Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:30])=O.CC#N.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2cc(Oc3ccc(F)cc3)ccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3)ccc2c1O
Yield: 68 %

Procedure:
A mixture of 7-(4-Fluoro-phenoxy)-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (14.33 g, 38.6 mmol), POBr3 (44.7 g, 154.4 mmol) and anhydrous methyl cyanide (290 ml) was refluxed gently with stirring for 75 min before NaHCO3 (100.8 g, 1.2 mol) was added in small portions with stirring. Subsequently, water (200 ml) was added slowly with stirring and the mixture was stirred vigorously for 1 h at ambient temperature before it was concentrated in vacuo to ca. ½ of its volume. Then water (200 ml) was added and the mixture was extracted with EtOAc (1×400 ml, 1×200 ml). The combined organic phases were dried over MgSO4 and evaporated in vacuo to give a tan solid. The tan solid was dissolved in CH2Cl2 and purified by filtration through a plug of silica gel. In vacuo concentration of the resulting CH2Cl2 solution yielded the title compound (11.4 g); 1H NMR (CDCl3) δ=11.89 (s, 1H), 8.36 (d, 1H), 7.57 (d, 1H), 7.44 to 7.50 (m, 1H), 7.08 to 7.16 (m, 4H), 4.47 (t, 2H), 1.78 to 1.93 (m, 2H), 1.38 to 1.58 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:38]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:21]=2)[C:14]([C:17]([NH2:18])=[O:38])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (76 mg, 0.264 mmol), 3-(pyrimidin-2-yl)aniline (64 mg, 0.375 mmol), K2CO3 (90 mg, 0.652 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 3 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-(pyrimidin-2-yl)phenylamino)pyrazine-2-carbonitrile (58 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-(pyrimidin-2-yl)phenylamino)pyrazine-2-carbonitrile (58 mg, 0.131 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 90 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (43 mg). MS 441.2 (M+H); UV 201.1, 249.3, 301.5 nm; t 0.462 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:17])SC2C=CC(C)=CC=2)=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][N:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O)=[O:41]>S1C=CC=C1C([O-])=O.[Cu+]>[CH3:1][C:2]1[C:7]([C:8]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:40]=[O:41])=[O:17])=[CH:6][C:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:4][N:3]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: Cc1ccc(SC(=O)c2cc(-c3ccccc3)cnc2C)cc1
Agent: [Cu+]
Agent: O=C([O-])c1cccs1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Product: Cc1ncc(-c2ccccc2)cc1C(=O)c1ccccc1C=O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
S-(4-methylphenyl) 2-methyl-5-phenylpyridine-3-carbothioate (100 mg, 0.31 mmol), copper (1) thiophene-2-carboxylate (89.6 mg, 0.47 mmol), Pd2 dba3CHCl3 (26 mg, 0.025 mmol), tri-2-furylphosphine (17.3 mg, 0.074 mmol) and 2-formylphenylboronic acid (51.7 mg, 0.34 mmol) were combined in a dry flask. The flask was purged with argon and 3.0 mL of THF were added. Argon was bubbled through the solution for 5 minutes and the solution was stirred and heated to 50° C. After 18 hours, the reaction mixture was diluted with EtOAc, washed with 1N HCl, brine, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography (100-70% hexanes/EtOAc gradient) to afford the title compound. LRMS (APCI) calculated for C20H16NO2 [M+H]+, 302.1; found 302.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=[C:19]([F:20])[C:14]=3[O:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:21]([C:17]2[CH:18]=[C:19]([F:20])[C:14]3[O:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:10])=[O:9])[C:15]=3[CH:16]=2)=[O:22])=[CH:37][CH:36]=1)[CH3:35]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2c(F)cc(C(=O)O)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2cc(F)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CO3)cc1

Procedure:
Reaction of 3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydrobenzooxazole-5-carboxylic acid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave 4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester. White solid, MS (ISP)=535.2 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([CH3:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+].CO>>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C:7]([CH3:23])=[N:6][C:5]=1[C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(C)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCCC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 82.1 %

Procedure:
A mixture of 4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (120 mg, 0.39 mmol) and beta-alanine (242 mg, 2.72 mmol) in 0.5 M NaOMe/MeOH solution (4.5 mL, 2.25 mmol) was microwaved at 120° C. for 30 min. Reaction mixture was concentrated and dissolved in water (100 mL). It was acidified by 1 N HCl to pH=3-4. Gummy precipitate was collected by filtration and dissolved in EtOAc. It was dried over MgSO4, filtered and concentrated to provide the title compound 116 mg (0.32 mmol) in 81% yield. LC-MS ESI−: 365.16 (M−1)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1F>CO.CS(C)=O.O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][C:25]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: Fc1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cccc(Oc2cc(C(F)(F)F)ccc2Cl)c1
Yield: 56.9 %

Procedure:
3-Hydroxybenzoic acid (3.45 g) was added to a solution of potassium hydroxide (2.8 g) in methanol. The solution was evaporated under reduced pressure to give a white solid. This was taken up in dry dimethylsulphoxide (25 ml). The resulting solution was stirred and heated at 170° with anhydrous potassium carbonate (1.25 g) and 4-chloro-3-fluorobenzotrifluoride (5 g) for 12 hours. The mixture was then cooled and poured into water, (500 ml). The mixture was extracted with ether and then acidified (HCl). The precipitate which formed was recrystallised from petroleum (b.p. 60°-80°) to give the required acid (4.5 g) with a melting point of 142°-143°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:18][C:12]3[C:13](=[O:17])[NH:14][N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH2:26][C:27]1[N:32]=[C:31]([O:33][CH2:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][CH2:37][N:36]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:30]=[CH:29][CH:28]=1)(=O)=O.O>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:18][C:12]3[C:13](=[O:17])[N:14]([CH2:26][C:27]4[N:32]=[C:31]([O:33][CH2:34][C@@H:35]5[CH2:40][CH2:39][CH2:38][CH2:37][N:36]5[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:30]=[CH:29][CH:28]=4)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1COc1cccc(COS(C)(=O)=O)n1
Reactant: COc1ccc(-c2cc3cn[nH]c(=O)c3s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2cc3cnn(Cc4cccc(OC[C@@H]5CCCCN5C(=O)OC(C)(C)C)n4)c(=O)c3s2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-methoxyphenyl)thieno[2,3-d]pyridazin-7(6H)-one (455 mg, 1.76 mmol) in DMF (5 ml), was added NaH 60% (110 mg, 2.52 mmol) in small portions. The mixture was stirred at rt. for 10 min before addition of tert-butyl (2S)-2-{[(6-{[(methylsulfonyl)oxy]methyl}pyridin-2-yl)oxy]methyl}piperidine-1-carboxylate (672 mg, 1.68 mmol) dissolved in DMF (3 ml). The reaction was stirred at rt. for 16 h, water (150 ml) and DCM (150 ml) added and the phases separated. The aqueous phase was extracted with DCM (150 ml). The combined organic phases were dried through a phase separator and evaporated in vacuo. Purification by silica gel flash chromatography using a 40+M Biotage column with a gradient of 30-100% EtOAc in heptane yielded the title compound as a light yellow solid. Yield: 354 mg (36%). 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.61 (m, 2H), 7.46 (t, 1H, J=7.8 Hz), 7.34 (s, 1H), 6.96 (m, 2H), 6.71 (d, 1H, J=7.3 Hz), 6.55 (d, 1H, J=8.2 Hz), 5.47 (s, 2H), 4.50 (m, 1H), 4.30 (m, 2H), 3.94 (d, 1H, J=10.7 Hz), 3.85 (s, 3H), 2.74 (t, 1H, J=12.2 Hz), 1.67-1.20 (m, 15H). MS (ESI+) 563.30 (M+1H+)
Reaction SMILES: [CH3:1][C:2]([C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])=[CH2:3].N1C=CC=CC=1.[C:16](Cl)(=[O:21])[O:17][CH:18]([Cl:20])[CH3:19]>CCOCC>[CH3:3][C:2]([C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])=[CH2:1].[C:16](=[O:21])([O-:5])[O:17][CH:18]([Cl:20])[CH3:19]
Reactant: CC(Cl)OC(=O)Cl
Agent: C=C(C)C(=O)OCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)[O-]
Reaction time: 0.5 h
Yield: 173.5 %

Procedure:
To 24 mL of HEMA (200 mmol) in 1000 mL of dry ether was added 16.8 mL (213 mmol) of pyridine at 4-10° C., under argon. To this solution was added 21.3 mL (200 mmol) of 1-chloroethyl chlorocarbonate, drop wise with stirring over 0.5 hour. After stirring for 0.5 hour at 4-10° C., the heavy precipitate was removed by filtration and the filtrate was concentrated to an oil in vacuo, yielding 44 g (100%) of HEMA-1-chloroethyl carbonate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[Cl:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:18])=[CH:14][C:13]=1[Cl:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(Nc1ccc(C(=O)O)cc1Cl)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc(NC(=O)OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
4-Benzyloxycarbonylamino-3-chlorobenzoic acid (0.80 g) was dissolved in N,N-dimethylformamide (24.0 ml) and admixed at room temperature with t-butyl glycinate (0.44 g) and triethylamine (0.77 ml). Diethyl cyanophosphate (0.43 ml) was added with ice-cooling, and the mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined and washed three times with water and then twice with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield t-butyl N-(4-benzyloxycarbonylamino-3-chlorobenzoyl)glycinate (0.93 g) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][NH:26][C:27]2=[O:32].B(Br)(Br)Br>>[OH:18][C:11]1([C:14]([F:17])([F:15])[F:16])[CH2:10][C:9]([CH3:19])([CH3:20])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:12]1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][NH:26][C:27]2=[O:32].[OH:18][C:11]1([C:14]([F:15])([F:16])[F:17])[CH2:10][C:9]([CH3:19])([CH3:20])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[CH:12]1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][NH:26][C:27]2=[O:32]
Reactant: Nc1cccc2c(=O)[nH]ncc12
Reactant: COc1ccccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c(=O)[nH]ncc23)c2cccc(O)c21
Product: COc1cccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ncc12

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 277 mg of 5-amino-phthalazin-1-one. As in Example 2, 32 mg of 5-{[2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one as fraction 1 and 35 mg of 5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one as fraction 3 are obtained by reaction of 470 mg of imine with 5.4 ml of BBr3 (1 M in dichloromethane).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:8]([NH:17][C:18]([C:20]2[N:21]([C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=3)[N:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=2)=[O:19])=[C:9]([Cl:16])[CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2)=[O:6])([CH3:3])[CH3:2].[OH-].[K+].CC([O-])(C)C.[K+].Cl[CH2:45][O:46][CH3:47]>C1COCC1.O.CCOC(C)=O>[CH:1]([NH:4][C:5]([C:7]1[C:8]([NH:17][C:18]([C:20]2[N:21]([C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=3)[N:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=2)=[O:19])=[C:9]([Cl:16])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:45][O:46][CH3:47])[N:13]=[CH:12]2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(Cl)cc2cn[nH]c12
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCn1ncc2cc(Cl)c(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(C(=O)NC(C)C)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-1H-indazole-7-carboxylic acid isopropylamide (1.00 g, 1.90 mmol), KOH (310 mgs, 5.70 mmol) and t-BuOK (6.4 mg, 0.02 mmol) in THF (5 mL) was treated dropwise with chloro-methoxy-methane (0.39 mL, 5.1 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h. AcOEt and water was added. The phases were separated. The aqueous layer was extracted with AcOEt. The organic layers were washed with water, combined, dried over MgSO4 and concentrated in vacuo. Purification of the residue by reverse phase HPLC affords the title product as a colorless solid. M.p. 180-182° C., LC/MS: 570/572 (M+H)+, 592/594 (M+Na)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:51].C(N(CC)CC)C.[NH:59]1[CH2:63][CH2:62][C@@H:61]([OH:64])[CH2:60]1>CN(C=O)C.O>[ClH:51].[OH:64][C@@H:61]1[CH2:62][CH2:63][N:59]([C:25]([C:24]2[CH:28]=[CH:29][C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)=[CH:22][CH:23]=2)=[O:26])[CH2:60]1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: O[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1)N1CC[C@@H](O)C1
Reaction time: 0.08 h
Yield: 8.7 %

Procedure:
To a solution of example 8 (0.150 g, 0.393 mmol) in DMF (1 ml), HOBT (0.063 g, 0.471 mmol), EDC-HCl (0.187 g, 0.983 mmol) and triethylamine (0.16 ml, 1.17 mmol) were added and stirred for 5 min, (R)-pyrrolidin-3-ol (0.030 g, 0.353 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the amide as a yellow solid (0.015 g). The amide was dissolved in THF (2 ml), ether saturated with HCl (2 ml) was added at 0° C. and stirred for 15 min. The precipitate formed was washed with ether and dried under vacuum to afford the title compound as a yellow solid (0.017 g, 10%), M.P.: 120-122° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.87 (d, J=2.9 Hz, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.38 (d, J=8.2 Hz, 1H), 8.30 (d, J=8.2 Hz, 2H), 8.17 (d, J=8.8 Hz, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.83 (d, J=8.7 Hz, 1H), 7.69 (m, 2H), 7.52 (dd, J=8.2, 4.1 Hz, 1H), 6.21 (s, 2H), 3.61 (m, 3H), 3.44 (m, 1H), 1.95-1.80 (m, 4H).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[N:12]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1)[CH3:13].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(N(CC)C=O)C.O>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[N:12]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1)[CH3:13]
Reactant: COC(=O)C(O)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reactant: BrCc1ccccc1
Agent: CCN(C=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.14 g) was added portionwise to a stirred solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-hydroxypropanoate (1.20 g) in dry N,N-diethyl formamide (20 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes prior to the addition of benzyl bromide (0.6 mL). Stirring was continued at room temperature for 3 hrs, then at 80° C. for 17 hrs before the mixture was cooled, diluted with water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined ethyl acetate layers were washed with water (4×500 mL) and brine (500 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 1% methanol in dichloromethane to afford the title compound, a gum, which was used in the next stage without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[N:4][N:3]=1.C[O-].[Na+].[Cl-:12].[NH4+:13]>>[ClH:12].[CH3:1][C:2]1[S:6][C:5]([C:7](=[NH:13])[NH2:8])=[N:4][N:3]=1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: Cc1nnc(C#N)s1
Agent: C[O-]
Agent: [Na+]
Product: Cc1nnc(C(=N)N)s1
Product: Cl
Yield: 70 %

Procedure:
5-methyl-1,3,4-thiadiazole-2-carbonitrile (1.25 g, 10 mmol) was reacted with sodium methoxide (0.54 g, 10 mmol) and ammonium chloride (0.64 g, 12 mmol) according to the procedure as described in Example 61, Step B to give the title compound as a yellowish solid (1.25 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: CC1C=CC(OC)=CC=1.C(O)(=O)C.O.[Na+].[Br-].[C:17](O)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>[Ti]>[CH:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)O)cc1
Agent: [Ti]
Agent: [Br-]
Agent: [Na+]
Solvent: COc1ccc(C)cc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C=O)cc1
Temperature: 121.11111111111111 °C
Reaction time: 0.5 h

Procedure:
Two hundred and thirty (230) g. (1.89 moles) p-methylanisole, 399 g. (6.65 moles) acetic acid, 21 g. (1.17 moles) water, 1.73 g. (0.007 moles) Co(OAc)2 0, 1.7 g. (0.007 moles) Mn(OAc)2.4H2 0 and 1.4 g. (0.014 moles) NaBr were combined in a two-liter titanium-clad autoclave. The reactor was heated to 250° F. and pressurized to 150 psi. The air rate was ramped up to reach a value of 0.78 scf/min after 15 minutes. During the oxidation the temperature and pressure were gradually increased to reach final values of 324° F. and 250 psi. The oxidation was complete after 30 minutes. Analysis of the reaction mixture showed p-anisic acid, 85 mole % yield, and p-anisaldehyde, 1.2 mole % yield.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Br:20][C:53]1[CH:54]=[CH:55][C:50]([NH:49][C:40](=[O:42])[C@@H:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=2)[CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[N:51][CH:52]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1Cl
Temperature: 0 °C
Yield: 74.9 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 97, 200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-aminopyridine (85 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (222 mg, 76%) as an off-white foam: [α]23589=−48.6° (c=0.105, chloroform); EI-HRMS m/e calcd for C20H22BrClN2O3S (M+) 484.0223, found 484.0223.