Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[C:13]2[N:15](C3CCCCO3)[N:16]=[CH:17][C:12]2=[C:11]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH:27]=[CH:28][CH:29]=2)[N:10]=1>C(Cl)Cl>[Cl:8][C:9]1[N:14]=[C:13]2[NH:15][N:16]=[CH:17][C:12]2=[C:11]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH:27]=[CH:28][CH:29]=2)[N:10]=1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3c2cnn3C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2,2-Trifluoroacetic acid (0.40 mL, 5.218 mmol) was added to a solution of N-(3-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide (20 mg, 0.052 mmol) in CH2Cl2 (4 mL) and the reaction mixture was stirred for 16 h at room temperature. The solvent was then removed in vacuo. The residue was purified by flash chromatography (6% CH3OH/CH2Cl2) to yield the title compound as an off white solid. 1H NMR (400 MHz, CDCl3): δ 8.72 (s, 1H), 8.59 (s, 1H), 8.01 (d, 1H, J=7.2 Hz), 7.82 (m, 1H), 7.57 (t, 1H, J=8.0 Hz), 6.43 (m, 2H), 5.80 (dd, 1H, J=2.8 and 8.8 Hz); ESI-MS: 300.10 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)[CH:3]([OH:6])[CH2:4][OH:5].C(N(CC)CC)C.C1C(=O)N([O:37][C:38]([CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])=O)C(=O)C1>CN(C=O)C>[CH2:45]([O:44][C:42](=[O:43])[NH:41][CH2:40][C:38](=[O:37])[NH:1][CH:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)[CH:3]([OH:6])[CH2:4][OH:5])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: NC(Cc1cc(F)cc(OCc2ccccc2)c1)C(O)CO
Reactant: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)NC(Cc1cc(F)cc(OCc2ccccc2)c1)C(O)CO
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a solution of 3-amino-4-(3-benzyloxy-5-fluoro-phenyl)-butane-1,2-diol (5.60 g, 18.34 mmol, 1.00 eq.), triethylamine (5.11 mL, 36.68 mmol, 2.00 eq.) and anhydrous DMF (100 mL) at 0° C. is added Z-glycine N-succinimidyl ester (6.18 g, 20.17 mmol, 1.10 eq.) with stirring under N2. After 2 hours, the reaction is quenched with 1N HCl, extracted with ethyl acetate, and washed with 10% NaHCO3 and then brine. The organic layer is then dried with MgSO4, filtered through Celite, and concentrated in vacuo, yielding the crude product as a light amber oil. Purification via flash chromatography in 5% MeOH/CHCl3 (rf. 0.33, KMnO4 stain), affords the final product as a white solid (5.40 g., 59% yield overall). Calculate mass for C27H29FN2O6: 496.20. Mass found for C27H29FN2O6: (OAMS) ES+: 497.5 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH3:16])[OH:15])[CH:10]=[C:11]([Br:13])[CH:12]=1.CN(C)[CH:26]=[O:27]>CCCCCC.C(OCC)C>[Br:13][C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([OH:15])[CH3:16])[CH:10]=1)[CH:26]=[O:27]
Reactant: CC(O)(c1ccc(F)cc1)c1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(O)(c1ccc(F)cc1)c1cc(Br)cc(C=O)c1
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (10.7 ml) was added dropwise to a stirred suspension of 3,5-dibromo-α-(4-fluorophenyl)-α-methylbenzenemethanol (5.90 g) in dry diethyl ether (160 ml) at -78° C. under an atmosphere of dry nitrogen. The resulting mixture was stirred at this temperature for 30 minutes and then N,N-dimethylformamide (2.93 g) was added dropwise. Stirring at -78° C. was continued for 1 hour and then the reaction was quenched by the addition of water. The temperature was allowed to reach room temperature and the organic layer was separated, washed with water and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution was commenced with hexane/dichloromethane (1:1), and the ratio was gradually changed to hexane/dichloromethane (1:5). The later product fractions were combined and evaporated to give the title compound as an oil (2.10 g), Rf 0.15 (SS 1). Found: C,55.39; H,3.78. C15H12BrO2F requires C,55.75; H,3.74%.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:38])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH:18]([CH3:22])[NH:19][CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.C(OC(=O)C)(=O)C>C(Cl)Cl>[F:38][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH:18]([CH3:22])[N:19]([C:2](=[O:1])[CH3:4])[CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1NCCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2C1C

Procedure:
A solution of N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.027 mmol), DIPEA (14.20 μL, 0.081 mmol), and acetic anhydride (3.8 μL, 0.041 mmol) in DCM (271 μL) was stirred at room temperature overnight. Purification by HPLC Method A gave the title compound as a TFA salt (8.9 mg) as an off-white film. 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.45 (d, J=6.8 Hz, 1.9H), 1.58 (d, J=6.8 Hz, 1.1H), 1.93-2.02 (m, 2H), 2.14 (dd, J=12.7, 3.4 Hz, 2H), 2.19-2.23 (m, 3H), 2.62-2.83 (m, 1.5H), 2.87-3.08 (m, 3.2H), 3.35-3.43 (m, 2H), 3.48-3.55 (m, 0.7H), 3.78 (sxtd, J=14.4, 4.2 Hz, 2H), 4.06 (dd, J=14.2, 5.4 Hz, 0.6H), 4.46 (dt, J=7.6, 3.5, Hz, 1H), 4.73 (dd, J=13.2, 5.4 Hz, 0.4H), 5.34 (q, J=6.8 Hz, 0.6H), 5.92-5.97 (m, 1H), 6.06 (dt, J=9.0, 4.3, Hz, 1H), 6.15-6.20 (m, 1H), 6.86-6.91 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 482.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14].CCN(CC)CC>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1ccc(Cl)nc1
Yield: 95 %

Procedure:
A solution of 6-chloropyridine-3-sulfonyl chloride (1 mmol), dimethylamine (2 mmol) and Et3N (2 mmol) in THF (2 mL) was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with brine, dried, filtered, and concentrated to give the title compound in 95% yield.
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)=[CH:15][CH:16]=2)[N:11]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:20]=[C:21]([NH:25][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:16]=2)[N:11]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[N:10]=1)=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(Nc3cccc(N)c3)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(Nc3cccc(NC(=O)c4ccccc4)c3)cc21
Yield: 96.3 %

Procedure:
To a solution of N-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine (91 mg, 0.2 mmol) and pyridine (0.081 mL, 1.0 mmol) in CH2Cl2 (0.5 mL) cooled to −5° C. under an atmosphere of argon was added benzoyl chloride (0.028 mL, 0.24 mmol). After 0.5 h the reaction was quenched with saturated NaHCO3(aq) then extracted 2×5 mL CH2Cl2. The pooled organic material was washed with brine (5 mL), dried with Na2SO4, decanted and concentrated under reduced pressure to give an oil. The crude material was purified by silica gel chromatography (eluting with hexane:EtOAc 3:2) to give N-(3-{3-Styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamino}-phenyl)-benzamide (108 mg, 96% yield). Rf sm 0.35, Rf p 0.44 (ethyl acetate hexane 1:1); FTIR (thin film) 3320, 2951, 2893, 1657, 1604, 1537, 1493, 1409, 1303, 1248, 1074 cm−1; LCMS (ESI) [M+H]/z Calc'd 561, Found 561. Anal. Calc'd: C, 72.82; H, 6.47; N, 9.99. Found: C, 72.33; H, 6.39; N, 9.81.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:40]([CH3:42])[CH3:41])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17][CH2:18][C:19](=[O:39])[C:20]1[CH:21]=[CH:22][C:23]2[C:32]3[CH:31]=[C:30]4[CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:29]4=[CH:28][C:27]=3[O:26][CH2:25][C:24]=2[CH:38]=1)=[O:16])=[O:8])=[O:4].[Br-:43].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CO.Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:40]([CH3:42])[CH3:41])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17][CH2:18][C:19]([C:20]1[CH:21]=[CH:22][C:23]2[C:32]3[CH:31]=[C:30]4[CH2:33][CH2:34][CH:35]([Br:43])[C:36](=[O:37])[C:29]4=[CH:28][C:27]=3[O:26][CH2:25][C:24]=2[CH:38]=1)=[O:39])=[O:16])=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O)C(C)C
Reactant: [Br-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,5S)-2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate (400 mg, 0.61 mmol) was dissolved in a solution of DCM (15 mL) and MeOH (6 mL), then treated with pyridinium tribromide (409 mg, 1.28 mmol). At 2 h, an additional portion of pyridinium tribromide (40 mg) was added. After stirring at RT for another 20 min, the reaction mixture was diluted with DCM and 10% HCl, and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude material was carried on without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: CC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Solvent: CCO
Product: CC(=O)N1CCc2ccc(N)cc2CC1
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 1-(7-nitro-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)ethanone (4.0 g) in ethanol (120 ml) 10% Pd/C was added (150 mg) and the mixture hydrogenated for 1 h under a pressure of 30 psi of H2. The mixture was filtered through a celite pad and concentrated to afford a white solid (3.15 g, 90% yield).
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:15])=[N-]>CO.C(OCC)C>[CH3:15][O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:12][CH:11]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C=Cc1ccc(I)cc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C=Cc1ccc(I)cc1
Temperature: 25 °C

Procedure:
A stirred, cooled (ice bath) solution of 4-iodo-cinnamic acid in methanol was treated with a solution of diazomethane in diethyl ether. The reaction mixture was allowed to warm to ambient temperature, the volatiles were evaporated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:20]=[C:19]([CH3:28])[N:18]=1>>[CH2:24]([NH:23][C:21]1[CH:20]=[C:19]([CH3:28])[N:18]=[C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: Cc1cc(NCC(C)C)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(NCC(C)C)n2)ccc1-n1cnc(C)c1
Yield: 89 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.30 mmol) and (2-chloro-6-methyl-pyrimidin-4-yl)-isobutyl-amine (66 mg, 0.33 mmol) in analogous manner as described in example 90. It was obtained in 89% yield as a yellow solid. MS ISP (m/e): 367.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.12 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 7.34 (d, 1H), 7.13 (d, 1H), 7.10 (br s, 1H), 7.01 (s, 1H), 5.87 (s, 1H), 3.78 (s, 3H), 3.16 (br s, 2H), 2.13 (s, 3H), 1.74 (sept, 1H), 0.91 (d, 6H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2I.[C:24]1([S:30]([O-:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+]>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2[S:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:32])=[O:31]
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1nc(S(=O)(=O)c2ccccc2)c2cc(C3OCCO3)ccc21

Procedure:
The title compound was prepared following the procedure described for Example 9A using 150 mg (0.336 mmol) 5-(1,3-dioxolan-2-yl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 6A) and 164 mg (1.01 mmol) sodium benzenesulfinate. After cooling, the reaction mixture was filtered, and the filtrate was purified by preparative RP-HPLC (acetonitrile/water+0.05% TFA gradient) to give 55 mg of a product mixture containing the title compound. This mixture was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>[N+](C1C=CC=CC=1)([O-])=O>[N+:9]([C:5]1[CH:4]=[N:3][C:2]2[NH:1][C:19]([C:18]3[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=3)=[N:8][C:7]=2[CH:6]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1
Temperature: 175 °C
Yield: 80.8 %

Procedure:
To a stirred solution of 2,3-diamino-5-nitropyridine (3) (400 mg, 2.6 mmol) in nitrobenzene (50 mL) was added 4-nitrobenzaldehyde (393 mg, 2.6 mmol) and the mixture heated at 175° C. for 24 h. The solvent was removed by distillation under reduced pressure and the resulting orange solid collected by filtration using CH3CN. The filter cake was washed with ether and air dried to give 4 as an orange solid (0.614 g, 2.1 mmol, 83%) that was used as is without further purification. 1H NMR (500 MHz, DMSO-d6) δ14.58 (br s, 1H), 9.28 (apparent d, 1H), 8.88 (br s, 1H), 8.51 (d, J=8.39 Hz, 2H), 8.45 (d, J=8.28 Hz, 2H). EIMS M−1 284.3. Rf=0.55 (silica, 19:1 DCM/MeOH)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10]3=[CH:13][C:14]([C:16](O)=[O:17])=[N:15][N:9]3[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.COC1C(OC)=CC2C(=O)[N:27]3N=C(C(N)=O)C=C3NC=2C=1>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10]3=[CH:13][C:14]([C:16]([NH2:27])=[O:17])=[N:15][N:9]3[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2[nH]c3cc(C(N)=O)nn3c(=O)c2cc1OC
Reactant: COc1cccc2c(=O)n3nc(C(=O)O)cc3[nH]c12
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c(=O)n3nc(C(N)=O)cc3[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4,9-dihydro-5-methoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (6.6 g; 0.025 mole) and phosphorous oxychloride (100 ml) is stirred at room temperature overnight. The solid is filtered off, washed with ether, dried and treated with cold (0° C.) ammonium hydroxide solution (58%; 50 ml). After standing overnight at room temperature the product is filtered off, dried and used in the next step without further purification. Yield 5.06 g; mp 265°-270° C. By the same procedure, starting with the corresponding 6,7-dimethoxy compound, the product obtained is 4,9-dihydro-6,7-dimethoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide.
Reaction SMILES: C1(N2C3C(=NC(OC)=CC=3)C(NC(=O)C)CC2C)CCCC1.[CH:23]([O:26][C:27]([N:29]1[CH:38]([CH2:39]C)[CH:37]([CH3:41])[CH:36]([NH:42][C:43]2[CH:44]=[N:45][C:46]3[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=3[CH:52]=2)[C:35]2[N:34]=[C:33]3[CH2:53][CH2:54][CH2:55][CH2:56][C:32]3=[CH:31][C:30]1=2)=[O:28])([CH3:25])[CH3:24].[F:57][C:58]([F:72])([F:71])[C:59]1[CH:60]=[C:61]([CH:64]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:66]=1)[CH2:62]Br.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH:23]([O:26][C:27]([N:29]1[CH:38]([CH3:39])[CH:37]([CH3:41])[CH:36]([N:42]([CH2:62][C:61]2[CH:64]=[C:65]([C:67]([F:69])([F:70])[F:68])[CH:66]=[C:59]([C:58]([F:57])([F:71])[F:72])[CH:60]=2)[C:43]2[CH:44]=[N:45][C:46]3[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=3[CH:52]=2)[C:35]2[N:34]=[C:33]3[CH2:53][CH2:54][CH2:55][CH2:56][C:32]3=[CH:31][C:30]1=2)=[O:28])([CH3:24])[CH3:25]
Reactant: CCC1C(C)C(Nc2cnc3c(c2)CCCC3)c2nc3c(cc2N1C(=O)OC(C)C)CCCC3
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: COc1ccc2c(n1)C(NC(C)=O)CC(C)N2C1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)OC(=O)N1c2cc3c(nc2C(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cnc4c(c2)CCCC4)C(C)C1C)CCCC3
Yield: 20 %

Procedure:
Prepare the title compound by essentially following the procedure described in Example 49, Step 2, by replacing (+/−)-N-(1-cyclopentyl-6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]napthyridin-4-yl)-acetamide, with 2-ethyl-3-methyl-4-(5,6,7,8-tetrahydro-quinolin-3-ylamino)-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,5]napthyridine-1-carboxylic acid isopropyl ester (0.175 g, 0.378 mmol), and using 3,5-bis trifluoromethyl benzyl bromide and lithium hexamethyldisilazide. Purify using silica gel column chromatography (gradient eluent, 50:50 ethyl acetate in hexane) to afford the title compound (0.052 g, 20%). MS (ES+): 689 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[C:11](=[N:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[C:12]([O:14]C)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1.Cl>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[N:16][NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24]([OH:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)[C:12](=[O:14])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[N:37]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(=NNc1ccc(S(=O)(=O)O)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: O=C1C(=NNc2ccc(S(=O)(=O)O)cc2)C(c2ccc([N+](=O)[O-])cc2)=NN1c1ccc(F)cc1

Procedure:
The crude product methyl 3-(4-nitrophenyl)-3-oxo-2-(2-(4-sulfophenyl)hydrazono)-propanoate (200 mg, 0.49 mmol) (synthesized as described for 11-1) was dissolved in ethanol (10 ml), and 4-fluorophenylhydrazine (96 mg, 0.59 mmol) and hydrochloric acid (37%, 0.2 ml) were added. The product 4-((1,5-dihydro-3-(4-nitrophenyl)-5-oxo-1-(4-fluorophenyl)-4H-pyrazol-4-ylidene)-hydrazino)-benzenesulfonic acid was isolated by filtration as a brown solid (yield 82%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH3:12])[CH2:4][S:5][C:6]1[S:7][C:8]([CH3:11])=[N:9][N:10]=1.C([O:21][C@@H:22]1[C@H:26]([O:27]C(=O)C2C=CC=CC=2)[C@@H:25]([CH2:36][O:37]C(=O)C2C=CC=CC=2)[O:24][C@H:23]1[N:46]1[CH:54]=[N:53][C:52]2[C:47]1=[N:48][C:49]([Cl:56])=[N:50][C:51]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:56][C:49]1[N:50]=[C:51]([NH:2][C@H:3]([CH3:12])[CH2:4][S:5][C:6]2[S:7][C:8]([CH3:11])=[N:9][N:10]=2)[C:52]2[N:53]=[CH:54][N:46]([C:47]=2[N:48]=1)[C@@H:23]1[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:27])[C@H:22]1[OH:21]
Reactant: Cc1nnc(SC[C@@H](C)N)s1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: N
Product: Cc1nnc(SC[C@@H](C)Nc2nc(Cl)nc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)s1
Yield: 53.2 %

Procedure:
The title compound was prepared according to method A as described above in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]-5-methyl-[ 1,3,4]-thiadiazole hydrochloride [prepared by alkylation of 2-mercapto-5-methyl-(1,3,4)-thiadiazole (1.32 g, 10 mmol) using methanesulphonic acid, 2-[(R)-N-tert-butyloxycarbonylamino]-1-propyl ester (3.04 g, 12 mmol) followed by acidic hydrolysis] (1.01 g, 4.47 mmol) with 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.36 g, 3.73 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N{(R)-1-[5-methyl(1,3,4-thiadiazol-2-yl)]thio-2-propyl}adenosine (0.94 g, 53%) as a foam after column chromatography. 1H NMR (DMSO-d6) δ 1.35 (3H, d, --CHCH3), 2.67 (3H, s, --CH3), 3.53-3.61 (2H, m, H-5'a and H-5'b), 3.96 (1H, q, H-4), 4.14 (1H, q, H-3'), 4.52 (1H, q, H- 2'), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 8.33-8.46 (2H, m, H-8 and --NH). HPLC retention time 9.9 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:25]([CH2:26][CH2:27][CH3:28])[C:24]([CH2:29][CH2:30][O:31][CH3:32])=[N:23][C:17]=3[C:18]([NH2:22])=[N:19][C:20]=2[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:22][C:18]1[C:17]2[N:23]=[C:24]([CH2:29][CH2:30][O:31][CH3:32])[N:25]([CH2:26][CH2:27][CH3:28])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:21][C:20]=2[N:19]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OCCCN)ccc3c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OCCCNC(=O)C(C)C)ccc3c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Isobutyryl chloride (0.375 nL, 3.58 mmol) was added dropwise to a slurry of 7-(3-aminopropoxy)-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 394, 1.28 g, 3.58 mmol) in dichloromethane (22 mL) at 0° C. The reaction mixture was allowed to stir for 30 minutes at 0° C., then the reaction mixture was allowed to stir for 16 hours at ambient temperature. Saturated aqueous sodium carbonate was added and the reaction mixture was stirred for 1 hour, resulting in the formation of a flocculent solid. The solid was isolated by filtration and dissolved in dichloromethane. The dichloromethane was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid was recrystallized from acetonitrile to afford 1.14 g of N-(3-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-methylpropanamide as an off-white solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].Cl[CH2:15][C:16]([O:18][CH3:19])=[O:17]>CCOCC>[CH3:19][O:18][C:16](=[O:17])[CH2:15][NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([Cl:6])[CH:8]=1
Reactant: COC(=O)CCl
Reactant: Nc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)CNc1cccc(Cl)c1
Reaction time: 6 h

Procedure:
A mixture of sodium bicarbonate (66 g), 3-chloroaniline (50 g) and methyl chloroacetate (51.5 ml) were stirred under nitrogen at 80°-100° for 6 h. Heating at 90° was continued overnight, and the mixture was then cooled and poured into ether (400 ml). The resultant suspension was stirred, chilled to 0°, the precipitated solid was filtered off and the filtrate was retained. The solid was dissolved in ethyl acetate (400 ml) and washed with water (2×200 ml), followed by dilute hydrochloric acid (200 ml). The organic phase was dried and concentrated in vacuo to give the title compound (16.4 g) as a solid, m.p. 75°-76°. The previously obtained filtrate was washed with dilute hydrochloric acid (200 ml), and the organic phase was separated, dried and concentrated in vacuo to give an oily solid. This was triturated with ether:hexane (1:1; 300 ml) and filtered off to give a further batch of the title compound (20 g).