Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([CH:8]=O)[CH:6]=[N:5][C:4]([S:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:3]1.[CH2:15]([O:17][CH2:18][C:19](OCC)=[O:20])[CH3:16].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH2:11]([S:10][C:4]1[N:5]=[CH:6][CH:7]2[CH:8]=[C:18]([O:17][CH2:15][CH3:16])[C:19](=[O:20])[NH:1][CH:2]2[N:3]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCSC1=NC(N)C(C=O)C=N1
Reactant: CCOCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCSC1=NC2NC(=O)C(OCC)=CC2C=N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Amino-2-butylsulfanyl-4,5-dihydro-pyrimidine-5-carbaldehyde (3 g, 14.2 mmol, furnished by scaleup) and ethyl ethoxyacetate (2.34 g, 2.4 ml, 17.75 mmol) were stirred in 80 ml toluene at 0°-5° C. under nitrogen. Potassium t-butoxide (1.75 g, 15.6 mmol) was added gradually. The mixture was stirred to ambient temperature, and then to 65° C. for 48 hours. An additional 20 ml of toluene and 2.4 ml ethyl ethoxyacetate were added and the reaction was maintained at 65° C. over the weekend. The reaction mixture was concentrated in vacuo and triturated with EtOAc to remove the remaining starting aldehyde. The remaining solid was further triturated with chloroform to remove additional impurities. 3.66 g of 2-Butylsulfanyl-6-ethoxy-8,8a-dihydro-4aHpyrido[2,3-d]pyrimidin-7-one (1A) of a purity greater than 80% as judged by MS/HPLC and NMR was collected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6]([Br:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6]([Br:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(Br)cc([N+](=O)[O-])cc2Br)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Br)cc([N+](=O)[O-])cc2Br)ccc1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.4 %

Procedure:
To a stirred solution of 3,5-dibromo-4-(3′-isopropyl-4′-methoxyphenoxy)-nitrobenzene (1.37 g, 2.98 mmol) in CH2Cl2 (30.0 mL) at −78° C. was added BBr3 (8.93 mL, 8.93 mmol, 1 M solution in CH2Cl2). The reaction mixture was stirred at room temperature for 2.5 h, quenched with ice/water, and stirred cold for several minutes. The reaction mixture was diluted with CH2Cl2 and H2O, partitioned, and the aqueous solution was extracted with CH2Cl2. The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:10) to afford 3,5-dibromo-4-(4′-hydroxy-3′-isopropylphenoxy)nitrobenzene as a solid (1.20 g, 90%): 1H NMR (300 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.64 (s, 2H), 6.73 (m, 2H), 6.37 (m, 1H), 3.12 (m, 1H), 1.16 (d, J=6.0 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:5); Rf=0.46.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[N:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[N:5][CH:4]=1)=[O:28]
Reactant: CSc1cncc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1cncc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
2-[6-(Methylthio)-2-pyrazinyl]-4H-1,3-benzothiazine-4-one (0.14 g, 0.50 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.11 g, 0.50 mmol) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.12 g, 79%) as pale yellow crystals.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:15]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:14](=[O:15])[N:2]([CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]2)[CH3:1])=[CH:18][CH:19]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CNC[C@H]1CC[C@H](CCO)CC1
Product: CN(C[C@H]1CC[C@H](CCO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.7, 0.325 g (1.90 mmol) of trans-2-(4-methylaminomethyl-cyclohexyl)-ethanol were acylated with 0.54 g (2.84 mmol) of 4-chlorophenyl chloroformate to yield 0.34 g (55%) trans-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 326 (MH+, 1Cl).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:14]4[O:22][CH:21]=[CH:20][C:15]=4[CH:16]=[N:17][C:18]=3[NH2:19])=[N:9][N:10]=2)[N:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:23]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:14]5[O:22][CH:21]=[CH:20][C:15]=5[CH:16]=[N:17][C:18]=4[NH2:19])=[N:9][N:10]=3)[N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ncc2ccoc2c1OCc1nnc2ccc(Cl)nn12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc2ccoc2c1OCc1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 7-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.047 mmol), phenylboronic acid (11.5 mg, 0.095 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (19.6 mg, 0.142 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=5.94 (s, 2H), 6.78 (d, J=2.3 Hz, 1H), 7.52-7.60 (m, 4H), 7.94-8.00 (m, 4H), 8.32 (d, J=9.6 Hz, 1H). MS (ES+): m/z 359.04 (100) [MH+]. HPLC: tR=2.21 min (ZQ3, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[CH:9]N(C)C)=[N:6][CH:7]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C([O-])(O)=O.[Na+]>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][N:8]=2)[CH:7]=1
Reactant: COC(=O)CBr
Reactant: CN(C)C=Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)c1cnc2ccc(Br)cn12
Temperature: 90 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
Reaction mixture containing N′-(5-bromopyridin-2-yl)-N,N-dimethylformimidamide (6.5 g, 28.5 mmol), methyl 2-bromoacetate (5.6 g, 3.5 mL, 37.0 mmol) and NaHCO3 (4.1 g, 48.8 mmol) in i-PrOH (60 mL) was heated at 90° C. under nitrogen. The heating was stopped after 12 h and cooled the dense heterogeneous reaction mixture to room temperature. The reaction mixture was concentrated and diluted with water. The resultant slurry was collected by suction filtration and obtained methyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (6.9 g) as a tan white solid upon drying. 1H NMR (300 MHz, DMSO-d6): δ 9.31 (d, J=1.8 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J=9.5 Hz, 1H), 7.71 (dd, J=9.5, 1.6 Hz, 1H), 3.88 (s, 4H). Ester hydrolysis was done by stirring a solution of methyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (2.5 g), LiOH.H2O (1.2 g) in THF/MeOH/H2O (1/1/1, 75 mL) at room temperature. Reaction mixture was concentrated upon complete hydrolysis of ester to corresponding acid, diluted with water/ice and acidified with 2N. aq HCl until pH 6. The resulting solid was filtered, suction dried followed by drying under P2O5 under vacuum to obtain 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (2.2 g) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 9.36 (s, 1H), 8.24 (s, 1H), 7.77 (d, J=9.5 Hz, 1H), 7.67 (d, J=9.5, 1.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:5][C:4]=2[N:3]=1>Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC(C)(C)O
Agent: Cl
Product: CCOCc1nc2c(N)nc3cc(OC4CCNCC4)ccc3c2n1CC(C)(C)O
Temperature: 65 °C
Yield: 99.9 %

Procedure:
tert-Butyl 4-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate (0.580 g, 1.13 mmol; prepared in Example 563) was taken up in 4.0 M ethanolic hydrogen chloride (5 mL). The reaction was heated at 65° C. for 1 hour, and then cooled to ambient temperature. The ethanol was removed under reduced pressure and the residue was dissolved in water (3 mL) and saturated aqueous sodium chloride (7 mL). The solution was adjusted to pH 13 with 50% aqueous sodium hydroxide and then extracted with chloroform. The combined organic fractions were sequentially washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. Trituration with acetonitrile yielded 0.467 g of 1-[4-amino-2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:24]=[C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:28]=[CH:29][CH:30]=1)([O-:22])=[O:21]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-nitrobenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-nitrophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[CH2:9][C:10]([O:12][CH3:13])=[O:11]>>[CH3:13][O:12][C:10](=[O:11])[CH2:9][P:3]([O:6][CH3:7])([O:4][CH3:5])=[O:2]
Reactant: COC(=O)CCl
Reactant: COP(OC)OC
Product: COC(=O)CP(=O)(OC)OC
Yield: 75.4 %

Procedure:
682 g (5.5 M) of trimethylphosphite have been slowly added (21/2 h) to 272 g (2.5 M) of methyl chloroacetate preliminarly heated to 118°. The temperature of the reaction mixture rose at the end of the addition to 125° and was kept at this value for 2 h, whereupon 962 g of raw material was isolated on distillation. A further distillation allowed the obtainment of 344 g (yield 75%) of methyl-dimethylphosphonoacetate having b.p. 125°/8 Torr.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1Cl.[C:23]([O:27][C:28]([NH:30][C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:29])[NH:30][CH:31]1[CH2:35][CH2:34][N:33]([C:6]2[N:5]([CH2:4][C:3]3[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=3[Br:1])[C:13]3[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=3[N:7]=2)[CH2:32]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2Br)n(C)c1=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: Cn1c(=O)c2c(nc(N3CCC(NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Br)n(C)c1=O

Procedure:
7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (10A) (100 mg, 0.26 mmol) and (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (243 mg, 1.30 mmol) were reacted and purified as described in example 3, step A, to give compound (11A) as brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.Cl.[O:34]1[CH:38]=[C:37]([CH:39]([NH2:41])[CH3:40])[N:36]=[CH:35]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[O:34]1[CH:38]=[C:37]([CH:39]([NH:41][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=2)=[O:22])[CH3:40])[N:36]=[CH:35]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(N)c1cocn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cocn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.7 %

Procedure:
A round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol) and 1-oxazol-2-yl-ethylamine dihydrochloride (crude from Step 3, 90 mg, 0.41 mmol). DMF (1.1 ml) was added followed by N,N-diisopropylethylamine (0.26 ml, 1.49 mmol) and HATU (95 mg, 0.25 mmol). The light yellow solution was stirred at room temperature for 48 h. Water was added and the resulting suspension was filtered. The solid was washed with water and petroleum ether then dried under high vacuum to afford 113 mg (93%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-4-yl-ethyl)-amide as an off-white powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].C(Cl)(=O)C1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](Cl)=O)=[CH:30][CH:29]=1>>[CH2:10]([N:5]1[C:6]2[C:7](=[O:8])[NH:9][C:35]([CH2:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)=[N:1][C:2]=2[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: O=C(Cl)c1ccccc1
Product: COc1ccc(Cc2nc3ncn(Cc4ccccc4)c3c(=O)[nH]2)cc1
Yield: 18 %

Procedure:
An amidation reaction was carried out under the same conditions as in Example 1 using 6.48 g (30 mmol) of 4-amino-1-benzyl-5-imidazole carboxamide obtained in Reference Example 2 and using, instead of benzoyl chloride, 4-methoxyphenylacetyl chloride which was separately prepared according to a conventional method. A crude amide product was obtained after the post-treatment. The crude amide was subjected to a cyclization reaction for 13 hours under the same conditions as in Example 1. 1.92 g of 7-benzyl-2-(4-methoxybenzyl)hypoxanthine was obtained after the post-treatment. Yield 18% (2 steps).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH2:10])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:17]=1.N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>CN(C1C=CN=CC=1)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:24](=[O:26])[CH3:25])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:17]=1
Reactant: Nc1nc2ccc(Br)cc2n1-c1ccccn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Br)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 60 h
Yield: 58.7 %

Procedure:
To a 250 mL round-bottomed flask was added 6-bromo-1-(pyridin-2-yl)-1H-benzo[d]imidazol-2-amine (1.00 g, 3.46 mmol), dichloromethane (35 mL), pyridine (0.419 mL, 5.19 mmol), acetic anhydride (0.343 mL, 3.63 mmol) and DMAP (0.0042 g, 0.035 mmol). The mixture was stirred at 25° C. for 2.5 days. The mixture was concentrated and taken up in MeOH/CH2Cl2 and then concentrated onto silica. Purification by silica gel chromatography (0.5 to 4.0% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a pink solid (0.673 g, 58%). MS (ESI, positive ion) m/z: 331 (M(79Br)+1).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])(=O)[CH2:2][CH3:3].NCCCCCCC#N.C(Cl)(=O)CC.C(C(N)CCCCCCN)CC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH2:2][CH3:3]
Reactant: CCC(=O)NCCCCCCC#N
Agent: CCC(=O)Cl
Agent: CCCC(N)CCCCCCN
Agent: N#CCCCCCCN
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCCNCCCCCCCN

Procedure:
The intermediate N-n-propyl-1,7-heptanediamine was prepared in two steps following the procedure described in Example 119. There was first obtained, as an amber liquid, 14.4 g. of 7-propionamidoheptanonitrile using 10.0 g. of 7-aminoheptanonitrile, 8.1 g. of propionyl chloride, 6.9 g. of pyridine and 100 ml. of benzene. Next was obtained 9.3 g. of n-propyl-1,7-heptanediamine, b.p. 112°-116° C. at 5 mm., using 8.0 g. of lithium aluminum hydride in 900 ml. of tetrahydrofuran and 18.2 g. of 7-propionamidoheptanonitrile in 100 ml. of tetrahydrofuran.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)Cc2cccc(Br)c2)cc1

Procedure:
A DMF (30 mL) solution of (3-bromophenyl)acetic acid (2.5 g, 11.6 mmol), cesium carbonate (3.78 g, 11.6 mmol) and 4-methoxybenzyl chloride (1.82 g, 11.6 mmol) was stirred overnight at room temperature. The solution was then partitioned between ethyl acetate and water. The organic phase was washed with water (3×), brine and dried over magnesium sulfate. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (400 MHz, CDCl3): δ 7.43-7.39 (m, 2H); 7.29-7.24 (m, 2H); 7.20-7.16 (m, 2H); 6.90-6.86 (m, 2H); 5.07 (s, 2H); 3.81 (s, 3H); 3.60 (s, 2H). LC1 3.70 min.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[CH3:5][CH:6]([CH3:15])[CH2:7][C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11]>O.C(O)(=O)C>[CH3:5][CH:6]([CH3:15])[CH2:7][C:8](=[O:14])[CH:9]([N+:1]([O-:3])=[O:2])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(=O)CC(C)C
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(C(=O)CC(C)C)[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of sodium nitrite (232 g, 3.36 mol) in water (560 mL) was added drop-wise over 1.5 hours to a solution of methyl 5-methyl-3-oxohexanoate (400 g, 2.53 mol) in glacial acetic acid (510 mL) at 20 to 25° C. Stirring was continued at room temperature for 2 hours. Water (1.3 L) was added, and the reaction mixture was stirred for an additional 18 hours. The mixture was then extracted with ethyl acetate (3×2.5 L), and the combined organic layers were washed sequentially with water (2.5 L), with aqueous sodium bicarbonate solution (2.5 L), and with saturated aqueous sodium chloride solution (1.0 L). After drying over sodium sulfate, the organic extracts were concentrated in vacuo to afford the product as a yellow liquid, which was used directly in the next step. Yield: 456 g, 2.24 mol, 89%.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27](O)[CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.CN(C)C=O>[N+:31]([C:30]1[CH:25]=[CH:26][C:27]([O:23][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[CH:28][CH:29]=1)([O-:33])=[O:32]
Reactant: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCCCCCCCCCNC(=O)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.7 %

Procedure:
In a solvent mixture (120 ml) of ethyl acetate and N,N-dimethylformamide (5:1) was dissolved N-carbobenzoxy-11-aminoundecanoic acid (10.1 g, 30 m mols) and p-nitrophenol (4.59 g, 33 m mols), followed by addition of N,N'-dicyclohexylcarbodiimide (6.80 g, 33 m mols). The mixture was stirred at room temperature for 15 hours, after which the precipitate was filtered off. The solvent was distilled off and the residue was crystallized in petroleum ether, recovered by filtration and recrystallized from ethyl acetate-petroleum ether. By the above procedure there was obtained 7.65 g of N-carbobenzoxy-11-aminoundecanoic acid p-nitrophenyl ester. m.p. 72°-73° C.; Rf1 =0.94.
Reaction SMILES: Cl.[CH3:2][C@H:3]([CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:4][NH2:5].[C:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[C:17]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])(O)=[O:12].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:36][O:35][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:25]=1[CH2:24][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([C:11](=[O:12])[NH:5][CH2:4][C@H:3]([CH3:2])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH:15]=2)[N:19]([CH3:23])[CH:18]=1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)O)cc23)c(OC)c1
Reactant: C[C@@H](CN)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc23)c(OC)c1
Reaction time: 18 h
Yield: 55.1 %

Procedure:
A mixture of (R)-2-methyl-4,4,4-trifluorobutylamine hydrochloride (9.79 g), methyl 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxybenzoate (20.55 g), 4-dimethylaminopyridine (7.45 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15.07 g) and triethylamine (9.3 mL) was dissolved in dry methylene chloride (240 mL) and the solution was stirred under an inert atmosphere for 18 h. The mixture was diluted with methylene chloride (200 mL) and washed twice with 1N hydrochloric acid. The combined acid washes were back extracted with methylene chloride and the combined organic extracts were washed (water, brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatography, eluting with 97:3 methylene chloride:ethyl acetate to give methyl (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoate (14.48 g, 55%) as a white solid; mp 150°-151° C.; partial NMR (300 MHz, CDCl3): 1.12 (d, 3H, CH3), 1.98-2.08 (m, 1H, CHCH3) 2.12-2.44 (m, 2H, CF3CH2), 3.30-3.58 (m, 2H, CH2N), 3.76 (s, 3H, NCH3), 3.90 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.13 (s, 2H, ARCH2Ar'), 6.23 (br t, 1H, NHCO).