Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1)(=O)[CH3:2].[C:19](#[N:21])C.CO[CH:24](OC)[N:25](C)C>>[CH3:12][O:11][C:8]1[C:9](=[O:10])[C:4]([C:1]2[N:21]([CH3:19])[N:25]=[CH:24][CH:2]=2)=[N:5][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC#N
Reactant: COc1cn(-c2ccccc2)nc(C(C)=O)c1=O
Product: COc1cn(-c2ccccc2)nc(-c2ccnn2C)c1=O
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
To a suspension of 3-acetyl-5-methoxy-1-phenylpyridazin-4(1H)-one (6.0 g) in dimethylformamide dimethylacetal (49.33 mL) was added acetonitrile (18 mL) and the mixture was stirred at 90° C. for 4.5 hr. The reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure to dryness. The residue was dissolved in ethanol (42.3 mL). To the reaction mixture was added dropwise with stirring under ice-cooling a solution of methylhydrazine (2.26 g) in 10% trifluoroacetic acid-containing ethanol (84.58 mL). The mixture was stirred at the same temperature for 10 min, allowed to warm to room temperature, and stirred for 18 hr. The crystals precipitated in the reaction mixture was collected by filtration, washed successively with ethanol and diisopropyl ether, and dried to give the title compound (3.81 g) as pale-yellow crystals. Furthermore, the filtrate and the washing were combined, and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (0.84 g) as pale-yellow crystals.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C(N[CH2:15][C:16]([OH:18])=[O:17])(=O)C.C([O-])(=[O:21])C.[Na+].Cl>C(OC(=O)C)(=O)C.O>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH2:1][C:15](=[O:21])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)NCC(=O)O
Reactant: COc1cccc(C=O)c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cccc(CC(=O)C(=O)O)c1
Yield: 34.1 %

Procedure:
m-Anisaldehyde (25.9 g), N-acetylglycine (15.2 g) and sodium acetate (7.8 g) were heated together under reflux in acetic anhydride (50 ml) for 3/4 hour. The mixture was allowed to cool, water (150 ml) was added and the mixture was filtered to give the crude azlactone (27.7 g) m.p. 145°-150°. Hydrolysis with boiling 1 N hydrochloric acid (450 ml) followed by cooling and ether extraction afforded 3-methoxyphenylpyruvic acid as a pale yellow oily solid (6.3 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O.C([O:19][C:20](=O)[C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])C>C(O)C>[OH:28][C:21]1[C:20](=[O:19])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:15]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[C:22]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCC(=O)C(=O)OCC
Reactant: O=Cc1cccs1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: CCCCCC1=C(O)C(=O)N(CCCn2ccnc2)C1c1cccs1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and Thiophene-2-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-octanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: C(O)C.[Na].[N:5]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:24](OCC)(=[O:30])[C:25](OCC)=[O:26]>C(O)(=O)C.O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:5]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:25]([OH:26])[C:24]([OH:30])=[C:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CN(CC(=O)OCC)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cn1c(C(=O)OCC)c(O)c(O)c1C(=O)OCC
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a 1000-mL round bottom flask was added containing a stir bar, and argon atmosphere, and outfitted with a reflux condenser was added ethanol (200 proof, 500 mL) and sodium metal (21.31 g, 927 mmol). When the sodium was completely dissolved, a mixture of triethyl nitrilotriacetate (56.20 g, 204 mmol) and diethyl oxalate (29.44 g, 204 mmol) was added. The mixture was refluxed overnight, whereupon it became a clear, gelatinous solution. After cooling to room temperature, the mixture was poured into 1200 mL of DI water, chilled in an ice bath and acidified with glacial acetic acid (200 mL). The resulting white precipitate was isolated via vacuum filtration and washed with several portions of DI water to yield 59.75 g (89%) of a white solid. mp 121.3-121.8° C.; 1H NMR (300 MHz, CDCl3): δ 7.51 (s, 2H), 5.32 (s, 2H), 4.39 (q, 4H, J=7.7 Hz), 4.20 (q, 2H, J=7.7 Hz), 1.38 (t, 6H, J=7.7 Hz), 1.27 (t, 3H, J=7.7 Hz); 13C NMR (75 MHz, CDCl3): δ 169.5, 162.4, 139.6, 111.1, 61.6, 47.9, 14.5, 14.4; HRMS (EI): Calcd for C14H19NO8 ([M]+), 329.1111, found m/z, 329.1111; Anal. Calcd for C14H19NO8: C, 51.06; H, 5.82; N, 4.25%, found: C, 50.79; H, 5.83; N, 4.22%.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.NC1C=CC=CC=1>C1COCC1.C(#N)C.CN(C)C1C=CN=CC=1>[C:3]([OH:5])(=[O:4])[C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH2:1]
Reactant: CC(CC(=O)O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CC#N
Product: C=C(CC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The enantiomer excess (hereinafter referred to as "e.e.") of the resulting methylsuccinic acid was determined as follows. A part (1.32 mg, 0.1 mmole) of the crude product was dissolved in 2 ml of THF and 2 ml of acetonitrile, and 45.4 mg (0.22 mmole) of N,N'-dicyclohexylcarbodiimide, 2.4 mg (0.02 mmole) of 4-dimethylaminopyridine, and 0.01 ml (0.11 mmole) of aniline were added to the solution, followed by stirring at room temperature overnight. The solvent was removed from the reaction mixture by distillation under reduced pressure. The residue was dissolved in chloroform, washed three times with a 5M hydrochloric acid aqueous solution and then once with a saturated sodium hydrogencarbonate aqueous solution in a successive manner, and dried over magnesium sulfate. The solvent was removed, and the crude dianilide was purified by silica gel column chromatography using diethyl ether as an eluent. The purified dianilide was subjected to high performance liquid chromatography (HPLC) using a chromatograph equipped with CHIRALCEL-OD® (manufactured by Daicel Chemical Industries, Ltd.) (eluent: isopropyl alcohol/hexane=10/90 by volume; detection: UV 254 nm; flow rate: 1 ml/min) to determine the e.e.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:20]I>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([N:8]([CH3:20])[C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C(=O)Nc1cccnc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ncccc1C(=O)N(C)c1cccnc1Cl
Reaction time: 0.33 h

Procedure:
To a stirred solution of N-(2-chloro-3-pyridinyl)-2-methylnicotinamide (1.48 g) in DMSO (20 mL) was added NaH (60% in oil, 0.26 g). After 20 minutes, methyl iodide (0.45 mL) was added, and stirring was continued for 30 minutes. The mixture was diluted with ethyl acetate, washed with water, dried (Na2SO4), filtered, and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave N-(2-chloro-3-pyridinyl)-N-methyl-2-methylnicotinamide (1.51 g).
Reaction SMILES: [H-].[Na+].CS(C)=O.Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[C:10]=1[CH3:17].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1>O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[C:10]([CH3:17])[C:11]=1[CH3:16]
Reactant: Cc1c(N)ccc(O)c1C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
Sodium hydride (60 wt %, 0.72 g) was added to dimethyl sulfoxide (10 ml). The mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-2,3-dimethylphenol hydrochloride (1.55 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue. The precipitated crystal was collected by suction filtration to give 0.94 g (yield 65%) of the title compound.
Reaction SMILES: [C:1]1([C:7]([OH:12])([CH2:9][CH:10]=C)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:13]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[C:1]1([C:7]([OH:12])([CH3:8])[CH2:9][CH2:10][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(C)(O)c1ccccc1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-phenylpent-4-en-2-ol (74 g, 0.457 mol) in dry CH2Cl2 (1 L) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH4(42.8 g, 1.143 mol) was added to the mixture in portions at −20° C. The mixture was stirred overnight at rt. The mixture was quenched with water and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give 3-phenylbutane-1,3-diol (67.8 g), which was used for the next step without purification.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=O.[Cl:8][C:9]1[C:10]([F:45])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][C@H:41]([NH2:44])[CH2:40][CH2:39]2)=[O:36])[CH:12]=[CH:13][CH:14]=1.C([N:48](CC)CC)C>O1CCOCC1>[Cl:8][C:9]1[C:10]([F:45])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][C@H:41]([NH:44][C:3]([NH2:48])=[O:5])[CH2:40][CH2:39]2)=[O:36])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(CC)CC
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N[C@H]2CC[C@H](N)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: C1COCCO1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N[C@H]2CC[C@H](NC(N)=O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-trans-cyclohexylamine trifluoroacetic acid salt (100 mg, 0.126 mmol) in 1,4-dioxane (5 mL), N-trimethylsilyl isocyanate (Aldrich, 42 uL, 0.316 mmol) was added followed by the addition of triethylamine (44 uL, 0.316 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC to give a white solid. 39 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[O:16])[C@@H:9]([CH2:17][C:18]([OH:20])=[O:19])[O:8][C@H:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1.[C:29]([O:35][CH2:36]Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC(C)C)C(C)C.O>CN(C)C=O.C(OCC)(=O)C>[C:29]([O:35][CH2:36][O:19][C:18](=[O:20])[CH2:17][C@H:9]1[O:8][C@H:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:6]2[CH:28]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:10]1=[O:16])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: CC(C)(C)C(=O)OCCl
Agent: CCN(CC(C)C)CC(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)[C@@H](CC(=O)OCOC(=O)C(C)(C)C)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (10 ml) was dissolved trans- 7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.5 g) obtained in Example 2. To the solution were added pivaloyloxymethyl chloride (0.43 ml), N,N-diisobutyl ethylamine (0.52 ml) and KI (0.2 g). The mixture was stirred at room temperature overnight. To the reaction mixture were added water (100 ml) and ethyl acetate (100 ml), followed by extraction. The ethyl acetate layer was washed with an aqueous solution of potassium hydrogensulfate, an aqueous solution of sodium hydrogencarbonate and water, successively, which was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to afford trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid pivaloyloxymethyl ester (0.55 g).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([OH:12])=O)=[N:7][O:8][C:4]=2[CH:3]=1.CN(C(O[N:23]1N=N[C:25]2C=CC=N[C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:39]N1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([NH:23][CH2:24][CH2:25][OH:39])=[O:12])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1noc2cc(Br)ccc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cc1noc2cc(Br)ccc12)NCCO
Reaction time: 0.17 h

Procedure:
A suspension of (6-bromo-1,2-benzisoxazol-3-yl)acetic acid (Intermediate 32) (0.10 g) and HATU (0.18 g) in tetrahydrofuran (5 ml) was stirred at room temp. for 10 min then treated with 1-hydroxybenzotriazole (0.05 g) 2-aminoethanol (0.03 ml) and diisopropylethylamine (0.2 ml). The mixture was stirred for a further 18 h then concentrated under vacuum. The residue was partitioned between dichloromethane (5 ml) and 2M aqueous sodium carbonate (5 ml). The organic layer was dried using a hydrophobic filter tube then applied to a Varian Bond-Elut SPE cartridge. Sequential elution with dichloromethane, ether, ethyl acetate, acetonitrile and acetone yieldded the title compound as a white solid (0.08 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:18][CH2:19][C:20]1([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[CH2:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.[O:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](Cl)=[O:55].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:4][CH2:5][C:6]([CH2:18][CH2:19][C:20]1([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([N:34]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[C:54]([C:50]3[O:49][CH:53]=[CH:52][CH:51]=3)=[O:55])[CH2:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)OCCC(CCC1(CCN2CCC(Nc3ccc(C)cc3)CC2)CCCCC1)(COC(C)=O)COC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCC(CCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cc3)CC2)CCCCC1)(COC(C)=O)COC(C)=O
Reaction time: 17 h

Procedure:
To a solution of 2-(acetoxymethyl)-2-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane (synthesized in Example 13) (324 mg) dissolved in dichloromethane (4 mL) was added triethylamine (0.16 mL). 2-Furoyl chloride (0.084 mL) was added to the solution under ice cooling, and the temperature was then allowed to rise to room temperature. The solution was stirred for 17 hours. A 10% aqueous citric acid solution was added to the solution and the solution was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (1:1)] to give the title compound (356 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24](C)[C:25]([NH2:27])=[O:26])=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.N1C=CC=C[CH:30]=1.O>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][N:27]([CH3:30])[C:25]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:10])[N:16]=3)=[CH:23][CH:22]=2)=[O:26])=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: ClSc1ccc(Cl)cc1
Reactant: CN(C(N)=O)c1ccc(Oc2cccc(Cl)n2)cc1
Solvent: CCCCCC
Solvent: O
Product: CN(Sc1ccc(Cl)cc1)C(=O)Nc1ccc(Oc2cccc(Cl)n2)cc1
Temperature: 30 °C

Procedure:
4-Chlorobenzenesulfenyl chloride (8.68 grams; 0.0496 mole) was added over a period of about 3 minutes to a solution of N'-(4-((6-chloro-2-pyridinyl)oxy)phenyl-N-methylurea (8.3 grams; 0.03 mole) in 50 ml. of dry pyridine. The resulting reaction mixture was stirred at a temperature of about 30° C. for a period of about one and one-half hours and then poured into 250 ml. of cold water. The resulting sticky product precipitate was dissolved in hot hexane, reprecipitated therefrom upon standing and the light-yellow, slightly sticky product obtained triturated with a small amount of cold acetonitrile. Filtration of the mixture gave the desired N-((4-chlorophenyl)thio)-N'-(4-((6-chloro-2-pyridinyl)oxy)phenyl)-N-methylurea compound as a white crystalline solid melting at 106°-109° C. The product was found to have carbon, hydrogen, nitrogen, chlorine and sulfur contents of 54.2, 3.5, 9.86, 17.0 and 7.46 percent, respectively, as compared with contents of 54.3, 3.6, 10.0, 16.87 and 7.6 percent, respectively, as calculated for the named structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:43][CH2:42][NH:41][C:40]1=[O:44].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17]([N:41]3[CH2:42][CH2:43][N:39]([CH3:38])[C:40]3=[O:44])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Reactant: CN1CCNC1=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C)C3=O)cn2)CN1C(=O)OC(C)(C)C
Temperature: 180 °C
Yield: 60.8 %

Procedure:
In a 2 mL glass microwave reaction vessel are placed in (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.32 mmol), 1-Methyl-imidazolidin-2-one (35 mg, 0.35 mmol), CuI (123.4 mg, 0.35 mmol), trans-1,2-cyclohexane (0.005 mL, 0.35 mmol), K2CO3 (88 mg, 0.64 mmol) in dry dioxane (2 mL). The reaction vessel is sealed and heated under microwave irradiation at 180° C. for 20 min. After completion of the reaction, the solvent is diluted with EtOAc and washed with sat. NH3 (aq.), water, dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel to give (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(3-methyl-2-oxo-imidazolidin-1-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)[CH2:5]O.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)[CH2:5][Cl:19]
Reactant: Cc1ccc(Sc2ccccc2)c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc(Sc2ccccc2)c(CCl)c1
Reaction time: 1.5 h

Procedure:
570.7 g of 3-methyl-6-(phenylthio)-benzyl alcohol are dissolved in 1.5 litres of benzene and heated under reflux. There are added dropwise thereto within 45 minutes 352 ml of thionyl chloride and the mixture is boiled for a further 90 minutes. Then the mixture is concentrated under reduced pressure and there is obtained 3-methyl-6-(phenylthio)-benzyl chloride as a red-brown oil. 194 g of potassium cyanide in 250 ml of water are heated under reflux for 17 hours under an argon atmosphere with 616.9 g of 3-methyl-6-(phenylthio)-benzyl chloride in 900 ml of ethanol. Then the ethanol is distilled off under reduced pressure, the residue then diluted with water and extracted with ether. The extracts are washed with water, dried over sodium sulphate and evaporated. There is obtained 3-methyl-6-(phenylthio)-phenylacetonitrile as an oil.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([O:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[C:14]([CH2:32][CH3:33])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:34].[Li+]>O1CCOCC1.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:21][CH2:22][CH2:23][NH:24][O:34][C:11]([CH3:16])([CH3:12])[CH3:10])[C:14]([CH2:32][CH3:33])=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OCCNC(=O)OC(C)(C)C
Reactant: [OH-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)O)c1OCCNOC(C)(C)C
Temperature: 130 °C
Yield: 131.6 %

Procedure:
A mixture of methyl 6-(benzenesulphonylmethyl)-2-(2-t-butoxycarbonylaminoethoxy)-3-ethylbenzoate (Intermediate 108, 0.125 g), and lithium hydroxide (0.066 g) in dioxane (1.4 ml) and water (0.4 ml) was stirred and heated in the microwave at 130° C. for 45 minutes. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified with hydrochloric acid (1M) and extracted with ethyl acetate, washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 6-(benzenesulphonylmethyl)-2-(2-t-butoxyaminoethoxy)-3-ethylbenzoic acid (0.075 g) as a colourless gum.