Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:34][NH2:35]>C(O)C>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:31])[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:35][N:34]=1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To N-{(3R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-3-piperidinyl}benzamide (83 mg, 0.19 mmol) in ethanol (2 mL) was added hydrazine monohydrate (0.5 mL, 10.2 mmol), and the reaction mixture was stirred overnight at 100° C. into a sealed tube. The solution was poured onto water (˜50 mL) and a precipitate formed. The aqueous mixture was filtered, and the solid was further washed with water. The material was dried under vacuum overnight at 45° C. to afford the title compound (52 mg) as an off-white solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.43-1.60 (m, 1H), 1.61-1.75 (m, 1H), 1.76-1.89 (m, 1H), 1.92-2.05 (m, 1H), 2.83 (d, J=4.0 Hz, 3H), 2.91-3.10 (m, 2H), 3.83-3.98 (m, 1H), 4.24-4.57 (m, 2H), 5.38 (s, 2H), 6.45-6.58 (m, 1H), 6.64 (s, 1H), 7.41-7.49 (m, 2H), 7.50-7.56 (m, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.71 (d, J=8.34 Hz, 1H), 7.82-7.90 (m, 2H), 7.98 (bs, 1H), 8.37 (d, J=7.6 Hz, 1H), 11.50 (s, 1H).
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[CH:7]([CH3:9])C)C.Cl[C:15](OCCl)=O.C(O)(=O)CCC>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH2:3][O:5][C:6](=[O:10])[CH2:7][CH2:9][CH3:15]
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Reactant: O=C(Cl)OCCl
Solvent: CCCC(=O)O
Product: CCCC(=O)OCOC(=O)SC

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing 1-chloroethyl chloroformate with chloromethyl chloroformate in Step A and replacing isobutyric acid with n-butyric acid in Step B affords O-(butanoyloxymethyl) S-methyl thiocarbonate (8) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.Br[CH2:25][CH:26]1[CH2:31][CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28][CH2:27]1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC2CCNCC2)cc1

Procedure:
The title compound was prepared by alkylation of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide with benzyl 4-(bromomethyl)piperidine-1-carboxylate according to the procedure described in example S-1, step b, followed by subsequent deprotection using the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 20° C., 0.05M in MeOH). 1H NMR (DMSO) δ 1.30-1.50 (2H, m), 1.85 (2H, d), 1.90-2.10 (1H, m), 2.71-2.81 (2H, m), 3.21 (2H, d), 3.92 (2H, d), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.21-8.30 (2H, m). LCMS (2) 3.13 min; m/z (ES+) 414.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][C:10]([F:18])([F:17])[CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])[NH2:5].[BH4-].[Na+].O.C(=O)([O-])[O-].[Na+].[Na+].[C:30](O)(=O)[CH3:31]>>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][C:10]([F:17])([F:18])[CH:11]([F:16])[C:12]([F:14])([F:15])[F:13])[NH:5][CH2:30][CH3:31]
Reactant: CC(=O)O
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCNc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Temperature: 25 °C

Procedure:
To a solution of 0.28 g 3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy) aniline in 8 mL glacial acetic acid at room temperature under an atmosphere of nitrogen was slowly added 0.31 g sodium borohydride. The addition was carried out over a 1.5 hour period through a solid addition funnel between 25-34° C. with ice water cooling. The mixture was stirred at room temperature over night. Then the reaction mixture was added to 80 mL water and the pH was carefully adjusted to 7 by adding solid sodium carbonate. The product was extracted with 80 mL ethyl acetate. The organic layer was separated, washed with brine solution, separated, and dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated under vacuum to give a brown oil 0.29 g. The product was chromatographed using a Michel-Miller low pressure silica gel column eluted with 9:1 heptane/ethyl acetate. Like fractions were pooled and concentrated under vacuum to give 0.19 g of a tan oil. 1H-NMR d 1.28 (t, 3H), 3.17 (q, 4H), 3.95 (bs, 1H), 4.94-5.21 (md, 1H), 6.59 (d, 1H). Anal. calcd C11H8Cl2F7N: C, 35.31; H, 2.16; N, 3.74. Found: C, 35.32; H, 2.14; N, 3.74.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=2[O:14][CH3:15])[CH2:3][CH2:2]1.[Br:16]Br.[NH4+].[OH-]>CO.C(Cl)Cl.O>[Br:16][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[C:6]([O:14][CH3:15])[CH:7]=1
Reactant: BrBr
Reactant: COc1cccc([N+](=O)[O-])c1NC1CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1cc(Br)cc([N+](=O)[O-])c1NC1CC1
Reaction time: 1 h

Procedure:
N-cyclopropyl-2-methoxy-6-nitroaniline (1.05 g, 5.04 mmol) was dissolved in MeOH (25 mL). Bromine (0.27 mL, 5.2 mmol) was added dropwise over 1 min, and the resulting mixture was stirred 1 h. Additional bromine (0.05 mL, 0.98 mmol) was then added and the resulting mixture was stirred for an additional 30 min. The mixture was then diluted with DCM (75 mL) and H2O (50 mL), and the aqueous phase was basified with saturated aqueous NH4OH (2 mL). The phases were separated, and the aqueous phase was extracted with DCM (30 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-25% EtOAc in hexanes) to afford 4-bromo-N-cyclopropyl-2-methoxy-6-nitroaniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C10H12BrN2O3: 287.0; found: 286.9.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]([CH3:11])[C:9]#[N:10])[CH2:4][CH2:3]1.CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]([CH3:11])[CH2:9][NH2:10])[CH2:4][CH2:3]1
Reactant: CC(C#N)N1CCN(C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(CN)N1CCN(C)CC1

Procedure:
2-(4-Methyl-1-piperazinyl)propionitrile (38.3 g.) in 50 ml. of dry ether is added in a dropwise manner to a stirred solution of 19 g. of lithium aluminum hydride in 600 ml. of dry ether. The resulting mixture is heated at reflux for 1 hour, cooled and treated in sequence with 10 ml. of water, 7.5 ml. of 20% aqueous sodium hydroxide, and 35 ml. of water. The mixture is filtered and the filtrate is evaporated. The residue is fractionated at reduced pressure to give 2-(4-methyl-1-piperazinyl)propylamine as an oil, b.p. 92°-93° C./9 mm.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])C1C=CC=CC=1>C(O)C.[Pd]>[CH3:14][N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:19])[F:20])[CH2:10]1
Reactant: CN1CCN(Cc2ccccc2)C(CNC(=O)C(F)(F)F)C1
Agent: [Pd]
Solvent: CCO
Product: CN1CCNC(CNC(=O)C(F)(F)F)C1
Yield: 94.1 %

Procedure:
A solution of (RS)-1-benzyl-4-methyl-2-(trifluoroacetylaminomethyl)piperazine (D3) (6.06 g, 0.0192 mol) in ethanol (300 ml) was hydrogenated at atmospheric pressure in the presence of 10% palladium on charcoal (6 g, 54% paste with water) for 18 h. The mixture was filtered through Kieselguhr and the filtrate evaporated in vacuo to furnish the title compound as a colourless gum (4.07 g, 94%).
Reaction SMILES: [CH:1]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:21]=2[O:30]CC2C=CC=CC=2)[N:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH:1]([C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([CH3:28])([CH3:27])[CH3:29])[C:21]=2[OH:30])[CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)c1cccc(-c2cccc(C(c3ccccc3)c3ccccc3)n2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cccc(-c2cccc(C(c3ccccc3)c3ccccc3)n2)c1O
Reaction time: 4 h
Yield: 77 %

Procedure:
Compound 12 (0.8 g, 1.66 mmol, 1.0 equiv) was dissolved in ethanol (30 mL) and 10% palladium (50% aqueous) on carbon (0.2 g) was added. The material was shaken on a Parr hydrogenator under a hydrogen atmosphere (30 psi) for 4 hr. The reaction was filtered through a bed of Celite and rinsed with dichloromethane (100 mL). The product was absorbed onto silica gel (3 g) by concentration under reduced pressure. This material was purified on a silica gel column (20 g) by eluting with heptanes (250 mL) and ethyl acetate (1%) in heptanes (500 mL). The desired product was isolated pure in 77% yield (0.5 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:20][CH3:21])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28]>N1C=CC=CC=1>[CH3:36][O:35][C:31]1[CH:30]=[C:26]([CH:25]=[C:24]([O:23][CH3:22])[C:32]=1[O:33][CH3:34])[C:27]([O:1][CH2:2][C:3]1([CH2:20][CH3:21])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)=[O:28]
Reactant: CCC1(CO)CCCN2CCc3c([nH]c4ccccc34)C21
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Product: CCC1(COC(=O)c2cc(OC)c(OC)c(OC)c2)CCCN2CCc3c([nH]c4ccccc34)C21
Yield: 93.5 %

Procedure:
1.30 g. (4.58 mmoles) of 1-hydroxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine and 2.30 g. (10 mmoles) of 3,4,5-trimethoxybenzoyl chloride are dissolved in 15 ml. of absolute pyridine, and the solution is heated on a steam bath for 10 hours under a reflux condenser. The solution is evaporated in vacuo, and the oily residue is stirred first with a 5% sodium hydrocarbonate solution and then with distilled water. The separated solids are filtered off, dried, and recrystallized from methanol. 2.05 g. (93.5%) of the title compound are obtained as white crystals melting at 170°-171° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([NH2:9])=O)([O-:3])=[O:2].CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CC(=O)OCC>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:7]#[N:9])([O-:3])=[O:2]
Reactant: NC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a mixture of 3-nitro-5-(trifluoromethyl)benzamide (1.5 g, 6.41 mmol) in DCM (20 mL) were added Et3N (1.314 mL, 9.61 mmol) and trifluoroacetic anhydride (1.357 mL, 9.61 mmol) at 20° C. The mixture was stirred at 20° C. for 2 h. TLC (PE/EA=3:1, Rf=0.6) showed the reaction was finished. The reaction was concentrated to give crude product, which was purified by column chromatography (PE/EA=3:1, Rf=0.6) to give 3-nitro-5-(trifluoromethyl)benzonitrile (1.2 g, 5.14 mmol, 80% yield): 1H NMR (400 MHz, CDCl3-d) δ 8.71 (s, 2H), 8.24 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=C3C[N+:8]([O-])=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:6]=2[CH:24]=1.[C:25]([O:28][C:29](=[O:31])[CH3:30])(=[O:27])[CH3:26]>C(O)(=O)C>[C:25]([OH:28])(=[O:27])[CH3:26].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=[C:30]3[CH:29]([OH:31])[N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Solvent: CC(=O)O
Product: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2O

Procedure:
A stirred mixture of 1.0 g of 8-chloro-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-5-oxide (III), 5 ml. of acetic anhydride and 3 ml. of acetic acid is warmed on the steam bath, under nitrogen, for 30 minutes and concentrated in vacuo. The residue is suspended in water, neutralized with sodium carbonate and extracted with methylene chloride. The extract is dried, concentrated and chromatographed on silica gel eluting with ethyl acetate to yield 8-chloro-4-hydroxy-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[SH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.BrC1C=C(C(F)(F)F)C=CC=1SC1C=CC(Cl)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][C:28]2[CH:29]=[CH:30][C:25]([C:24]([O:23][CH3:22])=[O:32])=[CH:26][CH:27]=2)([OH:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2S)CC1
Reactant: COC(=O)c1ccc(I)cc1
Agent: FC(F)(F)c1ccc(Sc2ccc(Cl)cc2)c(Br)c1
Product: COC(=O)c1ccc(Sc2ccccc2C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-tert-Butoxycarbonyl-4-[2-(4-methoxycarbonyl-phenylsulfanyl)-phenyl]-piperidine-4-ol (intermediate for 4a) was prepared from 4-hydroxy-4-(2-mercapto-phenyl)-piperidine-1-carboxylic acid tert-butyl ester, and 4-iodo-benzoic acid methyl ester by the palladium-catalysed coupling procedure described for 1-bromo-2-(4-chloro-phenylsulfanyl)-5-(trifluoromethyl)-benzene.
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[CH3:58][S:59][C:60]1[CH:65]=[CH:64][C:63]([NH:66][CH:67]2[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]2)=[CH:62][C:61]=1[C:73]([F:76])([F:75])[F:74]>CN(C)C=O.ClCCl.O1CCCC1>[CH3:58][S:59][C:60]1[CH:65]=[CH:64][C:63]([NH:66][CH:67]2[CH2:72][CH2:71][N:70]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:23])([F:2])[F:22])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:69][CH2:68]2)=[CH:62][C:61]=1[C:73]([F:76])([F:74])[F:75]
Reactant: CSc1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CSc1ccc(NC2CCN(C(=O)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 3), diisopropylethyl amine (18 μL; 0.10 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-methylsulfanyl-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 4) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 3 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (5 mg; 0.01 mmol). The structure was confirmed using Protocol I-B. Calculated mass=589; observed mass=589; HPLC retention time=4.83 min.
Reaction SMILES: C([O:4][CH:5]([CH2:21][O:22]C(=O)C)[CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-:20])=[CH:11][C:10]=2[N:9]=[CH:8]1)(=O)C>CO.C[O-].[Na+]>[OH:4][CH:5]([CH2:21][OH:22])[CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-:20])=[CH:11][C:10]=2[N:9]=[CH:8]1
Reactant: CC(=O)OCC(Cn1cnc2c[n+]([O-])c3ccccc3c21)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: [O-][n+]1cc2ncn(CC(O)CO)c2c2ccccc21

Procedure:
To a stirred solution of 4.0 g (0.0117 mole) of 1-(2,3-diacetoxypropyl)-1H-imidazo[4,5-c]quinolin-5-oxide (from Example 124, Part B) in 50 ml of methanol was added about 12 drops of 25% sodium methoxide solution. After one hour the product was collected by filtration, washed with methanol and recrystallized from ethanol to provide 1-(2,3-dihydroxypropyl)-1H-imidazo[4,5-c]quinolin-5-oxide, m.p. 240°-242° C. Analysis: Calculated for C13H13N3O3 : %C, 60.2; %H, 5.1; %N, 16.2; Found: %C, 60.0; %H, 5.0; %N, 15.8.
Reaction SMILES: [Se](=O)=[O:2].[ClH:4].[CH3:5][O:6][C:7]1[C:35]([O:36][CH3:37])=[CH:34][C:10]2[CH2:11][C:12](=[O:33])[N:13]([CH2:16][CH2:17][CH2:18][N:19]([CH3:32])[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:14][CH2:15][C:9]=2[CH:8]=1>O>[ClH:4].[CH3:5][O:6][C:7]1[C:35]([O:36][CH3:37])=[CH:34][C:10]2[C:11](=[O:2])[C:12](=[O:33])[N:13]([CH2:16][CH2:17][CH2:18][N:19]([CH3:32])[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:14][CH2:15][C:9]=2[CH:8]=1
Reactant: O=[Se]=O
Reactant: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Agent: Cl
Solvent: O
Product: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC
Reaction time: 0.25 h

Procedure:
3.5 gm of selenium dioxide were added to a mixture of 150 ml of diozane and 6 ml of water at 70° C.; the mixture was stirred for 15 minutes and then admixed with 3 gm of diatomaceous earth and 14.8 gm (0.03 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane hydrochloride. The mixture was refluxed for 6 hours, cooled and filtered. The filtrate was evaporated in vacuo and the residue was purified on a silica gel column with methylene chloride +1% of ethanol as the eluant. The fractions were evaporated in vacuo; the residue was dissolved in acetone, and the hydrochloride was precipitated with ethereal hydrochloric acid.
Reaction SMILES: CC1(C)CCC(=O)CC1.C([N:20]1[CH2:24][CH2:23][C@H:22]([N:25]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:26](=[O:36])[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:21]1)(OCC1C=CC=CC=1)=O>>[CH:37]1([N:25]([C:26](=[O:36])[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C@H:22]2[CH2:23][CH2:24][NH:20][CH2:21]2)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: CC(C)(C)OC(=O)NCC(=O)N(C1CCCCC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: CC1(C)CCC(=O)CC1
Product: CC(C)(C)OC(=O)NCC(=O)N(C1CCCCC1)[C@H]1CCNC1

Procedure:
The title compound was prepared following the procedure described in Step B of Intermediate 3 using the product of Step A, (3S)-1-Cbz-3-{cyclohexyl[(N-BOC)aminoacetyl]amino}pyrrolidine.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[CH2:11]([O:13][C:14](=[O:17])[CH2:15]Br)[CH3:12]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:17]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc(C)cc(C)c1C

Procedure:
Using 2,3,5-trimethylphenol and ethylbromoacetate, the title compound was synthesized in the same manner as in Reference Example 153. Yield: quantitative. Oily matter.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(C(=O)c2ccc(O)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(Cc2ccc(O)cc2)c1

Procedure:
Methyl 3-(4-hydroxybenzoyl)benzoate (0.1 mol) in absolute ethanol (500 ml) is shaken under 50 psi of hydrogen in the presence of 10% palladium on carbon (2 g). After consumption of the starting material the suspension is filtered and evaporated to give methyl 3-(4-hydroxybenzyl)benzoate.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=[C:3]12.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:22]([N:7]1[CH2:6][CH2:5][N:4]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=[C:3]2[C:2]1=[O:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc2n(n1)CCNC2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc2n(n1)CCN(Cc1ccccc1)C2=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (30 mg, 0.143 mmol) in acetonitrile (1 mL) was added cesium carbonate (93.4 mg, 0.287 mmol) and benzyl bromide (25.6 μL, 0.215 mmol). The reaction mixture was stirred overnight at 70° C. Upon cooling to room temperature, the cesium carbonate was removed by filtration and the solvent evaporated under reduced pressure to afford crude Intermediate 32. LC-MS: (AA) ES+300.
Reaction SMILES: [CH3:1][C:2]1([OH:26])[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[NH:5][CH2:4][CH2:3]1.O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[OH:26][C:2]1([CH3:1])[C:11]2=[N:10][C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[N:7]=[C:6]2[N:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:3]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)C(C)(O)CCN3)cc1
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CCC(C)(O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-methyl-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-ol (Intermediate G)(240 mg, 0.695 mmol) in DCE (10 ml) was added ethyl 7-oxoheptanoate (359 mg, 2.084 mmol) followed by sodium triacetoxyborohydride (442 mg, 2.084 mmol) and the resulting mixture was left to stir overnight at room temperature under an atmosphere of nitrogen. The reaction mixture was diluted with water and extracted with EtOAc (2×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown oil. The oil was purified by chromatography on silica eluting with EtOAc in iso-hexane to afford ethyl 7-(8-hydroxy-8-methyl-2,3-di-p-tolyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)heptanoate (Intermediate 15.1). This compound was passed through a 5 g Isolute® SCX-2 SPE cartridge (primed with MeOH—20 ml) and washing with MeOH (30 ml). The product was eluted with 2M NH3 in MeOH (20 ml). The basic eluent was concentrated under reduced pressure to afford a 1:2 mixture of ethyl 7-(8-hydroxy-8-methyl-2,3-di-p-tolyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)heptanoate compound: ethyl 7-(8-methoxy-8-methyl-2,3-d i-p-tolyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)heptanoate;