Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][CH:4]=1)=[O:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Yield: 39.8 %

Procedure:
4Hydroxybenzaldehyde (24.4 g, Aldrich) was dissolved in absolute ethanol (470 ml) and anhy. K2CO3 (27.6 g) and ethyl 2-bromoisobutyrate (39.0 g, Aldrich) added. The resulting mixture was refluxed overnight, allowed to cool and the solvent removed in vacuo. The residue was suspended in water (300 ml) and extracted with CH2Cl2. The combined organic layers were washed with 1.0N aqu. NaOH and water, then dried over MgSO4. Removal of the solvent in vacuo and vacuum distillation of the residue gave the desired product (18.8 g, bp 110°-118° C./0.1 mm Hg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=1)[CH3:15].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:23]([C:22]2[CH:21]=[N:20][C:19]([C:26]([F:28])([F:29])[F:27])=[CH:18][C:17]=2[S:16][CH2:14][CH3:15])=[O:24])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: CCSc1cc(C(F)(F)F)ncc1C(=O)O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCSc1cc(C(F)(F)F)ncc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
A mixture of 428 mg of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 562 mg of 4-ethylsulfanyl-6-trifluoromethylnicotinic acid, 645 mg of EDCI hydrochloride, 30 mg of HOBt and 2.5 ml of pyridine was stirred at room temperature for 5 hours, then allowed to stand at room temperature overnight. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 786 mg of 4-ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 4-Ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:31])[NH:20][C:21]([CH3:30])=[CH:22][C:23]=2[C:24]2C=CC=[CH:26][CH:25]=2)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[H][H].CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1>[Pd].CCO.C1COCC1>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[CH:2][CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:31])[NH:20][C:21]([CH3:30])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: Cc1cc(-c2ccccc2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cccc2c1cnn2C(C)C
Yield: 34.6 %

Procedure:
6-Bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (70.3 mg, 0.15 mmol) in 3:1 EtOH/THF (4 mL) was hydrogenated using Pd/C (10% wet Degussa type) and a balloon of hydrogen. The reactin mixture was stirred at room temperature overnight. It was filtered through Celite, washed with EtOAc and EtOH and the solvent was evaporated. DMF was added with some water and white solids that crashed out were filtered off, air-dried for 15 min and dried in a vacuum oven for 3 h. The residue was purified by Gilson reversed-phase HPLC (30×100 Varian Polaris C18, 15-80% gradient of MeCN in water with 0.1% TFA over 12 minutes). Most of the solvent was removed and saturated NaHCO3 was added. The solids that crashed out were filtered off, air-dried for 15 min and dried in vacuum oven overnight to give the title compound (19 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (br. s., 1H) 8.63 (br. s., 1H) 8.34 (s, 1H) 7.85 (d, J=8.34 Hz, 1H) 7.39-7.51 (m, 7H) 5.99 (s, 1H) 5.03 (quin, J=6.57 Hz, 1H) 4.22 (d, J=4.29 Hz, 2H) 2.21 (s, 3H) 1.49 (s, 3H) 1.47 (s, 3H). MS(ES) [M+H]+ 367.2.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH2:13]([O:15][C:16]([C:18]1[C:19]([Cl:27])=[N:20][CH:21]=[C:22]([C:24](O)=[O:25])[CH:23]=1)=[O:17])[CH3:14].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:15][C:16](=[O:17])[C:18]1[CH:23]=[C:22]([C:24](=[O:25])[NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[CH:21]=[N:20][C:19]=1[Cl:27])[CH3:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cc(C(=O)O)cnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Reaction time: 2 h

Procedure:
4-Trifluoromethoxyaniline (1.79 mL, 13.3 mmol) was added to a stirred solution of 2-chloropyridine-3,5-dicarboxylic acid ethyl ester (Stage 72.6, 3.20 g, 14 mmol), 1-hydroxybenzotriazole (3.20 g, 20.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (2.94 g, 15.3 mmol) in DMF (50 mL). The mixture was stirred for 2 h and then treated with EtOAc, washed with a sat. aq. solution of NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 0 to 50% EtOAc) and recrystallized from n-hexane/EtOAc to afford the title compound as a colorless crystalline solid. m.p. 135-137° C., HPLC (Condition 4) tR=6.59 min, UPLC-MS (Condition 8) tR=1.24 min, m/z=389.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.35 (t, J=7.23 Hz, 3H), 4.39 (q, J=7.04 Hz, 2H), 7.39 (d, J=8.60 Hz, 2H), 7.76-7.92 (m, 2H), 8.69 (d, J=2.35 Hz, 1H), 9.08 (d, J=2.35 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:43])=[O:42]>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:11]2[C@@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:9]([C:27]([N:49]3[CH2:48][CH2:47][N:46]([CH2:45][CH2:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH2:51][CH2:50]3)=[O:28])[C:8]([C:6]3[C:5]([O:30][CH2:31][CH3:32])=[CH:4][C:3]([C:33]([CH3:34])([CH3:35])[C:36]#[N:37])=[C:2]([Cl:1])[CH:7]=3)=[N:12]2)=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-5-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 730.3 [(M+H)+]
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:30][N:31]([CH3:45])[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:35]2([OH:38])[CH2:36][CH2:37][C:32]([N:31]([CH3:30])[CH3:45])([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:33][CH2:34]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(O)(c2cc3ccccc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
A solution of 1-benzenesulfonyl-1H-indol (600 mg, 2.33 mmol) in dry THF (30 ml) was cooled to −5° C. under a stream of argon. n-butyllithium (2.79 mmol, 1.75 ml of a 1.6 molar hexane solution) were added dropwise in such a way that a reaction temperature of 0° C. was not exceeded. Once all the substance had been added, the reaction mixture was stirred for 2 hours at 0° C. A solution of 4-dimethylamino-4-phenylcyclohexanone (493 mg, 2.33 mmol) in dry THF (5 ml) was added dropwise at 0° C. The mixture was stirred for 1 hour at 0° C. and then 3 days at ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), the organic phase was separated and the aqueous phase extracted four times with dichloromethane (20 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent removed under vacuum. Purification was carried out by flash chromatography with cyclohexane/ethylacetate (V:V=1:1) over silica gel. 232 mg 1-(1-benzenesulfonyl-1H-indol-2-yl)-4-dimethylamino-4-phenylcyclohexanol with a melting point of 173–176° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CC([O-])(C)C.[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Clc1ncccn1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1Oc1ncccn1
Temperature: 120 °C
Yield: 25 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (4 g, 25.6 mmol), 2-chloro-pyrimidine (5.4 g, 48 mmol), t-BuOK (3.5 g, 29 mmol) were mixed in DMF (20 mL). Then the mixture was heated for 2 hour at 120° C. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was dried over anhydrous Na2SO4 and concentrated to give title compound as a white solid (Yield: 1.5 g, 25%).
Reaction SMILES: [OH:1][CH:2](C=C)[CH2:3][O:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[O:7][N:6]=1.F[C:17]([F:30])([F:29])S(O[Si](C(C)(C)C)(C)C)(=O)=O.CC1C=CC=C(C)N=1.Cl>C1COCC1>[F:30][CH:17]([F:29])[CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[O:7][N:6]=1
Reactant: C=CC(O)COc1cc(C(=O)OC)on1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1cc(OCC(O)C(F)F)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
A mixture of methyl 3-[(2-hydroxybut-3-en-1-yl)oxy]isoxazole-5-carboxylate (2.71 g), t-butyldimethylsilyl trifluoromethanesulfonate (4.03 g), 2,6-dimethylpyridine (1.64 g) and THF (30 mL) was stirred at room temperature for 2 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, and then saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with tetraoxide osmium (7% immobilized catalyst, 2.31 g), sodium periodate (13.6 g), acetonitrile (30 mL), acetone (30 mL) and water (20 mL), and the obtained mixture was stirred at room temperature for 3 days. The precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with toluene (20 mL), diethylaminosulfur trifluoride (5.04 mL) was slowly added dropwise thereto at room temperature, and the obtained mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with THF (20 mL), tetrabutylammonium fluoride (1.0M THF solution, 25.4 mL) was slowly added dropwise thereto at 0° C., and the obtained mixture was stirred at 0° C. for 30 min. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white powder (370 mg).
Reaction SMILES: [CH2:1]([N:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1)[CH3:2].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>>[CH2:1]([N:3]1[CH2:6][CH:5]([O:7][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC(O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CCN1CC(Oc2ccc([N+](=O)[O-])cc2)C1

Procedure:
The title compound is prepared from 1-ethyl-3-azetidinol and 1-fluoro-4-nitrobenzene according to the procedures of Example 5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([NH2:19])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: Cc1ccc(C(=O)Cl)cc1OCc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C(N)=O)cc1OCc1ccccc1
Yield: 94 %

Procedure:
K2CO3 (18.1 g, 131.2 mmol) was added to a stirred solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 33 mmol) in DMF (50 mL) followed by benzyl bromide (11.8 g, 69 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filterate was diluted with water and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 11.3 g (crude) of 3-benzyloxy-4-methyl-benzoic acid benzyl ester which was such taken for the next step without purification. NaOH (4.0 g, 102 mmol) was added to a stirred solution of 3-benzyloxy-4-methyl-benzoic acid benzyl ester (11.3 g, 34 mmol) in a mixture of MeOH (50 mL) and H2O (50 mL), stirring was continued at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure Cold water was then added and acidified it with 10% aqueous HCl, the precipitate was collected to afford 7.21 g (87.8% Yield) of 3-benzyloxy-4-methyl-benzoic acid. A mixture of 3-benzyloxy-4-methyl-benzoic acid (7.21 g, 29.7 mmol) in thionyl chloride (50 mL) was stirred at 79° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure to afford 7.75 g (crude) of 3-benzyloxy-4-methyl-benzoyl chloride. A solution of 3-benzyloxy-4-methyl-benzoyl chloride (7.75 g) in THF (10 mL) was poured to cold aqueous solution of ammonia (50 mL) with stirring, The precipitate was collected to afford 6.7 g (94% Yield) of 3-benzyloxy-4-methyl-benzamide. A solution of 3-benzyloxy-4-methyl-benzamide (3.0 g, 12.4 mmol) in pyridine (4 mL) was cooled to −30° C. Imidazole (1.68 g, 24.8 mmol) followed by POCl3 (2.64 g, 49.6 mmol) were added to the cold solution with stirring and the reaction was continued at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water followed by 110% aqueous HCl solution. The organic layer separated was dried over sodium sulfate and concentrated under reduced pressure to afford 2.46 g (89% Yield) of 3-benzyloxy-4-methyl-benzonitrile. Pd/C (476 mg) was added to a stirred solution of 3-benzyloxy-4-methyl-benzonitrile (2.46 g, 11.0 mmol) in MeOH (25 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere at ambient temperature, overnight. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 1.367 g (93.6% Yield) of 3-hydroxy-4-methyl-benzonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:15][C:14](=[O:16])[C:13]([CH:17]([NH:19][C:20](=O)[CH3:21])[CH3:18])=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O>ClCCCl.C(=O)([O-])O.[Na+]>[CH3:18][C:17]1[N:19]=[C:20]([CH3:21])[N:12]2[C:13]=1[C:14](=[O:16])[NH:15][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[N:11]2
Reactant: CC(=O)NC(C)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(C)n2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c12
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A solution of 1.93 g (6.36 mmol) of N-{1-[3-(3-nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}acetamide from example 6A in 1,2-dichloroethane is treated with 2.93 g (1.78 ml, 19.09 mmol) of phosphoryl chloride. The mixture is stirred for 3 h at 95° C. After cooling, it is hydrolyzed using a couple of drops of aqueous sodium hydrogencarbonate solution. The solvent is removed in vacuo and the residue is purified by flash chromatography (eluent gradient: dichloromethane/methanol 100:1-50:1-30:1-20:1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([CH2:10][OH:11])=[N:3]1.[H-].[Na+].[CH3:14]OS(OC)(=O)=O.N>C1COCC1.O>[CH3:14][O:11][CH2:10][C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1
Reactant: Cn1cc([N+](=O)[O-])c(CO)n1
Reactant: COS(=O)(=O)OC
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1nn(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(1-Methyl-4-nitropyrazol-3-yl)methanol (2.0 g) was dissolved in THF (80 ml) and NaH (0.6 g, 60% in oil) added at <5° C. After 30 minutes, dimethylsulfate (1.92 g) was added and the reaction stirred overnight at room temperature. An additional 0.5 eq NaH was charged and the reaction warmed to 50° C. for 30 minutes. The reaction was cooled to room temperature, and water added dropwise (10 ml), then the mixture was poured into 5% aq. ammonia (100 ml). The organic phase was separated and the aqueous extracted with EtOAc (4×50 ml). The combined organic phases were washed with 5% aq. ammonia (2×50 ml), brine (50 ml), then dried, filtered and concentrated in vacuo to yield 3-(methoxymethyl)-1-methyl-4-nitropyrazole, 2.03 g, 94%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([OH:12])=O)[CH3:5].[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][C:27]([NH2:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][C:27]([NH:31][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:7]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH:8]=2)=[N:26]1
Reactant: Cc1cc(N)nn1C
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2cc(C)n(C)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (4.11 mmol) in DMF (10 mL) was treated with the 1,5-dimethyl-1H-pyrazol-3-ylamine (4.52 mmol), DIPEA (5.93 mmol) and HATU (3.85 mmol) and stirred at RT overnight, under an argon atmosphere. The mixture was poured onto water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with brine (20 mL) and evaporated in vacuo before chromatography on silica, eluting with 20-80% ethyl acetate in isohexane, to afford the desired compound as a yellow oil (1.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(NP1(N(CC)CC)N(C)CCCN1C)(C)(C)C.ClC1C(CC)=C(N[C@@H](C2OC(C3C=CC=CC=3)=NN=2)[C@@H](O)C)C=CC=1C#N>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]([C:12]2[O:13][C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[N:15][N:14]=2)[C@@H:26]([OH:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: CCN(CC)[PH]1(NC(C)(C)C)N(C)CCCN1C
Agent: CCc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccc(C#N)cc2)o1
Reaction time: 1 h

Procedure:
To a solution of N′-((2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (2 g, 5.03 mmol) in anhydrous THF (300 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (6.86 g) followed by p-TSCl (959 mg, 5.03 mmol) and the mixture was stirred for 1 h. The mixture was filtered and the residue washed with acetone (200 mL) followed by MeOH (200 mL). The filtrate was then concentrated and subjected to flash column chromatography [EtOAc-Hexanes (3:2)] to give two fractions. The second-eluted material was the desired 2-chloro-3-ethyl-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzonitrile (231 mg, 12%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.2 (d, J=8 Hz, 2H), 7.99 (d, J=8 Hz, 2H), 7.57 (d, J=8 Hz, 1H), 7.14 (s, 1H), 6.97 (d, J=8 Hz, 1H), 6.61 (d, J=8 Hz, 1H), 5.17-5.13 (m, 1H), 4.64-4.54 (m, 2H), 1.40 (d, J=6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=3)(=[O:38])=[O:37])[C@H:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:17])([F:16])[F:18])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C(F)(F)F)C[C@H]2C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (R)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-3-methylpiperazine (5.34 g, 21.86 mmol) in anhydrous dichloromethane (20 mL) was added diisopropylethylamine (10.3 mL, 59.1 mmol) at 0° C. The reaction mixture was stirred at room temperature for 15 minutes then 3-Methoxy benzene sulfonyl chloride (2.44 g, 11.82 mmol) dissolved in dichloromethane (10 mL) was introduced dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 0.5 hour. Reaction was complete as determined by TLC. The reaction mixture was diluted with dichloromethane washed with saturated NaHCO3 (aqueous), dried over MgSO4 and concentrated. The crude product was purified via flash column chromatography to yield (R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(3-methoxyphenylsulfonyl)-2-methylpiperazine in quantitative yield (5.10 g) as a white solid.