Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=2[CH3:22])=[CH:11][C:10]=1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][C:36]([CH3:43])(Br)[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([O:21][C:36]([CH3:43])([CH3:35])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:16][C:15]=2[CH3:22])=[CH:11][C:10]=1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)(=[O:26])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cc(O)cc(C)c1Cc1ccc(OCc2ccccc2)c(S(=O)(=O)c2ccc(F)cc2)c1
Product: CCOC(=O)C(C)(C)Oc1cc(C)c(Cc2ccc(OCc3ccccc3)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1

Procedure:
This compound was obtained analogously to Example XI starting from 4-{4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]benzyl}-3,5-dimethylphenol (Example X) and ethyl dimethylbromoacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1Br.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: Cc1cc(Br)c(Br)cc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
A mixture of 1,2-dibromo-4-methyl-5-nitrobenzene (84.3 g, 286 mmol), 2,4-difluorophenol (37.2 g, 286 mmol), and K2CO3 (43.5 g, 315 mmol) were heated to 100° C. for 45 hours. The reaction mixture was cooled to room temperature and then stored in a 5° C. refrigerator overnight. The reaction mixture was poured into 1200 mL of ice water all at once. The resulting damp solid was collected, partially ground up, and stirred in 900 mL H2O for 45 minutes. The solid was collected by filtration and rinsed with 700 mL of water portion-wise. The resulting solid was dried under high vacuum overnight to yield 93.5 g of a brown solid (95%yield). 1H NMR (400 mHz, CDCl3) δ 8.38 (s, 1H), 7.18 (m, 1H), 7.03 (m, 1H), 6.97 (m, 1H), 6.52 (s, 1H), 2.50 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1.N1C2C(=CC=CC=2)C(C(Cl)=O)=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]4[C:29]5[C:34]([CH:35]=[CH:36][C:21]3=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:16][CH:15]=2)=[O:12])=[CH:2]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C(Cl)c1c[nH]c2ccccc12
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3c[nH]c4ccccc34)cc2)c2ccc3ccccc3c2N1
Yield: 55 %

Procedure:
Indole-3-carboxylic acid (51 mg, 0.316 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.158 mmol) obtained in Example 1, (3), and indole-3-carboxylic acid chloride mentioned above, the title compound (40 mg, yield 55%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:37])[N:25]([CH2:29][CH2:30][C:31]2[O:35][N:34]=[C:33]([NH2:36])[N:32]=2)[CH:26]([CH3:28])[CH3:27])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[NH2:36][C:33]1[N:32]=[C:31]([CH2:30][CH2:29][N:25]([CH:26]([CH3:28])[CH3:27])[C:24](=[O:37])[C:19]2[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[CH:22]=[C:21]([Cl:23])[CH:20]=2)[O:35][N:34]=1
Reactant: CC(C)N(CCc1nc(N)no1)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CCc1nc(N)no1)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1

Procedure:
A solution of [2-(3-{[2-(3-amino[1,2,4]oxadiazol-5-yl)-ethyl]-isopropyl-carbamoyl}-5-chloro-phenoxy)-ethyl]-pyridin-4-yl-carbamic acid tert-butyl ester (0.064 g) in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 5 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc to give the title compound as a pale yellow foam (0.043 g).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:39]3[CH:38]=[CH:37][N:36]=[C:35]([Cl:34])[CH:40]=3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccnc(Cl)c1)N1CCC(N2CCCCC2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a yellow solid (35%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>CN(C)C1C=CN=CC=1.C(#N)C>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([NH:1][C:17](=[O:19])[CH3:18])=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(=O)Cl
Reactant: Nc1ncc([N+](=O)[O-])cn1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc([N+](=O)[O-])cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a solution of 2-amino-5-nitropyrimidine (3.00 g, 21.4 mmol), 4-dimethylaminopyridine (2.61 g, 21.4 mmol) and pyridine (10.4 ml, 128 mmol) in acetonitrile (100 ml) was added acetyl chloride (3.04 ml, 42.8 mmol), the mixture was stirred at 100° C. for 1 hour. To the mixture was added acetyl chloride (2.00 ml, 28.1 mmol) and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (1.22 g, 31.3%) as a solid.
Reaction SMILES: [C:1]([O:8]C)(=O)[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][C:1](=[O:8])[CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCN
Reactant: COC(=O)CC(=O)OC
Product: CCCCCNC(=O)CC(=O)OC
Reaction time: 1 h
Yield: 43.8 %

Procedure:
Dimethyl malonate (3.2 g, 24 mmol) and n-amylamine (2.1 g, 24 mmol) were mixed at room temperature. After stirring one hour solid began to precipitate. Diisopropyl ether (10 ml) was added and the mixture was left overnight at room temperature. The reaction mixture was concentrated in vacuo. The residue was chromatographed on silica gel (100 g, Baker for flash chromatography), eluting with CH2Cl2 and 2% MeOH in CH2Cl2 to give the title compound as an oil (1.97 g, 44%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[C:30]([NH:32][CH3:33])[C:29]([NH2:34])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.[CH3:44][O:45][C:46]([CH:48]1[CH2:50][CH:49]1[C:51](O)=O)=[O:47]>CN(C=O)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]2[N:34]=[C:51]([CH:49]3[CH2:50][CH:48]3[C:46]([O:45][CH3:44])=[O:47])[N:32]([CH3:33])[C:30]=2[CH:31]=1
Reactant: CNc1cc(Br)ccc1N
Reactant: COC(=O)C1CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CC1c1nc2ccc(Br)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
HATU (554 mg) was added to a solution of 5-bromo-N1-methylbenzene-1,2-diamine (279 mg), N,N-diisopropylethylamine (0.727 ml) and (1RS,2SR)-2-(methoxycarbonyl)cyclopropanecarboxylic acid (200 mg) in DMF (5 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (5 ml), and the mixture was stirred at 80° C. for 1 h. After concentration of the mixture, the residue was neutralized with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/EtOAc) to give the title compound (80 mg) as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:2].[NH2:20][OH:21].Cl.C([O-])(O)=O.[Na+]>CCO>[OH:21][NH:20][C:1](=[NH:2])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCCn1ccc2c(C#N)cccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCn1ccc2c(C(=N)NO)cccc21
Temperature: 55 °C

Procedure:
Ethyl 4-(4-cyano-1H-indol-1-yl)butanoate (D56) (8.25 g, 32.2 mmol) was dissolved in EtOH and treated with NH2OH.HCl (4.47 g, 64.4 mmol) and NaHCO3 (8.11 g, 97 mmol) and heated to 55° C. for 1 day and two nights. Further NH2OH.HCl (500 mg) and NaHCO3 (500 mg) were added and the reaction was heated for another 3 hours and then separated the inorganics by filtration, washing well with EtOH. The solvent was evaporated and the residue dried under high vacuum. Trituration with ether and dcm afforded two batches of the title compound N2668-20-A8 (5.14 g) and N2668-20-A9 (976 mg). δH (400 MHz, d6-DMSO) 1.15 (3H, t), 1.98 (2H, apparent quin), 2.25 (2H, t), 4.03 (2H, q), 4.21 (2H, t), 5.73 (2H, br s), 6.82 (1H, dd), 7.15 (1H, apparent t), 7.27 (1H, dd), 7.35 (1H, d), 7.51 (1H, d), 9.58 (1H, br s). MS (ES): C15H19N3O3 requires 289; found 290 (MH+).
Reaction SMILES: [CH2:1]1[CH:8]2[NH:9][CH:3]([CH2:4][C:5]([CH2:7]2)=[O:6])[CH2:2]1.Cl.O.C(Cl)Cl.[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([N:9]1[CH:8]2[CH2:1][CH2:2][CH:3]1[CH2:4][C:5](=[O:6])[CH2:7]2)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC2CCC(C1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1C2CCC1CC(=O)C2
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A suspension of nortropinone hydrochloride (1 g, 6.187 mmol) in acetic anhydride was stirred at 70° C. for 3 h. Water was added, the mixture was boiled for 30 min and cooled down to room temperature. CH2Cl2 and 1N aqueous NaOH was added until pH 9 was reached. The mixture was extracted 2 times with CH2Cl2, the combined organic layers were dried over Na2SO4, filtrated and the solution was evaporated to dryness to give 0.7 g of 8-Acetyl-8-aza-bicyclo[3.2.1]octan-3-one (4a).
Reaction SMILES: C(ON=O)(C)(C)C.[C:8]1([C:14]([CH2:16]Br)=[CH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)N)([O-:20])=[O:19].NC1C=CC=CC=1>CC#N>[N+:18]([C:21]1[CH:22]=[C:23]([CH2:16][C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH2:15])[CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)([O-:20])=[O:19]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C=C(CBr)c1ccccc1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: Nc1ccccc1
Product: C=C(Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Temperature: 25.5 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of t-butylnitrite (119 μl, 1.0 mmol) and 2-phenyl-3-brompropene (0.99 g, 5.0 mmol) in CH3CN (0.5 ml) was 3,5-dinitroaniline (92 mg, 0.5 mmol) added during 10 minutes, while maintaining the temperature of the reaction mixture at 23-28° C. At the end of the addition of the aniline extra t-butylnitrite (119 μl, 1.0 mmol) was added to the reaction mixture which then was heated to 35° C. for 5 minutes. The reaction mixture was stirred at 22° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 23:2) succeeded by crystallization from heptane gave 50 mg (35%) of 3,5-dinitro-1-(2-phenyl-2-propenyl)benzene as bright yellow needles. 1H NMR (CDCl3, 400 MHz) δ 8.88, (t, 1H, J=2.1 Hz), 8.42, (d, 2H, J=2.1 Hz), 7.42-7.37, (m, 2H), 7.36-7.24, (m, 3H), 5.65, (s, 1H), 5.22, (d, 1H, J=0.8 Hz), 4.08, (s, 2H).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:17][CH3:18])=[C:6]([O:15][CH3:16])[CH:7]=[C:8](C(=O)C)[C:9]=1[O:10][CH3:11])(=[O:3])[CH3:2].[C:19]([O:22]O)(=[O:21])[CH3:20]>>[C:19]([O:22][C:8]1[C:9]([O:10][CH3:11])=[C:4]([C:1](=[O:3])[CH3:2])[C:5]([O:17][CH3:18])=[C:6]([O:15][CH3:16])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: COc1cc(C(C)=O)c(OC)c(C(C)=O)c1OC
Reactant: CC(=O)OO
Product: COc1cc(OC(C)=O)c(OC)c(C(C)=O)c1OC
Yield: 30 %

Procedure:
It is moreover known from another class of substances that re action of 3, 5-diacetyl-1,2,4-trimethoxybenzene with peracetic acid provides 5-acetoxy-3acetyl-1,2,4-trimethoxybenzene as byproduct in 30% yield (H.H. Lee et al., J. Chem. Soc. 1965, 2743-2749).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][CH2:21][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23].C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:20][CH2:21][C:22](=[O:23])[NH:24][CH:25]([CH3:27])[CH3:26])=[O:9]
Reactant: CC(C)NC(=O)CN
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 365.4 %

Procedure:
To a solution of 5-fluoro-2-nitrobenzoic acid (2.3 g, 12.4 mmol) in dichloromethane (20 mL) was added oxalyl chloride (3.2 g, 2.2 mL, 24.8 mmol) dropwise. After 1 h the solution was concentrated to dryness. 2-Amino-N-isopropylacetamide (INTERMEDIATE I.1) (0.30 g, 2.6 mmol) was dissolved in dichloromethane (20 mL) and diisopropylethylamine (DIEA) (6.8 mL, 38.9 mmol) added. The acid chloride in dichloromethane (10 mL) was added dropwise and the reaction mixture stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, the residue dissolved in dichloromethane and washed with 1 N NaOH (aq.), 1 N HCl (aq.) and brine. The organic layers were dried (MgSO4) and concentrated in vacuo to yield 5-fluoro-N-(isopropylcarbamoylmethyl)-2-nitrobenzamide (2.7 g, 9.5 mmol, 81%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=O)[C:12]=2[OH:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:26]([C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=1)=[O:29])[NH2:27]>C(O)(C)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:27][NH:26][C:28]([C:30]3[CH:31]=[CH:32][C:33]([S:36]([NH:39][CH3:40])(=[O:37])=[O:38])=[CH:34][CH:35]=3)=[O:29])[C:12]=2[OH:25])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cn1nc(C(=O)c2ccccc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Reactant: CNS(=O)(=O)c1ccc(C(=O)NN)cc1
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccc(C(=O)NN=C(c2ccccc2)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1
Temperature: 100 °C
Reaction time: 19 h
Yield: 21.9 %

Procedure:
[5-(4-t-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl](phenyl)methanone (0.254 mmol, 85 mg), 4-(hydrazinocarbonyl)-N-methylbenzenesulfonamide (0.254 mmol, 58 mg) and p-tosylic acid monohydrate (30 mol %, 13 mg) were dissolved in isopropyl alcohol (8.5 mL) and stirred at 100° C. for 19 hours. Then, the solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform/methanol=10/1) to give the desired product as a yellow solid (30.3 mg, yield 22%).
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([NH2:11])=[S:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]([C:16]1[CH:25]=[CH:24][C:23]2[NH:22][C:21](=[O:26])[C:20]3[NH:27][CH:28]=[CH:29][C:19]=3[C:18]=2[CH:17]=1)=O.[CH2:30]([C:32]([O-:34])=[O:33])[CH3:31]>C(O)C>[O:26]=[C:21]1[C:20]2[NH:27][CH:28]=[CH:29][C:19]=2[C:18]2[CH:17]=[C:16]([C:14]3[N:11]=[C:9]([NH:8][NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:10][CH:13]=3)[CH:25]=[CH:24][C:23]=2[NH:22]1.[CH2:30]([C:32]([O-:34])=[O:33])[CH3:31]
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: NC(=S)NNc1ccccc1
Agent: CCC(=O)[O-]
Solvent: CCO
Product: O=c1[nH]c2ccc(-c3csc(NNc4ccccc4)n3)cc2c2cc[nH]c12
Temperature: 90 °C
Reaction time: 6 h
Yield: 42.1 %

Procedure:
66 mg (1.2 mmol) of 1-phenylthiosemicarbazide is added to a suspension of 124 mg (0.33 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3.5 mL of ethanol. The mixture is stirred at 90° C. for 6 hours then the mixture is cooled to room temperature. The solvent is evaporated, then the product is purified by preparative LCMS. After drying, 62 mg (42%) of 4-oxo-8-[2-(N′-phenyl-hydrazino)-thiazol-4-yl]-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>CCOCC>[CH3:15][O:14][C:12](=[O:13])[CH2:11][NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc(N)cc1C
Reactant: COC(=O)CBr
Solvent: CCOCC
Product: COC(=O)CNc1ccc(C)c(C)c1
Yield: 81.7 %

Procedure:
3,4-Dimethylaniline (70.0 g) and methyl bromoacetate (44.2 g) were stirred at 100° under nitrogen for 2 h. The cooled reaction mixture was poured into ether (700 ml) and filtered. The collected solid was washed with ether (2×100 ml) and the combined filtrates were concentrated to give a solid (45.6 g) which was purified by FCC on triethylamine deactivated silica eluting with dichloromethane: petroleum ether (1:3) to give a solid (21.8 g), a portion of which (2.5 g) was purified further by FCC as above to give the title compound (2.06 g), m.p. 53°-55°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CCN(CC)CC.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(N)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 6-methoxy-pyridin-3-amine (Aldrich, 10.0 g, 77 mmol) in anhydrous CH2Cl2 (100 ml) at 0° C. was added Et3N (13.9 ml, 100.1 mmol) and a solution of pivaloyl chloride (10.5 ml, 84.7 mmol) in CH2Cl2 (20 ml). The mixture was stirred at 0° C. for 10 min and at room temperature for 2 h. After quenched with ice, the reaction was diluted with CH2Cl2, washed with 1M NaOH, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH:14]=[C:15]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])[CH:16]=2)=[O:10])=[CH:4][C:3]=1[N:36]1[C:43]2[N:39]([N:40]=[C:41]([C:44]3[CH:45]=[N:46][NH:47][CH:48]=3)[CH:42]=2)[CH:38]=[CH:37]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[C:13]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:14]=[C:15]([S:17]([F:20])([F:22])([F:21])([F:18])[F:19])[CH:16]=2)=[CH:4][C:3]=1[N:36]1[C:43]2[N:39]([N:40]=[C:41]([C:44]3[CH:45]=[N:46][NH:47][CH:48]=3)[CH:42]=2)[CH:38]=[CH:37]1
Reactant: Cc1ccc(NC(=O)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(N3CCNCC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
210 mg (0.19 mmol, purity 61%) of the compound from Example 47A were stirred in 4.4 ml of a 25% strength solution of trifluoroacetic acid in methylene chloride at RT for 30 min. The mixture was then concentrated under reduced pressure. The residue was dissolved in a little methanol and added to semiconcentrated aqueous sodium bicarbonate solution. After 15 min of stirring at RT, 15 ml of ethyl acetate were added. The precipitate formed was filtered off, and the organic phase of the filtrate was separated off, washed with water, dried over sodium sulphate, filtered and concentrated. Drying of the residue under reduced pressure gave 41 mg (37% of theory) of the title compound.
Reaction SMILES: [H+].[B-](F)(F)(F)[F:3].N[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@@H:17]2[O:37][C@H:36]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:18]2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]([NH2:47])[N:9]=1.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:20]([O:19][C@H:18]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:36]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:37][C@H:17]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:8]([F:3])=[N:9][C:10]=2[NH2:47])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: F[B-](F)(F)F
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Agent: [H+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 8 h

Procedure:
HBF4 (48%) (150 ml) was added to a solution (5°) of 2-amino-9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)adenine (III, 4.6 g, 8.4 mmol) in CHCl3 (60 ml). The resulting mixture was cooled to -10° before a solution of N--NO2 (17 g, 25 mmol) in 4 ml of H2O was added dropwise with stirring. After the addition was complete, the mixture was stirred an additional 40 min. at -10° to -5° before it was diluted with CHCl3 (75 ml), cooled to -20°, and neutralized (pH 5-6) with 50% NaOH. The CHCl3 layer was separated, washed with H2O, dried (MgSO4), and evaporated to dryness in vacuo. The residue, primarily a mixture of II and 9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-2,6-difluoropurine, identified by TLC (1:1 CHCl3 -EtOAc), was dissolved in absolute EtOH, and the solution was saturated at 5° with dry NH3. After refrigeration overnight, the reaction solution was evaporated to dryness in vacuo. The residue was dissolved in CHCl3 (25 ml), and the solution was filtered through dry Celite to remove inorganic salts. The filtrate was adsorbed on a silica gel column (2.6×35 cm, packed and equilibrated with CHCl3). The column was eluted with 1:1 CHCl3 -EtOAc. The fractions containing II were combined and evaporated to dryness in vacuo, and the residue was recrystallized from C6H6 (40 ml); yield 1.7 g (36%); mp 157°-159°; λmax (mμ), pH 1, 7, 13, and EtOH--261, 272 (sh); vmax (cm-1) 3350, 3320, 3150 (NH), 2940, 2920, 2910, 2860 (CH), 1665, 1610, 1575 (NH, C=C, C=N), 1110, 1100, 1085, 1060 (COC), 730 (phenyl).