Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][C@@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 7 using 3-bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 7.1) and pyridin-3-ylboronic acid to afford a yellow solid. UPLC-MS (condition 1) tR=1.67 min, m/z=460.0 [M+H]+, m/z=458.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.73 (d, J=10.76 Hz, 2H) 3.24 (dd, J=10.51, 3.67 Hz, 2H) 3.85 (d, J=2.20 Hz, 2H) 5.03 (br. s, 2H) 6.92 (d, J=8.80 Hz, 1H) 7.33 (d, J=8.31 Hz, 2H) 7.48 (dd, J=7.46, 5.26 Hz, 1H) 7.76-7.83 (m, 2H) 7.83-7.89 (m, 2H) 7.91 (dd, J=8.80, 2.20 Hz, 1H) 8.55 (dd, J=4.77, 1.59 Hz, 1H) 8.62 (d, J=1.47 Hz, 1H) 10.10 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[NH2:18]>>[CH3:25][O:24][C:20]1[CH:19]=[C:17]([NH:18][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([OH:1])[CH:3]=2)[CH:16]=[C:15]([O:14][CH3:13])[C:21]=1[O:22][CH3:23]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1ccc(C(=O)O)cc1O
Product: COc1ccc(C(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1O
Yield: 34 %

Procedure:
Using 3-hydroxyl-4-methoxybenzoic acid and 3,4,5-trimethoxyaniline as materials, compound 87 is synthesized following a similar method as in Example 28. Yield: 34%.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]([F:42])([F:41])[C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[O:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[CH2:36][CH2:37][C:38](O)=[O:39])=[CH:23][CH:22]=3)[N:18]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.O>C1COCC1.P(C#N)(OCC)(OCC)=O.CN(C=O)C>[CH3:1][N:2]([CH3:3])[C:38](=[O:39])[CH2:37][CH2:36][C:32]1[N:31]([CH2:30][CH2:29][CH2:28][CH2:27][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:17]3[N:18]=[C:14](/[CH:13]=[CH:12]/[C:9]4[CH:8]=[CH:7][C:6]([C:5]([F:41])([F:4])[F:42])=[CH:11][CH:10]=4)[O:15][CH:16]=3)=[CH:26][CH:25]=2)[CH:35]=[CH:34][N:33]=1
Reactant: CNC
Reactant: O=C(O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reaction time: 0.25 h

Procedure:
A solution (2M; 0.557 ml) of N,N-dimethylamine in THF and diethyl cyanophosphate (67.6 μl) were added to a solution of 3-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]propionic acid (200 mg) in DMF (3 ml) at 0° C., and the mixture was stirred for 15 min. Triethylamine (77.6 μl) was added to the mixture at 0° C., and the mixture was stirred at room temperature for 16 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with water and saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; dichloromethane to dichloromethane:methanol=20:1) and recrystallized from diethyl ether-ethyl acetate-hexane to give the titled compound (146 mg) as a colorless crystal powder.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:3]1.Cl[CH2:32][C:33]1[CH:34]=[CH:35][C:36]2[O:41][CH2:40][C:39](=[O:42])[N:38]([CH2:43][CH2:44][CH2:45][O:46][CH3:47])[C:37]=2[CH:48]=1>>[CH3:47][O:46][CH2:45][CH2:44][CH2:43][N:38]1[C:37]2[CH:48]=[C:33]([CH2:32][O:1][CH:2]3[CH:7]([C:8]4[CH:9]=[CH:10][C:11]([O:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:12][CH:13]=4)[CH2:6][CH2:5][N:4]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:22])[CH2:3]3)[CH:34]=[CH:35][C:36]=2[O:41][CH2:40][C:39]1=[O:42]
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(Oc3ccccc3)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(Oc4ccccc4)cc3)cc21

Procedure:
Analogously to Method D, 0.100 g of benzyl 3-hydroxy-4-(4-phenoxyphenyl)piperidine-1-carboxylate and 0.0753 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a colourless resin. Rf=0.31 (1:1 EtOAc-heptane); Rt=5.74.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:28])[C:24]([NH:26][NH2:27])=[O:25])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:31](C1NC=CN=1)(C1NC=CN=1)=[O:32]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:24]3[O:25][C:31](=[O:32])[NH:27][N:26]=3)=[O:28])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)C(=O)NN
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.1 %

Procedure:
To a solution of (R)-ethyl 4-(5′-fluoro-2′-methoxy-[1,1′-biphenyl]-4-yl)-3-(2-hydrazinyl-2-oxoacetamido)butanoate (4.7 g, 11 mmol) in THF (115 mL) was added carbonyl diimidazole (2.4 g, 14 mmol) and the reaction mixture was stirred at room temperature for 24 hours then concentrated to a yellow oil than was purified by silica gel chromatography (40-45% ethyl acetate/hexane) to afford (R)-ethyl 4-(5′-fluoro-2′-methoxy-[1,1′-biphenyl]-4-yl)-3-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)butanoate 4.25 g (84%). LCMS Method 1 retention time 1.57 min ES+ M+H(+) 443.8; LCUV Method 2 retention time 7.44 min; 1H NMR (400 MHz, MeOH-d) δ ppm 7.44 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.03-7.05 (m, 3H), 4.67 (t, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.76 (s, 3H), 2.96 (d, J=6.8 Hz, 2H), 2.66 (d, J=6.8 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H)
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[O:11])=[CH:4][CH:3]=1.[Mg].Br[CH:14]=[CH:15][CH3:16]>C1COCC1>[CH3:1][C:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[C:5]([C:10](=[O:11])[CH:14]=[CH:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CC1=CC=C(C=O)C(C)(C)C1
Reactant: CC=CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CC=CC(=O)C1=CC=C(C)CC1(C)C
Temperature: 0 °C

Procedure:
32 g of 4,6,6-trimethyl-1,3-cyclohexadiene-1-carbaldehyde [prepared according to A. F. Thomas et al., Helv. Chim. Acta, 59 (1976), p. 2261-7] in 80 ml of THF were added dropwise to a Grignard compound which had been prepared beforehand from 6 g of magnesium turnings and 32 g of 1-bromo-1-propene in 120 ml of THF. The temperature was maintained at 20° with a water bath during the addition, after which the mixture was heated and kept at reflux over 30 minutes. The reaction mixture was poured into an ice/water ixture and then extracted with ether. The organic phase was washed to neutrality, dried and concentrated. The crude product was then oxidized with 210 g of activated manganese dioxyde (see Houben Weyl, Vol. 7, 1, page 178, 1951; E. M. Goldman, Org. Chem., 34, 1979, 1969) in 200 ml of petroleum ether.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][CH:9](F)[C:10](C(O)=O)([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:11](OCC)=[O:12].[OH-].[Na+]>O>[F:8]/[CH:9]=[C:10](\[CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)/[CH2:11][OH:12]
Reactant: CCOC(=O)C(CCc1ccc(F)cc1)(C(=O)O)C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: OC/C(=C/F)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cool to 0° C.-10° C. a toluene solution of ethyl 2-(difluoromethyl)-2-carboxy-4-(p-fluorophenyl)butyrate as prepared in Example 4.1. Add water (396 kg) and a 50% by weight aqueous solution of sodium hydroxide. Stir for 30 minutes. Separate the aqueous layer and cool the aqueous layer to 0° C.-5° C. Add tetrahydrofuran (421 kg). Stir for hour at 0° C. and then warm to 25° C. and stir for 3 hours. Separate the aqueous layer. Evaporate the organic layer in vacuo at a temperature of 40° C.-50° C. The evaporation is continued until tetrahydrofuran no longer comes over and then toluene is added. Evaporate in vacuo until there is no longer water visible in the condensate. Concentrate in vacuo to give the title compound as a 80-90% by weight solution in toluene. An analytical sample prepared by evaporation of solvent gave 1H NMR (CDCl3, 300 MHz) δ 1.28 (t, J=7.2Hz 3H), 2.58 (m, 2H), 2.71 (m, 2H) 4.21 (q, J=7.2Hz, 2H), 6.93 (m, 2H), 7.15 (m, 2H), 7.51 (d, J=81.9Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].CC[O-].[Na+].[CH:14]([CH:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:15].Cl>CC(C)=O.COCCO.C(O)CO>[OH:1][CH2:2][CH2:3][N:4]([CH:16]([CH:14]=[CH2:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: C=CC(Cl)c1ccccc1
Reactant: O=C(O)CCNCCO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COCCO
Solvent: OCCO
Product: C=CC(c1ccccc1)N(CCO)CCC(=O)O
Reaction time: 2 h

Procedure:
Into the same flask as in Example 1, N-(2-hydroxyethyl)-β-alanine (117 parts), sodium ethylate (68 parts), ethylene glycol (300 parts) and ethylene glycol monomethyl ether (150 parts) are charged, and the resultant mixture is heated at 100° C. under stirring. A mixture of vinylbenzyl chloride (152 parts) and ethylene glycol monomethyl ether (100 parts) is dropwise added thereto in 2 hours. Stirring under heating is further continued for 6 hours. The reaction mixture is neutralized with hydrochloric acid, and acetone is added thereto to precipitate a white solid substance. The white solid substance is collected by filtration and dried under reduced pressure to give N-(2-hydroxyethyl)-N-(vinylbenzyl)-β-alanine (191 parts) of the formula: ##STR21## of which the NMR chart is shown in FIG. 8.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:36][CH2:37]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:23][CH2:24][O:8][C:7]3[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[O:11][CH2:37][CH2:36]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)OCCN(CCOS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCOc3ccc([N+](=O)[O-])cc3OCC2)cc1

Procedure:
To dimethylformamide (200 mL) add 4-nitrocatechol (13.8 g, 89 mmol), 4-methyl-N,N-bis[2-[[(4-methylphenyl)sulfonyl]oxy]ethyl]benzenesulfonamide (50.7 g, 89.4 mmol), and K2CO3 (27 g, 0.19 mol). Stir and heat the reaction at 110° C. Monitor the progress of the reaction by thin-layer chromatography. Upon completion remove the heat and add water (1.3 L) and methanol (300 mL). Collect the precipitate on paper by suction filtration. Wash the solid with water (2 L). Chromatograph the material on silica (300 g) with CH2Cl2 to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].I[C:28]1[C:32]([O:33][CH3:34])=[CH:31][NH:30][N:29]=1>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:34][O:33][C:32]1[CH:28]=[N:29][NH:30][C:31]=1[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH3:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1c[nH]nc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(-c2[nH]ncc2OC)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
Into a 50-mL three neck round-bottom flask, purged and maintained with nitrogen, was placed a solution of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (414 mg, 1.50 mmol) in dioxane (6 mL). Potassium carbonate (2 M, 2.5 mL, 5.00 mmol), 3-iodo-4-methoxy-1H-pyrazole (compound 244.5, 224 mg, 1.00 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol) were added to the reaction and the resulting mixture was stirred overnight at 90° C. The resulting mixture was cooled, then diluted with EtOAc (80 mL) and washed with brine (2×30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography with ethyl acetate/petroleum ether (1/1) as eluent to obtain the title compound as a yellow oil (180 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[CH2:16][N:15]([CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>FC1C=CC=CC=1C#N>[C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][C:20]1[CH:19]=[C:18]([CH:17]2[CH2:16][N:15]([CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:14](=[O:31])[N:13]2[C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:33][CH:32]=3)=[CH:12][CH:11]=2)[CH:23]=[CH:22][CH:21]=1)#[N:13]
Reactant: CS(=O)(=O)CCN1CC(c2cccc(O)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Agent: N#Cc1ccccc1F
Product: CS(=O)(=O)CCN1CC(c2cccc(Oc3ccccc3C#N)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O

Procedure:
The title compound is prepared as described in Example 276 from Example 290 and 2-fluorobenzonitrile. 1H NMR (CDCl3) δ 7.66 (dd, J=7.6, 1.6 Hz, 1H), 7.45-7.40 (m, 1H), 7.40-7.36 (m, 2H), 7.27-7.23 (m, 3H), 7.18-7.13 (m, 2H), 7.01-6.98 (m, 2H), 6.90-6.86 (m, 4H), 6.68 (dd, J=8.8, 0.8 Hz, 1H), 5.22 (dd, J=9.2, 6.8 Hz, 1H), 4.06 (t, J=9.2 Hz, 1H), 3.90-3.76 (m, 2H), 3.44-3.29 (m, 3H), 3.00 (s, 3H); HPLC-MS calculated for C31H26ClN3O5S (M+H+): 588.1, found 588.1.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][NH:7][C:6](=[O:14])[C:5]=2[S:4][C:3]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:12][C:9]1([CH3:13])[CH2:8][NH:7][C:6](=[O:14])[C:5]2[S:4][C:3]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]=2[CH2:10]1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)CNC(=O)c2sc(N3CCOCC3)c(Br)c2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CNC(=O)c2sc(N3CCOCC3)c(-c3ccccc3)c2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 34.2 %

Procedure:
To a mixture of Example 116 (0.15 g, 0.41 mmol), phenylboronic acid (0.08 g, 0.63 mmol), palladium acetate (0.005 g, 0.02 mmol), 1,3-bis(diphenylphosphino)propane (0.02 g, 0.04 mmol) and K3PO4 (0.18 g, 0.82 mmol) was added DMF (2 mL). The reaction mixture was heated at 80° C. for 5 h and left standing for 16 h at r.t. Phenyl-boronic acid (0.08 g, 0.63 mmol), palladium acetate (0.005 g, 0.02 mmol), 1,3-bis(diphenylphosphino)propane (0.02 g, 0.04 mmol), K3PO4 (0.07 g, 0.33 mmol) and DMF (2 mL) were again added. The reaction mixture was heated at 90° C. for 16 h, then cooled to r.t. and diluted with EtOAc (5 mL). The solid was filtered and washed with EtOAc (25 mL). The organic filtrate was washed with water (5×10 mL), then brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (0.05 g, 37%) as a white solid. δH (DMSO-d6) 7.83 (1H, t, J 5.1 Hz), 7.46 (2H, t, J 7.4 Hz), 7.37-7.29 (3H, m), 3.49-3.47 (4H, m), 2.85 (2H, d, J 5.2 Hz), 2.79-2.77 (4H, m), 2.29 (2H, s), 0.86 (6H, s). MS (ES+) 357.0 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[C:18](O)=[C:17]([S:26]([CH3:29])(=[O:28])=[O:27])[C:16]1=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O=P(Cl)(Cl)[Cl:33]>>[CH2:8]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[C:18]([Cl:33])=[C:17]([S:26]([CH3:29])(=[O:28])=[O:27])[C:16]1=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1c(Cl)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 90 °C

Procedure:
Triethylamine (1.2 mL, 8.6 mmol) was added to a suspension of 1-benzyl-4-hydroxy-3-(methylsulfonyl)-[1,8]-naphthyridin-2(1H)-one (114) (0.94 g, 2.9 mmol) in neat POCl3 and heated at 90° C. for 3 h. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in water, neutralized by solid NaHCO3, and extracted by dichloromethane. The organic layer was subsequently washed by saturated NaHCO3 solution, water and brine, dried over Na2SO4, and evaporated to yield 1-benzyl-4-chloro-3-(methylsulfonyl)-[1,8]-naphthyridin-2(1H)-one (115) as yellow solid. Yield 0.92 g (92%), mp 191° C. 1H-NMR (DMSO-d6): δ 3.50 (s, 3H), 5.65 (s, 2H), 7.28 (m, 5H), 7.55 (m, 1H), 8.70 (dd, J=1.6, 8.4 Hz, 1H), 8.84 (dd, J=1.6, 4.4 Hz, 1H); EIMS m/z 349 (M+1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:14]=[CH:13][C:12]([I:15])=[CH:11][C:8]=1[C:9]#[N:10]>S(=O)(=O)(O)O.O>[Cl:3][C:7]1[N:14]=[CH:13][C:12]([I:15])=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc(I)cnc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1cc(I)cnc1Cl
Temperature: 110 °C
Yield: 389.6 %

Procedure:
30.7 ml (329 mmol) of phosphorus oxychloride at 0° C. and 6 drops of sulfuric acid are added to 9 g (6.6 mmol) of 2-hydroxy-5-iodonicotinonitrile. The reaction mixture is heated at 110° C. for 5 hours and then at room temperature overnight. The reaction mixture is poured in a beaker containing ice and a little water, and a precipitate is formed. The mixture is allowed to gradually return to room temperature and then is filtered and rinsed with water. The solid is dried to yield 6.8 g (70%) of 2-chloro-5-iodonicotinonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([CH2:31][CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[CH:30]=[C:29]([CH2:31][CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: CCc1cc2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc2s1
Product: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(-c3ccc(C(=O)OC)cc3)nc2s1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][N:10]=1)C1C=CC=CC=1.[ClH:21].O1CCOCC1>>[ClH:21].[N:15]1([C:12]2[CH:13]=[N:14][C:9]([OH:8])=[N:10][CH:11]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: c1ccc(COc2ncc(N3CCOCC3)cn2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1ncc(N2CCOCC2)cn1
Temperature: 50 °C

Procedure:
4N—HCl/dioxane (100 ml) was added to 4-(2-benzyloxy-pyrimidin-5-yl)-morpholine (8.4 g) and the resulting suspension was stirred at 50° C. for an hour. The reaction mixture was cooled to room temperature and the precipitated solid was collected by filtration, washed with hexane, dried to give the titled compound (7.49 g). MS (m/z): 182 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[C:25]([O:28][C@@H:29]([CH3:33])[C:30](Cl)=O)(=[O:27])[CH3:26]>O1CCCC1>[C:25]([O:28][C@H:29]([C:33]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:24])[C:10]2[N:11]=[C:12]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[S:13][C:14]=2[C:15](=[O:16])[N:17]=1)[CH3:30])(=[O:27])[CH3:26]
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)O[C@@H](C)c1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in Tetrahydrofuran (THF) (1363 μl) was added (1S)-2-chloro-1-methyl-2-oxoethyl acetate (82 mg, 0.545 mmol). The mixture was stirred at room temperature overnight, then additional (1S)-2-chloro-1-methyl-2-oxoethyl acetate (1 equiv.) was added and stirring was continued at 60° C. for 2 h. The mixture was quenched with methanol and concentrated. The residue was purified by reversed-phase HPLC to provide (1S)-1-[4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-7-oxo-4,7-dihydro[1,3]thiazolo[4,5-d]pyrimidin-5-yl]ethyl acetate. (11 mg, 9%); LC/MS: MS (ES+) m/e 463 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.3 Hz, 3H), 1.71 (s, 3H), 2.40 (s, 3H), 3.51-3.54 (m, 4H), 3.67 (m, 4H), 5.48-5.61 (m, 2H), 5.69 (q, J=6.3 Hz, 1H), 6.56 (d, J=7.6 Hz, 1H), 7.16 (m, 1H), 7.38 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(=O)OC(C)(C)C)CC3)s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(=O)O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 127.2 %

Procedure:
tert-Butyl 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclopropanecarboxylate (375 mg, 0.787 mmol) was taken up in CH2Cl2 (12 mL) before adding TFA (3 mL). The reaction was stirred at room temperature overnight. The reaction was evaporated to dryness, and the residue was azeotroped with DCE (3×) to provide 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclopropanecarboxylic acid (TFA salt) (421 mg, 100%) as a yellow solid. MS ESI: [M+H]+ m/z 421.0. 1H NMR (600 MHz, DMSO-d6) δ 13.15 (s, 10.21 (s, 1H), 8.80 (d, J=4.8, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.44 (s, 1H), 7.25 (d, J=4.9, 1H), 7.12 (s, 1H), 2.29 (s, 3H), 1.81-1.62 (m, 4H). rhSYK activity=+++
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.OS(O)(=O)=O.[CH3:20][CH2:21]O>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(OC)cc(OC)c1
Yield: 88 %

Procedure:
A solution of 3,5-dimethoxyphenylacetic acid (2.0 g; 10 mmol) and H2SO4 (conc.; 0.2 mL) in EtOH (50 mL) was refluxed overnight. The solution was concentrated, and the resultant material was dissolved in aqueous NaOH (1M). After extraction with ether (2×75 mL), washing of the combined organic phase with brine, drying (Na2SO4) and evaporating, 2.0 g (88%) of the sub-title compound was obtained.