Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](S(Cl)(=O)=O)C.NC1C2C=CC=CC=2OCCC1.C(N(CC)CC)C.[CH2:26]([S:28]([NH:31][CH:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH2:35][CH2:34][CH2:33]1)(=[O:30])=[O:29])[CH3:27].[H-].[Na+].CI>C1COCC1>[CH2:26]([S:28]([N:31]([CH:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH2:35][CH2:34][CH2:33]1)[CH3:1])(=[O:30])=[O:29])[CH3:27]
Reactant: CCS(=O)(=O)Cl
Reactant: CCS(=O)(=O)NC1CCCOc2ccccc21
Agent: NC1CCCOc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CI
Product: CCS(=O)(=O)N(C)C1CCCOc2ccccc21
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of 10.0 g (62 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one (J. Chem. Soc., Perkin Trans. 1 (1991), 2763) and 4.63 g (68 mmol) of hydroxylamine hydrochloride in 45 ml of ethanol and 45 ml of pyridine was heated under reflux for 5 h. After distilling off the solvents on a rotary evaporator, the residue was treated with water, adjusted to pH 2 with dil hydrochloric acid and stirred for 3 h. After filtering off the precipitated product with suction and drying it, 10.2 g of 3,4-dihydro-1-benzoxepin-5(2H)-one oxime were obtained, m.p. 96-98° C. b) A solution of 2.0 g (11.3 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one oxime in 15 ml of 1,2-dimethoxyethane (DME) was added dropwise at 0° C. under argon to a mixture of 4.5 g (23.7 mmol) of titanium tetrachloride and 1.79 g (47.4 mmol) of sodium borohydride in 50 ml of DME over the course of 20 min. After stirring at RT for 2 days, 100 ml of water were added dropwise and the mixture was rendered alkaline using conc. ammonia solution. After filtering off the precipitate with suction, the filtrate was extracted three times with EA. After washing with sodium chloride solution, drying over magnesium sulfate and concentrating, 2.1 g of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine were obtained. c) 0.86 g (6.7 mmol) of ethanesulfonyl chloride was added dropwise with ice cooling to a solution of 1.0 g (6.1 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine and 2.5 g (24 mmol) of triethylamine in 20 ml of THF. The mixture was allowed to come to room temperature and was stirred overnight, and the solvent was distilled off in vacuo. After stirring the residue with water, the deposited product was filtered off with suction. 1.1 g of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-berzoxepine were obtained, m.p. 109-111° C. d) A solution of 1.0 g (3.9 mmol) of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF were added dropwise under nitrogen to a suspension of 0.16 g (5.4 mmol) of 80 percent sodium hydride in 10 ml of THF. After stirring at RT for 3 h, 1.6 g (11 mmol) of methyl iodide were added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. The organic phase was concentrated in vacuo after drying over sodium sulfate. 1.0 g of 5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 122-124° C.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[OH:22])[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][CH3:18].S(OCC)(O[CH2:54][CH3:55])(=O)=O.[OH-].[Na+].O>O1CCOCC1.[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.ClCCl>[CH2:54]([O:22][CH:21]([CH2:20][O:19][CH2:1][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][CH3:18])[CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30])[CH3:55]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCOCC(COCCOCCO)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
3.7 g (5.8 millimole) of 1-O-octadecyl-3-O-[2-(2-trityloxyethoxy)ethyl]glycerol and 1.5g (10 millimole) of diethyl sulfate were dissolved in 10 ml of dioxane, to which 96 mg (0.3 millimole) of cetyltrimethylammonium chloride and 2.4 g (30 millimole) of 50% sodium hydroxide were added, and the mixture was stirred at room temperature for 72 hours. Water and dichloromethane were added to the mixture and the resulting mixture was shaken for partition. Dichloromethane was distilled off and the residue was dissolved in a mixture of 20 ml of methanol and 25 ml of dioxane, to which 3 ml of concentrated hydrochloric acid was added. The mixture was stirred at 80° C. for 16 hours and then water was added to the mixture. The organic solvent was distilled off under reduced pressure, and water and ether were added to the residue. The resulting mixture was shaken for partition and ether was distilled off. The residue was purified by silica gel column chromatography (Merck Co., Art. 7734, 100 g, Eluant: hexane-ethyl acetate=3:1-1:1), to give 1.95 g (73%) of the above-captioned compound.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:3]2[C:4]3=[N:9][C:8]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[CH:7][C:6](=[O:16])[N:5]3[CH2:17][C@@:2]2([CH3:1])[C:18]([F:21])([F:19])[F:20])=[CH:26][CH:27]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1CCc1ccc(Cl)cc1

Procedure:
The product is prepared according to the procedure described in stage k of Example 1, using 100 mg of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (Example 1j) and 87 mg of 1-(2-bromoethyl)-4-chlorobenzene, replacing the sodium hydride with 214 mg of caesium carbonate. After purification by preparative HPLC/MS (method C), 65 mg of (2S)-1-[2-(4-chlorophenyl)ethyl]-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CCC(C)=O>[CH3:39][O:38][C:36]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)=[O:37]
Reactant: COC(=O)CCCCCCCBr
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCCCCCCC(=O)OC)C(C)(C)CCC3(C)C)nc1

Procedure:
In a manner similar to that of Example 51, by reaction of 460 mg (1.06 mmol) of ethyl 6-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro 2-naphthylselanyl)nicotinate with 515 mg (2.17 mmol) of methyl 8-bromooctanoate and 295 mg of potassium carbonate in MEK (10 ml), 487 mg (78%) of a yellow oil are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:17])[N:6]([CH3:18])[CH2:5]1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:18][N:6]1[CH2:5][CH:4]([CH2:3][CH2:2][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7]1=[O:17]
Reactant: C1COCCN1
Reactant: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Product: CN1CC(CCN2CCOCC2)c2nc3ccccc3n2C1=O
Temperature: 60 °C

Procedure:
To 20 mL of morpholine was added 3.5 g (0.0133 mol) of 4-(2-chloroethyl)-3,4-dihydro-2-methylpyrimido[1,6-a]benzimidazol-1(2H)-one. The reaction mixture was heated in 60° C. for 24 hrs. The excess morpholine was removed by rotary evaporation and finally by high vacuum (0.5 mm Hg ~60° C.). The residue was dissolved in ~100 mL of CH2Cl2 washed with 3×50 ml of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was crystallized from isopropyl ether to give 2.7 g (65%) of analytically pure crystals, mp 111°-12° C.
Reaction SMILES: [C:1]1(/[C:7](/[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][C:13](OCC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[C:1]1(/[C:7](/[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCC/C=C(\c1ccccc1)c1cccnc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Ethyl (E)-7-phenyl-7-(3-pyridyl)-6-heptenoate (1.5 g, 4.8 mmoles) was dissolved in dry tetrahydrofuran (30 ml) and ice-cooled. Lithium aluminum hydride (0.5 g) was gradually added to the solution. The mixture was stirred at 0° C. for 30 minutes and a saturated aqueous Rochelle salt solution was added to precipiate the inorganic substance. The organic layer was separated and the precipitate was washed with tetrahydrofuran (30 ml). The tetrahydrofuran solutions were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as eluent to give (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (1.2 g, 94%) (Compound Id-14) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[N:6]([CH2:13][CH:14]([C:19]1([CH3:24])OCC[O:20]1)[C:15]([O:17][CH3:18])=[O:16])[C:5]2=[O:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[Cl:1])[C:5](=[O:25])[N:6]([CH2:13][CH:14]([C:19](=[O:20])[CH3:24])[C:15]([O:17][CH3:18])=[O:16])[C:7]2=[O:12]
Reactant: COC(=O)C(CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O)C(C)=O

Procedure:
Methyl 2-(5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (46 mg, 19%) in the same manner as described in the above example 6 (1) from methyl 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.24 g, 0.67 mmol) and p-toluenesulfonic acid monohydrate (51 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[CH:7]1)(=O)=O.[OH-].[Na+]>Cl>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[CH2:11][C:9]1[N:8]=[CH:7][NH:6][CH:10]=1
Reactant: CN(C)S(=O)(=O)n1cnc(Cc2cccs2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1csc(Cc2c[nH]cn2)c1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A solution of 4-thiophen-2-ylmethyl-imidazole-1-sulfonic acid dimethylamide (Intermediate-E2) (0.44 g) in 1.5 M HCl (10 mL) was heated to reflux for 3 h. The mixture was cooled to rt and basified with NaOH solution; The mixture was extracted with ethyl acetate (2×) and the organic solution was dried over Na2SO4, filtered and evaporated to give 4-thiophen-2-ylmethyl-1H-imidazole (Intermediate-E3) as a white solid ˜0.2 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:46]1([C:49](Cl)=[O:50])[CH2:48][CH2:47]1>C(Cl)Cl>[C:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:49]([CH:46]2[CH2:48][CH2:47]2)=[O:50])=[CH:3][CH:4]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]2[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=2[CH3:26])[CH2:13][CH2:14]1)#[N:38]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(NC(=O)C3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
To a solution of COMPOUND 142 (61 mg, 0.12 mmol) in CH2Cl2 (1 mL) and Et3N (33 μL, 0.24 mmol) was added cyclopropanecarbonyl chloride (17 μL, 0.18 mmol) and the solution was stirred at room temperature for 4 hours to afford COMPOUND 153 as a white solid (69 mg, 100%) following work-up and purification. 1H NMR (CDCl3) δ 0.75-0.83 (m, 2H), 1.01 (m, 6H), 1.01-1.16 (m, 1H), 1.42-1.61 (m, 2H), 1.61-1.77 (m, 3H), 2.15 (t, 1H, J=11.1 Hz), 2.30 (s, 6H), 2.55 (t, 1H, J=10.8 Hz), 2.74-2.86 (m, 3H), 3.28 (t, 1H, J=11.1 Hz), 3.54 (m, 1H), 3.76 (s, 2H), 3.85 (m, 1H), 6.50 (d, 2H, J=6.49 (d, 2H, J=8.4 Hz), 6.91-6.99 (m, 3H), 7.24 (d, 2H, J=9.3 Hz), 7.36-7.44 (m, 4H), 7.50 (br s, 1H), 8.40 (br s, 1H). 13C NMR (CDCl3) δ 7.98, 8.39, 13.77, 15.72, 19.54, 29.29, 30.57, 31.31, 40.14, 44.03, 48.66, 52.46, 57.39, 60.82, 112.78, 114.85, 119.40, 122.01, 127.67, 128.79, 129.56, 129.66, 130.50, 130.82, 131.47, 134.45, 138.91, 142.66, 145.31, 170.35, 172.09. ES-MS m/z 578 (M+H). Anal. Calcd. for C36H43N5O2.0.3CH2Cl2: C, 72.28; H, 7.28; N, 11.61. Found. C, 72.57; H, 7.38; N, 11.30.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.O>[CH3:17][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([O:14][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10]2)=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)c1ccc(CCN2CC[C@H](O)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)c1ccc(CCN2CC[C@H](OS(C)(=O)=O)C2)cc1

Procedure:
(S)-1-(4-dimethylaminophenethyl)-3-hydroxypyrrolidine (320 mg, 1.37 mmol) was dissolved in dichloromethane (10 ml). Triethylamine (152 mg, 1.50 mmol) and methanesulfonyl chloride (164 mg, 1.43 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred at 0° C. for 1 hour. The reaction liquid was distributed in dichloromethane and water. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a solvent mixture (50:1) of dichloromethane and methanol. The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-1-(4-dimethylaminophenethyl)-3-methanesulfonyloxy-pyrrolidine in the form of a light yellow oil (378 mg, 88%).
Reaction SMILES: C(Cl)Cl.CC1(C)C(C)(C)OB([C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)O1.Cl[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>O.[Cu]I>[N+:27]([C:26]1[C:21]([C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)=[N:22][CH:23]=[CH:24][CH:25]=1)([O-:29])=[O:28]
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cccnc1-c1cccc(O)c1
Yield: 48.9 %

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocnee]dichloropalladium(II), w/DCM (0.039 g, 0.047 mmol) was added to a solution containing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.292 g, 1.325 mmol), 2-chloro-3-nitropyridine (0.15 g, 0.946 mmol), Copper(I) iodide (0.018 g, 0.095 mmol) and Potassium carbonate (0.946 ml, 1.892 mmol). Heated the reaction to 110° C. for 15 mins. Cooled reaction to room temperature. Diluted with water and extracted with ethyl acetate. Combined organics, dried, filtered, concentrated and purified to afford 3-(3-nitropyridin-2-yl)phenol (0.1 g, 0.463 mmol, 48.9% yield).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][C:7](=[O:31])[CH2:8][C@H:9]1[O:15][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:12]=2[N:11]([CH:27]([CH3:29])[CH3:28])[C:10]1=[O:30])C.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:12]2[N:11]([CH:27]([CH3:28])[CH3:29])[C:10](=[O:30])[C@@H:9]([CH2:8][C:7]([NH:6][CH2:5][C:4]([OH:32])=[O:3])=[O:31])[O:15][C@@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:13]=2[CH:22]=1
Reactant: CCOC(=O)CNC(=O)C[C@H]1O[C@@H](c2ccccc2)c2cc(Cl)ccc2N(C(C)C)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)N1C(=O)[C@@H](CC(=O)NCC(=O)O)O[C@@H](c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.4 %

Procedure:
In a mixture of 2 ml of methanol and 1 ml of water was suspended 48 mg of N-(trans-7-chloro-1-isopropyl-5-phenyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ylacetyl)glycine ethyl ester obtained in Example 55. To the suspension was added 0.1 g of potassium carbonate. The mixture was stirred for 6 hours at room temperature. The reaction mixture was adjusted to pH 4 with dilute hydrochloric acid, which was subjected to extraction with ethyl acetate. The organic layer was washed with water and dried, then the solvent was distilled off under reduced pressure. Crystals obtained form the residue were recrystallized from ether and hexane to afford 29 mg of N-(cis-7-chloro-1-isopropyl-5-phenyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ylacetyl)glycine as white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]2[C:19](=[O:20])[NH:18][C:17](=[O:21])[C:16](C(O)=O)=[N:15]2)[CH:5]=[C:6]([Cl:13])[C:7]=1[C:8]([C:11]#[N:12])([CH3:10])[CH3:9]>SCC(O)=O>[Cl:13][C:6]1[CH:5]=[C:4]([N:14]2[C:19](=[O:20])[NH:18][C:17](=[O:21])[CH:16]=[N:15]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([CH3:10])([CH3:9])[C:11]#[N:12]
Reactant: CC(C)(C#N)c1c(Cl)cc(-n2nc(C(=O)O)c(=O)[nH]c2=O)cc1Cl
Agent: O=C(O)CS
Product: CC(C)(C#N)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 40.4 %

Procedure:
A suspension of intermediate (6) (0.28 mole) in mercaptoacetic acid (250 ml) was stirred for 4 hours at 100° C., then allowed to cool to RT and stirred overnight. The reaction mixture was poured out onto crushed ice and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. Toluene was added and azeotroped on the rotary evaporator. The residue was purified by short column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was stirred in DIPE, filtered off, washed with DIPE, then dried, yielding 36.8 g (41%) of 2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α,α-dimethylbenzeneacetonitrile. The filtrate was stirred in DIPE and the resulting precipitate was filtered off, washed with DIPE, and dried, yielding 2.5 g (3%) of 2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α,α-dimethylbenzeneacetonitrile (intermediate 7).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[CH2:6][N:5]([CH2:9][C:10]#[CH:11])[C:4]1=[O:12].[CH2:13]([O:15][N:16]=[CH:17]/[C:18](/[CH3:28])=[CH:19]/[C@@H:20]1[C@@H:22]([C:23](O)=[O:24])[C:21]1([CH3:27])[CH3:26])[CH3:14].C(Cl)(Cl)Cl.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.[Cl-].[Na+].O>[CH2:13]([O:15][N:16]=[CH:17]/[C:18](/[CH3:28])=[CH:19]/[C@@H:20]1[C@@H:22]([C:23]([O:1][CH2:2][N:3]2[C:7](=[O:8])[CH2:6][N:5]([CH2:9][C:10]#[CH:11])[C:4]2=[O:12])=[O:24])[C:21]1([CH3:27])[CH3:26])[CH3:14]
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@@H](/C=C(\C)C=NOCC)C2(C)C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
Under nitrogen atmosphere, to a mixture of 0.44 g of 3-hydroxymethyl-1-(2-propynyl)imidazolidine-2,4-dione, 0.58 g of (1R)-trans-3-[(E)-3-ethoxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylic acid, catalytic amount of 4-dimethylaminopyridine and 5 ml of anhydrous chloroform was added 0.50 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the mixture was stirred at room temperature overnight. Thereafter, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.34 g of 2,5-dioxo-3-(2-propynyl)imidazolidin-1-ylmethyl (1R)-trans-3-[(E)-3-ethoxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate (hereinafter, referred to as the present compound (2)) represented by the formula (2):
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14]([B-](F)(F)F)=[CH2:15].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:12]=[C:11]([CH:14]=[CH2:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(Br)cc1Cl
Reactant: C=C[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=Cc1ccc(C(=O)OCC)c(Cl)c1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
To a stirred solution of ethyl 2-chloro-4-bromobenzoate (2 g, 7.63 mmol) in dimethylsulfoxide (20 mL) was added potassium vinyltrifluoroborate (3.06 g, 22.9 mmol) and potassium carbonate (3.16 g, 22.9 mmol). The reaction mixture was degassed with argon for 30 min. Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.27 g, 0.38 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×50 mL), washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the compound as brown gummy material (1.1 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.70 (dd, J=17.6, 11.2 Hz, 1H), 5.87 (d, J=17.6 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 211.22 ([M+H]+); IR (thin film) 1729, 886 cm−1.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CCC(CC)C1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)C1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 47a (0.25 g, 0.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.2 g, 73%).