Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[C:10]1=[O:11].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Si:1]([N:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[C:10]1=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(=O)c2ccccc21
Temperature: 22 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
In a 250 mL flame dried round bottom flask equipped with a stir bar, tert-butyldimethylsilyl chloride (4.5 g, 30 mmol) is dissolved in 150 mL dichloromethane. To this solution, in a single portion, isatin (2.2 g, 15 mmol) and 4-dimethylaminopyridine (0.18 g, 1.5 mmol) are added. The flask is sealed with a rubber septum and purged with nitrogen. Triethylamine (6.3 mL, 45 mmol) is added in one portion through a syringe and mixture is allowed to stir for 24 h at 22° C. The volatiles are removed in vacuo and the resultant dark orange solid is purified by silica gel chromatography (hexanes to 1:1 hexanes:dichloromethane to dichloromethane) to afford an orange solid, which is recrystallized from hot EtOH (details below) to afford 14a (2.6 g, 9.9 mmol, 67% yield) as an orange crystalline solid. Please note that for long-term storage, N-tert-butyldimethylsilyl protected isatins should be kept under an inert atmosphere at −15° C. 1-(tert-Butyldimethylsilyl)indoline-2,3-dione (14a): M.p.=123-124° C. IR (neat): 2929 (w), 2853 (w), 1731 (s), 1603 (m), 1589 (m), 1463 (m), 1325 (m), 1252 (m), 1170 (m), 1139 (m), 927 (m), 835 (s), 796 (m), 752 (s), 686 (m), 466 (m), 424 (m) cm−1; 1H NMR (400 MHz, CDCl3): δ 7.63-7.61 (1H, m), 7.53-7.49 (1H, m), 7.10-7.03 (2H, m), 1.02 (9H, s), 0.56 (6H, s); 13C NMR (100 MHz, CDCl3): δ 184.2, 164.9, 155.4, 138.3, 125.6, 123.4, 120.0, 115.1, 26.4, 19.7, −3.3; HRMS Calcd for C14H20NO2Si [M+H]+: 262.12633. Found: 262.12608.
Reaction SMILES: O[C:2]1([C:15]2[N:16]=[C:17]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[NH:18][CH:19]=2)[C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1>[Pd].[Pt].CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH3:14])[O:5][CH2:4][CH2:3][CH:2]2[C:15]1[N:16]=[C:17]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[NH:18][CH:19]=1
Reactant: COc1cc2c(cc1C)OCCC2(O)c1c[nH]c(S(=O)(=O)N(C)C)n1
Agent: [Pd]
Agent: [Pt]
Solvent: CO
Product: COc1cc2c(cc1C)OCCC2c1c[nH]c(S(=O)(=O)N(C)C)n1
Reaction time: 2 h

Procedure:
A mixture of 0.1 gram (0.0004 mole) of {[4-(6-methoxy-7-methyl(2H-chromen-4-yl)imidazolyl]sulfonyl}dimethylamine (ix), 0.01 gram (catalyst) of 10% palladium on carbon, and 0.005 gram (catalyst) of 5% platinum on carbon in 75 mL of methanol was subjected to hydrogenation conditions during a two hour period using a Parr hydrogenator. After this time, the reaction mixture was passed through a column of silica gel to remove the catalysts. The eluate was concentrated under reduced pressure to a residue. An NMR spectrum of the residue was consistent with the proposed structure. The reaction was repeated on a larger scale, using 1.1 grams (0.0044 mole) of {[4-(6-methoxy-7-methyl(2H-chromen-4-yl)imidazolyl]sulfonyl}dimethylamine. The reaction product was purified by column chromatography on Grade II alumina (basic-3% water) using methylene chloride and a 99.5:0.5 mixture of methylene chloride and methanol, respectively, as eluants. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 0.38 gram of the subject compound, mp 138-139° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1(=O)O[CH2:12][CH2:11][CH2:10]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[CH2:9][CH2:10][CH2:11][CH2:12][O:8][C:4]=2[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C1CCCO1
Product: Brc1ccc2c(c1)OCCCC2

Procedure:
m-Bromophenol was reacted with γ-butyrolactone in analogy to Example 17, paragraphs B, C and D, to give 8-bromo-2,3,4,5-tetrahydro-1-benzoxepine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]([N:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])/[C:8]([O:10]CC)=[O:9])[N:6]=1.O.[OH-].[Na+]>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]([N:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCC(=O)N1CCCCCC1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1nc(/C(=N/OCC(=O)N2CCCCCC2)C(=O)O)cs1
Yield: 81.4 %

Procedure:
68 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[[(hexahydro-1H-azepin-1-yl)carbonyl]methoxy]imino]-acetate are dissolved in 2.5 l of methanol and 250 ml of water and the solution is treated with 220 ml of 1N aqueous sodium hydroxide solution. The methanol is removed under reduced pressure after 48 hours. The aqueous solution is washed with ethyl acetate and treated with 220 ml of 1N aqueous hydrochloric acid. The acid which crystallizes out is filtered off and dried. There are obtained 51 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-[[(hexahydro-1H-azepin-1-yl)carbonyl]methoxy]imino]-acetic acid of melting point 178°-179° C.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:10]1[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]([CH3:16])[N:5]([CH2:1][CH:2]=[CH:3][CH3:4])[C:9]=12)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 78.6 %

Procedure:
The title compound (cis/trans=21/79) was prepared as pale brown crystals in 78.6 % yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine [cis/trans (18/82)] and benzyl alcohol.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[F:36][C:33]([F:34])([F:35])[C:32]([C:29]1[CH:30]=[N:31][C:26]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[N:27][CH:28]=1)([OH:41])[C:37]([F:40])([F:39])[F:38]
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccccc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: O=S(=O)(c1ccccc1)c1ccc(-c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)cc1
Temperature: 100 °C
Yield: 71.1 %

Procedure:
A glass microwave reaction vessel was charged with 4,4,5,5-tetramethyl-2-(4-(phenylsulfonyl)phenyl)-1,3,2-dioxaborolane (196 mg, 0.57 mmol, Example 17, Step 2), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (145 mg, 0.52 mmol, Intermediate D), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (24 mg, 0.03 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (0.51 g, 1.56 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1 mL), and water (0.1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The reaction was diluted with EtOAc (about 10 mL) and water (about 10 mL). The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 10% to 20% EtOAc in hexane, to provide 1,1,1,3,3,3-hexafluoro-2-(2-(4-(phenylsulfonyl)phenyl)-5-pyrimidinyl)-2-propanol (171 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.28 (s, 2H), 8.69 (d, J=8.61 Hz, 2H), 8.22 (d, J=8.61 Hz, 2H), 8.04-8.10 (m, 2H), 7.68-7.82 (m, 4H); m/z (ESI, +ve ion) 463.1 (M+H)+. GK-GKRP IC50 (Binding)=0.484 μM. GKRP EC50 (LC MS/MS-2)=0.478 μM.
Reaction SMILES: [NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[OH:22].[CH:23](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:6]2[C:5]3[C:18]([F:21])=[C:19]([F:20])[C:2]4[N:1]=[CH:23][O:22][C:3]=4[C:4]=3[NH:8][C:7]2=[O:9])=[C:11]([F:17])[CH:12]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(F)c(F)c2c([nH]c(=O)n2-c2ccc(Br)cc2F)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(Br)cc1F
Yield: 65 %

Procedure:
Intermediate I-16a was prepared from 5-amino-1-(4-bromo-2-fluoro-phenyl)-6,7-difluoro-4-hydroxy-1,3-dihydro-benzoimidazol-2-one (I-14a: 800 mg, 2.14 mmol), triethyl orthoformate (3.7 mL) and p-toluene sulfonic acid (80 mg) using procedures analogous to those used to prepare Intermediate I-15a above to afford 550 mg of the product (65% yield). H1NMR (DMSO-d6, 300 MHz): δ 12.50 (s, 1H), 8.80 (s 1H), 7.97 (d, 1H), 7.65-7.55 (m, 2H). HPLC: 95.7%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:39]2[CH:51]=[CH:50][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:39]2[CH:40]=[CH:41][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:50][CH:51]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCSCC1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCSCC1
Temperature: 100 °C
Yield: 73 %

Procedure:
A solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-2-methylbenzamide (800 mg, 1.629 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (740 mg, 2.443 mmol), sodium carbonate (621 mg, 5.86 mmol) in 20 ml of dioxane was degassed with argon for 20 min, Pd(PPh3) (188 mg, 0.16 mmol) was added to the mixture and heated to 100° C. overnight. The reaction was cooled to room temperature and diluted with water, compound was extracted in 10% MeOH in DCM, dried over Na2SO4, concentrated and crude was purified by silica gel (100-200) chromatography to obtain the title compound (700 mg, 73.0%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH2:56]([O:58][C:59](=[O:68])[CH2:60][N:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH2:67])[CH2:62]1)[CH3:57]>CN(C=O)C>[CH2:56]([O:58][C:59](=[O:68])[CH2:60][N:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH:67][C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:62]1)[CH3:57]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)CN1CCCC(N)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCCC(NC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (500 mg, 1.6 mmol) in DMF (10 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (569 mg, 1.8 mmol), N,N-diisopropyl ethyl amine (1.38 mL, 8.1 mmol) and (3-amino-piperidin-1-yl)-acetic acid ethyl ester hydrochloride (459 mg, 1.8 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1 and then dichloromethane:methanol=9:1) afforded the title compound (622 mg, 81%) as a light brown gum. MS: m/e=479.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2nc3ccc(OC)cc3n2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2nc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)n(C)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.1 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (151 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 2.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (124 mg, 87%) as a white solid.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)=[O:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]([C@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][C@@H:33]([CH3:41])[CH2:32]2)[C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:17][O:16][C:14](=[O:15])[C:13]([CH3:19])([CH3:18])[CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([N:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:31]([N:27]([C:28](=[O:30])[CH3:29])[C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][C@@H:33]2[CH3:41])=[O:3])=[CH:5][CH:6]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)Nc2ccccc21
Reactant: COC(=O)C(C)(C)CCCc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.1 %

Procedure:
To the prepared methyl 5-[4-(chlorocarbonyl)phenyl]-2,2-dimethylpentanoate (2.9 mmol, 1.0 eq.) was added a solution of N-(4-chlorophenyl)-N-((2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)acetamide (754 mg, 2.4 mmol, 0.83 eq.) in methylene chloride (8 ml) followed by diisopropylethylamine (505 ul, 2.9 mmol, 1.0 eq.) and reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate/hexane: ⅓ to ½ gradient) to afford 5-(4-{(2S,4R)-4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-2,2-dimethyl-pentanoic acid methyl ester (675 mg, 50%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27]>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCc1cccs1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccs3)cc2F)cn1
Yield: 60.1 %

Procedure:
Using a method similar to Example 405, using 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.040 g, 0.154 mmol) and 2-(2-thienyl)ethylamine (0.0196 g, 0.154 mmol) gives the title compound (0.0344 g, 60.2%): TOF MS ES+ 372.1 (M+H)+, HRMS calcd for C19H19N3O2FS 372.1182 (M+H)+, found 372.1168, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.9 min, 100% purity.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[CH:3]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O.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>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Nc1nc(NCCNc2nc(Cl)cc3ncnn23)ccc1[N+](=O)[O-]
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: Nc1nc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3ncnn23)ccc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
60 mg (0.16 mmol) of N6-{2-[(7-chloro[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 6A), 30.3 mg (0.16 mmol) of (2,4-dichlorphenyl)boronic acid and 18.4 mg (0.016 mmol) of tetrakis(triphenylphosphine)palladium(0) are introduced into a mixture of 3.4 ml of dioxane and 1.1 ml of saturated aqueous sodium carbonate solution under argon. The mixture is degassed with argon and then heated in a microwave at 150° C. for 30 min Cooling is followed by filtration through an Extrelut® cartridge. Purification by preparative HPLC results in 10.9 mg (13% of theory) of the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([C:20](=O)[CH3:21])[CH:10]=[CH:11][C:12]=2[O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1.CO.C([BH3-])#[N:26].[Na+].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH:20]([NH2:26])[CH3:21])[CH:10]=[CH:11][C:12]=2[O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(OC2CCOCC2)c(-c2ccc(Cl)s2)c1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1ccc(OC2CCOCC2)c(-c2ccc(Cl)s2)c1

Procedure:
To a solution of the compound yielded from step 2 (1.20 g, 3.56 mmol) in MeOH (20 mL) ammonium acetate (2.75 g, 35.63 mmol) and sodium cyanoborohydride (224 mg, 3.56 mmol) were added. The reaction mixture was refluxed for 6 h. Then the cooled mixture was adjusted with trifluoroacetic acid to pH=2 and evaporated to dryness. Purification of the crude product by prep-HPLC and lyophilization of the relevant fractions lead to the desired product (420 mg, 26%).
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH:24]=[O:25])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(O)(=O)C>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:12])[C:24]=2[OH:25])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(C(=O)C=O)cc1
Reactant: CNN=CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: Cn1nc(C(=O)c2ccccc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
Oxo(phenyl)acetaldehyde methylhydrazone (5.46 mmol, 886 mg) synthesized in Reference Synthetic Example 36 and (4-t-butylphenyl)(oxo)acetaldehyde (5 mmol, 951 mg) were dissolved in acetic acid (26 mL) and stirred at 100° C. for about 2 hours. Then, the solvent was evaporated, and the residue was recrystallized from chloroform/n-hexane to give the desired product as a yellow solid (993 mg, yield 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.O>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
5-Aminoindole (100 mg, 0.757 mmol) was dissolved in DMF (2 mL), and the solution was added with EDCI (290 mg, 1.51 mmol), HOBT monohydrate (102 mg, 0.755 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (208 mg, 0.907 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using acetonitrile to obtain 5-[1-(tert-butoxycarbonyl)piperidine-4-carbonylamino]indole (142 mg, yield 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7](O)[N:6]=[CH:5]2.P(Cl)(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([Cl:17])[N:6]=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nc(O)ncc2cc1Br
Product: COc1cc2nc(Cl)ncc2cc1Br
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 6-bromo-7-methoxyquinazolin-2-ol (3.0 g, 11.8 mmol) in phosphoryl trichloride (30 mL) was refluxed at 130° C. for 5 hours. The reaction was cooled to room temperature, and most of phosphoryl trichloride was evaporated. The residue was dropwise added to ice water (100 mL), and the resulting precipitate was collected via filtration to give the title compound as a yellow solid (2.4 g, 75%). MS (ES+) C9H6BrClN2O requires: 272, 274, found: 273, 275 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[C:22]1([CH3:30])[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:30][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: Cc1cccc(C=O)c1
Product: Cc1cccc(C=CC(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)c1

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and m-tolualdehyde (75 ul, 0.633 mmol) similar to Example 6 and isolated as a pale yellow solid (76.2 mg, 29%). 1H NMR (CDCl3): 7.66 (d, J=15.9 Hz, 1H), 7.44 (d, J=15.6 Hz, 1H), 7.42-7.38 (m, 2H), 7.31-7.20 (m, 3H), 7.10 (dd, J=3.2, 8.9 Hz, 1H), 6.93 (d, J=9.0 Hz, 1H), 4.43-4.32 (m, 4H), 2.37 (s, 3H).