Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[F:24][C:25]([F:30])([F:29])[C:26](O)=[O:27]>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:26](=[O:27])[C:25]([F:30])([F:29])[F:24])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(C(=O)C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A mixture of 1-ethyl-6-chloro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1.7 g (0.005 mole), anhydrous trifluoroacetic acid 4.2 g (0.02 mole) and dichloromethane 4 ml was stirred at room temperature for 3 hours. The reaction mixture was evaporated under vacuum and the residue was recrystallized from a mixed solvent of DMF and ethanol to obtain 1.8 g (86%) of 1-ethyl-6-chloro-7-(4-trifluoroacetyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Colorless plates. Melting point: 297°-298° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][C:35]1=[O:41]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])=[C:28]([N:34]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][C:35]2=[O:41])[CH:29]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1N1CCCCCC1=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1CCCCCC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 1-(2-(aminomethyl)-5-fluorophenyl)azepan-2-one, derived from reduction of intermediate 113, 4-fluoro-2-(2-oxoazepan-1-yl)benzonitrile. 1HNMR 400 MHz (DMSO) δ ppm: 8.80 (1H, dd, (t), J=6.0 Hz), 7.46 (2H, m), 7.36 (4H, m), 7.08 (1H, dd, J=9.8, 2.8 Hz), 7.0 (1H, m), 5.09 (2H, s), 4.43 (1H, dd, J=15.2, 7.1 Hz), 4.06 (1H, dd, J=15.2, 5.0 Hz), 4.02 (2H, t, J=5.0 Hz), 3.90 (2H, t, J=5.0 Hz), 3.77 (1H, m), 3.51 (1H, m), 2.70 (1H, m), 2.51 (2H, m), 1.76 (6H, m), 1.56 (6H, s). LCMS (M+H)+ m/z 549.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([CH3:21])[C:15]=3[C:16](OCC)=O)[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C.[C:63](OC(=O)C)(=[O:65])[CH3:64]>O1CCCC1.O>[CH3:16][C:15]1[C:14]([CH3:21])=[N:13][N:10]2[CH:11]=[CH:12][C:7]3[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH:1][C:63](=[O:65])[CH3:64])[C:8]=3[C:9]=12
Reactant: CCOC(=O)c1c(C)nn2ccc3c(c12)C(CCN)CC3
Reactant: CC(=O)OC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCCC1CCc2ccn3nc(C)c(C)c3c21
Reaction time: 3 h
Yield: 34.5 %

Procedure:
To a solution of ethyl 9-(2-aminoethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (75.0 mg, 0.261 mmol) in tetrahydrofuran (2.6 mL) was added 1.5M diisobutylaluminum hydride toluene solution (2.1 mL, 3.2 mmol) at room temperature, and the mixture was stirred for 3 hr. Sodium sulfate decahydrate (2.1 g) was added and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure. To a mixture of the residue and triethylamine (54.6 μL, 0.392 mmol) in tetrahydrofuran (2.5 mL) was added acetic anhydride (37.0 μL, 0.391 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Water (70 μL) was added, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (24.4 mg, yield 34%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C1OCCOCCOCCOCCOC1.[H-].[Na+].Br[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=2)=[C:36]([O:50][CH3:51])[CH:35]=1>CN(C=O)C.O>[CH3:51][O:50][C:36]1[CH:35]=[C:34]([CH2:33][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])[CH:39]=[CH:38][C:37]=1[C:40]1[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: COC(=O)c1ccc(-c2ccc(CBr)cc2OC)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3=O)cc2OC)cc1
Temperature: 60 °C

Procedure:
A solution of Example 500B (328 mg, 1.64 mmol) in DMF (4 mL) at room temperature was treated with 15-crown-5 (361 mg, 1.64 mmol) and 60% sodium hydride in mineral oil (66 mg, 1.64 mmol). The mixture was treated with a solution of Example 500C (500 mg, 1.49 mmol) in DMF (2 mL), heated to 60° C. for 16 hours, cooled to room temperature, treated with water (20 mL), and extracted three times with ethyl acetate (50 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:1 ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: C1OC2C=CC(C3C4C(=CC=CC=4)C=C3C([O-])=O)=CC=2O1.[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([C:31]3(O)[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]([C:40]4[CH:45]=[CH:44][C:43]5[O:46][CH2:47][O:48][C:42]=5[CH:41]=4)=[C:32]3[C:49]([O:51]CC)=[O:50])=[CH:25][C:24]=2[O:23]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([CH:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]([C:40]4[CH:45]=[CH:44][C:43]5[O:46][CH2:47][O:48][C:42]=5[CH:41]=4)[CH:32]3[C:49]([OH:51])=[O:50])=[CH:25][C:24]=2[O:23]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])C1=Cc2ccccc2C1c1ccc2c(c1)OCO2
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
Ethyl (RS)-1,3-Di-(3,4-methylenedioxyphenylindene-2-carboxylate. To a solution of ethyl (1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate (0.29 g, 0.65 mmol) in CH2Cl2 (3 ml) at 0° C. under an argon atmosphere was added triethylsilane (91 mg, 0.78 mmol), followed by boron trifluoride etherate (0.3 ml, 2.4 mmnol). The reaction mixture was stirred for 10 min, at which time was added ice-cold 1 M HCl, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was placed on a small pad of silica gel, eluting with CH2Cl2 to provide the title compound (257 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClN1C(=[O:24])CCC1=O.CCOCC>C(O)(=O)C.P(=O)(O)(O)O.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]2=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Clc1cc(Cl)cc(-n2ccc3ccccc32)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1Cc2ccccc2N1c1cc(Cl)cc(Cl)c1
Yield: 70.9 %

Procedure:
To a solution of 7.8 g (29.9 mmol) of 1-(3,5-Dichlorophenyl)-1H-indole in 50 mL of acetic acid was added 4.0 g (30.1 mmol) of N-chlorosuccinimide. The mixture was warmed at reflux for 1hr, when TLC indicated the disappearance of starting material. The mixture was cooled and diluted with 16 mL of 70% aqueous phosphoric acid and 4 mL of water and warmed at reflux for 6 hr. The reaction was then cooled to afford a precipitate which was diluted with 50 mL of water and collected by filtration. The solid was partially dried by pulling vacuum through the filter cake and then dissolved in dichloromethane, dried (MgSO4), treated with carbon (Norit A), filtered through diatomaceous earth and concentrated to afford an orange solid. Trituration with ether gave 5.9 g (71%) of 1-(3,5-dichlorophenyl)-1,3-dihydro-indol-2-one which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(Cl)cc1F)C(=O)OC
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1F
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.80 g), 2-(4-chloro-2-fluorobenzyl)-3-oxopentanoic acid methyl ester (1.4 g), polyphosphoric acid (5 g) and dioxane (10 mL) was heated at 120° C. for 23 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3:7 to 7:10 by volume) to afford title compound, 0.20 g.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])[S:9][C:5]=2[CH:4]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>COCCOC>[NH2:2][CH2:1][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])[S:9][C:5]=2[CH:4]=1
Reactant: CCNC(=O)Nc1nc2ccc(C#N)cc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: CCNC(=O)Nc1nc2ccc(CN)cc2s1

Procedure:
About 0.05 g of N-(6-cyano-1,3-benzothiazol-2-yl)-N′-ethylurea was charged into about 10 mL of ethyleneglycol dimethylether. Introduced about 50 mg lithium aluminum hydride in several portions over about 12–24 hours. The slurry was quenched with about 5–10 mL ethyl acetate then about 1–2 mL of saturated aqueous sodium sulfate. The slurry was then diluted with water and extracted with ethyl acetate. Following drying and removal of solvents under reduced pressure, the product was isolated by preparative HPLC. 1H NMR 1.08 (t, 3H), 1.88 (s, 3H), 3.17 (m, 2H), 3.83 (s, 2H), 7.07 (m, 1H), 7.32 (m, 1H), 7.54 (d, 1H), 7.8 (s, 1H); LC/MS 1.86 min, 251 (M+1), 249 (M−1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:30]Br.O.O.O.O.O.O.O.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([Br:30])[CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCCc2ccccc2OCc2ccccc2)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Temperature: 25 °C

Procedure:
Benzyl 2-(2-benzyloxyethyl)phenyl ether (159 mg) and 123 mg of sodium acetate was suspended in 2 ml of acetic acid, 29 μl of bromine was added to the suspension with stirring at room temperature, and the mixture was subjected to 1 hour of reaction. Then, a solution of 100 mg of sodium sulfite heptahydrate in 20 ml of water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous saturated sodium bicarbonate solution and water in that order and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane/methylene chloride=2/1) to give 173 mg of benzyl 2-(2-benzyloxyethyl)-4-bromophenyl ether in an oily form.
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH3:7][O:8][C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])([CH2:13][CH2:14][CH3:15])[C:10](Cl)=[O:11]>C(#N)C>[CH3:7][O:8][C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])([CH2:13][CH2:14][CH3:15])[C:10]([N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1)=[O:11]
Reactant: CCCC(OC)(C(=O)Cl)c1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CC#N
Product: CCCC(OC)(C(=O)n1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 20 ml of acetonitrile was added 2.3 g of the sodium salt of imidazole, and 7.0 g of α-methoxy-α-n-propyl-2,4-dichlorophenylacetic acid chloride was then added dropwise at room temperature. The mixture was stirred for 2 hours, poured into 200 ml of ice water and extracted with 300 ml of chloroform. The extract was concentrated under reduced pressure, and the oily product obtained was purified by column chromatography on silica gel to obtain 2.5 g of N-(α-methoxy-α-n-propyl-2,4-dichlorophenylacetyl)imidazole (compound No. 43). m.p. 99°-101° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[Br:21][C:22]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=1[NH2:31].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:31][C:23]2[CH:24]=[CH:25][C:26]([CH:28]([CH3:29])[CH3:30])=[CH:27][C:22]=2[Br:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)c1ccc(N)c(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(Br)c1

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.97 g, 13 mmol) was dissolved in dry methylene chloride (25 mL) and dry pyridine (2.7 mL). To the reaction mixture was then added thionyl chloride (1.86 g, 15.6 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was then added successively, under nitrogen atmosphere, 2-bromo-4-isopropyl-phenylamine (3.0 g, 14 mmol), dry triethylamine (4.6 g, 45.5 mmol), dry methylene chloride (20 mL), 4-(dimethylamino)pyridine (0.16 g, 1.3 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then partitioned with aqueous 2N HCl and tert-Butyl methyl ether. The organic layer was washed with aqueous 2N HCl, aqueous NaHCO3, brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was recrystallized from ethyl acetate/hexanes to yield the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:12].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(Cl)Cl>[Cl:12][C:3]1[CH:4]=[C:5]([S:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)c(Cl)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-fluoro-3-chlorobenzenesulphonyl chloride (0.9 g) was stirred in dry DCM (10 ml) and morpholine (0.69 ml) added. The mixture was allowed to stir at RT for 1 h and then quenched with water, extracted with DCM, dried (MgSO4) and evaporated under reduced pressure to give a white solid (1.10 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:22]([CH3:39])[C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N:22]([CH3:39])[C:23](=[O:38])[C:24]2[CH:25]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=2)=[C:9]([OH:8])[CH:14]=1
Reactant: [H][H]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1O
Yield: 83.2 %

Procedure:
A solution of N-[4-(2-benzyloxy-4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (65 mg, 0.118 mmol, example 43) in MeOH (10 mL) was purged with argon for 20 minutes before 10% Pd—C (10 mg) was added. The resulting reaction mixture was hydrogenated under balloon pressure hydrogen at 25° C. for 16 hours. The reaction mixture was filtered through a bed of celite and the residue was further washed with EtOAc. The combined filtrate was concentrated in vacuo, and the crude material thus obtained was purified by column chromatography over silica gel (25-35% EtOAc in n-hexane) to give 45 mg of the desired compound. Off-white solid (60%). MS (ESI): m/z=459.0 [M+H]+.
Reaction SMILES: C[C:2]([O:5][C:6]([C@@H:8]([NH:14]C(OCC1C=CC=CC=1)=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])C.C1CCC(NC2CCCCC2)CC1.C1[O:40][CH:39]1CO.C(Cl)CCl.C(Cl)CCl.CN(C1C=CN=CC=1)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:2]([O:5][C:6](=[O:7])[C@H:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[NH2:14])[CH:4]1[O:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Reactant: OCC1CO1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: N[C@@H](CCC(=O)O)C(=O)OCC1CO1
Yield: 141.4 %

Procedure:
A solution of 1720 mg (3.38 mmol) of Z-Glu-OtBu DCHA in 17 mL of dichloromethane was cooled to 0° C. and treated with 0.448 mL (6.75 mmol, 2.0 equiv) of glycidol, 41.2 mg (0.338 mmol, 0.1 equiv) of DMAP and 970 mg (5.06 mmol, 1.5 equiv) of EDC according to the general procedure for EDC/DMAP esterification. Purification by flash chromatography (30×150 mm silica gel, 35% ethyl acetate/hexane) gave 971 mg (73%) of the title compound: 1H NMR (300 MHz, CD3OD) δ7.38-7.24 (m, 5H), 5.09 (s, 2H), 4.41 (dd, J=2.9, 12.4 Hz, 1H), 4.13-4.09 (overlapping dd, 1H), 3.91-3.84 (overlapping dd, 1H), 3.32-3.16 (m, 1H), 2.80-2.78 (overlapping t, 1H), 2.64-2.61 (overlapping dd, 1H), 2.47 (t, J=7.6 Hz, 2H), 2.20-2.08 (m, 1H), 1.97-1.84 (m, 1H), 1.45 (s, 9H); MS(FAB) 394 (M+1), 338, 294, 260.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[N:12].[ClH:14].[H][H]>CO>[ClH:14].[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH2:12]
Reactant: COC(=O)Cc1ccccc1C#N
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1ccccc1CN

Procedure:
To a solution of 3a in methanol (0.2 M) was added palladium, 10 weight % (dry basis) on activated carbon, wet, (0.1 eq) and concentrated hydrochloric acid (3.5 eq). The reaction mixture was shaken overnight on a Parr reactor, with hydrogen pressure equal to 70 psi. The reaction mixture was filtered through celite, concentrated in vacuo then triturated with ether. The product was obtained as a white solid. (85%) 1H NMR (300 MHz, DMSO-d6) δ 8.66 (br s, 2H), 7.55 (m, 1H), 7.32 (m, 3H), 4.01 (m, 2H), 3.89 (s, 2H), 3.61 (s, 3H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[CH:16]=[C:17]([CH2:22][C:23]([C:25]3[C:26]([C:33]([O:35]C)=O)=[C:27]([CH3:32])[N:28]([CH3:31])[C:29]=3[CH3:30])=O)[CH:18]=[CH:19][C:20]=2[F:21])=[O:14])[CH2:9][CH2:8]1)[CH3:5]>C(O)(=O)C>[CH2:4]([O:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=2[F:21])[CH2:22][C:23]2[C:25]3[C:26](=[C:27]([CH3:32])[N:28]([CH3:31])[C:29]=3[CH3:30])[C:33](=[O:35])[NH:2][N:3]=2)=[O:14])[CH2:11][CH2:12]1)[CH3:5]
Reactant: CCOC1CCN(C(=O)c2cc(CC(=O)c3c(C(=O)OC)c(C)n(C)c3C)ccc2F)CC1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c(C)n(C)c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.7 %

Procedure:
Hydrazine hydrate (0.028 mL, 0.38 mmol) was added to methyl 4-(2-(3-(4-ethoxypiperidine-1-carbonyl)-4-fluorophenyl)acetyl)-1,2,5-trimethyl-1H-pyrrole-3-carboxylate (55) (0.158 g, 0.34 mmol) in acetic acid (4 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford the crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.049 g, 32.3% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.29 (1H, m), 1.41 (1H, m), 1.72 (1H, m), 1.86 (1H, m), 2.29 (3H, s), 2.60 (3H, s), 3.05 (1H, m), 3.28 (3H, s), 3.46 (2H, m), 3.53 (3H, s), 3.96 (1H, m), 4.12 (2H, s), 7.16-7.28 (3H, m), 11.17 (1H, s); m/z (LC-MS, ESI+), RT=1.78 min (M+H=441.11).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[I-].[K+].Cl[CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>CN(C=O)C>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CN(C)C(=O)CCl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CC(=O)N(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.086 mmol), N,N-diisopropylaethylamine (0.26 mmol), potassium iodide (0.06 mmol) were mixed in DMF (0.4 mL), then 2-chloro-N,N-dimethylacetamide was added. The mixture was stirred at room temperature for ˜3 h and the product was purified by reverse-phase HPLC to give the desired product. LC-MS: m/z=+482 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:30]([O-])([N+]([O-])=O)=[O:31]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:30]=[O:31])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 81.9 %

Procedure:
3.5 g of 1-(2-chloroethyl)-3-n-pentyl-3-D-glucopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 3.1 g of 1-(2-chloroethyl)-1-nitroso-3-n-pentyl-3-D-glucopyranosylurea are thereby obtained as yellow caramel.