Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[N:17]([CH3:18])[CH:16]=[N:15][N:14]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CCOC(C)=O.CCO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[N:17]([CH3:18])[CH:16]=[N:15][N:14]=2)[CH:7]=[CH:8][C:9]=1[NH2:10])[CH3:2]
Reactant: CCOc1cc(-c2nncn2C)ccc1[N+](=O)[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2nncn2C)ccc1N

Procedure:
The title compound was prepared according to the method described for Preparation 107 using 3-(3-Ethoxy-4-nitrophenyl)-4-methyl-4H-1,2,4-triazole (Preparation 116) in EtOAc and EtOH (1:8 v:v).
Reaction SMILES: [CH2:1]([O:8][C:9]1([CH3:25])[CH2:18][CH2:17][C:16]2[N:15]=[CH:14][C:13]([C:19]([O:21]CC)=O)=[C:12](Cl)[C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>C(O)CCC>[CH2:1]([O:8][C:9]1([CH3:25])[CH2:10][CH2:11][C:16]2[NH:15][CH:14]=[C:13]3[C:19](=[O:21])[N:33]([C:30]4[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=4)[N:34]=[C:12]3[C:17]=2[CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CC(C)(OCc1ccccc1)CC2
Solvent: CCCCO
Product: CC1(OCc2ccccc2)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
A solution of ethyl 6-benzyloxy-4-chloro-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate (5.0 g) and p-chlorophenylhydrazine (2.0 g) in 75 mL of n-butanol is stirred at room temperature for 4 hours, then refluxed overnight. The reaction mixture is evaporated and the residue is treated with Et2O and 2N NaOH. The alkaline layer is separated, the pH is adjusted at 8 with dilute HCl, and the resulting precipitate is collected. This material is washed with EtOH/Et2O and air-dried to obtain 8-benzyloxy-2-p-chlorophenyl-8-methyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one.
Reaction SMILES: Cl.C([O:6][C:7](=[O:69])[C@H:8]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64]C(C)(C)C)=[CH:60][CH:59]=1)[NH:9][C:10]([C:12]1([CH2:17][C@H:18]([C:50]([O:52]C(C)(C)C)=[O:51])[CH2:19][NH:20][C:21](=[O:49])[C@H:22]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])(C)(C)C.C1(OC)C=CC=CC=1>ClCCl>[CH2:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([NH:20][CH2:19][C@@H:18]([C:50]([OH:52])=[O:51])[CH2:17][C:12]1([C:10]([NH:9][C@H:8]([C:7]([OH:69])=[O:6])[CH2:57][C:58]2[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=2)=[O:11])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:49])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)CC1(C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)OC(C)(C)C)CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: COc1ccccc1
Product: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)CCCC1)C(=O)O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
Hydrogen chloride gas was passed through a stirred, ice cold solution of N-{1-[3-(N2,N6 -dibenzyloxycarbonyl-(S)-lysylamino)-2-t- butryloxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)- tyrosine-t-butyl ester (from Example 81, 0.445 g, 0.47 mmole), and anisole (0.765 g, 7.1 mmole) in dry dichloromethane (10 ml) until saturation was achieved. A precipitate formed. After stirring for 1.5 hours, the solvent was evaporated under reduced pressure, and the residue azeotroped with dry dichloromethane. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The phases were separated, and the organic phase washed with two further portions of aqueous sodium bicarbonate. The combined aqueous phases were re-extracted with diethyl ether, and then acidified with 1M hydrochloric acid to pH 2. The aqueous phase was extracted with ethyl acetate (2x) and the combined organic phases dried (MgSO4), filtered and the solvent evaporated to yield a foam, which was azeotroped with methylene chloride to yield the title compound as a solid foam (0.325 g, 89%). Found: C,62.81; H,6.68; N,6.92. C41H50N4O11 0.4 CH2Cl2 requires C.61.17; H,6.33; N,6.93%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][NH:26][CH2:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[ClH:39].[N:40]1([C:45](N)=[NH:46])C=CC=N1>CN(C)C=O>[ClH:39].[ClH:39].[CH2:1]([O:3][C:4]([C:6]1([CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][N:26]([C:45](=[NH:40])[NH2:46])[CH2:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: N=C(N)n1cccn1
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CNCC3)CCN(c2ccncc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=N)N)CC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.9 %

Procedure:
To a solution of 1-(pyridin-4-yl)-4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-4-carboxylic acid ethyl ester (8.29 g) in dimethylformamide (50 ml) were added diisopropylethylamine (4.4 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (3.69 g), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and to the obtained residue was added diethyl ether (350 ml) and the supernatant was removed. The obtained oil was dissolved in methanol (20 ml) and thereto was dropwise added diethyl ether (700 ml) with stirring. The supernatant was removed and dried under reduced pressure. Fifty (50) mg from the obtained 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (10.0 g) was dissolved in ethanol and dil. hydrochloric acid was added. The mixture was concentrated and dried under reduced pressure to give the title compound (55 mg).
Reaction SMILES: BrC1[C:10]2C(Cl)=NC=[N:6][C:5]=2[N:4](C(C)C)C=1.ClC1C=C(C=C(C)N=1)C(Cl)=O.[NH2:26][C:27]1[C:28]2[C:35]([C:36]([C:38]3[CH:43]=[CH:42][CH:41]=C(N)N=3)=[O:37])=[CH:34][N:33]([CH:45]([CH3:47])[CH3:46])[C:29]=2[N:30]=[CH:31][N:32]=1>>[NH2:26][C:27]1[C:28]2[C:35]([C:36]([C:38]3[CH:43]=[C:42]([CH3:41])[N:4]=[C:5]([NH2:6])[CH:10]=3)=[O:37])=[CH:34][N:33]([CH:45]([CH3:46])[CH3:47])[C:29]=2[N:30]=[CH:31][N:32]=1
Reactant: CC(C)n1cc(C(=O)c2cccc(N)n2)c2c(N)ncnc21
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Agent: Cc1cc(C(=O)Cl)cc(Cl)n1
Product: Cc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(N)n1

Procedure:
The title compound was prepared from 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (15.8 g, 50.7 mmol) and 2-Chloro-6-methyl-isonicotinoyl chloride (9.6 g, 50.7 mmol) by procedures analogous to those described for the preparation (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(6-amino-pyridin-2-yl)-methanone. MS: 311.2 (MH+); HPLC Rf: 3.23 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(I)cc[nH]1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1ccc(I)cc1=O
Temperature: 25 °C

Procedure:
To 2.0 g (9.05 mmol) 4-iodo-2-pyridone in 10 mL DMF are added 1.00 mL (10.9 mmol) 1-bromopropane and 3.13 g (22.6 mmol) K2CO3. The reaction mixture is stirred at r.t. over night. The reaction is quenched by the addition of water. The resulting mixture is extracted with EtOAc. The organic layer is washed with aq. NaHCO3 solution, dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel, heptane/EtOAc. 70/30→50/50)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCCCC1
Temperature: 140 °C
Yield: 32.6 %

Procedure:
2,6-Dichloro-3-nitropyridine (5 g, 25.9 mmol) and cyclohexanamine (5.14 g, 51.8 mmol) were added to ethanol (17.5 mL). The reaction mixture was heated at 140° C. by microwave irradiation for 3 h. A yellow solid precipitated out. The solid was filtered, washed with cold ethanol, and dried under vacuum to afford the title compound (2.162 g) without further purification. LCMS m/z=256.40 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:25]=[N:24][C:16]2[NH:17][C:18]3[CH2:23][CH2:22][NH:21][CH2:20][C:19]=3[C:15]=2[CH:14]=1.O>N1C=CC=CC=1>[Cl:12][C:13]1[CH:25]=[N:24][C:16]2[NH:17][C:18]3[CH2:23][CH2:22][N:21]([S:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])[CH2:20][C:19]=3[C:15]=2[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
4-Chlorobenzenesulfonyl chloride (56 mg, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 33 (92 mg, 99% yield) as a yellow solid. LC-MS (M+H=382, obsd.=382).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([CH2:12][C:13]([O:15]CC)=[O:14])=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33]C)=[O:32])=[CH:21][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.C(=O)(O)[O-:37].[Na+].C(O)(=O)C>O>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([OH:33])=[O:32])=[CH:21][CH:20]=2)[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:9]([OH:37])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CC(=O)OCC)c(Cc2ccc(-c3ccccc3C(=O)OC)cc2)n1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1nc(O)c(CC(=O)O)c(Cc2ccc(-c3ccccc3C(=O)O)cc2)n1
Reaction time: 0.5 h

Procedure:
50 mg of the product of Example 7 were introduced into 1 ml of 6N hydrochloric acid and the mixture was heated to gentle reflux. The mixture was stirred for 2 hours 30 minutes and after cooling, the mixture was diluted with 2 ml of water. The pH was adjusted to 7-8 by the addition of sodium bicarbonate, then returned to pH 5-4 by the addition of acetic acid. The mixture was stirred for approximately 30 minutes, followed by separating, and rinsing with water to obtain 30 mg of the expected product melting approx. 220° C.
Reaction SMILES: Br[C:2]1[C:3]2[CH:9]([CH3:10])[CH:8]([CH3:11])[C:7](=O)[C:4]=2[S:5][CH:6]=1.[BH4-].[Na+].O>C1COCC1.CO>[CH3:10][CH:9]1[C:3]2[CH:2]=[CH:6][S:5][C:4]=2[CH:7]=[C:8]1[CH3:11]
Reactant: CC1C(=O)c2scc(Br)c2C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1=Cc2sccc2C1C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of 132.4 g (0.54 mol) of 3-bromo-4,5-dimethyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one in 750 ml of THF-methanol (2:1, vol.), 28.6 g (0.75 mol) of NaBH4 was added in small portions while vigorously stirring over 1 h at 5° C. This mixture was stirred overnight at ambient temperature and then added to ca. 1000 cm3 of cold water. The organic layer was separated; the aqueous layer was extracted with 2×300 ml of methyl-tert-butyl ether. The combined extract was dried over K2CO3 and evaporated to dryness. To a hot solution of the residue in 1500 cm3 of toluene, 0.5 g of para-toluenesulfonic acid was added. This mixture was refluxed for 15 min, cooled to room temperature, and passed through a short Silica Gel 60 column (40-63 μm, d 65 mm, 1 150 mm). The column was additionally washed with hexanes to isolate the product. The obtained solution was evaporated to dryness. Fractional distillation gave a colorless oil, bp 101-104° C./2 mm Hg. Yield 92.8 g (75%).
Reaction SMILES: [Cl:1]Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([Cl:9])=[O:8].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([Cl:1])[C:12]=1[CH3:13])[C:7]([Cl:9])=[O:8]
Reactant: ClCl
Reactant: Cc1ccc(C(=O)Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Temperature: 4 °C
Reaction time: 6 h

Procedure:
A jacketed kettle was equipped with a chiller, overhead stirrer, thermometer, and connections to a chlorine tank and a caustic scrubber. The kettle was charged with the previously prepared 3-chloro-4-methylbenzoyl chloride (1 part) and dichloromethane (6.8 parts). Aluminum trichloride (0.8 parts) was added, and the resulting red-brown mixture was cooled with agitation to 3-5° C. Chlorine (0.37 parts) was introduced at a sufficient rate to keep the reaction temperature below 10° C. The reactor was held at 0-5° C. for 6 hours. The reaction mixture was purged with nitrogen and slowly quenched by transfering into an agitated and chilled hydrochloric acid solution (4.4 parts) while maintaining the temperature below 5° C. Agitation was stopped and the lower organic layer was recovered. The solvent was removed by distillation.
Reaction SMILES: CNN.[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:12](=[O:25])[CH2:13][N:14]1[C:18](=[O:19])C2=CC=CC=C2C1=O.O.[CH3:35][C:36]1[CH:37]=[C:38]([N:42]=C=O)[CH:39]=[CH:40][CH:41]=1>ClCCl.O1CCCC1>[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH2:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[C:12](=[O:25])[CH2:13][NH:14][C:18]([NH:42][C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([CH3:35])[CH:37]=1)=[O:19]
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cc1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CN1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C)c1
Temperature: 20 °C
Reaction time: 30 h
Yield: 19.2 %

Procedure:
Methyl hydrazine (2.13 g) is added at a temperature in the region of 0° C. to a solution of tert-butyl 2-[N-(2-methylphenyl)-2-phthalimidoacetamido]acetate (5.5 g) in dichloromethane (90 cc). The reaction mixture is stirred for 30 hours at a temperature in the region of 20° C. and then for 1 hour under reflux. After cooling, water (100 cc) is added, the mixture is stirred and the aqueous phase is separated after settling has taken place and re-extracted with dichloromethane (2×60 cc). The organic phases are combined, washed with water (2×15 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. tert-Butyl 2-[2-amino-N-(2-methylphenyl)acetamido]acetate is thereby obtained in the form of an oil, which is dissolved in anhydrous tetrahydrofuran (40 cc). 3-Methylphenyl isocyanate (1.77 g) is added to this solution and the reaction mixture is then stirred for 1 hour at a temperature in the region of 20° C. and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallisation in petroleum ether, tert-butyl 2-{N-(2-methylphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (1.05 g), m.p. 133° C., is obtained.
Reaction SMILES: [S:1]([N:11]1[CH2:16][CH2:15][N:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]1[CH2:20][C:21]([OH:23])=O)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C@@H:58]([C:60]1[CH:71]=[CH:70][C:63]([CH2:64][NH:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[CH:62][CH:61]=1)[CH3:59]>C1COCC1.C(Cl)Cl>[C:66]([NH:65][CH2:64][C:63]1[CH:62]=[CH:61][C:60]([C@H:58]([NH:57][C:21](=[O:23])[CH2:20][CH:12]2[N:11]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[CH2:16][CH2:15][N:14]3[CH:17]=[CH:18][CH:19]=[C:13]23)[CH3:59])=[CH:71][CH:70]=1)([CH3:69])([CH3:67])[CH3:68]
Reactant: C[C@@H](N)c1ccc(CNC(C)(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)N[C@H](C)c2ccc(CNC(C)(C)C)cc2)cc1
Reaction time: 0.25 h
Yield: 29 %

Procedure:
To a suspension of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (405 mg, 1.2 mmol, 1.0 eq.) in THF (5 ml) were added DIPEA (1.0 ml, 6.0 mmol, 5.0 eq.) and HATU (547 mg, 1.4 mmol, 1.2 eq.) at 0° C. and the mixture was stirred for 15 min at the same temperature. A solution of (R)—N-(4-(1-aminoethyl)-benzyl)-2-methylpropan-2-amine (A54) (1.2 mmol, 1.0 eq.) in THF (3 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The mixture was diluted with DCM (70 ml) and washed with sat. NH4Cl solution (25 ml), sat. NaHCO3 solution (25 ml), water (25 ml) and brine (25 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 3% MeOH/DCM) to yield the desired product as a light brown solid. Yield: 29% (180 mg, 0.334 mmol); MS, Rt=2.9 min; m/z=523.1 [M H]+
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]1([CH2:14][CH2:15][SH:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][C:18]1[N:26]=[C:25](Cl)[N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[Cl-].[Na+].O>[NH2:17][C:18]1[N:26]=[C:25]([S:16][CH2:15][CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: SCCc1ccccc1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(SCCc2ccccc2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 36.2 %

Procedure:
Sodium hydride (300 mg, 7.5 mmol 60% in mineral oil) were added DMF (10 ml), 2-phenylethanethiol (1 ml, 7 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred at 100° C. for 10 hours. After addition of saturated brine the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (51 mg, yield 37%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:20]4[S:19][C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[CH:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1cc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc5ccccc5s4)cc3CC[C@@H]12
Yield: 80.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2-benzothiopheneboronic acid (140 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 17 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (70% ethyl acetate/hexanes eluent), to give 190 mg (81%) of the title compound as a white solid. mp 247°-250°. FDMS: m/e=361. α[D]589 =+93.33 (c=0.36, chloroform).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][CH2:17]1)[CH3:2].[OH-].[Na+].O>C(O)C>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][CH2:21]1)[CH3:2]
Reactant: CCOCCn1c(NC2CCN(CC(=O)OCC)CC2)nc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOCCn1c(NC2CCN(CC(=O)O)CC2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A mixture of 5.5 parts of ethyl 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidineacetate, 15 parts of a sodium hydroxide solution 1N, 100 parts of water and 16 parts of ethanol was stirred overnight at room temperature. The reaction mixture was evaporated. The residue was taken up in water, washed with dichloromethane and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (80:20 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 1 part (19.1%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidineacetic acid; mp. 227.3° C. (compound 182).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([N:18]=O)[CH2:9]2)=[CH:4][CH:3]=1.[Cl-].[NH4+].O.[CH3:23][C:24]([CH3:26])=O>[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([N:18]=[C:24]([CH3:26])[CH3:23])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=NN1CC(c2ccc(F)cc2)Cc2ccccc21
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: CC(C)=NN1CC(c2ccc(F)cc2)Cc2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-fluorophenyl)-1-nitroso-1,2,3,4-tetrahydroquinoline (0.27 g, 0.00105 mol) in acetone (15 mL) was added saturated ammonium chloride solution (1.5 mL) and water (1.5 mL) at RT. The resulting brown colored reaction mixture was cooled to 0° C., and zinc dust (0.411 g, 0.00632 mol) was added portionwise at 0° C. After addition, the reaction mixture was warmed to RT and stirred for 2 h. After completion of reaction (monitored by TLC), the solvent was removed under reduced pressure and the residue extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to obtain product as a brown colored oil (0.28 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(Cl)(Cl)Cl>[CH2:18]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1CCNCC1
Reactant: BrCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 924.2 %

Procedure:
To a solution of methyl piperidine-4-carboxylate (10.00 g, 6.4 mmol) and triethylamine (10.32 g, 10.2 mmol) in CHCl3 (100 mL), benzyl bromide (14.69 g, 8.6 mmol) was added under argon atmosphere while cooling with a water and ice bath. The mixture was stirred at room temperature overnight. CHCl3 and water were added and the two phases were separated. The aqueous phase was extracted with CHCl3. The organic phase was dried over Na2SO4 and concentrated to dryness, to afford 13.80 g of the desired compound as an orange solid (yield: 88%).