, filtered, evaporated, dissolved in tetrahydrofuran (25 ml) and filtered as solution A. t-Butyloxycarbonyl glycine (16.4 g, 93.8 mMol) was dissolved in tetrahydrofuran (75 ml), triethylamine (13.2 ml, 93.8 mMol) added and the solution cooled to -10° C. with dry ice/ethanol. Iso-butyl chloroformate (12.2 ml, 93.8 mMol) was added and the solution stirred cold 2 minutes, before adding solution A dropwise. The mixture was stirred cold 1 hour and at room temperature 2 hours, filtered, evaporated, dissolved in ethyl acetate (100 ml), washed with water (3× 50 ml), dried over magnesium sulfate and evaporated to an oil.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:9]2[C:10]([CH3:26])=[CH:11][C:12]([O:14][CH2:15][C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.CO.[OH-].[Na+]>C1COCC1>[CH3:26][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:27])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2cc(OCc3cc(C(F)(F)F)nn3C)cc(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2cc(C(F)(F)F)nn2C)cc2scc(CC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a mixture of methyl(4-methyl-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (132.1 mg), MeOH (2.0 mL) and THF (dry) (2.0 mL) was added 1N NaOH (0.663 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated. The mixture was neutralized with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (117 mg).