Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(CC3C=CC=CC=3)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][NH2:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN1CCCC1=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:43][CH2:42][CH:39]3[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28]
Reactant: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 105 °C
Yield: 90.1 %

Procedure:
Sulfone 9.1 (2.24 g, 5.4 mmol) was combined with N-tert-butoxycarbonyl-4-aminomethylpiperidine (5.6 g, 16.2 mmol) and 1-methyl-2-pyrrolidinone (9 mL). The mixture was heated to 100-110° C. for 2 hours at which time it was cooled to room temperature and ethyl acetate was added. The resultant white solid was filtered and washed with ethyl acetate to give 2.3 g of 3-(2-chlorophenyl)-7-[(1-tert-butoxycarbony-piperidin-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (MH+=473). Hydrogen chloride gas was bubbled into 2.1 g of the protected amine which was suspended in 1,4-dioxane (22 mL), and the suspension stirred for 1 hour, concentrated in vacuo and dried to give the intermediate 3-(2-chlorophenyl)-7-[(piperidin-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.C([Li])CCC.CCCCCC.[CH3:24][C:25](=[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[CH3:26].[Cl-].[NH4+]>O1CCCC1>[CH2:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([C:25]([CH3:26])([CH3:24])[CH2:1][C:2]2[N:3]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:5][N:6]=2)=[CH:28]1
Reactant: Cc1nccn1-c1ccccc1
Reactant: CC(C)=C1C=Cc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(Cc1nccn1-c1ccccc1)C1=CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 1.58 g 2-methyl-1-phenyl-1H-imidazole (10 mmol) in 15 ml of tetrahydrofuran was cooled to −78° C. and 6.25 ml of 15% n-butyl-lithium in hexane (10 mmol) were added. The resulting mixture was stirred for an additional 20 min and then treated with a solution of 1.56 g 1-(1-methylethylidene)-1H-indene (10 mmol) in 5 ml tetrahydrofuran with vigorous stirring while the temperature was maintained at −78° C. The reaction mixture was allowed to reach room temperature, stirred for 14 h and hydrolyzed with saturated ammonium chloride solution. The organic layer was isolated and the aqueous layer was extracted three times with dichloromethane. The organic layers were dried over MgSO4, filtered and the solvent removed. The crude product was purified by column chromatography with silica as stationary phase. At the beginning a 5/1 hexane/ethyl acetate elution mixture was used (for the separation from 1-(1-methylethylidene)-1H-indene). Then, the elution mixture was changed to 1/1 hexane/ethyl acetate. After removal of the solvent 2.13 g (69%) of 2-[2-(1H-inden-3-yl)-2-methylpropyl]-1-phenyl-1H-imidazole was obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Cl:19][CH2:20][S:21]([NH:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)CCl
Reactant: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Solvent: Clc1ccccc1Cl
Product: O=S(=O)(CCl)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 62.6 %

Procedure:
10 g (0.034 mole) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole are dissolved in 35 ml of pyridine. 21.4 g (0.068 mole) of 47% chloromethanesulphonyl chloride, dissolved in 1,2-dichlorobenzene, are added dropwise at 0° C. to 5° C. The mixture is stirred for five hours, during which the temperature slowly rises to 20° C. The mixture is then poured into ice-water and extracted with methylene chloride. The organic phase is separated off, washed with dilute hydrochloric acid and extracted three times with 100 ml of saturated sodium bicarbonate solution. The combined aqueous phases are brought to pH 1 with 10% strength hydrochloric acid and the product which has precipitated is taken up in methylene chloride. The methylene chloride phase is separated off, washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. 8.7 g (63% of theory) of 5-chloromethanesulphonamido-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole of melting point 63°-66° C. are obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:26][CH3:27])=[C:7]([CH:13]([N:15]3[C:19]4=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]4[C:17]([Br:25])=[N:16]3)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[CH3:11])[CH2:2]1.[CH2:28]([N:30](CC)CC)[CH3:29].BrCC#N>C(#N)C.CN(C=O)C>[NH2:24][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:15]([CH:13]([C:7]3[C:6]([O:26][CH3:27])=[C:5]([CH:3]4[CH2:4][N:1]([CH2:29][C:28]#[N:30])[CH2:2]4)[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=3)[CH3:14])[N:16]=[C:17]([Br:25])[C:18]=12
Reactant: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: CCN(CC)CC
Agent: N#CCBr
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(CC#N)C1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.2 mmol) and triethylamine (37 μL, 0.27 mmol) in acetonitrile (3 mL) was added bromoacetonitrile (19 μL, 0.27 mmol). The resulting mixture was stirred at room temp. After an hour, the reaction mixture was still cloudy with not all of the material in solution. Several drops of DMF were added which allowed for a clear solution. The mixture was stirred overnight at room temperature and then most of the solvents were evaporated. The resulting residue was purified on silica gel (eluted with 0-10% MeOH in dichloromethane) to give 29 mg (30%) of the desired product. LCMS calculated for C20H22BrClN7O (M+H)+: m/z=490.1; Found: 490.1.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1.[CH3:46][C:47](=[N:49]O)[CH3:48].CN(C)C=O>O>[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25]([O:27][N:49]=[C:47]([CH3:48])[CH3:46])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)=NO
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)O)c(Cl)cc2F)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=NOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h
Yield: 47.9 %

Procedure:
First, 0.13 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added to a mixture of 0.30 g of [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetic acid (compound a-2), 49 mg of acetone oxime, and 2 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred for 2 hours. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.16 g of acetone O-[3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetyloxime (compound a-98).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[O:17][CH3:18])[NH:9][C:5]=2[CH:4]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:12][C:11]=3[O:17][CH3:18])[NH:9][C:5]=2[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2nc(-c3ccc(O)cc3OC)[nH]c2c1
Product: COc1ccc2nc(-c3ccc(OS(C)(=O)=O)cc3OC)[nH]c2c1

Procedure:
Prepared analogously to Example 1 from 5-methoxy-2-(2'-methoxy-4'-hydroxy-phenyl)-benzimidazole and methanesulfonic acid chloride.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[N:13]=1>C1COCC1>[NH2:11][C:12]1[N:17]=[C:16]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[C:14]([Cl:19])[N:13]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OCc2ccccc2)n1
Reaction time: 0.42 h

Procedure:
To 30 ml of a THF solution of 1.35 ml of benzyl alcohol cooled to 0° C. was added 480 mg of sodium hydride (60% oil dispersion) in a nitrogen atmosphere. After the mixture was stirred at the same temperature for 25 minutes, 1.64 g of 2-amino-4,6-dichloropyrimidine was added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated to dryness, and 100 ml of water was added to the residue. The precipitate was collected by filtration to obtain 2.36 g of 2-amino-4-benzyloxy-6-chloropyrimidine as white powder. To the powder was added 30 ml of ethanol, and 3.11 ml of hydrazine monohydrate and 1.38 g of potassium carbonate were added thereto, followed by heat-refluxing for 21 hours. After cooling to room temperature, the reaction mixture was concentrated. Water was added to the residue, and the precipitate was collected by filtration to give 1.95 g of white powder. To the powder were added 30 ml of ethanol and then 1.57 g of ethyl ethoxymethyleneacetoacetate, and the mixture was stirred at room temperature for 1 hour and then refluxed for 5 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:1 by volume) as a developing solvent. The fraction containing the desired compound was concentrated to give 1.72 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:48](=[O:55])[C:49]2[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=2)[CH2:42][CH2:41]1
Reactant: O=C(Cl)c1ccncc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccncc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using of N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isonicotinoyl chloride as starting materials in 43% yield. LCMS for C30H30ClN8O2 (M+H)+: m/z=569.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:28]=1[C:29](Cl)=[O:30].IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:28]=1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: COc1cccc(C)c1C(=O)Cl
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: COc1cccc(C)c1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 61 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-methoxy-6-methylbenzoyl chloride, the title compound (yield 61%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[C:35]#[CH:36].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH:36]=[CH:35][C:34]([O:38][CH2:39][CH3:40])=[O:37])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Reactant: C#CC(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 25.0 g (53.2 mmol) of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]-cyclopentanecarboxylic acid benzyl ester and 10.8 mL (106 mmol, 2 equivalents) of ethyl propiolate in 200 mL of dry tetrahydrofuran at 1° C. was treated with 53.2 mL (53.2 mmol, 1 equivalent) of a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M) over 45 minutes. The resulting solution was allowed to warm slowly to ambient temperature and stirred overnight. The tetrahydrofuran was displaced with toluene at reduced pressure, and the toluene solution was washed with water and brine, diluted to 600 mL with toluene, stirred with 90 g of silica gel for three hours, filtered, and concentrated to 25.14 g (83%) of 1{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid benzyl ester as an orange oil. 1H NMR (CDCl3) indicated a 1.5:1 trans/cis ratio.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@H:12]([CH:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.CO[C:23](=O)[CH:24]([C:26]1C=CC=CC=1)N>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@@H:12]([C:17]3[CH:19]=[CH:26][CH:24]=[CH:23][CH:18]=3)[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(N)c1ccccc1
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(Br)cc2C1=O
Agent: Cl
Product: COC(=O)[C@H](c1ccccc1)N1Cc2ccc(Br)cc2C1=O

Procedure:
The compound of example 344 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and 2-phenyl glycine methyl ester hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)=[CH:10][C:9]=2[F:23])[C:6](=[O:24])[CH:5]=[CH:4][C:3]=1[C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.[CH:34]1([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[NH2:42])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:42][C@@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:40]([O:39][CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:47])[CH2:18][CH2:17]3)=[CH:10][C:9]=2[F:23])[C:6](=[O:24])[CH:5]=[CH:4][C:3]=1[C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1c(F)cc(OC2CCC(=O)CC2)cc1F
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Product: CC(C)C[C@H](NC1CCC(Oc2cc(F)c(-n3c(N)c(C(=O)c4ccc(F)cc4)ccc3=O)c(F)c2)CC1)C(=O)OC1CCCC1

Procedure:
From Intermediate 5 (120 mg, 0.263 mmol) and L-Leucine cyclopentyl ester (Intermediate 8). LCMS purity 100%, m/z 640 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 0.95-1.05 (6H, m), 1.50-2.00 (16H, m), 2.10-2.35 (3H, m), 3.15-3.20 (1H, m), 4.00-4.15 (1H, m), 4.40 and 4.75 (0.5H each, m), 5.25-5.35 (1H, m), 5.75 (1H, d), 6.85-6.95 (2H, m), 7.15-7.25 (2H, m), 7.55-7.65 (2H, m), 7.65-7.70 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])OC(C)(C)C)[C:3]=1[CH:16]=O.[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CC(O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH:16]3[N:22]([C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[CH2:21][CH2:20][CH2:19][N:18]3[C:9](=[O:15])[NH:8][C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN2C(=O)Nc3nccc(Cl)c3C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (4-chloro-3-formylpyridin-2-yl)carbamate (1.2 g, 4.67 mmol), tert-butyl (3-amino-propyl)carbamate (855 mg, 4.91 mmol), and AcOH (0.28 g, 4.67 mmol) were suspended in toluene (50 mL), and stirred overnight at room temperature. The reaction mixture was concentrated. The crude intermediate was dissolved in NMP (8 mL) in a 40 mL sealed tube, and stirred for 30 min. at 160 ° C. The reaction mixture was cooled, and the resulting precipitate was filtered, washed with MeOH, and dried under vacuum. LC-MS (M+H=339, obsd.=339).
Reaction SMILES: [NH:1]([C:35]([O:37]C(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:25]([O:27]N1C(=O)CCC1=O)=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[O:19]C(C)(C)C)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6]C(C)(C)C.[NH2:42][C@H:43](C(O)=O)[CH2:44][CH2:45][C:46](=[O:48])[OH:47].[CH3:52][N:53]1[C@@H:70]2[CH2:71][C:58]3[CH:59]=[CH:60][C:61]([O:72][CH3:73])=[C:62]4[O:63][C@H:64]5[C:65]([CH2:67][CH2:68][C@@H:69]2[C@:56]5([C:57]=34)[CH2:55][CH2:54]1)=[O:66]>>[NH2:42][C@H:43]([C:35]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:25]([OH:27])=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[OH:19])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[OH:6])=[O:37])[CH2:44][CH2:45][C:46](=[O:47])[OH:48].[CH3:52][N:53]1[C@@H:70]2[CH2:71][C:58]3[CH:59]=[CH:60][C:61]([O:72][CH3:73])=[C:62]4[O:63][C@H:64]5[C:65]([CH2:67][CH2:68][C@@H:69]2[C@:56]5([C:57]=34)[CH2:55][CH2:54]1)=[O:66]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Glu-Glu-Glu-Hydrocodone was prepared by a similar method to Example 9 except the amino acid starting material was Boc-Glu(OtBu)-Glu(OtBu)-OSu and the conjugate starting material was Glu-Hydrocodone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:12]([O:10][C:5]1[C:4]([F:11])=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cc(Br)cc(F)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-Bromo-3-fluoro-2-hydroxy-benzaldehyde (5 g, 22.8 mmol) in DMF (100 ml) is added benzyl bromide (5.7 ml, 48 mmol) and cesium carbonate (11.9 g, 37 mmol). The reaction mixture is stirred at room temperature for 20 hours then diluted with water (150 ml) and extracted with EtOAc (2×150 ml), the organic portions are combined, washed with brine (50 ml), dried over MgSO4 and concentrated in vacuo to give a waxy off-white solid. The solid is stirred in iso-hexanes (30 ml) for 30 minutes, filtered and dried under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][NH:5][CH2:6]2.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=2)[N:13]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][N:5]([C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=3)[N:13]=1)[CH2:6]2
Reactant: CN1C2CCCC1CNC2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1C2CCCC1CN(c1ccc3cc([N+](=O)[O-])ccc3n1)C2
Temperature: 25 °C

Procedure:
A mixture of 9-methyl-3,9-diaza-bicyclo[3.3.1]nonane (0.50 g, 3.56 mmol), 2-chloro-6-nitroquinoline (0.74 g, 3.56 mmol), N,N-diisopropylethylamine (0.92 g, 7.13 mmol) and dioxane (25 ml) was stirred at reflux for 40 h. The mixture was allowed to cool to room temperature. The precipitated product was filtered and was washed with diethylether. The crude product was purified by silica gel column chromatography using a solvent mixture of dichloromethane, methanol and aqueous ammonia (9:1:1%). The pure product was isolated. Yield 300 mg (27%). Mp 166.2° C. LC-ESI-HRMS of [M+H]+ shows 313.1674 Da. Calc. 313.166451 Da, dev. 3 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH3:37].O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:36][CH3:37])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added iodoethane (88 μL). The reaction mixture is allowed to stir at room temperature for 24 h. The resulting suspension is poured into water (25 mL), filtered, and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid is purified by recrystallization from ethanol to afford 325 mg (73%) of the title compound as a white solid.