Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]Br.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[O:1]=[C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1
Reactant: CCCCCCCCCCC(=O)CCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCC(=O)CCCCCNc1ccc(C(=O)OCC)cc1

Procedure:
A solution of 15 g. of 6-oxohexadecyl bromide and 15.6 g. of ethyl 4-aminobenzoate in 60 ml. of hexamethylphosphoramide is stirred at 120° C. for 18 hours, allowed to cool, and diluted with water. The mixture is filtered and the resulting solid is dissolved in methylene chloride. The solution is washed with diluted hydrochloric acid, dried, and evaporated to yield a brown solid. Crystallization from ethanol yields ethyl 4-(6-oxohexadecylamino)benzoate as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5]2.[CH:30]#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C.[Cu]I>[C:30]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:5]2)#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Reactant: C#CCCCCCC
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CCCCCCC#Cc1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of the product of Step C (0.2 g; 0.41 mmol), 1-octyne (0.091 ml; 0.62 mmol), Cl2Pd(PPh3)2 (0.02 g; 0.028 mmol) and CuI (0.005 g; 0.026 mmol) in anhydrous DMF (2 ml) was degassed under reduced pressure and saturated with dry N2. After addition of DIPEA (0.5 ml), the resulting mixture was stirred overnight at room temperature under N2. The solvents were removed in vacuo and the residue was diluted to 15 ml with EtOAc and washed with 5% citric acid, 5% NaHCO3, H2O, brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; hexane/EtOAc; 9:1) to give the title compound (0.17 g; 89%) as a colourless syrup. 1H-NMR (CDCl3) 0.93 (m, 3H); 1.34-1.64 (m, 8H); 2.4 (tr, 2H, J=7.1 Hz); 3.94 (s, 4H); 7.0-7.64 (m, 18H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][CH:22]([CH3:29])[CH2:23][C:24](=O)[C:25](O)=[O:26].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[C:11]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=[C:9]([N:8]2[C:25](=[O:26])[C:24]([CH2:23][CH:22]([CH3:29])[CH3:21])=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]2=3)[CH:10]=1
Reactant: CC(C)CC(=O)C(=O)O
Reactant: Nc1cccnc1Nc1cccc(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)Cc1nc2cccnc2n(-c2cccc(-c3ccccc3)c2)c1=O
Yield: 22 %

Procedure:
A mixture of 3-amino-2-(3-biphenylylamino)pyridine (157 mg) and 4-methyl-2-oxopentanoic acid (94 mg) in ethanol (3 ml) was stirred under reflux for 2 hours. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (hexane-ethyl acetate, 3:1) to give 4-(3-biphenylyl)-2-isobutyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (47 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15](F)[CH2:16][CH:17]([F:26])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CS(C)=O>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH:17]([F:26])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: NCc1ccccc1
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccccc1)C(F)CC(NCc1ccccc1)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
A mixture of γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride (4.0 g), benzylamine (20.0 g) and dimethylsulfoxide (100 ml) was stirred at 70° to 80°C for 8 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was sufficiently washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Treatment of the residue with ethanol afforded γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-4-benzylamino-2-fluorobutyrophenone. M.P. 158° - 165°C. IR νmaxNujol 3350, 1650 cm-1.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][C:6]2([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:4]([O:5]2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:1][N:2]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:4]([OH:5])[CH2:3]1
Reactant: CN1CCC2(c3ccccc3)OC2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN1CC[C@H](c2ccccc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-methyl-6-phenyl-7-oxa-3-azabicyclo[4.1.0]-heptane (1.00 g; 5.30 mmoles, described in Example 6) in anhydrous ether (10 ml) is added dropwise, with stirring to a slurry of lithium aluminum hydride (0.50 g, 13.2 mmoles) in anhydrous ether (50 ml). The mixture is stirred for 4 hours at room temperature. Excess lithium aluminum hydride is decomposed by slow addition of water (10 ml). The white precipitate is filtered and washed with ether. The combined ether layers are dried over potassium chloride and evaporated. The white solid residue is dried to give the title compound, mp 95°-97° C. (R. E. Lyle and W. E. Krueger, supra, reported mp 95°-97° C.).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]3[CH:13]=[N:14][N:15]=[C:11]3[C:10]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:9][CH:8]=2)=[CH:3]1.C=O.Cl[CH2:25]Cl.C([BH3-])#N.[Na+]>CO>[O:2]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]3[CH:13]=[N:14][N:15]=[C:11]3[C:10]([N:16]3[CH2:17][CH2:18][N:19]([CH3:25])[CH2:20][CH2:21]3)=[N:9][CH:8]=2)=[CH:3]1
Reactant: c1cc(-c2cnc(N3CCNCC3)c3nncn23)co1
Reactant: ClCCl
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CN1CCN(c2ncc(-c3ccoc3)n3cnnc23)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A 50 mL round bottom flask was charged with 5-(furan-3-yl)-8-(piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazine HCl salt (350 mg, 1.14 mmol), 40% aqueous formaldehyde (20 mL), dichloromethane (20 mL), methanol (20 mL) and sodium cyanoborohydride (245 mg, 3.90 mmol) at 0° C. The resulting mixture was stirred at 20° C. overnight. It was then concentrated in vacuo and the residue was extracted with dichloromethane. The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was re-crystallized from a 1/5 (v/v) dichloromethane/ethyl ether, to afford 0.16 g (49%) of the product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.83 (s, 1H), 7.76 (dd, J=1.5, 0.9 Hz, 1H), 7.62 (dd, J=1.8, 1.5 Hz, 1H), 7.36 (s, 1H), 6.68 (dd, J=1.8, 0.9 Hz, 1H), 4.41 (br, 4H), 2.59 (t, J=5.1 Hz, 4H), 2.36 (s, 3H). MS m/z: 285 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[C:18]([CH:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:11])[C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:18]([CH:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:32][CH:33]=1
Reactant: CC(=O)N1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(C(O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To the solution of 1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (100 mg, 0.23 mmol) in THF (4.5 mL) was added palladium hydroxide, 20 wt % pd (dry basis) on carbon, wet, degussa type e101 ne/w (31.8 mg, 0.045 mmol). The reaction mixture was stirred at RT under 1 atm of H2 for 40 h. The reaction mixture was filtered through a pad of celite and washed with THF. The filtrate was washed with a mixture 1 N NaOH and brine. The aqueous layer was extracted with Teac and MeOH (3×) and the combined organics were dried and concentrated. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 5% to 95% over 15 min then neutralization to provide 1-(4-(3-(4-((1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as white solid. MS (ESI, pos. ion) m/z: 444.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:4][C:5]1[C:6]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)COc1nc(OC)ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)COc1nc(OC)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-acetoxy-6-methoxy-2-(methoxycarbonyl)methoxypyridine, potassium carbonate and methanol is stirred for 3 hours at room temperature. The reaction solution is poured into water, and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 3-hydroxy-6-methoxy-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[CH:17](OCC)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:15][CH:14]3[N:16]([CH:17]=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1
Reactant: CCOC=O
Reactant: Clc1ccc(OC2CC3CCC(C2)N3)nc1
Product: O=CN1C2CCC1CC(Oc1ccc(Cl)cn1)C2

Procedure:
To 10 ml of ethyl format was added 0.4 g of 3-(5-Chloro-pyridin-2-yloxy)-8-aza-bicyclo[3.2.1]octane, the mixture was heated at reflux for 48 hours and evaporated to dryness, crystallized from ethyl acetate petroleum ether. Yield 200 mg (53%), Mp. 112-114° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH2:13]([O:15][C:16]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])[CH3:14]>C(#N)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:18][C:16]([O:15][CH2:13][CH3:14])=[O:17]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Solvent: CC#N
Product: CCOC(=O)C=Cc1ccc2ccccc2c1
Yield: 99.4 %

Procedure:
A solution of 3.00 g of 2-naphthaldehyde and 6.69 g of ethoxycarbonylmethylenetriphenylphosphorane in 100 ml of acetonitrile was heated under reflux for 1 hour, after which the reaction mixture was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.32 g (yield 99%) of ethyl 3-(2-naphthyl)-2-propenoate as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([C:35]([F:38])([F:37])[F:36])[C:33]=1[OH:34])[CH2:5][C@@H:6]([CH2:10][C:11](=[O:30])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:19]2=[O:29])[CH2:14][CH2:13]1)[C:7]([OH:9])=O.[O:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[C:33]=1[OH:34])[CH2:5][C@@H:6]([CH2:10][C:11]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:19]2=[O:29])[CH2:16][CH2:17]1)=[O:30])[C:7]([N:48]1[CH2:47][CH2:46][N:45]([CH:42]2[CH2:43][CH2:44][O:39][CH2:40][CH2:41]2)[CH2:50][CH2:49]1)=[O:9]
Reactant: O=C(O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Reactant: C1CN(C2CCOCC2)CCN1
Product: O=C(C[C@H](Cc1cc(Cl)c(O)c(C(F)(F)F)c1)C(=O)N1CCN(C2CCOCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
Prepared analogously to Example 7i from 70 mg (0.13 mmol) (S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 22 mg (0.13 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1([CH3:17])[NH:11][C:10]2[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:9]=2[O:8]1)[CH3:2].Cl[CH2:20][C:21]1[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=1)[O:24][CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1([CH3:17])[NH:11][C:10]2[CH:12]=[CH:13][C:14]([O:16][CH2:20][C:21]3[CH:38]=[CH:37][CH:36]=[C:23]([O:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[CH:22]=3)=[CH:15][C:9]=2[O:8]1)[CH3:2]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CCOC(=O)CCC1(C)Nc2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC1(C)Nc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of ethyl-3-(2,3-dihydro-6-hydroxy-2-methyl-benzoxazol-2-yl)propanoate, 3.1 g of 2-(3-chloromethylphenoxy)methylquinoline and 1.2 g potassium carbonate are combined in 25 ml of dimethylformamide and stirred at room temperature overnight, then at 60° C. for 4 hours. The reaction mixture is diluted with ethyl acetate and this solution washed with water, dried and concentrated. The residue is chromatographed on silica gel to give ethyl-3-(6-(3-(quinolin-2-ylmethyloxy)benzyloxy)-2,3-dihydro -2-methylbenzoxazol-2-yl)propanoate which is used, without further purification, for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:18][C:19](=O)[CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](OC(C)(C)C)=[O:12])[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:18][CH2:19][CH2:20][CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1cccc(CC(NC(=O)CC(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CC(CO)NCCC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
3-Methoxy-α-[(1-oxo-3,3-diphenylpropyl)amino]benzenepropionic acid, 1,1-dimethylethyl ester (1 eq, 1 mmole, 470 mg) was added portionwise to a mixture of lithium aluminum hydride (3 mmole, 3 ml of 1M in tetrahydrofuran) in tetrahydrofuran (5 ml) at 0° C. under argon. After the addition and the cessation of hydrogen evolution, the mixture was brought to reflux. The mixture was refluxed overnight, cooled to room temperature and quenched with solid sodium sulfate.10 water. The solids were removed by filtration through Celite, and the solvent was evaporated in vacuo to yield an oil which crystallized upon standing. The crystals were washed with hexanes/ether, collected, and dried to afford 299.9 mg of the title compound, melting point 89°-91° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:36][CH:35]=3)=[O:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:21])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].[NH2:52][C:53]1[CH:58]=[C:57]([O:59][C@H:60]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH3:61])[C:56]([N+:68]([O-:70])=[O:69])=[CH:55][C:54]=1[C:71]1[CH:89]=[CH:88][C:74]([C:75]([O:77][C:78]2[CH:87]=[CH:86][C:81]([O:82][CH:83](O)[CH3:84])=[CH:80][CH:79]=2)=[O:76])=[CH:73][CH:72]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:38][CH:39]=3)=[O:32])=[CH:27][C:23]=2[C:24]([O:26][CH2:84][CH2:83][O:82][C:81]2[CH:80]=[CH:79][C:78]([O:77][C:75](=[O:76])[C:74]3[CH:73]=[CH:72][C:71]([C:54]4[CH:55]=[C:56]([N+:68]([O-:70])=[O:69])[C:57]([O:59][C@H:60]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH3:61])=[CH:58][C:53]=4[NH2:52])=[CH:89][CH:88]=3)=[CH:87][CH:86]=2)=[O:25])=[O:21])=[CH:17][CH:18]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)Oc3ccc(OC(C)O)cc3)cc2)cc1[N+](=O)[O-]
Reactant: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)OCCOc3ccc(OC(=O)c4ccc(-c5cc([N+](=O)[O-])c(O[C@@H](C)CCCCCC)cc5N)cc4)cc3)c2)cc1

Procedure:
0.6 g of 2,5-bis (4-[6-acryloyloxyhexyloxy]phenylcarboxy)benzoic acid and 0.4 g of (4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoyloxy]phenoxy)ethanol, 0.04 g of 4-dimethylaminopyridine, 0.2 g N,N'-dicyclodicyclohexyldicarbodiimide and 20 ml of dichloromethane are reacted in an analogous manner to Example 1 to give (4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]-phenyl)benzoyloxy]phenoxy)ethyl 2,5-bis (4-[6-acryloyloxyhexyloxy]phenylcarboxy)benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:13][C:14]3[NH:15][CH2:16][CH2:17][N:18]=3)[C:8]=2[Br:12])[N:3]=1.[BH4-].[Na+].CC1CNC2C(=CC=CC=2Br)N1NC1NCCN=1>C(O)(=O)C>[CH3:1][CH:2]1[CH2:11][NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:13][C:14]3[NH:15][CH2:16][CH2:17][N:18]=3)[C:8]=2[Br:12])[NH:3]1
Reactant: Cc1cnc2c(Br)c(NC3=NCCN3)ccc2n1
Agent: CC1CNc2c(Br)cccc2N1NC1=NCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1CNc2c(ccc(NC3=NCCN3)c2Br)N1
Reaction time: 0.25 h
Yield: 53 %

Procedure:
A solution of 2-methyl-5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline (40.5 mg, 0.132 mmol) in acetic acid was cooled to 10° C. and carefully treated with NaBH4 (5.0 mg, 0.132 mmol). The reaction mixture was stirred for 15 minutes before the solvent was removed in vacuo. The residue was dissolved in H2O, treated with solid NaOH to pH 13 and extracted with CHCl3. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to yield a yellow oil. The crude material was chromatographed (SiO2, 80/20 CHCl3 /CH3OH saturated with NH3 (g)) to yield 21.8 mg (a yield of 53%) of a tan solid, mp 203-205° C. Using various analytical procedures, this tan solid was determined to be (±) 2-methyl-5-bromo-(2-imidazolin-2-ylamino)-1,2,3,4-tetrahydroquinoxaline.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([NH:6][CH2:7][C@@H:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])[CH2:4][I:5].[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[F:1][C:2]([F:18])([F:19])[CH:3]([NH:6][CH2:7][C@@H:8]([NH2:10])[CH3:9])[CH2:4][I:5]
Reactant: C[C@@H](CNC(CI)C(F)(F)F)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)CNC(CI)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl ((2S)-1-((1,1,1-trifluoro-3-iodopropan-2-yl)amino)propan-2-yl)carbamate (1.6 g, 4.04 mmol) and DCM (8.08 ml) was added TFA (6.22 ml, 81 mmol). Stirred for 1 hour at ambient temperature and then the solution was concentrated. The residue was azeotroped with toluene (3×10 ml) to provide (2S)—N1-(1,1,1-trifluoro-3-iodopropan-2-yl)propane-1,2-diamine 2,2,2-trifluoroacetate as a yellow oil that was used without further purification. LRMS m/z (M+H)+ 297.1 found, 297.0 required.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19](O)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:22][CH2:23][C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25].C(N1C2=NC=C(C(N[C@H](C3C=CC=CC=3)CO)=O)C(NC3CCOCC3)=C2C=N1)C>>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:22][CH2:23][C@@H:24]([OH:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NC[C@@H](O)c1ccccc1
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Agent: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)c3ccccc3)cnc21
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NC[C@@H](O)c3ccccc3)cnc21

Procedure:
Intermediate 48 was prepared from Intermediate 17 and (1S)-2-amino-1-phenylethanol (commercially available from Fluka) using an analogous method to that for Intermediate 42. LCMS showed MH+=410; TRET=2.62 min.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][N:22]=1>C(O)C>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][N:22]=[C:21]2[NH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Nc1ccc2nc(NC(=O)c3ccncc3)sc2c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CCO
Product: COc1cc2ncnc(Nc3ccc4nc(NC(=O)c5ccncc5)sc4c3)c2cc1OC

Procedure:
N-[6-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-2-yl]isonicotinamide was prepared by heating a mixture of N-(6-aminobenzothiazol-2-yl)isonicotinamide Intermediate 3, 50 mg, 0.185 mmol) and 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 42 mg, 0.185 mmol in ethanol (3 mL) to 80° C. for 2 h. The resulting precipitate was separated by filtration, washed with ethanol and dried (yellow solid, 82 mg, 0.179 mmol, 97%). LC/ESI-MS: m/z 459 [M+H]+; m/z=457 [M−H]−; Rt=2.65 min.