Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][N:8]1[C:17]2[C:12](=[C:13]([F:18])[CH:14]=[CH:15][CH:16]=2)[N:11]([C:19](=[O:42])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]4[CH:37]=[CH:38][CH:39]=[CH:40][C:31]3=4)=[O:29])=[CH:24][C:23]=2[CH3:41])[CH2:10][C:9]1=[O:43])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]([C:19](=[O:42])[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]4[CH:37]=[CH:38][CH:39]=[CH:40][C:31]3=4)=[O:29])=[CH:24][C:23]=1[CH3:41])[CH2:10][C:9](=[O:43])[N:8]2[CH2:7][C:6]([OH:44])=[O:5]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CC(=O)OC(C)(C)C)c2cccc(F)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CC(=O)O)c2cccc(F)c21
Reaction time: 1.5 h

Procedure:
To a solution of {5-fluoro-4-[2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylcarbamoyl]-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl}acetic acid tert-butyl ester from Example 7B (105 mg, 0.175 mmol) in dichloromethane (4.0 ml) was added trifluoroacetic acid (4.0 ml). The mixture was stirred for 1.5 h, evaporated in vacuo and azeotroped with toluene to give a white solid; yield 95 mg, 100%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:40])[NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:39])[CH2:23][C:24]([CH3:38])([CH3:37])[CH2:25][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][OH:28])[CH2:13]1.S(=O)(=O)=O.N1C=CC=CC=1>C(Cl)Cl.CS(C)=O>[CH3:8][O:9][C:10](=[O:40])[NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:39])[CH2:23][C:24]([CH3:38])([CH3:37])[CH2:25][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH:27]=[O:28])[CH2:13]1
Reactant: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C)C1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@@H](C=O)NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2.10 ml of triethylamine are added to a solution of 2.34 g of [1-(5(S)-tert-butoxycarbonylamino-6-hydroxy-3,3-dimethyl-hexanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl ester in 20 ml of methylene chloride under argon at 0° C. The mixture is stirred for 5 minutes at 0° C. and then a solution of 2.65 g of pyridine sulfur trioxide in 12 ml of dimethylsulfoxide is added dropwise at 0-5° C. over 1 hour. The mixture is stirred at 0-5° C. for 30 minutes and then ice water is added dropwise to the mixture at 0-10° C. The mixture is stirred at 10° C. for 10 minutes and then extracted with methylene chloride (3×). The combined organic layers are washed successively with 10% aqueous sodium hydrogensulfate solution, water, 10% aqueous sodium bicarbonate solution and brine, dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a white solid. Rf=0.44 (3:1 EtOAc-heptane); Rt=4.17 (gradient I).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:23][CH3:24])[C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:23][CH3:24])[C:16]2[C:21]([NH:22][CH2:25][CH3:26])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNc1cccnc1N(CC)CC1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-amino-2-pyridinyl)amino]methylpiperidine (EXAMPLE 177, 2.35 g, 7.27 mmol) is dissolved in 18 ml methanol and cooled to 0°. Acetaldehyde (0.45 ml, 8.0 mmol) and sodium cyanoborohydride (685 mg, 10.9 mmol) is added. The mixture is stirred at 0° for one hr, then warmed to 20°-25°. Acetaldehyde and sodium cyanoborohydride are added in the same amounts as above two more times, cooling to 0° before and warming to 20°-25° after each addition. The mixture is poured into 1N sodium hydroxide, extracted with chloroform, dried over sodium sulfate, filtered and concentrated. Flash column chromatography (silica gel, 100 g; methanol/chloroform (5/95)), gives the title compound, NMR (300 MHz, CD3OD) 7.58, 7.31, 6.98, 3.49, 3.18, 3.00, 2.87. 1.93, 1.70, 1.40, 1.15 and 1.01δ.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH3:16][N:15]([CH3:17])[CH:12]([CH2:13][CH3:14])[CH:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=3)[S:3][C:4]=2[CH:10]=1)[N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(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: [K+]
Solvent: COCCOC
Solvent: O
Product: CCC(C(c1ccc2nc(-c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 80 °C

Procedure:
A mixture of 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine (663 mg, 1.75 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (409 mg, 2.275 mmol), tetrakis(triphenylphosphine)palladium (505 mg, 0.437 mmol), potassium carbonate (725 mg, 5.25 mmol), DME (25 mL) and water (5 mL) was degassed, filled with N2, and heated to 80° C. for 3 h. The reaction mixture was evaporated, dissolved in 10% methanol in DCM, loaded onto a PTLC plate and eluted with 6% methanol in DCM to yield methyl 4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate. MS ESI: m/z 435.19 [M+1+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[N:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[N:22]([CH3:28])[C:21]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC.N>[Cu](I)I.CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH:25]4[CH2:26][CH2:27]4)[N:22]([CH3:28])[C:21]=3[CH:29]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cn1c(C2CC2)nc2ccc(Br)cc21
Agent: I[Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cc21
Temperature: 150 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
A mixture of 4-(benzyloxy)pyridin-2(1H)-one (1.60 g), 6-bromo-2-cyclopropyl-1-methyl-1H-benzimidazole (2 g), potassium carbonate (3.30 g), N,N′-dimethylethylenediamine (0.855 ml), copper iodide (1.52 g) and DMSO (40 ml) was stirred at 150° C. under Ar atmosphere for 1 h. The mixture was poured into 28% NH3 solution. The precipitate was collected by filtration and washed with water and EtOAc. The solid was dissolved in THF, put on through silica gel pad and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/MeOH). The resulting solid was dissolved in MeOH, and stirred with activated charcoal at room temperature for 10 min. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound (1.60 g) as an off-white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(N(CC)CC)C.CC1C=C(C)N=C(S[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])N=1>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)=[O:29]
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccc([N+](=O)[O-])cc2)n1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
To a clear solution of L-hydroxyproline methyl ester hydrochloride (27.2 g, 0.15 mol) and triethylamine (50 ml, 0.36 mol) in chloroform (500 ml) was added 4,6-dimethyl-2-(4-nitrobenzyloxycarbonylthio)pyrimidine (40.7 g, 0.13 mol) and then the resulting solution was stirred at room temperature for 12 hours, sequentially washed with H2O (200 ml), 0.5N NaOH (400 ml) and brine (200 ml) and dried (MgSO4). Concentration followed by silicagel column chromatography (Wakogel® C-300, ethyl acetate) afforded (2S, 4R)-4-hydroxy-N-(4-nitrobenzyloxycarbonyl)proline methyl ester (34.5 g, 70.9% yield) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: BrC1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C5CCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 73.5 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and bromo cyclopentane (103 mg, 0.691 mmol) gave 7-cyclopentyl-2-[5-(4-cyclopentyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (85 mg, 71%). MS(ESI) m/z 503.3 (M+H)+
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:16]=2)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:16]=2)=[S:33])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc(CN3CCCCC3)o2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=S)c2ccc(CN3CCCCC3)o2)CC1
Temperature: 70 °C

Procedure:
A solution of (4-isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-furan-2-yl)-methanone (Example 1, 1 equiv.) and Lawesson's reagent (2.1 equiv.) in THF is heated at reflux (70° C.) for 48 h. The reaction is cooled to room temperature and the solvent is removed in vacuo. Chromatography of the residue on a silica gel column using 1-6% 2 M NH3 in MeOH/DCM) provides the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1>C(O)(=O)C.O1CCOCC1>[N:1]1([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=2)[C:5]([OH:7])=[O:6])[CH:17]=[CH:21][CH:20]=[CH:19]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-n2cccc2)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 3-amino-5-(trifluoromethyl)benzoic acid (2.0 g) and 2,5-dimethoxytetrahydrofuran (1.52 ml) in a mixture of acetic acid (10 ml) and 1,4-dioxane (10 ml) was stirred at 100° C. for 2 hours. After cooling to room temperature, the mixture was concentrated and purified with column chromatography (silica gel, 50 ml, methanol:dichloromethane=10:90) to give crude solid. The solid was recrystallized from ethyl acetate (5.0 ml) and hexane (200 ml) to give 3-(pyrrol-1-yl)-5-(trifluoromethyl)-benzoic acid (1.72 g) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC1(C)N([O])C(C)(C)CCC1.Cl([O-])=[O:45].[Na+]>C(#N)C.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[OH-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:32])[C:30]([OH:45])=[O:31])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(CC)N1C(=O)[C@@](C)(CC(O)C(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 1.75 h

Procedure:
A mixture of 142 mg (0.30 mmol) of (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one (Example 81, Step A) and 28 mg (0.18 mmol) of TEMPO in a mixture of acetonitrile (6 mL) and sodium phosphate-sodium hydroxide buffer (pH 6.7, 4.5 mL) at 35° C. was treated simultaneously with a solution of 105 mg (1.16 mmol) of sodium chlorite in water (1.2 mL) and a solution of 106 μL (0.07 mmol) of bleach solution (ca. 0.7 N) in water (0.6 mL) over 10 min. The resulting dark orange solution was stirred at 35° C. for 1.75 h, and then was partitioned between 1 N HCl and EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 60% MeCN in water to 80% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound (mixture of alcohol epimers) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([CH2:24][CH3:25])([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=3)[CH2:14][CH3:15])[S:10][C:9]=2[CH:26]=1)=[O:4].Br[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:18]([CH3:23])[CH:17]=3)([CH2:24][CH3:25])[CH2:14][CH3:15])[S:10][C:9]=2[CH:26]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(C(=O)OC)cc2s1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)OC)cc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
A solution of 2-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzo[b]thiophene-6-carboxylic acid methyl ester (4.05 g, 11.0 mmol) and 1-bromopinacolone (2.36 g, 13.2 mmol) in acetone (100 mL) is treated with K2CO3 (3.04 g, 22.0 mmol) and stirred at RT for 16 h. The mixture is filtered, and the filtrate is concentrated. The residue is purified by silica gel column chromatography (10-15% EtOAc/Hex) to provide the title compound (4.50 g, 88%).
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH2:10][OH:11].[CH2:12](Br)[CH2:13][CH2:14][CH3:15]>C(O)C>[CH2:12]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH2:10][OH:11])[CH2:13][CH2:14][CH3:15]
Reactant: OCCC1CCCCN1
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN1CCCCC1CCO
Yield: 5.9 %

Procedure:
A! A solution of 1N sodium hydroxide (156 ml, 0.156 mole) was added to a mixture of 2-piperidine-ethanol (20 ml, 0.156 mole) and butyl bromide (21 ml, 0.187 mole) in ethanol (200 ml). The reaction mixture was refluxed for 4 hours, then the solvent was evaporated under vacuum. The aqueous solution was acidified with HCl and washed with ethyl ether, then it was treated with a 32% solution of sodium hydroxide until pH-12 and extracted with ethyl ether. The combined organic phases were anhydrified over sodium sulfate and the solvent was evaporated under vacuum. The resulting crude was purified by distillation yielding 1.7 g of N-butyl-2-piperidine-ethanol (b.p.: 88°-99° C./0mmHg) (yield: 40%).
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([O:13][CH3:14])(=[O:12])[C:8]([O:10]C)=O.[C:15]([C:18]1[C:19](=[O:39])[N:20]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21](=[O:31])[N:22]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=1)(=[O:17])[CH3:16]>C1COCC1>[CH2:24]([N:22]1[CH:23]=[C:18]([C:15](=[O:17])[CH:16]=[C:8]([OH:10])[C:7]([O:13][CH3:14])=[O:12])[C:19](=[O:39])[N:20]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]1=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(O)=CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.2 %

Procedure:
To a stirred solution of sodium t-butoxide (577 mg, 6 mmol) in anhydrous THF (15 ml) at room temperature was added, dropwise, dimethyl oxalate (472 mg, 4 mmol) in THF (7 ml) followed by 5-acetyl-1,3-dibenzyluracil (2a) (669 mg, 2 mmol) in THF (8 ml). The resulting mixture was stirred at room temperature for 4 h and then was acidified to pH=2. THF was evaporated. The residue in CH2Cl2 (100 ml) washed with brine (20 ml) and purified by column chromatography (hexane:ethyl acetate, 2:1). The appropriate fraction was concentrated and crystallized from ethanol to give 254 mg of a yellow solid. Yield was 29.1%. Mp. 158-159° C. 1HNMR (CDCl3): 15.04 (s, br, 1H), 8.36 (s, 1H), 7.72 (s, 1H), 7.29-7.49 (m, 10H), 5.18 (s, 2H), 5.05 (s, 2H), 3.92 (s, 3H). 13CNMR (CDCl3): 185.7, 168.8, 162.4, 159.7, 150.5, 148.5, 136.0, 134.0, 129.4, 129.1, 129.0, 128.5, 128.3, 127.9, 109.0, 101.6, 53.7, 53.2, 45.0. FAB-HRMS: [M+H]+ Calcd. for C23H21N2O6 421.1400. Found 421.1418.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[C:13]4[CH:14]=[CH:15][C:16]5[N:17]([C:18]([CH3:21])=[N:19][N:20]=5)[C:12]=4[CH:11]=3)=[N:6]2)[CH2:2]1.[C:31](Cl)(=[O:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[C:31]([N:1]1[CH2:2][CH:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[C:13]4[CH:14]=[CH:15][C:16]5[N:17]([C:18]([CH3:21])=[N:19][N:20]=5)[C:12]=4[CH:11]=3)=[N:6]2)[CH2:4]1)(=[O:33])[CH3:32]
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5CNC5)n4)n3Cc3cccc(Cl)c3)n12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(n2ccc(-c3cc4c(ccc5nnc(C)n54)n3Cc3cccc(Cl)c3)n2)C1
Reaction time: 0.03 h
Yield: 71.4 %

Procedure:
To 7-(1-azetidin-3-yl-1H-pyrazol-3-yl)-6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (6.0 mg, 0.014 mmol, from Step 1) was added acetyl chloride (1.2 μL, 0.017 mmol, Aldrich) in DCM (0.38 mL). Triethylamine (4.0 μL, 0.029 mmol) was then added and the reaction was complete in 2 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded clean product (4.6 mg, 70%).
Reaction SMILES: Cl.C1(C[O:9][C:10]2[CH:36]=[CH:35][C:13]3[O:14][CH:15]([CH2:18][NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]4[CH:34]=[CH:33][C:27]5[CH:28]=[CH:29][C:30](=[O:32])[O:31][C:26]=5[CH:25]=4)[CH2:16][O:17][C:12]=3[CH:11]=2)C=CC=CC=1>O.CO.[Pd]>[OH:9][C:10]1[CH:36]=[CH:35][C:13]2[O:14][CH:15]([CH2:18][NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:34]=[CH:33][C:27]4[CH:28]=[CH:29][C:30](=[O:32])[O:31][C:26]=4[CH:25]=3)[CH2:16][O:17][C:12]=2[CH:11]=1
Reactant: O=c1ccc2ccc(OCCCNCC3COc4cc(OCc5ccccc5)ccc4O3)cc2o1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1ccc2ccc(OCCCNCC3COc4cc(O)ccc4O3)cc2o1
Reaction time: 4.5 h

Procedure:
7-[3-[[(2,3-Dihydro-6-phenylmethoxy-1,4-benzodioxin-2-yl)methyl]amino]propoxy]-2H-1-benzopyran-2-one hydrochloride (0.82 g, 1.6 mmole), prepared in Example 4 above, was dissolved in a mixture of 150 ml of water and 10 ml of methanol, 300 mg of 5% palladium on carbon added, and the mixture hydrogenated at 25 psi on a Parr apparatus for 4.5 hours. It was then filtered through celite and concentrated to dryness in vacuum. The residue was redissolved in methanol and boiled on a hot plate, the methanol being gradually replaced with isopropanol, and an additional 2.8 ml of 4N HCl/isopropanol was added. Upon cooling 0.37 g of the title compound, m.p. 244° C. (d), precipitated as a white solid, monohydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.N12CCCN=C1CCCCC2.[CH2:23]([OH:26])[C:24]#[CH:25]>O1CCCC1.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>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([C:25]#[C:24][CH2:23][OH:26])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC#Cc1cccc(C(F)(F)F)c1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
To a degassed solution of 1-bromo-3-trifluoromethylbenzene (20.0 g, 88.8 mmol) in tetrahydrofuran (160 ml) were in the following order added: copper(I) iodide (506 mg, 2.66 mmol), tetrakis(triphenylphosphine)palladium (3.06 g, 26.6 mmol), and 1,8-diazabicyclo-[5.4.0]undec-7-ene (16.22 g, 106.6 mmol). The resulting mixture was degassed one more time, cooled in an ice bath and a solution of propargyl alcohol (5.94 g, 106.6 mmol) in tetrahydrofuran (10 mL) was added over period of 20 min. The reaction mixture was slowly heated up to 55° C. and then stirred at this temperature for 16 h. The mixture was diluted with diethyl ether (400 mL), washed with water (100 mL), 5% hydrochloric acid (100 mL) and saturated aqueous solution of sodium hydrogen carbonate (80 mL). The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 85:15) affording 3-(3-trifluoromethylphenyl)prop-2-yn-1-ol.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:29])[C:27]=1[NH2:28])[C:22]([OH:24])=[O:23]>CC(N(C)C)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[C:4]1[NH:18][C:19]2[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[CH:25]=[C:26]([CH3:29])[C:27]=2[N:28]=1
Reactant: COc1ncccc1-c1ccc(O)c(C=O)c1
Reactant: Cc1cc(C(=O)O)cc(N)c1N
Solvent: CC(=O)N(C)C
Product: COc1ncccc1-c1ccc(O)c(-c2nc3c(C)cc(C(=O)O)cc3[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To mixture of 2-hydroxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (144 mg, 0.4 mmol) and 3,4-diamino-5-methyl-benzoic acid (82 mg, 0.5 mol) was added DMA (0.8 mL) and the resulting solution was stirred at 0° C. for 0.5 h, and at the room temperature for 2.5 h. After it was heated open to the air at 110° C. for 15 h, the reaction mixture was concentrated under reduced pressure and the residual crude was used for the next step reaction without purification. ESI-MS m/z 376.3 (MH+).