Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].C(O)(=O)C.C(N(CC)CC)C.[O:15]1[CH:20]2[CH:16]1[C:17](=O)[CH2:18][C:19]2([OH:32])[CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.O>[CH3:1][S:2][C:17]1[C:16](=[O:15])[CH2:20][C:19]([OH:32])([CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:18]=1
Reactant: O=C1CC(O)(CCCCOc2ccccc2)C2OC12
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CSC1=CC(O)(CCCCOc2ccccc2)CC1=O
Yield: 90.4 %

Procedure:
To a solution of 1.5 g of sodium thiomethoxide dissolved in 80 ml of methanol was added 1.8 ml of acetic acid under ice-cooling and stirring. After the mixture was stirred for 5 minutes, 4.8 ml of triethylamine was added, and the solution of 1.38 g of 2,3-epoxy-4-hydroxy-4-(4-phenoxybutyl)cyclopentanone obtained in Example 549 dissolved in 20 ml of methanol was added. After the mixture was stirred for 4 hours, water was added and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtration and concentration, the concentrate was subjected to silica gel column chromatography to give 1.39 g (yield 83%) of 2-methylthio-4-hydroxy-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([O:16][CH3:17])[CH:9]=1>C(#N)C>[CH3:15][O:14][C:12]1[N:11]=[C:10]([O:16][CH3:17])[CH:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:13]=1
Reactant: C1CNCCN1
Reactant: COc1cc(Cl)nc(OC)n1
Solvent: CC#N
Product: COc1cc(N2CCNCC2)nc(OC)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
piperazine (1.23 g, 14.32 mmol) was treated with 6-chloro-2,4-dimethoxy pyrimidine (0.5 g, 2.86 mmol) in acetonitrile (5 mL) and the reaction mixture was stirred at room temperature for 6 hours. Subsequently the reaction mixture was poured onto ice-cold water (25 ml) and extracted with ethyl acetate (25 ml). The organic layer was washed with aqueous sodium bicarbonate solution and evaporated to furnish the required compound.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:49]1(B(O)O)[CH2:51][CH2:50]1.C([O-])([O-])=O.[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C1COCC1>[F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([CH:49]4[CH2:51][CH2:50]4)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(Cl)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C4CC4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
Methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (EXAMPLE 59 100 mg, 0.144 mmol), cyclopropylboronic acid (62.0 mg, 0.721 mmol), 1,1′-bis(di-tert-butylphosphino) ferrocene palladium dichloride (19.62 mg, 0.029 mmol), aqueous K2CO3 (1M, 1.010 mL, 1.010 mmol) and THF (1.002 mL) were stirred at 80° C. for 3.5 h then slowly cooled to ambient overnight. Volatiles were removed under reduced pressure. The resulting pot residue was worked up with brine, extracted with EtOAc, dried (Na2SO4), filtered and evaporated to a dark mixture. The mixture was purified by reverse-phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with MeCN/water+0.1% TFA (10% to 100% organic in 10 min, hold 100% in 2 min). Related fractions were pooled and evaporated in vacuo to afford an aqueous mixture. The aqueous mixture was extracted with EtOAc, washed with aqueous NaHCO3, dried (Na2SO4), filtered and concentrated to afford the titled compound. LCMS calc.=698.22; found=699.30 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C=CC(=O)O)cc1
Solvent: ClCCl
Product: Cc1ccc(C=CC(=O)Cl)cc1

Procedure:
To a stirred mixture of 100 g (0.62 moles) p-methylcinnamic acid in methylene chloride (about 30 ml), 88 g (0.74 moles) thionyl chloride was added dropwise. The reaction mixture was then refluxed for 24 hours. The methylene chloride was removed under reduced pressure and heat to give the corresponding p-methylcinnamic acid chloride. Fresh methylene chloride was added to the acid chloride; half of which was used in Step (b).
Reaction SMILES: [OH-].[Na+:2].[C:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]3[C:48](=[CH:49][CH:50]=2)[O:47][C:17]2([CH2:22][CH2:21][N:20]([C:23]([C:25]4[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42]C)=[O:41])=[CH:36][CH:35]=5)=[C:27]([O:44][CH2:45][CH3:46])[CH:26]=4)=[O:24])[CH2:19][CH2:18]2)[CH2:16][C:15]3=[O:51])=[N:10][CH:11]=1)(=[O:5])[NH2:4].CO>C1COCC1.O>[C:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]3[C:48](=[CH:49][CH:50]=2)[O:47][C:17]2([CH2:22][CH2:21][N:20]([C:23]([C:25]4[CH:26]=[C:27]([O:44][CH2:45][CH3:46])[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O-:42])=[O:41])=[CH:36][CH:35]=5)=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=4)=[O:24])[CH2:19][CH2:18]2)[CH2:16][C:15]3=[O:51])=[N:10][CH:11]=1)(=[O:5])[NH2:4].[Na+:2]
Reactant: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4ccc(C(N)=O)cn4)ccc2O3)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4ccc(C(N)=O)cn4)ccc2O3)cc(OCC)c1-c1ccc(C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 288 h
Yield: 52.4 %

Procedure:
Aqueous 1N NaOH (11.6 ml, 11.6 mmol) was added to a stirred solution of methyl 4′-({6-(5-carbamoylpyridin-2-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl}carbonyl)-2′,6′-diethoxybiphenyl-4-carboxylate (3.85 g, 5.80 mmol) in THF (40 ml)-MeOH (40 ml) and the mixture was stirred at room temperature for 12 days. After water was added to the mixture, the organic solvents were evaporated under reduced pressure. The aqueous residue was purified by ODS column chromatography eluting with H2O/MeOH and the residue was crystallized from MeOH to give intended compound as a pale red solid. The solid was diluted in H2O and aqueous 1N NaOH, and was purified by ODS column chromatography eluting with H2O/MeOH, and the residue was crystallized from MeOH to give intended compound (2.04 g, 3.04 mmol, 52.4% yield) as a pale red crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([C:65]([F:68])([F:67])[F:66])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([C:65]([F:67])([F:68])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(C(F)(F)F)c2)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.8 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5,6-difluoro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 106 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by two successive column chromatographies (8 g silica gel; EtOAc/heptane 1:4; second column eluted with n-hexane/EtOAc 9:1) to give 62 mg yellow viscous oil (35%). MS (ISP) 533.2 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:26])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][C@@H:32](C)[N:31]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][CH:47]3[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:53][CH:50]2[CH2:51][CH2:52][CH:47]([O:46][C:43]3[CH:44]=[CH:45][C:40]4[N:41]([C:37]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]5[CH3:29])=[N:38][N:39]=4)[CH:42]=3)[CH2:48][CH2:49]2)=[O:26])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(OC3CCC(N)CC3)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(OC3CCC(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)CC3)cn12
Temperature: 60 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A mixture of {5-tert-butyl-2-[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamic acid 2,2,2-trichloro-ethyl ester (WO 2007/063868, which is incorporated herein by reference in its entirety, 287.6 mg, 0.638 mmol), Intermediate 18a (140 mg, 0.425 mmol) and DIPEA (223 μL, 1.28 mmol) in dioxane (10 mL) was stirred at 60° C. for 18 h. The volatiles were concentrated in vacuo and the resultant residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound (222 mg, 82%). LCMS (Method 3): Rt 3.35 min, m/z 631 [MH+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[C:31]#[N:32])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OO.C(OCC)(=[O:40])C>CS(C)=O>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[C:31](=[O:40])[NH2:32])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2C#N)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Temperature: 63 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
In analogy to GP 5, 386 mg of {3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamic acid tert-butyl ester (0.69 mmol, 1 eq) were dissolved in 4.8 ml of DMSO and 0.24 ml of 3 M aq. sodium hydroxide solution (0.72 mmol, 10-80 eq) were added. The mixture was heated to 63° C. and 1.85 ml of hydrogen peroxide solution (aq., 30%) were added over the course of 20 min. The mixture was stirred for another 2 h at 65° C. (bath temp.). The reaction mixture was poured onto 175 ml of ice water. 300 ml of ethyl acetate were added and the phases separated. The aqueous phase was extracted one more time with 150 ml of ethyl acetate. The combined organic layers were washed one time with brine, dried over sodium sulfate, filtered off and concentrated. The concentrate was purified (FlashMaster column chromatography, hexane/ethyl acetate 99/1-60/40) to afford 169 mg (42% yield, 0.29 mmol) of the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]2[C:12]([CH3:41])=[C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([NH:32][C@H:33]([C:37]([O:39]C)=[O:38])[CH:34]([CH3:36])[CH3:35])(=[O:31])=[O:30])=[CH:25][CH:24]=4)=[CH:19][CH:18]=3)[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1.[OH-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.CO.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]2[C:12]([CH3:41])=[C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([NH:32][C@H:33]([C:37]([OH:39])=[O:38])[CH:34]([CH3:36])[CH3:35])(=[O:31])=[O:30])=[CH:25][CH:24]=4)=[CH:19][CH:18]=3)[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COCCCc1cccc2oc(COc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCCCc1cccc2oc(COc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c12
Yield: 91.3 %

Procedure:
To a solution of methyl N-[(4′-{[4-(3-methoxypropyl)-3-methyl-1-benzofuran-2-yl]methoxy}-1,1′-biphenyl-4-yl)sulfonyl]-L-valinate (192 mg, 0.331 mmol) in tetrahydrofuran (12 mL), methanol (8 mL), water (4 mL) was added lithium hydroxide (317 mg, 13.25 mmol). After stirring for 2.5 days at room temperature hydrochloric acid (13.25 mL, 1 N solution) was added followed by ethyl acetate (80 mL). The layers were separated and the organic phase was washed with water, dried over sodium sulfate, filtered and reduced to dryness. The solid material was recrystallized from a minimum amount of boiling isopropanol to furnish which furnished 171 mg (91%) of N-[(4′-{[4-(3-methoxypropyl)-3-methyl-1-benzofuran-2-yl]methoxy}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine as a white solid. MS (ES) m/z: 564.2 (M−H), 1129.4 (2M−H).
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([N:15]3[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]3)[CH:9]=2)[CH2:4][CH2:3]1.[K+].[C:24]([C:26]1[N:27]=[C:28]([C:39]([O-])=[O:40])[N:29](COCC[Si](C)(C)C)[CH:30]=1)#[N:25].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[O:22]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:39]([C:28]3[NH:29][CH:30]=[C:26]([C:24]#[N:25])[N:27]=3)=[O:40])=[C:10]([N:15]3[CH2:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH2:20]3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1CCN(c2cc(C3CCS(=O)(=O)CC3)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2cc(C3CCS(=O)(=O)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68 %

Procedure:
To a mixture of 4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenylamine (as prepared in the previous step, 16 mg, 0.050 mmol), 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium (as prepared in Example 3, step (d), 17 mg, 0.055 mmol) and PyBroP (35 mg, 0.075 mmol) in 1 mL of DCM was added DIEA (17 μL, 0.10 mmol). The resulting mixture was stirred at RT for 20 h under Ar. Treated with 30 mL of EtOAc, the mixture was washed with H2O (3×10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-2% EtOAc/DCM) gave 19 mg (68%) of the title compound as a colorless oil: 1H-NMR (CDCl3; 400 MHz): δ 10.4 (s, 1H), 8.29 (d, 1H, J=8.4 Hz), 7.79 (s, 1H), 7.02 (d, 1H, J=1.9 Hz), 6.99 (dd, 1H, J=8.4, 1.9 Hz), 5.97 (s, 2H), 3.67 (app t, 2H, J=8.3 Hz), 3.14 (m, 4H), 2.99 (d, 2H, J=12.0 Hz), 2.67-2.80 (m, 3H), 2.40 (m, 2H), 2.22 (m, 2H), 1.79 (m, 2H), 1.52-1.67 (m, 3H), 1.08 (d, 3H, J=5.9 Hz), 0.98 (app t, 2H, J=8.3 Hz), 0.001 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C28H41N5O4SSi, 572.3 (M+H), found 572.0.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]3[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([NH:23][O:24]C4CCCCO4)=[O:22])=[N:17][CH:18]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:31]>CO>[ClH:31].[ClH:31].[CH:1]1([N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]3[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([NH:23][OH:24])=[O:22])=[N:17][CH:18]=3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCN(C3CCCCC3)C2)cn1)NOC1CCCCO1
Agent: Cl
Solvent: CO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(C3CCCCC3)C2)cn1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-(5-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (274 mg) in methanol (6.6 mL) was added hydrogen chloride in methanol (0.659 mL). After stirring at room temperature for 1 hour, the reaction mixture was evaporated in vacuo and triturated with ethyl acetate to give (2E)-3-(5-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide dihydrochloride (252 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:17])[CH2:7][C:8]1[CH:16]=[CH:15][C:13]([OH:14])=[C:10]([O:11][CH3:12])[CH:9]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:17][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:13]([O:14][S:2]([CH3:1])(=[O:4])=[O:3])=[C:10]([O:11][CH3:12])[CH:9]=1)(=[O:4])=[O:3]
Reactant: COc1cc(CCO)ccc1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CCOS(C)(=O)=O)ccc1OS(C)(=O)=O
Temperature: 25 °C
Yield: 86.6 %

Procedure:
44 g (0.39 mole) methanesulfonyl chloride was slowly added to a solution of 30 g (0.178 mole) homovanillyl alcohol and 45.3 g (0.45 mmole) triethylamine in 500 ml dichloromethane at −10° C. After stirring at room temperature over night the salts were filtered off, the organic phase was washed with sodium bicarbonate and brine, dried (magnesium sulfate) and evaporated in vacuo to give 50 g (yield 86%) of 3-methoxy-4-(methylsulfonyloxy)phenethyl methanesulfonate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]Cl)[CH2:32][CH2:31]1>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[C:17]([CH3:29])[CH:16]=3)=[N:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[O:1][CH2:38][CH2:37][CH2:36][N:33]1[CH2:34][CH2:35][O:30][CH2:31][CH2:32]1
Reactant: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1O
Reactant: ClCCCN1CCOCC1
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1OCCCN1CCOCC1
Yield: 53 %

Procedure:
Using an analogous procedure to that described in Example 38, 6-hydroxy-7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline was reacted with 3-morpholinopropyl chloride to give 7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-(3-morpholinopropoxy)quinazoline in 53% yield;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:29][CH:28]=2)[C:12](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:13])=[CH:6][CH:5]=1.[OH:40]O.[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@@H:11]([C:12]([OH:13])=[O:40])[C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:29][CH:28]=2)=[CH:6][CH:5]=1
Reactant: OO
Reactant: COC(=O)c1ccc(CC(C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(C=CC(C)(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C[C@@H](C(=O)O)c2ccc(C=CC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 134.8 %

Procedure:
To a stirred solution of the (R)-diastereomer of 4-{3-(4-(R)-Benzyl-2-oxo-oxazolidin-3-yl)-2-[4-(3,3-dimethyl-but-1-enyl)-phenyl)-3-oxo-propyl}-benzoic acid methyl ester (0.43 g, 0.81 mmol) in THF/H2O (20 mL) (3:1) at room temperature were added H2O2 (2.2 mL, 8.1 mmol 35% in H2O) followed by LiOH (40 mg, 1.63 mmol). The reaction mixture was stirred for 3 h, at room temperature, quenched with (0.1 N HCl). The reaction mixture was extracted with ethyl acetate (100 mL) and dried over MgSO4, filtered and concentrated under reduced pressure to afford corresponding acid. The crude product was purified by column chromatography on silica gel, eluting with CH2Cl2/MeOH 2%-15% to afford the title compound (0.4 g, 100%).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[N:11]=[CH:10][C:9]([I:12])=[CH:8][C:5]=1[C:6]#[N:7]>CC(O)C>[I:12][C:9]1[CH:8]=[C:5]2[C:6]([NH2:7])=[N:2][NH:1][C:4]2=[N:11][CH:10]=1
Reactant: N#Cc1cc(I)cnc1Cl
Reactant: NN
Solvent: CC(C)O
Product: Nc1n[nH]c2ncc(I)cc12
Temperature: 85 °C
Yield: 87 %

Procedure:
Hydrazine (3.86 ml, 79 mmol) is added at room temperature to 7 g (26.5 mmol) of a solution of 2-chloro-5-iodonicotinonitrile in 25 ml of propan-2-ol. The reaction mixture is heated at 85° C. for 7 hours and then at room temperature overnight. The suspended solid is filtered, rinsed with isopropanol and then with ether and dried in an oven at 50° C. to give 6 g (87%) of 5-iodo-1H-pyrazolo[3,4-b]pyridine-3-amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:9]=[C:8]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]2=[O:27].[Cl-].[Cl:30][C:31]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][Zn+].[Cl-].[NH4+]>C1COCC1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[Cl:30][C:31]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[N:10]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:9]=[C:8]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]2=[O:27]
Reactant: Clc1cccc(C[Zn+])c1Cl
Reactant: CCOC(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c2c(F)cc(I)cc2c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c2c(F)cc(Cc3cccc(Cl)c3Cl)cc2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 101.7 %

Procedure:
Under an argon stream, the 1M THF solution (2.9 ml, 2.9 mmol) of 2,3-dichlorobenzylzinc chloride obtained in the same manner as in Reference Example 1 was added to THF (20 ml), then bis(dibenzylidenacetone)palladium(0) (22 mg, 0.039 mmol), tri(2-furyl)phosphine (18 mg, 0.077 mmol) and ethyl 1,4-dihydro-8-fluoro-6-iodo-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-quinolinecarboxylate (1.0 g, 1.9 mmol) obtained in Step 4 were added. The mixture was stirred at room temperature for 17 hr, a solution (1.0 ml, 1.0 mmol) of 2,3-dichlorobenzylzinc chloride in THF was further added, and the mixture was heated under reflux for 1 hr. After allowing to cool, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the insoluble material was filtered through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was crudely purified by silica gel chromatography (ethyl acetate:hexane=1:1) and successively purified by PTLC (ethyl acetate:chloroform=1:2) to give the object product (562 mg, yield 53%) as a pale-yellow oil.