Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:11]([C:12]([OH:14])=O)=[CH:10][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]2=[N:6][C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:78]([NH2:82])([CH3:81])([CH3:80])[CH3:79]>C(OCC)(=O)C.CN(C)C=O>[C:78]([NH:82][C:12]([C:11]1[C:4]2[C:5](=[N:6][C:7]([CH3:8])=[C:2]([Br:1])[N:3]=2)[N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=1)=[O:14])([CH3:81])([CH3:80])[CH3:79]
Reactant: Cc1nc2c(nc1Br)c(C(=O)O)cn2COCC[Si](C)(C)C
Reactant: CC(C)(C)N
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc2c(nc1Br)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A mixture of 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.16 g, 3 mmol), HBTU [1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide, hexafluorophosphate(1-) (1:1) (1.48 g, 3.9 mmol), N,N-dimethylformamide (12 mL) and triethylamine (0.61 g, 6 mmol) was stirred at room temperature for 1 h, and then tert-butylamine (0.63 mL, 6 mmol) was added. The mixture was stirred an additional hour and then diluted with ethyl acetate, washed once with 0.5 M sodium carbonate, twice with water, once with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica, 20% ethyl acetate in hexanes) gave 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (1.22 g, 92%) as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.09 (s, 9H), 0.83 (t, J=8.2 Hz, 2H), 1.43 (s, 9H), 2.71 (s, 3H), 3.54 (t, J=8.2 Hz, 2H), 5.64 (s, 2H), 7.64 (s, 1H), 8.49 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[I:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C.O>[I:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:14]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[N:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(I)c23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (0.128 mL, 0.938 mmol) was added to tert-butyl 4-(3-iodo-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.395 g, 0.782 mmol) and K2CO3 (0.130 g, 0.938 mmol) in DMF (10 mL). The reaction was stirred at room temperature for 2 hours. Ether (30 mL) and water (10 mL) were then added. The organic layer was separated, washed with brine, and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 3:1) to give tert-butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.33 g, 68%) as a solid. 1H NMR (400 Hz, CD2Cl2) δ 8.23 (s, 1H), 7.44 (m, 3H), 7.33 (d, J=8.8 Hz, 2H), 7.26 (m, 2H), 6.84 (d, J=8.8 Hz, 2H), 5.59 (s, 2H), 3.76 (s, 3H), 3.55 (m, 4H), 2.86 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13]Br>C(O)(=O)C>[NH2:1][C:2]1[C:11]([Br:13])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ccc2c(c1Br)C(=O)CCC2
Reaction time: 0.17 h
Yield: 102.4 %

Procedure:
7-Amino-1-tetralone (457 mg, 2.83 mmol) was dissolved in acetic acid (8 mL) and treated with bromine (150 mL, 2.91 mmol) dropwise. After 10 min., more bromine (17 mL) was added. Then the solvent was evaporated off to give a light brown solid. It was partitioned between Na2CO3 solution and EtOAc. From the organic phase was obtained a semi-solid (696 mg). It was dissolved in CHCl3 and flash chromatographed over silica gel 50 g) eluting with EtOAc/hexane (1:4) to afford a yellow solid (320 mg, 47% yield): mp 93-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:32])[CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.Cl[C:36]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:41]=1>>[CH2:36]([O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:33][CH3:34])(=[O:10])=[O:9])=[CH:15][CH:16]=2)=[O:21])=[CH:24][C:25]=1[F:32])[CH3:41]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1F

Procedure:
4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 505.18 (M+H+.), was prepared in analogy to example 9, steps 1 to 5. Step 4 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[C:5]([N+:20]([O-])=O)[CH:4]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:20][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)c(N)c1
Yield: 75.9 %

Procedure:
To a mixture of 4-methoxy-2-nitro-N-(4-chlorophenyl)benzenesulfonamide (37.2 g) and ammonium chloride (75.4 g) in a mixture of methanol (400 ml) and water (400 ml) was added iron (76.4 g) in small portions over a period of one and half hours at 100° C. The reaction mixture was refluxed for 8 hours and the hot mixture was filtrated. The filtrated cake was washed with hot methanol. The combined filtrates were evaporated under reduced pressure and the residue was extracted three times with ethyl acetate. The extracts were washed with water, dried, and concentrated to give crude product, which was purified by silica gel column-chromatography (elution by methylene chloride) to yield 2-amino-4-methoxy-N-(4-chlorophenyl) benzenesulfonamide (25.77 g).
Reaction SMILES: C(O)=O.[C:4]1([CH:10]2[O:15]C(=O)CC(=O)[O:11]2)C=CC=CC=1.[CH:18](=O)[C:19]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:21]([O:22][CH3:23])[CH:20]=1>C(N(CC)CC)C>[CH3:23][O:22][C:21]1[CH:20]=[C:19]([CH2:18][CH2:4][C:10]([OH:15])=[O:11])[CH:28]=[CH:27][C:24]=1[O:25][CH3:26]
Reactant: O=C1CC(=O)OC(c2ccccc2)O1
Reactant: COc1ccc(C=O)cc1OC
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
25 ml of the mixture of formic acid and triethylamine prepared as described in Example 1 were added to a mixture of 4.8 g (0.025 mol) of 2-phenyl-1,3-dioxane-4,6-dione (m.p.: 148° C.) and 4.15 g (0.025 mol) of veratraldehyde. The reaction was carried out according to Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[C:4]([O:25][CH3:26])[CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][NH:9][C:5]2[CH:6]=[C:7]([C:32]3[CH:33]=[C:28]([Cl:27])[CH:29]=[CH:30][C:31]=3[Cl:34])[C:2]([Cl:1])=[CH:3][C:4]=2[O:25][CH3:26])[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: COc1cc(Cl)c(I)cc1NCCN1CCN(C(=O)OC(C)(C)C)CC1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1NCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
A mixture of tert-butyl 4-(2-((4-chloro-5-iodo-2-methoxyphenyl)amino)ethyl)piperazine-1-carboxylate (180 mg, 0.36 mmol), (2,5-dichlorophenyl)boronic acid (138.9 mg, 0.72 mmol), Na2CO3 (114.5 mg, 1.08 mmol), Pd(PPh3)4 (42 mg, 0.036 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was stirred at 90° C. under argon for 16 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5:1) to afford the desired product (135 mg, 73% yield) as a solid. ESI-MS m/z: 514.3[M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[C:6](O[C:9](=[O:11])[CH:10]=1)=[O:7].NN>C1COCC1>[Br:4][C:5]1[C:6](=[O:7])[NH:2][NH:3][C:9](=[O:11])[CH:10]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(Br)c(=O)[nH][nH]1
Yield: 76.9 %

Procedure:
Hydrazine hydrate (28 ml, 576 mmol) was added dropwise to a stirred solution of bromomaleic anhydride (100 g, 565 mmol) in THF (1 l) cooled in an ice-bath so that the internal temperature did not exceed 10° C. After complete addition of the hydrazine the mixture was refluxed for 18 h. Solvent was removed by evaporation and the residues were dried by azeotroping with toluene. The residue was triturated and washed with diethyl ether to give the title compound as an orange solid (83 g, 77%). 1H NMR (250 MHz, d6-DMSO) δ 7.68 (1H, br s). MS (ES+) m/e 193 [MH]+, 191 [MH]+. This material was used without further purification.
Reaction SMILES: C1([N:7]2[C:23](=[O:24])[C:22]3[C:21]4[C:20]5[C:15](=[CH:16][C:17]([Br:27])=[C:18]([O:25][CH3:26])[CH:19]=5)[N:14]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:13]=4[C:12]([CH2:35]Br)=[CH:11][C:10]=3[C:8]2=[O:9])C=CC=CC=1.[CH3:37][NH:38][CH3:39].[CH:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:40]1([N:7]2[C:23](=[O:24])[C:22]3[C:21]4[C:20]5[C:15](=[CH:16][C:17]([Br:27])=[C:18]([O:25][CH3:26])[CH:19]=5)[N:14]([CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:13]=4[C:12]([CH2:35][N:38]([CH3:39])[CH3:37])=[CH:11][C:10]=3[C:8]2=[O:9])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cc2c3c4c(cc(CBr)c3n(Cc3ccccc3)c2cc1Br)C(=O)N(c1ccccc1)C4=O
Reactant: c1ccccc1
Reactant: CNC
Solvent: ClCCl
Product: COc1cc2c3c4c(cc(CN(C)C)c3n(Cc3ccccc3)c2cc1Br)C(=O)N(c1ccccc1)C4=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
450 mg of N-phenyl-9-benzyl-7-bromo-1-bromomethyl-6-methoxycarbazole-3,4-dicarboximide was dissolved in 5 ml of methylene chloride. Thereto was added 0.5 ml of 20% dimethylamine-benzene solution. The resulting mixture was stirred for 1 hour at room temperature. To the reaction mixture was added 10 ml of methylene chloride. The resulting mixture was washed with an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 370 mg (yield: 87%) of N-phenyl-9-benzyl-7-bromo-1-dimethylaminomethyl-6-methoxycarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.C1C(=O)N([Br:20])C(=O)C1>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][C:7]=1[Br:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cnc(N)cn1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(N)c(Br)n1
Yield: 78 %

Procedure:
To a solution of ethyl 5-aminopyrazine-2-carboxylate (880 mg, 5.26 mmol) in acetonitrile (20 mL) at RT was added NBS (984 mg, 5.53 mmol), the resultant solution was stirred at RT for 1 hour. The reaction mixture was diluted with EtOAc, washed with sat NaHCO3, brine and water, dried, filtered, and concentrated to afford the crude product, which was purified by ISCO 24 g silica gel column, 0 to 50% EtOAc in Heptane, 30 min). 1.01 g, 78% yield. LC-MS (m/z): 247.9 (MH+), 0.51 min.
Reaction SMILES: [CH3:1][C@H:2]1[O:6][CH:5]([CH2:7][OH:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:8][CH2:7][CH:5]2[CH2:4][CH2:3][C@@H:2]([CH3:1])[O:6]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: C[C@@H]1CCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CC[C@@H](C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of Example 64A (4.0 g, 25.8 mmol) in dichloromethane (100 mL) were added triethylamine (10.8 mL, 77.0 mmol) and p-toluenesulfonyl chloride (4.9 g, 25.8 mmol). The reaction mixture was stirred at room temperature overnight and then washed with water (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-25% ethyl acetate in hexanes) to provide 3.5 g (50%) of the title compound. MS (DCI+) m/z 288 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[O:31][C:32]1[CH:44]=[CH:43][C:35]2[N:36]=[C:37]([NH:39][C:40](=[O:42])[CH3:41])[S:38][C:34]=2[C:33]=1[C:45]#[N:46]>O1CCCC1.C(OCC)(=O)C>[C:40]([NH:39][C:37]1[S:38][C:34]2[C:33]([C:45]#[N:46])=[C:32]([O:31][C:30]3[CH:29]=[C:28]([NH:27][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=4[Cl:1])[CH:49]=[CH:48][CH:47]=3)[CH:44]=[CH:43][C:35]=2[N:36]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (165 mg, 0.74 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (79 μL, 0.93 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1.2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (200 mg, 0.62 mmol) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (12 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound (264 mg, 81%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[OH-].[Na+].Cl>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(4-nitrophenoxy)isobutyrate (49) was in methanol (50 mL) and water (50 mL) was added sodium hydroxide (5 g) at room temperature. The solution was stirred at room temperature for 30 min, then acidified with 1N HCl aqueous to pH ˜3. The aqueous solution was extracted with ethyl acetate (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate and solvent was removed under a reduced pressure to give 2-(4-nitrophenoxy)isobutyric acid (50).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[S:15](Cl)(=[O:17])=[O:16]>>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][C:6]=1[S:15]([NH:3][CH2:1][CH3:2])(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Reactant: CCN
Product: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1Br

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate EU using ethylamine and 2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. 1H NMR (500 MHz, CDCl3) δ 8.43-8.38 (m, 1H), 7.93-7.86 (dd, J=8.3, 0.9, 1H), 7.70-7.62 (m, 1H), 5.08 (s, 1H), 3.11-2.96 (m, 2H), 1.19-1.09 (t, J=7.2, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.O.[NH2:19][NH2:20]>O1CCCC1>[NH:19]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[NH2:20]
Reactant: NN
Reactant: COC(=O)c1ccc(-c2cnc(Cl)nn2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cnc(NN)nn2)cc1

Procedure:
To a solution of methyl 4-(3-chloro-1,2,4-triazin-6-yl)benzoate (1.1 g, 0.0044 mol) in tetrahydrofuran (30 mL) was added hydrazine hydrate (1.1 mL, 0.022 mol) at RT with stirring. The mixture was stirred at RT for 1 h, and concentrated under reduced pressure to give the desired product (quantitatively). Analytical LCMS: (M+H)+=245.9.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:23]=[N:22][N:21]([CH:24]4[CH2:28][CH:27]([OH:29])[CH:26]=[CH:25]4)[C:13]=3[N:14]=[C:15]([S:17][CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(Cl)(=[O:38])C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:23]=[N:22][N:21]([CH:24]4[CH2:25][CH2:26][CH:27]([OH:29])[CH:28]4[OH:38])[C:13]=3[N:14]=[C:15]([S:17][CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3C=CC(O)C3)c2n1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CCC(O)C3O)c2n1
Reaction time: 3 h

Procedure:
To a solution of the product of step d) (0.78 g), pyridine (0.43 ml) and 4-dimethylaminopyridine (1 mg) in dichloromethane (15 ml) was added acetyl chloride (0.16 ml). The solution was stirred for 3 hours and then concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate:hexane 1:1 as eluant) to afford the sub-title compound (0.75 g).
Reaction SMILES: [C:1]([O:4][CH:5]1[N:9]([CH3:10])[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[O:13])=[N:7][C:6]1=[O:22])(=O)C.Cl>CCOCC.C1COCC1.O>[Cl:21][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH:11][C:8]2[N:9]([CH3:10])[CH:5]([O:4][CH3:1])[C:6](=[O:22])[N:7]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)OC1C(=O)N=C(NC(=O)Nc2cccc(Cl)c2)N1C
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC1C(=O)N=C(NC(=O)Nc2cccc(Cl)c2)N1C
Temperature: 70 °C
Yield: 35 %

Procedure:
A solution of 10.00 g (0.031 mol) of N-(5-acetyloxy-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl)-N'-(3-chlorophenyl) urea. The compound from Example 1a, in 200 ml of anhydrous ether was treated with anhydrous HCl until no more precipitation occurred. The solid was filtered, with anhydrous ether and dissolved in 200 ml of warm (70° C.) methanol. The reaction mixture was cooled to room temperature and after 1 hr filtered. Concentration of the filtrate gave additional material which was combined with the first crop, dissolved in THF/water and extracted with ether. The combined ether layers were washed with water to pH 5-6, dried (MgSO4) and evaporated in vacuo. Crystallization of the residue from methanol and finally methanol/pentane (5:1) afforded 3.22 g (37%) of the title compound, mp 147°-149° C.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:19](=[O:23])[NH:18][C:17]([NH2:24])=[N:16][C:15]1=2)(=O)C1C=CC=CC=1.N>CO>[OH:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:19](=[O:23])[NH:18][C:17]([NH2:24])=[N:16][C:15]1=2
Reactant: Nc1nc2c(ncn2COCCOC(=O)c2ccccc2)c(=O)[nH]1
Agent: N
Solvent: CO
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Yield: 78.2 %

Procedure:
9-(benzoyloxyethoxymethyl)guanine (0.58g) and methanol (80ml) saturated with ammonia were heated in a bomb at 80° C. for 16 hours. The reaction mixture was removed from the bomb and the solvent evaporated under reduced pressure. The residue was thoroughly washed with ether and then recrystallized from methanol to give 9-(2-hydroxyethoxymethyl)guanine (0.31g., 75% of theoretical), m.p. 256.5°-257° C.
Reaction SMILES: I[CH2:2][C:3]1([CH3:19])[O:14][C:13]2[C:5](=[C:6]3[C:10](=[C:11]([CH3:16])[C:12]=2[CH3:15])[NH:9][C:8]([CH3:18])([CH3:17])[CH2:7]3)[CH2:4]1.[CH2:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][CH2:23][NH:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].[ClH:37].CO>CN(C)C(=O)C.CO.O>[ClH:37].[CH3:19][C:3]1([CH2:2][CH:24]2[CH2:25][CH2:30][C:29]3[CH:28]=[CH:27][CH:26]=[CH:20][C:21]=3[NH:22][CH2:23]2)[O:14][C:13]2[C:5](=[C:6]3[C:10](=[C:11]([CH3:16])[C:12]=2[CH3:15])[NH:9][C:8]([CH3:18])([CH3:17])[CH2:7]3)[CH2:4]1
Reactant: Cc1c(C)c2c(c3c1NC(C)(C)C3)CC(C)(CI)O2
Reactant: c1ccc2c(c1)CCNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(C)c2c(c3c1NC(C)(C)C3)CC(C)(CC1CCc3ccccc3NC1)O2
Temperature: 180 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A suspension of 1,6,7,8-tetrahydro-2-(iodomethyl)-2,4,5,7,7-pentamethyl-2H-furo[3,2-e]indole (520 mg, 1.40 mmol), 2,3,4,5-tetrahydro-1H-3-benzazepine (309 mg, 2.10 mmol) and potassium carbonate (387 mg, 2.80 mmol) in N,N-dimethylacetamide (3 mL) was stirred at 180° C. for 3 hours under the nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate two times, The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane-ethyl acetate 10:1) to obtain an oil. This was dissolved in methanol, a 10% hydrogen chloride-methanol solution was added to obtain 464 mg of the title compound.