Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:22])[NH:9][CH2:10][C:11]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:22][C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])=[CH:10][N:9]=1
Reactant: COC(=O)CCCCC(=O)NCC(=O)c1cc(Cl)ccc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCc1ncc(-c2cc(Cl)ccc2OC)o1
Reaction time: 17 h
Yield: 49.2 %

Procedure:
Dissolve 5-[2-(5-Chloro-2-methoxy-phenyl)-2-oxo-ethylcarbamoyl]-pentanoic acid methyl ester (9.39 g, 27.47 mmol) and 4-(dimethylamino)pyridine (6.54 g, 53.53 mmol) in 250 mL of CH2Cl2 and cool the reaction mixture in an ice bath. Add triphenylphosphinedibromide (22.54 g, 53.40 mmol) to the reaction portionwise over 15 minutes. Raise the reaction to ambient temperature and allow it to stir for 17 hours. Wash the reaction with water (1×) and brine (2×). Dry the organic layers with MgSO4. Filter off the drying agent and concentrate in vacuo to afford a crude residue. Purify the residue using silica gel chromatography eluting with hexanes/ethyl acetate mixtures to afford 4.38 g of the titled product (49%): mass spectrum: m/z=324.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:26])([CH3:25])[O:18][C:19]=3[C:20]([C:22](O)=[O:23])=[CH:21][C:11]=2[N:10]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N+:30]=1[O-].S(Cl)(Cl)=O.CCN(C(C)C)C(C)C>[Fe].C(O)(=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:26])([CH3:25])[O:18][C:19]=3[C:20]([C:22]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][N:30]=3)=[O:23])=[CH:21][C:11]=2[N:10]=1
Reactant: Nc1ccc(C(F)(F)F)c[n+]1[O-]
Reactant: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Agent: [Fe]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)Nc3ccc(C(F)(F)F)cn3)c3c(c21)CC(C)(C)O3
Yield: 9.2 %

Procedure:
The title compound was prepared by following the same procedure described for Example-205 by using 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylic acid (Intermediate-61, 0.200 g, 0.491 mmol), 2-Amino-5-(trifluoromethyl)pyridine 1-oxide (Intermediate-41, 0.131 g, 0.737 mmol), thionyl chloride (2 mL), DIPEA (10 mL), THF (5.0 mL), acetic acid (10.0 mL), iron powder (0.200 g) to afford 0.025 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 3.52 (s, 2H), 3.60 (s, 3H), 7.31 (s, 1H), 8.23 (d, J=10.5 Hz, 1H), 8.44 (s, 1H), 8.48 (s, 2H), 8.76 (s, 1H), 10.40 (s, 1H), 10.93 (s, 1H); MS [M]+: 551.07.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[CH2:8][C:6]=2[N:7]=1.[CH:22]([NH:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)=[O:27])([CH3:24])[CH3:23]>>[CH:12]1([CH2:11][N:9]2[CH2:10][C:5]3[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]4[CH3:21])=[N:3][C:2]([C:32]4[CH:31]=[CH:30][C:29]([NH:28][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])=[CH:34][CH:33]=4)=[N:7][C:6]=3[CH2:8]2)[CH2:14][CH2:13]1
Reactant: CC(C)NC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC1CC1)C2
Product: CC(C)NC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(CC2CC2)C3)cc1

Procedure:
Method as described for example 47 using intermediate 8 and 1-isopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials. Purified by prep. LCMS (low pH).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].N1C=CC=CC=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(Cl)CCl>C1COCC1.CC(N(C)C)=O.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:1](=[O:6])[C:2]#[C:3][CH3:4])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC#CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC#CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
But-2-ynoic acid (0.19 g, 2.36 mmol) followed by pyridine (0.6 ml), were added sequentially portion wise to a stirred solution of 4-(4-amino-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (0.2 g, 0.59 mmol) in THF/DMA (3:2, 5 ml) at room temperature. To this mixture was added EDC (0.6 g, 3.1 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with ethyl acetate (50 ml) and washed with water (100 ml), saturated NaHCO3 (100 ml) and HCl (100 ml, 2M). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum and the resulting residue was purified by flash column chromatography (elution, 20% ethyl acetate, 80% DCM) to give the title compound (0.05 g, 19% yield) as a white solid. Tr=4.12 min, m/z (ES+) (M+Na)+ 430.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[NH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[OH:24])[CH2:17]1.[BH4-].[Na+]>CO.ClCCl>[OH:24][CH:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:22][N:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([CH2:15][NH:14][CH2:12][C:9]2[CH:10]=[CH:11][C:5]3[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)[CH2:17]1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: COc1ccc2nccc(C(O)CN3CCC[C@@H](CN)C3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2nccc(C(O)CN3CCC[C@@H](CNCc4ccc5c(c4)NC(=O)CO5)C3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Molecular sieve, type 3A, (1.082 g) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.095 g, 0.54 mmol) were added to a solution of (3S)-2-(3-aminomethyl-piperidin-1-yl)-1-(6-methoxy-quinolin-4-yl)-ethanol (0.171 g, 0.54 mmol) in MeOH (1.6 ml) and dichloromethane (3.8 ml). The reaction mixture was stirred at room temperature for 16 hours and sodium borohydride (0.054 g, 1.43 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then filtered over Hydromatrix (wetted with an NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane/MeOH 9/1 1% NH4OH).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].[CH3:24][S:25]([CH2:28][C:29](O)=[O:30])(=[O:27])=[O:26].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:10]([CH3:12])[N:11]([C:29](=[O:30])[CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])[C:5]=2[CH:4]=1)#[N:2]
Reactant: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)CC(=O)O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2ccc(C#N)cc2N1C(=O)CS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a 0° C. solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (106 mg, 335 μmol) in pyridine (3.35 ml) was added 2-(methylsulfonyl)acetic acid (50.9 mg, 369 μmol) followed by phosphoryl chloride (61.3 μl, 670 μmol), dropwise. The reaction was stirred at 0° C. for 30 min, then quenched by the addition of H2O and extracted with EtOAc. The combined organic layers were washed with 1 N aq. citric acid, H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (137 mg, 94%) as a white solid. MS m/z 459 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]([O:15]CC)=O)=[CH:7]2.[NH3:18].CO>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]([NH2:18])=[O:15])=[CH:7]2
Reactant: N
Reactant: CCOC(=O)c1cc2cccc(Cl)c2c(=O)[nH]1
Solvent: CO
Product: NC(=O)c1cc2cccc(Cl)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vessel containing NH3/MeOH (10 mL) was added ethyl 8-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (500 mg, 1.99 mmol). The vessel was sealed and the resulting solution was stirred at RT for 1 hour. The reaction mixture was subsequently concentrated in vacuo to give the title compound, which was used without further purification (0.5 g, 98%). ESI-MS m/z [M+H]+ 223.1.
Reaction SMILES: [C:1](OC(C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)C(N1[C@@H](CC2C=CC=CC=2)COC1(C)C)=O)(=[O:3])[CH3:2].[CH2:39]([O:41][C:42](=[O:62])[CH:43]([C:45]1[O:49][C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[CH:47][CH:46]=1)[OH:44])[CH3:40]>>[CH2:39]([O:41][C:42](=[O:62])[CH:43]([O:44][C:1](=[O:3])[CH3:2])[C:45]1[O:49][C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[CH:47][CH:46]=1)[CH3:40]
Reactant: CC(=O)OC(C(=O)N1[C@@H](Cc2ccccc2)COC1(C)C)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Reactant: CCOC(=O)C(O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Product: CCOC(=O)C(OC(C)=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 83 %

Procedure:
According to the procedure described in Example 13 for the preparation of 2-acetoxy-1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)-ethanone, 2-(2-biphenyl-4-yl-furan-5-yl)-2-hydroxy-acetic acid ethyl ester was acylated to furnish in 83% yield 2-acetoxy-2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid ethyl ester which was used without purification. Flash column chromatography with 0-20% EtOAc/hex as eluant gave an analytically pure pink solid, mp 136-140° C. 1H NMR: δ 7.74 (d, 2H, J=8.5 Hz), 7.63 (d, 4H, J=8.5 Hz), 7.46 (t, 2H, =7.4 Hz), 7.36 (t, 1H, J=7.2 Hz), 6.68 (d, 1H, J=3.7 Hz), 658 (d, 1H, J=3.3 Hz), 6.57 (s, 1H), 4.29 (q, 2H, J=7.0 Hz), 2.21 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). Anal. Calculated for C22H20O5 : C, 72.51; H, 5.53. Found: C, 72.61; H, 5.63.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](O[C@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)[N:3]=1.[Br:40][C:41]1[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][C:42]=1[CH:48]([OH:53])[C:49]([F:52])([F:51])[F:50]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:53][C@H:48]([C:42]2[CH:43]=[C:44]([Br:47])[CH:45]=[CH:46][C:41]=2[Br:40])[C:49]([F:50])([F:51])[F:52])[N:3]=1
Reactant: OC(c1cc(Br)ccc1Br)C(F)(F)F
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Product: Nc1nc(O[C@H](c2cc(Br)ccc2Br)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with 1-(2,5-dibromophenyl)-2,2,2-trifluoroethanol.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.B.[Cl:23][CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([Cl:35])[CH:29]=1)=[O:27].Cl>O1CCCC1.CO>[Cl:23][CH2:24][CH2:25][C@@H:26]([C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([Cl:35])[CH:29]=1)[OH:27]
Reactant: O=C(CCCl)c1cc(F)cc(Cl)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O[C@@H](CCCl)c1cc(F)cc(Cl)c1
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (R)-2-methyl-CBS-oxazaborolidine (1.0 M in toluene, 1.5 mL, 1.5 mmol, 0.1 equiv.) in tetrahydrofuran (10 mL) under a nitrogen atmosphere at −25° C. was added a solution of borane (1.0 M in tetrahydrofuran, 9.0 mL, 9.0 mmol, 0.6 equiv.). A solution of 3-chloro-1-(3-chloro-5-fluorophenyl)propan-1-one (3.32 g, 15.0 mmol) in tetrahydrofuran (10 mL) was added dropwise over a period of 25 min, and the reaction mixture was stirred for an additional 30 min at −25° C. Methanol (10 mL) was added slowly to quench the reaction, followed by the slow addition of hydrogen chloride solution (1.0 M in diethyl ether, 20 mL) at −25° C. All volatiles were removed under reduced pressure. Hexane (100 mL) was added, and the white salt of the chiral auxiliary was filtered through a pad of celite and washed with hexane (2×25 mL). The filtrate was concentrated under reduced pressure to give (1S)-3-chloro-1-(3-chloro-5-fluorophenyl)propan-1-ol as viscous, colorless oil (Yield: 3.34 g (100%). Chiral purity: 93.4%, [□]D25=−10.3° (c=10 mg/mL, CHCl3)). This material was dissolved in 70 mL of methanol/acetonitrile. 500 □L of the resulting solution was repetitively injected onto the Supercritical Fluid Chromatography instrument, and the baseline resolved enantiomers were separately collected using the conditions described below. The chiral purity of each enantiomer was determined under the same Supercritical Fluid Chromatography conditions using a Chiralpak AD-H 5□m, 250 mm×4.6 mm ID column at 2.0 mL/min flow rate using Analytical Supercritical Fluid Chromatography (Berger Instruments, Inc. Newark, Del.). The chiral purity of the product was found to be 99.8%.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]([NH:11]C(OC(C)(C)C)=O)=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]>Cl.O1CCOCC1>[NH2:11][C:8]1[C:4]([C:5]([OH:7])=[O:6])=[C:3]([CH3:19])[C:2]([Br:1])=[CH:10][CH:9]=1
Reactant: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(Br)ccc(N)c1C(=O)O

Procedure:
A solution of Example 104B (300 mg, 0.9 mmol) in anhydrous 4N HCl/dioxane solution (10 mL) was stirred for 2 hours and concentrated to provide the desired product as the hydrochloride salt. MS (ESI(−)) m/e 228, 230 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.34 (d, 1H), 6.66 (d, 1H), 4.44 (br s, 3H), 2.34 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH:22](OC)OC)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:35][O:36][NH2:37]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH:22]=[N:37][O:36][CH3:35])=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)OC
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Product: CON=CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Yield: 69.4 %

Procedure:
In a solution of 152 mg of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-(2,2-dimethoxyethyl)-2-methyl benzoic acid amide (Compound of the present invention No. 5-083) synthesized similarly to Synthetic Example 5 in 14 ml of methaol-water (6:1) mixed solvent, 38 mg of methoxyamine hydrochloride was added, and stirred under reflux with heat for 8 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, diluted by adding 80 ml of ethyl acetate, washed with water (30 ml×2), and dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethylacetate-hexane (1:1), and 102 mg of the aimed product was obtained as colorless resinous substance.
Reaction SMILES: F[C:2](F)(F)S(OC1C=CC(C2NC(=O)CC2)=CC=1)(=O)=O.C(OC([N:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH2:31][C@H:30]([CH2:41][CH:42]=[CH2:43])[C:29]1=[O:44])=O)(C)(C)C>>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([C@@H:32]2[NH:28][C:29](=[O:44])[C@@H:30]([CH2:41][CH:42]=[CH2:43])[CH2:31]2)=[CH:38][C:37]=1[CH3:2])#[N:40]
Reactant: C=CC[C@H]1C[C@H](c2ccc(C#N)cc2)N(C(=O)OC(C)(C)C)C1=O
Reactant: O=C1CCC(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)N1
Product: C=CC[C@H]1C[C@H](c2ccc(C#N)c(C)c2)NC1=O

Procedure:
The title compound was prepared using a procedure analogous to that described in AMIDOXIME 1, Step B substituting trans-5-(4-trifluoromethanesulfonyloxy-3-methyl-phenyl)-3-(2-propenyl)-2-pyrrolidinone for 5-(4-trifluoromethanesulfonyloxyphenyl)-2-pyrrolidinone: 1H NMR δ 2.06-2.11 (m, 1H), 2.23-2.29 (m, 1H), 2.36-2.42 (m, 1H), 2.55-2.64 (m, 5H), 4.71-4.73 (m, 1H), 5.08-5.14 (m, 2H), 5.74-5.80 (m, 1H), 6.41 (br. s, 1H), 7.18 (d, J=8.0, 11H), 7.23 (br. s, 1H), 7.59 (d, J=7.8, 11H).
Reaction SMILES: [NH2:1][C:2]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][C:4](=[CH2:12])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:23]([NH:30][C@H:31]([C:33](O)=[O:34])[CH3:32])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>C(COC)OC>[CH3:29][C:26]([CH3:27])([O:25][C:23]([NH:30][C@H:31]([C:33]([NH:1][C:2]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:3][C:4](=[CH2:12])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:34])[CH3:32])=[O:24])[CH3:28]
Reactant: C=C(CCC(=O)OCC)CC(N)(C(=O)OCC)C(=O)OCC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: C=C(CCC(=O)OCC)CC(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A solution of 945 mg of the product of Step D of Example 1, 30 ml of dimethoxyethane and 621 mg of Boc-L-alanine was cooled to 0° C. and 678 mg of dicyclohexylcarbodiimide were added in small fractions over 10 minutes. The mixture was stirred at 0° C. for 16 hours. After filtering, the filtrate was evaporated to dryness under reduced pressure and chromatography was carried out on silica. Elution with a cyclohexane-ethyl acetate mixture (7-3) yielded 1.3 g of the expected product with a specific rotation of [α]D =-22°±2° (c=0.7% in CH2Cl2).
Reaction SMILES: [ClH:1].[O:2]([CH2:9][C:10]1([OH:16])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:17](O)=O.C=O.[OH-].[Na+]>O>[ClH:1].[CH3:17][N:12]1[CH2:13][CH2:14][CH2:15][C:10]([CH2:9][O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([OH:16])[CH2:11]1
Reactant: O=CO
Reactant: OC1(COc2ccccc2)CCCNC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1CCCC(O)(COc2ccccc2)C1
Yield: 67.9 %

Procedure:
A solution of 5 g (0.024 mole) of crude 3-(phenoxymethyl)-3-piperidinol monohydrochloride and 5 g (0.096 mole) of formic acid (88%) in 10 ml of water was treated with 3 ml (0.036 mole) of formalin (37%) and heated on a steam bath for 18 hours. The reaction mixture was diluted with water, made basic with 3N sodium hydroxide, and extracted with three 40 ml portions of methylene chloride. The extracts were combined over magnesium sulfate, filtered, and evaporated under reduced pressure to give a pale yellow oil (4.2 g). The oil was chromatographed on a 400 g column of florisol using an acetone-benzene gradient (0-2%) to elute the product. Fractions containing nearly pure product were combined and evaporated under reduced pressure. The residual oil was dissolved in acetone, treated with ethereal hydrogen chloride and allowed to stand overnight. Filtration afforded 1.8 g solid, which was recrystallized from cold acetone (charcoal pretreatment) to give 1.3 g of hydrochloride salt, m.p. 151° -152° C.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]([C:10]1[N:15]=[C:14](O)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]>CCN(CC)CC>[C:6]([C:10]1[N:15]=[C:14]([Cl:3])[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cnc(C(C)(C)C)nc1O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(C(C)(C)C)nc1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To ice cold (0-5° C.) POCl3 (35 mL) was added dropwise Et3N (0.4 mL), followed by methyl 2-t-butyl-4-hydroxypyrimidine-5-carboxylate (3.45 g, 16.4 mmol). The mixture was then warmed to 40° C. and stirred under Ar for 1 h, then concentrated and diluted with CHCl3 (100 mL) and poured carefully onto ice (˜300 g) and stirred at RT until the ice all melted. The organic phase was separated, washed with NaHCO3 (100 mL), H2O (100 mL), dried (Na2SO4), concentrated and dried to yield methyl 2-t-butyl-4-chloropyrimidine-5-carboxylate (3.28 g, 87% yield). 1H NMR (400 MHz, DMSO-d6): δ 1.35 (s, 9H), 3.90 (s, 3H), 9.14 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][S:8](=[O:11])(=[O:10])[N:7]([CH3:12])[C:6]=2[CH:13]=1.CN1[C:19](=O)[CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+].BrCC1CC1>C(OCC)(=O)C.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[S:8](=[O:11])(=[O:10])[N:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: CN1CCCC1=O
Reactant: CN1c2cc(Br)ccc2NS1(=O)=O
Agent: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1c2cc(Br)ccc2N(CC2CC2)S1(=O)=O
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a round bottom flask was added 6-bromo-1-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1-3) (5.32 g, 20.2 mmol), anhydrous NMP (10 mL), anhydrous 1,4 Dioxane (100 mL), cesium carbonate (13.2 g, 40.4 mmol), followed by (bromomethyl)cyclopropane (3.00 g, 22.2 mmol). The reaction mixture was then heated to 100° C. while stirring in a hot oil bath for 18 hours. The crude reaction mixture was then cooled to room temperature, then suspended in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-40% EtOAc/Hex) to give 5-bromo-1-(cyclopropylmethyl)-3-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1-4) as a tan solid. HRMS (M+H)+: observed=316.9953, calculated=316.9954.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C(O)(=O)C.[C:21]1([CH2:27][N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[OH-]>CCO>[C:21]1([CH2:27][N:28]2[CH2:33][CH2:32][C:31]3([C:16]4=[C:15]5[C:10](=[N:9][C:8]4=[C:3]4[C:2](=[CH:7][CH:6]=[CH:5][CH2:4]4)[NH:1]3)[CH:11]=[CH:12][CH:13]=[CH:14]5)[CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: C1=CCC2=C3N=c4ccccc4=C3C3(CCN(Cc4ccccc4)CC3)NC2=C1

Procedure:
To a mixture prepared from 7.6 g of 2-(2-aminophenyl)indole, 2.5 ml of acetic acid and 90 ml of ethanol was added 7.4 ml of 1-phenylmethyl-4-piperidone. The resultant solution was refluxed for 6 hours. Concentration gave a solid/gum mixture which was taken up in EtOH and treated with dilute NH4OH. Filtration gave 12.45 g of yellow solid. This was recrystallized from CH3OH/H2O to give 9.0 g of yellow solid. High vacuum drying (90°) gave 2.6 g of dark yellow solid, m.p. 155°-157° C.