Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=1
Reactant: COC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 3-tert-butoxycarbonylmethoxy-benzoic acid methyl ester (1.00 g, 3.75 mmol) in methylene chloride (4 mL), add trifluoroacetic acid (0.50 mL, 6.6 mmol). Stir the mixture overnight at room temperature in an open vial to allow the solvent to escape. Add an additional portion of trifluoroacetic acid (0.50 mL, 6.6 mmol) and stir the reaction mixture for an additional 24 hours. Add an additional portion of trifluoroacetic acid (1.50 mL, 19.8 mmol) and stir the reaction at room temperature for 3 days. Concentrate under reduced pressure to provide 0.750 g (95.0%) of 3-carboxymethoxy-benzoic acid methyl ester as a light brown solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:10]([OH:12])=O)[S:6][C:7]=1[CH:8]=[O:9])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:35][C:36]1([CH3:56])[O:40][C@@H:39]([CH2:41][O:42][C:43]2[C:52]([CH3:53])=[CH:51][C:46]([C:47]([NH:49]O)=[NH:48])=[CH:45][C:44]=2[CH2:54][CH3:55])[CH2:38][O:37]1>CN(C=O)C>[CH3:35][C:36]1([CH3:56])[O:40][C@@H:39]([CH2:41][O:42][C:43]2[C:52]([CH3:53])=[CH:51][C:46]([C:47]3[N:49]=[C:10]([C:5]4[S:6][C:7]([CH:8]=[O:9])=[C:3]([CH2:1][CH3:2])[CH:4]=4)[O:12][N:48]=3)=[CH:45][C:44]=2[CH2:54][CH3:55])[CH2:38][O:37]1
Reactant: CCc1cc(C(=O)O)sc1C=O
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@H]1COC(C)(C)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@H]4COC(C)(C)O4)c(CC)c3)no2)sc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-ethyl-5-formyl-thiophene-2-carboxylic acid (20 mg, 0.109 mmol), HOBt (18 mg, 0.131 mmol), and EDC HCl (23 mg, 0.120 mmol) in DMF (0.75 mL) is stirred at rt for 5 min before (S)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-N-hydroxy-5-methyl-benzamidine (34 mg, 0.109 mmol) is added. The mixture is stirred at rt for 1 h, then at 85° C. for 2 days. The title compound is isolated as a colourless oil (28 mg) by separating the reaction mixture by prep. HPLC (column: Atlantis T3, 30×75 mm, 10 μm, eluting with a gradient of acetonitrile in water containing 0.5% of formic acid); LC-MS: tR=1.06 min; [M+1]+=457.19.
Reaction SMILES: [SiH:1]([Cl:4])([Cl:3])[Cl:2].[CH2:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:15]2[S:19][C:18]([C:20]3[S:21][C:22]([N:25]([C:32]4[CH:37]=[CH:36][C:35]([CH2:38][CH:39]=[CH2:40])=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:23][CH:24]=3)=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[CH:6]=[CH2:7]>C1(C)C=CC=CC=1.C1([Pt-](Cl)C2C=CC=C2)C=CC=C1>[Cl:2][Si:1]([CH2:40][CH2:39][CH2:38][C:35]1[CH:34]=[CH:33][C:32]([N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]2[S:21][C:20]([C:18]3[S:19][C:15]([N:14]([C:11]4[CH:10]=[CH:9][C:8]([CH2:5][CH2:6][CH2:7][Si:1]([Cl:4])([Cl:3])[Cl:2])=[CH:13][CH:12]=4)[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[CH:16][CH:17]=3)=[CH:24][CH:23]=2)=[CH:37][CH:36]=1)([Cl:4])[Cl:3]
Reactant: C=CCc1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(CC=C)cc4)s3)s2)cc1
Reactant: Cl[SiH](Cl)Cl
Agent: Cl[Pt-](C1C=CC=C1)C1C=CC=C1
Solvent: Cc1ccccc1
Product: Cl[Si](Cl)(Cl)CCCc1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(CCC[Si](Cl)(Cl)Cl)cc4)s3)s2)cc1
Temperature: 60 °C

Procedure:
Excess HSiCl3 (0.09 mL, 8.609×10−4 mol) and a few grains of dicyclopentadienylplatinum(II) chloride (Cp2PtCl2) catalyst were added in a glove box to a solution of Compound 4 (0.050 g, 8.609×10−5 mol) in about 10 mL anhydrous toluene. The solution was transferred to a Schlenk line where it was heated to 60° C. with stirring and left under static N2 to prevent evaporation of the HSiCl3. The reaction progress was monitored by 1H NMR, and cooled to room temperature after 42 h. Toluene and excess HSiCl3 were next removed in vacuo. Upon trituration of the crude product with 15 mL of a dry 1:1 toluene:pentane solution, a solid formed and was removed via cannula filtration.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][N:10]=2)=[CH:3][CH:2]=1.C1COCC1>CO.[OH-].[Na+].Cl>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(OCc2ccc(-c3ccccc3)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccc(-c3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
To a solution of methyl 6-(4-biphenylylmethoxy)nicotinate (2.0 g) in methanol (20 ml)/THF(40 ml) was added iN aqueous sodium hydroxide (13 ml) at room temperature. After stirring at room temperature for 4 hr the reaction mixture was diluted with 1 N hydrochloric acid (13 ml) and concentrated. The precipitate was collected by filtration and washed with water and diethyl ether sequentially to obtain the titled compound (1.6 g) as amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][C:12]([CH2:17][CH2:18]Cl)([CH2:15][CH3:16])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([OH:33])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH2:16][CH2:15][C:12]2([CH2:17][CH3:18])[CH2:11][CH2:10][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=4[N:6]=3)[CH2:14][CH2:13]2)[CH:27]=1
Reactant: CCC1(CCCl)CCN(c2nc3ccc(Cl)cc3s2)CC1
Reactant: COC(=O)Cc1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1(CCOc2cc(CC(=O)OC)ccc2Cl)CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 75 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
A mixture of 6-chloro-2-[4-(2-chloroethyl)-4-ethyl piperidine-1-yl]benzothiazole (150 mg), (4-chloro-3-hydroxyphenyl)acetic acid methyl ester (176 mg), cesium carbonate (285 mg) and dimethylformamide (2 mL) was stirred at 75° C. for 24 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (174 mg). Yield: 79%.
Reaction SMILES: S(Cl)(Cl)=O.CN(C=O)C.[C:10]1([N:16]2[C:28]([CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[C:27]3[C:18]([C:19](=O)[NH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=43)=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:38]CCl>C(#N)C>[Cl:38][C:19]1[C:18]2=[N:17][N:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:28]([CH2:29][CH2:30][CH:31]3[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]3)=[C:27]2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: O=c1[nH]c2ccccc2c2c(CCC3CCNCC3)n(-c3ccccc3)nc12
Reactant: ClCCl
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1nc2ccccc2c2c(CCC3CCNCC3)n(-c3ccccc3)nc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Thionyl chloride (1.0 mL) and DMF (1.0 mL) were combined and added dropwise to a mixture of 2-phenyl-1-(2-piperidin-4-ylethyl)-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (200 mg, 0.537 mmol) and dichloromethane (10 mL) at 0° C. The resulting suspension was stirred 5 minutes at 0° C. before warming to ambient temperature and stirring 55 minutes. The suspension was concentrated under reduced pressure to afford a light yellow oil that was stirred in acetonitrile and filtered to obtain a white solid. The solid was combined with additional acetonitrile and concentrated under reduced pressure to afford 100 mg of 4-chloro-2-phenyl-1-(2-piperidin-4-ylethyl)-2H-pyrazolo[3,4-c]quinoline.HCl as a white powder, mp 194° C. MS (APCI) m/z 391 (M+H)+; Anal. calcd for C23H23ClN4.1.0H2O.1.0HCl: C, 62.02; H, 5.88; N, 12.58. Found: C, 61.91; H, 5.67; N, 12.48.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[S:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:3]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:4]1[S:5][C:6]2[CH:11]=[C:10]([C:12]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:14])[CH:9]=[CH:8][C:7]=2[C:2](=[O:1])[N:3]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc2c(=O)nc(-c3ccccn3)sc2c1
Solvent: C1CCOC1
Product: O=C(c1ccc2c(=O)nc(-c3ccccn3)sc2c1)N1CCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 11.7 %

Procedure:
N,N′-carbonyldiimidazole (445 mg, 2.7 mmol) was added to a mixture of 4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-carboxylic acid (600 mg, 2.1 mmol) and tetrahydrofuran (20 ml), and the mixture was stirred at 60° C. for 2 hrs. Successively, pyrrolidine (300 mg, 4.2 mmol) was added to the reaction mixture, and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (83 mg, 11%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2=[O:14])=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([N:24]([CH:34]2[CH2:36][CH2:35]2)CC2C=CC(OC)=CC=2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1.Br[CH2:43][C:44]([NH2:46])=[O:45].C([O-])([O-])=O.[K+].[K+].C(O)(C(F)(F)F)=O>CN(C=O)C.ClC(Cl)C.C1(OC)C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:17][C:18]2[N:23]=[C:22]([NH:24][CH:34]3[CH2:35][CH2:36]3)[C:21]3=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]3[N:19]=2)=[CH:4][C:5]([C:15]#[N:16])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:43][C:44]([NH2:46])=[O:45])[CH2:10][C:9]1=[O:14]
Reactant: NC(=O)CBr
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNCC4=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCN(CC(N)=O)CC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To solution of 2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 628)(10 mg, 0.018 mmol) in DMF (0.5 mL) was added 2-bromoacetamide (4.85 mg, 0.035 mmol) followed by K2CO3 (29.1 mg, 0.211 mmol) and it was stirred at room temperature for 1 h, LC-MS indicated completion. Purification via flash chromatography (0-10% MeOH in DCM, 12 g) gave 9 mg of the PMB protected product. This was dissolved in 1 mL of dichloroethane and then 1 drop of anisole was added followed by 0.5 mL of TFA. The solution was heated at 60° C. for 1 h. LC-MS indicated completion, and then it was cooled and concentrated. The crude was dissolved in methanol and neutralized with 7N ammonia in methanol. After stirring for 10 min it was concentrated, purification via preparative HPLC gave the title compound as a yellow solid (4.7 mg).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14](=[O:33])[CH:15]([NH:22]C(OCC1C=CC=CC=1)=O)P(OC)(OC)=O.[CH3:34][C:35]1[CH:36]=[C:37]([CH:43]=O)[C:38](=[CH:41][CH:42]=1)[CH:39]=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:34][C:35]1[CH:36]=[C:37]2[C:38](=[CH:41][CH:42]=1)[CH:39]=[N:22][C:15]([C:14]([O:13][CH3:12])=[O:33])=[CH:43]2
Reactant: Cc1ccc(C=O)c(C=O)c1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc2cc(C)ccc2cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.6 %

Procedure:
DBU (4.71 mL, 31.5 mmol) and methyl{[(benzyloxy)carbonyl]amino}(dimethoxyphosphoryl)acetate (10.43 g, 31.5 mmol) are dissolved in CH2Cl2 (175 mL). The resulting solution is added drop-wise a solution of 4-methylphthalaldehyde (4.24 g, 28.6 mmol) in CH2Cl2 (200 mL) at 0° C. The reaction is stirred cold for 1 hour at 0° C. and then for an additional 18 hours at rt. The volatiles are evaporated to an orange oil, which is dissolved in CHCl3 (200 mL). DBU (4.79 mL, 32.0 mmol) and TFAA (4.52 mL, 32.0 mmol) are added. The reaction is stirred under N2 for 3 hours. Upon completion, the reaction is quenched with 250 mL of saturated NaHCO3 solution. The organic layer is separated and the aqueous layer is extracted with 2×250 mL of CHCl3. The organic layers are combined, dried (MgSO4), filtered, and concentrated. The crude reaction mixture is purified by column chromatography using a step gradient of 20% EtOAc to 26% EtOAc in hexanes in 2% intervals. The resulting product-containing fractions are concentrated and purified via preparative achiral HPLC to yield 0.84 g of methyl 6-methyl-isoquinoline-3-carboxylate as a yellow solid. HRMS (FAB) calculated for C12H11N O2+H+: 202.0868, found 202.0863.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.N1CCCCC1>C(O)C>[OH:9][C:8]1[CH:10]=[CH:11][C:3](/[CH:2]=[C:20](/[C:17]2[CH:18]=[N:19][C:14]([C:13]([F:24])([F:12])[F:23])=[CH:15][CH:16]=2)\[C:21]#[N:22])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: COc1cc(C=O)ccc1O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(/C=C(\C#N)c2ccc(C(F)(F)F)nc2)ccc1O
Temperature: 25 °C

Procedure:
A suspension of vanillin (1.0 g, 6.57 mmol), 2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (1.222 g, 6.57 mmol) and piperidine (0.71 mL, 7.23 mmol) in absolute ethanol (10 mL) was stirred at reflux for forty-eight hours and then allowed to cool to room temperature. The resulting precipitate was filtered off, washed with water and dried. Recrystallisation from isopropanol afforded (Z)-3-(4-hydroxy-3-methoxyphenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acrylonitrile as white crystals, 0.904 g (43%).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:18])[CH2:14]C(O)=O)[CH3:11].N1CCCCC1>N1C=CC=CC=1>[CH2:10]([O:12][C:13](=[O:18])[CH:14]=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[CH3:11]
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1ccc(C)cc1
Yield: 79 %

Procedure:
Application of the previously unused Knoevenagel condensation (Silva, N. M. et al., Eur. J. Med. Chem. 2002, 37, 163-170; Díaz, J. L. et al., Chem. Mater. 2002, 14, 2240-2251; Ren, X. et al., Tetrahedron: Asymmetry 2002, 13, 1799-1804) of p-tolualdehyde with malonic acid monoethyl ester (Breslow, D. S. et al., J. Am. Chem. Soc. 1944, 66, 1286-1288) in pyridine containing a catalytic amount of piperidine gave the known α,β-unsaturated ethyl cinnamate 5 (Tsuge, O. et al., J. Org. Chem. 1982, 47, 5171-5177; Colas, C.; Goeldner, M. Eur. J. Org. Chem. 1999, 1357-1366; Chuzel, O.; Piva, O. Synth. Commun. 2003, 33, 393-402) in 79% yield. Reaction of 5 with (p-tolylsulfonyl)methyl isocyanide (TosMIC) afforded β-substituted pyrrole 6 (a known compound with incomplete data (Di Santo, R. et al., Med. Chem. Res. 1997, 7, 98-108)) in 74% yield. Removal of the ethoxycarbonyl group of pyrrole 6 by treatment with NaOH in ethylene glycol at 160° C. gave the known β-substituted pyrrole 7 (Sakai, K. et al., Chem. Pharm. Bull. 1980, 28, 2384-2393; Campi, E. M. et al., Aust. J. Chem. 1992, 45, 1167-1178; Pavri, N, P.; Trudell, M. L. J. Org. Chem. 1997, 62, 2649-2651) in 71% yield. Vilsmeier-Haack formylation of 7 yielded a mixture of regioisomers owing to substitution at the 2- or 5-position. After column chromatography, the two regioisomers were determined to be present in ˜13:1 ratio by 1H NMR integration of the methyl unit of the p-tolyl group. Selective precipitation readily afforded the major regioisomer 8 in 64% yield (Scheme 3).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.[C:19]([NH2:23])(=[O:22])[CH:20]=[CH2:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:18][C:4]1[CH:3]=[C:2]([CH:21]=[CH:20][C:19]([NH2:23])=[O:22])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[CH:5]=1
Reactant: C=CC(N)=O
Reactant: Oc1ccc(-c2cc3cc(O)cc(Br)c3o2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)C=Cc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Yield: 51.8 %

Procedure:
To a solution of 7-bromo-2-(4-hydroxy-phenyl)-benzofuran-5-ol 58 (0.3 g, 0.98 mmol) in triethylamine (5 mL) and acetonitrile (5 mL) was added acrylamide (0.077 g, 1.08 mmol) and tri-(o-tolyl) phosphine (0.060 g, 0.2 mmol). This mixture was purged with nitrogen for 10 minutes. Then palladium (II) acetate (0.022 g, 0.098 mmol) was added and the reaction was heated at reflux for 3.5 hours. To the cooled reaction was added 2N HCl and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and the solvent removed in vacuo. The residue was purified via flash chromatography on silica gel, eluting with 10% methanol in dichloromethane to give 0.15 g of 3-[5-hydroxy-2-(4-hydroxyphenyl)-benzofuran-7-yl]-acrylamide 61: Mp=275° C. (dec); 1H NMR (DMSO-d6) δ 9.89 (s, 1 H), 9.35 (s, 1 H), 7.86 (br s, 1 H), 7.83 (d, 2 H, J=8.6 Hz), 7.53 (d, 1 H, J=15.9 Hz), 7.23 (br s, 1 H), 7.11 (s, 1 H), 7.04 (d, 1 H, J=15.9 Hz), 6.94 (d, 1 H, J=2.4 Hz), 6.90 (d, 2 H, 8.7 Hz), 6.83 (d, 1 H, J=2.3 Hz); MS 296 (M+H)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:19]=2)[C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([NH2:37])=[CH:35][C:34]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([NH:37][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:15]=[N:16][CH:17]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:19]=4)[C:3]=3[CH3:24])=[CH:35][C:34]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2cncc(S(C)(=O)=O)c2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cncc(S(C)(=O)=O)c2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
A screw-cap vial was charged with 4-chloro-5,7-difluoro-3-methyl-2-(5-(methylsulfonyl)pyridin-3-yl)quinoline (40 mg, 0.11 mmol), 2,5-dimorpholinopyridin-3-amine (28.7 mg, 0.11 mmol), tris(dibenzylideneacetone)dipalladium (0) (10.0 mg, 11.0 μmol), X-Phos (10.3 mg, 0.022 mmol), sodium tert-butoxide (31.3 mg, 0.33 mmol), and toluene (1.1 mL). The reaction was stirred at 105° C. for 30 min, then cond. The resulting residue was partitioned between DCM and water, and extracted twice with DCM. The combined organic layer was dried over magnesium sulfate and cond, and the crude product was purified by flash chromatography (basic alumina, 0-60% EtOAc in hexanes). This afforded N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(5-(methylsulfonyl)pyridin-3-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=597.0 (M+1). 1H NMR (500 MHz, CDCl3) δ ppm 9.26 (1H, d, J=2.2 Hz), 9.16 (1H, s), 8.56 (1H, s), 7.89 (1H, s), 7.72 (1H, s), 7.63 (1H, s), 7.09 (1H, s), 6.43 (1H, s), 3.88-4.08 (4H, m), 3.85 (4H, br. s.), 3.23 (4H, br. s.), 3.08 (4H, br. s.), 2.18 (3H, s), 1.57 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([F:12])[CH:3]=1.S(Cl)([Cl:15])=O.CN(C=O)C>CC(=O)OCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:15])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(Br)cc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (0.1 g, 0.429 mmol) in sulfurous dichloride (5 mL, 0.429 mmol) was added DMF (3.32 μL, 0.043 mmol). The resulting mixture was stirred at 60° C. After 2 h, TLC analysis (PE/EA=1/1) showed the starting material had disappeared. The solvent was removed in vacuo to give 2-(4-bromo-2-fluorophenyl)acetyl chloride (110 mg, 0.416 mmol, 97% yield). A solution of 2-(4-bromo-2-fluorophenyl)acetyl chloride (110 mg, 0.437 mmol) in THF (5 mL) was added to ammonium hydroxide (10 mL, 257 mmol). The resulting mixture was stirred at 0° C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (50 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried and concentrated to give a white solid of 2-(4-bromo-2-fluorophenyl)acetamide (100 mg, 0.280 mmol, 63.9% yield), which was used into the next step without further purification: 1H NMR (400 MHz, CD3OD) δ 7.32-7.30 (m, 2H), 7.24 (t, J=8.2 Hz, 1H), 3.54 (s, 2H); ES-LCMS m/z 232.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([O-:3])=[O:2]
Reactant: Clc1ncccn1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(Oc2ncccn2)c1
Temperature: 150 °C
Yield: 76.2 %

Procedure:
A mixture of 3-nitrophenol (6.85 g), 2-chloropyrimidine (5.13 g) and potassium carbonate (6.81 g) in dimethylsulfoxide (50 ml) was heated at 150° C. for 30 minutes. The mixture was cooled and poured into a mixture of ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resulting solid was collected and washed with isopropyl ether to give 2-(3-nitrophenoxy)pyrimidine (7.41 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[CH3:23][C:24]([CH3:30])([CH:28]=[CH2:29])[CH2:25][CH:26]=O.C1CCN2C(=NCCC2)CC1>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[CH:29][CH2:28][C:24]([CH3:30])([CH3:23])[CH:25]=[CH2:26]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: C=CC(C)(C)CC=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=CC(C)(C)CC=C(NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (34.3 g, 103 mmol, 1.0 equiv) was dissolved in dry THF (250 mL) and the solution was cooled to 0° C. 3,3-Dimethyl-pent-4-en-al (11.6 g, 103 mmol, 1.0 equiv) and DBU (15.5 mL, 103 mmol, 1.0 equiv) were added and the reaction mixture was stirred for 16 h. The solution was diluted with 500 mL of CH2Cl2 and washed with 1×150 mL water, and 1×150 mL brine. The organic layer was dried over Na2SO4, decanted and concentrated in vacuo to provide 2-benzyloxycarbonylamino-5,5-dimethyl-hept-2,6-dienoic acid methyl ester as a thick oil (31 g, 95% crude). The enamide is purified by flash chromatography on silica using hexanes/EtOAc as mobile phase to yield 2-benzyloxyearbonylamino-5,5-dimethyl-hept-2,6-dienoic acid methyl ester as a thick oil that solidifies on standing.