Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:6](=[O:7])[C:5]2=[CH:17][CH:18]=1.[F:19][C:20]([F:33])([F:32])C1C=C2C(=O)OC(=O)C2=CC=1>C(OCC)(=O)C>[F:19][C:20]([F:33])([F:32])[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:6](=[O:7])[C:5]2=[CH:17][CH:18]=1
Reactant: O=C1c2ccc(Cl)cc2C(=O)N1CCC(F)(F)F
Reactant: O=C1OC(=O)c2cc(C(F)(F)F)ccc21
Solvent: CCOC(C)=O
Product: O=C1c2ccc(C(F)(F)F)cc2C(=O)N1CCC(F)(F)F

Procedure:
4-Trifluoromethyl-N-(3,3,3-trifluoropropyl)phthalimide is prepared in a similar manner to 4-chloro-N-(3,3,3-trifluoropropyl)phthalimide described in Example 26, starting with 4-trifluoromethylphthalic anhydride, Rf=0.12, (thin layer chromatography on silica gel, eluent: ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Br:11])[N+:3]=1[O-].O>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)[n+]([O-])c(Br)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Br)nc(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
2,6-dibromo-4-nitro pyridine 1-oxide (14.5 g, 48.6 mmol) was taken up in 130 mL of acetic acid and iron powder (11 g, 196.9 mmol) was added in portionwise and the mixture was stirred at room temperature for 45 minutes. 500 mL of water was added and the product was extracted with EtOAc (500 mL). The organic layer was washed with 300 mL of water then with 300 mL of a sat K2CO3 sol and then with 300 mL of brine. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give 11.1 g of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=[O:31])[CH:26]=[CH:27][CH:28]=1>CN(C=O)C>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4](=[O:18])[C:3]=1[C:30](=[O:31])[CH2:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:33])([F:21])[F:34])[CH:24]=1
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(C(F)(F)F)c1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (953 mg, 4.0 mmol) in DMF (32 mL) was added sodium hydride (purity of about 60%, 352 mg, 8.8 mmol, 2.2 eq.), and the mixture was stirred at a room temperature for 35 minutes. Then, 3-trifluoromethylphenylacetyl chloride (4.8 mmol, 1.2 eq.) was added thereto with cooling in an ice bath, and the mixture was stirred at a room temperature for 1.5 hours. Thereafter, the resulting mixture was purified by a flash column chromatography to give 4-hydroxy-1-phenyl-3-(3-trifluoromethylphenylacetyl)-1,8-naphthyridin-2(1H)-one as a form of crystal (1.04 g, yield 61%).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](OCC)=[O:11])=[N:8][CH:9]=1>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[N:8][CH:9]=1
Reactant: CCOC(=O)c1ccc(Br)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
To a solution of NaBH4 (0.822 g, 21.73 mmol) in MeOH (25 mL) was added ethyl 5-bromopicolinate (1.0 g, 4.35 mmol) portion-wise over a period of 10 min at room temperature. The mixture was stirred at room temperature for 10 min and then heated to 70° C. for 30 min. The solvent was removed in vacuo, and the resulting residue was diluted with EtOAc and water. The aqueous phase was adjusted to pH 7 with 1 N aq. HCl, and extracted with EtOAc. The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound (0.65 g, 80% yield) as a white solid. LCMS, [M+H]+=187.9.
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:17])[CH2:16][CH2:15][CH2:14]1)[N:8]([CH3:18])[C:7]2=[O:19].[CH3:21][C@@H:22]1[C:26]2[NH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[C:24](=[O:39])[NH:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[F:20][C:3]1[C:2]([C:28]2[NH:27][C:26]3[C@@H:22]([CH3:21])[NH:23][C:24](=[O:39])[C:25]=3[CH:29]=2)=[C:11]2[C:6]([C:7](=[O:19])[N:8]([CH3:18])[C:9]([NH:12][C:13]3([CH3:17])[CH2:16][CH2:15][CH2:14]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: Cn1c(NC2(C)CCC2)nc2c(Br)c(F)ccc2c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1NC(=O)c2cc(-c3c(F)ccc4c(=O)n(C)c(NC5(C)CCC5)nc34)[nH]c21
Temperature: 80 °C
Yield: 17.3 %

Procedure:
A mixture of 8-bromo-7-fluoro-3-methyl-2-((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (502a, 120 mg, 0.353 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 237 mg, 0.705 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium (II) (12.49 mg, 0.018 mmol), and potassium phosphate (225 mg, 1.058 mmol) in 1,4-dioxane (2.82 mL)/water (0.70 mL) was sparged with nitrogen for 3 min at RT; the red reaction mixture was then heated to 80° C. for 45 min. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (2×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-5% 2 M ammonia in MeOH/DCM to give (R)-7-fluoro-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (502, 24 mg, 0.061 mmol, 17% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.58 (s, 3H) 1.78 (s, 3H) 1.98-2.15 (m, 2H) 2.27-2.42 (m, 3H) 2.42-2.52 (m, 1H) 3.56 (s, 3H) 4.69 (q, J=6.65 Hz, 1H) 5.08 (s, 1H) 6.01 (s, 1H) 7.00 (dd, J=11.54, 8.80 Hz, 1H) 7.08 (d, J=4.11 Hz, 1H) 8.01 (dd, J=8.80, 6.06 Hz, 1H) 12.76 (br. s., 1H). 19F NMR (376 MHz, CDCl3) δ ppm −99.57 (s, 1F). MS (ESI, pos. ion) m/z: 369.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].[CH3:24][Mg]Cl.C1COCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([CH3:24])([OH:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: CC(=O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Yield: 96 %

Procedure:
To a stirred solution of 1-(6-Bromo-5-(2,4-difluorophenoxy)-1H-indazol-1-yl)propan-2-one (3.81 g, 10.0 mmol) in toluene (100 mL) at 21° C. was added a 3.0 M solution of methylmagnesium chloride in THF (5.0 mL, 15 mmol) in one portion. The temperature of the resulting solution rose to 34° C. and was stirred without any temperature control. After a total of 60 min the reaction mixture was quenched by addition of saturated ammonium chloride (50 mL). The resulting mixture was vigorously stirred for 20 min, then transferred to a separatory funnel and shaken. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure to afford the title compound as an orange oil (3.79 g, 96%) that slowly crystallized on standing.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[CH2:21]([N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:24][CH3:25])[CH3:22]>C(O)C>[CH2:21]([N:23]([CH2:26][CH2:27][CH2:28][NH:29][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1)[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)CCCN
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Solvent: CCO
Product: CCN(CC)CCCNCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
Using the method of Example 1, 5-bromomethyl-2-nitro-3-phenylbenzofuran is reacted with 3-(N,N-diethylamino)propylamine in ethanol to provide light tan crystals of 5-[3-(N,N-diethylamino)propylaminomethyl]-2-nitro-3-phenylbenzofuran dihydrochloridemonohydrate, m.p. 143°-150° C., having the structure ##STR10##
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:31](Cl)(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:31]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cccc2cccnc12)N1CCNCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 22.1 %

Procedure:
1-tert-Butoxycarbonylpiperazine (2.22 g) and triethylamine (2.0 mL) were dissolved in dichloromethane (100 mL), and 8-quinolinesulfonyl chloride (2.71 g) was added thereto. The mixture was stirred at room temperature for 14 hr. 10% citric acid solution was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (5 mL) was added thereto. The mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with chloroform, and the extract was dried and concentrated under reduced pressure to give 1-(8-quinolinesulfonyl)piperazine (0.73 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:22]=1.C(O)(C(F)(F)F)=O>ClCCl>[S:30]([N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]3([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]3)[C:2]2=[O:1])=[CH:22]1)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:31])=[O:32]
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN3CCCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c3ccccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(CN3CCCC4(CCNCC4)C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 144.1 %

Procedure:
To a solution of tert-butyl 1-oxo-2-((1-tosyl-1H-indol-3-yl)methyl)-2,9-diazaspiro[5.5]undecane-9-carboxylate (5.3 g, 8.45 mmol) in dichloromethane (30 mL) was added TFA (4.93 mL, 63.4 mmol). The solution was stirred for 70 min at rt. After completion of the reaction the mixture was evaporated to dryness. The residue was crystallized in THF/heptane 3:1 to yield the title compound as white crystals (5.5 g, quant.). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.43 (br. s, 2H), 7.89 (d, J=8.28 Hz, 1H), 7.82 (d, J=8.28 Hz, 2H), 7.78 (s, 1H), 7.56 (d, J=7.78 Hz, 1H), 7.38-7.31 (m, 3H), 7.24-7.20 (m, 1H), 4.59 (s, 2H), 3.29-3.19 (m, 2H), 3.12 (t, J=5.77 Hz, 2H), 3.07-2.95 (m, 2H), 2.30 (s, 3H), 2.10 (ddd, J=14.24, 10.35, 4.02 Hz, 2H), 1.75-1.59 (m, 4H), 1.58-1.48 (m, 2H); LCMS RtA=0.88 min, [M+H]+=452.3].
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:6]([CH3:8])=[O:7]>C1C=CC=CC=1>[CH2:5]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:3])=[O:14])=[CH:11][CH:10]=1)[C:6]([CH3:8])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Cc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Product: CC(=O)Cc1ccc(C(=O)Cl)cc1

Procedure:
Thionyl chloride (1.45 ml) was added to 4-acetonylbenzoic acid (3.56 g) in benzene and the mixture refluxed for 1 hour. Benzene was evaporated to give the title compound as a yellow oil, 2.61 g, (bp 135°-140°/0.5 mm). γ(CDCl3) 7.78 (3H, s), 6.17 (2H, s), 2.63 (2H, d, J=9 Hz), 1.88 (2H, d, J=9 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:42]=[C:43]1[CH2:47][CH2:46][CH2:45][N:44]1[CH2:48][CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH2:68])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:58][CH:57]=1>CN(C=O)C>[O:42]=[C:43]1[CH2:47][CH2:46][CH2:45][N:44]1[CH2:48][CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH:68][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:55][C:56]1[CH:57]=[CH:58][C:59]([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)=[CH:60][CH:61]=1
Reactant: O=C(O)c1c[nH]nn1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCCN1CCCC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20.2 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-(2-oxo-pyrrolidin-1-yl)-ethyl ester (52.6 mg, 124 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (13 mg; purity 95%). MS m/z [M+H]+ calc'd for C28H33N5O5, 520.25. found 520.4.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6](O)[C:7]3[CH2:8][C:9]([CH3:19])([CH3:18])[CH2:10][C:11](=[O:17])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH2:8][C:9]([CH3:19])([CH3:18])[CH2:10][C:11](=[O:17])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)c2c(n(O)c3ccc(Cl)cc3c2=O)C1
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)c2c([nH]c3ccc(Cl)cc3c2=O)C1
Yield: 74.2 %

Procedure:
20 g (0.066 mole) of 7-chloro-3,3-dimethyl-10-hydroxy-1-oxo-1,2,3,4-tetrahydro-9(10H)-acridone were suspended in 320 ml of chloroform and, after heating on a steam bath, combined dropwise with 11.3 ml (0.13 mole) of phosphorus trichloride. Upon cooling, 16 g of 7-chloro-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-9(10H)-acridone crystallized in the form of the hydrochloride. This compound was dissolved in a mixture of 300 ml of methanol and 50 ml of binormal sodium hydroxide solution, the solution was filtered, the filtrate was concentrated under reduced pressure and the base that had crystallized was filtered off with suction. 13.5 g (74 % ) of 7-chloro-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-9(10H)-acridone were obtained. Decomposition point 300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]([F:18])([F:17])[F:19])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1c(N)ccc2c1CCC(NCC(F)(F)F)CC2
Product: COc1c(Nc2ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc2c1CCC(NCC(F)(F)F)CC2
Yield: 3.3 %

Procedure:
In an analogous procedure to Example 651, part c, 1-methoxy-N*7*-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield (1S,2S,3R,4R)-3-{5-Chloro-2-[1-methoxy-7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (3.14 g, 3.3% yield) as an off white amorphous solid. 1H-NMR (CDCl3) δ 8.18 (d, J=8.2 Hz, 1H), 7.89 (s, 1H), 7.39 (s, 1H), 6.96 (m, 1H), 6.86 (d, J=8.3 Hz, 1H), 6.35 (m, 1H), 6.31 (m, 1H), 5.59 (br s, 1H), 5.35 (br s, 1H), 4.35 (m, 1H), 3.72 (s, 3H), 3.24 (m, 3H), 3.07 (s, 1H), 2.94-2.78 (m, 3H), 2.66 (m, 1H), 2.50 (m, 2H), 2.22 (d, J=9.6 Hz, 1H), 2.09 (m, 2H), 1.33 (m, 2H). LC/MS (ESI+)=551 (M+H).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Br:37])[CH:31]=1>>[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH:38][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Br:37])[CH:31]=1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Br)c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)c(Br)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid was coupled to (S)-2-amino-3-(3-bromo-4-chloro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=10.85 min. MS (ESI+): mass calcd. for C23H17BrClIN4O5S2, 735.80; m/z found, 735/737 [M+H]+. 1H NMR (500 MHz, CDCl3): 11.31 (s, 1H), 8.36 (d, J=7.1, 1H), 8.22 (d, J=8.7, 1H), 8.08 (d, J=1.4, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.36-7.28 (m, 3H), 6.96-6.90 (m, 2H), 6.46 (d, J=7.1, 1H), 4.93 (q, J=5.5, 1H), 3.82 (s, 3H), 3.23-3.10 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](Cl)=[O:19].O.[NH3:24]>O1CCCC1>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([NH2:24])=[O:19]
Reactant: N
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)Cl)C(C)(C)CCC1
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(N)=O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
10 g (0.031 mole) of retinoic acid chloride as prepared according to the procedure described in Example 2 was added to the mixture of 300 ml of ammonia water (35%) and 100 ml of tetrahydrofuran and then stirred at room temperature for 20 hours. The reaction solution was distilled under reduced pressure and then concentrated. The residue was extracted with methylene chloride. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, filtered and then distilled under reduced pressure to obtain 9.43 g (Yield 99%) of the desired retinamide.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20](=O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:17][O:16][C:14]([C:12]1[CH:11]=[CH:10][N:9]2[C:8]([CH:13]=1)=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[CH3:29])=[CH:19]2)=[O:15]
Reactant: COC(=O)c1ccnc(Cc2ccccc2)c1
Reactant: Cc1c(F)cccc1CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccn2cc(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
The compound of step 1 (1.555 g, 6.84 mmol) and the compound of example 1, step 2 (1.677 g, 6.84 mmol) were dissolved in 28.5 ml of acetone and the solution was heated to reflux overnight. The mixture was then evaporated to dryness under reduced pressure and the residue dissolved in 28.5 ml of isopropanol. Sodium carbonate (2.176 g, 20.53 mmol) was added and the mixture was heated at 105° C. with stirring for 2 h. The solids were filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 95:5) to give 0.497 g of the title compound as a yellow solid melting at 55° C.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13]([CH2:14]Cl)=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3].[NH2:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13]([CH2:14][C:19]3([NH2:18])[N:23]=[C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]4=[N:20]3)=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3]
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: Nc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2CC2(N)N=c3ccccc3=N2)cc1
Temperature: 80 °C

Procedure:
The compound described in Example 26, Step 1 [1-(4-cyanobenzyl)-5-(chloromethyl)imidazole hydrochloride] (0.75 mmol, 0.20 g), 2-aminobenzimidazole (0.90 mmol, 0. 12 g) and diisopropylethylamine (2.25 mmol, 0.29 g) were dissolved in acetonitrile and placed in a nitrogen purged sealed tube and warmed at 80° C. for 18 hr. The precipitate was filtered off to yield 1-(4-cyanobenzyl)-5-(2-amino-1-benzimidazolylmethyl)imidazole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:12](Br)[C:13]#[CH:14]>CN(C)C=O.C(OCC)(=O)C>[CH2:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1)[C:13]#[CH:12]
Reactant: c1ccc2[nH]ncc2c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCn1ncc2ccccc21
Reaction time: 0.17 h

Procedure:
Indazole (530 mg, 4.49 mmol) was dissolved in dimethylformamide (4 mL). Sodium hydride (60% suspension in mineral oil, 231 mg, 5.78 mmol) was added slowly, and the mixture was stirred for 10 minutes. Propargyl bromide (80% wt in toluene, 5.0 mL) was added, and the mixture was stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed excessively with water, absorbed on silica gel, and purified by silica gel chromatography eluting with a gradient of 5-30% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 157.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7](OC1C=CC=CC=1)=[O:8].Br.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH2:28])=[CH:21][CH:20]=1.C(N(CC)CC)C>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])=[O:8])=[CH:21][CH:20]=1
Reactant: O=C1CCCN1C(=O)Oc1ccccc1
Reactant: COc1ccc(OCCN)cc1
Agent: Br
Solvent: CCN(CC)CC
Product: COc1ccc(OCCNC(=O)N2CCCC2=O)cc1
Temperature: 110 °C
Yield: 118.5 %

Procedure:
A mixture of 1.16 g (5.64 mmol) of 2-oxo-1-phenoxycarbonylpyrrolidine (II) were added 2.0 g (8.06 mmol) of 2-(4-methoxyphenyloxy)ethylamine hydrobromide and 1.63 g (16.1 mmol) of triethylamine was heated at 110° C. for 3 hr. After evaporation of the solvent, the residue was refined by silica gel column chromatography, whereby 1.86 g of the objective compound (I a-42) was obtained as crystals from the eluate with toluene/ethyl acetate (5/1-3/1 v/v). Yield: 83.0%