Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:22]([C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[C:6]([C:5]1[CH:10]=[CH:11][C:2]([O:1][CH:22]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:3]([CH2:12][CH2:13][CH3:14])[CH:4]=1)([O:8][CH3:9])=[O:7]
Reactant: CCCc1cc(C(=O)OC)ccc1O
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 2 L three necked 24/40 round bottom flask equipped with a mechanical stirrer, a nitrogen inlet and a dropping funnel was first added a solution of 36.0 g (0.185 mol) of methyl 4-hydroxy-3-n-propylbenzoate dissolved in 700 mL of anhydrous DMF followed by 66.4 g (0.204 mol) of cesium carbonate. The flask was purged with nitrogen and the reaction mixture was stirred at room temperature for 2 hours. A solution of 58.5 g (0.204 mol) of ethyl α-bromo-3,4-methylenedioxyphenylacetate dissolved in 100 mL of DMF was then added via an addition funnel over a 15 minute period. The reaction mixture was stirred an additional 1 hour at room temperature then quenched by addition to 5 L of a 5% aqueous citric acid solution. The organic product was extracted into diethylether (2×4 L), the organic layers were separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated. The residue was applied to a silica gel (2 kg; 70-230 mesh) column equillibrated in 10% CH2Cl2 -hexane. The column was then eluted successively with 12 L of 10% CH2Cl2 -hexane, 12 L of 5% EtOAc-hexane, 4 L of 7.5% EtOAc-hexane, 12 L of 10% EtOAc-hexane, and finally 8 L of 20% EtOAc-hexane. Combination of the purified fractions and evaporation in vacuo afforded 76.3 g (74.2 theoretical) of the title compound as a pale yellow oil which was used without further purification in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]2=[O:17])=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:25](=[O:34])[N:26]([CH3:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)C=1>>[CH3:16][C:11]1([CH3:15])[CH2:10][C:9](=[O:17])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:25](=[O:34])[N:26]([CH3:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:7][CH:6]=2)[C:13](=[O:14])[CH2:12]1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: CC1(C)CC(=O)N(c2ccc(O)cc2)C(=O)C1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(N2C(=O)CC(C)(C)CC2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 1-(4-hydroxyphenyl)-4,4-dimethylpiperidine-2,6-dione (233 mg, 1.00 mmol)) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol) by applying general procedure 3 (192 mg, 52%, white solid). HPLC-MS m/z=367 (M+1); Rt=3.78 min.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2](OC)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=1.C[O-].[Na+].[Na].C([O-])(=[O:27])CCC>CO>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:27])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[CH:12][CH:11]=1
Reactant: CCCC(=O)[O-]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl oxalate (15.27 g, 0,129 mol), and 4'-chloroacetophenone (20.0 g, 0.129 mol) were added to methanol (300 mL). Sodium methoxide (25 wt. % in methanol, 70 mL) was added dropwise over about 0.5 hour. The reaction was stirred at room temperature for 16 hours, whereupon the sodium salt of the butanoate precipitated from solution. The mixture was treated with 70 mL of conc. HCl and the white suspension was stirred vigorously at room temperature for 1 hour. The suspension was cooled to 0° C. and held for 0.5 hour. The solid was filtered, and the filter cake was washed with cold water (100 mL). After drying in vacuo, methyl 4-[4-(chloro)phenyl]-3-ketobutyrate was obtained (16.94 g, 54.4%) as the enol: 1H NMR (CDCl3 /300 MHz) 8 7.94 (d, J=8.66 Hz, 2H), 7.48 (d, J=8.66 Hz, 2H), 7.04 (s, 1H), 3.95 (s, 3H), 3.48 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=2)[C:13](O)=[O:14])=[CH:4][C:3]=1[O:19][CH3:20].C(N(CC)CC)C.ClC(OCC)=O>C1COCC1>[Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]([C:10]2[CH:11]=[C:12]([CH2:13][OH:14])[CH:16]=[CH:17][N:18]=2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(-c2cc(C(=O)O)ccn2)cc(OC)c1Cl
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(-c2cc(CO)ccn2)cc(OC)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 2-(4-chloro-3,5-dimethoxyphenyl)isonicotinic acid (7.20 g) and triethylamine (5.6 mL) in THF (70 mL) was added ethyl chloroformate (2.8 mL). The mixture was stirred at room temperature for 1 hour and filtered. To the filtrate was then added a solution of sodium borohydride (1.25 g) in water (4 mL). The mixture was stirred at room temperature for another hour and evaporated. Water was added to the residue and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to silica gel column chromatography using chloroform-methanol (20:1) and then chloroform-methanol (15:1) to give the title compound.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>ClCCl>[OH:21][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: O=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(c1ccccc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (3.8 mg, 0.025 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (1.82 mg, 0.005 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[CH:6]=[CH:7][C:8]=1[C:9]1[S:13][CH:12]=[N:11][CH:10]=1.[CH2:15]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24](Cl)[N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:14][C:5]2[CH:6]=[CH:7][C:8]([C:9]3[S:13][CH:12]=[N:11][CH:10]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-c1cncs1
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-c1cncs1

Procedure:
The title compound was prepared from 3-methoxy-4-thiazol-5-yl-phenylamine (118 mg, 0.57 mmol) and 4-benzyl-2-chloro-6-methyl-pyrimidine (125 mg, 0.57 mmol) in analogous manner to the procedure described in example 1e). Obtained as a colorless wax (70 mg, 32%).
Reaction SMILES: [Na+].[F:2][C:3]([F:22])([F:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([O-:18])=O)=[CH:14][N:13]=2)=[CH:7][CH:6]=1.CN1CCOCC1.[Cl:30]C1N=C(OC)N=C(OC)N=1.[NH:41]1[CH2:45][CH2:44][CH2:43][C@H:42]1[CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1>ClCCl>[ClH:30].[ClH:30].[N:47]1([CH2:46][C@@H:42]2[CH2:43][CH2:44][CH2:45][N:41]2[C:16]([C:15]2[CH:14]=[N:13][C:12]([S:11][C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]([F:2])([F:22])[F:21])=[CH:10][CH:9]=3)=[CH:20][CH:19]=2)=[O:18])[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: O=C([O-])c1ccc(Sc2ccc(OC(F)(F)F)cc2)nc1
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cl
Product: O=C(c1ccc(Sc2ccc(OC(F)(F)F)cc2)nc1)N1CCC[C@H]1CN1CCCC1
Reaction time: 0.75 h

Procedure:
To a stirring solution of 6-(4-trifluoromethoxy-phenylsulfanyl)-nicotinic acid sodium salt (54 mg, 0.158 mmol) (see Intermediate 8) and n-methyl morpholine (0.02 mL, 0.158 mmol) in dichloromethane (2.0 mL) in a 0° C. ice bath, add 2-chloro-4,6-dimethoxy-1,3,5-triazine (28 mg, 0.158 mmol). Remove the ice bath and stir for 45 minutes. After this time, add (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (24 mg, 0.158 mmol) and stir at room temperature for 2 hours. After this time, wash the reaction with saturated aqueous sodium bicarbonate while extracting with 10% isopropanol/dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Purify via chromatography eluting with 2M ammonia in methanol and dichloromethane. Dissolve the purified free base in minimal dichloromethane and add 1M HCl in ether in slight excess followed by hexane. Concentrate in vacuo to give the titled compound. MS (m/e): 452.2 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](OC2C=CC=CC=2)=[O:12])[N:7]([C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[CH:48]=[CH:47][C:35]([O:36][C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]([NH:45][CH3:46])=[O:44])[CH:38]=2)=[CH:34][C:33]=1[F:49].C(N(CC)CC)C>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:12])[NH:31][C:32]2[CH:48]=[CH:47][C:35]([O:36][C:37]3[CH:42]=[CH:41][N:40]=[C:39]([C:43](=[O:44])[NH:45][CH3:46])[CH:38]=3)=[CH:34][C:33]=2[F:49])[N:7]([C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C(=O)NC)c3)cc2F)c1
Yield: 57.6 %

Procedure:
A solution of ethyl 3-{3-tert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazol-1-yl}benzoate (9.36 g, 22.0 mmol), 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide (5.0 g, 19.1 mmol; prepared as described in Dumas et al., PCT Int. Appl. WO 2004078748 (2004)) and triethyl amine (3.87 g, 38.3 mmol) in anhydrous THF (100 mL) was stirred at room temperature overnight. The crude product was purified by column chromatography (CH2Cl2 plus 1% to 3% of 2M NH3 in MeOH), followed by recrystallization from EtOAc/hexanes to give the desired product as an off-white crystalline solid (6.32 g, 57%). MS m/z 575.1 (M+H)+; calcd. mass 574. Retention time (LC-MS): 3.75 min. 1H-NMR (DMSO-d6): δ 8.97 (m, 1H); 8.89 (m, 1H); 8.80 (m, 1H); 8.52 (d, J=5.6 Hz, 1H); 8.16 (t, 1H); 8.06 (m, 1H); 7.99 (m, 1H); 7.85 (m, 1H); 7.71 (t, 1H); 7.39 (m, 1H); 7.33 (m, 1H); 7.17 (m, 1H); 7.06 (m, 1H); 6.42 (s, 1H); 4.36 (q, 2H); 2.78 (d, J=5.2 Hz, 3H); 1.31 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][NH2:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C#N)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc(CN)ccc1Cl
Reaction time: 0.5 h

Procedure:
To a mixture of 5-chloro-6-methylpicolinonitrile (3) (200 mg, 1.31 mmol) in MeOH (10 mL) was added NaBH4 (150 mg, 3.94 mmol), CoCl2 (5 mg) at room temperature. After 30 min, the mixture was filtered and purified by reverse phase chromatography (X bridge Prep C18OBD, 40-60% MeOH in water with 10 mmol NH4HCO3 modifier) to afford the compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][O:12][CH2:13][CH:14]=2)=[CH:5][C:4]=1[N+:15]([O-])=O>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH2:15]
Reactant: COc1ccc(C2=CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
To a stirred solution of 3.30 g (14.0 mmol) 4-(4-methoxy-3-nitro-phenyl)-3,6-dihydro-2H-pyran in 70 ml methanol and 70 ml dichloromethane was added a spatula end of 10% palladium on charcoal and the mixture was then stirred for 20 minutes at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo to afford 2.75 g (95%) 2-methoxy-5-(tetrahydro-pyran-4-yl)-phenylamine as an off-white crystalline solid. ES-MS m/e (%): 208 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])C=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Cl:23])C(=O)C1.[C:24]([Cl:28])(Cl)(Cl)Cl>>[NH2:1][C:2]1[C:11]([Cl:23])=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:24]([Cl:28])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Cl
Product: COC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1N
Temperature: 80 °C
Yield: 97 %

Procedure:
To a solution of dimethyl 2-aminoterephthalate (500 g, 2.39 mol) in CCl4 (4 L) at 60° C. was slowly added NCS (957 g, 7.17 mol). The reaction mixture was heated at 80° C. for 16 hours, cooled to room temperature and filtered. The solid was washed with dichloromethane (2×500 mL) and the combined organic solution was washed with 1 N NaOH (2×3 L), water (3 L) and brine (1 L). The mixture was dried over Na2SO4, and concentrated under reduced pressure to afford dimethyl 2-amino-3,5-dichloroterephthalate (645 g, yield: 97%) as a red oil. 1H NMR (400 MHz, DMSO-d6) δ 3.81 (s, 3H), 3.87 (s, 3H), 7.04 (s, 2H), 7.77 (s, 1H). LCMS (ESI) m/z: 210.0 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:12][CH2:11]2)[C:3]1=[O:13].[N+:14]([O-])([OH:16])=[O:15].O>C(O)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[CH:8][CH:9]=2)[C:4]2([CH2:12][CH2:11]2)[C:3]1=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CN1C(=O)C2(CC2)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)C2(CC2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1′-methyl-spiro[cyclopropane-1,3′-indoline]-2′-one (8 g) in acetic acid (150 ml) is added nitric acid (fuming, 5.5 ml) over a period of 15 min at 15° C. The mixture is stirred at RT for 3 h and then poured into water. The precipitate is collected by filtration and washed with water, 2-propanol and tertbutyl-methyl-ether to give the title compound (8.80 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]#[C:10][NH2:11].Cl.[N+:13]([O-:16])([O-:15])=[O:14].[NH4+]>C(O)C>[N+:13]([O-:16])([OH:15])=[O:14].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]([NH2:11])=[NH:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=[N+]([O-])[O-]
Reactant: N#CN
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: N=C(N)Nc1cccc(Cl)c1
Product: O=[N+]([O-])O
Reaction time: 20 h

Procedure:
4.12 ml (39.12 mmol) of 3-chloro-aniline are placed in 25 ml of ethanol, and 3.3 g (78.4 mmol) of cyanamide are added. 5.3 ml (62.7 mmol) of concentrated hydrochloric acid are added dropwise to the brown solution. The reaction solution is then stirred for 20 hours at 78°. After concentration under reduced pressure, the residue is dissolved in 25 ml of water, and 6.3 g (78.4 mmol) of ammonium nitrate are added. The precipitated substance is isolated by filtration, washed with water and dried at 60° under HV. 3-chloro-phenyl-guanidine nitrate is obtained; 1H-NMR (dimethyl sulfoxide): 7.2-7.8 (7H,m), 9.9 (1H,br,s).
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].Br[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24]>>[NH2:1][C:2]1[C:3]([C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: COc1ccc(F)cc1Br
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Product: COc1ccc(F)cc1C(=O)c1ccc(Cl)nc1N

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 2-bromo-4-fluoroanisole (Aldrich) using the procedure described in Example 7. HRMS, observed: 280.0417, Calcd for M+: 280.0415.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:24]([C:26]([O:28]CC)=[O:27])[S:25][C:17]3=4)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[OH-].[Na+].CCO>O>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[C:24]([C:26]([OH:28])=[O:27])[S:25][C:17]3=4)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(OCCN3CCOCC3)cc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1sc2c(ccc(=O)n2-c2ccc(OCCN3CCOCC3)cc2)c1-c1ccccc1
Yield: 44.2 %

Procedure:
A mixture of the compound of Example 92 (230 mg, 0.46 mmol), sodium hydroxide (91 mg, 2.28 mmol) and EtOH (5 mL) was heated at reflux for 18 h. EtOH was removed in vacuo and the residue treated with 2M HCl(aq) (2 mL) to give a white solid. The reaction was diluted with water and then freeze dried. The resultant solid was extracted with isopropanol and the extracts concentrated in vacuo to give the title compound as a white solid (97 mg). δH (DMSO-d6) 7.62–7.37 (8H, m), 7.21–7.16 (2H, m), 6.50 (1H, J 9.6 Hz), 4.20 (2H, t, J 5.7 Hz), 3.62–3.59 (4H, m), 2.76 (2H, t, J 5.7 Hz), 2.54–2.51 (4H, m). LCMS (ES+) RT 2.35 minutes, 477 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.CN.[CH3:35][N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:36][CH3:35])=[O:5]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 81.5 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 35 mg, 0.081 mmol), methanamine-HCl (8.24 mg, 0.122 mmol), HATU (40.2 mg, 0.106 mmol), and 4-methylmorpholine (32.9 mg, 0.325 mmol) were added to DMF (1 mL). The reaction mixture was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention 13.0 min) to provide (R/S)-2-hydroxy-N-methyl-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (30 mg, 0.066 mmol, 82% yield): LCMS=444.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.07-8.15 (2 H, m), 7.51-7.71(7 H, m), 5.11(1 H, s), 3.35(1 H, s), 2.79 (3 H, s); HPLC peak RT=7.4 min (Method A).
Reaction SMILES: [CH3:1]C(N(C)C)=O.[NH2:7][C:8]1[C:9]([OH:27])=[C:10]([N:16]2[C:21](=[O:22])[N:20]([CH3:23])[C:19](=[S:24])[N:18]([CH3:25])[C:17]2=[O:26])[C:11]([F:15])=[CH:12][C:13]=1[Cl:14]>CO>[Cl:14][C:13]1[C:8]2[N:7]=[CH:1][O:27][C:9]=2[C:10]([N:16]2[C:21](=[O:22])[N:20]([CH3:23])[C:19](=[S:24])[N:18]([CH3:25])[C:17]2=[O:26])=[C:11]([F:15])[CH:12]=1
Reactant: Cn1c(=S)n(C)c(=O)n(-c2c(F)cc(Cl)c(N)c2O)c1=O
Reactant: CC(=O)N(C)C
Solvent: CO
Product: Cn1c(=S)n(C)c(=O)n(-c2c(F)cc(Cl)c3ncoc23)c1=O

Procedure:
5.0 g (48.1 mmol) of trimethylformamide were added dropwise to a solution of 502 mg (1.50 mmol) of 3-(3-amino-4-chloro-6-fluoro-2-hydroxyphenyl)-1,5-dimethyl-6-thioxo-[1,3,5]-triazinane-2,4-dione in 10 ml of methanol. The mixture was then heated at reflux temperature for 9 hours. The reaction mixture was subsequently concentrated under reduced pressure. The resulting crude product was purified by means of column chromatography (mobile phase: cyclohexane/ethyl acetate=20:1). Yield: 240 mg (46%); m.p.: 209-211° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[C:41]=3[Cl:50])[CH2:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CCOCC>[ClH:50].[Cl:50][C:41]1[C:42]([C:46]([F:47])([F:48])[F:49])=[CH:43][CH:44]=[CH:45][C:40]=1[CH2:39][N:24]([CH2:25][CH:26]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][CH2:22][CH2:21][O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(N3CCNCC3)n2)CC(c2ccccc2)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirring solution of [4-{6-(3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.05 mmol) in methanol (0.8 ml) was added 1 N HCl in Et2O. The reaction mixture was stirred at RT for 4 h and concentrated under vacuum to provide the title compound as an off-white solid, 31 mg (91%). MS (ESI) 609.2 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[CH2:16]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH3:17].C(OC1C=CC=CC=1NC1N=C(C(F)(F)F)C(C(OC)=O)=CN=1)C>>[CH2:16]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=2)=[CH:21][CH:20]=1)[CH3:17]
Reactant: CCOc1ccc(N)cc1
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: CCOc1ccccc1Nc1ncc(C(=O)OC)c(C(F)(F)F)n1
Product: CCOc1ccc(Nc2ncc(C(=O)OC)c(C(F)(F)F)n2)cc1

Procedure:
In like manner to the preparation of N-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-L-phenylalanine Ethyl Ester, 2-chloro-5-methoxycarbonyl-4-trifluoromethylpyrimidine and 4-ethoxyaniline were reacted to prepare N2-(2-ethoxyphenyl)-5-methoxycarbonyl-4-trifluoromethyl-2-pyrimidineamine. 1H NMR (CDCl3): δ 8.98 (s, 1H), 7.47 (m, 3H), 6.91 (dd, 2H, J=2.1 and 6.9 Hz), 4.05 (q, 2H, 6.9 Hz), 1.42 (t, 3H, J=6.8 Hz); 19F NMR (CDCl3): −19105; LCMS: ret. time: 33.87 min; purity: 100%; MS (m/e): 342 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[C:27]([Cu])#[N:28].CN1C(=O)CCC1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]2=[C:10]([C:27]#[N:28])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)c(F)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccc(F)c(F)c1

Procedure:
2,3-Dibromo-1-(3,4-difluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (4.98 g) was brominated similar to the synthesis of Example 103(a) to give the crude tribromo product, which was subjected to a cyanation condition CuCN/NMP similar to that of Example 105(a) to give the C-7 CN title product. The title compound, ESI MS (m/z): 514 (M+H)+.