Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@:6]1([CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][CH:37]=2)=[C:31]([Cl:44])[CH:30]=1)OC)(=O)[CH3:2].C1(C)C=CC=CC=1.B(F)(F)F.O(CC)CC.[OH2:61]>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@:6]21[C:34]1[C:29](=[CH:30][C:31]([Cl:44])=[C:32]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][CH:37]=3)[CH:33]=1)[O:28][CH2:27][CH2:26]2)(=[O:61])[CH3:2]
Reactant: CCc1ccc(Cc2ccc(OCC[C@]3(OC)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc2Cl)cc1
Reactant: O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2cc3c(cc2Cl)OCC[C@]32O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
(2S,3R,4S,5R,6R)-6-(Acetoxymethyl)-2-(2-(3-chloro-4-(4-ethylbenzyl)phenoxy)ethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (18) (19 mg, 0.03 mmol) was azeotropically dried (3×) with toluene, then dissolved in CH2Cl2 (0.4 mL), cooled to 0° C., and treated with BF3—OEt2 (approx 8 drops of a 48% solution). After 24 h, the reaction was concentrated onto celite and chromatographed over SiO2 (ISCO system, 0-40% EtOAc/hexanes) to provide a film (9.6 mg, 53%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.35 (s, 1H), 7.09 (s, 4H), 6.83 (s, 1H), 5.63 (d, J=9.9 Hz, 1H), 5.40 (t, J=9.6 Hz, 1H), 5.18 (t, J=10.2 Hz, 1H), 4.26-4.33 (m, 1H), 4.05-4.20 (m, 4H), 3.95 (s, 2H), 3.93 (m, 2H), 2.60 (q, J=15, 7.5 Hz, 2H), 2.04 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 1.83 (s, 3H), 1.21 (t, J=7.8 Hz, 3H). LC/MS 99.7% (ELSD) tR=2.93 min, calcd for C31H35ClO10: 602.19, found 620.4 (M+H2O)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:33])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[C:22]=4[Cl:32])[CH:15]=[CH:16][C:17]=3[F:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1.N1C=CC=CC=1.O>O1CCCC1.C(OCC)(=O)C>[Cl:32][C:22]1[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([F:18])=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:33]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(F)c(Oc3ccc4nc(N)sc4c3)c2)c1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(F)c(Oc3ccc4nc(NC(=O)C5CC5)sc4c3)c2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-fluorophenyl}-2-chloro-3-(1-cyano-1-methylethyl)benzamide (350 mg, 0.73 mmol) produced in Example A47(ii) in tetrahydrofuran (20 mL) were added cyclopropanecarbonyl chloride (114 mg, 1.09 mmol) and pyridine (86 mg, 1.09 mmol), and the mixture was stirred at room temperature for 30 min. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the mixture was stirred for 30 min. The organic layer was separated, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=20/80→0/100), and triturated with ethyl acetate/hexane to give the title compound (162 mg, 40%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].O.O.O.C([O-])(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[CH3:1][C:2]([CH3:42])([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: COc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)CCN2CCOCC2)cn3COCC[Si](C)(C)C)cc(OC)c1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)CCN4CCOCC4)c3n2)cc(OC)c1OC
Reaction time: 16 h
Yield: 74.7 %

Procedure:
A solution of 2,2-dimethyl-4-morpholin-4-yl-1-[2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butan-1-one (0.024 g, 0.040 mmol) in 1 mL of dichloromethane and 0.5 mL of trifluoroacetic acid was stirred for 3 h, then concentrated. The resulting residue was dissolved in 1 mL of ethanol and treated with sodium acetate trihydrate (0.054 g, 0.40 mmol). The mixture was stirred for 16 h, then concentrated to a residue. Column chromatography (0→10% MeOH/CH2Cl2) afforded 0.014 g (75%) of 2,2-dimethyl-4-morpholin-4-yl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butan-1-one as a brown solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(#N)C.O.I([O-])(=O)(=O)=[O:29].[Na+]>C(Cl)(Cl)Cl.O.[Ru](=O)=O>[CH3:1][C@H:2]1[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[C:4](=[O:29])[N:3]1[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18]
Reactant: C[C@H]1Cn2c(nnc2-c2cnccn2)CN1C(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a solution of (S)-tert-butyl 6-methyl-3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (1.0 g, 3.2 mmol) in chloroform (12 mL) was added acetonitrile (12 mL), water (30 mL), sodium metaperiodate (3.2 g, 14.9 mmol) and ruthenium (IV) oxide hydrate (62 mg, 0.4 mmol) and the reaction mixture was vigorously stirred for 30 minutes. The reaction mixture was filtered through celite, extracted with DCM, the organic layers were washed with brine, dried with Na2SO4, filtered, concentrated and purified by flash column chromatography (0-100% EtOAc in hexanes) to provide the desired compound (0.50 g, 48%). 1H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 8.83 (s, 2H), 5.01-4.92 (m, 1H), 4.89-4.79 (m, 1H), 4.73-4.66 (m, 1H), 1.52 (s, 9H), 1.21 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[O:7]=[C:8]1[CH:12]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:11][CH2:10][O:9]1.Cl>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]([N:13]([CH:12]1[CH2:11][CH2:10][O:9][C:8]1=[O:7])[C:14]1[C:15]([CH3:21])=[CH:16][CH:17]=[CH:18][C:19]=1[CH3:20])=[O:5]
Reactant: COCC(=O)Cl
Reactant: Cc1cccc(C)c1NC1CCOC1=O
Agent: Cl
Solvent: Cc1ccccc1C
Product: COCC(=O)N(c1c(C)cccc1C)C1CCOC1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Over 2 hours, 113 g (1.04 moles) of methoxyacetyl chloride are added at 60°-70° C. and under a pressure of 70°-80 mbar to a suspension of 205 g (1.0 mole) of N-(2-oxotetrahydro-3-furyl)-2,6-dimethylaniline in 500 ml of xylene. Towards the end of the addition of methoxyacetyl chloride the reaction mixture begins to boil, with hydrogen chloride gas evolving. When the addition of methoxyacetyl chloride is complete, the reaction mixture is stirred for 3 hours under weak reflux at 60°-65° C. and under a pressure of 70-80 mbar, and the hydrogen chloride evolving during the reaction is removed. Subsequently, half of the xylene is distilled off, the reaction mixture is cooled to 20° C., the precipitated product is filtered off, washed with xylene and dried, affording 263 g (95% of theory) of N-methoxyacetyl-N-(2-oxotetrahydro-3-furyl)-2,6-dimethylaniline with a melting point of 118°-120° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:17]([OH:19])=[O:18])[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10]2)=[C:5]([F:20])[CH:4]=1)#[N:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:32][CH:33](O)[CH3:34]>C(Cl)Cl.CCN(CC)CC>[CH:33]([O:18][C:17]([C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[F:20])[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[CH2:11][CH2:10]1)=[O:19])([CH3:34])[CH3:32]
Reactant: N#Cc1ccc(C2(C(=O)O)CCc3cncn32)c(F)c1
Reactant: CC(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)C1(c2ccc(C#N)cc2F)CCc2cncn21

Procedure:
5-(4-Cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (0.15 g, 0.279 mmol) is suspended in CH2Cl2 (3 mL) and DMF (0.01 ml) and cooled to 0° C. A solution of oxalyl chloride (0.31 mL, 2 M) in CH2Cl2 is added dropwise. After 1 h i-PrOH (3 mL) is added. After 2 h Et3N is added until basic and the solution is concentrated. The resulting slurry is dissolved in CH2Cl2, washed with aqueous saturated NaHCO3/H2O (1:1) and brine, then dried over Na2SO4. After concentration, the residue is purified by HPLC (2-38% MeCN/H2O containing 0.1% TFA) to give 5-(4-cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid isopropyl ester as solid. MS (ESI) m/z 314.0 (M+H); 1H NMR (400 MHz, CD3CN) (TFA salt) δ ppm 1.22 (d, J=6.06 Hz, 3H), 1.23 (d, J=6.06 Hz, 3H), 3.01-3.18 (m, 3H), 3.38-3.45 (m, 1H), 5.08-5.18 (m, 1H), 7.20 (s, 1H), 7.34 (app t, J=8.08 Hz, 1H), 7.62-7.68 (m, 2H) 8.52 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35]C)[CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[I-].[Na+].S1(CCCC1)(=O)=O.C[Si](C)(C)Cl>CC(C)=O.CCCCCCC.O>[C:37]1([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)[C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=4)=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1cccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4cccc(OC)c4)cc3)cc2)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Solvent: O=S1(=O)CCCC1
Product: Oc1cccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4cccc(O)c4)cc3)cc2)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
N,N'-diphenyl-N,N'-bis(3-hydroxyphenyl)-(1,1'-biphenyl)-4,4'-diamine was prepared, for example, from N,N'-di(3-methoxyphenyl)-N,N'-diphenyl-[1,1'-biphenyl]-4,4'diamine by placing into a two liter three-necked round bottom flask, equipped with a mechanical stirrer and an argon gas inlet, 137.5 gms, N,N'-diphenyl-N,N'-bis(3-methoxy phenyl)-[1,1'-biphenyl]-4,4'diamine (0.25 moles), 223.5 gms anhydrous sodium iodide (1.5 moles) and 500 milliliters warm sulfolane (distilled). The contents of the flask were heated to 120° C. and then cooled to 60° C. Five milliliters of D.I. water was added dropwise, followed by 190.5 milliliters of trimethyl(chlorosilane) (1.5 moles). The contents were allowed to reflux for six hours. HPLC analysis was utilized to determine when the reaction was complete. The contents of the flask were poured into a 3 liter Erlenmeyer flask containing 1.5 liter of deionized water. The water layer was decanted and the dark oily residue taken up into 500 milliliters methanol. The methanol solution was extracted with two 400 milliliter portions of hexane to remove the hexamethyldisiloxane by-products. The methanol solution was roto-evaporated to remove the solvents. The residue was taken up in 500 milliliters of acetone and then precipitated into 1.5 liters deionized water. The off-white solid was filtered and then washed with deionized water and dried in vacuo. The crude N,N'diphenyl-N,N'-bis(3-hydroxyphenyl)-(1,1'-biphenyl)-4,4'-diamine was placed into a two liter round-bottom flask containing a magnetic stirrer and one liter toluene. Fifty gms. of Florisil® (Florisil is a registered trademark of Floridin Co.) was added to the flask and allowed to stir for two hours. The dark Florisil® was filtered off, leaving a pale yellow toluene solution. The toluene was roto-evaporated to yield a pale yellow viscous oil. The oily product was dissolved in 400 milliliters acetone, then diluted with 400 milliliters heptane and allowed to crystallize. The colorless crystals were filtered. Additional product was obtained by roto-evaporating the acetone from the filtrate. Yield was 85 percent, m.p. 113°-17° C.
Reaction SMILES: F[B-](F)(F)F.N#[O+].[CH2:8]([O:10][P:11]([CH:16]([NH:25][C:26]1[CH:31]=[CH:30][C:29](N)=[CH:28][N:27]=1)[P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9].[S-2:33].[Na+].[Na+]>C(Cl)Cl>[CH2:8]([O:10][P:11]([CH:16]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([SH:33])=[CH:28][N:27]=1)[P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9]
Reactant: [S-2]
Reactant: CCOP(=O)(OCC)C(Nc1ccc(N)cn1)P(=O)(OCC)OCC
Agent: F[B-](F)(F)F
Agent: N#[O+]
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(Nc1ccc(S)cn1)P(=O)(OCC)OCC
Reaction time: 3 h

Procedure:
To nitrosonium tetrafluoroborate (NOBF4) (22 mg, 0.19 mmol) in methylene chloride (6 ml) at room temperature is added [(5-amino-2-pyridinyl)aminomethylene]bis[phosphonic acid] tetraethyl ester (75 mg, 0.19 mmol). The reaction mixture is stirred 3 hours then concentrated under reduced pressure. The crude residue is dissolved in acetonitrile (6 ml) and sodium sulfide (46 mg, 0.19 mmol) is added. After stirring 12 hours at room temperature, the reaction is quenched by the addition of water and the mixture is extracted with methylene chloride. The organic extracts are combined and washed with 10% aqueous Na2S2O3. The organic extracts are then dried over sodium sulfate, filtered and concentrated under reduced pressure. The desired thiol is obtained by flash chromatography purification with 2% isopropanol in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16].[Cl:17][S:18](O)(=[O:20])=[O:19].O>S(Cl)(Cl)=O>[Cl:17][S:18]([C:15]1[C:2]([Cl:1])=[C:3]([Cl:16])[C:4]2[O:8][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][C:5]=2[CH:14]=1)(=[O:20])=[O:19]
Reactant: CCOC(=O)C1Cc2ccc(Cl)c(Cl)c2O1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)C1Cc2cc(S(=O)(=O)Cl)c(Cl)c(Cl)c2O1
Yield: 101.6 %

Procedure:
To a solution (2.5 ml) of 1 g (3.83 mmol) of ethyl 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylate (1) in 2.5 ml of thionyl chloride is dropwise added 1.25 g of chlorosulfonic acid under ice-cooling and the mixture allowed to react at room temperature for 2 hours. The reaction mixture is poured into iced water and extracted with 60 ml of ethyl acetate. The organic layer is dried and evaporated to give about 1.4 g of ethyl 5-chlorosulfonyl-6,7-dichloro-2,3-dihydrobenzofuran-carboxylate (2) as an oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:10][C@@H:9]2[CH2:11][CH2:12][CH2:13][C@@H:8]2[C:7]1=[O:14])C.[NH3:16]>CO>[O:14]=[C:7]1[C@H:8]2[CH2:13][CH2:12][CH2:11][C@H:9]2[CH2:10][N:6]1[CH2:5][C:4]([NH2:16])=[O:3]
Reactant: N
Reactant: CCOC(=O)CN1C[C@@H]2CCC[C@@H]2C1=O
Solvent: CO
Product: NC(=O)CN1C[C@@H]2CCC[C@@H]2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of cis-hexahydro-1-oxo-cyclopenta[c]pyrrole-2(1H)-acetic acid ethyl ester (25 g, 0.0154 mole) in methanol is saturated with anhydrous ammonia and the mixture is stirred at room temperature 24 hours. The solution is concentrated at reduced pressure to yield a solid with mp 138°-141° C. Recrystallization (acetonitrile) yields pure cis-hexahydro-1-oxo-cyclopenta[c]pyrrole-2(1H)-acetamide with mp 142.5°-143.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]([CH3:17])=C)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:18]1CCOCC1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+]>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15](=[O:18])[CH3:17])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-methylpent-4-enoate (500 mg, 2.055 mmol) in a solvent mixture of 1,4-dioxane (10 mL) and water (2.5 mL) at 0° C., was added 2,6-lutidine (0.479 mL, 4.11 mmol) and osmium tetroxide (2.5% in 2-methyl-2-propanol) (0.516 mL, 0.041 mmol), followed by sodium metaperiodate (1.758 g, 8.22 mmol). The reaction mixture was stirred at 0° C. for 15 min and warmed to room temperature and stirred for an additional 3 h. The mixture was diluted with ethyl acetate (150 mL) and washed with 10% aqueous NaHCO3. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-oxopentanoate (500 mg, 2.040 mmol, 100% crude yield) as a yellow liquid. The material was carried on without further purification. 1H NMR (400 MHz, CDCl3): δ ppm 5.48 (s, 1H), 4.51 (t, J=8.00 Hz, 1H), 3.75 (s, 3H), 3.23 (d, J=4.00 Hz, 1H), 3.17 (d, J=4.00 Hz, 1H), 2.18 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:11]1[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8].C([O:25][C:26](=[O:29])[CH2:27]Br)(C)(C)C.[NH4+].[Cl-]>CS(C)=O.C(O)(C(F)(F)F)=O>[C:7]([C:11]1[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:13]([CH2:27][C:26]([OH:29])=[O:25])[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(C(C)(C)C)nn1CC(=O)O
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
Potassium t-butoxide (2.6 g, 23 mmol) was dissolved in DMSO (10 mL) and to this solution was added ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (4.5 g, 23 mmol) in small portions and stirred under Ar for 15 min. To this solution was added t-butyl-bromoacetate (5.4 g, 28 mmol) slowly at 0° C. with stirring for 45 min at RT. Sat. NH4Cl solution was added and product was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford (7.0 g) coupled product as a pasty mass. The above pasty mass was dissolved in TFA (10 mL) and stirred for 3 h at RT. Solvents were removed, water (100 mL) was added and product was extracted with DCM (3×50 ml). The combined organic extracts were washed with brine solution, dried (Na2SO4) and concentrated to yield 2-(3-tert-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid (5.8 gm, 100%) as a pasty mass. 1H NMR (400 MHz, Acetone-d6): δ 6.78 (s, 1H), 5.25 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 1.35-1.30 (m, 12H); MS (ESI) m/z: 255.2 (M+H+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.[CH:16](OCC)=[O:17].Cl>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH:16]=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
Then, 4.19 g of sodium hydride (60% in oil) was suspended in 150 ml of tetrahydrofuran, to which a solution of 19.0 g of ethyl 4-chlorophenylacetate in 150 ml of tetrahydrofuran was added dropwise at 5° to 10° C. After stirring at room temperature for 1.5 hours, 8.42 g of ethyl formate was added, and the mixture was further stirred at room temperature for 4.5 hours. After completion of the reaction, the reaction mixture was cooled to ice temperature, neutralized by the addition of diluted hydrochloric acid, and concentrated. The residue was subjected to phase separation with ethyl acetate-water, and the organic layer was dried and then concentrated. The residue was subjected to silica gel chromatography, which afforded 17.0 g of ethyl 2-(4'-chlorophenyl)-2-formylacetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Br:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.Br[CH2:12][C:13](=[C:15]([C:18]#[N:19])[C:16]#[N:17])[CH3:14]>C(O)(C)C.O1CCCC1>[NH2:19][C:18]1[N:8]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([Br:10])=[CH:5][C:6]=2[Br:9])[CH:12]=[C:13]([CH3:14])[C:15]=1[C:16]#[N:17]
Reactant: CC(CBr)=C(C#N)C#N
Reactant: Nc1c(Cl)cc(Br)cc1Br
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1cn(-c2c(Cl)cc(Br)cc2Br)c(N)c1C#N
Yield: 26.3 %

Procedure:
A mixture of 5.3 g of 6-chloro-2,4-dibromoaniline and 3.5 g of 2-(2-bromo-1-methylethylidene)malononitrile was dissolved in a mixed solution of 10 ml of isopropanol and 10 ml of tetrahydrofuran. The reaction mixture was heated for 2 hours while being concentrated at 120° C. Water was poured into the reaction mixture. The reaction mixture was extracted with chloroform. The organic layer was ;washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure and was allowed to stand for crystallization to yield 1.9 g of 2-amino-4-methyl-1-(2,4-dibromo-6-chlorophenyl)pyrrole-3-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[C:13]([Cl:21])=[C:14]([Cl:20])[C:15]([O:18]C)=[C:16]([Cl:17])[C:11]=2[O:10][N:9]=1.Cl.N1C=CC=CC=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[C:13]([Cl:21])=[C:14]([Cl:20])[C:15]([OH:18])=[C:16]([Cl:17])[C:11]=2[O:10][N:9]=1
Reactant: COc1c(Cl)c(Cl)c2c(-c3ccccc3F)noc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Oc1c(Cl)c(Cl)c2c(-c3ccccc3F)noc2c1Cl

Procedure:
To 12.5 g of 3-(2-fluorophenyl)-6-methoxy-4,5,7-trichloro-1,2-benzisoxazole is added 80.0 g of pyridine hydrochloride. The mixture is immersed in an oil bath at 200° C. for thirty minutes with stirring. The melt is poured into one liter of iced-hydrochloric acid solution, stirred for thirty minutes, and the resultant precipitate collected and dried to yield 3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole, mp 110° C. (dec). To 50 ml of dry dimethylformamide is added 12 g of 3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole, 4.4 ml of ethyl bromoacetate and 20 g of potassium carbonate. The reaction is stirred at 70° C. for 2 hrs, filtered and solvent evaporated to afford an oil, which is stirred with 500 ml water for ten minutes and then extracted with ether/ethyl acetate. The organic extract is washed with water (2X), saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate followed by recrystallization from 95% ethanol yields ethyl {[3-(2-fluorophenyl)-4,5,7-trichloro-1,2-benzisoxazol-6-yl]oxy}acetate, mp 140°-3° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][NH:2]1.C[O:7][C:8](=O)[CH:9]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:10]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=1)=O>N1C=CC=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[C:8](=[O:7])[N:2]3[CH2:3][CH2:4][CH2:5][N:1]3[C:10]=2[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)C(C(=O)c1ccnc(SC)n1)c1ccc(F)cc1
Reactant: C1CNNC1
Solvent: c1ccncc1
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CCC3)n1
Temperature: 90 °C
Yield: 37 %

Procedure:
To a solution of pyrazolidine (7.8 g, 54.16 mmol) in pyridine (100 mL) is added 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-oxo-propionic acid methyl ester, 3, (11.5 g, 36.1 mmol). The reaction mixture is heated to 90° C. for 16 hours. The solvent is removed in vacuo and the resulting residue purified over silica (100% EtOAc, followed by 10% MeOH/EtOAc) to afford 3.9 g (37% yield) of the desired product as a yellow solid.