Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)(=O)C.[Br:12][C:13]1[CH:14]=C2[C:20](=[CH:21][CH:22]=1)[C:19]([CH3:24])([CH3:23])[CH2:18][CH2:17]C2>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[Br:12][C:13]1[CH:14]=[C:6]2[C:20]([C:19]([CH3:23])([CH3:24])[CH2:18][CH2:17][C:5]2=[O:7])=[CH:21][CH:22]=1
Reactant: CC1(C)CCCc2cc(Br)ccc21
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC1(C)CCC(=O)c2cc(Br)ccc21
Reaction time: 1 h

Procedure:
To a cold mixture (0° C.) of 209 g (200 mmol) of chromium trioxide, 100 ml (1.06 mol) of acetic anhydride and 200 ml (3.5 mol) of acetic acid was added a solution of 10 g (41.8 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 125 ml of benzene. The reaction mixture was stirred for 1 hour, quenched with ice cold water and extracted with Et2O (3×100 ml). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (silica, 10% EtOAc-hexane) to give the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:37])[NH:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:30][CH:29]1[CH:31]=[CH2:32])=O)(C)(C)C.Cl.Cl.O1CCOCC1.[C:46]([O:50][C:51]([NH:53][CH:54]([CH:58]1[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1)[C:55](O)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH3:36][O:35][C:33]([C:28]1([NH:27][C:26]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[CH:17]=[CH:16][N:15]=3)[CH2:12][N:8]2[C:55](=[O:56])[CH:54]([NH:53][C:51]([O:50][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:52])[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]2)=[O:37])[CH2:30][CH:29]1[CH:31]=[CH2:32])=[O:34]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)OC
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=CC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1)C(=O)OC
Reaction time: 4 h
Yield: 156.8 %

Procedure:
A solution of 2-(1-methoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in Example 27; 0.50 g, 0.98 mmol) in THF (3 mL) was treated with 4M HCl in dioxanes (1.2 mL, 4.9 mmol) at rt. After 4 h, additional 2-(1-methoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.58 mmol) and 4M HCl/dioxane solution (5 mL) were added. After an additional 4 h, the solvent was removed in vacuo and the resulting foamy white solid was taken up in DMF (3 mL) and treated with tert-Butoxycarbonylamino-cyclohexyl-acetic acid (0.55 g, 2.1 mmol), HATU (1.0 g, 2.7 mmol) and DIPEA (0.78 mL, 4.5 mmol) at rt and allowed to age overnight. The reaction mixture was diluted in EtOAc and washed consecutively with saturated NaHCO3, brine and then dried over anhydrous Na2SO4. After concentration in vacuo, the residue was purified via column chromatography on SiO2 (0-75% EtOAc/hex) to produce 1.0 g (89% over two steps) of 1-{[1-(2-tert-butoxycarbonylamino-2-cyclohexyl-acetyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid methyl ester as an off-white solid. LCMS found 651.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7](Cl)(=[O:9])=[O:8])[N:4]=[CH:3]1.[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12]1.ClCCl>C(#N)C>[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][S:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)(=[O:9])=[O:8])[CH2:13][CH2:12]1
Reactant: NCCCN1CCOCC1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCCCN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of 30 g (0.17 mol) of 1-methylimidazole-4-sulfonyl chloride from Example C-1 in 150 ml of acetonitrile is added dropwise to a solution of 24 ml (0.17 mol) of 3-morpholinopropylamine in 50 ml of acetonitrile (or dichloromethane). The temperature of the reaction mixture is kept at room temperature or below by external cooling with ice-water. Stirring is continued for 6 h at room temperature. The precipitate deposited is filtered off with suction and recrystallized from acetonitrile in order to give 46 g (85% of theory) of the title compound (hydrochloride) of melting point 207°-208° C.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[O:6][CH:5]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:18][CH:17]=[CH2:16])=[CH:12][C:7]=2[O:6][CH:5]=1
Reactant: C=CCBr
Reactant: CC(C)(C)Cc1coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(CC(C)(C)C)coc2c1
Reaction time: 2 h

Procedure:
A stirred solution of the product from Step E (2.880 grams) in dry DMF (30 mL) was treated with allyl bromide (1.282 mL) followed by cesium carbonate (4.828 grams). After 2 hours, the mixture was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried over magnesium sulfate and filtered. Concentration gave the title compound in such purity that further processing was not required.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[C:7](Br)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([O:14][C:15](=[O:35])[C@@H:16]([O:33][CH3:34])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]CC(OC(C)(C)C)=O)=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[C@@H:16]([O:33][CH3:34])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])([CH3:9])[CH3:8])=[CH:22][CH:23]=1)[CH3:13]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)OC(C)(C)C)cc1)OC
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Product: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)OC

Procedure:
The title compound was prepared from (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ester (Preparation 1) and 2-bromo-2-methyl-propionic acid tert-butyl ester via the same procedure used to prepare (2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (example 121, step 1) to produce a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]=2[C:11](O)=[O:12])[CH:7]=1.O[N:21]1[C:25]2N=CC=CC=2N=N1.Cl.CN.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C(OC(=O)C)C.ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]=2[C:11]([NH:21][CH3:25])=[O:12])[CH:7]=1
Reactant: O=C(O)c1c(-c2ccccc2)nn2cc(I)ccc12
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccccc2)nn2cc(I)ccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.8 %

Procedure:
To a 250 mL round-bottomed flask equipped with a magnetic stir bar was charged 6-iodo-2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid (200 mg, 0.549 mmol), 1-Hydroxy-7-azabenzotriazole (74.8 mg, 0.549 mmol), methylamine hydrochloride (55.6 mg, 0.824 mmol), diisopropylethylamine (671 μL, 3.84 mmol), dichloromethane (5000 μL) and dimethylfomamide (500 μL). To this yellow solution 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (147 mg, 0.769 mmol) was added. The reaction was stirred at room temperature for six hours and diluted with ethylacetate (200 mL). The organic portion was washed 5× with 0.5N hydrochloric acid, 1× saturated sodium bicarbonate and 2× brine. The organic portion was dried over magnesium sulfate. The solvent was removed by rotary evaporation. The residue was place under vacuum overnight to give a white solid (130 mg, 90%). 1H NMR (500 MHz, MeOD) δ ppm 2.87 (m, 3H) 7.51 (m, 3H) 7.63 (dd, J=9.31, 1.37 Hz, 1H) 7.76 (m, 3H) 8.94 (s, 1H). LCMS: 1.8 minutes, M+1=378.
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[C:5](Cl)=[S:6])([CH3:3])[CH3:2].[OH:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22]>>[O:22]=[C:13]1[C:14]2[C:15](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:17])[N:12]1[O:11][C:5](=[S:6])[N:4]([CH:8]([CH3:10])[CH3:9])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)N(C(=S)Cl)C(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Product: CC(C)N(C(=S)ON1C(=O)c2ccccc2C1=O)C(C)C

Procedure:
This compound was prepared in analogy to example 8 starting from 32.35 g (0.18 mol) of diisopropyl-thiocarbamoyl chloride (prepared as described in (Chem. Ber., 101, (1968), 113) and N-hydroxyphthalimide. Yield 21.44 g of white crystals after recrystallization from hexane, mp. 73-75° C.
Reaction SMILES: [F:1][C:2]([C:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]([O:16]CC)=[O:15])[N:7]([CH3:19])[N:6]=1)([CH3:4])[CH3:3].[OH-].[K+].O>CO>[F:1][C:2]([C:5]1[C:9]([C:10]([F:11])([F:12])[F:13])=[C:8]([C:14]([OH:16])=[O:15])[N:7]([CH3:19])[N:6]=1)([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1c(C(F)(F)F)c(C(C)(C)F)nn1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nc(C(C)(C)F)c(C(F)(F)F)c1C(=O)O
Temperature: 50 °C

Procedure:
A solution of 700 mg (2.48 mmol) of ethyl 3-(2-fluoropropan-2-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate in 10 ml of methanol is admixed with 208 mg (3.72 mmol) of potassium hydroxide and 1 ml of water and heated at 50° C. for one hour. The reaction mixture is concentrated by evaporation, admixed with water and extracted with diethyl ether. The aqueous phase is acidified with dilute hydrochloric acid and extracted twice with ethyl acetate, and the organic phase is dried over sodium sulphate and, after filtration, is concentrated by evaporation. This gives 498 mg of 3-(2-fluoropropan-2-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[NH:11][C:10](=O)[N:9]=2)=[CH:4][C:3]=1[CH3:16].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:16])[CH:4]=2)[CH:13]=[C:12]([CH3:14])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(=O)[nH]1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(4-chloro-3-methyl-phenyl)-6-methyl-1H-pyrimidin-2-one (9.78 g, 41.7 mmol) and phosphoroxychloride (98 mL) according to the general procedure I. Obtained as an off-white solid (7.38 g, 70%). MS (ISP) 253.1 [(M+H)+]; mp 131° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[O:2][CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: COc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 59.6 %

Procedure:
To a stirred solution of 0.362 g of 2-methoxybenzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered through hydrous magnesium silicate and evaporated in vacuo to give a solid which is purified by crystallization from ethyl acetate to give 0.430 g of the desired product as a crystalline solid, m.p. 185-188° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27]Cl)[CH3:24]>>[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)=[CH:14][N:13]=2)[CH2:16][CH2:17]1)[CH3:24]
Reactant: FC(F)(F)c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Reactant: CCN(CC)CCCl
Product: CCN(CC)CCN1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 2-diethylaminoethylchloride.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27]([NH:29][CH2:30][C:31]([N:33]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][CH2:41][CH2:42][O:43][Si](C(C)(C)C)(C)C)=[O:32])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:26][C:27]([NH:29][CH2:30][C:31]([N:33]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][CH2:41][CH2:42][OH:43])=[O:32])=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CNC(=O)OCc1ccccc1)c1ccccc1CCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN(C(=O)CNC(=O)OCc1ccccc1)c1ccccc1CCCO
Reaction time: 1.5 h

Procedure:
Tetrabutylammonium fluoride (1.0M in THF/10 ml, 10 mmol) was added to a solution of N-(benzyloxycarbonylaminomethylcarbonyl)-N-(tert-butyloxycarbonyl-methyl)-2-(3-tert-butyldimethylsilyloxypropyl)aniline(3.87 g, 6.8 mmol) in THF (25 ml) at room temperature. After stirring for 90 minutes the reaction mixture was diluted with ethyl acetate (150 ml), washed with water (150 ml), brine (150 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by flash chromatography on silica gel with ethyl acetate-hexane (2:1) as eluant (2.39 g, 77%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C@@H:5]([OH:10])[C@@H:6]([CH3:9])[CH2:7][CH3:8])[CH3:2].CC([O-])=O.[Na+].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:11])[C:5](=[O:10])[C@@H:6]([CH3:9])[CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)[C@@H](O)[C@@H](C)CC
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)[C@@H](C)CC
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
To a solution of (+)-hydroxy ester [3] (2.0 g, 12.5 mmol) in 20 ml of CH2Cl2 at room temperature were added successively NaOAc (312 mg, 3.8 mmol) and PCC (pyridinium chlorochromate, 4.04 g, 18.75 mmol). After 24 h at room temperature, the conversion was only 60% and 2.02 g PCC were re-added. The mixture was stirred 96 h at room temperature, rapidly filtered on SiO2, concentrated and purified by flash chromatography on SiO2 to give 1.58 g of ester [4]. At this stage, a GC control on chiral column (CHIRASIL-DEX CB, 25 m×0.25 mm, isoth. 80°) showed a purity of 100% and an ee (enantiomeric excess) of 100%. After bulb-to-bulb distillation (Eb=100°, 16 mbars), 1.51 g (yield: 76.3%) of pure (+)-ester [4] were obtained.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH2:12][C:13]([OH:15])=O.[CH2:16]([C@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C@H:23]1[CH2:27][N:26]([C:13](=[O:15])[CH2:12][N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)[C@H:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)CN1CCc2ccccc2C1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CN1CCc2ccccc2C1
Yield: 34.7 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3,4-dihydroisoquinolin-2(1H)-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 82, (2S,4R)-4-benzyl-1-(2-(3,4-dihydroisoquinolin-2(1H)-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (13.7 mg, 34.7%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.98 (s, 1H), 7.56 (d, 2H), 7.23-7.15 (m, 10H), 7.09 (m, 3H), 6.94 (m, 2H), 4.49 (m, 1H), 3.74 (m, 1H), 3.63 (d, 2H), 3.36 (m, 1H), 3.29 (s, 2H), 2.78-2.73 (m, 4H), 2.61 (m, 3H), 1.91 (m, 2H). MS (EI) for C35H34FN3O3. found 564.7 (MH+).
Reaction SMILES: C(NCC(O)=O)C(O)=O.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH2:26])=[CH:23][CH:22]=1.[Cl:29]C1C=CC=CC=1C=C.ClC1C=C(C=CC=1)C=C>[Pd]>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH2:26])=[CH:23][CH:22]=1.[Cl:29][C:17]1[CH:18]=[C:19]2[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]2)=[CH:15][CH:16]=1
Reactant: C=Cc1ccccc1Cl
Reactant: c1ccc2ccccc2c1
Agent: [Pd]
Agent: C=Cc1ccc(Cl)cc1
Agent: C=Cc1cccc(Cl)c1
Product: Clc1ccc2ccccc2c1

Procedure:
Microwave irradiation of styrene 5 in either 1,2-dichloroethane (DCE) at 180° C. for 30 min or 1,1,1-trifluorotoluene at 180° C. for 180 minutes afforded the cyclopenta-naphthalene derivative 6 in nearly quantitative yield with no additional purification required of the final product (entries 1 and 2, Table 1). With conditions for an efficient and high yielding IMDA reaction utilizing a lower boiling solvent in hand, scope and limitations investigations were initiated. First, substitution on the aryl group was examined; exchanging a hydrogen atom for a chlorine atom was deemed valuable, enabling access to a wide-range of naphthalene derivatives via palladium-catalyzed cross coupling reactions. Moreover, a chlorine atom is more stable and accessible than other halides or groups used for coupling, such as triflates. Styrenyl derivatives 5b, 5c, and 5d were prepared and subjected to microwave irradiation. The para-chlorostyrene 5b gave 7-chloronaphthalene 6b in quantitative yield after 200 min (entry 3). The ortho-chlorostyrene 5c also produced only one product, the 5-chloronaphthalene 6c in 86% yield, even though two products are possible (entry 4). The meta-chlorostyrene 5d gave an inseparable 1.4:1 mixture of the 6-chloro- and 8-chloronaphthalenes, 6d and 6d′ in 79% yield (entry 5).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[O:10][C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[N:15][CH:16]=1)=[N+]=[N-].BrC1N=CC(O[C@@H]2CCCC[C@H]2O)=CC=1.BrC1C=CC(O[C@@H]2CCC[C@H]2O)=CC=1.BrC1C=CC(O[C@@H]2CCC[C@@H]2N=[N+]=[N-])=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Br:17][C:14]1[N:15]=[CH:16][C:11]([O:10][C@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]2[NH2:1])=[CH:12][CH:13]=1
Reactant: [N-]=[N+]=N[C@H]1CCCC[C@H]1Oc1ccc(Br)nc1
Agent: O[C@@H]1CCCC[C@H]1Oc1ccc(Br)nc1
Agent: O[C@@H]1CCC[C@H]1Oc1ccc(Br)cc1
Agent: [N-]=[N+]=N[C@H]1CCC[C@H]1Oc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H]1CCCC[C@@H]1Oc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Cis-5-[(2-azidocyclohexyl)oxy]-2-bromopyridine, prepared from trans-2-[(6-bromopyridin-3-yl)oxy]cyclohexanol by the general procedures described in Example 5 for the conversion of trans-2-(4-bromophenoxy)cyclopentanol to cis-2-azidocyclopentyl 4-bromophenyl ether) (13.5 g, 45.4 mmol) was dissolved in tetrahydrofuran (292 mL) and water (23 mL), and the solution was treated with triphenylphosphine (23.8 g, 90.7 mmol). The reaction was stirred for 18 hours at room temperature, then partitioned between ethyl acetate (500 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water (2×200 mL) and saturated aqueous sodium chloride solution (200 mL). The organic layer was then extracted with aqueous 1N hydrochloric acid (4×150 mL), and the combined aqueous layers were washed with ethyl acetate (150 mL). The aqueous layer was then cooled in an ice bath and slowly treated with an aqueous 2N solution of sodium hydroxide, until the mixture was a cloudy white; it was then extracted with ethyl acetate (3×150 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Cis-2-[(6-bromopyridin-3-yl)oxy]cyclohexanamine was obtained as a yellow oil. Yield: 8.00 g, 29.5 mmol, 65%. 1H NMR (500 MHz, CDCl3) δ 1.34 (d, J=6.8 Hz, 3H), 1.35 (d, J=6.7 Hz, 3H), 1.35-1.52 (m, 4H), 1.79-1.85 (m, 3H), 2.02 (m, 1H), 3.11 (septet, J=6.8 Hz, 1H), 3.53 (m, 1H), 4.59 (br s, 1H), 4.68 (m, 1H), 7.19 (dd, J=8.7, 3.1 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 8.07 (d, J=3.2 Hz, 1H).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])=[CH:23][CH:22]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1ccc2oc(C(Cl)C3CCCCC3)c(C)c2c1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(C)cc3c2C)C2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 66.4 %

Procedure:
A mixture of 2-[chloro(cyclohexyl)methyl]-3,5-dimethyl-1-benzofuran (400 mg) synthesized in Example A90(4), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (363 mg) synthesized in Example 2(2), sodium iodide (327 mg), sodium carbonate (231 mg) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (45% ethyl acetate/hexane) to give the title object compound (471 mg, 66%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:30])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[N+:23]([O-])=O)[CH2:14][C:13](=[O:26])[NH:12][CH:11]3[C:27]([CH3:29])=[CH2:28])[C:5]2=[CH:4][CH:3]=1.NN.O>CO.[Ni]>[NH2:23][C:17]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=1[CH:15]1[CH2:14][C:13](=[O:26])[NH:12][CH:11]([C:27]([CH3:29])=[CH2:28])[C:10]21[C:5]1[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[NH:8][C:9]2=[O:30]
Reactant: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2[N+](=O)[O-])C12C(=O)Nc1cc(Cl)ccc12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2N)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
The reaction mixture of racemic (2′R,3R,4′S)-6-chloro-4′-(5-chloro-2-nitro-phenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (290 mg, 0.65 mmol), Raney Ni (39 mg) and NH2NH2.H2O (320 mg) in methanol was stirred at 80° C. for 0.5 h. The mixture was cooled to 4° C., and concentrated. To the residue were added ethyl acetate (10 mL) and water (10 mL). The organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography to give the title compound as a solid (Yield: 260 mg).