Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[C:5]1[C:4](=[O:7])[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:2](=[O:1])[NH:6]1
Reactant: O=Cc1cccc(O)c1
Reactant: N#Cc1ccc(N2C(=O)CNC2=O)c2ccccc12
Product: N#Cc1ccc(N2C(=O)NC(=Cc3cccc(O)c3)C2=O)c2ccccc12

Procedure:
The title compound was obtained as an off-white solid (38.5 mg, 18.2%) from compound 1C and 3-hydroxybenzaldehyde in the same manner as that used in the preparation of Example 1 by acidifying the aqueous washings and recrystallization of the crude product from MeOH. LC/MS m/z 356 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[NH2:44][C:45]1[CH:46]=[CH:47][C:48](Br)=[N:49][CH:50]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.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]>[NH2:44][C:45]1[CH:46]=[CH:47][C:48]([C:32]2[CH:31]=[CH:30][C:29]([C:9]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:13](=[O:14])[C:12]4[CH:15]=[N:16][N:17]([C:18]5[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH:21]=[CH:22][CH:23]=5)[C:11]=4[N:10]=3)=[CH:34][CH:33]=2)=[N:49][CH:50]=1
Reactant: Nc1ccc(Br)nc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(NS(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of N-(3-{5-(4-chloro-phenyl)-4-oxo-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)phenyl]-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl}-phenyl)-methane sulfonamide (prepared as described in example 35, 0.28 g, 0.453 mmol) in N,N-dimethylformamide (15 mL) is degassed with argon for 0.5 h. Then 5-amino-2-bromopyridine (0.120 g, 0.679 mmol), cesium carbonate (0.30 g, 0.90 mmol), Pd(dppf)2Cl2 (0.016 g, 0.020 mmol) are added and the resulting solution is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 12 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford N-{3-[6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-phenyl}-methane sulfonamide. 1H NMR (CD3OD, 400 MHz) δ 8.37 (s, 1H), 8.30 (s, 1H), 7.95 (m, 2H), 7.90 (d, 1H), 7.71 (m, 5H), 7.50 (t, 1H), 7.35 (m, 4H), 7.20 (d, 1H), 2.99 (s, 3H); LC-MS calculated for C29H22ClN7O3S (M+H+) 584.1, found 584.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[C:19](=[C:20]([O:25]CC4C=CC=CC=4)[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1.C>C(O)C.C(OCC)(=O)C.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Fc1cc(-n2ncc3c(OCc4ccccc4)cccc32)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccc(-n2ncc3c(O)cccc32)cc1F
Yield: 81.5 %

Procedure:
A mixture of 1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indazole (D2) (307 mg) in ethanol/ethyl acetate (˜50 mL, 1:1) was hydrogenated in the presence of 10% Pd on charcoal (150 mg) at atmospheric pressure and room temperature for 3 hrs. The mixture was filtered and concentrated and then chromatographed on silica gel (elution with 0-50% ethyl acetate in hexane) to give an off white solid. This was dissolved in ethyl acetate and stirred with charcoal (Norit SX+, 10 mg) for 30 minutes. The mixture was filtered and concentrated to give the title compound (E1) (144 mg).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[OH:38][C:34]1[CH:33]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:37]=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3cccc(O)c3)cc2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 25, 100 mg, 0.248 mmol) and THF (1.5 mL). To the resulting solution was added 3-aminophenol (29.8 mg, 0.273 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The solid precipitate that formed was filtered and washed with THF yielding 70% (86 mg, 0.174 mmol) of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13](O)[C:12]([CH3:17])([CH3:16])[C:11]=2[CH:18]=1)#[N:6].N1C=CC=CC=1>ClCCl>[Cl:3][CH:13]1[C:12]([CH3:17])([CH3:16])[C:11]2[CH:18]=[C:7]([C:5]#[N:6])[CH:8]=[CH:9][C:10]=2[O:14]1
Reactant: CC1(C)c2cc(C#N)ccc2OC1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)c2cc(C#N)ccc2OC1Cl
Yield: 78.2 %

Procedure:
Thionyl chloride (9.3 g) in dichloromethane (10 ml) was added dropwise with stirring and cooling to 5-cyano-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (11.3 g) prepared as in Example 10 and pyridine (6.2 g) in dichloromethane (60 ml.) The mixture was stirred for 2 hours at room temperature prior to washing with water, dilute sodium hydroxide solution and water again, drying over magnesium sulphate and evaporating under vacuum. Recrystallisation from toluene and petroleum ether (bp 80°-100° C.) gave 9.7 g of the title compound, mp 105°-106° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:21]([NH:23][CH3:24])=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:29][CH2:30][N:31]([CH2:2][C:3]2[CH:16]=[N:15][C:6]3[C:7]4[N:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[O:11])[NH:10][C:5]=3[CH:4]=2)[CH2:32][CH2:33]1)[C:21]([NH:23][CH3:24])=[O:22]
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)c(Cl)c1
Temperature: 95 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (25.00 mg, 0.116 mmol), 3-chloro-N-methyl-4-(piperazin-1-yl)benzamide (36.8 mg, 0.145 mmol) and (cyanomethyl)trimethylphosphonium iodide (45.2 mg, 0.186 mmol) in Propiononitrile (Volume: 1.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.101 mL, 0.581 mmol) at 23° C. The reaction was stirred at 95° C. for 6 hr. The suspension was cooled to 23° C., filtered, rinsed with ACN (3×1 mL) and dried in vacuo to provide 3-chloro-N-methyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.0387 g, 0.086 mmol, 73.9% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54-2.66 (m, 4 H) 2.76 (d, J=4.29 Hz, 3 H) 2.96-3.18 (m, 4 H) 3.65 (s, 2 H) 6.71-6.77 (m, 1 H) 7.08 (dd, J=3.54, 1.52 Hz, 1 H) 7.19 (d, J=8.34 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.68 (dd, J=3.03, 1.52 Hz, 1 H) 7.76 (dd, J=8.34, 2.02 Hz, 1 H) 7.86 (d, J=2.02 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 8.42 (q, J=4.38 Hz, 1 H) 11.63 (s, 1 H). ESI-MS: m/z 451.3 (M+H)+. mp=259.9-265.8° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][C:9]([C:11]1[CH:12]=[CH:13][C:14](O)=[CH:15][C:16]=1[OH:17])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl.CCOCC>[OH:17][C:16]1[CH:15]=[C:14]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:13]=[CH:12][C:11]=1[C:9](=[O:10])[CH3:8]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: OC1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1ccc(OC2CCOCC2)cc1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 31.3 %

Procedure:
A mixture of tetrahydro-4H-pyran-4-ol (1.53 g, 15 mmol), 2,4-dihydroxyacetophenone (1.52 g, 10 mmol), and triphenylphosphine, polymerbound (5 g, 3 mmol P/g resin, 15 mmol) in CH2Cl2 (150 mL) was treated with diethylazodicarboxylate (2.61 g, 15 mmol) and stirred at 20° C. for 20 h. The reaction mixture was treated with ether (200 mL) and the resin was filtered off and discarded. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 25% ether in hexanes) to yield the white solid product (0.74 g, 31%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH3:29][NH:30][CH3:31]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:30]([CH3:31])[CH3:29])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: CNC
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)N(C)C)cc3C)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N,N,3-trimethylbenzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and dimethylamine following the procedures described for Example 117. 1H NMR (CDCl3): δ 8.68 (s, 1H), 8.32 (s, 1H), 8.04 (d, 1H), 7.66 (s, 1H), 7.31 (d, 1H), 7.06-7.18 (m, 3H), 3.08-3.19 (m, 4H), 2.96 (d, 3H), 2.54 (s, 3H), 2.33 (s, 3H), 2.05 (s, 3H). LRMS [M+H]=399.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19](C2C=CC(F)=CC=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH2:35]([CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1)[C:36]#[CH:37]>>[C:25]([C:22]1([C:20]([NH:19][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[CH:15]=[C:16]([C:37]#[C:36][CH2:35][CH:38]5[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]5)[S:17][C:10]=34)=[C:2]([F:1])[CH:3]=2)=[O:21])[CH2:24][CH2:23]1)(=[O:26])[NH2:27]
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N1CCC(CC#Cc2cc3nccc(Oc4ccc(NC(=O)C5(C(N)=O)CC5)cc4F)c3s2)CC1
Yield: 49.9 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 50 mg, 0.0845 mmol) and tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (37.8 mg, 0.169 mmol) using the procedure described for Example 6, Step B. The reaction was purified by preparative TLC (1 mm thickness, Rf=0.52), eluting with 10% MeOH/DCM. The product was subject to a second preparative TLC purification (0.5 mm thickness, Rf=0.09), eluting with 1:1 EtOA/hexanes. The product was obtained as a beige powder (25 mg, 31%). LRMS (APCI−): m/z 685 (M−1) detected.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]=3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[H-].[Na+].[CH2:42]([O:49][C:50](Cl)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CC(O)=O>CN(C=O)C>[F:39][C:2]([F:1])([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]([CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]=3[C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C:50]([O:49][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:51])(=[O:18])=[O:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)c1c(CNS(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1c(CN(C(=O)OCc2ccccc2)S(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A solution of Example 9E (1.255 g, 2.25 mmol) in DMF (20 mL) under N2 at 0° C. was treated with NaH (60% dispersion in mineral oil, 180 mg, 4.50 mmol) and allowed to stirr for 30 minutes. Benzylchloroformate (0.68 mL, 4.50 mmol) was added, the mixture was allowed to stir for 2 hours, and HOAc was added. The solvent was removed and the residue was dissolved in ethyl acetate (100 mL), washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. Purification over silica gel with 30% hexanes/CH2Cl2 provided 1.19 g (77%) of the desired compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][CH3:10])[CH:3]=1.C(#N)C.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(Br)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COc1cc(Br)ccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
To a solution of 4-bromo-1-iodo-2-methoxybenzene (1.634 g, 5.221 mmol) in dry acetonitrile (20 mL) CuI (49.7 mg, 0.261 mmol) and Pd(Ph3P)2Cl2 (183.2 mg, 0.261 mmol) were added under Argon atmosphere and the mixture was degassed and backfilled with Argon for three times. TEA (0.728 mL, 5.221 mmol) and (ethynyl)trimethylsilane (1.48 mL, 1.03 g, 10.442 mmol) were added with a syringe and the reaction mixture, that darkened within 10 min, was stirred at room temperature for 1 h. The solvent was removed under vacuum and the residue was taken up with EtOAc (100 mL), washed with brine (3×20 mL), water (20 mL), dried over sodium sulphate and evaporated to dryness. The crude was purified by chromatography on silica gel (petroleum ether/diethyl ether 9/1) to yield the title compound as an orange solid (1.426 g, 96.5%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:31])[NH:22][C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])=[CH:17][C:16]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C@H:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH3:24])=[O:31])=[CH:17][C:16]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of (S)-{4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(1-phenyl-ethylcarbamoyl)-phenylsulfanyl]-phenyl}-carbamic acid tert-butyl ester (80 mg) in dichloromethane (1.6 mL) was added trifluoroacetic acid [TFA] (0.40 mL) dropwise at room temperature and the mixture was stirred at room temperature for 1 hour. The reaction mixture was portioned between AcOEt and aqueous K2CO3. The organic layer was separated, washed with H2O and brine, dried over MgSO4, and evaporated to pale yellow amorphous, which was solidified by trituration in i-Pr2O. The resulting solid was collected by filtration, washed with i-Pr2O, and dried at 40° C. overnight under reduced pressure to give the title compound as yellow crystal (57 mg, 85%). 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=7.0 Hz, 6H), 1.45 (d, J=7.3 Hz, 3H), 3.23 (septet, J=7.0 Hz, 1H), 5.15 (quintet, J=7.3 Hz, 1H), 5.58 (s, 2H), 6.62 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.5 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 7.16-7.25 (m, 1H), 7.25-7.40 (m, 4H), 7.63 (d, J=8.4 Hz, 1H), 7.71 (dd, J=8.5, 1.8 Hz, 1H), 7.88 (d, J=1.8 Hz, 1H), 8.57 (s, 1H), 8.75 (d, J=7.3 Hz, 1H), 8.87 (d, J=8.5 Hz, 1H), 10.12 (s, 1H) MS ESI+ m/z: 535 (M+H)
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].Cl.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([C:21]3[CH:30]=[C:29]4[C:24]([CH2:25][CH2:26][N:27]([C:31](=[O:39])[CH2:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[CH2:28]4)=[CH:23][CH:22]=3)[N:18]=[C:17]([NH2:40])[N:16]=2)[CH2:11][CH2:10]1>>[CH2:1]([S:3]([N:36]1[CH2:35][CH2:34][CH:33]([CH2:32][C:31]([N:27]2[CH2:26][CH2:25][C:24]3[C:29](=[CH:30][C:21]([C:19]4[CH:20]=[C:15]([N:12]5[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]5)[N:16]=[C:17]([NH2:40])[N:18]=4)=[CH:22][CH:23]=3)[CH2:28]2)=[O:39])[CH2:38][CH2:37]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNCC3)CC4)nc(N)n2)CC1
Agent: Cl
Product: CCS(=O)(=O)N1CCC(CC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 71, Step 4 starting from ethanesulfonyl chloride and 4-(4-methylpiperazin-1-yl)-6-[2-(piperidin-4-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=542.3.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[H][H]>C(O)C.O.[Pt]=O>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: O=[Pt]
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1ccc(F)cc1F
Yield: 99.7 %

Procedure:
A mixture of 2,4-difluorocinnamic acid (30.0 g, 0.16 mol, Aldrich) and platinum oxide hydrate (0.5 g, EM Scientific) in 95% ethanol (140 mL) was placed on Parr hydrogenation apparatus. After the appropriate amount of hydrogen was taken up, the catalyst was filtered and the filtrate was concentrated in vacuo to give 29.7 g (98%) of 3-(2,4difluorophenyl)propanoic acid as a white solid. Recrystallization of 1.0 g from acetonitrile; water mixtures gave 0.61 g of 3-(2,4-difluorophenyl)propanoic acid as a white solid: mp 104-106° C.; NMR (DMSO-d6); d 12.2 (br, 1H), 6.98-7.40 (m, 3H), 2.81 (t, 2H), 2.51 (t, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[F:69][C:70]1[C:75]([F:76])=[CH:74][C:73](B2OC(=O)CN(C)CC(=O)O2)=[C:72]([O:88][C@H:89]([CH2:91][CH:92]=[CH2:93])[CH3:90])[CH:71]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:73]5[CH:74]=[C:75]([F:76])[C:70]([F:69])=[CH:71][C:72]=5[O:88][C@H:89]([CH2:91][CH:92]=[CH2:93])[CH3:90])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1B1OC(=O)CN(C)CC(=O)O1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Temperature: 80 °C
Yield: 83.1 %

Procedure:
A mixture of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (0.25 g, 0.42 mmol, 1 equiv), Sphos (34 mg, 0.084 mmol, 0.2 equiv), (S)-2-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (0.18 g, 0.52 mmol, 1.25 equiv), K3PO4 (1.05 g, 4.59 mmol, 11 equiv), and Pd(OAc)2 (9 mg, 0.042 mmol, 0.1 equiv) in dioxane (5 mL) and water (1 mL) was heated at 80° C. for 1.5 h. Upon cooling to ambient temperature, the reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (0.25 g, 84%) as a white solid. LCMS (ESI, M+1): 716.70.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:42])[NH:21][CH:22]1[C:28](=[O:29])[NH:27][C:26]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:25]=2[C:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:23]1)[C@H:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[F:44][C:2]([F:1])([F:43])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:42])[NH:21][CH:22]1[C:28](=[O:29])[NH:27][C:26]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:25]=2[C:24]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[N:23]1)[C@H:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:7]([OH:9])=[O:8]
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NC(NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)OC(C)(C)C)C(=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(c1ccccc1)=NC(NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)O)C(=O)N2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Intermediate 7D (1.03 mg, 0.836 mmol) in CH2Cl2 (8 mL) at 0° C. under a nitrogen atmosphere, was added trifluoroacetic acid (3 mL) dropwise over two minutes. The reaction mixture was stirred at 0° C. for one hour and then stirred at room temperature for five hours. The reaction mixture was then concentrated and treated with ice cold water (50 grams). After stirring for fifteen minutes, the off-white precipitate was filtered, washed with water (5 mL) and dried to provide Intermediate 7E as a white solid: yield=500 mg (84%); HPLC: RT=2.282 (H2O/AcCN with NH4OAc, PUROSPHER® Star RP-18 (4×55) mm, 3 μm, gradient=3 min, wavelength=220 nm); MS(ES):m/z=572 [M−H+]; 1H NMR (DMSO-d6: as mixture of diastereomers) δ 10.67 (s, 1H), 9.51-9.54 (t, J=7.2 Hz, 1H), 7.5-7.6 (m, 3H), 7.5 (m, 2H), 7.1-7.3 (m, 4H), 6.771 (s, 1H), 5.29 (t, J=8.0 Hz, 1H), 3.7 (s, 3H), 2.80-2.91 (m, 1H), 2.70 (m, 1H), 2.50 (m, 1H), 2.10-2.34 (m, 3H), 1.50-1.90 (m, 3H).