Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH2:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.O.[C:14]([OH:18])(=[O:17])[CH:15]=[O:16].C(=O)(O)[O-].[Na+].C(=O)(O)[O-].S(=O)(=O)(O)[O-].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH:15]([OH:16])[C:14]([OH:18])=[O:17])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NC(=O)Cc1cc(F)cc(F)c1
Reactant: O=CC(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Cc1cc(F)cc(F)c1)NC(O)C(=O)O

Procedure:
A mixture of 7.2 g of (3,5-difluorophenyl)acetamide 1 and 4.6 g of glyoxylic acid hydrate in 75 mL of acetone was refluxed 24 hours. The solvent was evaporated and the residue was dissolved in 300 mL of ethyl acetate. This solution washed with 150 mL of distilled water. The aqueous phase was discarded. The organic phase was extracted with a solution prepared by diluting 50 mL of a saturated aqueous solution of sodium bicarbonate with 150 mL of distilled water. The organic phase was discarded and the aqueous bicarbonate solution was acidified with 80 mL of 1 N aqueous sodium bisulfate solution. The acidified solution was extracted with three successive 125 mL portions of ethyl acetate. The combined organic extracts were washed with brine and then dried over magnesium sulfate. The solution was filtered and the solvent was evaporated to yield 2-[(3,5-difluorophenyl)acetylamino]-2-hydroxyacetic acid as 5.2 g of a white solid. 1H-NMR (DMSO-d6): δ 8.95 (d, J=8 Hz, 1H), 7.15-6.90 (m, 3H), 5.37 (d, J=8 Hz, 1H), 3.50 (s, 2H). 13C-NMR (DMSO-d66) δ 171.5, 169.4, 162.4 (dd, JC-F=13, 244 Hz), 140.6 (t, JC-F=10 Hz), 112.6 (dd, JC-F=8, 17 Hz), 71.5, 41.7. MS (CI+): m/z 246. EA Calc'd for C10H9F2NO4: C, 48.98; H, 3.71; N, 5.71. Found: C, 49.02; H, 3.72; N, 5.51.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([C:30]([OH:37])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[N:25]=[C:24]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([C:30]([OH:37])([CH:31]([CH3:33])[CH3:32])[CH:34]([CH3:35])[CH3:36])[N:25]=[C:24]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:18][CH:17]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCCCc1nc(C(O)(C(C)C)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(O)(C(C)C)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
10 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 500 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-[1-hydroxy-2-methyl-1-(1-methylethyl)propyl]imidazole-5-carbonitrile [prepared as described in step (a) above] in 10 ml of ethanol, and the resulting mixture was heated under reflux for 20 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to give 220 mg of the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1>>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:36][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[C:15]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: NC1CCC1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Product: N#CC(=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCC1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 85 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.400 g, 0.8 mmol) was stirred in cyclobutylamine (0.70 ml) at 60° C. for 20 h. Work up as described in Example 1, 2) gave 354 mg (85%) of the title compound as white crystals. Mp 190.5-193° C. 1H NMR (300 MHz, CDCl3): δ=1.5 (m, 2H), 1.72 (m, 1H), 2.0 (m, 3H), 3.63 (sextet, 1H), 7.42 (s, 2H), 7.48 (d, 2H), 7.67 (s, 1H), 7.79 (d, 2H); MA calc for C21H16ClF6N3O2S: C, 48.15%; H, 3.08%; N, 8.02%. Found: C, 48.38%; H, 3.09%; N, 7.96%.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][C:13]([OH:15])=O)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][N:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:13](=[O:15])[CH2:12][C:10]2[NH:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:26][CH2:27]1
Reactant: O=C(O)Cc1nc(-c2ccccc2)n[nH]1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1nc(-c2ccccc2)n[nH]1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
(3-Phenyl-1H-1,2,4-triazol-5-yl)acetic acid (0.020 g) and N,N′-carbonyl diimidazole (0.016 g) in dichloromethane was stirred under nitrogen for 3 minutes. 1-(3,4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0.031 g) and triethylamine (0.036 g) was then added and allowed to stir for 1 hour under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to a white solid. This was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). Saturated sodium hydrogen carbonate was added to the pooled collected fractions with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-(3-phenyl-1H-1,2,4-triazol-5-yl)acetamide(0.031 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:20]([O:1][C:2]1[C:3]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(CCc2ncccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCc2ncccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of methyl 4-[2-(3-hydroxy-2-pyridyl)ethyl]benzoate (1.1 g, 4.3 mmol) in DMF (30 ml) was treated with benzyl bromide (0.89 g, 5.2 mmol) and potassium carbonate (0.72 g, 5.2 mmol). The reaction was stirred at ambient temperature overnight and then, partitioned between EtOAc/water. The organic phase was washed well with water, dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2) eluting with CH2Cl2 /EtOAc to give methyl 4-[2-(3-benzyloxy-2-pyridyl)ethyl]benzoate (0.94 g, 53%) as a low melting yellow solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=1)[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[N:21]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:13]=[C:12]([NH:11][C:8]([C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:33]=[CH:32][CH:31]=4)=[N:21][N:20]3[CH:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)s1
Yield: 71.1 %

Procedure:
Using 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (78.8 mg, 0.50 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (129 mg, 0.417 mmol), 1-hydroxybenzotriazole (68 mg, 0.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol), triethylamine (50 mg, 0.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (133 mg, 71%) was obtained as a white powder. melting point 249° C.
Reaction SMILES: CN(C)[CH:3]1[C:14]2[C:6](=[CH:7][CH:8]=[C:9]3[C:13]=2[S:12](=C)[CH:11]=[N:10]3)[NH:5][C:4]1=[O:16].[CH2:18]([OH:20])[CH3:19]>C(OCC)C>[CH3:4][N:5]([C:6]1[CH:14]=[CH:13][C:9]([NH:10]/[CH:11]=[C:3]2\[C:4](=[O:16])[NH:5][C:6]3[C:14]\2=[C:13]2[S:12][CH:11]=[N:10][C:9]2=[CH:8][CH:7]=3)=[CH:8][CH:7]=1)[C:18](=[O:20])[CH3:19]
Reactant: CCO
Reactant: C=S1C=Nc2ccc3c(c21)C(N(C)C)C(=O)N3
Solvent: CCOCC
Product: CC(=O)N(C)c1ccc(N/C=C2\C(=O)Nc3ccc4ncsc4c32)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A mixture of 8-dimethylamino-methylene-6,8dihydro-1-thia-3,6-diaza-as-indacen-7-one (Procedure E, 0.040 g, 0.163 mmol), 4-amino-N-methylacetanilide (0.040 g, 0.244 mmol) in absolute ethanol (5 ml) was heated with stirring at 90° C. for 16 h. The reaction was diluted with ethanol and diethyl ether and the product collected by filtration to yield 0.038 g (64%) of the title compound. 1H NMR (DMSO-d6): δ 11.03 (d,1 H, J=12.3 Hz), 10.84 (s,1H), 9.23 (s,1H), 8.02 (d,1H, J=12.3 Hz), 7.78 (d,1H, J=8.4 Hz), 7.48 (d,2H, J=8.2 Hz), 7.35 (d,2H, J=8.2 Hz), 7.09 (d,1H, J=8.4 Hz), 3.11 (s,3H), 1.76 (s, 3H); ES-MS m/z 363 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([SH:14])=[N:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.S(OC)(O[CH3:23])(=O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[N:12][C:11]([S:14][CH3:23])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2cnc(S)n2)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-n2cnc(SC)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of 8 parts of 1-(4-methoxyphenyl)-1H-1,2,4-triazole-3-thiol, 3.1 parts of sodium hydroxide and 40 parts of methanol is stirred for 30 minutes at room temperature. Then there are added 4.9 parts of dimethyl sulfate and stirring at room temperature is continued for 3 hours. Water is added to the reaction mixture and the product is extracted twice with 1,1'-oxybisethane. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 5.6 parts (65%) of 1-(4-methoxyphenyl)-3-(methylthio)-1H-1,2,4-triazole; mp. 54.9° C.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16]([Br:30])=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([O:26]C(=O)C)[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CN>C(O)C>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16]([Br:30])=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[NH:21][C:20](=[O:26])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(=O)Oc1ccc2c(Br)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Agent: CN
Solvent: CCO
Product: Cc1cc2[nH]c(=O)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 78 °C

Procedure:
To the solution of (S)-2-(2-acetoxy-5-bromo-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate (130 mg) in ethanol (7.5 mL) was added aqueous methylamine solution (0.5 mL, 50%). The mixture was heated at 78° C. for 80 min. Concentration and purification gave (S)-2-(5-bromo-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyethyl pivalate. LCMS-ESI+ (m/z): 438.2, 440.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:13][C:14]=2[OH:15])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C1(=O)O[CH2:31][CH2:30][O:29]1.Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=[CH:13][C:14]=2[O:15][CH2:31][CH2:30][OH:29])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccccc2)cc1Sc1cccc(F)c1
Reactant: O=C1OCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(-c2ccccc2)cc1Sc1cccc(F)c1
Temperature: 100 °C

Procedure:
3-(3-Fluoro-phenylsulfanyl)-biphenyl-4-ol (2.65 g, 8.94 mmol) and potassium carbonate (2.113 g, 15.3 mmol) was dissolved in DMF (30 mL). Ethylene carbonate (1.601 g, 18.2 mmol) was added and the reaction was heated at 100° C. for 150 minutes. The solution was allowed to cool before the solution was carefully poured into 2M HCl (50 mL). The product was extracted with diethyl ether (50 mL). The separated organic phase was washed with water (4×50 mL), 4% aq. MgSO4, brine and then the separated organic phase was dried (MgSO4). The title product was isolated after concentration in vacuo. Yield: 2.96 g, 97%
Reaction SMILES: [I-:1].[CH2:2]([N+:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:19][N:20]([CH3:33])[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:31]=O)=[CH:23][CH:22]=1>C(OC(=O)C)(=O)C>[I-:1].[CH3:19][N:20]([CH3:33])[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](/[CH:31]=[CH:18]/[C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:9]=2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:23][CH:22]=1
Reactant: CCCCCCC[n+]1c(C)sc2ccccc21
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Agent: [I-]
Solvent: CC(=O)OC(C)=O
Product: CCCCCCC[n+]1c(/C=C/c2ccc(N(C)C)c3ccccc23)sc2ccccc21

Procedure:
A mixture of 3-heptyl-2-methylbenzothiazolium iodide (0.50 g, 1.33 mmol) and 4-dimethylamino-1-naphthaldehyde (0.40 g, 2.01 mmol) in 5 mL of acetic anhydride under nitrogen was heated. Upon refluxing, the mixture turned purple and all solids seemed to be in solution. The solution was refluxed for 15 minutes and on cooling, solid formed. The mixture was filtered and washed with ethyl acetate to give (E)-2-[2-(4-dimethylaminonaphthalen-1-yl)vinyl]-3-heptylbenzothiazol-3-ium iodide as a dark brown solid, mp 195-197° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([NH:30][OH:31])=[NH:29])[CH2:24][CH2:23]3)[O:19][C:16]2=[CH:17][N:18]=1.[C:32](Cl)(=O)[CH:33]([CH3:35])[CH3:34]>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[N:29]=[C:32]([CH:33]([CH3:35])[CH3:34])[O:31][N:30]=4)[CH2:26][CH2:27]3)[O:19][C:16]2=[CH:17][N:18]=1
Reactant: CC(C)C(=O)Cl
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)c(F)c1
Product: CC(C)c1nc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5F)ncc4O3)CC2)no1

Procedure:
The title compound is prepared from 4-[5-(2-fluoro-4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-N-hydroxy-piperidine-1-carboxamidine and isobutyryl chloride following a procedure analogous to that described in Example 8. LC (method 6): tR=1.59 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH2:3][N:4]1[C:10](=O)[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:16]=[CH:17][CH:18]=[CH:19][C:5]1=2.C([O-])(=O)C.[NH4+:31].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C>[C:21]1([CH3:26])[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[N:31]=[C:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][C:6]3[N:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]2[CH:3]=1
Reactant: [NH4+]
Reactant: Cc1ccccc1C(=O)CN1C(=O)c2ccccc2Nc2ncccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccccc1-c1cn2c(n1)-c1ccccc1Nc1ncccc1-2
Temperature: 120 °C
Reaction time: 48 h
Yield: 52.9 %

Procedure:
To a solution of 5-(2-oxo-2-(o-tolyl)ethyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.6 g, 1 eq.) in acetic acid (10 mL) was added ammonium acetate (2.7 g, 20 eq.). The reaction was stirred at 120° C. for 48 hours. The reaction was poured onto water (50 mL) and ethyl acetate (150 mL). The pH was adjusted to 9 by the addition of NaOH 1N. The phases were separated and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (10% ethyl acetate in dichloromethane) gave the 2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.3 g, 53%). M.p.: 215-217° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.60 (s, 1H), 8.18 (dd, JA=4.4 Hz, JB=1.2 Hz, 1H), 7.99 (dd, JA=8.0 Hz, JB=1.2 Hz, 1H), 7.91-7.85 (m, 2H), 7.82 (s, 1H), 7.34-7.20 (m, 5H), 7.14 (dd, JA=8.0 Hz, JB=4.8 Hz, 1H), 7.05 (t, J=8.4 Hz, 1H), 2.56 (s, 3H); LCMS: 325 [M+H].
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[C:29](O)(=[O:35])[CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34].C1CCC(N=C=NC2CCCCC2)CC1.C(OC)(C)(C)C>C(Cl)Cl>[C:29]([C@:18]1([OH:19])[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)(=[O:35])[CH:30]=[CH:31][CH2:32][CH2:33][CH3:34]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C=CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CCCC=CC(=O)[C@]1(O)CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of cholesterol (2.0 g, 5.17 mM) in methylene chloride (20 mL) was added 5-hexenoic acid (0.68 mL, 5.69 mM) followed by the addition of DCC (1.60 g, 7.76 mM) and 4-PP (0.115 g, 0.78 mM) under nitrogen atmosphere. The resulting reaction mixture was stirred at ambient temperature for 1 h and worked up with the addition of methyl t-butyl ether (60 mL). The urea was filtered off, and the product was transferred to a separatory funnel, washed with 1N HCl (10 mL), water (30 mL) and brine (30 mL). The product was filtered after drying over MgSO4 and the solvent was evaporated to leave a residue. The product obtained in >95% yield was characterized by 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].S([O-])(O)=O.[Na+].CN(C)C(=O)C.[CH3:28][C:29]1[NH:30][CH:31]=[C:32]([CH3:36])[C:33]=1[CH:34]=O>O>[CH3:28][C:29]1[NH:30][CH:31]=[C:32]([CH3:36])[C:33]=1[C:34]1[NH:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:15]=2[N:16]=1
Reactant: Cc1c[nH]c(C)c1C=O
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c[nH]c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.9 %

Procedure:
3,4-Diaminobenzophenone (1.48 g) and sodium hydrogensulfite (0.87 g) were added to N,N-dimethylacetamide (5 ml) at 130° C., and stirred for 5 minutes. 2,4-Dimethyl-3-formyl-pyrrole (1.03 g) was added and stirred at 130° C. for 8 hours. The reaction mixture was cooled to room temperature and stirred, and after addition of water to reaction mixture, precipitate was collected by filtration, and dried in vacuo to afford 2-(2,4-dimethyl-pyrrol-3-yl)-5-benzoylbenzimidazole (1.78 g, 81%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@H:6]([CH3:13])[NH:5]2.Cl[C:15]([O:17][C:18]([CH3:20])=[CH2:19])=[O:16]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:15]([O:17][C:18]([CH3:20])=[CH2:19])=[O:16])[C:7](=[O:12])[C@H:6]([CH3:13])[NH:5]2
Reactant: C=C(C)OC(=O)Cl
Reactant: C[C@@H]1Nc2nc(Cl)ccc2NC1=O
Solvent: c1ccncc1
Product: C=C(C)OC(=O)N1C(=O)[C@H](C)Nc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound of Example 2 (988 mg, 5.0 mmol) was dissolved in 30 ml of anhydrous pyridine. After addition of 0.6 ml (5.5 mmol) of isopropenyl chloroformate, the mixture was stirred at room temperature for 4 h and subsequently concentrated. The residue was dissolved in ethyl acetate and washed three times with water, dried (sodium sulfate) and concentrated. After chromatography on silica gel (ethyl acetate/heptane=1:2), the desired compound was isolated and crystallized from diethyl ether/pentane; yield 380 mg (27%) of melting point 86°-87° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([O:30][C@@H:31]1[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:35]([O:41][C:42](=[O:44])[CH3:43])[C@@H:34]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[O:33][C@H:32]1[C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[CH:52][C:51]=1[O:57][CH2:58][CH3:59])(=[O:29])[CH3:28]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:27]([O:30][C@@H:31]1[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:35]([O:41][C:42](=[O:44])[CH3:43])[C@@H:34]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[O:33][C@H:32]1[C:50]1[CH:55]=[C:54]([CH2:56][Br:1])[CH:53]=[CH:52][C:51]=1[O:57][CH2:58][CH3:59])(=[O:29])[CH3:28]
Reactant: CCOc1ccc(C)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1ccc(CBr)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 32.4 %

Procedure:
N-bromosuccinimide (1.7 g) and benzoyl peroxide (0.1 g) were added to a solution of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(2-ethoxy-5-methylphenyl)-D-glucitol (3.7 g) in carbon tetrachloride (30.0 ml) and the mixture was refluxed with heating for one hour. The reaction mixture was diluted with chloroform and the diluted product was washed with saturated aqueous solution of sodium hydrogencarbonate, saturated aqueous solution of sodium thiosulfate, and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The resulting precipitates were collected by filtration to obtain (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2-ethoxyphenyl]-D-glucitol (1.4 g).
Reaction SMILES: C([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1)C1C=CC=CC=1.CC(C)([O-])C.[K+]>CS(C)=O>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[N:9]1
Reactant: c1ccc(Cc2n[nH]c3ccccc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzyl-indazole is dissolved in dimethylsulfoxide and potassium tert-butoxide (1 M solution in tetrahydrofuran) is added at room temperature. Oxygen is then bubbled into the solution for 5 minutes. The reaction is allowed to stir at room temperature for 18 h. The reaction is quenched with aqueous saturated ammonium chloride then extracted three times with ethyl acetate. The combined organic extracts are dried over sodium sulfate, and concentrated. Purification by flash chromatography provides the deprotected indazole.