Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)C(=O)[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33].O.[NH2:38][NH2:39].[C:40](=[O:43])([O-])O.[Na+]>CN(C=O)C>[F:21][C:19]([F:22])([F:20])[O:18][C:14]1[CH:13]=[C:12]([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:38][N:39]=[C:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:33])([F:34])[F:35])[C:3]=3[C:40]2=[O:43])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])O
Reactant: O=C(Cc1ccccc1C(F)(F)F)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3C(F)(F)F)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethoxyphenyl)-3-(2-trifluoromethylphenylacetyl)-1,8-naphthyridin-2(1H)-one (763 mg, 1.5 mmol) produced in Synthesis Example 20 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 291 μL), and the mixture was stirred at 100 to 110° C. for 1 hour. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 5-(3-trifluoromethoxyphenyl)-3-(2-trifluoromethylbenzyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (520 mg, yield 69%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([C:28]3[CH:36]=[C:35]4[C:31]([C:32]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])=[N:33][N:34]4OCOCC[Si](C)(C)C)=[CH:30][CH:29]=3)=[CH:27][C:22]=2CO1.[C:52](OCC)(=[O:54])C>O1CCCC1>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([C:28]3[CH:36]=[C:35]4[C:31]([C:32]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])=[N:33][NH:34]4)=[CH:30][CH:29]=3)=[CH:27][C:22]=2[O:54][CH2:52]1
Reactant: CCCC(=O)Nc1nn(OCOCC[Si](C)(C)C)c2cc(-c3ccc4c(c3)COO4)ccc12
Reactant: CCOC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc4c(c3)OCO4)ccc12
Temperature: 67 °C

Procedure:
2 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 600 mg of N-[6-(benzodioxol-5-yl)-1-[[2-(trimethylsilyl)ethoxy]methoxy]-1H-indazol-3-yl]butanamide, described previously, in 12 cm3 of tetrahydrofuran. The medium is then maintained at 67° C. for 16 hours. The mixture is then allowed to return to 19° C. and 60 μm3 of ethyl acetate are added, after which it is washed with 30 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 2×30 cm3 of distilled water and finally with 30 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 45° C.). The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 15-40 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 50° C.), 260 mg of N-[6-(1,3-benzodioxol-5-yl)-1H-indazol-3-yl]butanamide are obtained in the form of a white solid melting at 240° C.
Reaction SMILES: CN(C(ON1N=N[C:11]2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)=[CH:34][C:33]2=[O:47])=[CH:28][C:27]=1[NH:48][CH3:49].[CH:50](N(CC)C(C)C)(C)C.C(O)(=O)CC>CN(C=O)C>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][O:38][C:35]2[CH:36]=[CH:37][N:32]([C:29]3[CH:30]=[CH:31][C:26]4[N:25]=[C:49]([CH2:10][CH3:11])[N:48]([CH3:50])[C:27]=4[CH:28]=3)[C:33](=[O:47])[CH:34]=2)=[CH:41][CH:42]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCC(=O)O
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HATU (321 mg) was added to a solution of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (250 mg), N,N-diisopropylethylamine (0.367 ml) and propionic acid (57.3 mg) in DMF (3 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue in AcOH (1 ml) was stirred at 80° C. for 1 h. After evaporation of the solvent, the residue was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The resulting solid was recrystallized twice from EtOH followed by THF to give the title compound (114 mg) as a white solid.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][C:21](Br)=[O:22]>ClCCl.C(OCC)(=O)C>[CH2:7]([C:6]1[CH:5]=[CH:4][C:2]([O:3][C:21](=[O:22])[CH2:20][Br:19])=[C:1]([O:11][CH3:12])[CH:10]=1)[CH:8]=[CH2:9]
Reactant: O=C(Br)CBr
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCc1ccc(OC(=O)CBr)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solution of eugenol (500 mg, 3.03 mmol) in dichloromethane (5 mL) were added K2CO3 (1.0 g, 7.57 mmol) followed by bromo acetyl bromide (931 mg, 4.54 mmol) at 0° C. The mixture was allowed to stir at room temperature (25° C.) over a period of 1 hr. The resulting mixture was diluted with ethyl acetate (200 mL), washed with water (2×200 mL) and dried over sodium sulphate. The crude product obtained up on evaporation of the solvent was further purified by silica gel column chromatography to obtain bromo-acetic acid 4-allyl-2-methoxy-phenylester as viscous oil (550 mg, 63%).
Reaction SMILES: S1C=CC=C1.C(O)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]3[C:35]([CH3:36])=[CH:34][C:33]([N+:37]([O-])=O)=[CH:32][C:31]=3[CH3:40])=[O:28])[CH:22]([CH2:41][OH:42])[CH2:21]2)=[CH:12][CH:11]=1.[H][H]>[Pt].CO>[NH2:37][C:33]1[CH:32]=[C:31]([CH3:40])[C:30]([NH:29][C:27](=[O:28])[CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][CH:16]([C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=3)[C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[CH2:21][CH:22]2[CH2:41][OH:42])=[C:35]([CH3:36])[CH:34]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1CO
Agent: [Pt]
Solvent: CCO
Solvent: CO
Solvent: c1ccsc1
Product: Cc1cc(N)cc(C)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1CO
Yield: 54 %

Procedure:
To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol were added 3.4 parts of 4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethyl-4-nitrophenyl)-2-(hydroxymethyl)-1-piperazineacetamide and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue solidified on cooling in a 2-propanone/CO2 -bath. The product was dried, yielding 1.73 parts (54%) of N-(4-amino-2,6-dimethylphenyl)-4-[4,4-bis(4-fluorophenyl)butyl]-2-(hydroxymethyl)-1-piperazineacetamide; mp. 85.2° C. (compound 156).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:22])=[C:12]3[S:18][C:17]([CH2:19][OH:20])=[C:16]([CH3:21])[C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:18][C:17]([CH2:19][OH:20])=[C:16]([CH3:21])[C:13]=3[N:14]([CH3:25])[CH:15]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(CO)sc2c(O)c(C(=O)NCc3ccc(F)cc3)cnc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95 %

Procedure:
To a slurry of 3.34 g (9.64 mmol) N-(4-fluorobenzyl)-7-hydroxy-2-(hydroxymethyl)-3-methylthieno[3,2-b]pyridine-6-carboxamide and 1.99 g (14.4 mmol) potassium carbonate in 50 mL anhydrous DMF, was added 0.89 mL (14.3 mmol) iodomethane. The mixture was stirred at room temperature. After 40 minutes the slurry became homogeneous and then cloudy. After another 15 minutes the mixture became a thick slurry that stopped stirring. An additional 30 mL of anhydrous DMF was added and the thick slurry was stirred at room temperature over night. Then, 150 mL of water was added to the slurry and the solids were collected by vacuum filtration and dried in a vacuum oven at 60° C. to provide 3.30 g of title compound as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(N5CCCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 150 °C
Yield: 5.9 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene, from the procedure for 249, (470 mg, 1.0 mmol), Pyrrolidine (85 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 294 (31.3 mg, yield: 5.9%). 1HNMR (DMSO-d6, 400 MHz): δ8.81 (s, 1H), 8.38 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.98-7.97 (m, 1H), 7.78-7.77 (m, 1H), 7.76-7.78 (m, 2H), 7.46-7.40 (m, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.51 (t, J=8.8 Hz, 1H), 7.48 (t, J=4.4 Hz, 1H), 7.26 (s, 1H), 6.60 (d, J=8.8 Hz, 1H), 4.38 (s, 2H), 3.54 (s, 3H), 3.22 (s, 2H), 2.07 (s, 4H). ESI-MS: m/z=529 [M+H+]
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]=[N+]=[N-])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+]>CO>[CH2:23]([NH:1][CH2:2][CH2:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(Oc2ccc(CCN)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
Take up the mixture of 4-[4-(2-aminoethyl)phenoxy] benzenesulfonyl azide (0.210 g, 0.661 mmol) in methanol (9.9 mL). Add benzaldehyde (0.20 mL, 1.98 mmol) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (0.075 g, 1.98 mmol) and stir for 1.5 hours. Filter the reaction mixture and purify by flash 40 chromatography, eluting with 3% (2.0 M NH3 in methanol), 30% hexanes and 67% ethyl acetate to give the title compound (0.0696 g, 25.8%): TOF MS ES+ 383.1 (M+H)+, HRMS calcd for C21H23N2O3S 383.1429 (M+H)+, found 383.1436, time 0.33 min; TLC [silica gel 60 F254, 10% (2.0 M NH3 in methanol) in dichloromethane] Rf=0.31.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[S:21][CH:22]=[C:23]([CH2:25][OH:26])[N:24]=1)=[CH:16][CH:15]=3.I[CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[S:21][CH:22]=[C:23]([CH2:25][O:26][CH2:33][CH3:34])[N:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4nc(CO)cs4)ccc3n(C)c21
Reactant: CCI
Product: CCOCc1csc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 101 above, with the compound from Example 95 above, 3-(2,4-dichlorophenyl)-6-(4-hydroxymethylthiazol-2-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodoethane
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1.[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:7]1[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:6]=1[Cl:5]
Reactant: BrBr
Reactant: COC(=O)c1ccc(Cl)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(Cl)s1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a 1 L round bottom flask was added aluminum chloride (11.32 g, 85 mmol) and methyl 5-chloro-2-thiophenecarboxylate (10 g, 56.6 mmol) dissolved in CHCl3 (250 mL). Br2 (4.08 ml, 79 mmol) was added dropwise over 10 minutes. After stirring for 6 h at 25° C., the light orange reaction solution was washed with sat NaHCO3. The organic layer was dried Na2SO4, filtered and concentrated. The residue was purified on silica gel [hexanes/EtOAc, 9:1] to give the product [12 g, 80%] as a white solid. LCMS (ES) m/z 256 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[CH:11]([C:12]([O:14]CC)=[O:13])[S:10][CH2:9][C:8](=[O:17])[C:7]=2[CH:18]=1.[OH-].[K+].O>CO>[CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[S:10][CH2:9][C:8](=[O:17])[C:7]=2[CH:18]=1
Reactant: CCOC(=O)C1SCC(=O)c2cc(OC)c(OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1OC)C(C(=O)O)SCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
In methanol (20 ml) was suspended ethyl 6,7-di-methoxy-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (6 g) followed by addition of 2N-KOH (15 ml) and the mixture was stirred at room temperature for one hour. The reaction mixture was then poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 6,7-dimethoxy-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (4.4 g, yield 82%). Recrystallization from methanol gave colorless prisms. m.p. 212°-213° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[O:5][C:6]=1[CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:7]([C:6]1[O:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][C:2]=1[C:24]1[N:20]([CH3:19])[N:21]=[CH:22][CH:23]=1)[CH3:8]
Reactant: CCc1oc(C(=O)OC)cc1Br
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1oc(C(=O)OC)cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A solution of methyl 4-bromo-5-ethyl-2-furancarboxylate (1.1 g, 4.72 mmol), potassium carbonate (3.26 g, 23.60 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.178 g, 5.66 mmol) [prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.121 g, 0.24 mmol) were combined in a sealed tube and stirred at 80° C. for 1 h. LCMS showed 4:1 pdt/sm. Additional 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.178 g, 5.66 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.121 g, 0.24 mmol) were added and the solution stirred an additional 2 h where crude LCMS showed nearly complete conversion to product. The reaction contents were then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (950 mg, 3.37 mmol, 71.3% yield) as a yellow oil: LCMS (ES) m/e 235 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:18]([N+:19]([O-])=O)=[C:17]([N+:22]([O-])=O)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[ClH:25].[H][H]>CO.[Pd]>[ClH:25].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:15]3[CH:16]=[C:17]([NH2:22])[C:18]([NH2:19])=[CH:12][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: [H][H]
Reactant: O=C(O)c1ccc(-c2nc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3[nH]2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cc2nc(-c3ccc(C(=O)O)cc3)[nH]c2cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of 5 g (16.7 mmole) of 2-[p-carboxyphenyl]-5,6-dinitrobenzimidazole (as prepared in Example I) in 200 ml of methanol at 0° C was thoroughly purged with nitrogen. To this was added 500 mg of 10% palladium on charcoal, and 30 ml of concentrated HCl. The hydrogenation flask was then pressurized with 55 lbs/in2 of hydrogen, and the flask was shaken at room temperature for 8 hours. After the reaction period had elapsed, the solution was filtered by suction, and the filtrate evaporated to dryness in vacuo. The residual yellow solid was redissolved in a minimum amount of boiling methanol (which contained a trace of HCl), and the filtered solution added to 50 ml of concentrated HCl. Removal of the methanol from the solution in vacuo and subsequent cooling in ice yielded 4.2 g (82%) of 2-[p-carboxyphenyl]-5,6-diaminobenzimidazole hydrochloride as fluffy yellow needles.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]([C:9]2[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:19])[CH:10]=2)[C:5]1=[O:20].[C:21]1(C)[C:22]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1.Cl[CH2:33]Cl>N1C=CC=CC=1>[CH3:19][C:11]1[CH:10]=[C:9]([N:6]2[CH2:7][CH2:8][N:4]([CH2:3][CH2:2][O:1][S:27]([C:22]3[CH:21]=[CH:26][C:25]([CH3:33])=[CH:24][CH:23]=3)(=[O:28])=[O:29])[C:5]2=[O:20])[S:13][C:12]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: ClCCl
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1sc(N2CCN(CCO)C2=O)cc1C
Solvent: c1ccncc1
Product: CCOC(=O)c1sc(N2CCN(CCOS(=O)(=O)c3ccc(C)cc3)C2=O)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
To a stirred solution of ethyl 5-(3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylate (0.61 g, 2.04 mmol) in dichloromethane (6 mL) and pyridine (0.25 mL) at 0° C. was added toluenesulfonyl chloride in dichloromethane (1 mL). The resulting mixture was allowed to warm to ambient temperature, stirred for 18 h and diluted with dichloromethane (100 mL). The organic layer was washed sequentially with 10% aqueous hydrochloric acid (2×50 mL) and saturated aqueous sodium bicarbonate solution (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-10% ethyl acetate in dichloromethane to afford the title compound as a colorless solid in 56% yield (0.52 g): 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 6.11 (s, 1H), 4.31-4.20 (m, 4H), 3.77-3.61 (m, 4H), 3.54 (t, J=4.8 Hz, 2H), 2.49 (s, 3H), 2.36 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); MS (ES+) m/z 453.3 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[C:16]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([CH3:27])[C:24]([CH3:26])=[CH:25][C:19]=4[N:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[CH3:26][C:24]1[C:23]([CH3:27])=[CH:22][C:20]2[NH:21][C:17]([C:16]3[C:10]4[CH2:9][NH:8][CH2:13][CH2:12][C:11]=4[NH:14][N:15]=3)=[N:18][C:19]=2[CH:25]=1
Reactant: Cc1cc2nc(-c3n[nH]c4c3CN(C(=O)OC(C)(C)C)CC4)[nH]c2cc1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(-c3n[nH]c4c3CNCC4)[nH]c2cc1C
Reaction time: 16 h
Yield: 70.9 %

Procedure:
A solution of 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester [1.014 g, Example 252(a)] in methanol (20 ml) was treated with a solution of hydrogen chloride in dioxane (5 ml, 4M). After stirring for 16 hours the reaction mixture was evaporated. The resulting beige solid was triturated with methanol to yield 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (0.523 g) as a pale yellow solid. LC-MS (METHOD B): RT=0.63 minutes; 268 (M+H)+. (b) 3-(5-Chloro-6-methyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[CH2:25][S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:5]=[CH:6][CH:7]=1.B1([O-])OO1.[OH2:38].[OH2:39].O.O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[CH2:25][S:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:39])=[O:38])[CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: Cc1c(Cl)cccc1Cn1c(CSc2ccccc2)nc(=O)c2sc(N3CCOCC3)nc21
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: Cc1c(Cl)cccc1Cn1c(CS(=O)(=O)c2ccccc2)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-[(phenylthio)methyl][1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (37 mg, 0.074 mmol) in Acetic Acid (371 Ml) was added to a stirred suspension of sodiumperborate tetrahydrate (45.6 mg, 0.297 mmol) and Acetic Acid (371 μl). The mixture was stirred at room temperature overnight, and then concentrated. The residue was taken up in dichloromethane/water and eluted through a hydromatrix cartridge. The eluate was concentrated and purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-[(phenylsulfonyl)methyl][1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (8 mg, 20%); LC/MS: MS (ES+) m/e 531 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H), 3.49-3.55 (m, 4H), 3.64-3.71 (m, 4H), 4.82 (s, 2H), 5.64 (s, 2H), 6.43 (d, J=7.6 Hz, 1H), 7.13 (m, 1H), 7.39 (d, J=7.83 Hz, 1H), 7.65 (t, J=7.8 Hz, 2H), 7.75-7.83 (m, 1H), 7.84-7.90 (m, 2H).