Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:22]3=[N:23][CH:24]=[CH:25][C:26](Cl)=[C:21]3[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:22]3=[N:23][CH:24]=[CH:25][C:26]([N:30]4[N:31]=[CH:32][CH:33]=[N:29]4)=[C:21]3[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]nn1
Reactant: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(Cl)ccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(-n3nccn3)ccnc12

Procedure:
Example 205 and 206. In a sealed tube -(4-benzoyl-piperazin-1-yl)-2-(7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione (30 mg, 0.076 mmol), 1H-1,2,3-triazole (160 mg, 2.3 mmol), Cu(0) (10 mg, 0.16 mmol) and K2CO3 (11 mg, 0.080 mmol) were heated at 160° C. for 16 h. The reaction mixture was diluted with MeOH, filtered through celite and concentrated. The reaction mixture was diluted with MeOH, filtered through celite and concentrated. The residue was purified by preparative HPLC to provide 1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-2-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione: 1H NMR (300 MHz, CD3OD) δ 8.79 (d, J=6.6 Hz, 1H), 8.79 (s, 1H), 8.48 (d, J=6.6 Hz, 1H), 8.40 (s, 2H), 7.48 (br s, 5H), 4.00-3.55 (m, 8H). MS m/z (M+H)+ calcd for C22H20N7O3: 430.15; found 430.29. HPLC retention time 0.91 min (Column G); and 1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-1-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione: 1H NMR (300 MHz, CD3OD) δ 8.97 (d, J=61.2 Hz, 1H), 8.70 (d, J=5.6 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.47 (br s, 5H), 4.00-3.45 (m, 8H). MS m/z (M+H)+ calcd for C22H20N7O3: 430.15; found 430.29. HPLC retention time 0.90 min (Column G).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:19]=[C:18]([N:20]3[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[N:21]3)[CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:36][C:37]([F:50])([F:49])[C:38]1[CH:43]=[CH:42][C:41]([CH:44]=[CH:45]B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:26][C:25]([F:28])([F:27])[C:24]1[N:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6][C:5]3[CH:34]=[CH:35][C:2](/[CH:45]=[CH:44]/[C:41]4[CH:40]=[CH:39][C:38]([C:37]([F:36])([F:49])[F:50])=[CH:43][CH:42]=4)=[CH:3][CH:4]=3)[N:19]=2)[N:21]=[CH:22][C:23]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: OB(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(Br)cc3)n2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(/C=C/c4ccc(C(F)(F)F)cc4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a vial containing the title compound from Example 2 Step A (50.0 mg, 0.092 mmol) were added 2-(4-trifluoromethylphenyl)vinyl boronic acid (29.6 mg, 0.137 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (6.4 mg, 0.009 mmol). Acetonitrile (0.400 mL) and sodium carbonate (0.229 mL, 1.0 M aqueous, 0.229 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction vial was capped and placed in a pre-heated oil bath (70° C.). After 18 h, the reaction mixture was allowed to cool to ambient temperature and was poured into water. The mixture was extracted with DCM, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 638.4 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=8.0 Hz, 1H), 8.13 (s, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.88 (t, J=7.5 Hz, 1H), 7.61 (br s, 4H), 7.54 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.41-7.39 (m, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.21-7.06 (m, 4H), 5.18 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=O)[N:2]=1.ON1C2C=CC=CC=2N=N1.[H-].CN(C)CCCN=C=NCC.[C:32]([C:34]1[CH:66]=[CH:65][CH:64]=[CH:63][C:35]=1[O:36][C:37]1[C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=2)=[CH:50][C:40]2[NH:41]C(C3C=CC=CN=3)=[N:43][C:39]=2[CH:38]=1)#[N:33]>C(OCC)(=O)C.CN1CCCC1=O>[C:32]([C:34]1[CH:66]=[CH:65][CH:64]=[CH:63][C:35]=1[O:36][C:37]1[C:51]([O:52][C:53]2[CH:54]=[CH:55][C:56]([S:59]([CH3:62])(=[O:60])=[O:61])=[CH:57][CH:58]=2)=[CH:50][C:40]2[NH:41][C:7]([C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:43][C:39]=2[CH:38]=1)#[N:33]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2C#N)cc1
Reactant: O=C(O)c1cccnn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cccnn4)nc3cc2Oc2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.3 mg of pyridazine-3-carboxylic acid, 15 mg of 1-hydroxybenzotriazole and 15 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydride were added in order to an N-methylpyrrolidone (0.3 ml) solution of 15 mg of 4-(2-cyano-phenoxy)-5-(4-methanesulfonyl-phenoxy)-benzene-1,2-diamine obtained in Example 17, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with ethyl acetate, and washed with saturated sodium bicarbonate solution, and the solvent was evaporated away under reduced pressure. The resulting residue was dissolved in 0.2 ml of N-methylpyrrolidone, and 5 mg of ytterbium trifluoromethanesulfonate was added to it, and the reaction liquid was stirred overnight at 140° C. The reaction mixture was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was evaporated away under reduced pressure to obtain the entitled compound as a brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:29][CH2:28][C@H:27]([F:30])[C@@H:26]3[C@H:22]2[CH2:23][NH:24][CH2:25]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:24]1[CH2:23][C@@H:22]2[C@@H:26]([C@@H:27]([F:30])[CH2:28][CH2:29][C:21]2([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:25]1)=[O:12]
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: F[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Agent: Cl
Product: CN(C)c1ccccc1CC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2F
Yield: 27 %

Procedure:
By carrying out the procedure as in Example 9 below, using 0.16 g of 2-dimethylaminophenylacetic acid and 0.30 g of (3aR, 7S, 7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride, 0.11 g of (3aR, 7S, 7aR)-2-[(2-dimethylaminophenyl)acetyl]4,4-diphenyl-7-fluoroperhydroisoindole is obtained in the form of a white meringue.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:20]>>[ClH:20].[F:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][N:11]=[C:10]([CH:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]3)[C:14]=2[CH:15]=1
Reactant: CC(=O)N1CCC(c2noc3ccc(F)cc23)CC1
Agent: Cl
Product: Fc1ccc2onc(C3CCNCC3)c2c1
Yield: 83 %

Procedure:
A mixture of 17.5 g of 3-(1-acetyl-4-piperidyl)-5-fluoro-1,2-benzisoxazole and 110 ml of 6 N hydrochloric acid was stirred under reflux for 6 hrs. After standing at ambient temperature for ca 12 hrs, a solid was collected, washed with acetone and dried to yield 14.2 g (83%) of product as the hydrochloride salt, mp 297°-299°.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C1(O)C=CC=CC=1.O>[CH3:17][C:18]1[CH:19]=[C:20]([N:21]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[CH2:12][CH2:13]2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Reactant: Cc1cccc(N)c1
Solvent: Oc1ccccc1
Solvent: O
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1cccc(C)c1
Temperature: 190 °C
Yield: 75.1 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 7 ml of phenol in a pressure tube and 3-methylaniline (268 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 190° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 230 mg of desired compound as solid in 76% of yield.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:28](Cl)([Cl:30])=[O:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:28]([Cl:30])=[O:29])=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cn2ncnc2[C@H]2CCCN2)cc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)N1CCC[C@@H]1c1ncnn1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 75.8 %

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-5-(pyrrolidin-2-yl)-1H-1,2,4-triazole (216 mg, 0.82 mmol) and DIEA (233 mg, 1.90 mmol) in 5 mL of dry DCM was cooled to −20° C. under Ar, and a solution of phosgene (0.89 mL of 20% solution in toluene, 0.89 mmol) was added. The reaction mixture was stirred at RT for 2.5 days and the solvent was evaporated in vacuo. The residue was purified by chromatography (silica gel, hexane:EtOAc (1:1)) to give 202 mg of the desired product.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([Mg]Br)[CH3:16]>>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([CH:11]([OH:12])[CH2:15][CH3:16])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Product: CCC(O)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 43b (313 mg, 1.71 mmol) and ethylmagnesium bromide (3.42 mL, 3.42 mmol, 1 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Light yellow solid. Yield: 298 mg, 82%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.90-0.95 (m, 3H) 1.71-1.88 (m, 2H) 4.62 (t, J=6.62 Hz, 1H) 7.38-7.43 (m, 1H) 7.43-7.49 (m, 2H) 7.64-7.67 (m, 1H) 7.69-7.73 (m, 1H) 7.92-7.96 (m, 2H) 8.54 (d, J=2.21 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=9.9, 31.7, 73.2, 120.3, 126.8, 128.7, 128.8, 134.5, 138.3, 139.0, 147.7, 156.5; MS (ESI): m/z=214.28 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:34][C:35]([C@@H:37]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:60]([S:62][CH2:63][CH3:64])[CH3:61].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([O:47][CH:60]([S:62][CH2:63][CH3:64])[CH3:61])[CH2:19][C@@H:20]([NH:34][C:35](=[O:36])[C@H:37]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:42][C:43]([O:44][CH3:45])=[O:46])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCSCC
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCSC(C)O[C@@H](C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C
Yield: 94.8 %

Procedure:
To a solution of the compound of Example 111 (0.200 g, 0.248 mmol) and ethyl sulfide (0.70 mL, 6.48 mmol) in acetonitrile (2.0 mL) at 0° C. was added benzoyl peroxide (0.38 g, 1.57 mmol) in three portions over 2 hours. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (0.210 g, 95% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>N1C=CC=CC=1.O>[S:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: OCCCCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Reaction time: 16 h

Procedure:
A solution of 3-chloro-1-propanol (1.88 g, 20 mmole) in 20 ml of pyridine was treated at 0° with tosyl chloride (7.6 g, 40 mmole). The solution was warmed to 23°, and stirred 16 hours. The reaction was diluted with 100 mL of H2O and stirred for 90 minutes, and extracted with Et2O. The extracts were washed with 1N HCl, dried, and the solvents thoroughly removed, and gave the titled product, 2.3 g (46%). MS (ESI) 188 (MH+).
Reaction SMILES: [C:1](O)(=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:1]([OH:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO
Temperature: 40 °C

Procedure:
Triacontanol is prepared from triacontanoic acid by suspending 0.1 mol of the acid in 40 ml of anhydrous chloroform followed by the addition of thionyl chloride while maintaining the temperature at 40° C. for 2 hours. Chloroform and excess thionyl chloride were removed in a rotary evaporator, and the resulting acid chloride was reacted with 10 ml of absolute ethanol to form the ester. Excess ethanol was removed in a similar manner, and the ester was dissolved in 100 ml of anhydrous ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=[C:10]([CH3:18])[CH:9]=2)=[C:4]([F:19])[CH:3]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[C:10]([CH3:18])[CH:9]=2)=[C:4]([F:19])[CH:3]=1
Reactant: COC(=O)c1cnc(C)cc1-c1ccc(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(-c2ccc(Cl)cc2F)c(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a solution of Methyl 4-(4-chloro-2-fluorophenyl)-6-methylnicotinate (700 mg, 2.50 mmol) in MeOH (5 mL) was added NaOH (200 mg, 7.51 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 2 h. Then it was evaporated under reduced pressure and the residue obtained was adjusted to pH ˜3 by adding 1.5N HCl solution. The product was extracted with dichloromethane. The organic phase was dried over Na2SO4, and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-6-methylnicotinic acid (500 mg, 1.730 mmol, 69% crude yield) as white solid. The material was carried forward without further purification. LC/MS (ESI) m/e 266.0 [(M+H)+, calcd for C13H10ClFNO2 266.0]; LC/MS retention time (Method I): tR=1.51 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8]C2C=CC3OC(=O)NC=3C=2)[C:5]([CH3:19])=[CH:4][N:3]=1.Cl.CS(C1C=C([NH2:31])C=CC=1)(=O)=O.C(O)(C(F)(F)F)=O>CC(O)C>[CH3:19][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:31])=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N)nc1N
Temperature: 87.5 °C
Reaction time: 40 h
Yield: 49 %

Procedure:
To a vial with 5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (138.3 mg, 0.5 mmol) and 3-(methylsulfonyl)benzenamine hydrochloride (207.7 mg, 1.0 mmol), i-PrOH (10 mL) was added, followed by TFA (116 μL, 1.5 mmol). The vial was tightly closed, and the reaction mixture was stirred at 85-90° C. for 40 h. The solvent was removed in vacuo, and the crude product was purified by RP-HPLC. N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-(3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine was obtained as a mono-trifluoroacetate salt: an off-white solid, 129 mg (49% yield); 1H NMR (300 MHz, DMSO) δ 11.60 (s, 1H), 9.43 (s, 1H), 8.43 (s, 1H), 8.20 (s, 1H), 8.11 (br d, J=7.5, 1H), 7.96 (d, J=0.8, 1H), 7.49-7.33 (m, 4H), 7.27 (d, J=8.5, 1H), 3.13 (s, 3H), 2.16 (s, 3H); LCMS (M+) m/z 412.47.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CCOC(C)=O>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:32][CH:33]([CH3:34])[CH3:35])[S:40]([CH3:39])(=[O:42])=[O:41])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC(C)CNc1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)CN(c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)S(C)(=O)=O
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(isobutylamino)-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (9.2 mg, 0.0165 mmol) in pyridine (300 μL) was added methanesulfonyl chloride (100 μL, 1.29 mmol) and excess 4-dimethylaminopyridine. The reaction was stirred at 65° C. for 4 hours and then diluted with EtOAc (15 mL), and washed with 1 N HCl (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (60% EtOAc/hexanes) N-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]-N-isobutylmethanesulfonamide. Rf=0.25 (60% EtOAc/hexanes). LCMS=637.4 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.80 (s, 2H), 7.34-2.46 (m, 3H), 5.79-5.76 (m, 1H), 4.90-4.58 (m, 2H), 4.19-4.14 (m, 1H), 3.51-3.46 (m, 1H), 3.34-3.32 (m, 1H), 2.97 (m, 3H), 1.25 (m, 1H), 0.93-0.87 (m, 6H), 0.70-0.66 (m, 3H).
Reaction SMILES: C(OC([N:8]([C:22]1[N:23]=[C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]2[C:31]=1[CH3:32])[S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])=O)(C)(C)C.Cl>O1CCOCC1>[CH3:32][C:31]1[N:25]2[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]2=[N:23][C:22]=1[NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3c(C)cccn3c2C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2nc3c(C)cccn3c2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To compound 2-C (0.693 g, 1.51 mmol) was added 4N HCl in dioxane (30 mL) and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure, the solid triturated with ether, filtered, and the solid washed with ether and dried in vacuo to afford compound 2-D as a white solid (0.601 g, 100%). MS: m/z 360.1 (MH+).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>C1(C)C=CC=CC=1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:34]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)NC2=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g) and triethylamine (0.4 ml), and 3-methoxybenzoyl chloride (0.7 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[C:23]([F:32])[CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1>>[CH3:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:6]([C:8]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:31])[N:28]([CH3:29])[CH3:30])=[C:23]([F:32])[CH:22]=3)[C:11]3[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:35][CH:36]=1
Reactant: Cc1ccc(N)nc1
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)OC(C)(C)C)cc3c2CC(C)(CO)O3)cc1F
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)c(F)c3)c3c(c2)OC(C)(CO)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (229a) and 2-amino-5-methyl-pyridine. 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1 H) 8.23 (d, J=8.59 Hz, 1 H) 8.09 (s, 1 H) 7.57 (dd, J=8.46, 1.89 Hz, 1 H) 7.38 (t, J=8.08 Hz, 1 H) 7.13 (s, 1 H) 7.10 (s, 1 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.71 (dd, J=10.61, 2.27 Hz, 1 H) 3.70-3.77 (m, 1 H) 3.57-3.66 (m, 1 H) 3.19 (d, J=16.67 Hz, 1 H) 3.13 (s, 3 H) 2.98 (d, J=1.52 Hz, 3 H) 2.81 (d, J=16.67 Hz, 1 H) 2.31 (s, 3 H) 1.46 (s, 3 H); LCMS for C26H26FN3O5 m/z 480.00 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1C=O.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(O)(=O)C>CO>[CH:13]1([NH:16][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: Cn1c(C=O)cc2ccccc21
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(NC2CC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 1-methylindole-2-carboxaldehyde (1.5 g, 10 mmole), cyclopropylamine (1.14 g, 20 mmole), and glacial acetic acid (0.6 mL, 10 mmole) in MeOH (30 mL) was added NaB3CN (0.69 g, 11 mmole). The reaction was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 10% NaOH and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (1.3 g, 65%) as a semi-solid: MS (ES) m/e 201 (M+H)+.