Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1COCC1.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>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=Cc1ccc(Br)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: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(C=O)cc1
Temperature: 85 °C
Yield: 91.8 %

Procedure:
To a stirred degassed solution of 4-bromobenzaldehyde (218 mg, 1.18 mmol) and 2-methoxybenzeneboronic acid (188 mg, 1.24 mmol) in DME/THF (5 mL, 4:1) were added a 2 M Na2CO3 solution (1.6 mL) and Pd(PPh3)4 (63 mg, 0.055 mmol). The reaction mixture was flushed with argon and maintained under argon while being heated at 85° C. overnight. The mixture was then cooled and diluted with EtOAc (25 mL) and water (25 mL). The aqueous layer was washed with EtOAc (2×10 mL) and the combined organic extracts dried (Na2SO4), filtered and concentrated. Purification of the resultant oil by column chromatography with silica gel (Hexanes/Et2O, 80:20) afforded the title compound (230 mg, 92%) as a clear oil. 1H NMR (CDCl3) δ 3.84 (s, 3H), 7.01–7.09 (m, 2H), 7.33–7.39 (m, 2H), 7.71 (d, 2H, J=6 Hz), 7.93 (d, 2H, J=6 Hz), 10.05 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C@@H:12]([C:21]([OH:23])=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C@@H:12]([C:21]([OH:23])=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1N)C(=O)O
Yield: 84.4 %

Procedure:
In 500 ml of methanol is dissolved 30 g of O-(o-nitrophenyl)-Boc-L-serine obtained in Example 1, and catalytic reduction is conducted in a stream of hydrogen at ordinary temperature and at atmospheric pressure with 1 g of 10% palladium-carbon used as a catalyst. The catalyst is filtered off, and the filtrate is concentrated under reduced pressure. The resulting residue is recrystallized from ethyl acetate to give 23 g of O-(o-aminophenyl)-Boc-L-serine as colorless crystals, melting at 90°-91° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][NH:11][O:12][CH2:13][CH2:14][C@H:15]([NH:22]C(OCC1C=CC=CC=1)=O)[C:16]([N:18]([O:20][CH3:21])[CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl>CO.[Pd]>[NH2:22][C@@H:15]([CH2:14][CH2:13][O:12][NH:11][CH:10]=[N:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]([N:18]([O:20][CH3:21])[CH3:19])=[O:17]
Reactant: CON(C)C(=O)[C@H](CCONC=NNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CON(C)C(=O)[C@@H](N)CCONC=NNC(=O)OC(C)(C)C
Yield: 92.8 %

Procedure:
A suspension of (2S)-4-({[(tert-butoxy)carbonylamino]iminomethyl}aminooxy)-N-methoxy-N-methyl-2-[(phenylmethoxy)carbonylamino] butanamide (120 mg, 0.27 mmol), as prepared in the preceding step, and 10% Pd/C (18 mg) in methanol (5.0 mL) and chloroform (158 mL, 1.32 mmol) was hydrogenated with a balloon until all starting amine was consumed (in about 6 to 7 h). The mixture was filtered through Celite. The filtrate was concentrated to give the title compound (80 mg, 95% yield) as a colorless oil. Mass spectrum (LCMS, ESI) calcd. for C12H26N5O5 320.4 (M+H); found: 320.0.
Reaction SMILES: O[C:2]([CH3:30])([CH3:29])[CH2:3][C@@:4]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.O.[C:32]1(C)C=CC(S(O)(=O)=O)=C[CH:33]=1.COC(OC)(OC)C>C(OCC)(=O)C>[CH3:29][C:2](=[CH2:30])[CH2:3][C@:4]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]3[O:18][C:32]([CH3:33])=[N:20][N:19]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@@H](c1ccc(C(=O)NN)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: COC(C)(OC)OC
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)C[C@@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3nnc(C)o3)cc2)C(=O)O1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazin-an-3-yl]-ethyl}-benzoic acid hydrazide (90 mg), toluene-4-sulfonic acid monohydrate (10 mg), and 1,1,1-trimethoxy-ethane (1 ml) was stirred at room temperature for 1 h, at 80° C. for 2 h, and finally at reflux temperature for 1.5 h. After cooling to ambient temperature, ethyl acetate was added and the resulting mixture was washed with aqueous NaHCO3 solution and brine. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 99:1→95:5) to afford the title compound as a colorless resin-like solid.
Reaction SMILES: N[N:2]1[CH:6]=[CH:5][N:4]=[C:3]1C1C=[CH:11][C:10]([O:13]C)=CC=1.CN(C)C1C=CC(C=[O:22])=CC=1>C(O)(=O)C>[C:10]([O-:13])(=[O:22])[CH3:11].[NH+:2]1[CH:6]=[CH:5][NH:4][CH:3]=1
Reactant: COc1ccc(-c2nccn2N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: CC(=O)O
Product: CC(=O)[O-]
Product: c1c[nH+]c[nH]1
Reaction time: 24 h

Procedure:
9 g of 1-amino-2-(p-methoxyphenyl)imidazole are dissolved in 300 ml of glacial acetic acid, whereupon the solution is treated with 21.3 g of p-(dimethylamino) benzaldehyde. After 24 hours, the mixture is evaporated and the residue is placed on a column loaded with 300 g of silica gel. The product is eluted with dichloro-methane/methanol (95:5). The dark eluate is treated with active carbon and evaporated. The product is crystallized twice from methylene chloride/petroleum ether. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-p-methoxyphenyl)imidazolium acetate of melting point 93°. The resulting salt is treated with aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract is dried over sodium sulfate and evaporated. The product is crystallized from petroleum ether. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-(p-methoxyphenyl)imidazole of melting point 108°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH:13]1([O:12][C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrC1CCCC1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
2-Methyloxy-5-nitrophenol (14.27 g, 84.4 mmol) was dissolved in dry dimethylformamide (80 ml). Cyclopentylbromide (176 g, 127 ml, 118.2 mmol) and cesium carbonate (38.5 g, 118.2 mmol) were added and the suspension stirred overnight at room temperature. The mixture was poured into saturated Na2CO3 (200 ml) and extracted with ethyl acetate (700 ml). The organic layer was washed with saturated Na2CO3 until no yellow colour was detected. The organic layer was then dried (MgSO4) and concentrated in vacuo to give the title Compound as a yellow solid (15.0 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:6][C@@H:5]1[CH3:40])(=[O:3])[CH3:2].C([Cl:44])(=O)C>CO>[ClH:44].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[N:18][C:17]([N:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:33][C:34](=[O:35])[O:36][CH:37]([CH3:38])[CH3:39])[CH2:6][C@@H:5]1[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)N1c2ccc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(N4CCNCC4)nc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Product: Cl

Procedure:
The remaining 1,1-dimethylethyl 4-{5-[(cis)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-2-pyridinyl}-1-piperazinecarboxylate was dissolved in methanol and 0.5 mL acetyl chloride was added. Solvents were evaporated to yield Example 9, 1-methylethyl {(cis)-1-acetyl-2-methyl-6-[6-(1-piperazinyl)-3-pyridinyl]-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride as a pale yellow solid (40 mg). LCMS (Method C): Rt=0.59, MH+=452
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[S:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:21]([CH:23]1[CH:26](OC(=O)C)[NH:25][C:24]1=[O:31])[CH3:22]>[OH-].[Na+].O1CCOCC1>[CH2:21]([CH:23]1[CH:26]([S:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][NH:12][C:10]([O:9][CH2:8][C:7]2[CH:19]=[CH:20][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])[NH:25][C:24]1=[O:31])[CH3:22]
Reactant: O=C(NCCCC(O)=S)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCC1C(=O)NC1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC1C(=O)NC1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution, prepared in the cold, of 7.95 g (26.7 mmole) of 4-p-nitrobenzyloxycarbonylaminothiobutyric acid in 26.7 ml of 1N sodium hydroxide solution is added dropwise to a pre-cooled solution of 3.24 g (20 mmole) of 3-ethyl-4-acetoxyazetidin-2-one (racemic cis-trans compound in a ratio of 6:4) in 50 ml of dioxan and the mixture is stirred for 2 hours at room temperature. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1, 4.1 and 1:1) and yields the title compound with the following physico-chemical properties.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][C:10](=O)[CH3:11])[O:3]1.[Cl:14][C:15]1[CH:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[CH:17][N:16]=1.O>O1CCOCC1>[Cl:14][C:15]1[CH:20]=[C:19]([N:21]2[C:10]([CH3:11])=[CH:9][C:4]([OH:3])=[CH:5][C:6]2=[O:8])[C:18]([CH3:22])=[CH:17][N:16]=1
Reactant: Cc1cnc(Cl)cc1N
Reactant: CC(=O)CC1=CC(=O)OC(C)(C)O1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(Cl)cc1-n1c(C)cc(O)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a screw top vial with rubber septa inset was added 2,2-dimethyl-6-(2-oxo-propyl)-[1,3]dioxin-4-one, prepared as described in Organic Letters, 11(21), 4910-4913; 2009, (500 mg, 2.7 mmol) and 2-chloro-5-methyl-pyridin-4-ylamine (575 mg, 4 mmol, 1.5 eq). The mixture was dissolved in anhydrous 1,4-dioxane (10 mL). Once the mixture was homogeneous the vial was placed on a stirrer/hot plate preset to 90° C. The reaction vessel was heated at this temperature for 3.5 h. The reaction vial was removed from heat and analyzed by HPLC which showed that the reaction was >95% complete. The vial was placed back on the hot plate. To the heated mixture was added H2SO4 (250 μL) and the reaction was heated for 1 h. The reaction vial was removed from the heat and after cooling to ambient temperature, the dioxane was removed by passing a stream of air over the top of the open vial to give a brown residue. Water (˜4 mL) was added to the vial, and the mixture was stirred for 30 min. The resulting tan solid was filtered off with washing from additional water and the diethyl ether to give the desired product (531 mg, 57% based on being the sulfate salt) as a tan solid which by HPLC was ˜95% pure: MS (ES) m/e 250 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9][CH:10]([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:13][C:14]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:15]=1[C:16]([NH:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([S:9][CH:10]([F:12])[F:11])=[CH:8][C:2]=1[F:1])=[O:20])=[O:17]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(SC(F)F)cc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(SC(F)F)cc1F
Reaction time: 0.5 h
Yield: 77 %

Procedure:
In 15 ml of toluene was dissolved 1.0 g of 2-fluoro-4-difluoromethylthioaniline, and 1.0 g of 2,6-difluorobenzoyl isocyanate was added dropwise to the solution at room temperature (20° to 25° C.). After the reaction was allowed to proceed at the same temperature for 30 minutes, the crystals, which separated out, were recovered by filtration and washed with toluene to give 1.5 g of N-(2,6-difluorobenzoyl)-N'-(2-fluoro-4-difluoromethylthiophenyl)urea (Compound No. 55). Recrystallization from acetone gave crystals having a melting point of 172°-173° C.
Reaction SMILES: [ClH:1].[CH2:2]([N:5]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[C:6]([C:8]1[CH:28]=[CH:27][C:11]2[N:12]([CH3:26])[C:13]([CH2:15][S:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][CH:18]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7])[CH2:3][CH3:4].[OH-].[Na+].O>C(O)C>[ClH:1].[CH2:2]([N:5]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:6]([C:8]1[CH:28]=[CH:27][C:11]2[N:12]([CH3:26])[C:13]([CH2:15][S:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[NH:24])[NH2:25])=[CH:19][CH:18]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7])[CH2:3][CH3:4]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCN(CCC(=O)O)C(=O)c1ccc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.52 g (1.0 mmol) of 1-Methyl-2-[(4-amidinophenyl)thiomethyl]benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride was dissolved in 15 ml ethanol, mixed with 5 ml of 2N sodium hydroxide solution and stirred for 2 hours at room temperature. Then 5 ml of water were added, the alcohol was distilled off, and it was acidified with concentrated hydrochloric acid. The water was distilled off in vacuo, and the crude product was taken up in 5 ml of ethanol and filtered to remove the insoluble sodium chloride. After the solvent had been distilled off, the title compound was obtained as a white solid.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH:8]=1)O)([O-:3])=[O:2].CS(Cl)(=O)=O.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[N+:1]([CH:4]=[CH:5][C:7]1[CH:8]=[C:9]([O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])CC(O)c1cccc(OCC(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])C=Cc1cccc(OCC(F)(F)F)c1
Reaction time: 2 h

Procedure:
Combine 2-nitro-1-(3-trifluoroethoxyphenyl)ethanol (6.1 g, 24.2 mmol) and methanesulfonyl chloride (2.02 mL) in dichloromethane (50 mL) and cool in an ice-bath. Add dropwise, triethylamine (7.28 mL) while maintaining the temperature near 0° C. After 2 hours, pour into ethyl acetate, wash with water, dry with Na2SO4, filter, and then concentrate to residue. Chromatograph the residue on silica gel to give 3-(2-nitrovinyl)-1-trifluoroethoxybenzene: MS (MH+) 234; 1H NMR (CDCl3) 7.97 (1H, d, J=13.6 Hz), 7.57 (1H, d, J=13.6 Hz), 7.53–7.48 (2H, m), 7.40–7.35 (2H, m).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[C:18]([CH2:23]O)=[CH:17][N:16]=2)=[CH:10][CH:9]=1>C(Cl)Cl>[ClH:3].[Cl:3][CH2:23][C:18]1[C:19]([O:21][CH3:22])=[N:20][C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([O:7][CH:6]([F:25])[F:5])=[CH:9][CH:10]=2)=[N:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: COc1nc(Nc2ccc(OC(F)F)cc2)ncc1CO
Solvent: ClCCl
Product: COc1nc(Nc2ccc(OC(F)F)cc2)ncc1CCl
Product: Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
Thionyl chloride (0.295 mL, 4.04 mmol) was added to a suspension of ((2-((4-(difluoromethoxy)phenyl)amino)-4-methoxypyrimidin-5-yl)methanol (0.3 g, 1.009 mmol) in DCM (10 mL) cooled to 0° C. The mixture was stirred for 18 h while warming to room temperature. The reaction mixture was concentrated and dried under vacuum to give 5-(chloromethyl)-N-(4-(difluoromethoxy)phenyl)-4-methoxypyrimidin-2-amine hydrochloride as a beige solid (0.35 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.98 (s, 1H), 8.34 (s, 1H), 7.87-7.72 (m, 2H), 7.42-6.86 (m, 3H), 4.67 (s, 2H), 4.02 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]([C:19]3[CH2:23][C:22]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][N:20]=3)=[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:34]1(Br)[CH2:38][CH2:37][CH2:36][CH2:35]1>C(#N)C>[CH:34]1([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:11]3[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=4[N:8]=[CH:9][C:10]=3[C:19]3[CH2:23][C:22]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][N:20]=3)[CH2:18][CH2:17]2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCn1ncc2c(NC3CCNCC3)c(C3=NOC4(CCCC4)C3)cnc21
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1ncc2c(NC3CCN(C4CCCC4)CC3)c(C3=NOC4(CCCC4)C3)cnc21

Procedure:
1-Ethyl-5-(1-oxa-2-azaspiro[4.4]non-2-en-3-yl)-N-piperidin-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine (70 mg, 0.0018 mole) (example 31) was taken in acetonitrile and potassium carbonate (126 mg, 0.0009 mole) and cyclopentyl bromide (0.020 ml, 0.0002 mole) were added. The reaction mixture was stirred at refluxing temperature overnight. Acetonitrile was removed and water was added to the residue. Extraction was done with ethyl acetate and washings were done with brine. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure and the crude product was purified by preparative thin layer chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([S:11][C:12](=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])[N:4]=1.[OH-].[K+].C(O)C>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([S:11][C:12](=[CH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: COC(=O)C(=Cc1ccccc1)Sc1nc(OC)cc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)nc(SC(=Cc2ccccc2)C(=O)O)n1
Temperature: 50 °C

Procedure:
0.5 g (1.5 mmol) Methyl 2-(4,6-dimethoxy-2-pyrimidinylthio)-3-phenylacrylate and 95 mg (1.7 mmol) potassium hydroxide were added to a mixture of 5 ml water and 5 ml ethanol and the mixture heated at 50° C. for 8 hours. It was then diluted with about 100 ml water and extracted with ethyl acetate. The aqueous phase was acidified with 10% hydrochloric acid until it was pH 2 and extracted with ethyl acetate. After drying the ethyl acetate phase over magnesium sulphate, the solvent was evaporated under reduced pressure and the residue recrystallised from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][C:12]1[C:13]([NH:25][C:26]2[S:27][CH:28]=[C:29]([CH3:31])[N:30]=2)=[N:14][CH:15]=[C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1.C([Cl:37])(=O)OCC.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42]>O>[ClH:1].[ClH:37].[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:42][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])=[O:7])=[CH:4][C:3]=1[O:11][C:12]1[C:13]([NH:25][C:26]2[S:27][CH:28]=[C:29]([CH3:31])[N:30]=2)=[N:14][CH:15]=[C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1
Reactant: CN(C)CCN
Reactant: Cc1csc(Nc2ncc(Sc3ccccc3)cc2Oc2cc(C(=O)O)ccc2Cl)n1
Reactant: CCOC(=O)Cl
Solvent: O
Product: Cc1csc(Nc2ncc(Sc3ccccc3)cc2Oc2cc(C(=O)NCCN(C)C)ccc2Cl)n1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-3-(2-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yloxy)benzoic acid (prepared according to Example 71; 0.131 g, 0.279 mmol) and TEA (0.117 mL, 0.836 mmol) were placed in a flask and cooled to 0° C. Ethyl carbonochloridate (0.0303 g, 0.279 mmol) was added, and the reaction mixture was stirred at 0° C. for 30 minutes. N1,N1-dimethylethane-1,2-diamine (0.0306 mL, 0.279 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Water was added and the reaction mixture was extracted with CH2Cl2. The organic layer was concentrated and the residue was purified first by silica gel chromatography and then by reverse phase chromatography to provide the desired product as the free base. The free base was dissolved in CH2Cl2 and HCl in ether was added to give 4-chloro-N-(2-(dimethylamino)ethyl)-3-(2-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yloxy)benzamide dihydrochloride (0.069 g, 40.4% yield). 1H NMR (d6-DMSO) δ 9.83 (bs, 1H), 8.90 (m, 1H), 8.24 (m, 1H), 7.75 (m, 2H), 7.58 (s, 1H), 7.30 (m, 2H), 7.19 (m, 4H), 6.67 (s, 1H), 3.59 (m, 2H), 3.23 (m, 2H), 2.80 (d, 6H), 2.25 (s, 3H); Mass spectrum (esi) m/z=540.1 (100) (M+H-2HCl).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](=[N:23]/[O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[N:35]=[C:36]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[O:37][C:38]=3[CH3:39])=[CH:28][CH:27]=2)/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:8][CH:7]=1.O.Cl>O1CCCC1.CO>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9](/[C:12](=[N:23]/[O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[N:35]=[C:36]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[O:37][C:38]=3[CH3:39])=[CH:28][CH:27]=2)/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:10][CH:11]=1
Reactant: COC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(/C(CCCCCCC(=O)O)=N/OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Lithium hydroxide monohydrate (128 mg) was added to a solution of methyl E-8-(4-methoxyphenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate (580 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (3.1 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-(4-methoxyphenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoic acid (528 mg, yield 93%) as colorless crystals. m.p. 69-70° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:35][C:36]1[C:37]([F:46])=[C:38]2[C:44]([NH2:45])=[CH:43][NH:42][C:39]2=[N:40][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:35][C:36]1[C:37]([F:46])=[C:38]2[C:44]([NH:45][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:12])=[CH:43][NH:42][C:39]2=[N:40][CH:41]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
trans-2-Phenylcyclopropanecarboxylic acid (705 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 was added (50 mL). The resulting suspension was filtered and the solid rinsed with DCM and water. After drying, trans-N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylcyclopropanecarboxamide (503 mg, 61.8% yield) was obtained as a solid.