Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:35](O)[CH2:36][CH2:37][OH:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:35][CH2:36][CH2:37][OH:38]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 5-methyl-3-(2-nitrophenylsulfonyloxy)phenol (1.1 g, 4.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (1.22 g, 6.0 mmol) and 1,3-propanediol (1.52 g, 20 mmol) in anhydrous tetrahydrofuran (40 mL) was added 1,1'-(azodicarbonyl)dipiperidine (1.51 g, 6.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (60 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (1.05 g, 71%). 1H-NMR (300 MHz, CDCl3) δ 7.99 (d, J=7.7 Hz, 1H), 7.84 (m, 2H), 7.70 (m, 1H), 6.65 (s, 1H), 6.61 (s, 1H), 6.58 (s, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.82 (t, J=5.9 Hz, 2H), 2.27 (s, 3H), 2.00 (t, J=6.0 Hz, 2H), 1.67 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:24])([C:7]3[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:25].[H][H]>[Pd].N1C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:24])([C:7]3[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:25]
Reactant: [H][H]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(C#Cc4ccccc4)cc3CC[C@@H]12
Agent: [Pd]
Solvent: c1ccncc1
Product: CN1C(=O)CC[C@]2(C)c3ccc(C=Cc4ccccc4)cc3CC[C@@H]12

Procedure:
A 300 mg portion of the product of Example 284 was hydrogenated over palladium/barium sulfate catalyst in 25 mL of pyridine at 15 psi hydrogen pressure at ambient temperature for 1 h. The mixture was then filtered and concentrated under vacuum, and the residue was purified by chromatography on silica gel, eluting with 75% ethyl acetate/hexane. The product thereby obtained was further purified on a Chromatatron, eluting with 5% isopropanol in chloroform to obtain the desired product in the form of a yellow oil. High resolution mass spectroscopy showed the correct molecular ion of 332.201440.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH2:23][CH2:24][CH2:25][Br:26])[C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O>[Br:26][CH2:25][CH2:24][CH2:23][CH:18]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: COC(=O)C(Br)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCCBr)Oc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-nitrophenol (0.7 g), powdery potassium carbonate (0.7 g), methyl 2,5-dibromovalerate (1.37 g) and dimethylformamide (10 ml) was stirred at room temperature for 4 hours, to which was added ice-water, followed by extraction with ether. The ether layer was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was purified by means of silica gel chromatography [eluted with hexane-ethyl acetate (1:4)] to obtain methyl 5-bromo-2-(2-nitrophenoxy)valerate as an oily product. The yield was 1.30 g (77.8%).
Reaction SMILES: [CH3:1][C:2]1([CH:15]=O)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO>[CH3:1][C:2]1([CH:15]=[N:18][OH:19])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: NO
Reactant: CC1(C=O)OCCc2c1[nH]c1ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C=NO)OCCc2c1[nH]c1ccccc21
Reaction time: 16 h

Procedure:
A solution of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxaldehyde (547 mg), described in Example 777, aqueous hydroxylamine hydrochloride (2.5 ml of 5N) and aqueous sodium acetate (2.5 ml of 5N) and methanol (5 ml) is heated at 50° - 60° C. for 5 min. and then kept at 4° C. for 16 hr. The precipitate is collected and recrystallized from ethanol water to afford 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxaldehyde oxime, m.p. 176° - 178° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:15](=[O:16])[C:14](=[C:17]2[S:21][CH:20]=[CH:19][S:18]2)[C:13](=[O:22])[CH:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28]I.O>CN(C)C=O>[CH2:3]([N:10]1[C:15](=[O:16])[C:14](=[C:17]2[S:18][CH:19]=[CH:20][S:21]2)[C:13](=[O:22])[C:12]([CH3:28])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CCOC(=O)C1CN(Cc2ccccc2)C(=O)C(=C2SC=CS2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)C(=O)C(=C2SC=CS2)C1=O
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 175 mg) is suspended in dimethylformamide (10 ml), and thereto is added dropwise a solution of ethyl 1-benzyl-5-(1,3-dithiol-2-ylidene)-4,6-dioxopiperidine-3-carboxylate (1.3 g) in dimethylformamide (30 ml) under ice-cooling. The mixture is stirred at the same temperature for 20 minutes. Methyl iodide (0.7 ml) is added to the mixture, and the mixture is stirred under ice-cooling for 1.5 hours and then at room temperature for 1.5 hours. The mixture is poured into water and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane to give ethyl 1-benzyl-5-(1,3-dithiol-2-ylidene)-3-methyl-4,6-dioxopiperidine-3-carboxylate (1.15 g, 85.2%) as pale yellow needles, m.p. 111°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:37]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:37])=[O:25])=[CH:16][CH:15]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)CCCC(c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)c1cccnc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCC(c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)c1cccnc1
Reaction time: 8 h

Procedure:
2.0 g of 5-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-5-(3-pyridyl)pentanoic acid are dissolved in 30 ml of methanol and mixed with 3 ml of thionyl chloride at 0° C. The solution is stirred overnight, then rotary evaporated and the residue is chromatographed over a silica gel column.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[S:8][C:9]([C:34]#[C:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][OH:39])=[CH:10][C:11]=1[N:12]([C:25]([CH:27]1[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]1)=[O:26])[CH:13]1[CH2:18][CH2:17][CH:16]([O:19][CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)[CH2:15][CH2:14]1)=[O:6]>CO.C1COCC1>[OH:39][CH2:38][CH2:37][C:36]([CH3:40])([CH3:41])[C:35]#[C:34][C:9]1[S:8][C:7]([C:5]([OH:6])=[O:4])=[C:11]([N:12]([C:25]([CH:27]2[CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])[CH:13]2[CH2:14][CH2:15][CH:16]([O:19][CH:20]3[CH2:24][CH2:23][O:22][CH2:21]3)[CH2:17][CH2:18]2)[CH:10]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)CCO)cc1N(C(=O)C1CCC(C)CC1)C1CCC(OC2CCOC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)CCO)sc2C(=O)O)C2CCC(OC3CCOC3)CC2)CC1
Yield: 34 %

Procedure:
NaOH (0.500 mL of a 1.0 N aqueous solution) was added dropwise to a solution of 5-(5-hydroxy-3,3-dimethyl-pent-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(tetrahydro-furan-3-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (157 mg, 0.28 mmol) in methanol (1.5 mL) and THF (1.5 mL) at room temperature. The reaction was stirred until TLC indicated that all of the starting material was consumed. The reaction was evaporated to dryness to give a solid residue that was purified by column chromatography on reverse phase C18 silica gel (100% water to 5% acetonitrile/water). Fractions containing product were pooled and evaporated to provide 5-(5-hydroxy-3,3-dimethyl-pent-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(tetrahydro-furan-3-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid (Compound 314)(52 mg, 33%) as a solid. MS (m/z): 546.0 [M+H]+; HPLC retention time 3.75 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2(C(O)=O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Solvent: O
Solvent: CS(C)=O
Product: Brc1ccc(C2CCC3(CC2)OCCO3)nc1
Yield: 95.5 %

Procedure:
A solution of 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid (776 mg) in dimethylsulfoxide (3 ml) was stirred at 150° C. for 1.5 hours. After completion of the reaction, the reaction solution was left stand to room temperature, water was added and extracted with ethyl acetate. The organic solution was washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 5-bromo-2-(1,4-dioxaspiro[4,5]decane-8-yl)pyridine (646 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].FC(F)(F)S(O[CH2:38][CH:39]([F:41])[F:40])(=O)=O>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:38][CH:39]([F:41])[F:40])[N:11]=[CH:10]2)[CH2:17][C:18]([N:20]([N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH3:21])=[O:19])[CH3:2]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cn[nH]c2cc1C
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cnn(CC(F)F)c2cc1C
Yield: 70.3 %

Procedure:
Using the compound (767 mg, 1.82 mmol) of Example 241, step B and 2,2-difluoroethyl trifluoromethanesulfonate (534 mg, 2.49 mmol), and according to the method of Example 241, step C, the title compound (621 mg, yield 70%) was obtained as a colorless amorphous solid.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C@:9]1([NH2:31])[C@H:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([O:27]CC)=[O:26])=[O:8])C.Cl>O1CCCC1.O>[NH2:31][C@@:9]1([C:7]([OH:8])=[O:6])[C@H:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
12 mg of lithium hydroxide hydrate was added to 41 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 0.8 mL of tetrahydrofuran and 0.4 mL of water, and the mixture was stirred for 5.5 days at room temperature. The mixture was adjusted to pH=3 with 1N hydrochloric acid in an ice bath. 30 mL of water was added thereto, and after the mixture was stirred for 1 hour at room temperature and then purified by ion exchange resin (AG 50W-X8 Resin (H form), eluent: water, a 40% aqueous solution of tetrahydrofuran and a 10% aqueous solution of pyridine), the obtained solids were further washed with tetrahydrofuran, thereby yielding 26 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:17][N:18]1[C:22]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:21][CH:20]=[N:19]1
Reactant: COC(=O)c1cc(Br)cs1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)cs1
Yield: 99.5 %

Procedure:
A solution of methyl 4-bromo-2-thiophenecarboxylate (2.5 g, 11.31 mmol), potassium carbonate (7.81 g, 56.5 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.59 g, 12.44 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.289 g, 0.565 mmol) in 1,4-dioxane (47.1 ml) and water (9.42 ml) was stirred at 80° C. in a sealed tube for 1 h. The mixture was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-40% EtOAc in hexanes) affording methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.5 g, 11.25 mmol, 99% yield) as a yellow solid:
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][C:7]1[C:12](=[O:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[N:20]=[CH:21][CH:22]=[CH:23][C:9]=2[N:8]=1)([O-])=O.C(O)(=O)C>C(O)C.[Fe]>[NH2:1][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][C:7]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]2[N:20]=[CH:21][CH:22]=[CH:23][C:9]=2[N:8]=1
Reactant: O=c1c(Cc2ccccc2[N+](=O)[O-])nc2cccnc2n1-c1ccccc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccccc1Cc1nc2cccnc2n(-c2ccccc2)c1=O
Yield: 9.4 %

Procedure:
The mixture of 2-(2-nitrobenzyl)-3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine (1.39 g), iron (2.17 g) and acetic acid (1.16 g) in ethanol (15 ml) was refluxed for 3 hours. The reaction mixture was cooled and filtered. To the filtrate was added saturated sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was dried and evaporated. The crude product was purified by silica column chromatography to obtain 2-(2-aminobenzyl)-3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine (120 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[CH2:20]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH2:20]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:43])=[CH:37][CH:36]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(C(=O)OCC)c2)cc1
Reaction time: 2.5 h

Procedure:
A solution of 10.13 g of ethyl 3-amino-benzoate and 6.82 g of triethylamine in 100 ml of methylene 35 chloride is added dropwise to a solution of p-tetradecyloxyphenylacetyl chloride in 100 ml of methylene chloride over 15 minutes. The mixture is stirred for an additional 2.5 hours then washed with dilute hydrochloric acid. The organic layer is evaporated and the residue dissolved in 1.5 liter of ether then washed with dilute sodium hydroxide. The organic layer is dried and evaporated to a residue which is crystallized from carbon tetrachloride:hexane to give 24.4 g of the desired product as a white solid, m.p. 91°-94° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31](=[O:44])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31](=[O:44])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-propoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J35) (251 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (369 mg, 88%).
Reaction SMILES: [CH2:1]([S:9](Cl)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[O:27]=[C:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][S:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:11])=[O:10])=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CCCCCCCCS(=O)(=O)Cl
Agent: Cl
Product: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 1-octanesulfonyl chloride and 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, J=5.4 Hz, 3H), 1.15-1.40 (m, 10H), 1.60-1.75 (m, 2H), 2.40 (t, J=4.5 Hz, 4H), 2.94 (t, J=5.7 Hz, 2H), 3.54 (t, J=4.5 Hz, 4H), 6.99 (d, J=6.9 Hz, 2H), 7.09 (d, J=6.9 Hz, 2H), 9.31 (s, 1H); MS (ES) m/z: 367.0 (MH+); HRMS Calcd. for C19H30N2O2S(M+): 366.1977. Found: 366.1969. Anal. Calcd. for C19H30N2O2S: C, 62.26; H, 8.25; N, 7.64. Found: C, 62.40; H, 7.98; N, 7.59.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Cl[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8](=[O:19])[C:7]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C>C(O)C>[CH2:17]([O:16][C:14]([CH2:13][N:9]1[C:10]([CH3:12])=[CH:11][C:6]([S:1][CH2:2][CH2:3][OH:4])=[C:7]([N+:20]([O-:22])=[O:21])[C:8]1=[O:19])=[O:15])[CH3:18]
Reactant: CCOC(=O)Cn1c(C)cc(Cl)c([N+](=O)[O-])c1=O
Reactant: OCCS
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Cn1c(C)cc(SCCO)c([N+](=O)[O-])c1=O

Procedure:
2-Mercaptoethanol (0.168 mL, 2.4 mmol) was added to a stirred mixture of 4-chloro-1-ethyloxycarbonylmethyl-6-methyl-3-nitro-2-pyridinone (the product of Example 3, Step B, 549 mg, 2.0 mmol) and triethylamine (0.613 mL, 4.4 mmol) in ethanol (4 mL) and the mixture was heated to reflux for 15 min. The reaction was cooled and evaporated to a solid which was purified by flash column chromatography on silica gel (eluting with ethyl acetate), to give the title compound as a pale yellow crystalline solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[NH:12][C:13]2[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][C:18]=3[NH:17][C:16]3[N:24]=[CH:25][CH:26]=[CH:27][C:15]=3[C:14]=2[N:28]=1.[C-:29]#[N:30].[Na+]>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:29]#[N:30])[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[NH:12][C:13]2[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][C:18]=3[NH:17][C:16]3[N:24]=[CH:25][CH:26]=[CH:27][C:15]=3[C:14]=2[N:28]=1
Reactant: [C-]#N
Reactant: ClCc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: N#CCc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Yield: 45.3 %

Procedure:
A solution of 2-[2,6-dichloro-4-(chloromethyl)phenyl]-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepine (8.7 mg, 0.02 mmol), sodium cyanide (2.0 mg, 0.04 mmol) in dimethyl sulfoxide (1.0 mL) was stirred at 25° C. for 1 hour. The reaction mixture was diluted with methanol and purified on preparative LCMS at pH 10 to give the desired product (3.8 mg, 45%). LC/MS: 419 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([C:42](Cl)=[O:43])[CH:36]=[CH:35]2.C(=O)(O)[O-].[Na+]>ClCCl>[F:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([C:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]3)=[CH:22][CH:23]=1)=[O:43])[CH:36]=[CH:35]2
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Reactant: O=C(Cl)c1ccc2cc(F)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4cc(F)ccc4c3)cc2)c2ccccc12
Yield: 54.4 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (about 1.0 mmol) obtained in the last step and triethylamine (1.4 mL) were dissolved in dichloromethane (15 mL). In an ice bath, dichloromethane solution (10 mL) of the prepared 6-fluoro-2-naphthoyl chloride (about 1.2 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was removed under reduced pressure, and the resulting residue was chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 262 mg, at a total yield over two steps of reactions of 54.4%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12][NH:11]1)([O-])=O.[C:24](OCC)(=[O:26])C>COCCOC.[Pd]>[C:18]1([CH2:17][N:14]2[CH2:15][CH2:16][N:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:24](=[O:26])[N:11]3[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CCN1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: COCCOC
Product: O=C1Nc2ccccc2N2CCN(Cc3ccccc3)CCN12

Procedure:
Hexahydro-1-(2-nitrophenyl)-5-(phenylmethyl)-1H-1,2,5-triazepine (10.0 g) in 1,2-dimethoxyethane (250 ml) was hydrogenated at over 10% palladium on carbon (2.5 g) at room temperature and atmospheric pressure until theoretical uptake had been achieved. At this stage the reaction solution was colorless and t.l.c. on Alox-25 uv254 plates (Brinkmann) with ethyl acetate as developer showed a single component. The mixture was filtered through Celite and the filter pad washed with 1,2-dimethyloxyethane. The filtrate was evaporated to approximately 150 ml and 1,1-carbonyldiimidazole (20 g) was added. The solution was evaporated to dryness and the residue was dissolved in chloroform and applied to a column (75×6.4 cm) of dry column grade neutral alumina prepacked in chloroform. Elution with chloroform removed a major component from the column. Fractions were monitored by t.l.c. on Alox-25 un254 plates with ethyl acetate as developer. Appropriate fractions were evaporated and the crude titled product was crystallized from chloroform-heptane (seeding); wt. 7.56 g (77%), mp=129°-131°. Two crystallizations from the same solvent gave pure product, mp=127°-128°.