Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([C@:10]1([OH:41])[C@H:14]2[O:15][CH2:16][C@@H:17]([O:18][C:19]3[NH:20][C:21]4[C:22]([N:40]=3)=[N:23][C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:30][CH:29]=3)=[C:25]([Cl:27])[CH:26]=4)[C@H:13]2[O:12][CH2:11]1)[CH:8]=C.C[OH:43].C(Cl)Cl>C(#N)C.O.CCOC(C)=O.O.[Ru](Cl)(Cl)Cl>[Cl:27][C:25]1[CH:26]=[C:21]2[NH:20][C:19]([O:18][C@@H:17]3[CH2:16][O:15][C@@H:14]4[C@:10]([CH2:7][CH:8]=[O:43])([OH:41])[CH2:11][O:12][C@H:13]34)=[N:40][C:22]2=[N:23][C:24]=1[C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:32][CH:33]=1
Reactant: CO
Reactant: C=CC[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CC[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ruthenium(III) chloride hydrate (3.7 mg, 0.016 mmol) and sodium periodate (121.7 mg, 0.569 mmol) were added to a stirred solution of (3R,3aR,6R,6aS)-6-allyl-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-3,3a,5,6a-tetrahydro-2H-furo[3,2-b]furan-6-ol (122.5 mg, 0.250 mmol) in acetonitrile (2.14 ml) and water (0.36 ml). The reaction mixture was stirred at room temperature for 3 h, then partitioned between EtOAc (75 ml) and saturated aqueous sodium thiosulfate (40 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a colorless residue. This material was dissolved in EtOAc and loaded onto three 500 micron 20 cm×20 cm silica gel plates, which were developed using 10% MeOH/DCM. The silica containing the product band was collected and eluted with 10% MeOH/DCM (80 ml). The solvent was evaporated under reduced pressure and the resulting residue was lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C26H22ClN3O5 491.12 observed m/e: 492.18 (M+H)+ (Rt 1.18/2 min).
Reaction SMILES: C(OC([N:8]1[C@H:17]([C:18](=[O:41])[NH:19][C@H:20]([C:37]([O:39][CH3:40])=[O:38])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[C:30]=3[CH3:36])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:42][CH2:43][C@H:44]([C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][C:54]5[CH:59]=[CH:58][C:57]([Cl:60])=[C:56]([Cl:61])[CH:55]=5)[CH:47]=4)[O:45][C:12]3=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:62]>C(Cl)Cl>[ClH:60].[ClH:62].[CH3:40][O:39][C:37](=[O:38])[C@@H:20]([NH:19][C:18]([C@@H:17]1[CH2:16][C:15]2[CH:14]=[C:13]3[O:42][CH2:43][C@H:44]([C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][C:54]5[CH:59]=[CH:58][C:57]([Cl:60])=[C:56]([Cl:61])[CH:55]=5)[CH:47]=4)[O:45][C:12]3=[CH:11][C:10]=2[CH2:9][NH:8]1)=[O:41])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[C:30]=2[CH3:36])=[CH:26][CH:27]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]-isoquinoline-7-carboxylic acid tert-butyl ester (50 mg) was taken in 2 mL of DCM and cooled to 0° C., HCl (0.5 mL, 4N in dioxane) was added and stirred at room temperature for 2 hours. All volatiles were evaporated and residue was washed with hexanes and dried under vacuum to get (S)-2-({(3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride (46 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([I:41])[C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34]>ClCCl>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([I:41])[C:38]=1[O:39][CH3:40])[C:33]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:34]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1I
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (1.65 g) and 37% formalin (1.09 mL) in the same manner as in Example 1 was dissolved in dichloromethane (15 mL), and diisopropylethylamine (3.0 mL) and 3-chloro-5-iodo-4-methoxybenzoyl chloride (3.05 g) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from a mixture of n-hexane and ethyl acetate in a mixing ratio of 1:1 to obtain the title compound (2.44 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH:12]([CH3:20])[C:13]([O:15]C(C)(C)C)=[O:14])=[CH:4][C:3]=1[C:21](=[O:34])[NH:22][CH2:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH:12]([CH3:20])[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[C:21](=[O:34])[NH:22][CH2:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2
Reactant: CC(NCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(NCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)C(=O)O
Yield: 5.6 %

Procedure:
To a solution of [2-[4-chloro-3-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)carbamoyl-phenylamino]-ethylamino]-propionic acid, 1,1-dimethylethyl ester (0.20 g, Example 7a) in dichloromethane (5 ml), was added trifluoroacetic acid (2 ml). After 15 h the solution was concentrated and purified by RPHPLC (eluting with 15-95% MeCN in 0.1% AcONH4 aqueous) to afford the title compound as a solid (0.010 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:9]=1[NH:20][C:21](=[O:33])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:33]=[C:21]1[CH2:22][C:23]([C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[C:31]#[N:32])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][C:9]=2[NH:20]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccccn4)cc3NC(=O)C2)c1

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-pyridin-2-yl-phenyl}-carbamic acid tert.-butyl ester (Example K13) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a brown powder (29 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:3]=1[CH2:14]O.[Br:16]P(Br)Br>ClCCl>[Br:16][CH2:14][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: BrP(Br)Br
Reactant: CCN(CC)Cc1cccc(Cl)c1CO
Solvent: ClCCl
Product: CCN(CC)Cc1cccc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To {2-chloro-6-[(diethylamino)methyl]phenyl}methanol (3.0 g, 13.2 mmol) in anhydrous dichloromethane (80 mL) was added dropwise tribromophosphane (2.5 mL, 26.4 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dried in vacuo, affording {[2-(bromomethyl)-3-chlorophenyl]methyl}diethylamine. The product was used without further purification.
Reaction SMILES: [C:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:5][C:6]([OH:8])=O)#[N:2].[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[N+](C1C=C(B(O)O)C=CC=1)([O-])=O>C1(C)C=CC=CC=1>[C:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:5][C:6]([N:23]([CH3:22])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:8])#[N:2]
Reactant: COc1ccc(C(C#N)(CCC(=O)O)C(C)C)cc1OC
Reactant: CNCCc1ccccc1
Agent: O=[N+]([O-])c1cccc(B(O)O)c1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C#N)(CCC(=O)N(C)CCc2ccccc2)C(C)C)cc1OC

Procedure:
5.0 g of 4-cyano-4-(3,4-dimethoxy-phenyl)-5-methyl hexanoic acid (0.0172 mol) and 2.32 g, 2.50 ml of N-methylphenethylamine (0.0172 mol) in the presence of 30 mg of 3-nitrophenylboronic acid (~1 mol %) were set to reflux in 80 mls of toluene. The formed water was removed by use of Dean and Stark apparatus. After overnight heating GC/MS analysis indicated complete conversion of the acid (RT=25.07 mins) to the amide (RT=38.33 mins, m/z 408). After allowing to cool, the toluene solution was washed with 100 ml of 1.0N NaOH solution. The basic aqueous layer was re-extracted with 100 ml of toluene. The organic layers were combined and washed with 100 ml of water. The organic layers were dried over MgSO4, filtered and evaporated to dryness giving the amide in essentially quantitative yield as a yellow/green coloured oil. IR (liq film) ν (C=0)=1649.9 cm-1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:18][C:19]1[C:20]([CH3:48])=[C:21]([C:25]2[N:26]=[C:27]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[O:41])=[CH:36][CH:35]=3)[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CCO>[C:14]([C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([CH2:2][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[N:26]=[C:27]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:40]([N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[O:41])=[CH:38][CH:39]=4)[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=3)[C:20]=2[CH3:48])[CH:13]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1c(N)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1
Reactant: CCOC(=O)c1ccc(C(C)(C)C)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1ccc(C(C)(C)C)cc1CNc1cccc(-c2cn(C)c(=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)c1C
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A 48-mL sealed tube equipped with a magnetic stirring bar was charged with bromide 101c (120 mg, 0.4 mmol), aniline 101g (168 mg, 0.4 mmol), diisopropyethylamine (0.08 mL, 0.48 mmol) in EtOH (3 mL). After the mixture was stirred at 100° C. for 16 h, aqueous Na2CO3 (5 mL) was added. The aqueous phase was extracted with EtOAc (2×5 mL), and the combined organic extracts were washed with brine (5 mL), dried with Na2SO4 and concentrated. The residue was chromatographed with (gradient, 50%-100% EtOAc/hexanes) to afford 100 mg (42%) of 101h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][CH2:28][S:29][CH3:30])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:43])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:32])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:30])=[O:43])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CSCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: -74 °C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
To a stirred solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-(methylthio)ethyl]-1-naphthalenecarboxamide (i.e. the title product of Step A) (100 mg) in dichloromethane (10 mL) was added MCPBA (47 mg, 70%) at −78° C. The reaction mixture was stirred at −78 to −70° C. for 2.5 h, then quenched with saturated sodium bicarbonate, extracted with dichloromethane, washed with brine, dried with sodium sulfate, and concentrated to afford the title compound as a white solid (102 mg, 99% yield).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:15]3=[N:16][CH:17]=[C:18]([C:20]#[N:21])[CH:19]=[C:14]3[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([Cl:31])[CH:24]=3)[C:12]2=[O:32])[CH2:7][CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[Cl:31][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH3:30])[CH2:22][N:13]1[C:14]2[C:15](=[N:16][CH:17]=[C:18]([C:20]#[N:21])[CH:19]=2)[N:11]([C@H:8]2[CH2:7][CH2:6][C@@H:5]([OH:4])[CH2:10][CH2:9]2)[C:12]1=[O:32]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@@H](OC(C)=O)CC3)c3ncc(C#N)cc32)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@@H](O)CC3)c3ncc(C#N)cc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-(cis-4-acetoxycyclohexyl)-1-(3-chloro-4-methoxybenzyl)-6-cyano-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (150 mg) in methanol (3 ml) was added potassium carbonate (180 mg). The mixture was stirred at ambient temperature for 2 hours, then potassium carbonate (180 mg) was added thereto. After stirring for 2 hours, the mixture was added with potassium carbonate (180 mg). After stirring overnight, the mixture was added with water and extracted with chloroform. The extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a preparative thin-layer chromatography on silica gel developing with a mixture of ethyl acetate and n-hexane (2:1) to give 1-(3-chloro-4-methoxybenzyl)-6-cyano-3-(cis-4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (50 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]2[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:23]([O:25]C)=[O:24])=[O:7])([CH3:4])[CH3:3].[OH-].[Li+]>O1CCCC1.O>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]2[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:23]([OH:25])=[O:24])=[O:7])([CH3:1])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](C2CCN(S(C)(=O)=O)CC2)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](C2CCN(S(C)(=O)=O)CC2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of the compound prepared in Example 62 (2.87 g, 7.36 mmol) in tetrahydrofuran (20 mL) and water (20 mL) at 0° C. was added lithium hydroxide (0.35 g, 14.7 mmol). The reaction was warmed to room temperature and stirred overnight whereupon it was partitioned between methyl tert-butyl ether and water. The aqueous layer was separated and carefully acidified to pH 1 with 6 N hydrochloric acid. The aqueous solution was extracted with ethyl acetate (2×300 mL) and the combined organic extracts concentrated to give the title compound (2.35 g, 85%) as a white solid.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>O1CCOCC1.CCOCC>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1cccc2c(Cl)c(C(=O)C(C)C)cnc12
Reactant: Cc1ccccc1N
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cccc2c(Nc3ccccc3C)c(C(=O)C(C)C)cnc12
Yield: 19.2 %

Procedure:
3-isobutyryl-4-chloro-8-methoxyquinoline (6.0 g, 0.022 mol) and o-toluidine (6 ml, 0.055 mol) were heated in 1,4-dioxan (100 ml) for 45 minutes. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and brine. The solution was dried and evaporated to an oil, which was chromatographed (silica gel, dichloromethane) to afford a yellow oil. Trituration in ether gave yellow crystals of 3-isobutyryl-4-(2-methylphenylamino)-8-methoxyquinoline (1.41 g, 18.3%), m.p. 116°-8°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:32])([CH3:31])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([N+:27]([O-])=O)[CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:30])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.[Zn]>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:32])([CH3:31])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([NH2:27])[CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:30])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc([N+](=O)[O-])ccc2NC1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc(N)ccc2NC1=O
Yield: 85.4 %

Procedure:
To a solution of 310 mg (0.73 mmol) 2-benzyloxycarbonylamino-2-methyl- N-[7-nitro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]propanamide (Step B) in 20 mL of methanol was added 78 mg (1.5 mmol) of ammonium chloride followed by 669 mg (10.2 mmol) of zinc dust. The resulting mixture was heated at reflux for four hours. The solids were removed by filtration through Celite. The filter pad was washed with 30 mL of hot methanol. The filtrate was combined and the solvent was removed under vacuum. The residue was dissolved in 10 mL of 1 N aqueous hydrochloric acid and the solids were filtered away. To the resulting solution was added sufficient 5 N aqueous sodium hydroxide until the pH was approximately 12. The solution was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water then brine, dried over magnesium sulfate and filtered. The solvent was removed under vacuum to afford 256 mg (85%) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.48 (s, 3H), 1.50 (s, 3H), 1.78 (m, 1H), 2.47 (m, 1H), 2.71 (m, 1H), 2.82 (m, 1H), 3.67 (s, 2H), 4.44 (m, 1H), 5.05 (s, 2H), 5.39 (s, 1H), 6.50 (m, 2H), 6.74 (d, 8 Hz, 1H), 7.04 (d, 7 Hz, 1H), 7.32 (m, 6H). FAB-MS: calculated for C22H26N4O4 410; found 411 (M+H, 100%).
Reaction SMILES: C(Cl)Cl.COC([N-:8][N+:9]([O-:11])=[O:10])=O.[NH4+:12].N>CC#N>[NH-:8][N+:9]([O-:11])=[O:10].[NH-:8][N+:9]([O-:11])=[O:10].[NH4+:12].[NH4+:8]
Reactant: COC(=O)[N-][N+](=O)[O-]
Agent: N
Agent: [NH4+]
Solvent: CC#N
Solvent: ClCCl
Product: [NH-][N+](=O)[O-]
Temperature: -60 °C
Reaction time: 1 h
Yield: 121.4 %

Procedure:
A suspension/solution of 100 mmoles of N2O5 in 175 ml. of CH2Cl2 was prepared by ozonolysis of N2O4 at -60° C. This suspension was diluted by adding 60 ml. of CH3CN, cooled to -78° C., and 100 mmoles (13.7 grams) of the ammonium N(methoxycarbonyl)N-nitro-amide (ammonium N-nitromethylcarbamate) made in Example IV was added to the reaction mixture. The mixture was then stirred for 1 hour while it was allowed to slowly warm to -60° C. over that hour. Excess ammonia gas was then added until the pH reached 9. A thick precipitate developed. The reaction mass was concentrated in vacuo in a rotary evaporator, and 100 ml. of CH3CN and 100 ml. of ethylacetate were then added. The reaction mixture was then filtered and then washed with ethylacetate. The filtrate was then concentrated to approximately 30 ml. and 200 ml. of CHCl3 was then added to precipitate the product from the filtrate. The solid ammonium dinitramide product was then filtered and collected. The product was then dried in vacuo to yield 6.4 grams (52%) of ammonium dinitramide salt.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH2:49])[CH2:42][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)C>CN(C=O)C>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([NH:49][C:12]([CH:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:42][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Solvent: CN1CCOCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A solution of 87 mg (0.34 mmol) of (S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (Example 1, Step B) and 0.131 mL (1.2 mmol) 4-methylmorpholine was stirred at 25° C. for 30 minutes, after which 136 mg (0.36 mmol) 0-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate in 4 mL dry DMF was added. The resulting solution was cooled in an ice-bath and 150 mg (0.34 mmol) 2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethylamine (Example 3, Step D) was added. The resulting solution was warmed to 25° C. and stirred for 30 minutes. The mixture was then poured into 35 mL diethyl ether, and washed sequentially with 25 mL each of 2.5% aqueous HCl solution, brine, saturated aqueous sodium bicarbonate solution, and finally twice with brine. The mixture was then dried over anhydrous sodium sulfate and concentrated at reduced pressure to give an amber oil that was purified by preparative thin-layer chromatography on a 1000 μm silica gel plate with 50:50:1 ethyl acetate:hexane:methanol as eluant to give 46 mg (24%) of the title compound as a pale amber glass.
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[CH2:16][CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:15])=[CH:11]/[C:12]([OH:14])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>>[CH2:33]([N:35]([CH2:36][CH3:37])[C:12](=[O:14])/[CH:11]=[C:10](\[CH3:15])/[CH2:9][CH2:8]/[CH:7]=[C:6](/[CH2:5][O:4][C:1](=[O:3])[CH3:2])\[CH2:16][CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:34]
Reactant: CCNCC
Reactant: CC(=O)OC/C(=C/CC/C(C)=C/C(=O)O)CC/C=C(\C)CCC=C(C)C
Agent: O=C(Cl)C(=O)Cl
Product: CCN(CC)C(=O)/C=C(\C)CC/C=C(\CC/C=C(\C)CCC=C(C)C)COC(C)=O

Procedure:
Following the same manner as in Example 12, 1.0 g of (E,Z,E) and (E,E,E)-7-acetoxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraenoic acid was converted to the corresponding acid chloride with 1.5 ml of oxalyl chloride and the reaction with 1.0 ml of diethylamine afforded 820 mg of the end product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)=[C:6]([N+:17]([O-])=O)[CH:5]=1.CC(=O)OCC>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][C:13]([F:15])([F:16])[CH2:12]2)=[C:6]([NH2:17])[CH:5]=1
Reactant: COC(=O)c1ccc(OC2CC(F)(F)C2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OC2CC(F)(F)C2)c(N)c1
Reaction time: 16 h
Yield: 79.8 %

Procedure:
1.4 g of 4-(3,3-Difluoro-cyclobutoxy)-3-nitro-benzoic acid methyl ester were dissolved using 50 ml of EA and 10 ml of acetic acid, 200 mg of Pd/C 10% (50% water) added and hydrogenated under an atmosphere of hydrogen at normal pressure for 16 h at room temperature. The reaction mixture was filtrated, 100 ml of EA added and washed twice using 30 ml of a saturated aqueous Na2CO3-solution. The organic layer was dried using MgSO4 and volatiles were evaporated to yield 1.0 g of the title compound that was used without further purification.