Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH:39]([NH2:41])[CH3:40]>C(Cl)Cl>[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH:39]([NH:41][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH:8]([CH3:9])[CH3:10])=[O:13])[CH3:40]
Reactant: CC(N)c1nc2ccccc2s1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CC(C)OC(=O)N[C@H](C(=O)NC(C)c1nc2ccccc2s1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
0.3 g of N-methylpiperidine was added to a solution containing 0.6 g of N-isopropoxycarbonyl-L-valine dissolved in 40 mL of methylene chloride, at -20° C., and then the mixture was stirred for 10 minutes at the same temperature. 0.4 g of isobutyl chloroformate was added to the mixture at -40° C., and then stirred for 1 hour at -40° C. to -15° C. After 0.5 g of 1-(2-benzothiazolyl)ethylamine was added to this mixture at -60° C. and the refrigerant was put off, the reaction mixture was warmed naturally to room temperature while being stirred. After completion of the reaction, the reaction mixture was washed successively with water, a 5% aqueous solution of sodium bicarbonate, and water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue, which was a crude crystal, was purified by column chromatography on silica gel, thus yielding 0.6 g of the desired product in the form of a white powder (yield: 59%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][OH:17])[CH:12]=[CH:13][C:14]=1[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[F:15])[CH:16]=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(F)c(OCc2ccccc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(F)c(OCc2ccccc2)c1
Reaction time: 22 h
Yield: 93.7 %

Procedure:
To a stirring solution of [3-(benzyloxy)-4-fluorophenyl]methanol (14 mg) in DCM (0.7 mL) was added manganese dioxide (140 mg) at ambient temperature. After 22 hours, the reaction mixture was filtered through a bed of Celite and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=10:1) to give 3-(benzyloxy)-4-fluorobenzaldehyde (13 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30]/[CH:31]=[CH:32]/[C:33]([O:35]C)=[O:34])[C:14]1=[O:37])=[O:11].O1CCCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.O.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30]/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])[C:14]1=[O:37])=[O:11]
Reactant: COC(=O)/C=C/CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)/C=C/CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
A mixture of (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-1-[(E)-3-methoxycarbonyl-2-propenyl]-5-phenyl-2H-1,4-benzodiazepine-2-one (0.47 g), tetrahydrofuran (15 ml), methanol (7.5 ml) and 1N aqueous sodium hydroxide (1 ml) was stirred for 1.0 hour at room temperature and cooled. To the cooled reaction mixture were added water (100 ml) and ethyl acetate (100 ml) and the mixture was adjusted to pH 4.0 with 6N hydrochloric acid under stirring. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with an eluent of a mixture of chloroform and methanol (1:1) to give (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino )-1-[(E)-3-carboxy-2-propenyl]-5-phenyl-2H-1,4-benzodiazepine-2-one (80 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36](C(OC(C)(C)C)=O)[CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:19]1([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1cccnc1)c1cc(-c2cn[nH]c2)ccc1OCc1ccccc1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 310 mg, 0.81 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (262 mg, 0.89 mmol), 1,4-dioxane (3 ml), sodium carbonate (1.62 ml, 1.62 mmol) and tetrakis(triphenylphosphine)palladium(0) (56.1 mg, 0.05 mmol). The vial was sealed and heated to 120° C. for 25 min under microwave conditions. The mixture was evaporated under reduced pressure and water (5 ml) was added to the residue. The mixture was extracted with ethyl acetate (3×10 ml). The organics were combined and evaporated under reduced pressure, and the residue was purified using the MDAP to yield the title compound. 44 mg.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][O:4][C:5]1[C:10]([N+:11]([O-])=O)=[C:9]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:8]=[C:7]([CH3:20])[N:6]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].S(=O)(=O)(O)O.N>C(O)(C)C.O>[NH2:11][C:10]1[C:5]([O:4][CH2:3][C:2]([F:22])([F:1])[F:21])=[N:6][C:7]([CH3:20])=[CH:8][C:9]=1[O:14][CH2:15][C:16]([F:18])([F:19])[F:17]
Reactant: Cc1cc(OCC(F)(F)F)c([N+](=O)[O-])c(OCC(F)(F)F)n1
Agent: N
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(OCC(F)(F)F)c(N)c(OCC(F)(F)F)n1
Temperature: 80 °C
Yield: 80.3 %

Procedure:
2,4-Bis(2,2,2-trifluoroethoxy)-6-methyl-3-nitropyridine (45.00 g, 134.7 mmol) was dissolved in isopropanol (300 mL). While stirring the solution at 80° C., a solution of sodium dithionite (78.00 g, 448.0 mmol) in water (300 mL) was added, followed by stirring for 15 minutes. A solution of sodium dithionite (16.50 g, 94.8 mmol) in water (51 mL) was added, and the mixture was stirred for 10 minutes. Further, a solution of sodium dithionite (11.10 g, 63.8 mmol) in water (51 mL) was added, followed by stirring for 10 minutes. A 4 mol/L aqueous solution of sulfuric acid (201 mL) was added, and the mixture was stirred at 90° C. for 30 minutes. After allowing the reaction mixture to cool down to room temperature, 28% aqueous ammonia (310 mL) was added to the reaction mixture in an ice bath, followed by stirring for 30 minutes. The mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain the title compound (32.91 g, 80%) as pale yellow needles.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:13][Si:14]1(C2C=CC=CC=2)[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:16][CH2:15]1>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:13][Si@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:16][CH2:15]2)=[CH:7][CH:8]=1
Reactant: COCCCCCC1CC[Si](CBr)(c2ccccc2)CC1
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: COCCCCC[C@H]1CC[Si@H](COc2ccc(C(F)(F)F)cc2)CC1

Procedure:
The general procedure of Example 9 was repeated using 4-trifluoromethylphenol and 4-bromomethyl-1-(5-methoxypentyl)-4-phenyl-4-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Na].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CO>[CH2:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Br:13])=[CH:7][CH:6]=1)[C:9]([CH3:10])=[O:11]
Reactant: BrCCCCCCCCCCBr
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: [Na]
Solvent: CO
Product: CC(=O)Cc1ccc(OCCCCCCCCCCBr)cc1
Reaction time: 0.17 h

Procedure:
A solution of 4-hydroxyphenyl propan-2-one, ethylene ketal (5.26 g) in methanol at room temperature, was treated with sodium (0.66 g) and allowed to stir for 10 minutes. The resulting solution was then added dropwise over 15 minutes to a solution of 1,10-dibromodecane (9.0 g) in methanol under reflux and the reaction mixture heated for 3 h. The mixture was allowed to cool and the solvent was removed in vacuo. The residue was partitioned between diethylether and water, the organic layer separated, dried (magnesium sulphate), and the solvent removed in vacuo to give an oil which was chromatographed on silica. Elution with chloroform gave 10-(4-acetonylphenoxy)decyl bromide, ethylene ketal (3.0 g) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=[O:10])=[CH:5][CH:4]=1)#[N:2].O[C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:22](=[O:27])[CH2:23]S(C)=O.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:21][O:20][C:19]1[C:14]2[O:10][C:9]([CH:8]=[CH:7][C:6]3[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[CH:23][C:22](=[O:27])[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1ccc(C=CC=O)cc1
Reactant: COc1cccc(C(=O)CS(C)=O)c1O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1cccc2c(=O)cc(C=Cc3ccc(C#N)cc3)oc12

Procedure:
A mixture of 7.85 g of 4-cyanocinnamaldehyde (U.S. Pat. No. 2,993,834), 11.4 g of 2'-hydroxy-3'-methoxy-2-(methylsulfinyl)acetophenone, 250 ml of toluene, and 0.5 ml of piperidine was refluxed for 3 hrs. The mixture was chilled, and the crystalline ppt. filtered, and recrystallized from toluene, mp. 274°-75°; yield 7 g (46%); λ max mμ (ε) 222 (20,600), 328 (42,500); ν max 745 (m), 845 (m), 1060 (m), 1275 (m), 1570 (m), 1595 (m), 1655 (ms), 2230 (m) cm-1.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[O:12]=[C:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.[OH-].[K+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:5]([O:4][CH2:3][CH2:2][N:18]1[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:14][C:13]1=[O:12])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)C1
Reaction time: 4 h
Yield: 48.4 %

Procedure:
A solution of (2-bromoethoxy)-tert-butyldimethylsilane (4.71 g, 19.7 mmol) in tetrahydrofuran (20 ml) was added dropwise at room temperature to a stirred solution of tert-butyl 3-oxopiperazine-1-carboxylate (3.94 g, 19.7 mmol), powdered potassium hydroxide (1.32 g, 23.6 mmol) and tetrabutylammonium bromide (1.27 g, 3.94 mmol) in tetrahydrofuran (30 ml) and the resulting mixture was stirred for 4 hours. The mixture was filtered and then evaporated to leave a colourless viscous oil which was purified by silica gel chromatography eluting with methyl tert-butyl ether as eluent to give tert-butyl 4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-oxopiperazine-1-carboxylate (3.42 g, 45% yield) as a colourless oil:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([NH2:16])[C:9]([N+:13]([O-])=O)=[CH:10][C:11]=1[F:12].[H][H]>CO.[Pd]>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([NH2:16])[C:9]([NH2:13])=[CH:10][C:11]=1[F:12]
Reactant: CN(C)CCNc1cc(N)c([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCNc1cc(N)c(N)cc1F

Procedure:
1.29 g of N3-(2-dimethylaminoethyl)-4-fluoro-6-nitrobenzene-1,3-diamine in solution in 30 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 130 mg of palladium-on-charcoal at 25° C. for 16 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 1 g of N4-(2-dimethylaminoethyl)-5-fluorobenzene-1,2,4-triamine are recovered in the form of a black resin. The product is used as it is for the subsequent stage.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:15][NH2:16]>C(O)C>[C:2]1([C:1]2[CH2:9][CH2:10][C:11](=[O:13])[NH:15][N:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccccc2)=NN1

Procedure:
A mixture of 3-benzoylpropionic acid (89 g), 80% hydrazine hydrate (25.5 ml) in ethanol (1000 ml) is refluxed for 6 hrs, cooled and filtered to give 75.6 g of 6-phenyl-4,5-dihydro-3(2H)-pyridazinone. Bromine (70 g) is added dropwise to a solution of the above pyridazinone in acetic acid (200 ml) at 80° C. After the addition is over, the mixture is heated to 100° C. for 15 minutes, cooled, filtered and washed with isopropyl ether. The solid is slurried in water, adjusted to pH 10 and filtered to give 60 g of the product 6-phenyl-3(2H)-pyridazinone.
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17]([NH:21][C:22]([NH2:24])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH3:18][C:17]([NH:21][C:22]1[O:23][C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:24]=1)([CH3:20])[CH3:19]
Reactant: CCOC(=O)C(=O)C(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)NC(N)=O
Product: CCOC(=O)c1nc(NC(C)(C)C)oc1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
A reaction vessel was charged with 6.5 g (25 mmol) of ethyl 3-chloro-3-(m-chlorophenyl)pyruvate and 2.9 g (25 mmol) of tert-butyl urea. The reaction mixture was heated at 105°-115° C. for 2 hours. The mixture was cooled to ambient temperature and 1.71 g of tert-butyl urea starting material was removed by crystallization in hexane-ethyl acetate solution. The remaining 10.16 g of a brown oil was subjected to Kugelrohr distillation (70°-80° C. @ 0.3 mm Hg) to yield 5.08 g of a gold viscous oil. This oil was chromatographed on silica gel using a Waters Prep 500 system and 10% ethyl acetate-in-hexane eluent to yield product identified in Table 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4Cl)c3O2)cc1
Yield: 72.3 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (3.00 g, 7.83 mmol) with 3-chlorophenylboronic acid (1.84 g, 11.74 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.308 g, 0.391 mmol), and potassium carbonate (2.70 g, 19.57 mmol) generally according to the procedure described for Intermediate 37 provided 2.35 g (72%) of (±)-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a tan solid. mp 100-103° C.; Anal. calcd. for C22H19ClO4S: C, 63.69; H, 4.62. Found: C, 63.43; H, 4.69.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[S:31]([NH:2][CH2:3][CH:4]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)[CH3:5])(=[O:33])=[O:32]
Reactant: CC(CN)c1ccc(OCC(=O)O)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(CNS(=O)(=O)c1cc(Cl)ccc1Cl)c1ccc(OCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2.95 g of (±)-4-(2-amino-1-methylethyl)phenoxyacetic acid hydrochloride, 3.82 g of sodium carbonate, 30 ml of water and 3.1 g of 2,5-dichlorophenylsulfonyl chloride is stirred at 80° C. for 3 hours. The reaction mixture is treated in the same manner as described in Example 43, whereby (±)-4-[2-(2,5-dichlorophenyl)sulfonylamino-1-methylethyl)phenoxyacetic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.3 %

Procedure:
To a solution of 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (85 mg, 69%).
Reaction SMILES: [Li+].[BH4-].C[Si](Cl)(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:18][CH2:17][C@@H:16]1[C:19](O)=[O:20])=[O:14])([CH3:11])([CH3:10])[CH3:9].CO>C1COCC1.O>[OH:20][CH2:19][C@H:16]1[CH2:17][CH2:18][N:15]1[C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1C(=O)O
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 2M LiBH4 (200 ml, 400 mmol) in THF at 0° C. was added TMSCl (101 ml, 800 mmol) slowly. The mixture was warmed up to r.t and stirred at r.t. for 30 min. To the mixture at 0° C. was added a solution of (R)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (40 g, 200 mmol) in 200 ml THF with an additional funnel over 1 hour. The mixture was warmed up to r.t and stirred at r.t. for 2 hours. The mixture was cooled down to 0° C. and then treated with 32 mL MeOH followed by 40 mL H2O. After removal of THF, the residue was extracted with 300 mL EtOAc and washed with 300 mL brine. The organic layer was dried and concentrated to give (R)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate as a colorless oil (32.5 g, 87%). LRMS (M−100+H+) m/z 132.1.
Reaction SMILES: [C:1]([C@@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:24][CH3:25])=[CH:11][C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[C:7](O)=[CH:6]1)([O:3][CH3:4])=[O:2].C(OCC)(=O)C.Cl.[H][H]>CO.[Pd]>[C:1]([C@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:24][CH3:25])=[CH:11][C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1C=C(O)c2cc(OC)cc3c2[C@@H]1C[C@H](c1ccccc1)C3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1CCc2cc(OC)cc3c2[C@@H]1C[C@H](c1ccccc1)C3

Procedure:
To a solution of 0.46 g. (1.3 mmol) of [1R,8S,9aR] 1-carbomethoxy-5-methoxy-3-hydroxy-8-phenyl-7,8,9,9a-tetrahydrophenalene, from Step 3, in 50 mL of methanol, 50 mL of ethyl acetate, and 0.1 mL of concentrated hydrochloric acid is added 0.2 g of 5% palladium supported on carbon and the mixture is shaken under 4 atmospheres of hydrogen until the hydrogen uptake ceases. The catalyst is filtered through Celite filter aid and concentrated to give the title compound, which is carried on without further purification.
Reaction SMILES: C([N:8]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:15]2[C:10](=[C:11]([Cl:30])[C:12]([O:28][CH3:29])=[CH:13][CH:14]=2)[CH2:9]1)C1C=CC=CC=1.Cl>C(O)C>[Cl:30][C:11]1[C:12]([O:28][CH3:29])=[CH:13][CH:14]=[C:15]2[C:10]=1[CH2:9][NH:8][CH2:17][CH:16]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1
Reactant: COc1ccc(C2CN(Cc3ccccc3)Cc3c2ccc(OC)c3Cl)cc1OC
Agent: Cl
Solvent: CCO
Product: COc1ccc(C2CNCc3c2ccc(OC)c3Cl)cc1OC
Yield: 65.2 %

Procedure:
1.13 g of 2-benzyl-8-chloro-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 28 ml of ethanol, and after adding thereto 0.22 ml of 12 N hydrochloric acid, hydrogenation reaction was performed by addition of 0.1 g of 10%-paradium-carbon. After the hydrogenation reaction was over, the reaction solution was filtered, and concentrated. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 580 mg of 8-chloro-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, m.p. 130°-132° C. ##STR56##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[C:13]([O:17][C:18](=[O:35])[NH:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][N:21]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:35])[NH:19][C:20]1[CH:25]=[C:24]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH:23]=[CH:22][N:21]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Fc1ccc(C(F)(F)F)cc1I
Reactant: CC(C)(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: CC(C)(C)OC(=O)Nc1cc(-c2cc(C(F)(F)F)ccc2F)ccn1
Yield: 41 %

Procedure:
Prepared according to Preparation 21 using 1-fluoro-2-iodo-4-(trifluoromethyl)benzene and tert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (Preparation 24, 430 mg, 1.0 mmol). The residue was purified by silica gel column chromatography (ISCO™, 0-30% ethyl acetate in heptane gradient elution, 2×12 g SiO2) to give title compound as a green solid (0.105 g, 41%).
Reaction SMILES: [Cl:1][C:2]([N:5]=[C:6]=[O:7])([Cl:4])[Cl:3].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][OH:17])[CH:12]=[CH:13][C:14]=1[Cl:15]>C(OCC)C>[Cl:1][C:2]([Cl:4])([Cl:3])[NH:5][C:6]([N:16]([C:11]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=1)[OH:17])=[O:7]
Reactant: ONc1ccc(Cl)c(Cl)c1
Reactant: O=C=NC(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(NC(Cl)(Cl)Cl)N(O)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
A solution of trichloromethyl isocyanate (16 grams; 0.1 mol) in diethyl ether (40 ml) is added dropwise, with stirring, to a solution of N-(3,4-dichlorophenyl) hydroxylamine (17.8 grams; 0.1 mol) in diethyl ether (60 ml) at room temperature. Stirring is continued for a period of about 1 hour resulting in the formation of a precipitate. The precipitate is recovered by filtration, is washed and dried to yield 1-trichloromethyl-3-(3',4'-dichlorophenyl)-3-hydroxyurea.