Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[C:17]=1[O:18][CH:19]([CH3:21])[CH3:20])([O-:5])=[O:4].I[CH3:23]>CN(C=O)C>[CH3:23][N:15]1[C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[C:17]([O:18][CH:19]([CH3:21])[CH3:20])[C:10]=2[CH2:11][CH2:12][CH2:13][C:14]1=[O:16]
Reactant: CC(C)Oc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
750 mg of potassium nitrate are added, in portions, to a solution of 1.3 g of 6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 13 ml of trifluoroacetic anhydride brought back to −5° C. The reaction medium is stirred for 5 minutes at −5° C. and then brought back to pH 5 by adding a saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate and the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of heptane and of ethyl acetate (80/20 to 50/50). 450 mg of 7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are obtained in the form of a beige solid. 91 mg of sodium hydride at 50% are added to a solution of 445 mg of 7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 10 ml of DMF. The reaction medium is stirred for 10 minutes at ambient temperature and then 263 mg of iodomethane are added. The reaction medium is stirred for 1 hour at ambient temperature, poured into ice-cold water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure, so as to give 417 mg of 1-methyl-7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a yellow gum.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][CH2:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:4][CH2:3]1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.CO.[ClH:32]>C(O)C>[ClH:32].[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21]([CH:28]=[C:10]2[O:9][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]2=[O:18])=[CH:20]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N2CCN(C)CC2)OCC1=O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)C1=C(N2CCN(C)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 9 %

Procedure:
To a solution of ethyl 2-(4-methylpiperazinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.038 g, 0.15 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in methanol (0.17 mL, 0.34 mmol) was added at ambient temperature. The mixture was refluxed for 40 min. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.0069 g, y. 9%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42](F)(=[O:44])=[O:43]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[S:42]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[F:35])(=[O:44])=[O:43])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2ccn3C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(F)c1ccccc1F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2cc(S(=O)(=O)c2ccccc2F)n3C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 42.9 %

Procedure:
To a −75° C. solution of 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester 2 (500 mg, 1.25 mmol) in THF (25 mL) was slowly added t-BuLi (1.47 mL, 2.5 mmol). The reaction mixture was stirred for 30 minutes at which time 2-fluoro-benzenesulfonyl fluoride 2a (222 mg, 1.5 mmol) was added. The reaction was stirred for 1.5 h at which time the ice bath was removed and the reaction was allowed to warm over 45 min. The reaction mixture was quenched with a saturated solution of ammonium chloride (55 mL). The mixture was then extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with brine (25 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a yellow oil. The oil was chromatographed over silica eluting with hexane:ethyl acetate (17:3) to afford 300 mg (43%) of 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-(2-fluoro-benzenesulfonyl)-indole-1-carboxylic acid tert-butyl ester (1-3).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C:13]=1[NH2:20].[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O1CCCC1.O>[CH3:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C:13]=1[NH:20][C:28](=[O:29])[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1sc(C(=O)O)cc1N
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1NC(=O)Cc1ccccc1
Reaction time: 24 h
Yield: 77.8 %

Procedure:
Diisopropylethylamine (3.33 g, 25.8 mmol) was added to a stirred suspension of 5-methyl-4-amino-thiophene-2-carboxylic acid hydrochloride (1.4 g, 7.0 mmol) in tetrahydrofuran (25 mL) under an inert atmosphere at room temperature. After 1½ hours, phenylacetyl chloride (1.1 g, 7.2 mmol) was added. After 24 hours, the mixture was diluted with water (200 mL) and acidified with dilute aqueous hydrochloric acid. After 12 hours the precipitate was filtered off, rinsed with water, and dried to afford 1.5 g of 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid. Recrystallization of a sample from acetonitrile gave product with a mp 249-250° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33]>CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in MeOH (30 ml). The mixture was stirred at room temperature for 4.5 h. Then, it was filtered and concentration by vacuum distillation until a solid appeared. The concentrated solution was heated to reflux and 60 ml of acetonitrile was dripped into the mixture over 50 min. Turbidity was observed and the mixture was cooled slowly to room temperature and stirred over night. The product was isolated by filtration under nitrogen, washed with acetonitrile (60 ml) and dried at 50EC in a vacuum oven for 24 h to obtain fluvastatin sodium Form VII (2.54 g, 83.1%).
Reaction SMILES: [CH3:1][C:2]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:3]=1[CH2:4][O:5][C:6]1[CH:44]=[CH:43][CH:42]=[CH:41][C:7]=1[CH2:8][C:9]1[C:10]([O:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37]C(=O)C)[C@@H:29]([O:30]C(=O)C)[C@H:24]([O:25]C(=O)C)[C@H:19]2[O:20]C(=O)C)=[N:11][NH:12][C:13]=1[CH:14]([CH3:16])[CH3:15].C[O-].[Na+].Cl>O1CCCC1.CO>[CH3:1][C:2]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:3]=1[CH2:4][O:5][C:6]1[CH:44]=[CH:43][CH:42]=[CH:41][C:7]=1[CH2:8][C:9]1[C:10]([O:17][C@@H:18]2[O:35][C@H:34]([CH2:36][OH:37])[C@@H:29]([OH:30])[C@H:24]([OH:25])[C@H:19]2[OH:20])=[N:11][NH:12][C:13]=1[CH:14]([CH3:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccccc2OCc2cc(C)ccc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C)c(COc2ccccc2Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(2,5-dimethylbenzyloxy)benzyl]-5-isopropyl-1,2-dihydropyrazol-3-one (152 mg) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, 18 mg), and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added a solution of acetobromo-α-D-glucose (214 mg) in N,N-dimethylformamide (1 mL), and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane=1/1-ethyl acetate) to give 4-[2-(2,5-dimethylbenzyloxy)benzyl]-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole. To a solution of 4-[2-(2,5-dimethylbenzyloxy)benzyl]-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added sodium methoxide (28% methanol solution, 0.400 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 2 mol/L hydrochloric acid and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol=10/1–5/1) to give the title compound (33 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pd].C(O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(-c2ccccn2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2ccccn2)c1
Yield: 87.9 %

Procedure:
To a solution of 2-(3-nitrophenyl)pyridine (prepared as described in J. Chem. Soc. 1958 p. 1759) (12.7 g, 63.5 mmol) in abs. ethanol is added palladium catalyst (1.3 g 5% Pd on activated carbon) and the mixture is hydrogenated at ambient pressure until the hydrogen uptake has ceased. The mixture is filtered through celite and the filtrate is concentrated under reduced pressure. The residue is purified by column-chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (9:1) as the eluent to afford 2f (9.5 g, 88%) as a light brown oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[C:23]([CH2:28][NH2:29])=[N:24][CH:25]=[CH:26][CH:27]=1>CCCCO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:29][CH2:28][C:23]2[C:22]([CH3:21])=[CH:27][CH:26]=[CH:25][N:24]=2)[N:10]=1
Reactant: Cc1cccnc1CN
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CNc1nc(F)nc2[nH]cnc12
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.4 g, 2.3 mmol) in n-BuOH (50 ml) under an argon atmosphere at 0° C., was added DIEA (2.5 ml, 14.7 mmol) followed by (3-methylpyridin-2-yl)methanamine (0.36 g, 2.95 mmol). The reaction mixture was stirred at this temperature for 1 h and then allowed to return to room temperature and stirred for 4 h, it was still seen incomplete, hence heated the reaction to 100° C. and left at that temperature for 8 h. The solvent was evaporated in vacuo and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→90:10), to afford the product as a white solid; Yield: 0.3 g (51%). δH (CDCl3, 500 MHz) 2.35 (3 H, s, CH3), 4.71 (3 H, m, NH and NHCH2), 7.24 (1 H, s, br, ArH), 7.63 (1 H, s, br, ArH), 8.28 (1 H, s, br, ArH), 8.38 (1 H, s, br, ArH); δC (CDCl3, 500 MHz) 161.03 (C), 158.49 (C), 154.77 (C), 152.16 (C), 144.86 (CH), 137.53 (CH), 137.14 (CH), 130.67 (C), 121.58 (CH), 118.73 (C), 42.87 (CH2), 18.16 (CH3); m/z 259.3 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([C:30](=[O:31])[CH2:29][C:27]#[N:28])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)CC#N)CC4)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (54.0 mg, 0.14 mmol) in a mixture of dichloromethane and DMF (8 mL/2 mL) were added 2-cyanoacetic acid (30.7 mg, 0.36 mmol), Et3N (52.1 mg, 0.52 mmol) and HATU (164.2 mg, 0.43 mmol). The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by preparative TLC (MeOH/DCM (V/V)=1/10) to give the title compound as a light yellow solid (53.0 mg, 83.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:12]([OH:14])[CH3:13].Cl>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7](=[NH:8])[O:14][CH2:12][CH3:13]
Reactant: CCO
Reactant: COc1ccc(Cl)cc1C#N
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)c1cc(Cl)ccc1OC
Reaction time: 120 h
Yield: 101.4 %

Procedure:
A cooled solution of 5-chloro-2-methoxybenzonitrile (9.3 g, 0.056 mol, Maybridge) and ethanol (16.2 mL, 0.28 mol) in CH2Cl2 (40 mL) was bubbled with HCl gas at 0° C. for 30 min. The reaction mixture was kept in refrigerator for 5 days. The reaction mixture was then concentrated and triturated with diethyl ether to remove unreacted starting material. The precipitate was dried under reduced pressure to obtain 7.1 g (51%) of the title compound. MS (ESI+) m/z 214 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:38][B:37](B2OC(C)(C)C(C)(C)O2)[O:36]1.C([O-])(=O)C.[K+]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Pd].O1CCOCC1>[F:25][C:23]1[CH:22]=[C:21]([F:26])[CH:20]=[C:19]2[C:24]=1[C:15]([NH:14][C:4]1[CH:3]=[C:2]([B:37]([OH:38])[OH:36])[CH:7]=[N:6][C:5]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[C:16]([CH3:33])[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[N:18]2
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCOCC1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(B(O)O)cnc1N1CCOCC1
Temperature: 93 °C
Reaction time: 24 h

Procedure:
A solution of N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (395 mg, 0.77 mmol; described herein), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (215 mg, 0.85 mmol), bis(tricyclohexylphosphine)palladium(o) (25.7 mg, 0.039 mmol), potassium acetate (113 mg, 1.16 mmol), and 1,4-dioxane (10.6 mL) was stirred at 93° C. for 24 h. The reaction was then cooled to rt and partitioned between EtOAc and water. The organic layer was dried (magnesium sulfate) and concentrated, and chromatography afforded 5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-6-morpholinopyridin-3-ylboronic acid as a yellow solid. Mass Spectrum (ESI) m/e=478.1 (M+1).
Reaction SMILES: NCCCNCCCCNCCCN.[C@@H:15]1([O:46]P(O)(O)=O)[C@@H:20]([O:21]P(O)(O)=O)[C@H:19]([O:26]P(O)(O)=O)[C@@H:18]([O:31]P(O)(O)=O)[C@@H:17]([O:36]P(O)(O)=O)[C@H:16]1[O:41]P(O)(O)=O>>[O:21]=[CH:20][C@@H:19]([C@H:18]([C@@H:17]([C@@H:16]([CH2:15][OH:46])[OH:41])[OH:36])[OH:31])[OH:26]
Reactant: O=P(O)(O)O[C@H]1[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H]1OP(=O)(O)O
Agent: NCCCNCCCCNCCCN
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A composition contemplated by the instant invention was prepared by dissolving human insulin with spermine and phytic acid in double distilled water (“DDW”) containing NaOH. The solution was then lyophilized and suspended with sodium dodecanoate (SD), octanol and geraniol in a mixture of mineral oil, medium chain triglyceride (MCT) oil and castor oil. Components and concentrations are detailed in Table 1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])[CH3:2].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[CH3:11]
Reactant: CCc1cccc(N)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(CNc1cccc(CC)c1)OCC
Yield: 34.6 %

Procedure:
To a 250-mL round bottom flask was added 3-ethylaniline (10.1 g, 83.2 mmol), bromoacetaldehyde diethyl acetal (10.8 g, 54.8 mmol) and sodium bicarbonate (7.04 g, 83.8 mmol) in absolute ethanol (40 mL). The resulting mixture was stirred at reflux for 5 d. The mixture was concentrated, diluted with ether (30 mL) and washed with water (2×60 mL). The organic solution was dried (MgSO4) and concentrated at reduced pressure. The residue was purified by flash chromatography (SiO2, 5% then 15% EtOAc/hexanes) to give the title compound (4.5 g, 75%) as a white solid. 1H NMR (DMSO-d6) δ 6.98 (m, 1H), 6.42 (m, 2H), 5.34 (m, 1H), 4.53 (m, 1H), 3.59–3.35 (m, 4H), 3.19 (m, 2H), 2.41 (m, 2H), 1.17 (m, 9H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[CH:4][CH:3]=1.[PH2](=O)O.N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O>[C:5]1([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(c3ccc(N)cc3)C2)nc1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(c3ccccc3)C2)nc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{[(3R)-1-(4-aminophenyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (178 mg) and 50% phosphinic acid (5 mL) was added sodium nitrite (62.7 mg) in H2O at 4° C. The reaction mixture was stirred for 2 hours at 4° C. The resulting mixture was neutrized with saturated NaHCO3 and extracted with chloroform. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (49.0 mg).
Reaction SMILES: [I:1]C1C=C(C=C(OC)C=1)N.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)N>>[I:1][C:15]1[CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=[C:13]([O:12][CH3:11])[CH:14]=1
Reactant: COc1cc(N)cc(I)c1
Reactant: COc1cc(N)cc([N+](=O)[O-])c1
Product: COc1cc(I)cc([N+](=O)[O-])c1

Procedure:
Certain 5-alkoxy-3-aminophenyl substituted olefinic amine compounds of the present invention such as (E)-N-methyl-5-(5-methoxy-3-aminophenyl)-4-penten-2-amine, can be synthesized by coupling a 3-halo-5-alkoxyaniline such as 3-bromo-5-methoxyaniline or 3-iodo-5-methoxyaniline (protected by a phthaloyl functionality) with an olefin containing a secondary alcohol functionality, 4-penten-2-ol, under Heck reaction conditions. The resulting secondary alcohol intermediate can be converted to its p-toluenesulfonate ester, followed by treatment with methylamine (which also removes the protecting group). Alternatively, certain 5-alkoxy-3-aminophenyl substituted olefinic amine compounds can be synthesized by coupling a 3-halo-5-alkoxyaniline such as 3-bromo-5-methoxyaniline or 3-iodo-5-methoxyaniline (protected by a phthaloyl functionality) with an olefinic side chain compound, such as N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine, followed by removal of the protecting groups. The required 3-halo-5-alkoxyaniline compounds such as 3-bromo-5-methoxyaniline and 3-iodo-5-methoxyaniline can be prepared using the techniques of T. A. Emokpae et al., J. Chem. Soc., Perkin Trans 2 (1):14-17 (1977) and B. Liedholm, Acta Chem. Scand., Ser. B 38:877-884 (1984). In the former method, 3-bromo-5-methoxyaniline and 3-iodo-5-methoxyaniline can be prepared starting from commercially available 1,3,5-trinitrobenzene. Treatment of the latter compound with refluxing sodium methoxide produces 3,5-dinitroanisole. One of the nitro groups is then reduced to give 3-methoxy-5-nitroaniline. The latter compound can be diazotized and treated with copper(I) bromide to give 1-bromo-3-methoxy-5-nitrobenzene. Reduction with tin and hydrochloric acid gives 3-bromo-5-methoxyaniline. In a similar manner, 3-iodo-5-methoxyaniline can be prepared by diazotizing 3-methoxy-5-nitroaniline to give 1-iodo-3-methoxy-5-nitrobenzene. The latter compound can be reduced with iron filings and hydrochloric acid to give 3-iodo-5-methoxyaniline. Other 3-halo-5-alkoxyanilines such as 3-bromo-5-ethoxyaniline, 3-bromo-5-isopropoxyaniline, and 3-bromo-5-sec-butoxyaniline can be prepared using similar techniques. As such, compounds of the present invention such as (E)-N-methyl-5-(5-ethoxy-3-aminophenyl)-4-penten-2-amine, (E)-N-methyl-5-(5-isopropoxy-3-aminophenyl)-4-penten-2-amine, and (E)-N-methyl-5-(5-sec-butoxy-3-aminophenyl)-4-penten-2-amine can be similarly prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH:29]C(=O)OC(C)(C)C)=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:46][CH:47]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(N)nc3)n2)cc1
Yield: 95.2 %

Procedure:
A solution of tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-ylcarbamate (0.145 g, 0.228 mmol) and TFA (Aldrich) (1.0 mL, 13 mmol) in DCM (3 mL) was stirred at rt for 1 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (40 mL) and DCM (20 mL). The aqueous phase was extracted with 25% iPrOH in CHCl3+1% NH4OH (2×40 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (25 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-10%) to give N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)pyridine-2,5-diamine (0.116 g, 95%) as an orange solid. 1H NMR (300 MHz, CDCl3) δ 11.51 (s, 1H); 8.80 (dd, J=7.67, 1.53 Hz, 1H); 8.18-8.33 (m, 1H); 8.12 (d, J=1.75 Hz, 1H); 7.78 (dd, J=8.70, 2.27 Hz, 1H); 7.19 (t, J=8.84 Hz, 4H); 6.85 (t, J=8.84 Hz, 4H); 6.70 (dd, J=7.67, 4.75 Hz, 1H); 6.50 (d, J=8.77 Hz, 1H); 4.83 (d, J=6.58 Hz, 4H); 4.26 (br. s., 2H); 3.69-3.91 (m, 6H); 2.56 (s, 3H). m/z (ESI, +ve ion) 535.1 (M+H)−.