Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH2:37][CH3:38])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.N1C[CH2:51][O:50][CH2:49][CH2:48]1>>[CH2:37]([C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:40][CH2:51][O:50][CH2:49][CH2:48]3)=[O:39])=[O:23])[CH2:25][CH2:26]2)=[N:31][CH:32]=1)[CH3:38]
Reactant: C1COCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N3CCOCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 809 and morpholine (41 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (19 mg) was obtained.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]([CH3:18])[S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C1(P([N:33]=[N+:34]=[N-:35])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C1COCC1>[N:33]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]([CH3:18])[S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(CO)cc(N(C)S(C)(=O)=O)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc(CN=[N+]=[N-])cc(N(C)S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 130 mg (0.475 mmol) of methyl 3-(hydroxymethyl)-5-(N-methylmethylsulfonamido)benzoate in 7 mL of toluene and 4 mL of THF was added 120 μL of diphenyl phosphoryl azide (DPPA). The solution was cooled to 0° C. and 86 μL (0.568 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) was added. The ice bath was removed, and stirring was continued with warming to room temperature. After about 16 h, the solution was diluted with EtOAc and H2O, and 1N HCl was added to a pH=8. The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the crude product was purified by flash silica gel chromatography (50% EtOAc/hexanes) to give 151 mg of methyl 3-(azidomethyl)-5-(N-methylmethylsulfonamido)benzoate as a yellow oil.
Reaction SMILES: S(=O)(=O)=O.[BrH:5].[CH3:6][C:7]1[C:8]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[N:9][CH:10]=[CH:11][CH:12]=1.BrBr>FC(Cl)(F)C(Cl)(Cl)F>[Br:5][C:11]1[CH:12]=[C:7]([CH3:6])[C:8]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[N:9][CH:10]=1
Reactant: Cc1cccnc1CCCCN
Reactant: Br
Agent: BrBr
Agent: O=S(=O)=O
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: Cc1cc(Br)cnc1CCCCN
Yield: 46.1 %

Procedure:
A solution of sulphur trioxide (150 ml) in 1,1,2-trifluorotrichloroethane (550 ml) was added over 30 min to a suspension of 4-(3-methyl-2-pyridyl)butylamine hydrobromide (14.2 g) [prepared by reacting 4-(3-methyl-2-pyridyl)butylamine with hydrobromic acid (0.89M)] in 1,1,2-trifluorotrichloroethane and to this mixture was added liquid bromine (5.56 g). The mixture was heated under reflux for ca 16 hr. The solvent was removed by distillation and unbrominated starting material was removed by acetylation as described in Example 1(b) to yield 4-(5-bromo-3-methyl-2-pyridyl)-butylamine (6.49 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O.S(=O)(=O)(O)O>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][NH:13][CH2:12][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CCNCC(O)c2ccccc2)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OC)C(c1ccccc1)CNCC2
Temperature: 25 °C

Procedure:
A solution of 30.1 g. (0.1 mol) of N-[2-(3,4-dimethoxyphenyl)ethyl] -2-phenyl-2-hydroxyethylamine in 120 ml. of trifluoroacetic acid and 8.2 ml. of concentrated sulfuric acid is heated at reflux for 2 hours. After cooling to room temperature, the trifluoroacetic acid is removed under reduced pressure and 100 ml. of ice-water is added. This mixture is basified to pH 9-10 with 10% sodium hydroxide solution and thoroughly extracted with ethyl acetate. The extract is dried and evaporated to give 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine as an oil. Various salts can readily be prepared from the free base. For example, 5 g. (0.0176 mol) dissolved in dry ether is treated with methanesulfonic acid dropwise until no further precipitate is formed. The solid is filtered and washed with dry ether to give 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine methanesulfonate, m.p. 133°-136° C.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C>CS(C)=O>[CH2:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNc1nc(CO)cs1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCCCCCNc1nc(C=O)cs1

Procedure:
The reaction described in Preparation 44 was repeated, but using 1.3 g of 2-octylaminothiazol-4-ylmethanol, 2.6 g of pyrid:ne sulfur trioxide complex, 1.6 g of triethylamine and 20 ml of dimethyl sulfoxide. giving the title compound as pale brown needles.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.[C:16](Cl)(=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].Cl>C(=O)([O-])[O-].[K+].[K+]>[C:16]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])(=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:24]
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Reactant: O=C(Cl)CCCCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)[C@@H]1CSC(c2ccccc2O)N1C(=O)CCCCCCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a stirred solution of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid (6.8 g) in 1M potassium carbonate (45 ml), octanedioyl dichloride (3.2 g) was added dropwise under ice-cooling. After the addition, the reaction mixture was stirred for 1 hour at the same temperature and for additional 1 hour at room temperature. The solution was acidified with dilute hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residual oil was purified by silica gel column chromatography to give 7.6 g (86%) of the titled compound: mp 93°-97° C. (dec.); [α]D27 +123.6° (c=0.5, methanol). IR (nujol, cm-1): 1720 (COOH), 1620 (CON), 1600 (aromatic), 1230, 1090, 855, 765. NMR (CD3OD) δ: 0.7-1.7 (8H, m, --CH2 --CH2)4CH2 --), 1.8-2.4 (4H, m, --CH2 --CH2)4CH2), 3.25 (4H, d, J=7.5 Hz, C5 --H), 4.81 (2H, t, J=7.5 Hz, C4 --H), 6.35 (2H, s, C2 --H), 6.7-8.0 (8H, m, arom. H). TLC: Rf value* 0.34.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:11][C:12]1[C:13]([C:21]([NH2:23])=[O:22])=[N:14][C:15]([CH2:19][CH3:20])=[C:16](Cl)[N:17]=1.C(N(C(C)C)CC)(C)C.O1CCOCC1>O>[Cl:11][C:12]1[C:13]([C:21]([NH2:23])=[O:22])=[N:14][C:15]([CH2:19][CH3:20])=[C:16]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:17]=1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Reactant: O=[N+]([O-])c1cccc(O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 3-nitrophenol (1 g), 3,5-dichloro-6-ethylpyrazine-2-carboxamide (1.74 g), diisopropylethylamine (2.63 mL), and dioxane (10 mL) was stirred at 80° C. overnight. To the reaction mixture was added water, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 3-chloro-6-ethyl-5-(3-nitrophenoxy)pyrazine-2-carboxamide (1.68 g) as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=5)=[O:39])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3]C.[CH3:50][S:51]([OH:54])(=[O:53])=[O:52]>C(OCC)(=O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S@:38]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=5)=[O:39])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH3:3].[CH3:50][S:51]([O-:54])(=[O:53])=[O:52]
Reactant: CS(=O)(=O)O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3CCC)cc1
Solvent: CCOC(C)=O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([S@@](=O)Cc4cncn4CCC)cc2)CCCN3CCC)cc1
Product: CS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of (−)-8-[4-(2-butoxyethoxy)phenyl)-1-propyl-N-[4-[[(1-propyl-1H-imidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (201.5 mg) in ethyl acetate (4 ml) was added methanesulfonic acid (28.9 mg) at room temperature, and the mixture was stirred at room temperature overnight. The resultant was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate to give (S)-(−)-8-[4-(2-propoxyethoxy)phenyl]-1-propyl-N-[4-[[(1-propyl-1H-imidazol-5-yl]methyl)sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide/methanesulfonate (118.6 mg) (Compound 45) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[CH3:23]I.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH3:23])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Br)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Br

Procedure:
using 1-(4-bromo-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and methyl iodide with sodium hydride in dimethylformamide there is obtained 1-(4-bromo-2-fluoro-5-methoxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 175°-177° C.;
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[CH:3]1>C(O)C(C)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:3]3[NH:4][CH2:5][CH2:6][N:2]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2cc(N)ccc21
Solvent: CC(C)CO
Product: Cn1cnc2cc(NC3=NCCN3)ccc21
Yield: 101.8 %

Procedure:
A solution of 1-methyl-5-aminobenzimidazole (0.15 g, 1.1 mmol) and ISA (0.30 g, 2.2 mmol) in 3 ml of isobutanol was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding an oily residue which was purified on silica gel column chromatography (NH3 sat'd 20% isopropanol/EtOAc) to yield 0.12 g (0.56 mmol, 51%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from isopropanol to afford 0.11 g (30%) of the product as a white-crystal: mp 210-211° C.; Anal. Calc. for C11H13N5.1.0C4H4O4. 0.3H2O requires C, 35.36; H, 5.28; N,20.74. Found: C, 53.67; H, 5.13; N, 20.70.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:21]1[CH:32]=[CH:31][C:24]2[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=2[CH:22]=1)[OH:20].C(N(C(C)C)CC)(C)C.Cl[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48].C(=O)(O)[O-].[Na+]>ClCCl>[NH3:2].[CH3:36][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:18][C@@H:19]([C:21]1[CH:32]=[CH:31][C:24]2[O:25][C:26]([CH3:29])([CH3:30])[O:27][CH2:28][C:23]=2[CH:22]=1)[OH:20])[C:47](=[O:48])[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(C)c1cccc(COCCOCCCCCCNC[C@H](O)c2ccc3c(c2)COC(C)(C)O3)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)c1cccc(COCCOCCCCCCN(C[C@H](O)c2ccc3c(c2)COC(C)(C)O3)C(=O)OCc2ccccc2)c1
Product: N
Reaction time: 4 h

Procedure:
A solution of (1R)-2-{[6-(2-{[3-(dimethylamino)benzyl]oxy}ethoxy)hexyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (200 mg) in dichloromethane (10 ml) was treated under nitrogen with diisopropylethylamine (0.09 ml) followed by benzyl chloroformate (0.099 ml) and the mixture was stirred at 20° for 4 h. Saturated sodium bicarbonate solution was added and the mixture extracted with dichloromethane. The extract was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by SPE (silica, 10 g). Elution with dichloromethane-ethanol-0.880 ammonia (250:8:1) gave the title compound (220 mg). LCMS RT=3.87 min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17]Br)=[N:13][NH:12][C:11]=1[NH2:19].[CH3:20][NH2:21]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][NH:21][CH3:20])=[N:13][NH:12][C:11]=1[NH2:19]
Reactant: CN
Reactant: Nc1[nH]nc(CCCBr)c1-c1nc2ccccc2s1
Solvent: C1CCOC1
Product: CNCCCc1n[nH]c(N)c1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 60 h
Yield: 32 %

Procedure:
A mixture of 4-benzothiazol-2-yl-5-(3-bromopropyl)-2H-pyrazol-3-ylamine (130 mg, 0.39 mmol) and methylamine (5 mL of a 2 M solution in THF, 10 mmol) was stirred at room temperature for 60 hrs. The resulting solid was isolated by filtration, washed with THF, and then with water. The product was air dried to yield 38 mg (32%) of the title compound as an off white solid. MS (m/z, ES+): 288.2 (M+1, 100%).
Reaction SMILES: [CH3:1][C@:2]([C:14]([NH:16][C@H:17]([CH2:25][OH:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:3].[C:27]12([CH2:37][C:38](Cl)=[O:39])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2>C1COCC1>[OH:26][CH2:25][CH:17]([NH:16][C:14](=[O:15])[C:2]([CH3:1])([NH:3][C:38](=[O:39])[CH2:37][C:27]12[CH2:36][CH:31]3[CH2:30][CH:29]([CH2:35][CH:33]([CH2:32]3)[CH2:34]1)[CH2:28]2)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: C[C@@](N)(Cc1c[nH]c2ccccc12)C(=O)N[C@H](CO)Cc1ccccc1
Solvent: C1CCOC1
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)CC12CC3CC(CC(C3)C1)C2)C(=O)NC(CO)Cc1ccccc1
Yield: 113 %

Procedure:
A solution of α-methyl-D-tryptophyl-L-phenylalaninol (1 g, 2.85 mmol) and 4-N,N-dimethylaminopyridine (0.35 g, 2.87 mmol) in dry THF (50 mL) at 0° C. was treated dropwise, with stirring, with a solution of 1-adamantylacetyl chloride (0.605 g, 2.85 mmol). A precipitate formed immediately. The reaction mixture was left until all starting materials were consumed as assayed by TLC and IR spectroscopy. The final TLC showed three spots (10% MeOH:90% CH2Cl2). The reaction mixture was washed with 1M citric acid solution and extracted into ethyl acetate. The organic phase was then washed with water and dried over MgSO4. Concentration in vacuo gave a syrup (1.7 g) which was chromatographed over silica using 2% MeOH:98% CH2Cl2 as eluant to yield the title compound (1.35 g, 90%) as a white solid crystallized from ethyl acetate-hexane, mp 91°-94° C. (EtOAc-hexane); IR (KBr) 3304 and 1652 cm- 1 ; NMR (CDCl3) δ 1.48 (9H, m), 1.59 (6H, m), 1.76 (2H, q, J 13 Hz), 1.9 (3H, m), 2.74 (2H, d, J 7 Hz),3.21 (1H, half Abq J 14.5 Hz), 3.30 (1H, 6, J 6 Hz), 3.40 (1H, half Abq J 14.5 Hz), 3.45 (1H, m), 3.70 (1H, m), 4.16 (1H, m), 5.91 (1H, s), 6.38 (1H, d, J 8 Hz), 6.92 (1H, d, J 3 Hz), 7.07-7.27 (7 H, m), 7.35 (1H, d, J 8 Hz), 7.56 (1H, d, J 8 Hz), and 8.54 (1H, s); Anal. (C33H41N3O3.0.25 H2O), C, H, N.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])=[O:3].[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH2:6]([N+:13]1[CH:14]=[CH:15][N:11]([CH3:10])[CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOS(C)(=O)=O
Reactant: Cn1ccnc1
Product: CCCC[n+]1ccn(C)c1
Product: CS(=O)(=O)[O-]
Temperature: 100 °C

Procedure:
In a 100 cm3 round-bottomed flask, was added butyl methanesulfonate (15.3 g, 0.10 mol) and 1-methylimidazole (8.21 g, 0.10 mol). A reflux condenser was attached and the mixture heated at 100° C. for 48 hours. A vacuum was applied to the flask (1 mm Hg) to remove unreacted starting materials for 12 hours at 80° C. The low-melting salt [bmim] [Oms] (22.3 g, 95%) solidified on cooling.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[C:12](=[O:33])[N:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)[C:14]3[C:19]([C:20]=2O)=[CH:18][CH:17]=[CH:16][N:15]=3)=O)=[CH:4][CH:3]=1.O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:11]3[C:12](=[O:33])[N:13]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:30])[F:31])[CH:23]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:20]=3[NH:36][N:35]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(F)cc1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccc(F)cc3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-(4-fluorophenylacetyl)-4-hydroxy-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (229 mg, 0.5 mmol) produced in Synthesis Example 28 in DMF (4 mL) was added hydrazine monohydrate (purity of 80%, 80 μL), and the mixture was stirred at 110 to 120° C. for 3 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(4-fluorobenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (203 mg, yield 89%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[O:24][CH2:25][CH3:26].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[C:17]([O:24][CH2:25][CH3:26])[CH:18]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C=O)ccc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (5.0 g, 25.0 mmol, 1.0 equiv), 4-chloro-3-ethoxy-benzaldehyde (5.54 g, 30.0 mmol, 1.2 equiv; intermediate D2, vide infra) and acetic acid (5.7 mL, 6.01 g, 100.0 mmol, 4.0 equiv) in ethanol (25 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyanoborohydride (3.14 g, 50.0 mmol, 2.0 equiv), dissolved in ethanol (10 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 10 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.91 g (42%) of the title compound. MS (ISP): 369.0 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:15][NH:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].C1COCC1.[CH:36]1[CH:41]=[CH:40][C:39]([CH2:42][O:43][C:44](Cl)=[O:45])=[CH:38][CH:37]=1>O>[CH2:42]([O:43][C:44]([N:14]1[CH2:15][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:11][C@H:12]([C:22]([O:24][CH3:25])=[O:23])[C@@H:13]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN[C@H]1c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Yield: 102.3 %

Procedure:
To a stirred and ice-cooled mixture of (2R*,3S*,5R*)-5-(tert-butyldimethylsilyloxy)methyl-3-methoxycarbonyl-2-phenylpiperidine (4.86 g, 13.4 mmol), NaHCO3 (1.68 g, 20.1 mmol), THF (5.0 ml), and H2O (30.0 ml) was added Cbz-Cl (2.51 g, 14.7 mmol), and the mixture was stirred with ice-cooling for 30 minutes. The mixture was extracted with AcOEt (40.0 ml×3). The combined AcOEt extracts were washed with sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give a viscous pale yellow oil (6.82 g). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 80.0 g). Elution with n-hexane-AcOEt (30:1/20: 1) gave title compound (6.51 g, 97.9%) as a viscous colorless oil. IRmax (film): 1735(s), 1700(s), 1605(w), 1585(w), 1495(m), 1250(s), 1115(s), 775(s), 740(m), 700(s) cm-1 ; 1H-NMR δ: 7.45-7.31(m, 4H), 7.31-7.15(m, 6H), 6.05(d, J=5.5 Hz, 0.6H), 5.87(d, J=5.5 Hz, 0.4H), 5.32-5.10(5.30, 5.25, 5.21, 5.18, and 5.13; m, 2H), 4.20-4.05(m, 1H), 3.65-3.45(m, 2.4H), 3.60(br.s, 3H), 3.40(dd, J=9.9, 6.6 Hz, 0.6H), 3.08-2.91(m, 1H), 2.63(dd, J=11.7, 11.7 Hz, 0.4H), 2.52(dd, J=13.6, 11.7 Hz, 0.6H), 2.11-1.98(m, 1H), 1.98-1.70(m, 2H), 0.86(s, 3.6H), 0.83(s, 5.4H), 0.026, 0.018, and 0.008(each s, total 6H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH3:22])[C:17]([C:19](O)=[O:20])=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH3:22])[C:17]([C:19]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[O:20])=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CN1CCNCC1
Reactant: Cc1ccc(Nc2ncnn3cc(C(=O)O)c(C)c23)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2ncnn3cc(C(=O)N4CCN(C)CC4)c(C)c23)cc1O
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a solution of Example 20 (7 mg, 0.023 mmol) in DMF (0.4 mL) at 25° C. was added N-methyl piperazine (3.5 μL, 0.03 mmol), 1-hydroxybenzotriazole (3 mg, 0.023 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7 mg, 0.05 mmol). After 24 hrs., the mixture was concentrated, diluted with water (2 mL), and extracted with ethyl acetate (5×2 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (2×5 mL). The crude material was purified by chromatography on silica gel eluting with a gradient of 5–10% methanol in chloroform to provide 6.23 mg (70%) of the title compound as white solid.