Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.Cl.Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=2)[CH2:24][CH2:23]1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1
Yield: 97.2 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (15.0 g), 1-(2-pyrimidyl)piperazine dihydrochloride (19.8 g) and potassium carbonate (42.0 g) in dimethylformamide (200 ml) was stirred at 80° C. for 8.5 hr. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (24.0 g). The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give a pale-brown oil (18.7 g). The obtained pale-brown oil was crystallized from ethyl acetate: hexane (5:1, 100 ml) and the crystals were recrystallized from ethyl acetate:hexane (10:1, 100 ml) to give the title compound (12.8 g) as white crystals,
Reaction SMILES: [NH:1]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>C(O)C.O.[Li+].[OH-]>[N:1]1([CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCNCCCNCCNC1
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(CN2CCCNCCNCCCNCC2)cc1
Reaction time: 5 h
Yield: 66.6 %

Procedure:
To solution of Cyclam (0.913 g, 4.5 mmol) dissolved in a mixture of ethanol:water (5:1 by vol.) (18 ml) was added a solution of 4-chloromethylbenzoic acid (0.157 g, 0.92 mmol) in aqueous LiOH (53 mg in 4 ml of water). This mixture was thereafter refluxed vigorously with stirring for 5 hours. Then the solvent was removed at reduced pressure, and the residue was dissolved in 13 ml of water. The aqueous solution obtained was then extracted with chloroform (10 times 3 ml) and the aqueous layer was concentrated at reduced pressure down to 2 ml. The product as a white solid was precipitated by adding the solution of concentrated HCl and ethanol and purified by recrystallizing from ethanol/water/HCl to yield 0.205 g of the title compound. According to the LC-MS, the assay of 4-(1,4,8,11-tetraazacyclotetradec-1-ylmethyl)-benzoic acid hydrochloride was >95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])N.[C:31]([N:50]=[C:51]=[O:52])(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>>[C:31]([NH:50][C:51](=[O:52])[O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N=C=O
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: NC(=O)[O-]
Product: CCCCCCCCCCCCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 42 %

Procedure:
The compound 89 (245 mg, 0.6 mmol) was converted to the carbamate with stearoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 96 (179 mg, 42%). Mp. 73-77° C. Rf 0.46 (EtOAc).
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.BrC[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C.O>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:5][CH2:4][C:3]([OH:11])=[O:10])([O-:24])=[O:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1ccccc1[N+](=O)[O-]
Reaction time: 0.05 h
Yield: 56.9 %

Procedure:
Sodium hydride (60% in paraffin oil, 1.0 g, 25 mmol) was added to a solution of diethyl malonate (3.2 g, 20 mmol) in DMF (20 ml) and the mixture was stirred for 3 min. 1-Bromomethyl-2-nitrobenzene (4.3 g, 20 mmol) was then added in portions during 5 min. The reaction mixture was stirred for 3 h, diluted with water, and extracted twice with ethyl acetate. The combined organic phases was washed with water and evaporated. The residue was suspended in acetic acid (40 ml) and 7.5 M HCl (10 ml) was added. The mixture was refluxed for 19 h, cooled and partitioned between diethyl ether and saturated aqueous NaHCO3. The organic phase was washed with saturated aqueous NaHCO3 and then acidified with 2M HCl. The precipitate was collected by filtration and dried to give the title compound (2.22 g, 77%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].B.CSC.Cl>C1COCC1>[C:11]1([CH2:10][CH2:9][NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCCCCCNC(=O)Cc1ccccc1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CCCCCCCNCCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
N-Heptyl-2-phenylacetamide (0.886 g, 3.797 mmol) was dissolved in THF (10 ml) and was cooled to 0° C. under argon atmosphere. (Methylthio)methane compound with borane (1:1) (0.721 g, 9.492 mmol) was added and the mixture was refluxed for 5 hours. After the mixture was cooled to room temperature, 5 ml HCl (10%) was gently added and the mixture was stirred overnight. The solvent was removed by evaporation. EtOAc (20 ml) was added and the organic phase was washed with K2CO3 (2M, 2×20 ml). The crude was purified by flash chromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 0.584 g of N-(2-phenylethyl)heptan-1-amine (yield 70.1%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:19][CH3:20].Cl.[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29]Cl)[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:19][CH3:20])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1
Reactant: COc1cc(CCl)cc(Cl)n1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2cc3ncnc(Oc4ccccc4)c3cc2OC)cc(Cl)n1
Temperature: 80 °C
Yield: 83.5 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.1 g, 4.1 mmol), (prepared as described for the starting material in Example 13), 2-chloro-4-chloromethyl-6-methoxypyridine hydrochloride (0.88 g, 3.9 mmol) and potassium carbonate (2.0 g, 14 mmol) in DMF (20 ml) was heated at 80° C. for 1 hour. The mixture was allowed to cool, diluted with water and the precipitated product collected by filtration, washed with water and dried to give 7-((2-chloro-6-methoxy-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline (1.38 g, 79%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1>[Pd].C(O)C.C(O)(=O)C>[OH:2][CH2:1][CH2:3][NH:4][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCO
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCCO)CC1

Procedure:
A slurry of 10% palladium on charcoal (catalytic) in dry ethanol (3 mL) and acetic acid (5 drops) was added to a solution of ethanolamine (0.24 mL) and tert-butyl 4-oxopiperidine-1-carboxylate (0.80 g) in dry ethanol (10 mL) and hydrogenated at 2 bar for 26 hours. The solution was filtered through a glass fibre filter and the filtrate concentrated in vacuo to give the sub-titled compound (0.98 g) as a pale yellow oil.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O>[C:1]([NH:5][C:6]1[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC(C)(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To a solution of methyl 3-(tert-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (120 mg, 0.34 mmol) in THF (20 mL) and water (2 mL) was added sodium hydroxide (54.39 mg, 1.36 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), adjusted to pH 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 3-(tert-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (80 mg, 66%).
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[CH:5][CH:4]=1.[CH3:14][N:15]1[C:27]2[CH:26]=[CH:25][C:24]([CH:28]=O)=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2.N1CCCCC1>C(O)C>[I-:1].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](/[CH:13]=[CH:28]/[C:24]2[CH:25]=[CH:26][C:27]3[N:15]([CH3:14])[C:16]4[C:21]([C:22]=3[CH:23]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:5][CH:4]=1
Reactant: Cc1cc[n+](C)c2ccccc12
Reactant: Cn1c2ccccc2c2cc(C=O)ccc21
Agent: [I-]
Solvent: C1CCNCC1
Solvent: CCO
Product: Cn1c2ccccc2c2cc(/C=C/c3cc[n+](C)c4ccccc34)ccc21
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A solution mixture of 1,4-dimethylquinolinium iodide (0.14 g, 0.5 mmol), 3b (0.13 g, 0.6 mmol) and piperidine (0.1 mL) in ethanol (40 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by precipitation from methanol and ethyl acetate to afford Me-SLM (0.14 g) in 62% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J=6.4 Hz, 1H), 9.12 (d, J=8.4 Hz, 1H), 8.86 (s, 1H), 8.49 (d, J=6.4 Hz, 1H), 8.45-8.23 (m, 5H), 8.15 (d, J=8.8 Hz, 1H), 8.06 (t, J=7.6 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 4.51 (s, 3H), 3.95 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 152.9, 147.3, 144.8, 142.2, 141.2, 138.7, 134.8, 128.8, 127.4, 126.6, 126.4, 126.3, 126.0, 122.6, 122.0, 121.8, 120.4, 119.7, 119.1, 116.0, 115.0, 109.8, 109.7, 44.3, 29.3. HRMS (MALDI-TOF) m/z Calcd for C25H21N2 349.1699. Found 349.1694 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=O)[O:29][C:27](=[O:28])[C:26]2=[CH:32][CH:33]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl.O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:30](=[O:29])[C:25]3[C:26](=[CH:32][CH:33]=[C:23]([Br:22])[CH:24]=3)[C:27]2=[O:28])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(N2C(=O)c3ccc(Br)cc3C2=O)cc1)NC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 70.3 %

Procedure:
To a suspension of 4-amino-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (6.78 mmol, 1.99 g) in dichloromethane (90 mL) was added a solution of 4-bromophthalic anhydride (6.78 mmol, 1.54 g) in dichloromethane (30 mL) and 1,1′-carbonyldiimidazole (6.78 mmol, 1.1 g) at room temperature. The resulting solution was stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with water (100 mL) and layers were separated. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave a crude product which was purified by silica gel column chromatography to obtained 2.4 g (70%) of a white solid: mp 168-170° C. HR MS C23H23BrN2O6): Obs mass, 525.0656. Calcd mass, 525.0637 (M+Na).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1c[nH]c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1c[nH]c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-hydroxy-1H-indole-3-carboxylic acid (1.05 g) in N,N-dimethylformamide (11.0 mL) were added sodium carbonate (722 mg) and benzyl bromide (0.775 mL), followed by stirring at room temperature overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain benzyl 6-hydroxy-1H-indole-3-carboxylate (1.04 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:21]2)[CH:12]=[CH:11]1>>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)[CH:12]=[CH:11]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4cc[nH]c34)CC2)c1
Reactant: Clc1cccc(I)c1Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4ccn(-c5cccc(Cl)c5Cl)c34)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1,2-dichloro-3-iodobenzene and N-{3-[1-(1H-indol-7-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[C:15]([CH2:20][O:21][CH2:22][CH3:23])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][CH:15]([CH2:20][O:21][CH2:22][CH3:23])[C:16]=3[C:17]=2[C:18]=1[CH3:19])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOCc1cccc2[nH]c3cnc(C(=O)OCC)c(C)c3c12
Agent: [Pd]
Solvent: CCO
Product: CCOCC1CCCc2[nH]c3cnc(C(=O)OCC)c(C)c3c21
Reaction time: 2 h

Procedure:
5-Ethoxymethyl-4-methyl-beta-carboline-3-carboxylic acid ethyl ester (1 g) is shaken in ethanol (80 ml) with 10% palladium carbon (0.3 g) at a hydrogen pressure of 40 bars and a temperature of 70° C. for 2 hours. After filtering off of the catalyst, the reaction solution is evaporated, the residue is crystallized by treatment with a mixture of acetic acid and ethanol. The yield in 5,6,7,8-tetrahydro-5-ethoxymethyl-4-methyl-beta-carboline-3-carboxylic acid ethyl ester is 0.66 g.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([NH:27][CH2:19][CH:16]2[CH2:17][CH2:18][N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[CH2:14][CH2:15]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCCC1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Product: c1cc(N2CCC(CNC3CCCCC3)CC2)ccc1CN1CCCC1

Procedure:
Prepared from the product of Example 16 and cyclohexylamine.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1)([O-:31])=[O:30]>O1CCCC1>[ClH:21].[ClH:1].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:39]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:37][CH:36]=3)=[O:40])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccc([N+](=O)[O-])cc1
Yield: 110.5 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), tetrahydrofuran (50 ml), triethylamine (4.2 ml; 30 mmole) and 4-nitrophenyl isocyanate (1.64 g; 10 mmole). Recrystallization from methanol/water provided the title compound (2.79 g; 55% yield) as yellow-white crystals, m.p. 230°-231° C. (dec.).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[C:10]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:32][C:33]=3[CH3:34])=[C:23]([O:41][CH3:42])[CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[C:10]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:32][C:33]=3[CH3:34])=[C:23]([O:41][CH3:42])[CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(Cc3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A mixture of ethyl [1-benzyl-3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetate (539 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-benzyl-3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetic acid (423 mg, yield 83%). The crystals were recrystallized from ethanol-hexane. melting point: 99–100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([S:50]([C:53]2[CH:58]=[CH:57][C:56]([NH:59][C:60]3[N:65]=[CH:64][C:63]([NH2:66])=[CH:62][N:61]=3)=[CH:55][CH:54]=2)(=[O:52])=[O:51])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl>[C:37]([O:41][C:42]([N:44]1[CH2:45][CH2:46][CH:47]([S:50]([C:53]2[CH:54]=[CH:55][C:56]([NH:59][C:60]3[N:65]=[CH:64][C:63]([NH:66][C:4](=[O:6])[C:3]4[CH:7]=[C:8]([NH:11][C:12]([C:14]5[S:15][CH:16]=[CH:17][CH:18]=5)=[O:13])[CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:62][N:61]=3)=[CH:57][CH:58]=2)(=[O:51])=[O:52])[CH2:48][CH2:49]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5cccs5)ccc4Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
Intermediate 15 (Example 23) (0.124 g, 0.439 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.093 g, 0.53 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.10 mL, 0.88 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.20 g, 0.462 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.1 g, 32%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CS(O[CH2:18][C@H:19]1[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1)(=O)=O.O>CN(C=O)C>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[CH2:18][C@H:19]1[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 112.5 °C
Reaction time: 16 h
Yield: 86388.6 %

Procedure:
Potassium phthalimide (28.4 g 0.15 mol) was added to a solution of (S)-tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (37.7 g, 0.13 mmol) in DMF (256 mL). The resulting mixture was stirred at 110-115° C. for 16 hr, and then cooled to room temperature and poured into water (500 mL). The aqueous layer was extracted with CH2Cl2 (3×250 mL). The combined organic layers were then washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was diluted in hexanes (200 mL) and then stirred vigorously while adding slowly Et2O (100 mL). The oil turned into a solid, which was filtered on a Buchner funnel. The filter cake was washed with hexanes and dried under reduced pressure. The mother liquor was concentrated, and the crude residue purified by silica gel flash chromatography (10-60% EtOAc in hexanes) to produce a second crop of solid. Both solids were combined to provide the title compound (38.9 g, 88%). 1H NMR (300 MHz, CDCl3) δ ppm 1.45 (s, 9 H), 2.68-2.82 (m, 1H), 2.91-3.04 (m, 1H), 3.44 (dt, J=11.45, 2.81 Hz, 1H), 3.63-3.79 (m, 3H), 3.82-4.03 (m, 3H), 7.70-7.78 (m, 2H), 7.84-7.88 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17]O)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)([CH2:16][CH2:17][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: C1CCNC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CCCC2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and pyrrolidine following procedures analogous to those described in Example 178. LC-MS Method 2 tR=1.167 min, m/z=475.1; 1H NMR (CDCl3) 1.48 (d, 3H), 2.00 (m, 2H), 2.13 (m, 2H), 2.22 (m, 1H), 2.32 (m, 1H), 2.43 (m, 1H), 2.58 (m, 1H), 2.76 (m, 2H), 2.88 (m, 1H), 3.18 (m, 1H), 3.61 (m, 1H), 3.75 (m, 1H), 4.41 (s, 2H), 5.52 (m, 1H), 6.80 (d, 2H), 7.02 (t, 2H), 7.13 (m, 2H), 7.24 (m, 2H).