Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][C:70]([O:73][CH2:74][CH3:75])=[CH:71][CH:72]=2)[C:56]=1[CH3:76].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][C:70]([O:73][CH2:74][CH3:75])=[CH:71][CH:72]=4)[C:56]=3[CH3:76])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: CCOc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)cn1
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: CCOc1ccc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)cn1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.048 mmol), 2,5-dimorpholinopyridin-3-amine (0.095 g, 0.36 mmol), 4-chloro-2-(6-ethoxypyridin-3-yl)-5,7-difluoro-3-methylquinoline (0.1 g, 0.30 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.045 g, 0.47 mmol) in toluene (3.0 mL) at 100° C. for 2 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-2-(6-ethoxypyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.46 (1H, d, J=2.0 Hz), 8.01 (1H, dd, J=8.6, 2.4 Hz), 7.79 (1H, d, J=5.6 Hz), 7.65 (1H, dd, J=9.8, 1.7 Hz), 7.56 (1H, d, J=2.4 Hz), 7.47 (1H, ddd, J=13.1, 9.4, 2.4 Hz), 6.96 (1H, d, J=8.6 Hz), 6.44 (1H, d, J=2.7 Hz), 4.40 (2H, q, J=6.9 Hz), 3.58-3.83 (9H, m), 3.16 (2H, br. s.), 2.94-3.06 (5H, m), 2.84 (2H, br. s.), 2.11 (3H, s), 1.37 (3H, t, J=7.1 Hz). Mass Spectrum (ESI) m/e=563.3 (M+1).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:16]#[N:17])[CH2:15][CH2:14]1.[CH:18]1([CH2:23]Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>CCCCCC.O1CCCC1.O.CN1CCCN(C)C1=O>[CH:18]1([CH2:23][C:13]2([C:16]#[N:17])[CH2:15][CH2:14]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrCC1CCCC1
Reactant: N#CC1CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: N#CC1(CC2CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
A solution of butyllithium in hexane (2.5M; 80 ml) was added to a solution of diisopropylamine (27.8 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (28.6 ml) in tetrahydrofuran (188 ml) stirring at 0° C. Stirring was continued for 0.5 hours then the mixture was cooled to -78° C. and cyclopropanecarbonitrile (13.4 g) was added. After stirring at -78° C. for a further 1 hour cyclopentylmethylbromide (37.6 g) was added slowly, then the mixture allowed to warm to ambient temperature and stirred for a further 18 hours. The mixture was poured onto water (11) then extracted with ethyl acetate (4×150 ml). The combined extracts were washed with brine then dried over magnesium sulphate and then the solvent was removed in vacuo. Solid material was removed by filtration and the residual oil triturated with ether, solid material again being removed by filtration. The residual oil was then purified by distillation under reduced pressure giving 1-(cyclopentylmethyl)cyclopropanecarbonitrile (8.9 g) as an oil, bp 50° C./1 mbar.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:13][CH3:14])[C:7]=2[CH:15]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:13][CH3:14])[C:7]=2[CH:15]=1
Reactant: CCN1CCCCc2ccc(OC)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCN1CCCCc2ccc(O)cc21
Temperature: -20 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
To a solution of 8-methoxy-2,3,4,5-tetrahydro-1-ethylbenzo[b]azepine (0.54 g) in CH2Cl2 (25 mL) cooled to −78° C., BBr3 (1.24 mL) was added, and the reaction allowed to gradually warm to −20° C. After stirring for 3 hours, the reaction was quenched with MeOH, allowed to warm to room temperature, and then concentrated. The residue was dissolved in HCl (1M, 40 mL) and stirred for 1 hour. This solution was brought to pH 12 with K2CO3 (sat. aq.) and extracted with EtOAc (40 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (gradient of EtOAc in heptane) to provide the title compound (0.37 g) as a clear oil: 1H NMR (DMSO-d6) δ 8.88 (s, 1H), 6.79 (d, 1H); 6.29 (d, 1H), 6.16 (dd, 1H), 3.02 (q, 2H), 2.82-2.79 (m, 2H), 2.57-2.53 (m, 2H), 1.65-1.57 (m, 2H), 1.48-1.42 (m, 2H), 1.09 (t, 3H); MS expected 192 (C12H18NO, M+1), found 192.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:21])=[C:7]([C:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29]>>[C:1]([C:5]1[C:6]([OH:21])=[C:7]([C:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][CH2:15][C:16]([NH2:22])=[O:17])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)CCCC(=O)O)c1
Agent: NCCCCCCN
Product: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)CCCC(N)=O)c1

Procedure:
14.6 Parts of 5-(3-t-butyl-2-hydroxy-5-methyl-phenyl)-5-methyl-hexanoic acid from Example 46 and 2.9 parts of hexamethylene diamine were heated at 150° C. for 24 hours. The solid obtained on cooling was crystallised from toluene and gave bis-5-(3-t-butyl-2-hydroxy-5-methyl-phenyl)-5-methyl-hexanoic acid amide of 1,6-diaminohexane m.p. 139°-42° C. with the following percentage composition by weight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:20]=[C:21]([C:24](O)=[O:25])[S:22][CH:23]=2)=[N:10]1.CC[N:29]=C=NCCCN(C)C.Cl>CC(N(C)C)=O.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:20]=[C:21]([C:24]([NH2:29])=[O:25])[S:22][CH:23]=2)=[N:10]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cs1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: NC(=O)c1cc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 4-(1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (30.0 mg) obtained in Example 37 in DMA (2 mL) were added EDCI hydrochloride (18.5 mg) and HOBt ammonium salt (14.7 mg) at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate to ethyl acetate) to give the title compound (21.2 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(N(CC)CC)C.[CH:16]1([C:22]#[CH:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CCCCCC>COCCOC.C(OCC)(=O)C.[Cu]I.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>[CH:16]1([C:22]#[C:23][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C#CC1CCCCC1
Reactant: Cc1cccc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cccc(C#CC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
2-Bromo-6-methyl pyridine (2.0 g, 11.6 mmol) and CuI (440 mg, 2.3 mmol) were combined in DME (30 mL), and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (8.0 mL, 58 mmol) and PdCl2(PPh3)2 (814 mg, 1.16 mmol) were added, followed by the dropwise addition of cyclohexylethyne (1.25 g, 11.6 mmol). The reaction was stirred at ambient temperature overnight. GC/MS showed no starting 2-bromo-6-methylpyridine remaining. The mixture was diluted with ethyl acetate (100 mL), and filtered through Celite™. The pad was then thoroughly washed with ethyl acetate and the combined filtrates were washed with water (200 mL), brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography eluting with hexane then 98:2, 96:4 hexane:ethyl acetate to afford 2-(cyclohexylethynyl)-6-methylpyridine (1.78 g, 77% yield) as a pale brown liquid that partially solidified on standing in the freezer. 1H NMR (CDCl3, 300 MHz) δ 7.52-7.46 (m, 1H), 7.20 (d, J=9 Hz, 1H), 7.03 (d, J=9 Hz, 1H), 2.6 (m, 1H), 2.54 (s, 3H), 2.93-2.89 (m, 2H), 1.78-1.73 (m, 2H), 1.57-1.54 (m, 3H), 1.36-1.32 (m, 3H). MS (ESI) 200.1 (M++H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[H-].[Na+].[O:13]1[CH:20]2[CH:14]1[CH2:15][CH2:16][O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=12>CN1C(=O)N(C)CCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2](=[O:1])[N:3]([C@@H:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[O:17][CH2:16][CH2:15][C@H:14]2[OH:13])[CH:4]=1)([O-:10])=[O:9]
Reactant: c1ccc2c(c1)OCCC1OC21
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: O=c1ccc([N+](=O)[O-])cn1[C@@H]1c2ccccc2OCC[C@H]1O
Temperature: 95 °C
Reaction time: 0.33 h

Procedure:
7.85 g (56 mmol) of 2-hydroxy-5-nitro-pyridine are added in portions to 1.61 g (56 mmol) of sodium hydride (80% dispersion in mineral oil) in 30 ml of DMPU (1,3-dimethyl-tetrahydro-2(1H)-pyrimidinone) under argon. After evolution of gas has ceased the mixture is stirred for 20 minutes. Then, at room temperature, a solution of 4,5-epoxy-2,3,4,5-tetrahydro-1-benzoxepin in 10 ml of DMPU is added dropwise. The mixture is subsequently heated at 95° C. for 6 hours. The mixture is poured into ice/water, stirring vigorously, and precipitated solid is filtered off with suction. The solid is chromatographed on silica gel (ethyl acetate/cyclohexane 2:1), and the pale yellow oil obtained in this way is crystallized in methyl tert.-butyl ether. Melting point 152°-155° C.
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C:3]([OH:5])=[O:4].[H][H]>[Pt]=O.CO>[CH3:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(=Cc1cccc(F)c1)C(=O)O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CC(Cc1cccc(F)c1)C(=O)O

Procedure:
15.6 G. of the above product from Example 4 was hydrogenated at 40 pounds per square inch in 800 ml. of methanol with 3 g. of platinum oxide catalyst. After the theoretical uptake of hydrogen, the hydrogenation was stopped. The catalyst was removed by filtration and the solvent removed in vacuo giving a theoretical yield of the desired product, α-methyl-3-fluorohydrocinnamic acid.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)N)[CH3:7].N([O-])=O.[Na+].[BrH:19]>[Cu]Br>[Br:19][C:10]1[CH:12]=[CH:13][CH:14]=[C:8]([CH2:6][CH3:7])[CH:9]=1
Reactant: CCc1cccc(N)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Product: CCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
To an aqueous 50% sulfuric acid solution (43.6 g) containing 3-ethylaniline (10.0 g, 82.5 mmol) was added dropwise an aqueous solution (16.5 mL) of sodium nitrite (6.83 g, 99.0 mmol) at 0° C. over 30 min. The obtained reaction mixture was stirred at 0° C. for 45 min. A solution of this diazonium salt was added by small portions to a 48% hydrobromic acid solution (82.5 mL) containing copper(I) bromide (12.4 g, 86.6 mmol) with heating under gentle reflux. After the addition, the reaction mixture was heated under reflux for 30 min. The reaction mixture was cooled to room temperature and extracted with ethyl ether. The extract was washed successively with 1N aqueous sodium hydroxide solution and saturated brine, filtered, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=20:1) to give the title compound (6.13 g, yield 40%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=C1)[CH2:7]3.[C:11]([O-:14])([O-])=O.C([O-])([O-])=[O:16].OO.OO.OO.[Na+].[Na+].[Na+].[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH2:7]1[CH:6]2[CH:10]3[O:16][CH:9]3[CH:8]1[CH:4]1[CH:5]2[CH:1]2[O:14][CH:11]2[CH2:3]1
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C1C2OC2C2C1C1CC2C2OC12
Temperature: 60 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
Dicyclopentadiene (1.32 g, 10 mmol) was dissolved in toluene (25 ml), and a composition containing sodium percarbonate (10.5 g, 66.7 mmol) and acetic anhydride (10.2 g, 100 mmol) was added thereto. The mixture was stirred at 60° C. After 12 hours, the reaction solution was washed with water to thereby completely remove acetic acid and sodium acetate, which were generated as by-products, and the remaining H2O2. Toluene was distilled off from the organic phase by distillation, and as a result, 1.62 g (99% yields) of dicyclopentadiene diepoxide with a GC purity of 100% was obtained.
Reaction SMILES: [N:1]([C:4]1[CH:22]=[CH:21][CH:20]=[C:6]2[C:7]([N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[C:10](=[O:11])[C:5]=12)=[O:8])=[N+:2]=[N-:3].S(Cl)([Cl:25])=O>CN(C)C=O>[N:1]([C:4]1[CH:22]=[CH:21][CH:20]=[C:6]2[C:7]([N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([Cl:25])=[O:18])[C:10](=[O:11])[C:5]=12)=[O:8])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=Nc1cccc2c1C(=O)N(CCCCCC(=O)O)C2=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(CCCCCC(=O)Cl)C2=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
15.0 g (0.05 mol) of the 6-(3-azidophthalimidyl)-caproic acid obtained according to Example 8 are dissolved in 327 g (2.75 mols) of thionyl chloride, and the solution is warmed to 80° C., the operations being carried out under yellow light. At 80° C., 0.5 ml of N,N-dimethylformamide is added to the clear solution obtained. The reaction mixture is stirred for 15 minutes at 80° C. and is then cooled to room temperature. This produces a beige-coloured suspension, which is filtered with suction, under N2. The crude product is recrystallised from 250 ml of dry ligroin. 12.5 g (75.4% of theory) of 6-(3-azidophthalimidyl)-caproyl chloride are obtained; melting point 68°-69° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:32])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([O:22][CH3:23])[C@H:18]([NH:24]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=1B(O)O>>[NH2:24][C@H:18]1[C@@H:19]([O:22][CH3:23])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:32])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[C:34]([F:33])=[CH:39][CH:38]=[CH:37][C:36]=3[F:40])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: OB(O)c1c(F)cccc1F
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3csc(Br)n3)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-methoxyoxepan-4-yl)carbamate (Intermediate 101), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,6-difluorophenyl)boronic acid gave 221. 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.65 (s, 1H), 7.92 (s, 1H), 7.74-7.62 (m, 1H), 7.38 (t, J=8.8 Hz, 2H), 5.08 (t, J=5.7 Hz, 1H), 3.93-3.75 (m, 2H), 3.72 (s, 3H), 3.52-3.44 (m, 1H), 3.03 (s, 3H), 2.44-2.32 (m, 1H), 1.81-1.53 (m, 3H). LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:5]([CH3:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[N:25][N:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[CH3:20][O:19][C:17](=[O:18])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]#[C:8][C:6]1[C:5]([CH3:21])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)[CH:27]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C
Temperature: 120 °C

Procedure:
A suspension of methyl 2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)acetate (K7) (0.100 g, 0.333 mmol), tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (A124) (0.089 g, 0.333 mmol), Cs2CO3 (0.433 g, 1.33 mmol), Pd2(dba)3 (0.030 g, 0.033 mmol) and Xantphos (0.058 g, 0.100 mmol) in 1,4-dioxane (6 mL) was degassed with nitrogen for 5 minutes before heating under microwave irradiation for 30 minutes at 120° C. The resulting mixture was diluted with EtOAc (100 mL) and washed with water (2×25 mL), brine (25 mL), dried (Na2SO4) then concentrated under reduced pressure. The resulting brown oil was purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in hexanes) to give the title compound A125 as a yellow foam (0.096 g, 54%); 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.89 (s, 1H), 7.57 (dd, J=7.6, 1.3 Hz, 1H), 7.44 (s, 1H), 7.36-7.22 (m, 2H), 7.19 (s, 1H), 6.87 (s, 1H), 4.22-4.12 (m, 3H), 3.88 (s, 2H), 3.62 (s, 3H), 2.82 (t, J=11.9 Hz, 2H), 2.26 (s, 3H), 2.11-2.02 (m, 2H), 1.89 (qd, J=12.4, 4.4 Hz, 2H), 1.40 (s, 9H). LCMS-A: rt 6.358 min; m/z 531 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:16].[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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]>[C:17]([C:19]1[N:23]([CH3:24])[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)(=[O:10])=[O:9])=[CH:4][C:3]=2[F:16])=[CH:21][CH:20]=1)#[N:18]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(NCC1CC1)c1ccc(Br)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NCC2CC2)cc1F
Reaction time: 16 h
Yield: 13.2 %

Procedure:
According to general procedure B, 4-bromo-N-(cyclopropylmethyl)-3-fluorobenzenesulfonamide (182 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-3-fluorobenzenesulfonamide (26 mg, 13%) was provided after purification. HRMS: calcd for C16H16FN3O2S+H+, 334.10200; found (ESI, [M+H]+), 334.1024. HPLC purity 100.0% at 210-370 nm, 9.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][CH2:27][C@@H:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH2:29])([CH3:25])([CH3:24])[CH3:23].N1C(C)=CC=CC=1C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([NH:29][C@H:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)OC[C@H](NC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
(2R)-{[(Benzyloxy)carbonyl]amino}(phenyl)acetic acid (Z-(R)-Phg-OH) (2.0 g, 7.0 mmol) and tert-butyl O-(tert-butyl)-L-serinate (2.0 g, 7.9 mmol) and 2.6-lutidine were dissolved in DCM (30 ml). After stirring 5 minutes at 0° C. TBTU (2.5 g, 7.8 mmol) was added and stirring was continued 30 minutes at 0° C. and 4 hours at room temperature. The reaction mixture was washed with water (2×100 ml), dried and purified with flash chromatography (DCM) to give the title compound (3.3 g, 97%). NMR (300 MHz, CD3OD): 1.05 (s, 9H), 1.45 (s, 9H), 3.4-3.8 (m, 2H), 4.5 (bs, 1H), 4.85 (s, 2H), 5.1 (s, 2H), 5.4 (s, 1H), 7.25-7.5 (m, 10 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([NH:16][C@H:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:18]3[CH:23]=[CH:22][C:21]([P:24]([CH3:29])(=[O:28])[O:25]CC)=[CH:20][CH:19]=3)=[O:15])=[CH:9][N:8]=2)[CH:6]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([NH:16][C@H:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:18]3[CH:19]=[CH:20][C:21]([P:24]([CH3:29])(=[O:25])[OH:28])=[CH:22][CH:23]=3)=[O:15])=[CH:9][N:8]=2)[CH:6]=1
Reactant: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cc(F)cn3)nc2O)c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1ccc([C@H](NC(=O)c2cnc(-n3cc(F)cn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of compound 29-a (4 g, 7.8 mmol) in 30 ml of dioxane was treated with 7 ml of 3N NaOH. The mixture was heated at 80° C. for one hour. The mixture was then concentrated under vacuum and the resulting residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with conc. HCl to pH=1 and the expected product, 29-1, crashed out (700 mg of crude). The product can be further purified via prep-HPLC (152 mg, 5%). 1H NMR (300 MHz, CD3OD): δ 8.66 (s, 1H), 8.57 (d, 1H), 7.81 (d, 1H), 7.77 (m, 2H), 7.52 (m, 2H), 7.20 (m, 2H), 7.13 (m, 2H), 6.38 (s, 1H), 1.65 (d, 3H). (M+H)+=486.2.