Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6][C@H:5]1[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N+:2]=[N-:3].[CH:40](OC(=O)C)=[CH2:41]>>[C:36]([O:35][C:33]([NH:32][C@H:5]1[C@@H:4]([N:1]2[CH:41]=[CH:40][N:3]=[N:2]2)[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6]1)=[O:34])([CH3:38])([CH3:37])[CH3:39]
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Reactant: C=COC(C)=O
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Yield: 21.1 %

Procedure:
A solution of di-tert-butyl (4-{(3R,4S,5S)-4-azido-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)imidodicarbonate (0.37 g, 0.67 mmol) in acetic acid ethenyl ester (5.50 mL, 59.7 mmol) in a sealed flask was heated at 115° C. for 40 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica using a CombiFlash® apparatus (50 to 100% EtOAc in hexanes) to give the sub-title compound (81 mg, 21%). LCMS calc. for C28H44N7O6 (M+H)+: m/z=574.3. Found: 574.4.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[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][CH3:22].C(O)(=O)CCCCCCCCCCCCCCCCCCCCCCC.C(O)(=O)CCCCCCCCCCCCCCCCCCC.C(O)(=O)CCCCCCCCCCC/C=C\CCCCCCCC.[OH-].[Na+:98]>C(O)(C)(C)C.O>[C:1]([O-:24])(=[O:23])[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][CH3:22].[Na+:98]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 75 °C
Reaction time: 1 h

Procedure:
87.6 kg of behenic acid (Henkel Co., trade name: Edenor C22-85R: the content of behenic acid being 88 mol %, lignoceric acid 2 mol %, arachidic acid 6 mol %, erucic acid 0.3 mol % and, others 3.7 mol %), 423 L of distilled water, 49.2 L of an aqueous sodium hydroxide solution at the concentration of 5 mol/L, 120 L of t-butyl alcohol were admixed, and subjected to a reaction with stirring at 75° C. for one hour to give a solution A of a sodium behenate. Separately, 206.2 L of an aqueous solution of 40.4 kg of silver nitrate (pH 4.0) was provided, and kept at a temperature of 10° C. A reaction vessel charged with 635 L of distilled water and 30 L of t-butyl alcohol was kept at 30° C., and thereto were added the total amount of the solution A of a sodium behenate and the total amount of the aqueous silver nitrate solution with sufficient stirring at a constant flow rate over 93 minutes and 15 seconds, and 90 minutes, respectively. Upon this operation, during first 11 minutes following the initiation of adding the aqueous silver nitrate solution, the added material was restricted to the aqueous silver nitrate solution alone. The addition of the solution A of a sodium behenate was thereafter started, and during 14 minutes and 15 seconds following the completion of adding the aqueous silver nitrate solution, the added material was restricted to the solution A of a sodium behenate alone. The temperature inside of the reaction vessel was then set to be 30° C., and the temperature outside was controlled so that the liquid temperature could be kept constant. In addition, the temperature of a pipeline for the addition system of the solution A of a sodium behenate was kept constant by circulation of warm water outside of a double wall pipe, so that the temperature of the liquid at an outlet in the leading edge of the nozzle for addition was adjusted to be 75° C. Further, the temperature of a pipeline for the addition system of the aqueous silver nitrate solution was kept constant by circulation of cool water outside of a double wall pipe. Position at which the solution A of a sodium behenate was added and the position at which the aqueous silver nitrate solution was added were arranged symmetrically with a shaft for stirring located at a center. Moreover, both of the positions were adjusted to avoid contact with the reaction liquid.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH:11]1[CH2:16][CH:15]=[C:14]([CH2:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1.[CH3:23][C:24]1([CH3:40])[C:33](=[O:34])[NH:32][C:31]2[N:30]=[CH:29][C:28](/[CH:35]=[CH:36]/[C:37](O)=[O:38])=[CH:27][C:26]=2[CH2:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:23][C:24]1([CH3:40])[CH2:25][C:26]2[C:31](=[N:30][CH:29]=[C:28](/[CH:35]=[CH:36]/[C:37](=[O:38])[N:11]3[CH2:12][CH2:13][C:14]([CH2:17][C:18]4[S:19][CH:20]=[CH:21][N:22]=4)=[CH:15][CH2:16]3)[CH:27]=2)[NH:32][C:33]1=[O:34]
Reactant: CC1(C)Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Reactant: C1=C(Cc2nccs2)CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc2NC1=O
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
DIPEA (0.33 mL, 1.83 mmol) was added to a stirred solution of 2-((1,2,3,6-tetrahydro-pyridin-4-yl)methyl)thiazole hydrochloride (Intermediate-2) (158 mg, 0.73 mmol), (E)-3-(6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (Intermediate-22) (150 mg, 0.61 mmol), HOBt (98 mg, 0.73 mmol) and EDC.HCl (232 mg, 1.22 mmol) in dry DMF (2 mL) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 4% methanol/dichloromethane as an eluent to get the desired compound as an off-white solid (160 mg, 51%); 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.71 (d, J=2.9 Hz, 1H), 7.61 (d, J=3.0 Hz, 1H), 7.45 (d, J=15.2 Hz, 1H), 7.30-7.14 (m, 1H), 5.68-5.65 (m, 1H), 4.28-4.20 (m, 1H), 4.08-4.02 (m, 1H), 3.80-3.72 (m, 3H), 3.68-3.60 (m, 1H), 2.79 (s, 2H), 2.18-2.04 (m, 2H), 1.08 (s, 6H); LC-MS: 409.2 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[CH2:16]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(O)c(Cc2ccccc2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Trifluoromethanesulfonic anhydride (10.0 mL, 60 mmol) was added over 3 min to a solution of 2-benzyl-4-methoxyphenol (10.71 g, 50 mmol; prepared according to J. Am. Chem. Soc. 1949, 71, 64) and anhydrous 2,6-lutidine (12.0 mL, 100 mmol) in anhydrous CH2Cl2 (250 mL) at −78° C. under argon. The reaction was stirred at −78° C. for 0.5 h, then was warmed to RT. After 1 h, the reaction was diluted with hexanes (250 mL) and washed sequentially with 1.0 N HCl (2×100 mL), 1.0 N NaOH (2×50 mL), H2O (100 mL) and brine (50 mL). Drying (Na2SO4), concentration, and silica gel chromatography (10% EtOAc/hexanes) gave the title compound as a light yellow solid (16.65 g, 96%): TLC Rf 0.51 (10% EtOAc/hexanes); 1H NMR (250 MHz, CDCl3) δ 7.10-7.40 (m, 6H), 6.77 (dd, J=9.0, 3.1 Hz, 1H), 6.66 (d, J=3.1 Hz, 1H), 4.03 (s, 2H), 3.73 (s, 3H); FTIR (CCl4) 1492, 1423, 1405, 1249, 1216, 1161, 1144, 1039, 869 cm−1; MS (ES) m/e 369 (M+Na)+, 364.0 (M+NH4)+, 347.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9](O)=O)=[CH:5][CH:4]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[CH:14]1([NH:17][CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=2)[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: COc1ccc(OCC(=O)O)cc1
Product: COc1ccc(OCCNC2CC2)cc1

Procedure:
Synthesized according to typical procedures C and D from (4-methoxyphenoxy)-acetic acid and cyclopropylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19](O)=[O:20])[C:13]1=[O:22].B.ClCCl.[OH-].[Na+]>C1COCC1>[OH:20][CH2:19][CH2:18][C:14]1[C:13](=[O:22])[N:12]([C:4]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=2[O:2][CH3:1])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cccc(CC(=O)O)c1=O
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Temperature: 27 °C
Reaction time: 8 h

Procedure:
21.0 g (69.0 mmol) of [1-(2-methoxy-4-nitrophenyl)-2-oxo-1,2-dihydropyridin-3-yl]acetic acid were introduced as initial charge in 210 ml of THF, and 104 ml of 1M borane solution in THF were added dropwise at RT. The temperature increased to 27° C. during this addition. The reaction mixture was stirred overnight at RT. Following dilution with 400 ml of dichloromethane, 400 ml of 1N sodium hydroxide solution were added with cooling and the mixture was stirred for 30 min. The phases were separated, and the organic phase was washed with water, dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. This gave 17.0 g (85%) of crude product which were further reacted without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:11]([C:9]1[N:10]=[C:5]2[N:4]=[CH:3][C:2]([C:22]#[C:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)c1nc2ncc(Br)cn2n1
Product: CC(C)(C)c1nc2ncc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, a yellow solid, MS: m/e=277.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 42, step 1) and phenylacetylene.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[O:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([S:35]([N:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)(=[O:37])=[O:36])[CH:39]=1
Reactant: O=S(=O)(c1cccc(B(O)O)c1)N1CCOCC1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cccc(S(=O)(=O)N4CCOCC4)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.13 mmol) were added (3-(morpholinosulfonyl)phenyl)boronic acid (54 mg, 0.2 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11 mg, 0.01 mmol) and 133 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (50 to 100%, hexane-ethyl acetate) to give 58 mg (73% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>C1(C)C=CC=CC=1>[S:16]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][Cl:1])(=[O:18])(=[O:17])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCCl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCCl
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(2-chloroethoxy)ethanol (15.3 g, 123 mmol) in toluene (100 ml) kept at 5° C. was added triethylamine (50 g, 500 mmol). A solution of methanesulfonyl chloride (28 g, 245 mmol) in toluene (50 ml) was carefully added keeping the temperature around 5° C. When addition was complete the reaction mixture was stirred at 5° C. for 45 minutes and then 75 minutes at ambient temperature. Water (100 ml) was added and the mixture was stirred for 15 minutes. The phases were separated and the organic phase was washed with water, brine and dried over magnesium sulphate. The solvent was evaporated in vacuo to give crude 2-(2-chloroethoxy)ethyl mesylate as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[O:12][CH2:13][C:14]3[CH:15]=[N:16][S:17][C:18]=3[C:5]2=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[O:12][CH2:13][C:14]3[CH:15]=[N:16][S:17][C:18]=3[C:5]2=[CH:4][CH:3]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1OCc1cnsc1-2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1cnsc1-2
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a stirred solution of methyl 7-amino-4H-chromeno[3,4-d]isothiazole-6-carboxylate (Intermediate 74, 0.300 g) in DCM (15 mL) was added pyridine (2.5 mL), followed by 2-bromo-4-fluorobenzenesulfonyl chloride (0.468 g). The resultant mixture was stirred at room temperature overnight. A further amount of 2-bromo-4-fluorobenzenesulfonyl chloride (0.300 g) was added and stirring was continued overnight. The mixture was diluted with DCM and washed with 0.5M hydrochloric acid and aqueous sodium bicarbonate. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 15-45% to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-chromeno[3,4-d]isothiazole-6-carboxylate (0.460 g) as a cream solid.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[C:15]([C:17]1([NH:26][C:27](=[O:35])[CH:28]([NH2:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]1)#[N:16]>>[C:15]([C:17]1([NH:26][C:27](=[O:35])[CH:28]([NH:34][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]1)#[N:16]
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC(C)(C)C)CC1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC(C)(C)C)NC2=NS(=O)(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared starting from 3-chloro-benzo[d]isothiazole 1,1-dioxide and 2-amino -4,4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride salt according to the procedure from Example 81, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to acetonitrile. MS, m/z 460=M+1.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]([OH:18])[C:16]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:31])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[Cl:30][C:25]1[CH:24]=[C:23]([C:16]2([C:19]([F:21])([F:20])[F:22])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:32])=[O:5])=[C:8]([CH3:31])[CH:9]=3)[CH:17]2[OH:18])[CH:28]=[C:27]([Cl:29])[CH:26]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2O)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-4-hydroxy-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (Example 12.1) (500 mg) in dichloromethane (20 ml) was added trifluoroacetic acid (“TFA”) (4 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. To the reaction mixture was diluted with water and the phases were separated. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was suspended in diisopropyl ether/pentane (1:3). The solids were isolated by filtration and washed with pentane to give 4-[5-(3,5-dichloro-phenyl)-4-hydroxy-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (395 mg) as a white solid. M.p. 215-217° C. 1H-NMR (CDCl3, 400 MHz): 7.98 (d, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.52 (s, 2H), 7.40 (s, 1H), 5.76 (s, 1H), 2.61 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](/[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)\[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl[CH2:27][C:28]1[CH:47]=[CH:46][C:31]([O:32][CH2:33][C:34]2[N:35]=[C:36]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[O:37][C:38]=2[CH3:39])=[CH:30][CH:29]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:39][C:38]1[O:37][C:36]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[N:35][C:34]=1[CH2:33][O:32][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][O:3]/[N:4]=[C:5](/[C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:18]=2)\[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:47][CH:46]=1
Reactant: CCOC(=O)CC/C(=N\O)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Oc2ccccc2)cc1
Reaction time: 1 h
Yield: 66.2 %

Procedure:
Sodium hydride (60% in oil, 211 mg) was added to a solution of ethyl E-4-(hydroxyimino)-4-(4phenoxyphenyl)butyrate(1.50 g) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.50 g) in N,N-dimethylformamide (15 ml) at room temperature under nitrogen atmosphere and stirred for 1 hour. 1N hydrochloric acid (7 ml) was added, an aqueous saturated solution of sodium bicarbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain crystals from an ethyl acetate-hexane (1:4, v/v)-eluted fraction. The crystals were recrystallized from ethyl acetate-hexane to obtain ethyl E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-phenoxyphenyl)butyrate (1.87 g, yield 66%) as colorless crystals. m.p. 118-119° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[CH2:16]([NH2:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:24][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)CCCOc1ccccc1C=O
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ccccc1C=NCCc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
A solution of 32.5 g of 2-(3-dimethylaminopropoxy)benzaldehyde and 18.9 g of phenethylamine in 150 ml of toluene is heated at reflux for one hour. After 30 minutes, one mole equivalent of water is collected in a Dean-Stark trap. After cooling to approximately 50° C., the solvent is removed using a rotary evaporator and the oily residue is distilled to give 36.2 g of the title compound, boiling point 165°-167° C. at 0.05 mm of Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]1=2.[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O.[OH-].[Na+].C(=O)(O)[O-].[Na+]>>[CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][C:3]1=2
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CCC(=O)Nc2ccccc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC1(C)CCC(=O)Nc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5,5-Dimethyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (514 mg, 2.716 mmol), WO 2005066165, was added to a 0° C. solution of 5 mL nitric acid and 5 mL sulfuric acid. The solution was stirred for 10 minutes at 0° C. ° C. The reaction was poured into a dilute NaOH/ice mixture. NaOH and sodium bicarbonate were added until the solution pH was neutral. A white precipitate formed, which was filtered off, washed with water and dried (485 mg, 76%) to yield 5,5-Dimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one. mp 208° C.; LCMS: m/z=235.03 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.35 (s, 1H), 8.10 (d, 1H, J=8.9 Hz), 7.06 (d, 1H, J=8.6 Hz), 2.50 (m, 2H), 2.17 (m, 2H° C.), 1.48 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:20][CH2:19][CH2:18][C@@H:17]3[N:12]2[C:13](=[O:22])[CH:14](I)[CH2:15][CH2:16]3)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:20][CH2:19][CH2:18][C@H:17]3[N:12]2[C:13](=[O:22])[CH:14]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH2:15][CH2:16]3)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)c1ccc([C@H]2CCC[C@H]3CCC(I)C(=O)N32)cc1
Product: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3ccc(C(=O)OC)cc3)N2C1=O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of (6R*,9aS*)-6-(4-carbomethoxyphenyl)-3-iodooctahydroquinolizin-4-one (180 mg) with triethyl phosphite (2 mL) was stirred at 120° C. for two hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 185 mg of the title compound. The property value of the compound is as follows.