Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]1=[O:22])([O-])=O.[OH-].[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CC(C)=O.O>[NH2:1][C:4]1[C:5]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]1=[O:22]
Reactant: COCCOc1cc2c(cc1[N+](=O)[O-])[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COCCOc1cc2c(cc1N)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a refluxing solution of compound 94 (506 mg, 1.35 mmol) in acetone (120 mL), H2O (24 mL) and aqueous 1 M NaOH (24 mL, 24.0 mmol) was portionwise added with care solid Na2S2O4 (3.89 g, 18.97 mmol). The reflux was continued for 2 h then the acetone was removed under vacuum. More H2O (50 mL) was added and the aqueous phase was extracted with CH2Cl2 (4×). The organic phase was dried (MgSO4), filtered then rotary evaporated. The crude solid was purified by flash chromatography (SiO2) using 3:7 to 1:1 EtOAc/Hexanes as eluent to give compound 95 (228 mg, 49%) as a foamy solid. 1H NMR (CDCl3) δ 0.88 (3H, s), 1.37-2.78 (14H, m), 3.41 (3H, s), 3.71 (2H, t, J=5.0 Hz), 4.09 (2H, 2.9 Hz), 6.52 (1H, s), 6.65 (1H, s).
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:12]=[C:11](F)[C:10]([F:14])=[CH:9][C:6]=1[C:7]#[N:8].[CH3:15][OH:16]>>[F:14][C:10]1[C:11]([O:16][CH3:15])=[CH:12][C:5]([O:2][CH3:1])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COc1cc(OC)c(C#N)cc1F
Yield: 95 %

Procedure:
Sodium methoxide (25% wt in MeOH, 32 mL) was added dropwise to a solution of 2,4,5-trifluorobenzonitrile (10 g, 63.7 mmol) in MeOH (160 mL) under nitrogen at 0° C. The resulting reaction mixture was stirred at reflux for 48 h. The reaction was then quenched with 1 M citric acid and the MeOH was removed in vacuo. The residue was taken up in EtOAc, washed with brine, dried over Na2SO4, concentrated in vacuo and recrystallized from EtOAc/hexane to furnish the desired product in 95% yield (11 g). 1H NMR (300 MHz, CDCl3) δ 7.25 (d, 1H, J=10.2 Hz), 6.52 (d, 1H, J=6.8 Hz), 3.97 (s, 3H), 3.93 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.3, 159.2, 152.8, 152.6, 147.6, 144.4, 119.8, 119.5, 115.8, 115.7, 97.4, 97.3, 92.1, 92.0, 56.6, 56.5; 19F NMR (282 MHz, CDCl3) δ −143.4 (dd, 1 F); mass spectrum, calculated for C9H8FNO2 (MH+) 182.1, Found 182.1.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([OH:17])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[H-].[Na+].I[CH3:21].[CH3:22][N:23]([CH:25]=O)[CH3:24]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([O:17][CH3:22])[CH:8]=[C:9]([C:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[CH2:1]([C:3]1[C:11]2[C:25](=[C:7]([O:17][CH3:21])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:23]([CH3:24])[N:4]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CI
Reactant: CCOC(=O)c1cc(O)c2[nH]nc(CC)c2c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC)c2c(c1)c(CC)nn2C
Product: CCc1n[nH]c2c(OC)cc(C(=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %
Yield: 41 %

Procedure:
To a 0° C. solution of ethyl 3-ethyl-7-hydroxy-1H-indazole-5-carboxylate (prepared as described in Acid Preparation 2) (50 mg, 0.21 mmol) in DMF (1 mL) was added 60% NaH oil dispersion (8.5 mg, 0.21 mmol). This mixture was stirred for 30 minutes before addition of iodomethane (0.011 mL, 0.17 mmol). The reaction was kept at 0° C. for 2 hours before allowing to alowly warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and saturated aqueous NaHCO3. The organic phase was isolated and the aqueous phase was back extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The crude product was purified by CombiFlash (12 g column, 0-30% EtOAc/hexanes) to provide 3-ethyl-7-methoxy-1H-indazole-5-carboxylate (22 mg, 41%) and ethyl 3-ethyl-7-methoxy-1-methyl-1H-indazole-5-carboxylate (46 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](OCC)=[C:9]([CH3:16])[C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:20][NH2:21].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:21][N:20]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:9]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: CCOC(=C(C)C(=O)C(F)(F)F)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1c(C(F)(F)F)n[nH]c1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A solution of 5.5 g of 4-(4-chlorophenyl)-4-ethoxy-1,1,1-trifluoro-3-methyl-3-buten-2-one in 20 mL of MeOH was slowly treated with 0.70 mL of NH2NH2 and allowed to stir for two hours. Water was added to the reaction mixture and a precipitate formed. The solid was collected by filtration and washed with hexanes to yield 3.87 g of 5-(4-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazole as a white powdery product: mp 139.0° C.; 1HNMR (CDCl3) δ 2.09 (s, 3H), 7.39 (m, 2H), 7.45 (m, 2H, 8.5 Hz), 11.75 (bs, 1H). 19 FNMR (CDCl3) δ -62.34 (3F). Anal. Calcd for C11H8 N2F3Cl: C, 50.69; H, 3,09; N, 10.57. Found: C, 50.68; H, 3.05; N, 10.81.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:28])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]2[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=2[F:8])=[O:28])=[CH:26][CH:25]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1F
Product: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(4-chlorobenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[N:6]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=[C:7]=[O:8]>C(Cl)Cl>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:7](=[O:8])[NH:6][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Reactant: CNCCO
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N(C)CCO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 112.1 %

Procedure:
To an ice-cooled solution of N-methylethanolamine (0.600 g, 7.99 mmol) in DCM (80 mL) was added methyl 4-isocyanatobenzoate (1.56 g, 8.79 mmol). After 20 minutes the coolant was removed and the reaction mixture was stirred for 2 hours. The solvent was evaporated at reduced pressure and the residue was purified by flash column chromatography eluting with 0 to 100% ethyl acetate/iso-hexane to afford the title compound (2.26 g, 112%).
Reaction SMILES: [OH-].[NH4+:2].[C:3]([P:7](=[O:14])([O:11]CC)[O:8][CH2:9][CH3:10])(OC)=[O:4]>>[C:3]([P:7](=[O:14])([O-:11])[O:8][CH2:9][CH3:10])(=[O:4])[NH2:2].[NH4+:2]
Reactant: CCOP(=O)(OCC)C(=O)OC
Agent: [NH4+]
Agent: [OH-]
Product: CCOP(=O)([O-])C(N)=O
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
A solution of 48.5 parts of 29% aqueous ammonium hydroxide is stirred and cooled with an external ice bath to 15° C. To the cooled solution 20.5 parts of diethyl carbomethoxyphosphonate is slowly added over a 10 minute period. The mixture turns cloudy, but clears up after about 15 minutes. During this time, the mixture is allowed to warm spontaneously to about 30° C. and stirring is continued for 2 hours. The clear solution is stripped under reduced pressure (15 mm of Hg) at a water-bath temperature of 70° C. The residue is a white crystalline solid which is recrystallized from absolute ethyl alcohol, giving 11.7 parts of ammonium ethyl carbamoylphosphonate, m.m. 173°-176° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.[CH:25]1[CH:30]=[C:29]([CH:31]=[O:32])[C:28]([CH:33]=O)=[CH:27][CH:26]=1.C(O)(=O)C>C(#N)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:33][C:28]5[C:29](=[CH:30][CH:25]=[CH:26][CH:27]=5)[C:31]4=[O:32])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Reactant: O=Cc1ccccc1C=O
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C1c2ccccc2CN1c1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1

Procedure:
4-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine (338.4 mg, 1.0 mmol) was reacted at reflux for 30 min with o-phthaldialdehyde (147.5 mg, 1.1 mmol) and a catalytic amount of acetic acid (57 μL, 0.1 mmol) in acetonitrile (100 mL) to give the title compound. The product obtained was purified by elution through a flash column (silica gel 40, 230–400 mesh, 100:8:1, CH2Cl:EtOH:NH4OH) to give a yellow crystalline material, yield=245 mg (53.9%). mp 175.9° C. MS (APCI): 455 [M+H]+. 1H-NMR (dmso-d6, δ): 2.59 (m, 2H) 2.66 (m, 4H) 2.77 (m, 2H) 3.43 (m, 4H) 4.98 (s, 2H) 7.30 (d, J=8.79 Hz, 2H) 7.40 (dd, J=8.67, 7.45 Hz, 1H) 7.52 (m, 2H) 7.64 (m, 2H) 7.77 (m, 3H) 8.03 (d, J=9.28 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[C:7]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[CH:6]=1.[OH-].[K+].[I:27]I>CN(C=O)C>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([I:27])=[N:10][NH:11]2)=[C:7]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[CH:6]=1
Reactant: OCC(O)COc1cc(Oc2ccc(F)cc2F)cc2[nH]ncc12
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OCC(O)COc1cc(Oc2ccc(F)cc2F)cc2[nH]nc(I)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
3-[6-(2,4-Difluoro-phenoxy)-1H-indazol-4-yloxy]-propane-1,2-diol (0.45 g, 1.34 mmol) was dissolved in 5 mL of dry DMF, and powdered KOH (0.288 g, 5.1 mmol) was added. The reaction mixture was stirred under nitrogen for 10 minutes at room temperature, and iodine (0.536 g, 2.11 mmol) was added in two portions. The reaction mixture was stirred for 90 minutes. The reaction mixture was partitioned between EtOAc and 5% aqueous sodium bisulfite solution, and the organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-5% MeOH in dichloromethane) to give 0.408 g of 3-[6-(2,4-difluoro-phenoxy)-3-iodo-1H-indazol-4-yloxy]-propane-1,2-diol, MS(M+H)=436.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].[Cl:5][C:6]1[CH:42]=[CH:41][C:9]2[N:10]([C:22](=[O:40])[C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[CH:25][C:24]=3[CH3:39])[CH2:11][CH2:12][CH2:13][CH:14]([O:15][C:16](=[O:21])[NH:17][CH2:18][CH2:19]Cl)[C:8]=2[CH:7]=1>C(O)C>[Cl-:5].[Cl:5][C:6]1[CH:42]=[CH:41][C:9]2[N:10]([C:22](=[O:40])[C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[CH:25][C:24]=3[CH3:39])[CH2:11][CH2:12][CH2:13][CH:14]([O:15][C:16]([NH:17][CH2:18][CH2:19][N+:2]([CH3:4])([CH3:3])[CH3:1])=[O:21])[C:8]=2[CH:7]=1
Reactant: CN(C)C
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)NCCCl)c3cc(Cl)ccc32)c(C)c1
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)NCC[N+](C)(C)C)c3cc(Cl)ccc32)c(C)c1
Product: [Cl-]
Temperature: 170 °C

Procedure:
Trimethylamine (30% solution, 0.5 ml) was added to an ethanol solution (10 ml) of {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}(2-chloroethy)carbamate (330 mg), and the mixture was heated at 170° C. for 15 minutes (microwave reactor). After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the resulted precipitates were collected by filtration and dried to obtain 120 mg of (2-{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylamino}-ethyl)-trimethyl-ammonium chloride as white powder.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=C)[N:9]1[CH:15]=[CH:16][N:17]=[C:8]1[C:7]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:6]2.C[N+]1([O-])CC[O:29]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][C:7]1[C:8]2[N:9]([CH:15]=[CH:16][N:17]=2)[C:10]2[C:5]([N:6]=1)=[CH:4][C:3]([C:2]([F:1])([F:23])[F:24])=[C:12]([CH:13]=[O:29])[CH:11]=2
Reactant: C=Cc1cc2c(cc1C(F)(F)F)nc(NCCCO)c1nccn12
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1cc2c(cc1C(F)(F)F)nc(NCCCO)c1nccn12
Temperature: 30 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
A solution of 3-{[7-(trifluoromethyl)-8-vinylimidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol (110 mg; 0.32 mmol; 1 eq), osmium tetroxide (2.5% in tert-butanol, 166 mg; 0.016 mmol; 0.05 eq), N-methylmorpholine oxide (76 mg; 0.654 mmol; 2 eq) in acetone (3 ml) and water (0.33 ml) is stirred at 30° C. during 3 days. A suspension of sodium periodate (280 mg; 1.31 mmol; 4 eq) in water (1.6 ml) is then added and the resulting reaction mixture is stirred at 30° C. during 16 h. Partition (aqueous sodium sulfite/ethyl acetate), extraction of the aqueous phase (ethyl acetate), reunion of the organic phases, drying (magnesium sulphate) and purification by prep CCM on silicagel (dichloromethane/methanol 95:5) affords the title product as an off-white powder (64 mg; 0.19 mmol; 59%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]2[N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:17]=[C:18]([CH3:19])[C:3]=12.Cl.C([OH:29])C>>[CH3:19][C:18]1[C:3]2[C:2](=[O:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[NH:5][C:4]=2[N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:17]=1
Reactant: CCO
Reactant: Cc1nn(-c2ccccn2)c2nc3ccc(C(F)(F)F)cc3c(Cl)c12
Agent: Cl
Product: Cc1nn(-c2ccccn2)c2[nH]c3ccc(C(F)(F)F)cc3c(=O)c12
Temperature: 25 °C
Yield: 76 %

Procedure:
To a solution of 4-chloro-3-methyl-1-(2-pyridinyl)-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]quinoline (6.50 g, 17.9 mmol) in ethanol (300 mL), 6N hydrochloric acid (10 mL, 60 mmol) was added and the mixture was heated under reflux for 5 hours. The solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and air dried, and recrystallized from ethanol to give the title compound (4.69 g, 76% yield).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]([O:9][C:10]([C:12]2([C:18]3[CH:30]=[CH:29][C:21]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:20][CH:19]=3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:7][CH:6]=1)=[O:4].ClCCl.FC(F)(F)C(O)=O>C(OCC)(=O)C>[OH:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]([C:12]2([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:29][CH:30]=3)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:11])=[CH:31][CH:32]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)c1ccc(C2(C(=O)Oc3ccc(C(=O)NO)cc3)CCCCC2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C2(C(=O)Oc3ccc(C(=O)NO)cc3)CCCCC2)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of tert-butyl 4-[1-({4-[(hydroxyamino)carbonyl]phenoxy}-carbonyl)cyclohexyl]-benzoate (PX118926) (0.12 g, 0.27 mmol), dichloromethane (4 ml), and trifluoroacetic acid (1 ml) was stirred under argon atmosphere at room temperature until the starting material disappeared (ca. 2 hours). The mixture was supplemented with ethyl acetate (150 ml), the obtained solution was washed successively with water (2×100 ml), brine (50 ml), and dried (Na2SO4). The solvents were evaporated and the residue was chromatographed on silica gel with chloroform-isopropanol (9:1) as eluent to give the title compound in 48% yield as crystals, m.p. 169-170° C. 1H NMR (DMSO-d6, HMDSO) δ: 1.18-2.05 (8H, m); 2.34-2.69 (2H, m, overlapped with a signal of DMSO); 7.05 (2H, d, J=8.5 Hz); 7.62 (2H, d, J=8.4 Hz); 7.78 (2H, d, J=8.5 Hz); 7.99 (2H, d, J=8.4 Hz); 9.09 (1H, br s); 11.26 (1H, br s). HPLC analysis on Chromasil 100 C18 column: impurities 5% (column size 4.6×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 60:40; detector UV 254 nm; sample concentration 1.0 mg/ml; flow rate 1.5 ml/min). Anal. Calcd for C21H21NO6*0.25H2O, %: C, 65.02; H, 5.59; N, 3.61. Found, %: C, 64.88; H, 5.49; N, 3.45.
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][C:7]([C:9](O)=O)=[CH:8][C:4]2=[CH:3][S:2]1.[CH3:12][O:13][C:14]1[C:15]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:16][C:17]2[O:21][CH2:20][CH2:19][C:18]=2[CH:22]=1>>[CH2:1]1[C:5]2=[CH:6][C:7]([CH2:9][N:26]3[CH2:27][CH2:28][N:23]([C:15]4[C:14]([O:13][CH3:12])=[CH:22][C:18]5[CH2:19][CH2:20][O:21][C:17]=5[CH:16]=4)[CH2:24][CH2:25]3)=[CH:8][C:4]2=[CH:3][S:2]1
Reactant: O=C(O)C1=CC2=CSCC2=C1
Reactant: COc1cc2c(cc1N1CCNCC1)OCC2
Product: COc1cc2c(cc1N1CCN(CC3=CC4=CSCC4=C3)CC1)OCC2

Procedure:
Prepared as described in Example 9, starting from (cyclopenta[c]thien-5-yl)carboxylic acid (Preparation 7) and 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The title compound melts at 156°-158° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[N+:7]=1[O-].[ClH:13].[CH2:14](N(CC)CC)C>C(OCC)(=O)C.C(O)C>[Cl:13][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:14])=[O:10])[CH:5]=1
Reactant: Cl
Reactant: COC(=O)c1cccc(C)[n+]1[O-]
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Cl)cc(C)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 6-methylpyridine-2-carboxylate N-oxide (2.29 g), a 4N solution of hydrogen chloride in ethyl acetate (5 ml) and ethyl acetate (15 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the resultant residue was combined with phosphorus oxychloride (17.90 g), and stirred at 90° C. for 2 hours with heating. The reaction mixture was concentrated, and the resultant residue was diluted with ice-water and then combined with an aqueous solution of potassium carbonate to make the solution basic. The mixture was extracted with dichloromethane, and the organic phase was dried and concentrated. A solution of the residue obtained and triethylamine (5 ml) in ethanol (50) was heated under reflux for 10 hours. The reaction mixture was concentrated, and the residue was combined with water and ethyl acetate, and the organic phase was isolated, dried and concentrated to obtain the title compound (1.74 g) as a tan oil.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([N:9]2[C:21]3[C:20]4[CH:19]=[C:18]([C:22]5[CH:33]=[N:32][C:25]6[N:26](C)[C:27](=O)[O:28][CH2:29][C:24]=6[CH:23]=5)[CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:11]([CH3:34])[C:10]2=[O:35])[C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2]>O1CCOCC1.[Li+].[OH-].CCOC(C)=O>[OH:28][CH2:29][C:24]1[CH:23]=[C:22]([C:18]2[CH:17]=[CH:16][C:15]3[N:14]=[CH:13][C:12]4[N:11]([CH3:34])[C:10](=[O:35])[N:9]([C:7]5[C:6]([CH3:36])=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=5)[C:21]=4[C:20]=3[CH:19]=2)[CH:33]=[N:32][C:25]=1[NH:26][CH3:27]
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(c4)COC(=O)N5C)cc3c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C(C)C)nc2C)c(=O)n4C)cc1CO

Procedure:
A solution of 1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 170, 0.04 mmol) in dioxane (0.32 ml) and 1 M aqueous LiOH (0.08 ml) was stirred for 1.5 h at rt. The reaction mixture was diluted with EtOAc and quenched with 2 M aqueous HCl (0.12 ml) and water. Then was added saturated aqueous NaHCO3 and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as an off-white solid. (HPLC: tR 2.09 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.20 (s, 1H), 8.09-8.01 (m, 2H), 7.83-7.79 (m, 1H), 7.52-7.49 (m, 1H), 7.45-7.42 (m, 1H), 6.10 (q, br, 1H), 5.21 (t, 1H), 4.56 (qt, 1H), 4.38 (d, 2H), 3.57 (s, 3H), 2.86 (d, 3H), 1.95 (s, 3H), 1.49-1.45 (m, 6H))
Reaction SMILES: Cl[CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1N.[ClH:10].N([O-])=O.[Na+].[I-:15].[K+]>O.C1CCCCC1>[Cl:10][C:6]1[CH:4]=[C:3]([CH3:2])[CH:9]=[CH:8][C:7]=1[I:15]
Reactant: Cl
Reactant: Nc1ccccc1CCl
Reactant: [I-]
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: Cc1ccc(I)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A stirred mixture of 2-chloromethylaniline (25.00 g, 0.177 mol) and 36% hydrochloric acid is warmed gently to obtain a solution, then cooled to -5° C. and a solution of sodium nitrite (13.45 g, 0.195 mol) in water is added dropwise whilst maintaining the temperature at -5° C. The mixture is stirred at 0° C. for 30 minutes, 100 ml of cyclohexane is added and a solution of potassium iodide (58.77 g, 0.354 mol) in water is added dropwise at a temperature of between 0° and 5° C. The mixture is stirred at room temperature (overnight for convenience) and the product is extracted into ether (×2). The combined organic extracts are washed with sodium metabisulphite, 10% sodium hydroxide, water and dried (MgSO4). The solvent is in vacuo to yield 35.0 g (87%) off-white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:34]2[CH2:39][CH2:38][CH2:37][C:36]([NH:41]C(=O)OC(C)(C)C)([CH3:40])[CH2:35]2)=[C:27]2[CH2:33][CH2:32][CH2:31][C:28]2=[N:29][CH:30]=1)=[O:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:34]2[CH2:39][CH2:38][CH2:37][C:36]([NH2:41])([CH3:40])[CH2:35]2)=[C:27]2[CH2:33][CH2:32][CH2:31][C:28]2=[N:29][CH:30]=1)=[O:23]
Reactant: CC1(NC(=O)OC(C)(C)C)CCCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnc3c2CCC3)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(N)CCCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A mixture of tert-butyl {1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-methylpiperidin-3-yl}carbamate (8.4 mg, 0.012 mmol), DCM (0.12 mL) and TFA (0.12 mL, 1.6 mmol) was stirred at room temperature for 30 min. The solution was then concentrated under reduced pressure and the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a white powder (3.5 mg, 59%). LCMS calc. for C24H27F2N6OS (M+H)+: m/z=485.2. Found: 485.2.