Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.[C:26](Cl)(=[O:34])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[C:26](=[O:34])([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:2]([NH2:1])=[N:3][C:4]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:5]=4[C:6]=3[CH:7]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: CCCCCCOC(=O)Cl
Product: CCCCCCOC(=O)Oc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl hexyl carbonate was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedures described for Example 138, but using hexyl carbonochloridate. LRMS [M+H]=458.2.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][CH2:15][C:9]2[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:28][CH2:27]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)nn1-c1ccccc1

Procedure:
96 mg (66%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 1-(2-fluorophenyl)piperazine (59 mg, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[CH:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:38])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[N:30]=[N:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33](Br)[CH:32]=3)=[N:27]2)=[CH:21][CH:20]=1)([CH3:14])([CH3:13])[CH3:12].[Na]>>[C:11]([O:15][C:16](=[O:38])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[N:30]=[N:29][C:28]([C:31]3[CH:32]=[CH:33][CH:34]=[C:35]([C:10]#[C:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH:36]=3)=[N:27]2)=[CH:21][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: C#CCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cn2nnc(-c3cccc(Br)c3)n2)cc1
Agent: [Na]
Product: CC(C)(C)OC(=O)COc1ccc(Cn2nnc(-c3cccc(C#CCc4ccc(F)cc4)c3)n2)cc1
Yield: 68.9 %

Procedure:
This reaction was carried out as described in Example D1, Step (c) using 1-fluoro-4-prop-2-ynyl-benzene (0.23 g, 1.7 mmol) and {4-[5-(3-bromophenyl) tetrazol-2-ylmethyl]phenoxy}acetic acid tert-butyl ester (0.30 g, 0.67 mmol) in place of 4-[5-(3-bromophenyl)tetrazol-2-ylmethyl]-benzenesulfonic acid, sodium salt. This afforded 0.23 g of the product (68.5% yield).
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:11](=O)(O)[O-:12].[Na+].C(O)(=O)C>CO>[Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:12][CH3:11]
Reactant: Cc1cccc(CBr)c1Br
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCc1cccc(C)c1Br
Yield: 99 %

Procedure:
To a stirred solution of 2-bromo-3-methylbenzylbromide (5.2 g, 0.0197 mol) in methanol (30 ml) was added saturated sodiumbicarbonate (5 ml) and the mixture was refluxed overnight. The mixture was neutralised with acetic acid and the solvent was evaporated under reduced pressure. Chromatography of the residue on silica gel using hexane: methylene chloride (7/3) as eluent gave 4.2 g (99%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)c1cc(CCO)ccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(OCc3ccccc3)c(C(N)=O)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
To a solution of 2-benzyloxy-5-(2-hydroxyethyl)benzamide (519 mg) in dichloromethane (6 ml) were added triethylamine (290 μl), N,N-dimethylaminopyridine (24 mg) and p-toluenesulfonyl chloride (400 mg) subsequently, and the mixture was stirred for 17 hours at room temperature. After concentration of the reaction mixture under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent:diethyl ether/dichloromethane=1/1) gave 2-benzyloxy-5-[2-(p-toluenesulfonyloxy)ethyl]benzamide (627 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.CN(C)C1C=CN=CC=1>[Si:20]([O:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCC1CCNc2ccccc21
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCC1CCNc2ccccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To a solution of 4-(hydroxymethyl)-1,2,3,4-tetrahydroquinoline (16.07 g, 0.098 mol) in dichloromethane (100 mL) at 0° C. were added sequentially triethylamine (16.3 mL, 0.12 mol), tert-butyldiphenylsilylchloride (28.4 g, 0.103 mol) and 4-(dimethylamino)pyridine (0.6 g, 4.9 mmol). After 30 minutes, the solution was warmed to room temperature and stirred for another 2 hours. The reaction mixture was diluted with dichlormethane (200 mL), washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layers were collected, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to provide 22.1 g (56%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[C:13]=1[Cl:19]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[C:13]=2[Cl:19])=[CH:4][CH:3]=1
Reactant: Clc1cccc(I)c1Cl
Reactant: Clc1ccc2cc[nH]c2c1
Product: Clc1ccc2ccn(-c3cccc(Cl)c3Cl)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1,2-dichloro-3-iodobenzene: ESMS m/e: 296.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[N:16][C:17]([NH:19][C:20]3[CH:29]=[C:28]4[C:23]([CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27]4)=[CH:22][CH:21]=3)=[N:18][C:11]=2[N:10]2[CH:37]=[CH:38][N:39]=[C:9]12.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[N:16][C:17]([NH:19][C:20]3[CH:29]=[C:28]4[C:23]([CH2:24][CH2:25][NH:26][CH2:27]4)=[CH:22][CH:21]=3)=[N:18][C:11]=2[N:10]2[CH:37]=[CH:38][N:39]=[C:9]12.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3ncc4c(=O)n(-c5ccccc5Cl)c5nccn5c4n3)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2cnc(Nc3ccc4c(c3)CNCC4)nc2n2ccnc2n1-c1ccccc1Cl

Procedure:
A mixture of Example 20 (0.357 g, 0.656 mmol) and trifluoroacetic acid (0.506 mL, 6.56 mmol) in CH2Cl2 (6 mL) was stirred at room temperature for 6 hours. The reaction mixture was concentrated and purified by HPLC as described in Example 1F to provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, CD3OD) δ ppm 3.14 (t, J=6.35 Hz, 2H), 3.54 (t, J=6.35 Hz, 2H), 4.43 (s, 2H), 7.07 (d, J=1.98 Hz, 1H), 7.31 (d, J=8.33 Hz, 1H), 7.52-7.63 (m, 3H), 7.66-7.72 (m, 2H), 7.76 (s, 1H), 7.87 (d, J=1.98 Hz, 1H), 9.18 (s, 1H). MS (ESI+) m/z 444.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[Cl:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[C:3]([Cl:19])[CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1Cl
Product: Nc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(Cl)c2)c1[N+](=O)[O-]
Yield: 74 %

Procedure:
Method H3 was used with 4-(4-amino-3-chlorophenoxy)-3-nitropyridin-2-amine and 4-chloro-3-trifluoromethyl-phenyl isocyanate to afford the title compound (530 mg, 74%). 1H-NMR (δ, ppm, DMSO-d6): 6.05 (d, 1H, HPy,5, J=5.7 Hz), 7.19 (m, 3H, Harom), 7.43 (d, 1H, HPh,11or12, J=2.7 Hz), 7.61 (s, 2H, NH2,Py), 8.01 (d, 1H, HPy,6, J=5.7 Hz), 8.09 (s, 1H, Harom), 8.17 (d, 1H, Harom, J=9.1 Hz), 8.49 (s, 1H, NHurea1), 9.85 (s, 1H, NHurea3). LC-MS (m/z): 502 (M+H, 100).
Reaction SMILES: [CH:1]([NH:3][C:4]1[N:9]=[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2].[Se](=O)=[O:17]>O1CCOCC1>[CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: CCOC(=O)Cc1cccc(NC=O)n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)c1cccc(NC=O)n1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a solution of ethyl 2-(6-formamidopyridin-2-yl)acetate (26 g.) in dioxane (260 ml.) was added selenium dioxide (16.65 g.) in small portions at 85° to 90° C. over one hour and stirred at the same temperature for one hour. After cooling the resultant solution the dioxane layer was separated and concentrated under reduced pressure and then the residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and treated with activated charcoal and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (14.3 g.), mp. 124° to 126° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:8][C@H:7]2[N:18]([CH3:19])[C@@H:4]1[CH2:5][CH2:6]2.[H-].[Na+].[CH2:22](OS([O-])(=O)=O)[CH3:23].O>C1COCC1>[CH2:22]([O:1][CH2:2][C@@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:8][C@H:7]2[N:18]([CH3:19])[C@@H:4]1[CH2:5][CH2:6]2)[CH3:23]
Reactant: CN1[C@H]2CC[C@@H]1[C@H](CO)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Reactant: CCOS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC[C@@H]1[C@@H](c2ccc(Cl)c(Cl)c2)C[C@@H]2CC[C@H]1N2C
Temperature: 35 °C
Reaction time: 8 h
Yield: 111.1 %

Procedure:
(1R, 2R, 3S)-2-hydroxymethyl-3(3,4-dichlorophenyl)tropane (26.9 g, 0.09 mol) in THF (200 ml) was added sodium hydride 60% in oil (4.6 g, 0.12 mol) and ethylsulphate (15.7 ml, 0.12 mol) and heated to 30-40° C. on an oil bath for ½ hour. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture is then heated to 30-40° C. on an oil bath for 1 hour and poured into water (500 ml). The mixture was extracted twice with tert.butylmethylether, the organic phases was washed with water and dried over MgSO4 and evaporated to yield the 32.82 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23](O)=O.[F:26][C:27]1[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=1>C1(C)C=CC=CC=1.O>[F:26][C:27]1[CH:32]=[CH:31][C:30]2[NH:33][C:23]([CH2:22][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([C:14]5=[CH:15][C:16]6[O:20][CH2:19][O:18][C:17]=6[CH:21]=[C:13]5[O:12][CH2:11]4)[C:2]3=[O:1])=[N:34][C:29]=2[CH:28]=1
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: Nc1ccc(F)cc1N
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1N(Cc2nc3cc(F)ccc3[nH]2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 25.7 %

Procedure:
A mixture of (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetic acid (0.50 g, 1.47 mmol) and 4-fluorobenzene-1,2-diamine (0.15 g, 1.18 mmol) in anhydrous toluene (20.0 mL) was refluxed overnight under N2. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 2/1) to give the title compound (0.13 g, 22%): mp 138-142° C.; 1H NMR (300 MHz, CDCl3) δ 7.47-7.39 (m, 1H), 7.32-7.22 (m, 2H), 7.16-6.93 (m, 3H), 6.18 (s, 1H), 6.07 (s, 1H), 5.84-5.78 (m, 2H), 5.20-5.14 (m, 2H), 4.98 (d, 1H), 4.60 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 179.2, 161.3, 158.1, 156.2, 149.2, 149.1, 142.5, 141.2, 131.5, 129.5, 124.4, 124.0, 118.0, 111.6, 111.2, 109.9, 103.1, 101.7, 93.5, 80.5, 58.5, 38.9; MS (ES+) m/z 430.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([C:20]([O-])=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:20][OH:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)[O-])OCc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCc1ccc(Cl)cc1
Yield: 56 %

Procedure:
In 30 ml of tetrahydrofuran was dissolved 1.0 g of methyl (N-(4-chlorobenzyloxycarbonyl)-tyrosinate. To the solution was added dropwise 10 ml of tetrahydrofuran solution containing 4.2 ml of sodium dihydro-bis-(2-methoxyethoxy) aluminate (65% toluene solution) with stirring while cooling with ice. The mixture was stirred at room temperature for one hour. After addition of 200 ml of 3% hydrochloric acid, the reaction mixture was concentrated in vacuo and extracted with ethyl acetate. The extract was washed with water. dried and concentrated to dryness. The residue was dissolved in chloroform and subjected to column chromatography with 10 g of silicagel to give 509 mg of N-(4-chlorobenzyloxycarbonyl)-tyrosinol: yield 56%.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.O1CCCC1>[C:19]([NH:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC(Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture containing 8.21 g of L-Phenylalanine, 5.565 g of Na2CO3 in 40 ml of water and 20 ml of tetrahydrofuran (THF) was stirred at room temperature. Benzoyl chloride, 7.73 g, dissolved in 20 ml of anhydrous THF, was added gradually over a period of 45 minutes with continued stirring at room temperature. Stirring was allowed to continue for an additional hour, at which time the reaction mixture was transferred to a rotary evaporator at 30° C. to remove the THF. An excess of water was then added and the reaction mixture extracted four times with ethyl acetate. The aqueous phase was then titrated to pH 2 with 3N HCl. A white crystalline precipitate formed which was recovered by filtration, washed three times with cold dilute HCl and three times with cold water, and dried in a vacuum oven over P2O5 at about 50° C. The product was recrystallized from aqueous 30 ethanol, yielding 8.37 g, m.p. 183° C.- 184° C., which migrated as a single compound on thin layer chromatography in five separate solvent systems.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:34]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:50]2[CH2:51][CH2:52][CH2:53][N:47]([C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:48][CH2:49]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(C(F)(F)F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(2-methoxy-5-trifluoromethylbenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([O:23][C:24](=O)[C:25]3C=CC=CC=3)[CH:20]=[CH:21][CH:22]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:35](OC1C=CC=CC=1NCCN)(C)C>>[CH:24]([O:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]1[CH:10]=[C:9]([C:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:8])[CH:34]=[CH:33][CH:32]=1)([CH3:35])[CH3:25]
Reactant: O=C(Oc1cccc(OCCNCc2cccc(C(=O)N3CCCCC3)c2)c1)c1ccccc1
Reactant: CC(C)Oc1ccccc1NCCN
Product: CC(C)Oc1cccc(OCCNCc2cccc(C(=O)N3CCCCC3)c2)c1

Procedure:
Benzoic acid 3-{2-[3-(piperidine-1-carbonyl)-benzylamino]-ethoxy}-phenyl ester. The title compound was prepared as in Example 1, steps D and E, substituting benzoic acid 3-(2-amino-ethoxy)-phenyl ester for N1-(2-isopropoxy-phenyl)-ethane-1,2-diamine in step E. MS (ESI): mass calculated for C28H30N2O4, 458.22; m/z found, 459.2 [M+H]+, 481.2 [M+Na]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[C:23]2[C:28]([CH:29]=[C:30]3[C:35]=1[CH:34]=[CH:33][CH:32]=[CH:31]3)=[CH:27][CH:26]=[CH:25][CH:24]=2>>[CH:24]1[C:23]2[C:28](=[CH:29][C:30]3[C:35]([C:22]=2[CH2:21][N:7]2[C:8]([O:9][C:10]4[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=4)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:26][CH:25]=1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCc1c2ccccc2cc2ccccc12
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2c3ccccc3cc3ccccc23)c(=O)[nH]c1=O
Yield: 41.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 9-chloromethyl anthracene were reacted by the same way with the example 1 to obtain the titled compound (187 mg, yield: 41.5%).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]1=[O:11].Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:22]1([N:19]2[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][N:7]3[CH2:8][CH2:9][C:10]4[NH:1][C:2](=[O:11])[CH:3]=[CH:4][C:5]=4[CH2:6]3)[CH2:17][CH2:18]2)[CH2:25][CH2:24][CH2:23]1
Reactant: O=c1ccc2c([nH]1)CCNC2
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCc2[nH]c(=O)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one (98 mg, 0.653 mmol), 1-(chloroacetyl)-4-cyclobutylpiperazine (142 mg, 0.653 mmol), K2CO3 (360 mg, 2.61 mmol) and KI (12 mg, 0.07 mmol) in CH3CN (15 mL) is stirred at rt overnight. The solvent is removed in vacuo and the residue is partitioned between water (10 mL) and EtOAc (20 mL). The layers are separated and the aqueous layer is extracted with EtOAc (2×10 mL) and the combined extracts are dried and evaporated. The resulting oil is purified by PTLC with DCM/MeOH/NH4OH (100:5:0.5) to give the title compound as a light yellow solid. MS (M+1): 331.2; 1H NMR (δ, CDCl3): 7.13 (d, 1H0, 6.38 (d, 1H), 3.60 (q, 4H), 3.44 (s, 2H), 3.35 (s, 2H), 2.79 (s, 2H), 2.63-2.75 (m, 1H), 2.26 (q, 4H), 1.63-2.06 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]([C:15](=[O:26])[NH:16][CH2:17][CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[C@@H:12]([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](O)(=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:28]([O:14][C@@H:12]([CH3:13])[C@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27])[C:15]([NH:16][CH2:17][CH2:18][CH:19]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])=[O:26])(=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCOC(CCNC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](C)O)OCC
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)O[C@@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC(OCC)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
To a solution of [(1S,2S)-1-(3,3-diethoxy-propylcarbamoyl)-2-hydroxy-propyl]carbamic acid benzyl ester (300 mg, 0.785 mmol, obtained from Reference Example 17) in methylene chloride (5 ml) was added myristic acid (163 mg, 0.714 mmol), dicyclohexylcarbodiimide (162 mg, 0.785 mmol) and dimethylaminopyridine (9 mg, 0.074 mmol). The resulting mixture was stirred under nitrogen at room temperature for 18 hours. The mixture was filtered, the filtrate was washed with 2% hydrochloric acid, aqueous sodium bicarbonate and saturated sodium chloride solutions, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 30% ethyl acetate in hexane) to provide (1S,2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(3,3-diethoxypropyl)amino]-1-methyl-3-oxopropyl myristate (352 mg, 83%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[C:3]([NH2:5])=[O:4]>[Pd].C(OCC)(=O)C.CO>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:2]([CH3:1])[C:3]([NH2:5])=[O:4])=[CH:7][CH:8]=1
Reactant: CN(C(N)=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C(N)=O)c1ccc(N)cc1
Reaction time: 5 h
Yield: 100.3 %

Procedure:
A 100-mL round bottom flask was charged with 1-methyl-1-(4-nitrophenyl)urea (0.63 g, 3.26 mmol) and 10% palladium on carbon (0.15 g) in 1:1 ethyl acetate/methanol (20 mL). This mixture was vigorously stirred under H2 (1 atm) for 5 h. After this time, the mixture was filtered through celite to afford the title compound (0.54 g, 100%) as a white solid. MW=165.19. 1H NMR (DMSO-d6, 500 MHz) δ 6.90-6.86 (m, 2H), 6.57-6.53 (m, 2H), 5.29 (br s, 2H), 5.11 (s, 2H), 3.00 (s, 3H).