Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:19])([CH3:18])[CH2:7][C:8]2([CH2:12][C:13]([O:15]CC)=[O:14])O)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:19])([CH3:18])[CH2:7]/[C:8]/2=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1(O)CC(C)(C)c2ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)C/C(=C\C(=O)O)c2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
A solution of ethyl 2-(6-fluoro-1-hydroxy-3,3-dimethyl-1-indanyl)acetate (16 g, 0.0601 mol) in 1N sodium hydroxide (60.1 ml, 0.0601 mol) and ethanol (60 ml) was stirred for 20 h. The solution was concentrated to a small volume by spin evaporation in vacuo, diluted with deionized water (100 ml), and acidified to pH 3 with 1N hydrochloric acid. This biphasic solution was extracted with dichloromethane (2×100 ml). The extracts were combined, washed with deionized water (20 ml), dried with magnesium sulfate (Mallinckrodt), and concentrated by spin evaporation in vacuo. The residue was dissolved in dichloromethane (30 ml), cooled to 0° C., and diluted with 400 ml of a cold (0° C.) solution of trifluoroacetic acid (45 g, Aldrich) in dichloromethane (400 ml). After 15 min, the solution was concentrated by spin evaporation in vacuo and the residue was crystallized by adding hexanes to give 9.23 g (70%) of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetic acid as a white crystalline solid, m.p., 202-203.5° C.:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl.[NH2:27][CH:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29]1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:27][CH:28]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: NC1Cc2ccccc2C1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2Cc3ccccc3C2)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-aminoindan hydrochloride.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15]1)(C1C=CC=CC=1)[C:2]1C=CC=CC=1.C(N(CC)CC)C.C(Cl)(=[O:36])C>[OH-].[Pd+2].[OH-].[C].CO>[C:1]([N:14]1[CH2:17][CH:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15]1)(=[O:36])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(=O)Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N1CC(N(C)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
tert-Butyl N-(1-benzhydrylazetidin-3-yl)-N-methylcarbamate (I-149) (0.40 g, 1.13 mmol) was dissolved methanol (20 ml), then 20% palladium hydroxide-carbon (containing about 50% water, 20 g) was added, followed by stirring at room temperature under hydrogen atmosphere for 15 hours, and the catalyst was removed by filtration. The solvent was evaporated away under reduced pressure, the resulting residue was dissolved in dichloromethane (10 ml), and triethylamine (0.20 ml, 3.44 mmol) and acetyl chloride (90.0 μl, 26 mmol) were added.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CC1C=C(O)C=CC=1C.[C:20]1([CH:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]2[C:35]3[C:30](=[CH:31][C:32]([F:36])=[CH:33][CH:34]=3)[C:29](=[O:37])[C:28]2=[O:38])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[C:39]1([CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]2[C:35]3[C:30](=[CH:31][C:32]([F:36])=[CH:33][CH:34]=3)[C:29]([OH:37])([C:8]3[C:7]([OH:10])=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=3)[C:28]2=[O:38])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccc(F)cc21
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccc(F)cc2C1(O)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 2,3-dihydrobenzofuran-6-ol to replace 3,4-dimethylphenol, and 1-(diphenylmethyl)-5-fluoro-1H-indole-2,3-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 1-(diphenylmethyl)-5-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one was obtained (99%): 1H NMR (300 MHz, CDCl3) δ 8.94 (s, 1H), 7.36-7.19 (m, 11H), 6.94 (s, 1H), 6.82-6.75 (m, 1H), 6.63 (s, 1H), 6.48-6.38 (m, 2H), 4.53 (t, J=9.0 Hz, 2H), 4.38 (br s, 1H), 3.06-3.00 (m, 2H); MS (ES+) m/z 466.4 (M−1).
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[OH:9][OH:10].S(=O)(=O)(O)O.[OH-].[Na+]>>[O-:9][OH:10].[CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7]
Reactant: OO
Agent: O=S(=O)(O)O
Agent: OCCCCCCO
Agent: [Na+]
Product: [O-]O

Procedure:
Hexylene glycol hydroperoxide was prepared by reaction of 118.1 g (1.0 mol) hexylene glycol and 145.7 gr (3 mol) hydrogen peroxide in the presence of sulfuric acid at a temperature of 30° C. for 1 hour. The reaction mixture was cooled down to 20° C. and neutralized with sodium hydroxide until pH=6.8. After separation the underlayer was drained. The remaining crude hexylene glycol hydroperoxide was converted to sodium salt by the addition of 160 g of a 25% NaOH solution. Subsequently, the sodium salt was extracted 3 times with ethyl ether in order to lower the dialkyl peroxide content (di(3-hydroxy-1,1-dimethylbutyl)peroxide). The remaining sodium salt of hexylene glycol hydroperoxide was acidified with H2SO4 25% until pH 3. Hexylene glycol hydroperoxide was isolated from the solution with ethyl ether. After evaporation of the ethyl ether the resulting product was analysed and found to contain 92% hexylene glycol hydroperoxide.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[N:3]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][C@@H:14]([CH3:18])[NH:13]1>CS(C)=O>[CH3:11][C@H:12]1[NH:13][C@@H:14]([CH3:18])[CH2:15][N:16]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[N:3]=2)[CH2:17]1
Reactant: O=Cc1ccc(Cl)nc1O
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CS(C)=O
Product: C[C@@H]1CN(c2ccc(C=O)c(O)n2)C[C@H](C)N1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Chloro-2-hydroxynicotinaldehyde (1.06 g, 6.76 mmol) was dissolved in DMSO (20 mL) at room temperature. The solution was treated with cis-2,6-dimethylpiperazine (1.16 g, 10.18 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 3 hours and cooled to room temperature to yield crude 6-(cis-3,5-dimethylpiperazin-1-yl)-2-hydroxynicotinaldehyde. MS m/z 236 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([C:18]2[C:25](F)=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[F:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[K].Cl.[O:31]1CCCC1>O>[Cl:1][C:2]1[C:3](=[O:28])[N:4]([C:18]2[C:25]([OH:31])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[F:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: C1CCOC1
Reactant: N#Cc1cc(F)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1
Agent: Cl
Agent: [K]
Solvent: O
Product: N#Cc1cc(O)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzonitrile (522 mg, 1.28 mmol) and potassium trimethylsilonate 90% (655 mg, 4.60 mmol) are combined in 8 ml anhydrous tetrahydrofuran and stirred under nitrogen at room temperature for 2 hours. The precipitated potassium salt of was collected by filtration, washed with a minimum of tetrahydrofuran, and dried in vacuo. A portion of this salt (275 mg, 0.618 mmol) was dissolved in 5 ml water, the pH was adjusted below 6 with concentrated hydrochloric acid, the product collected by filtration, washed with water, sucked dry under a blanket of dry nitrogen, and dried further in vacuo overnight (251 mg, 100%, 98% overall). 1H-NMR (400 MHz, DMSO-d6) δ 11.46 (br s, 1H), 7.74 (d, J=7.81 Hz, 1H), 7.67 (quartet, J=6.76 Hz, 1H), 7.52 (d, J=8.76, 1H), 7.364, (dt, J=10.18, 2.37 Hz, 1H), 7.24 (br s, 1H), 7.17 (br t, J=8.75, 1H), 6.74 (d, J=8.04 Hz, 1H), 5.39 (s, 2H). 19F-NMR (400 MHz, DMSO-d6) δ −109.26 (quintet, J=8.50 Hz, 1F), −113.52 (quartet, J=9.29 Hz, 1F), −118.06 (d, J=9.38 Hz, 1F). LC/MS tr=5.13 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes, then 95% acetonitrile for 2 minutes, at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 407 (M+H). ES-HRMS m/z 407.0381 (M+H calcd for C19H11ClF3N2O3 requires 407.0405).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:20]([C:21](=O)[C:22]=2[CH:23]=1)=[CH:19][C:18]1[C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:26])[CH:15]=2)[CH2:10][C:9]=1[CH:8]=3>COCCOCCOC>[CH3:26][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][C:18]3[C:9]([CH:10]=2)=[CH:8][C:7]2[C:20](=[CH:21][C:22]4[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:23]=4)[CH:19]=3)[CH:15]=1
Reactant: Cc1ccc2c(c1)C(=O)c1cc3c(cc1C2)Cc1ccc(C)cc1C3=O
Solvent: COCCOCCOC
Product: Cc1ccc2cc3cc4cc5ccc(C)cc5cc4cc3cc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1 gram of 3,9-dimethylpentacene-5,7(12H,14H)-dione and 10 mL of 2-methoxyethyl ether was stirred and flushed with nitrogen for 15 minutes. To this was added 0.948 grams of sodium borohydride and stirring was continued at room temperature overnight. To the mixture was added 6.3 mL of methanol and stirring was continued for 1.5 hours at room temperature. To the mixture was added 15 mL of acetic acid and 10 mL of concentrated hydrochloric acid. The mixture was stirred for one hour at room temperature followed by heating for one hour at 60° C. To the mixture was added 50 mL of water and the solid was isolated by filtration and washed with water. The solid was washed with tetrahydrofuran until a pale filtrate resulted. The resulting solid was washed with heptane and dried under an atmosphere of nitrogen to give 2,10-dimethylpentacene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24]CC)=[O:23].BrC1N=C(N)C=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:46]=[C:45]([NH2:47])[NH:44][N:43]=2)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:47][C:45]3[NH:44][N:43]=[C:42]([C:39]4[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=4)[CH:46]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: Nc1cc(-c2ccc(F)cc2)n[nH]1
Agent: Nc1cccc(Br)n1
Product: O=C(Nc1cc(-c2ccc(F)cc2)n[nH]1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1

Procedure:
Prepared according to the method of Example 39, substituting 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid in Step A with 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid and 6-bromopyridin-2-amine with 3-(4-fluorophenyl)-1H-pyrazol-5-amine. MS (apci) m/z=508.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:24][N:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:26]=3)[CH2:28][CH2:29]2)=[O:15])[O:4][N:3]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)on1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)on1
Yield: 40.6 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (3-methylisoxazol-5-yl)carbamate (302 mg, 1.11 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (300 mg, 1.33 mmol) and diisopropylethylamine (0.212 ml, 1.33 mmol) in dimethyl sulfoxide (3.7 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 167 mg (40.6%) of the desired product as a solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[CH2:20](I)[CH3:21].[OH-].[Na+]>CN(C)C=O>[C:8]([C:7]1[C:2](=[O:1])[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]([CH2:20][CH3:21])[CH:6]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCI
Reactant: Cn1cc2c(O)c(C(=O)c3ccccc3)cnc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)c2ccccc2)c(=O)c2cn(C)nc21

Procedure:
25.3 g. of (4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenylmethanone (0.1 mol.), 17.1 g. of ethyl iodide (0.11 mol.) and 5 g. of sodium hydroxide are heated together in 150 ml. of dimethylformamide for 12 hours with continuous stirring at 100°. The mixture is filtered hot, evaporated to dryness and the residue is recrystallized from butanol to obtain 5-benzoyl-7-ethyl-2,7-dihydro-2-methyl-4H-pyrazolo[3,4-b]pyridin-4-one, yield 20.3 g. (72%); m.p. 217°-218°.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[N:12]=[C:11]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[N:21]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1[S:3][C:4]2[C:13]3[N:12]=[C:11]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6][C:5]=2[N:21]=1
Reactant: Cc1nc2c(s1)-c1nc(Nc3ccccc3)ncc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc2ccc3cnc(Nc4ccccc4)nc3c2s1
Yield: 41.8 %

Procedure:
(2-Methyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-8-yl)-phenyl-amine (52 mg, 0.18 mmol) and DDQ (48 mg, 0.21 mmol) in toluene (10 mL) were heated under reflux for 16 h using anhydrous conditions. The reaction mixture was diluted with EtOAc, filtered, and concentrated under vacuum. Purification of the residue by flash column chromatography (20% EtOAc:hexane) afforded the title product as a yellow solid (22 mg, 43%): mp 216° C. (dec). Anal. RP-HPLC: tR 15.1 min (0-60% MeCN, purity 100%). 1H-NMR (DMSO-d6): δ 10.11 (s, 1H, NH), 9.38 (s, 1H, Py-H), 7.98 (d, 2H, J 7.7, Ph-H), 7.93 (d, 1H, J 8.7, CH), 7.84 (d, 1H, J 8.7, CH), 7.36 (t, 2H, J7.7, Ph-H), 7.02 (t, 1H, J 7.7, Ph-H), 2.91 (s, 3H, CH3). MS (ESI+): m/z 293.07 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Br:17])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Br:17])[C:12]([N+:18]([O-:20])=[O:19])=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)cc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(Br)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-Benzyloxy-1-bromo-4-methoxybenzene, 36, (1 g, 3.4 mmol) was dissolved in 50 mL acetic acid in a 100 mL round-bottomed flask and cooled to 0° C. using an ice bath. 2.5 mL nitric acid (70%) in 6 mL acetic acid was added dropwise. The reaction mixture was allowed to slowly rise to room temperature. After 3 h no starting material was detected by thin layer chromatography. Evaporation of acetic acid gave the crude product, which was filtered through a short silica gel column using a 80:20 mixture of hexanes:ethyl acetate to give 3-benzyloxy-4-methoxy-6-nitrobromobenzene (1.15 g) in quantitative yield; mp 134-135° C.; IR (KBr) 2946, 1577, 1518, 1468, 1382, 1329, 1266, 1211 cm−1; UV (MeOH) 246, 212 nm (log ε=3.91, 4.13); 1H NMR (CDCl3) δ3.93 (3H, s), 5.19 (2H. s), 7.17 (1H, s), 7.38-7.45 (5H, m), 7.57 (1H, s); 13C NMR δ56.99, 71.98, 107.69, 109.74, 118.73, 127.98, 129.11, 129.36, 135.50, 142.42, 149.18, 152.44; HRMS (EI) calcd for C14H12NO4Br m/z: 336.9950; found: 336.9941.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:20]=[CH:21][C:22]([N+:27]([O-:29])=[O:28])=[C:23]([CH:26]=1)[C:24]#[N:25]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:19]3[CH:20]=[CH:21][C:22]([N+:27]([O-:29])=[O:28])=[C:23]([CH:26]=3)[C:24]#[N:25])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Sc2cccc3cnccc23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
According to the method in Example 10, a mixture of 5-isoquinolinethiol 1.20 g (7.4 mmol), DMF 40 ml, potassium carbonate 2.00 g (14.5 mmol) and 5-chloro-2-nitrobenzonitrile 1.30 g (7.1 mmol) was stirred at room temperature for 2 hours, and 5-(5-isoquinolylsulfanyl)-2-nitrobenzonitrile 2.14 g (97.8%) was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH3:23])=[CH:10][C:11]=2[CH3:13])[C:6](=[O:24])[CH:5]([C:25]([O:27]C)=[O:26])[C:4]1=[O:29])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH3:23])=[CH:10][C:11]=2[CH3:13])[C:6](=[O:24])[CH:5]([C:25]([OH:27])=[O:26])[C:4]1=[O:29])[CH3:2]
Reactant: CCN1C(=O)C(C(=O)OC)C(=O)c2cc(Nc3ccc(OC)cc3C)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCN1C(=O)C(C(=O)O)C(=O)c2cc(Nc3ccc(OC)cc3C)cc(C)c21
Temperature: 60 °C

Procedure:
Methyl 1-ethyl-6-(4-methoxy-2-methylphenylamino)-8-methyl-4-oxo-1,4-dihydroquinolone-3-carboxylate (30 mg) was dissolved in 5 ml of dioxane, 2.5 equivalents of a 1 N NaOH solution were added, and the mixture was heated at 60° C. for 4 h. Removal of the solvent in vacuo was followed by chromatography on an HPLC system to purify the product. This entailed use of a Merck Purospher-RP18 column and an acetonitrile:water mixture as eluent; the initial acetonitrile content was 15% and rose to 95% over the course of 20 minutes.
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[C:22]([S:28][CH3:29])[CH:21]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)#[N:6]>C(Cl)Cl>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([S:28][CH3:29])[CH:21]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)#[N:6]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(SC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(O)c(SC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1M solution of BBr3 in CH2Cl2 (4.5 ml, 4.5 mmol) was added at −78° C. to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(4-methoxy-3-methylsulphanyl-phenyl)-acetate (320 mg, 0.899 mmol) obtained in Example 167.2 in CH2Cl2 (10 ml). The mixture was stirred at −78° C. for 5 min., at 0° C. for 30 min. and at room temperature for 2 h. Ice-water was added and the mixture was stirred for 10 min. The mixture was extracted with CH2Cl2. The organic phase was dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 2:1). Ethyl (RS)-(4-cyano-phenylamino)-(4-hydroxy-3-methylsulphanyl-phenyl)-acetate was obtained as a colorless oil (198 mg, 64%); MS: 343 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.Cl>O1CCOCC1>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12][N:7]3[CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)CCCN1CCCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCCN1CCCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
To the product from Example 60 (37 mg, 0.0885 mmol) in 1,4-dioxane (1.5 mL) was added 12N HCl (1 mL) and the resulting mixture was stirred at 55° C. for 5 h. The solvent was removed in vacuo to obtain the product as a solid. The oil was triturated with diethyl ether (4 mL) to obtain the product as a creamish red solid. (39 mg, 99%): MS; m/z 404 (M+H): LCMS (UV) 94%; 1H NMR (400 MHz, DMSO-d6) δ 1.54-1.57 (m, 1H), 1.80-1.96 (m, 5H), 2.32-2.36 (m, 2H), 3.12-3.22 (m, 3H), 3.37-3.41 (m, 3H), 3.60-3.64 (m, 1H), 4.25-4.35 (m, 2H), 6.94 (d, 2H, J=6.8 Hz), 7.06 (s, 4H), 7.4 (d, 2H, J=6.4 Hz), 10.15 (s, 1H), 12.3 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:21][CH:20]=4)[C:16]([C:17]#[N:18])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:32].[Na+].OO>CS(C)=O.C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:21][CH:20]=4)[C:16]([C:17]([NH2:18])=[O:32])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(N)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(N)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carbonitrile (130 mg, 0.32 mmol) in DMSO (2 mL) and ethanol (2 mL) was added a solution of 5 N NaOH aqueous solution (1 mL) and H2O2 (1 mL). The mixture was stirred at 60° C. for 30 minutes, concentrated and partitioned between EA (100 mL) and brine (100 mL). Organic layer was separated, washed with brine (3×100 mL), dried over Na2SO4 and purified by chromatography column on silica gel eluting with PE/EA to afford 35 mg (26%) of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J=8.4 Hz, 2H), 7.40-7.33 (m, 2H), 7.16 (t, J=7.6 Hz, 1H), 7.06 (d, J=8.0 Hz, 2H), 7.03 (d, J=8.4 Hz, 2H), 6.97 (t, J=7.6 Hz, 1H), 6.76 (s, 1H), 6.44 (d, J=8.4 Hz, 1H), 6.23-6.21 (m, 2H), 5.30-5.25 (m, 1H), 5.09 (s, 2H), 3.30-3.28 (m, 1H), 3.12-3.02 (m, 1H), 2.34-2.26 (m, 1H), 2.05-2.01 (m, 1H). MS (ESI) m/e [M+1]+ 426.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:11])=[C:5]([CH3:10])[C:6]=1[C:7](O)=[O:8].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]([CH3:11])=[C:5]([CH3:10])[C:6]=1[C:7]([Cl:14])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(C)c(C(=O)O)c1C
Solvent: Cc1ccccc1
Product: Cc1oc(C)c(C(=O)Cl)c1C

Procedure:
2,4,5-Trimethyl-3-furancarbonyl chloride was prepared by refluxing 2,4,5-trimethyl-3-furancarboxylic acid (20.0 g) with thionyl chloride (20 ml) in toluene (75 ml) for 3 hours. The toluene and excess thionyl chloride were removed on a rotary evaporator and the residue distilled (b.p. 95°-97° C. at ca. 12 mm).