Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[CH:10]=[C:9]([CH:11]=C)[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])=[O:4].O.I([O-])(=O)(=O)=[O:35].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH3:32][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[C:9]([CH:11]=[O:35])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=O)c1cc(C=O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
To a mixed solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-4-vinylphenyl)amide (774 mg) in acetone (10 mL)-water (10 mL) were added osmium tetroxide (10% (w/w) microcapsule; 449 mg) and sodium metaperiodate (944 mg). The mixture was stirred at room temperature for 4 hours and filtered through a Celite pad. The filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2, v/v) to give the title compound (570 mg).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[S:30][C:29]([S:31]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[S:30][C:29]([S:31]([N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)(=[O:32])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN1CCN(S(=O)(=O)c2ccc(C#Cc3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)s2)CC1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 1-(5-bromo-thiophene-2-sulfonyl)-4-methyl-piperazine (example B.50) (163 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (200 mg, 69%). MS (EI) 581.1 [(M)+]; mp 226° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([CH:25]=[O:26])=[CH:24][C:16]=2[F:15])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: O=Cc1ccc(C(=O)O)c(F)c1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Nc2ccc(Cc3ccccc3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzylbenzenamine (0.100 g, 0.55 mmol), 2-fluoro-4-formylbenzoic acid (0.092 g, 0.55 mmol), N,N-diethylpropan-2-amine (0.10 ml, 0.65 mmol) in DMF (2.00ml) was added HBTU. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, washed with water and dried over MgSO4. The solvent was evaporated and the residue was purified by flash chromatography in a EtOAc/Hexene system to give the title compound. MS (ESI) m/z: Calculated; 333.3: Observed; 332.1. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.05-10.10 (1H, m), 8.31-8.44 (2H, m), 7.80-7.85 (1H, m), 7.67-7.73 (1H, m), 7.56-7.62 (2H, m), 7.15-7.40 (6H, m), 3.99 (2H, s)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:18][C:19]([OH:21])=[O:20])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.7 %

Procedure:
To a stirred solution of tert-butyl 3-methyl4-(N′-phenylureido)phenylacetate (1.12 g, 3.29 mmol) in CH2Cl2 (10 ml) was added TFA (10 ml) and the reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated to a small volume and poured into ice-H2O. The resulting precipitate was collected under a reduced pressure and the crude solid was recrystallized from MeOH—CHCl3 to give 3-methyl4-(N′-phenylureido)phenylacetic acid (680 mg, 73%) as white needles. 1H-NMR (DMSO-d6) δ 2.22 (s, 3 H), 3.46 (s, 2 H), 6.93–7.05 (m, 3 H), 7.25–7.29 (m, 2 H), 7.43–7.46 (m, 2 H), 7.72–7.74 (m, 1 H), 7.90 (s, 1 H), 8.98 (s, 1 H), 12.26 (br s, 1 H); Anal. Calcd for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.47; H, 5.68; N, 9.73.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=CC=3)=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:14]=[CH:16][CH:27]=[CH:26][C:19]=3[O:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1ccccc1N1CCN(c2ccncc2)CC1
Temperature: 4 °C
Reaction time: 2 h

Procedure:
A stirred solution of the product of Example 1 (550 mg) in methanol (10 ml) was treated with a M sodium hydroxide solution (1.65 ml) and stirring continued for a further 2 hours. The mixture was diluted with water (10 ml) and the resulting solution concentrated in vacuo. Water (20 ml) was added and then a M hydrochloric acid solution (1.65 ml). On cooling to 4° C., a solid precipitated. This mixture was concentrated in vacuo, the solid collected and washed with ice-water, then dried to give the title compound, 320 mg, as a solid: m.p. 294°-296° C.; NMR (d6DMSO+TFA) δ 8.34(2H,d), 7.95(2H,d), 7.26(2H,d), 7.10(2H,d), 5.06(2H,s), 4.82(2H,s), 4.06(4H,bs), 3.52(4H,bs); m/e 356(M+H)+ ; calculated for C19H21N3O4 : C, 64.2; H, 6.0; N, 11.8. found: C, 64.1; H, 6.1; N, 11.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC(=O)NN=3)C=2)C=CN=1>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccc(Cl)cc2)ccn1
Agent: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2)ccn1
Product: Nc1cc(-c2cn(C3=NNC(=O)CC3)nc2-c2ccc(Cl)cc2)ccn1
Yield: 48.9 %

Procedure:
The reaction was carried out in the same manner as in Example 49 except for using 300 mg (0.82 mmol) of 4-(2-aminopyridin-4-yl)-3-(4-chlorophenyl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 23-4) in place of 4-(2-aminopyridin-4-yl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-3-phenyl-1H-pyrazole to obtain 147 mg of the title compound as a white powder. (Yield: 49%).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:13](=[O:35])[NH:14][C:15]3[C:20]([C:21]=2[C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[O:29]C)=[CH:19][C:18]([C:31]([F:34])([F:33])[F:32])=[CH:17][CH:16]=3)=[CH:7][CH:6]=1)C.Cl.N1C=CC=CC=1>>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]([OH:29])=[C:22]([C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:31]([F:32])([F:33])[F:34])[CH:19]=3)[NH:14][C:13](=[O:35])[C:12]=2[S:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:36])=[O:3])=[CH:6][CH:7]=2)[CH:27]=1
Reactant: CCOC(=O)c1ccc(Sc2c(-c3cc(Cl)ccc3OC)c3cc(C(F)(F)F)ccc3[nH]c2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1ccc(Sc2c(-c3cc(Cl)ccc3O)c3cc(C(F)(F)F)ccc3[nH]c2=O)cc1
Temperature: 220 °C
Reaction time: 0.67 h
Yield: 83.7 %

Procedure:
A 25 mL round-bottomed flask equipped with a stir bar and a 19 cm glass sleeve was charged with 0.27 g (0.51 mmol) of 4-[4-(5-Chloro-2-methoxy-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-quinolin-3-ylsulfanyl]-benzoic acid ethyl ester and 2.7 g (23.3 mmol) of pyridine hydrochloride. The flask was flushed with nitrogen and a pipet emitting a stream of nitrogen was placed into the glass sleeve. The flask was placed in an oil bath pre-heated to 220° C. The TLC after 40 minutes showed the reaction was complete. The mixture was poured into 150 ml of 1 N HCl and then sonicated for 5 minutes to completely dissolve the pyridine hydrochloride. The white solid precipitate was filtered, washed with 1N HCl and dried to a constant weight to afford 0.21 g (84%) of the title compound. 1H NMR 300 MHz (DMSOd6) 6.98 (d, 1H, J=8.7 Hz), 7.25 (m, 4H), 7.35 (dd, 1H, J=6.1, 2.7 Hz), 7.59 (d, 1H, J=8.5, Hz), 7.75 (d, 2H, J=8.5 Hz), 7.91 (1H, dd, J=8.7, 1.8 Hz). IR cm−1 3206 (br), 1684, 1654, 1628, 1594, 1314. MS m/z 490 (M−H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@@H:19]1[C@@H:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:25]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:24]([CH2:43][CH2:44][OH:45])[O:23][C@H:20]1[O:21][CH3:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C(Cl)(Cl)Cl.O>[CH2:11]([O:18][C@@H:19]1[C@@H:26]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C@H:25]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C@@H:24]([CH2:43][CH:44]=[O:45])[O:23][C@H:20]1[O:21][CH3:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CO[C@@H]1O[C@H](CCO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CO[C@@H]1O[C@H](CC=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of oxalyl chloride (110 μl), 1.3 mmol) in dry dichloromethane (1.55 ml) was stirred under nitrogen atmosphere and cooled to -78° C. Dimethyl sulfoxide (0.178 ml, 2.5 mmol) in dichloromethane (0.67 ml) was added dropwise over 10 min. After stirring for 5 min methyl 2,3,4-tri-O-benzyl-6-deoxy-β-D-gluco-hepto-1,5-pyranoside (0.40 g, 0.8 mmol) dissolved in dichloromethane (0.67 ml) was added dropwise over 5 min. After stirring for another 15 min at -78° C., triethylamine (0.88 ml, 0.8 mmol) was added. The reaction mixture was allowed to warm to room temperature (30 min). Dichloromethane (1 ml) and water (4 ml) was added. The organic layer was extracted with water (4 ml) and brine (4 ml), dried (MgSO4), filtered and concentrated. The residue was co-concentrated with toluene (2×3 ml) to give a colorless syrup in 93% (0.37 g) yield, [α]D20 =+18.07° (c 1.4, CHCl3). 13C-NMR (CDCl3):δ200 (C-7), 97.8 (C-1), 81.6, 80.7 and 79.9 (C-2, C-3, C-4); 75.5, 74.8 and 73.2 (3×CH2OPh); 65.4 (C-5), 55.3 (OCH3); 45.6 (C-6).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]([C:8]([OH:10])=[O:9])[NH2:7].[CH2:14]=O>Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[CH2:14][NH:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5]2
Reactant: NC(Cc1cccc(F)c1)C(=O)O
Reactant: C=O
Agent: Cl
Product: O=C(O)C1Cc2cc(F)ccc2CN1
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 3-fluoro-DL-phenylalanine (100 g) in conc. HCl (1.0 L) was added aq. formaldehyde solution (37% wt.; 400 mL). The reaction mixture was heated to 90° C. and stirred for 3.5 h, then cooled to RT and stirred overnight and filtered. The filtrate was concentrated and the residue was combined with the precipitate to give 6-fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, which was used without further purification. LRMS (M+H+) m/z 196.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][C:23](O)=[O:24].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:23](=[O:24])[CH2:22][C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[Cl:14])[CH:5]=1
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC)c(NC(=O)Cc2ccc(Cl)cc2Cl)c1

Procedure:
To a solution of 1.1 g 3-Amino-4-methoxy-benzoic acid methyl ester and 1 g (2,4-Dichloro-phenyl)-acetic acid in 15 ml CH2Cl2, 2.7 ml NEt3 and 1.24 g BOP-Cl and 10 mg DMAP were added. After stirring over night the solvent was removed under reduced pressure and the residue directly purified by chromatography on silica with ethyl acetate/heptane 1:5->1:1 to yield the ester as a yellow oil.
Reaction SMILES: [CH3:1][O:2][P:3]([O:6]C)[O:4][CH3:5].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>>[CH3:1][O:2][P:3]([CH2:13][C:12]1[CH:15]=[CH:16][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:6])[O:4][CH3:5]
Reactant: Clc1ccc(CBr)cc1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc(Cl)cc1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
To a stirred solution of trimethylphosphite (0.57 ml, 4.9 mmol) was added 4-chlorobenzylbromide (1.0 g, 4.9 mmol) at rt. The resulting mixture was stirred at rt for 5 min. and then heated in an oil bath at 80° C. for 20 min. It was cooled to rt and the product purified on a silica-gel column with 25% EtOAc in hexane to give 1.05 g of (4-chloro-benzyl)-phosphonic acid dimethyl ester (93%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[N:29]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[S:31][CH:32]=4)=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[N:29]=[C:30]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[S:31][CH:32]=4)=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
After a mixture of ethyl 3-[3-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1110 mg), 1N sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (630 mg, yield: 60%). This was recrystallized from acetone-hexane. Melting point: 132–133° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:14](=[O:15])[NH:13][C:12]([CH:16]([F:18])[F:17])=[N:11]2)=[C:4]([F:19])[CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:14](=[O:15])[N:13]([CH3:20])[C:12]([CH:16]([F:17])[F:18])=[N:11]2)=[C:4]([F:19])[CH:3]=1
Reactant: COc1cc(-n2nc(C(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(-n2nc(C(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A stirred mixture of 2.0 g (0.0067 mole) of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-3-difluoromethyl-4,5-dihydro-1,2,4-triazol-5(1H)-one and 2.1 g (0.015 mole) of potassium carbonate in 50 mL of acetone was heated at reflux for 30 minutes forming a thick slurry. Iodomethane (4.3 g, 0.03 mole) was added in one portion to the refluxing reaction mixture. After complete addition the mixture was stirred at reflux for 45 minutes. The mixture was cooled to room temperature and the solvent evaporated under reduced pressure leaving a solid residue. This residue was partitioned between water and methylene chloride. The two phase mixture was filtered through a celite pad. The organic phase was removed and was washed in succession with four portions of an aqueous 10% sodium hydroxide solution, and one portion each of an aqueous 10% hydrochloric acid solution, a saturated aqueous sodium carbonate solution, and water. After washing, the organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.6 g of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-3-difluoromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one. A portion of this material was recrystallized from ethanol and water to provide the product as a light tan solid (mp 127°-129° C.), Compound 22.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[C:4]([CH:38]=[CH:39][CH:40]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:37])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][C:28]3C=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:23][CH:24]=2)[C:19]([C:34](=[O:36])[CH3:35])=[CH:18]1)=[O:8].ClC1C(F)=C(C=CC=1)C[NH:47]C([C@@H]1C[C@@H](F)CN1C(=O)CN1C2C(=CC(O)=CC=2)C(C(=O)C)=C1)=O.C(=O)([O-])[O-].[Cs+].[Cs+].ClCC1N=CC=CN=1>CS(C)=O>[Cl:1][C:2]1[C:3]([F:41])=[C:4]([CH:38]=[CH:39][CH:40]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:37])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][C:28]3[N:47]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:23][CH:24]=2)[C:19]([C:34](=[O:36])[CH3:35])=[CH:18]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(OCc3ccccn3)cc12
Reactant: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(O)cc12
Agent: ClCc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(OCc3ncccn3)cc12

Procedure:
The title compound was prepared according to procedure described for the preparation of Example 589 (2S,4R)-1-{2-[3-acetyl-5-(pyridin-2-ylmethoxy)-indol-1-yl]-acetyl}-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide from (2S,4R)-1-[2-(3-acetyl-5-hydroxy-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide Example 579 (23.0 mg, 0.047 mmol), cesium carbonate (61 mg, 0.188 mmol) and 2-(chloromethyl)pyrimidine (0.012 mg, 0.070 mmol) in DMSO (2 mL). White solid. MS (LC/MS): 582/583 [M+H]+; tR (HPLC conditions k): 3.19 min.
Reaction SMILES: NC(N)=S.[CH3:5][N:6]([CH3:19])[S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:18])(=[O:9])=[O:8].[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[S:30]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:29]([NH:28][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=2[F:20])=[S:30])=[C:11]([OH:18])[C:10]=1[S:7]([N:6]([CH3:19])[CH3:5])(=[O:9])=[O:8]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: Fc1cccc(N=C=S)c1F
Agent: NC(N)=S
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(F)c2F)c1O
Yield: 55.3 %

Procedure:
Following the general procedure for thiourea formation outlined in example 12, N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (500 mg, 2 mmol) and 2,3-difluorophenylisothiocyanate (342 mg, 2 mmol) were coupled to form the desired thiourea (467 mg, 54%). EI-MS m/z 422.2 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:26]1[O:27][C:28]2[C:29]([N:35]=1)=[N:30][CH:31]=[C:32]([F:34])[CH:33]=2.Cl.N>ClCCl>[F:34][C:32]1[CH:33]=[C:28]2[O:27][C:26]([C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]4[CH:9]=[N:10][N:11]([CH:13]5[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]5)[CH:12]=4)[CH:4]=3)=[N:35][C:29]2=[N:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ncc(F)cc5o4)c3)cn2)CC1
Agent: Cl
Agent: N
Solvent: ClCCl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ncc(F)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A suspension of tert-butyl 4-[4-[6-amino-5-(6-fluorooxazolo[4,5-b]pyridin-2-yl)-3-pyridyl]pyrazol-1-yl]piperidine-1-carboxylate (190 mg) and hydrogen chloride (4M solution in dioxane) (4.95 ml) in dichloromethane (2 ml) was stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to afford a solid, which was taken up into 5% methanolic ammonia (7 N) in dichloromethane (20 ml) and stirred for 10 minutes. The suspension was filtered, concentrated and the resulting solid was stirred in acetonitrile (2 ml) for 2 hours at room temperature. It was collected by filtration and dried to a constant weight to afford 3-(6-fluorooxazolo[4,5-b]pyridin-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (110 mg). NMR Spectrum: (CDCl3) 1.88-2.03 (m, 2H), 2.18-2.27 (m, 2H), 2.76-2.84 (m, 2H), 3.23-3.33 (m, 2H), 4.23-4.33 (m, 1H), 6.86 (bs, 2H), 7.67 (dd, 1H), 7.70 (s, 1H), 7.78 (s, 1H), 8.36 (d, 1H), 8.44 (d, 1H), 8.48 (dd, 1H); Mass spectrum: M+H+ 380.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[Br:19]Br.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:19][CH:9]([C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:18])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCCCC(=O)c1ccc(F)cc1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCCC(Br)C(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Ethyl 6-(4-fluorophenyl)-6-oxohexanoate (14.0 g) was dissolved in methylene chloride (100 ml), and bromine (8.87 g) was added dropwise with stirring at room temperature. After an hour of stirring at room temperature, a 10% aqueous solution of sodium sulfite was carefully added until disappearance of the red color of bromine, and the mixture was then extracted with diethyl ether (100 ml×2). The organic layer was washed with a 10% aqueous solution of sodium hydrogen carbonate (100 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 5-bromo-6-(4-fluorophenyl)-6-oxohexanoate as an oil (17.6 g, quantitative).