Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][C:8]([F:14])=[CH:7][CH:6]=2)[CH3:2].[I:15]I.C([O-])([O-])=O.[Na+].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11](=[O:13])[C:12]=1[I:15])=[CH:9][C:8]([F:14])=[CH:7][CH:6]=2)[CH3:2]
Reactant: II
Reactant: CCc1cc(=O)c2cc(F)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1[nH]c2ccc(F)cc2c(=O)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 2-ethyl-6-fluoroquinolin-4(1H)-one (4.00 g, 21 mmol), I2 (10.62 g, 2.0 eq) and Na2CO3 (3.33 g, 1.5 eq) in THF (100 mL) was stirred at rt overnight. To the reaction mixture was added Na2S2O3 solution, after 2 min the resulted mixture was filtered, washed with water and dried in the air to give a white solid as 2-ethyl-6-fluoro-3-iodoquinolin-4(1H)-one. Mass Spectrum (ESI) m/e=318 (M+1). A mixture of 2-ethyl-6-fluoro-3-iodoquinolin-4(1H)-one (400 mg, 1.3 mmol), 3,5-difluorophenylboronic acid (398 mg, 2.0 eq), Na2CO3 (401 mg, 3.0 eq) and tetrakis(triphenylphosphine)palladium(0) (73 mg, 0.05 eq) in acetonitrile/water (15 mL/5 mL) was purged with N2 and heated to reflux. After overnight, the reaction mixture was cooled at rt, partitioned between water and EtOAc. The layers were separated and the aq layer was extracted with EtOAc (10 mL×2). The combined organic layers were washed with water (10 mL×2), brine (10 mL), dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by combiflash on silica gel (EtOAc/DCM, 1:2) to give 3-(3,5-difluorophenyl)-2-ethyl-6-fluoroquinolin-4(1H)-one as a white solid. Mass Spectrum (ESI) m/e=304 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6][CH2:5]1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][CH2:3][C:4]1([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: COCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: COCC1(Nc2ccccc2)CCNCC1

Procedure:
A mixture of 10 parts of 4-(methoxymethyl)-N-phenyl-1-(phenylmethyl)-4-piperidinamine and 200 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in water, cooled and alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) saturated with gaseous ammonia, as eluent. The pure fractions are collected and the eluent is evaporated, yielding 4.5 parts of 4-(methoxymethyl)-N-phenyl-4-piperidinamine as an oily residue.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:17]3[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.C([O-])(=O)C.[K+].Br[C:29]1[CH:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>CC(N(C)C)=O.C(#N)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH2:12][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[CH:3][C:2]([C:29]3[CH:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=3)=[CH:11]4)=[N:14][N:15]=2)[N:18]=1
Reactant: OCCn1cc(Br)cn1
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(Br)cc4c3)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(CCO)c5)cc4c3)n2n1

Procedure:
To a microwave vessel was added 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (80 mg, 0.23 mmol, 1 equiv), bis(pinacol)borane (69 mg, 0.27 mmol, 1.2 equiv), potassium acetate (66 mg, 0.67 mmol, 3.0 equiv) followed by dimethylacetamide (0.8 mL). The solution was degassed for 10 min and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (7 mg, 0.01 mmol, 0.048 equiv added. The microwave vessel was capped and reacted in a microwave reactor at 120° C. for 1 hour. The microwave vessel was cooled and then 2-(4-bromo-pyrazol-1-yl)-ethanol (0.18 mmol, 0.8 equiv) dissolved in dimethylacetamide (0.6 mL) was added, followed by 2 M aqueous sodium carbonate (0.6 mL). The solution was degassed for 10 min and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (7 mg, 0.01 mmol, 0.048 equiv) added. The microwave vessel was capped and reacted in a microwave reactor at 120° C. for 2 hours. After cooling, Na2SO4 (3 g) was added and the mixture diluted with acetonitrile and filtered through a pad of celite. The filtrate was concentrated onto silica gel and purified by either flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-80:20) or preparative HPLC to return the title compound. Analytical data presented in Table 2.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([O:28][C:29](=[O:47])[C:30]([CH3:46])([N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)[CH3:31])C>>[CH3:46][C:30]([N:32]1[CH:36]=[C:35]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:34]=[N:33]1)([CH3:31])[C:29]([OH:47])=[O:28]
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(C(=O)O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionic acid ethyl ester to give 211. MS(ESI+) 505.1
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][C@H:18]2[CH2:24][OH:25])[N:3]=1.Cl.[CH:27]12[NH:34][CH:31]([CH2:32][CH2:33]1)[CH2:30][O:29][CH2:28]2.C(N(CC)CC)C>C(O)C>[CH:31]12[N:34]([C:2]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=4)[N:5]=[C:4]([N:17]4[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][C@H:18]4[CH2:24][OH:25])[N:3]=3)[CH:27]([CH2:33][CH2:32]1)[CH2:28][O:29][CH2:30]2
Reactant: C1CC2COCC1N2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-c2nc(N3C4CCC3COC4)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1
Temperature: 130 °C

Procedure:
A suspension of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (0.91 g, 2.5 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.37 g, 2.5 mmol) in ethanol (13 mL) was treated with triethylamine (1 mL) and heated in a microwave reactor for 20 minutes at 130° C. The reaction mixture was purified by automated flash chromatography (methanol/chloroform) to provide the title compound as a hard peach colored foam. MS (ES+)=443.2 (M+H)+
Reaction SMILES: Br[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]2[CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[S:16][C:4]=2[C:3]=1[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([O:9][C:7]([N:6]1[C:2]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[C:3]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:4]2[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][C:5]1=2)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(Br)n2C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 69 %

Procedure:
A solution (0.1 M) of methyl 5-bromo-4-(tert-butoxycarbonyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in EtOH/toluene (1:1) was treated with 4-chlorophenylboronic acid (1.3 eq.) and LiCl (2 eq.). Aqueous Na2CO3 (2 N, 2.5 eq.) was added and the solution was degassed, then Pd(PPh3)4 (0.1 eq.) was added. The mixture was heated to 80° C. for 18 h, then cooled and diluted with AcOEt. The organic phase was washed sequentially with water, aqueous HCl (1 N) and brine, then dried and concentrated giving a residue that was purified by flash chromatography on silica gel (1:9 AcOEt/petroleum ether) to afford the title compound (69%) as a solid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([CH2:35][OH:36])[N:34]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(Cl)Cl.CCOC(C)=O>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([CH:35]=[O:36])[N:34]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(CO)cs1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(C=O)cs1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 132) (40.9 mg, 0.070 mmol) in CH2Cl2 (5 mL) was added DMP (59.4 mg, 0.140 mmol). The reaction was warmed to room temperature and stirred for 45 minutes. Next the reaction was diluted with EtOAc (40 mL) and washed with 1N NaOH (2×15 mL) and brine (2×15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (50% EtOAc/hexanes) afforded 2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbaldehyde. Rf=0.24 (40% EtOAc/hexanes). LCMS=583.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 10.09 (s, 1H), 8.33 (s, 1H), 7.87 (s, 2H), 7.82 (d, J=8.2 Hz, 1H), 7.79 (s, 2H), 7.72, (d, J=8.1 Hz, 1H), 5.70 (d, J=8.0 Hz, 1H), 5.13 (d, J=16.0 Hz, 1H), 4.83 (d, J=16.0 Hz, 1H), 4.23 (m, 1H), 0.75 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:5][CH:4]=1)[CH3:2].[Br:19]Br.S(OS(O)=O)(O)=O.[Na]>CN(C=O)C>[Br:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][C:6]2[CH:17]=[CH:18][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:9]=1
Reactant: CCc1ccc(Cn2ccc3ccccc32)cc1
Reactant: BrBr
Agent: O=S(O)OS(=O)O
Agent: [Na]
Solvent: CN(C)C=O
Product: CCc1ccc(Cn2cc(Br)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
A solution of 1-(4-ethylbenzyl)-1H-indole (2.0 g, 8.50 mmol) in DMF (20 mL) was added dropwise to a solution of bromine (0.46 mL, 8.93 mmol) in DMF (20 mL) at room temperature. The reaction mixture was stirred for two hours, and then poured into an ice-cooled sodium pyrosulfurous acid aqueous solution. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The residue was recrystallized from ethyl acetate and n-hexane to obtain the title compound (1.68 g, 63%).
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[C:14]=2[F:21])[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[C:23](=[CH2:25])[CH3:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)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]>[F:21][C:14]1[C:15]([F:20])=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=1[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]#[N:12])=[C:2]1[CH2:24][C:23]([CH3:25])=[CH2:22]
Reactant: N#Cc1c(Br)n(-c2ccc(O)c(F)c2F)c2ccccc12
Reactant: C=C(C)C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: C=C(C)Cc1c(C#N)c2ccccc2n1-c1ccc(O)c(F)c1F
Temperature: 80 °C

Procedure:
A mixture of 2-bromo-1-(2,3-difluoro-4-hydroxyphenyl)-1H-indole-3-carbonitrile (Example 103), methallyltri-n-butyltin (2 eq), Pd2(dba)3 (0.05%) and tri(o-tolyl)phosphine (20%) was dissolved in DMF, degassed with N2 and heated at 80° C. over night. The reaction mixture was quenched by addition of sat. NH4Cl, diluted with EtOAc, and washed with brine and then dried over Na2SO4. The residue was subjected to reversed phase preparative HPLC. Appropriate fractions were combined and evaporated, and identified by 1H NMR. ES/MS m/z: 289.11 (M+H), 287.15 (M−H); 1H NMR (chloroform-d, 500 MHz): 7.76 (m, 1H), 7.28 (m, 1H), 7.23 (m, 1H), 7.17 (m, 2H), 7.13 (m, 1H), 6.98 (m, 2H), 5.86 (m, 1H), 1.98 (d, 3H, J=1.3 Hz) and 1.89 (d, 3H, J=1.2 Hz).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[C:6]([C:19]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=2[I:33])[C:26]([O:28][CH3:29])=[O:27])=O)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[Br-].[CH3:35]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[I:33][C:32]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:22][CH:21]=[C:19]([C:6]1[C:5]([CH3:4])=[CH:14][C:13]2[C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:17])([CH3:18])[C:8]=2[CH:7]=1)[CH3:35]
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(I)c(OCC(=O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(I)c(OC=C(C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1

Procedure:
Sodium methoxide (0.62 ml, 3.17 mmol) is added over 8 hours to a mixture of methyl 3-(3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl-methyloxy)-4-iodobenzoate (1.6 g, 3.1 mmol) and methyltriphenylphosphine bromide (1.51 g, 4.2 mmol) in THF (15 ml).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:9]=2[N:10]=1.[CH:32]1[CH:37]=[CH:36][C:35]([O:38][C:39](OC2C=CC=CC=2)=[N:40][C:41]#[N:42])=[CH:34][CH:33]=1>C(O)(C)C>[C:41]([NH:40][C:39](=[N:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=3[F:22])[C:9]=2[N:10]=1)[O:38][C:35]1[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=1)#[N:42]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: CC(C)O
Product: Cc1cc(F)ccc1-c1nc(NCCN=C(NC#N)Oc2ccccc2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.5 h

Procedure:
The title compound from Example 8 [8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[(2-aminoethyl)amino]-8H-pyrido[2,3-d]pyrimidin-7-one](0.382 g, 0.0009 mol) was treated with stirring with diphenylcyanocarbonimidate (0.214 g, 0.0009 mol) in isopropanol (5 mL). Stirred at 23° for 0.5 hours. LC/MS showed a new major peak corresponding to the desired product and no starting material in the solution. LC MS (m/e)=570(MH+). Rt=2.24 min.
Reaction SMILES: O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:11].[Mg+2].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>O>[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N+:23]=1[O-:11]
Reactant: Cc1cccnc1C
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: Cc1ccc[n+]([O-])c1C
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
46.2 g of magnesium monoperoxyphthalate hexahydrate in 150 ml of water were slowly added at room temperature to a solution of 11.32 ml (0.100 mole) of 2,3-dimethylpyridine and 11.2 g of potassium carbonate in 50 ml of water. The reaction was carried out at a pH of 6.5-7.0, adjusted by a solution of potassium carbonate, and the reaction mixture was stirred for three hours at a temperature of from 25 to 30° C. At the end of the reaction, the pH was adjusted to 7.5-8.0, 40 g of sodium chloride were added and the 2,3-dimethylpyridine N-oxide was extracted with methylene chloride. The extraction was repeated from saturated reaction solution. The combined organic phases were dried with sodium sulphate and concentrated to a volume of 60 ml. The yield was 97-98%, determined by HPLC.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]#[N:13])[C:9]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:16][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>C[O-].[Na+].CO>[C:12]([C:10]1[C:9]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:16][C:8]=2[C:7]([OH:23])=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[N:11]=1)#[N:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2nc(-c3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 4-cyano-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (39 mg, 0.12 mmole) and glycine (182 mg, 2.41 mmole) in 0.5 M sodium methoxide/methanol (4.6 ml) was refluxed for 28 hours before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (15 ml) and extracted twice with methyl tert-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3.5 ml). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (34 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.73 (br s, 1H), 8.20 (m, 2H), 7.66 (m, 3H), 4.02 (d, J=6.2 Hz, 2H); MS: (−) m/z 352.82 (M−1).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH2:22][C:23]4([O:37][CH3:38])[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH2:22][C:23]4([O:37][CH3:38])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC1(COc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CCCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(COc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CCCNCC1
Yield: 124.5 %

Procedure:
tert-butyl 4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)methyl)-4-methoxyazepane-1-carboxylate (0.032 g, 0.061 mmol) was added to a mixture of trifluoroacetic acid and DCM (1:1) for 1 hour. The reaction was concentrated and co-evaporated several times with diethyl ether to yield 32 mgs of the desired product as a white solid. MS ESI (+) m/z 422 (M+1) detected.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:14])/[CH:15]=[CH:4]/[C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Br:1]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1Br
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(Cl)cc1Br
Yield: 60.7 %

Procedure:
2-Bromo-4-chlorobenzaldehyde (Boegesoe, Klaus P. et al., J. Med. Chem. (1983), 26(7), 93547) (6.3g, 28.7 mmol) and methoxycarbonylmethylenetriphenylphosphor-ane (10.5 g, 31.6 mmol) were refluxed in toluene (143 ml) for 1 hour. The reaction mixture was cooled and purified via chromatography (SiO2, acetone/hexanes 5/95) to yield the title compound as colorless crystals (4.8 g, 61%).
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C-]#N.[Na+].[N:26]12CCN(CC1)C[CH2:27]2>CS(C)=O.CC(O)C.O.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([C:27]#[N:26])[N:12]=2)=[CH:16][CH:17]=1
Reactant: C1CN2CCN1CC2
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CS(C)=O
Product: COc1ccc(N(C)c2nc(C#N)nc3ccccc23)cc1
Temperature: 35 °C
Yield: 139.4 %

Procedure:
To a solution of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine hydrochloride (56 mg, 0.17 mmol) in 1 mL of DMSO and 0.5 mL of 2-propanol were added sodium cyanide (16 mg, 0.34 mmol) and 1,4-diazabicyclo[2.2.2]octane (9 mg, 0.084 mmol). The mixture was heated at 35° C. for 1 d with stirring. The solution was diluted with 5 mL of water and 10 mL of ethyl acetate. The organic layer was washed with water, then dried and concentrated. The resulting crude material was purified by silica gel column chromatography to give the title compound (34 mg, 70%). 1H NMR (CDCl3, 400 MHz) δ 7.85 (d, 1H, J=8.4 Hz), 7.64 (t, 1H, J=6.8 Hz), 7.14 (m, 3H), 6.96 (m, 3H), 3.86 (s, 3H), 3.61 (s, 3H); ESI-MS m/z 291 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([OH:25])=O)[CH2:12]1.[ClH:26].[C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)#[N:28]>CN(C=O)C>[ClH:26].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:15][NH:14][C@H:13]([C:23]([N:30]2[CH2:31][CH2:32][CH2:33][C@H:29]2[C:27]#[N:28])=[O:25])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Nc2nc3ccccc3o2)C[C@H]1C(=O)O
Reactant: N#C[C@@H]1CCCN1
Agent: Cl
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@H](Nc2nc3ccccc3o2)CN1

Procedure:
(2S,4S)-4-(2-Benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (title compound of Reference Example 5, 1.04 g) and (S)-2-cyanopyrrolidine hydrochloride (0.40 g) were dissolved in DMF (5 mL), and triethylamine (0.84 mL), HOBT (0.51 g) and EDC hydrochloride (0.63 g) were successively added thereto. The mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (S)-1-[(2S,4S)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine (0.86 g) as amorphous.