Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:24](OCC)[O:25]CC)=[N:4][C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:6]([F:16])[C:7]=1[N:8]=C1C=CC(=O)C=C1.S(=O)(=O)(O)O.C(#N)C.O>C(Cl)Cl>[NH2:8][C:7]1[C:6]([F:16])=[C:5]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=[C:3]([CH:24]=[O:25])[C:2]=1[Cl:1]
Reactant: CCOC(OCC)c1nc(-c2ccc(Cl)cc2)c(F)c(N=C2C=CC(=O)C=C2)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Nc1c(F)c(-c2ccc(Cl)cc2)nc(C=O)c1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A mixture of 4-((3-chloro-6-(4-chlorophenyl)-2-(diethoxymethyl)-5-fluoropyridin-4-yl)imino)cyclohexa-2,5-dienone (180 milligrams (mg), 0.401 mmol) and 0.1 molar (M) sulfuric acid (H2SO4; 0.5 mL) in a 1:1 mixture of acetonitrile/water (4 mL) was heated to 80° C. for 1 h. After stirring at room temperature for 2 h, the reaction mixture was added to CH2Cl2 (20 mL). The organic layer was washed with a saturated solution of NaCl and dried (MgSO4), and the solvent was removed leaving 4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinaldehyde (82 mg, 0.273 mmol, 68% yield) as an off-white solid: mp 166-169° C.; 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 7.96 (m, 2H), 7.48 (m, 2H), 4.99 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −137.68; ESIMS m/z 285.64 ([M+H]+).
Reaction SMILES: [C:1]1([C:7](=[CH2:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>O1CCCC1.CN(C)C(=N)N(C)C>[N:14]1([CH2:13][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: C=C(C(=O)OCC)c1ccccc1
Reactant: c1c[nH]cn1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Cn1ccnc1)c1ccccc1
Yield: 81.9 %

Procedure:
A solution of ethyl 2-phenylprop-2-enoate (160 g, 0.45 mol), imidazole (36.7 g 0.54 mol) and tetramethylguanidine (2 g, 0.017 mol) in dry tetrahydrofuran (1 L) was heated at reflux temperature for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in dilute hydrochloric acid. The resulting aqueous solution was washed with ether, basified with dilute aqueous sodium hydroxide and extracted with chloroform. The organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield ethyl 3-(imidazol-1-yl)-2-phenylpropanoate (90 g).
Reaction SMILES: [Si]([O:18][CH2:19][CH:20]([F:35])[CH2:21][N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]1=[O:34])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:35][CH:20]([CH2:19][OH:18])[CH2:21][N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]1=[O:34]
Reactant: COc1ccc2ncc(=O)n(CC(F)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2ncc(=O)n(CC(F)CO)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
1-(3-{[tert-Butyl(diphenyl)silyl]oxy}-2-fluoropropyl)-7-methoxyquinoxalin-2(1H)-one (690 mg, 1.41 mmol) was dissolved in tetrahydrofuran (7 ml). Tetrabutyl ammonium fluoride (1M tetrahydrofuran solution; 1.83 ml, 1.83 mmol) was added to the solution under cooling on ice and the mixture was stirred at room temperature for 5 hours. Saturated sodium bicarbonate water was added to the reaction solution and the resultant was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield 348 mg (98%) of the title compound in the form of a yellowish solid.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([O:4][C:5](=[O:38])[NH:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[C:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([O:27]CC1C=CC=CC=1)=[O:26])[CH3:3].[H][H]>CO.[C].[Pd]>[CH3:3][C:2]([CH3:39])([O:4][C:5](=[O:38])[NH:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([OH:27])=[O:26])[CH3:1]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCOCC#Cc1cccc(C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of benzyl 3-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicos-19-yn-20-yl)benzoate (16 g, 29.52 mmol, 1.00 equiv) in methanol (200 mL), Palladium carbon (10 g). Hydrogen gas was introduced into the reaction vessel. The resulting solution was stirred for 3 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:1). This resulted in 7 g (52%) of 3-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-yl)benzoic acid as pale-yellow oil. LC-MS (ES, m/z): 456 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 7.76 (dd, J=6.0 Hz, 2H), 7.37-7.47 (m, 2H), 6.73 (s, 1H), 3.35-3.52 (m, 16H), 3.05 (dd, J=11.7 Hz, 2H), 2.69 (t, J=7.5 Hz, 2H), 1.76-1.85 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:19]3=[C:20]4[C:10](=[CH:11][CH:12]=[C:13](B(O)O)[C:14]4=[CH:15][CH:16]=[C:17]3[CH:18]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>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>[C:30]1([CH:36]2[CH:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:7]3[CH:8]=[CH:9][C:10]([C:11]4[CH:12]=[CH:13][C:14]5[C:6]6=[C:7]7[C:19](=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:18][C:17]7=[CH:16][CH:15]=5)[CH:17]=[CH:18][C:5]=46)=[CH:20][C:19]=3[C:19]3[C:7]2=[CH:8][CH:9]=[C:10]([C:11]2[CH:12]=[CH:11][C:10]4[C:20]5=[C:16]6[C:15](=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:18][C:17]6=[CH:8][CH:9]=4)[CH:14]=[CH:13][C:12]=25)[CH:20]=3)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)c1cc2ccc3ccc(B(O)O)c4ccc(c1)c2c34
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: [K+]
Product: CC(C)(C)c1cc2ccc3ccc(-c4ccc5c(c4)-c4cc(-c6ccc7ccc8cc(C(C)(C)C)cc9ccc6c7c89)ccc4C(c4ccccc4)C5c4ccccc4)c4ccc(c1)c2c34
Temperature: 60 °C
Yield: 75 %

Procedure:
As illustrated in Formula 7, the product 4a in Formula 6 (1.2 g, 2.46 mmol), 7-tert-butylpyren-1-ylboronic acid (2.23 g, 7.38 mmol), potassium carbonate solution (2.0 M, 10 mL), and dried toluene (30 mL) were charged in a two-necked bottle. The bottle was deoxygenated and purged with nitrogen, and the mixture in the bottle was stirred at 60° C. until it was totally dissolved. The nitrogen pressure of the bottle was increased, and Pd(PPh3)4 (289 mg, 0.25 mmol) was rapidly added into the bottle. The reaction was heated to 110° C., and stirred for 48 hours. The resulting was cooled to room temperature to precipitate a solid, and the solid was collected by filtering. The solid was sublimated at a temperature of 330° C. to obtain a white solid of 1.56 g (yield=75%).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[C:23](=[O:28])[N:24]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccc[nH]c1=O
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: O=c1cccn[nH]1
Product: Cc1cccn(-c2ccc3nc([C@H]4C[C@H](N5CCCC5)C4)sc3c2)c1=O

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 62A for the product of Example 1E and substituting 3-methyl-2-pyridone for 3(2H)-pyridazinone. 1H NMR (300 MHz, CDCl3) δ ppm 8.03 (t, J=8.31 Hz, 1H) 7.89 (d, J=2.03 Hz, 1H) 7.44 (t, 1H) 7.27-7.33 (m, 1H) 6.18 (q, 2H) 3.55-3.75 (m, 1H) 3.03-3.15 (m, 1H) 2.39-2.76 (m, 6H) 2.21 (s, 3H) 1.79-1.99 (m, 4H) 1.50-1.70 (m, 2H). MS: (M+H)+=366.
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:6][C:3]=1[C:4]#[N:5].N(OCCC(C)C)=O>C1COCC1.CC(OC)(C)C>[F:17][C:16]([F:18])([F:19])[CH2:15][O:14][C:7]1[CH:6]=[C:3]([CH:2]=[CH:9][C:8]=1[C:10]([F:13])([F:11])[F:12])[C:4]#[N:5]
Reactant: N#Cc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Agent: CC(C)CCON=O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Yield: 79.1 %

Procedure:
To a solution of 2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile from step 4 (14.47 g, 50.9 mmol) in dry THF (153 mL) was added isoamyl nitrite (15.0 mL, 112.0 mmol), and the mixture was refluxed for 20 h. The solvent was removed in vacuum to give an orange oil, which was dissolved in TBME, washed with 1 N HCl, sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown solid (15.05 g), which was purified by Kugelrohr distillation (up to 155° C. bath temperature at 1.2 mbar) to give the title compound as a light yellow solid (10.83 g, 79%). MS (EI) 269 [M].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-])[CH:5]=[CH:6][C:7]=1[Cl:8].COS(OC)(=O)=O.[C-:25]#[N:26].[Na+]>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[N:12]=[C:13]([C:25]#[N:26])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [O-][n+]1ccccc1C=Cc1ccc(Cl)c(Cl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCCCCC
Product: N#Cc1cccc(C=Cc2ccc(Cl)c(Cl)c2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(3,4-dichloro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a white crystalline material. Mp. 124-125° C. (hexane), MS: m/e=274 (M+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([F:31])[CH:25]=1>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)=[CH:25][C:26]=1[F:31])(=[O:3])[CH3:2]
Reactant: Nc1ccc(OCc2ccccn2)cc1F
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Product: CC(=O)Oc1ccc2ncnc(Nc3ccc(OCc4ccccn4)cc3F)c2c1
Yield: 94 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-acetoxy-4-chloroquinazoline was reacted with 4-amino-3-fluorophenyl 2-pyridylmethyl ether to give 6-acetoxy-4-[2-fluoro-4-(2-pyridylmethoxy)anilino]quinazoline in 94% yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:28]=3[O:29][CH3:30])=[CH:19][CH:18]=1)[NH:9][CH2:8][CH2:7]2.C=O.[C:33]([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:28]=3[O:29][CH3:30])=[CH:21][CH:22]=1)[N:9]([CH3:33])[CH2:8][CH2:7]2
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(-c3cnccc3OC)cc1)NCC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: COc1cc2c(cc1OC)C(Cc1ccc(-c3cnccc3OC)cc1)N(C)CC2

Procedure:
The synthesis of 6,7-dimethoxy-1-[4-(4-methoxypyridin-3-yl)benzyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride 23 is shown in Scheme 6. 6,7-Dimethoxy-1-[4-(4-methoxypyridin-3-yl)benzyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 20 was prepared by the reaction of 1-(4-bromobenzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 1 with 4-methoxypyridine-3-boronic acid 19 in the presence of Palladium(II) acetate, triphenylphosphine, and Na2CO3 in anhydrous isopropanol. Reaction of compound 20 with 2 M HCl solution in diethylether gave 6,7-dimethoxy-1-[4-(4-methoxypyridin-3-yl)benzyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride salt 21. Reaction of 21 with formaldehyde, sodium cyanoborohydride, and zinc chloride in methanol furnished 6,7-dimethoxy-1-[4-(4-methoxypyridin-3-yl)benzyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline 22 which was then reacted with 2 M HCl solution in diethylether to yield the compound 23.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10](=[CH2:14])C(O)=O)=[CH:7][C:6]=1[NH:17][S:18]([CH3:21])(=[O:20])=[O:19].[C:27](OCC)(=[O:29])C>>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[C:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][C:8]2[O:9][CH:10]=[CH:14][C:27](=[O:29])[C:15]=2[CH:16]=1
Reactant: C=C(Oc1ccc(Oc2ccc(F)cc2F)c(NS(C)(=O)=O)c1)C(=O)O
Reactant: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
30 g of polyphosphoric acid was added to 1.0 g of trans-3-[4-(2,4-difluorophenoxy)-3-methylsulfonylaminophenoxylacrylic acid. The mixture was stirred for 1 hour at 55°-65° C. The reaction mixture was introduced into 200 ml of ice water. 50 ml of ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 5 : 1 mixture of toluene and ethyl acetate) to obtain 0.4 g (yield: 42.0%) of 6-(2,4-difluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one. Melting point: 182.2°-182.8° C. (recrystallized from ethyl acetate)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.ClC(Cl)(Cl)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]=[N:22][CH:21]=[CH:20]2)=[O:13].C1CCN2C(=NCCC2)CC1.O>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:12]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[CH:23]=[N:22][CH:21]=[CH:20]3)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl
Reactant: NCc1ccc(Br)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CO
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2ccncc12

Procedure:
The title compound was prepared using 4-bromobenzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) m/z 356 (M+H)+; 1H NMR (DMSO-d6) δ 9.52 (s, 1H), 9.15 (s, 1H), 8.49 (d, 1H), 8.11 (d, 1H), 7.77 (d, 1H), 7.67 (t, 1H), 7.55 (m, 3H) 7.32 (d, 2H), 7.25 (t, 1H), 4.34 (d, 2H); Anal. Calcd for C17H14BrN3O*0.25 H2O*0.16 MeOH: C 56.34, H 4.17, N 11.49. Found C, 56.32, H 4.45, N 11.70.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:12]3[C:13](=[O:16])[NH:14][CH2:15][C:11]=3[CH:10]=[C:9]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[N:8]=2)[CH:4]=[N:3]1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][C:10]1[C:11]2[CH2:15][NH:14][C:13](=[O:16])[C:12]=2[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:8][C:9]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Solvent: ClCCl
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Br)c3c2C(=O)NC3)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.4 %

Procedure:
To a round bottomed flask was added tert-butyl (1S,2R)-2-(4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (124 mg, 0.291 mmol) in DCM (30 mL). The resulting white suspension was heated with a heat gun while stirring until all the starting material was dissolved. The solution was cooled to 0° C., and while stirring, 1-bromopyrrolidine-2,5-dione (51.7 mg, 0.291 mmol) was added. The reaction mixture was allowed to warm to RT and was stirred for 30 min. The solution was diluted with DCM (20 mL) and was washed with saturated aq NaHCO3 (20 mL), water (20 mL), and brine (20 mL). The organic layer was collected and concentrated to an orange solid, which was treated with Et2O (5 mL). Solids began to precipitate after the solution was allowed to sit undisturbed for 5 min. The mixture was allowed to sit for 1 h and was then filtered through paper. The solids were washed with Et2O (5 mL) and collected to give the title compound as a tan solid (137.3 mg, 93%). [M+H] calc'd for C22H29BrN6O3, 505; found, 505.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:2]3[CH:3]=[N:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH:12]=2)=[O:28])=[CH:22][CH:21]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)Nc2cccc(-c3cnc4ccccc4n3)c2)cc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (2.21 g, 10 mmol) in hot toluene, 4-methoxyphenyl isocyanate (1.42 g, 10 mmol) was added and the reaction mixture was heated at reflux for 2 hrs. The mixture was cooled to room temperature, the resulting precipitate was filtered, washed with hexane and dried to afford 1-(4-methoxyphenyl)-3-[3-(quinoxalin-2-yl)phenyl]urea (2.3 g, 62% yield). LCMS calculated for C22H18N4O2 (M+H): 370.41. found 371. 1H-NMR (DMSO-d6, 250 Mhz) δH: 9.52 (1H, s), 8.95 (1H, br. s), 8.55 (1H, br. s), 8.42 (1H, m), 8.20-8.10 (2H, m), 7.96-7.80 (3H, m), 7.75-7.65 (1H, m), 7.55-7.46 (1H, m), 7.45-7.35 (2H, m), 6.92-6.85 (2H, m), 3.72 (3H, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14](OCC)=[O:15])=[CH:8]1.C(OCC)(=O)C.O>CCOCC>[O:7]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][OH:15])=[CH:8]1
Reactant: CCOC(=O)CCc1ccoc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: OCCCc1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1.05 g (27.6 mmol) of lithium aluminum hydride in 100 ml of ether, a solution of 3.090 g (18.37 mmol) of ethyl 3-(3-furyl)propionate in 20 ml of ether was added dropwise under ice-cooling, followed by stirring at room temperature for 1 hour. To decompose the excess lithium aluminum hydride, ethyl acetate was added dropwise to the reaction mixture under ice-cooling; subsequently, water was added until a white precipitate formed. The white precipitate was filtered using Celite and washed with ethyl acetate 3 times. The combined filtrate was evaporated under reduced pressure. The obtained crude 3-(3-furyl)propanol was used for the next reaction without purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[N:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[C:29](Cl)=[O:30].C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:29]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][N:23]=3)=[O:30])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cnccn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cnccn4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.63 g, 1.9 mmol), 2-pyrazinecarbonylchloride (0.25 g, 1.9 mmol) and triethylamine (0.61 g, 6.0 mmol) in THF (30 mL) was stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting the product with 95:5 methylene chloride-methanol. This material dissolved in 4 mL acetonitrile, and this solution was poured into 50 mL of water, resulting in precipitation of the product, which was filtered, washed with additional water (20 mL), and dried, providing 0.46 g (61% yield): mp>260° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H), 2.54-2.65 (m, 2H), 2.84-2.91 (m, 1H), 4.97 (d, J=6.3 Hz, 2H), 5.18 (dd, J=12.0 Hz, d=5.4 Hz, 1H), 7.69-7.83 (m, 3H), 8.29 (t, J=1.9 Hz, 1H), 8.91 (d, J=2.5 Hz, 1H), 9.21 (d, J=1.4 Hz, 1H), 9.61 (t, J=6.3 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.3, 48.9, 121.9, 127.2, 131.2, 131.6, 133.0, 134.7, 143.5, 143.6, 144.5, 147.7, 163.4, 167.0, 167.6, 169.8, 172.8; Anal. calcd for C19H15N5O5.0.5H2O: C, 56.71; H, 4.01; N, 17.41. Found: C, 56.64; H, 3.75; N, 17.28.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH:16]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)([CH3:18])[CH3:17].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH:16]([CH3:18])[CH3:17])([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)c1ncc[nH]1
Reactant: C=CC(=O)NC(C)(C)c1ccc(Cl)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)c1nccn1CCC(=O)NC(C)(C)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 68a (alternative procedure), a mixture of N-[1-(4-chlorophenyl)-1methylethyl]acrylamide (6.7 g), 2-isopropylimidazole (3.3 g), 1,4-dioxane (100 ml) and benzyltrimethyl-ammonium hydroxide (Triton B) (5 ml of 40% solution in methanol) gave N-[1-(4-chlorophenyl)-1-methylethyl]-3-(2-isopropylimidazol-1-yl)propionamide as an oil not distilled.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:34])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[OH-].[Li+]>O1CCOCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13]2)=[O:34])=[CH:17][C:18]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(C)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
The compound of example 13 (1.92 g, 4.18 mmol) was dissolved in dioxane (40 ml), lithium hydroxide (10 ml, 1 M solution in water) was added and the mixture was stirred for 30 min at 60° C. The mixture was partitioned between 2 N hydrochloric acid and EA, the aqueous phase extracted with EA, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was stirred overnight in EA, filtered, and the crystals were dried in vacuo to give 1.35 g of the title compound.