Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([N:20]([CH3:22])[CH3:21])([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:23]S(O)(=O)=O>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([N:20]([CH3:22])[CH3:21])([C:18]([NH2:19])=[O:23])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: CN(C)C1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vigorously stirred solution of 1-benzhydryl-3-dimethylaminoazetidine-3-carbonitrile (I-3A-3a; 1.55 g, 5.32 mmol) in methylene chloride (30 ml) cooled in an ice bath was treated with H2SO4 (3.0 ml, 54 mmol), dropwise. After warming to room temperature and stirring overnight, the reaction was cooled in an ice bath and then carefully quenched with concentrated aqueous NH4OH to pH 11. The mixture was extracted with methylene chloride. The combined organic layers were dried (Na2SO4) and then concentrated. The crude product (4:1 product to starting material) was then purified on a Biotage™ Flash 40M column using 3% methanol in methylene chloride as eluant. The residue (1.04 g) was then triturated from ether to afford I-3A-3b (0.75 g, 45%): +ESI MS (M+1) 310.3; 1H NMR (400 MHz, CD3OD) δ 7.40 (d, J=7.5 Hz, 4H), 7.24 (t, J=7.5 Hz, 4H), 7.17 (t, J=7.3 Hz, 2H), 4.42 (s, 1H), 3.41 (d, J=8.7 Hz, 2H), 3.12 (d, J=8.7 Hz, 2H), 2.26 (s, 6H).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([NH:13][C:14]3[C:19](=[O:20])[NH:18][C:17]([C:21]([NH2:23])=[O:22])=[C:16]([CH3:24])[N:15]=3)[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C.[Fe](Cl)(Cl)Cl>[CH3:24][C:16]1[N:15]=[C:14]([NH:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[CH:12]=2)[C:19](=[O:20])[N:18]2[C:25]3([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[NH:23][C:21](=[O:22])[C:17]=12
Reactant: O=C1CCCCC1
Reactant: Cc1nc(Nc2ccnc(NC(=O)C3CC3)c2)c(=O)[nH]c1C(N)=O
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Product: Cc1nc(Nc2ccnc(NC(=O)C3CC3)c2)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 80 °C
Yield: 13.4 %

Procedure:
5-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxamide (8, 600 mg, 1.83 mmol) and cyclohexanone (538 mg, 5.48 mmol) were charged in acetonitrile in a 20 mL microwave vial. Iron(III) chloride (889 mg, 1.83 mmol) was added and heated the reaction mixture at 80° C. for 16 h. On completion of the reaction, solvent was removed under vacuum and purified the compound by silica gel (200-400 mesh) column chromatography eluting with 5% methanol in dichloromethane. Appropriate column fractions were concentrated under reduced pressure to afford N-(4-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyrazin]-6′-yl)amino)pyridin-2-yl)cyclopropanecarboxamide (10, 100 mg, crude) as light brown crude solid which was directly forwarded to next step. MS (ESI) m/z 409.43 [M+1]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][P:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])([CH3:18])=[O:17])[CH3:14].[CH3:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]([CH2:32][N+:33]([O-:35])=[O:34])[CH2:18][P:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])(=[O:17])[O:15][CH2:13][CH3:14])=[CH:36][CH:37]=1
Reactant: Cc1ccc(C=C[N+](=O)[O-])cc1
Reactant: CCOC(OCC)P(C)(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(C)cc1)OCC
Reaction time: 0.17 h

Procedure:
To a solution of 8.7 g of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 53.6 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 15.0 g of ethyl(diethoxymethyl)methylphosphinate in 20 ml of tetrahydrofuran is added. This mixture is then stirred for a period of 1 hour at -78° C. after which time a solution of 11.6 g of 4-methyl-β-nitrostyrene in 20 ml of tetrahydrofuran is introduced. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product chromatographed on silica gel using ethyl acetate as an eluent to give ethyl 2-(4-methylphenyl)-3-nitropropyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+42.5 and +42.1 ppm (CDCl3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16](NC1C=C2OCOC2=CC=1C(=O)C)=[O:17])(=[O:10])=[O:9].[NH2:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:34]=1[C:35]#[N:36]>>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:34]=1[C:35]#[N:36])=[O:17])(=[O:9])=[O:10]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Product: COc1cc(C#N)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)cc1OC

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148) except that 2-amino-4,5-dimethoxybenzonitrile was used instead of 2'-amino-4',5'-(methylenedioxy)acetophenone. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[{2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide was obtained via HPLC purification as a light brown powder (36% yield, m.p. 53°-56° C.).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)(C)C>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccc(O)cc1
Reactant: BrCCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: OCCc1ccc(OCCCCOc2ccccc2)cc1
Yield: 70.5 %

Procedure:
A mixture of 10.31 g (45 mmol) of 4-phenoxybutylbromide, 6.22 g (45 mmol) of 2-(4-hydroxyphenyl)ethanol and 6.22 g (45 mmol) of pulverized potassium carbonate in 45 ml of isopropanol was refluxed for 24 hours. The resulting mixture was cooled, mixed with water and then extracted three times with ethyl acetate. The combined extracts were washed with water and then with saturated aqueous sodium bicarbonate. They were dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on 500 g of silica gel (Merck Si60, 0.04-0.063 mm) using methylene chloride/methanol (98:2) as eluent. The product-containing fractions were evaporated in vacuo to yield 2-[4-(Phenoxybutoxy)phenyl]ethanol in the form of 9.08 g of crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[C:26]([CH2:25][CH2:24][CH2:23][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:3][C:2]=1[Cl:1])([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=C1CCC(c2ccc(O)c(Cl)c2)=NN1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Yield: 75.7 %

Procedure:
A mixture of 1.500 mg (6.675 mmol) of 6-(3-chloro-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone, prepared by the method of Eur. Pat. Appl. 178,189, 1.010 g (7.34 mmol) K2CO3, and 1.463 g (7.50 mmol) of ethyl 4-bromobutyrate in 30 ml of DMF is heated at 100° C. for 2 hrs under N2. The DMF is removed under vacuum and the residue taken up in 150 ml of EtOAc and 50 ml of water. The organic phase is washed with 50 ml of 5% NaOH, then saturated NaCl solution, dried (MgSO4), and the solvent removed to leave a white solid. This solid is recrystallized from hexane-EtoAc to give 1.711 g of 6-[4-carboethoxypropyloxy-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone as white needles, m.p. 109°-110° C. Yield, 82%.
Reaction SMILES: N12CCCN=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[C:12]12([C:22](=[O:25])[CH:23]=[CH2:24])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.[Cl-].[O:27]=C(C)C[N+]1C=CC=CC=1>C(O)C>[C:12]12([C:7]3[CH:6]=[C:5]([OH:27])[CH:4]=[CH:3][CH:2]=3)[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]3)[CH2:19]1)[CH2:13]2.[C:12]12([C:22](=[O:25])[CH:23]=[CH2:24])[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][CH:14]([CH2:20]3)[CH2:13]1)[CH2:21]2
Reactant: CC(=O)C[n+]1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Agent: C=CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: [Cl-]
Solvent: CCO
Product: Oc1cccc(C23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A THF solution (20.0 mL, 10.0 mmol) comprising 1 mol/L of vinylmagnesium bromide was slowly added dropwise to a THF (45 mL) solution comprising 2.23 g (5.00 mmol) of N-methoxy-N-methyladamantan-1-carboxamide that had been cooled in a bath containing ice and salt while keeping the THF solution at −10 to 0° C. Thereafter, the mixture was stirred at 0° C. for 1 hour, and stirred at room temperature overnight. The reaction mixture was slowly added dropwise, using a Pasteur pipette, to saturated ammonium chloride water that had been cooled in a bath containing ice and salt, while keeping it at −10 to −5° C. After the completion of the dropwise addition, the mixture was heated to 0° C. Since the mixture comprises two layers, the water layer was separated, and ethyl acetate extraction was performed three times. Subsequently, the primarily separated organic layer and the combined ethyl acetate layers were combined, and the organic layer was washed with saturated ammonium chloride water 5 times, and with brine once. Drying over sodium sulfate, filtration, condensation, and drying under reduced pressure at room temperature for 3 hours were performed, thereby giving the crude product of 1-(adamantan-1-yl)prop-2-en-1-on (containing 1.56 g of impurities such as 3-[methoxy(methyl)amino]-1-(adamantan-1-yl)propan-1-on, etc.) The crude product was used in the next reaction without purification. Under an Ar atmosphere, 1.43 g of 1,8-diazabicyclo[5.4.0]undeca-7-en (DBU) was added to an ice-cooled suspension comprising 1.18 g of the crude product of 1-(adamantan-1-yl)prop-2-en-1-on, 1.60 g of 1-(2-oxopropyl)pyridinium chloride, 1.18 g of molecular sieves 4A, and ethanol (24 mL), and the mixture was stirred at room temperature for 2 days. Under ice-cooling, 1N HClaq. was added to the reaction mixture, the pH was adjusted to 1, and ethyl acetate extraction was performed. The organic layer was separated, and washed with brine three times, followed by drying over sodium sulfate, filtration, condensation, and drying under reduced pressure at room temperature for 1 hour, thereby giving the crude product (936 mg) of 3-(adamantan-1-yl)phenol. This crude product and the crude product of 3-(adamantan-1-yl)phenol (456 mg) obtained from the crude product of 400 mg of 1-(adamantan-1-yl)propa-2-en-1-on under the same conditions were combined. Then this crude product was separated and purified by silica gel column chromatography, thereby giving 222 mg of 3-(adamantan-1-yl)phenol (yield: 9.7%).
Reaction SMILES: C(OC([N:8]1[CH2:29][CH2:28][C:11]2([N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]2=[O:27])[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:36]>C(OCC)C>[ClH:36].[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:13]2[C:12](=[O:27])[C:11]3([CH2:10][CH2:9][NH:8][CH2:29][CH2:28]3)[N:15]([CH3:16])[C:14]2=[O:17])=[CH:24][CH:23]=1
Reactant: COc1ccc(CN2C(=O)N(C)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc(CN2C(=O)N(C)C3(CCNCC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
403 mg (1 mmol) of 3-(4-methoxy-benzyl)-1-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester were dissolved in a minimum of diethyl ether before adding 3 mL of a solution of dioxane/HCl 4N. The reaction mixture was agitated 10 minutes at room temperature and then evaporated. The yellow crude was triturated with diethyl ether and filtered to yield 115.3 mg (34%) of 3-(4-methoxy-benzyl)-1-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:4][CH:3]1[CH2:5][C:6]([OH:8])=[O:7].Br[CH2:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].[I-].[Na+].C(N(CC)CC)C>CN(C)C=O.O>[F:1][C:2]1([F:9])[CH2:4][CH:3]1[CH2:5][C:6]([O:8][CH2:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])=[O:7]
Reactant: O=C(O)CC1CC1(F)F
Reactant: O=C(CBr)N1CCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC1CC1(F)F)OCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 2.72 g (0.02 mol) 2,2-difluorocyclopropyl-acetic acid and 3.84 g (0.02 mol) N-(bromoacetyl)-pyrrolidine in 10 ml dimethylformamide was treated, at room temperature, with 0.3 g sodium iodide and 2.8 ml (0.02 ml) triethylamine and the mixture stirred at room temperature for 10 hours. It was then poured into water and extracted three times with ethyl acetate. The combined ethyl acetate phases were washed with first with aqueous 2% sodium hydrogen carbonate and then with water, dried over magnesium sulphate and concentrated. The crude product was purified by silica gel column chromatography using hexane/ethyl acetate (1:1) as eluent. A sample was analysed by thin layer chromatography using hexane/ethyl acetate (1:1) as eluent (Rf :0.18). 3.3 g (66% of theory) of product was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)C1C=CC=CC=1.[CH3:29][CH2:30]O>[Pd]>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=2)[CH:14]=[C:9]([OH:8])[CH:10]=1)[CH3:30]
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)Cc1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 5 h
Yield: 93 %

Procedure:
To a solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (2.5 g, 5.5 mmol) in EtOH (50 mL) was added 10% Pd/C (5% wt) and the resultant black suspension stirred under an atmosphere of H2 for 5 hours. The resultant mixture was filtered through celite and evaporated to dryness. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give 2.3 g (93%) (5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[Cl:20][C:21]1[CH:30]=[CH:29][C:24]([CH:25]=[CH:26][CH2:27]Cl)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:30]=[CH:29][C:24]([CH:25]=[CH:26][CH2:27][N:7]2[C:6](=[O:19])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)=[N:8]2)=[CH:23][CH:22]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(SC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 82.3 %

Procedure:
Using 4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 4-chlorocinnamyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 82.3%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH2:14]Cl)[CH2:7][C:6]1=[O:16].[NH:17]1[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:38])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.[OH:48][C:49]1[CH:56]=[CH:55][C:52]([CH2:53][NH2:54])=[CH:51][CH:50]=1>CN(C=O)C>[OH:48][C:49]1[CH:56]=[CH:55][C:52]([CH2:53][NH:54][CH2:2][CH2:3][CH2:4][N:5]2[C:6](=[O:16])[CH2:7][N:8]([CH2:12][CH2:13][CH2:14][N:17]3[CH2:18][CH2:19][CH:20]([O:23][C:24](=[O:38])[NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:21][CH2:22]3)[C:9](=[O:11])[CH2:10]2)=[CH:51][CH:50]=1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reactant: NCc1ccc(O)cc1
Reactant: O=C1CN(CCCCl)C(=O)CN1CCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCCN2CC(=O)N(CCCNCc3ccc(O)cc3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a stirred solution of 1,4-bis(3-chloropropyl)piperazine-2,5-dione (40 mg, 0.15 mmol; prepared as described in Preparation 7) in DMF (1.5 mL) was added biphenyl-2-ylcarbamic acid piperidin-4-yl ester (44 mg, 0.15 mmol; prepared as described in Preparation 3) and DIPEA (0.078 mL, 0.45 mmol) and the reaction was allowed to stir overnight at room temperature. After overnight, 4-hydroxybenzyl amine (18.5 mg, 0.15 mmol) was added and the reaction heated to 50° C. for 16 hours. Next the reaction mixture was concentrated in vacuo and then dissolved in 1:1 mixture HOAc:H2O (1.5 mL) and purified on reverse-phase silica gel (gradient elution, 10-50% ACN/H2O) to afford the title compound in 10% yield (over 2 step) (13 mg, 0.015 mmol). MS m/z: [M+H+] calcd for C35H43N5O5, 614.4; found, 614.2).
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][NH2:54])[CH:48]=1>>[Cl:2][C:3]1[CH:4]=[C:5]([C:14]2[N:53]([C:49]3[CH:48]=[N:47][CH:52]=[CH:51][CH:50]=3)[N:54]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Cl)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1

Procedure:
500 mg (1.23 mmol) of the compound of Example 4A is reacted analogously to the synthesis of the compound of Example 20A with 197 mg (1.36 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 203 mg (43% of theory) of the title compound is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].C[CH2:19][N:20](CC)CC.CN>CO>[CH3:14][O:13][C:12]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:2][N:20]([CH3:19])[C:5]2=[O:6]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1CBr
Reactant: CCN(CC)CC
Agent: CN
Solvent: CO
Product: COc1c([N+](=O)[O-])ccc2c1CN(C)C2=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
To a solution of methyl 2-(bromomethyl)-3-methoxy-4-nitrobenzoate (300 mg, 1.0 mmol) in MeOH (10 mL) was added Et3N (120 mg, 1.2 mmol) and CH3NH2 (1.0 mL, 4M in MeOH). The solution was stirred at 70° C. for 4 h. The solvent was evaporated in vacuo, and the residue was purified by silica gel-column (eluting with PE/EA=10:1) to afford 4-methoxy-2-methyl-5-nitroisoindolin-1-one as a yellow solid (110 mg, yield 50%). m/z (ES+APCI)+: [M+H]+223.1.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([C:55]#[N:56])=[N:33][C:34]=2[NH:38][CH2:39][CH:40]([C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1)[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)(=O)C1C=CC=CC=1.N.[CH:58]([N:61]([CH:72]([CH3:74])[CH3:73])[CH2:62][CH2:63][NH:64][C:65](N1C=CN=C1)=[O:66])([CH3:60])[CH3:59].N1C=CN=C1>C(O)C.[Pd].ClCCl.C(O)(C)C>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([CH:40]([C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)[CH2:39][NH:38][C:34]2[N:33]=[C:32]([CH2:55][NH:56][C:65]([NH:64][CH2:63][CH2:62][N:61]([CH:72]([CH3:74])[CH3:73])[CH:58]([CH3:59])[CH3:60])=[O:66])[N:31]=[C:30]3[C:35]=2[N:36]=[CH:37][N:29]3[C@@H:11]2[O:12][C@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[C@@H:14]([OH:15])[C@H:10]2[OH:9])=[CH:46][CH:45]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Agent: [Pd]
Agent: N
Agent: c1c[nH]cn1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(CNC(=O)NCCN(C(C)C)C(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.4 %

Procedure:
(2R,3R,4S,5S)-4-(Benzoyloxy)-2-(6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (220 mg, 0.28 mmol) (Preparation 68) was added to a saturated solution of ammonia in ethanol (15 ml). 10% Palladium on carbon (40 mg) was added and the suspension was stirred under an atmosphere of hydrogen gas (413.7 kPa, 60 psi) at room temperature for 16 hours. The reaction temperature was then stirred at 60° C. under an atmosphere of hydrogen gas (413.7 kPa, 50 psi) for a further 48 hours. The reaction mixture was filtered through Arbocel (Trade Mark) and the solvent was removed under reduced pressure. The crude residue was dissolved in toluene (8 ml) and isopropyl alcohol (2 ml) and N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (50 mg, 0.21 mmol) (Preparation 27) were added. The solution was heated under reflux for 3 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:2 by volume). The solvent was removed under reduced pressure give a product that was contaminated with imidazole. The product was dissolved in dichloromethane (60 ml) and the resulting solution was washed three times with water (50 mg) and dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to give the title compound (53 mg) as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][Si](C)(C)C)[C:5]([NH2:8])=[N:6][CH:7]=1.CC([O-])(C)C.[K+].CCOC(C)=O.Cl>CC(O)(C)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[CH:9]=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cc(Br)cnc1N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Brc1cnc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 89.1 %

Procedure:
To a solution of 5-bromo-3-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (B-7-2) (9.5 g, 35.3 mmol) in t-BuOH (100 mL) was added t-BuOK (10.5 g, 141.3 mmol). The mixture was stirred at 80° C. for 20 hours. TLC (Petroleum ether: EtOAc=5:1) showed that the reaction was complete. Then the mixture was cooled to room temperature. Concentrated hydrochoric acid (50 mL) was added to the mixture. Then the mixture was heated to reflux for 8 hours. TLC (Petroleum ether: EtOAc=5:1) showed that the reaction was complete. The mixture was cooled to room temperature and poured into water (100 mL). The mixture was filtered through a bed of Celite. The filtrate was diluted with water (100 mL) and made basic by the addition of 50% sodium hydroxide. The mixture was extracted with EtOAc (150 mL×3). The organic layers were washed with water (100 mL) and saturated sodium chloride (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 5-bromo-1H-pyrrolo[2,3-b]pyridine (B-7-3) (6.2 g, 88.6%) as a light yellow solid.