Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Cl[C:43]1[CH:44]=[CH:45][C:46]2[N:47]([CH:49]=[C:50]([NH:52][C:53](=[O:55])[CH3:54])[N:51]=2)[N:48]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.O1CCOCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:4]2[CH:3]=[C:2]([C:43]3[CH:44]=[CH:45][C:46]4[N:47]([CH:49]=[C:50]([NH:52][C:53](=[O:55])[CH3:54])[N:51]=4)[N:48]=3)[CH:7]=[N:6][CH:5]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Reactant: O=S(=O)(Nc1cncc(Br)c1)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cn2nc(-c3cncc(NS(=O)(=O)c4ccc(F)cc4)c3)ccc2n1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
To a 25-mL, round-bottomed flask was added N-(5-bromopyridin-3-yl)-4-fluorobenzenesulfonamide (0.15 g, 0.45 mmol), bis(pinacolato)diboron (0.17 g, 0.68 mmol), potassium acetate (0.18 g, 1.8 mmol) and 1,4-dioxane (4.0 mL). The mixture was carefully evacuated and backfilled with N2. To this mixture was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.033 g, 0.045 mmol, Strem Chemicals, Inc., Newburyport, Mass.). The mixture was carefully evacuated and backfilled with N2. The mixture was stirred at 90° C. for 19 h then allowed to cool to room temperature. To the solution was added DMF (4.0 mL), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1, Step 4) (0.075 g, 0.36 mmol) and aq. Na2CO3 (0.89 mL, 1.8 mmol, 2 M). The mixture was carefully evacuated and backfilled with N2. To the mixture was added trans-dichlorobis(triphenylphosphine)palladium (II) (0.025 g, 0.036 mmol, Strem Chemical, Inc., Newburyport, Mass.). Once again the mixture was carefully evacuated and backfilled with N2. The mixture was stirred at 90° C. for 2 h and then was allowed to cool to room temperature. The solution was poured into water (100 mL), extracted with 25% iPrOH/CHCl3 (3×75 mL) and the combined extracts were washed with brine, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (2 to 8% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a tan solid. MS (ESI pos. ion) m/z: 427 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 10.84 (s, 1H), 8.92 (d, J=1.8 Hz, 1H), 8.41 (d, J=2.5 Hz, 1H), 8.31 (s, 1H), 8.09-8.13 (m, 2H), 7.88-7.91 (m, 2H), 7.76 (d, J=9.4 Hz, 1H), 7.42 (d, J=8.8 Hz, 2H), 2.12 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:29]1[N:28]=[C:18]([C:17]2[CH:21]=[CH:22][C:14]([N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]3[CH3:7])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[O:20][N:30]=1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(N3CCCCC3C)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (106 μL; 1.25 mmol; 3 eq.), Intermediate 24 (120 mg; 0.42 mmol; 1 eq.), Intermediate 1 (69 mg; 0.42 mmol, 1 eq.) and DIEA (93 μL; 1.25 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 80/20) followed by precipitation from n-pentane afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:7]([OH:9])=O.[CH3:20][C:21]1[N:26]=[CH:25][C:24]([C@H:27]([NH2:29])[CH3:28])=[CH:23][N:22]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:7]([NH:29][C@@H:27]([C:24]1[CH:23]=[N:22][C:21]([CH3:20])=[N:26][CH:25]=1)[CH3:28])=[O:9]
Reactant: COCc1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Reactant: Cc1ncc([C@@H](C)N)cn1
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: COCc1cc(C(=O)N[C@H](C)c2cnc(C)nc2)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(methoxymethyl)-5-(5-methylpyridin-2-yl)benzoic acid (30 mg, 0.12 mmol) in N,N-dimethylformamide (1.5 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (40 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[N:7]([CH3:14])[CH:6]=[C:5]2[CH:15]([CH3:17])[CH3:16].[CH3:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:14][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:22]3[CH:23]=[N:24][C:19]([CH3:18])=[CH:20][CH:21]=3)=[CH:10][C:9]=2[C:11]([OH:13])=[O:12])[C:5]([CH:15]([CH3:17])[CH3:16])=[CH:6]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC(C)c1cn(C)c2c(C(=O)O)cc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)c3c(c2)c(C(C)C)cn3C)cn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a 40 mL vial was added 5-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylic acid (0.850 g, 2.87 mmol), (6-methyl-3-pyridinyl)boronic acid (0.432 g, 3.16 mmol), K2CO3 (1.190 g, 8.61 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.234 g, 0.287 mmol). The reagents were diluted with 1,2-dimethoxyethane (21.5 mL) and water (7.2 mL). The reaction was heated to 100° C. with stirring for 30 minutes, then filtered and concentrated under vacuum to give a thick brown residue. The residue was diluted with saturated NaHCO3 (15 mL) and water (10 mL) and aqueous solution washed with EtOAc (3×40 mL). The aqueous solution was then slowly added to a rapidly stirred, cooled (0° C.) solution of 1 N HCl. The mixture was stirred for 20 min and the solids collected by vacuum filtration. LCMS showed the solids contained only a small amount of desired product. The solids were discarded. The acidic aqueous solution was extracted with EtOAc (3×250 mL). LCMS showed the desired product in both layers. Thus, both the organic and aqueous layers were concentrated. The residue was purified by reverse phase HPLC (Gemini 50×100 mm column, acetonitrile and 0.1% formic acid/water) to give 1-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxylic acid (590 mg, 66.6% yield) as light tan solid. MS (ES) [M+H]+ 309.5.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)[N:17]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl>[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37]([N:39]1[CH2:40][CH2:41][N:42]([C:27]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:18]3[N:17]=[C:16]([C:13]4[CH:14]=[CH:15][C:10]([S:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)(=[O:9])=[O:8])=[CH:11][CH:12]=4)[CH:21]=[CH:20][N:19]=3)=[CH:31][CH:30]=2)=[O:28])[CH2:43][CH2:44]1)=[O:38]
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1ccc(Nc2nccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)n2)cc1)N1CCN(C(=O)c2ccco2)CC1
Reaction time: 12 h
Yield: 51.5 %

Procedure:
4-{4-[4-(Morpholine-4-sulfonyl)-phenyl]-pyrimidin-2-ylamino}-benzoic acid (0.25 g, 0.57 mmol) was dissolved in THF (5 mL). To this solution was added 1-furoylpiperazine (0.123 g), EDCI (0.131 g), and HOBt (0.092 g). The mixture was stirred 12 h. The mixture was then diluted with CH2Cl2 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude solid was subjected to preparatory HPLC (20-70 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na2SO4), filtered, and concentrated to afford [4-(furan-2-carbonyl)piperazin-1-yl](4-{4-[4-(morpholine-4-sulfonyl)-phenyl]pyrimidin-2-ylamino}phenyl)methanone (0.177 g, 52%): HPLC Retention Time; 9.62 min. (Method B) M+H=603.3
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([N:14]1[C:18]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:17][C:16](=[O:27])[NH:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:12]([N:14]1[C:18]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:17][C:16]([O:27][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[N:15]1)[CH3:13]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CCn1[nH]c(=O)cc1-c1cccc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCn1nc(Oc2ccc(C(F)(F)F)cc2)cc1-c1cccc(C#N)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
1-fluoro-4-(trifluoromethyl)benzene (2.5 mL, 20 mmol, 6.0 equiv) was added to a mixture of 3-(2-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (688 mg, 3.23 mmol, 1 equiv) and potassium carbonate (1.11 g, 8.07 mmol, 2.50 equiv) in dimethyl sulfoxide (8 mL) in a high pressure reaction vessel. The vessel was sealed, and the reaction mixture was heated to 160° C. After stirring for 4 hours, the high pressure vessel was cooled to 22° C. and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 40% ethyl acetate-hexanes) to afford 3-{1-ethyl-3-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-5-yl}benzonitrile (700 mg, 61%) as a white solid. Calcd (M+1)+: 358.1. Found: 358.0.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>[OH-].[Na+].O1CCOCC1>[C:1]1([S:7]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
Benzenesulfonyl chloride (2.5 ml, 19 mmol) was added to a solution of 6-aminohexanoic acid (1 g, 7.62 mmol) in 2N NaOH (22 ml) and dioxane (3 ml), while stirring at 0° C.-5° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was washed with ethyl acetate (50 ml), then acidified to pH 2 with 37% hydrochloric acid and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over sodium sulfate and concentrated. The residue was triturated with hexane. The solid was collected by filtration and dried under vacuum at 50° C. affording 1.1 g of the title compound (55% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:34]=[CH:33][C:19]([O:20][C:21]2[C:26]3=[N:27][CH:28]=[C:29]([NH:31][CH3:32])[N:30]=[C:25]3[N:24]=[CH:23][CH:22]=2)=[CH:18][C:17]=1[F:35]>>[F:35][C:17]1[CH:18]=[C:19]([O:20][C:21]2[C:26]3=[N:27][CH:28]=[C:29]([NH:31][CH3:32])[N:30]=[C:25]3[N:24]=[CH:23][CH:22]=2)[CH:33]=[CH:34][C:16]=1[NH:15][C:13]([NH:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])=[O:14]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CNc1cnc2c(Oc3ccc(N)c(F)c3)ccnc2n1
Product: CNc1cnc2c(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)ccnc2n1

Procedure:
Method F2 was used with 2-fluoro-5-(trifluoromethyl)phenyl isocyanate and 8-(4-amino-3-fluorophenoxy)-N-methylpyrido[3,2-b]pyrazin-3-amine to give the title compound as a white solid. Yield: 56 mg (80%).
Reaction SMILES: N[CH2:2][C:3]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:16]([C:18]1([C:21]3[CH:29]=[CH:28][C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)[CH2:20][CH2:19]1)=[O:17])=[CH:10][CH:9]=2)(C)[CH3:4].C(=O)([O-])[O-].[K+].[K+].IC.O.[CH3:39][N:40]([CH:42]=O)[CH3:41]>>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([C:18]3([C:16]([NH:15][C:11]4[CH:12]=[C:13]5[C:8](=[CH:9][CH:10]=4)[NH:7][C:6]([C:3]([CH3:4])([CH3:2])[CH2:42][N:40]([CH3:39])[CH3:41])=[CH:14]5)=[O:17])[CH2:20][CH2:19]3)=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: CC(C)(CN)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CN(C)CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of N-(2-(1-amino-2-methylpropan-2-yl)-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (20 mg, 0.051 mmol) in DMF (1 mL) was added potassium carbonate (35 mg, 0.26 mmol) and iodomethane (7.0 μL, 0.11 mmol). The mixture was stirred for 2 h. Water was added and the mixture was extracted with dichloromethane. Combined organic phases were dried over magnesium sulfate, evaporated, coevaporated with toluene (3×) and purified by silica gel chromatography (0-30% EtOAc in hexane) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(1-(dimethylamino)-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (7 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.20 (d, J=8.6 Hz, 1H), 7.15 (s, 1H), 7.01-6.95 (m, 3H), 6.85 (d, J=7.9 Hz, 1H), 6.10 (d, J=0.9 Hz, 1H), 6.02 (s, 2H), 2.43 (s, 2H), 2.24 (s, 6H), 1.68 (dd, J=3.7, 6.7 Hz, 2H), 1.33 (s, 6H), 1.08 (dd, J=3.7, 6.8 Hz, 2H).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)[C:22]([Cl:35])=[CH:21][C:20]=2[CH2:36][O:37][CH2:38][C:39]#[CH:40])[O:7][C@@H:6]1[CH2:41][O:42]C(=O)C)(=O)C.O[Li].O>C1COCC1.CO.O>[Cl:35][C:22]1[C:23]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH3:34])=[CH:30][CH:31]=2)=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:41][OH:42])[O:7]2)=[C:20]([CH2:36][O:37][CH2:38][C:39]#[CH:40])[CH:21]=1
Reactant: C#CCOCc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#CCOCc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
To a stirred solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-5-(4-ethoxybenzyl)-2-((prop-2-ynyloxy)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (prepared using methods analogous to those in Example 1 and Example 5 above, 251 mg, 0.39 mmol) in THF:MeOH:H2O (2:3:1, 6.0 mL) at 15° C., was added LiOH—H2O (19.7 mg, 0.47 mmol). After stirring for 12 h at room temperature, the reaction was complete, as indicated by HPLC. The reaction mixture was concentrated and the residue was dissolved in 20 mL of ethyl acetate. The organic layer was washed with brine (20 mL), 5% KHSO4 in brine (20 mL), dried over anhydrous sodium sulfate, evaporated, and the residue was purified by preparative TLC (PE:EtOAc:MeOH=8:80:1, Rf=0.45) to obtain 156 mg of title compound as a white solid (yield 84%; purity 99.2%, as determined by HPLC). 1H-NMR (CD3OD, 400 MHz) δ 7.48 (s, 1H), 7.42 (s, 1H), 7.11 (s, 4H), 4.86 (d, J=12.4 Hz, 1H), 4.60 (d, J=12.4 Hz, 1H), 4.52 (d, J=9.2 Hz, 1H), 4.20 (s, 2H), 4.12 (d, J=14.8 Hz, 1H), 4.06 (d, J=14.8 Hz, 1H), 3.98 (q, J=6.8 Hz, 2H), 3.86 (d, J=12.4 Hz, 1H), 3.70-3.66 (m, 1H), 3.52-3.41 (m, 4H), 2.63 (s, 1H), 1.36 (t, J=6.8 Hz, 3H); LC-MS (m/z) 477 [(M+1)+], 521 [(M+45)−].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=[CH:21][CH:20]=3)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)[CH:7]=1.C(N(CC)CC)C.[CH:36]1([NH2:39])[CH2:38][CH2:37]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[C:24]([C:25]([NH:39][CH:36]4[CH2:38][CH2:37]4)=[O:27])=[CH:23][N:22]=[CH:21][CH:20]=3)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)[CH:7]=1
Reactant: NC1CC1
Reactant: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.3 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-yl-amino]-nicotinic acid (40 mg, 0.10 mmol, 1 eq) in dry DMF (1 ml) was added triethylamine (15 μl, 0.11 mmol, 1.1 eq) followed by cyclopropylamine (70 μl, 0.10 mmol, 10 eq). To the suspension was added a solution of PyBrOP (56 mg, 0.21 mmol, 1.2 eq) in DMF (500 μl) dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the residue was triturated with ether (2×20 ml). The crude residue was purified by flash column chromatography (0-5% MeOH in CHCl3) to give 4-[2-(5-Chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-ylamino]-N-cyclopropyl nicotinamide, compound of formula (45), (15 mg, 34%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14][Cl:15])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[Cl:19][C:20]1[C:28]2[C:27]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:26][O:25][C:24]=2[CH:23]=[C:22]([Cl:35])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C1(C)C=CC=CC=1.CN(C)C=O>[ClH:15].[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14][N:32]3[CH2:33][CH2:34][CH:29]([C:27]4[C:28]5[C:20]([Cl:19])=[CH:21][C:22]([Cl:35])=[CH:23][C:24]=5[O:25][CH:26]=4)[CH2:30][CH2:31]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCc1c(CCCl)sc2c1CCN(C(C)=O)C2
Reactant: Clc1cc(Cl)c2c(C3CCNCC3)coc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(CCN2CCC(c3coc4cc(Cl)cc(Cl)c34)CC2)sc2c1CCN(C(C)=O)C2
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 0.9 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 1.0 g of 4-(4,6-dichlorobenzo(b)furan-3-yl)piperidine hydrochloride, 0.5 g of potassium carbonate, 0.5 g of potassium iodide, 25 ml of dimethylformamide and 25 ml of toluene was stirred at 80° C. for 6 hours and then poured into water. The toluene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and then dissolved into ethanol to make a hydrochloride. The resulting crystals were recrystallized from isopropyl alcohol to give 6-acetyl-2-(2-(4-(4,6-dichlorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride, m.p. 260° C. (decomposition).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:8]#[N:9].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=3)[CH2:36]2)[C:8]#[N:9])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COc1ccc(C(C#N)(CCCCCBr)Sc2ccccn2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccccn2)cc1OC
Yield: 58.4 %

Procedure:
A mixture, under argon, of 1.5 g of product from Example 118, 0.790 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, 7 ml of N,N-diisopropyl ethylamine and 60 ml of acetonitrile is heated at reflux temperature overnight. The reaction is cooled and concentrated in vacuo to give an oil. The oil is purified by chromatography (silica gel: 1 and 2% methyl alcohol/methylene chloride) to give 1.1 g of the desired product as a glassy yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].C(N(CC)CC)C.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:40]=1)=[O:37]>O1CCCC1>[Cl:27][C:8]1[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][C:36]([O:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:44]=2)=[O:37])[CH3:6])=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To a suspension of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg) in tetrahydrofuran were added triethylamine (18.8 mg) and 4-methoxycarbonylphenyl chloroformate (39.8 mg) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed, and ethyl acetate and water were added to the residue. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (ethyl acetate:n-hexane=2:1, V/V) to give 8-[2,6-dichloro-3-[N-[(4-methoxycarbonylphenoxycarbonyl)glycyl]-N-methylamino]benzyloxy]-2-methylquinoline (30 mg) as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][CH2:10][C@H:9]2[C:13]([N:15]2[CH2:24][C@@H:23]([N:25]([CH:32]3[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33]3)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][C@H:16]2[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:14])=[CH:4][CH:3]=1.[CH3:40][C:41](O)=[O:42]>>[C:41]([N:11]1[CH2:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:9]([C:13]([N:15]2[CH2:24][CH:23]([N:25]([CH:32]3[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33]3)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][C@H:16]2[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:14])[CH2:10]1)(=[O:42])[CH3:40]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: CC(=O)O
Product: CC(=O)N1C[C@@H](C(=O)N2CC(N(C(=O)C(C)(C)C)C3CCC(C)(C)CC3)C[C@H]2C(=O)N(C)C)[C@H](c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the procedure described in Step F of Example A1 using (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolineamide (84 mg, 0.15 mmol) prepared in Example E1-1 and AcOH via amide coupling reaction.