Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)[CH:2]=[CH2:3].CC1C=C(C=C(C)C=1)CBr>C1(C)C=CC=CC=1>[CH:1]([NH:4][C:5](=[O:17])[C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]([F:15])([F:16])[F:14])=[CH:10][CH:11]=1)=[CH:2][CH3:3]
Reactant: C=CCNC(=O)c1ccc(OC(F)(F)F)cc1
Agent: Cc1cc(C)cc(CBr)c1
Solvent: Cc1ccccc1
Product: CC=CNC(=O)c1ccc(OC(F)(F)F)cc1
Yield: 65 %

Procedure:
Compound 11 (100 mg, 0.57 mmol) was combined with 3,5-dimethylbenzyl bromide (0.57 mmol) and heated in toluene to 100° C. for 2 hours. The resulting mixture was cooled and washed with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extract was dried (sodium sulfate), filtered, and purified by silica gel chromatography (methylene chloride, methanol) to yield 12 (example 21) (65%). 1H NMR (400 MHz, CDCl3) δ8.57 (d, J=8.0 Hz, 1 H, Ar), 7.13 (dd, J=2.8, 9.2 Hz, 1 H, Ar), 6.99 (d, J=7.2 Hz, 1 H, Ar), 6.89 (s, 3 H, Ar), 6.85 (d, J=2.8 Hz, 1 H, Ar), 6.42 (d, J=7.2 Hz, 1 H, Ar), 5.36 (s, 2 H, CH2), 3.90 (s, 3 H, CH3O), 2.24 (s, 6 H, CH3); M/Z (ESI+) 293 ([M+H]+).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]2[CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]3[O:22][C:5]=2[CH:4]=1.C(N1CC=CC(O)C1)(OC(C)(C)C)=O.[Br:37]C1C=CC=C(Br)C=1O>>[Br:37][C:4]1[C:5]2[O:22][CH:10]3[CH:9]([C:6]=2[CH:7]=[CH:8][CH:3]=1)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3
Reactant: Oc1c(Br)cccc1Br
Reactant: COc1ccc2c(c1)OC1CN(C(=O)OC(C)(C)C)CCC21
Agent: CC(C)(C)OC(=O)N1CC=CC(O)C1
Product: CC(C)(C)OC(=O)N1CCC2c3cccc(Br)c3OC2C1

Procedure:
Prepared as described for tert-butyl 7-methoxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from N-boc-3-hydroxy-1,2,3,6-tetrahydropyridine and 2,6-dibromo-phenol.
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:26]([O:28][CH3:29])=[O:27])=[C:10]([CH3:25])[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH2:2]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:26]([O:28][CH3:29])=[O:27])=[C:10]([CH3:25])[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH3:3]
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(=O)(=O)C(C)C)cc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Iodoethane (3.35 mL, 41.4 mmol) was added slowly to a mixture of methyl 7-hydroxy-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (12.90 g, 27.6 mmol) and cesium carbonate (27.0 g, 83 mmol) in dimethyl sulfoxide (150 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with methylene chloride. The phases were separated, and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified via column chromatography (ISCO, 330 g silica, 0-20% ethyl acetate/methylene chloride) to afford a solid residue that was triturated from methanol to give methyl 7-(ethyloxy)-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (11.39 g, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ8.24 (s, 1H), 7.98-8.04 (m, 2H), 7.91 (d, J=7.78 Hz, 1H), 7.76-7.82 (m, 2H), 4.39 (q, J=7.03 Hz, 2H), 4.09 (s, 3H), 3.85 (quin, J=6.84 Hz, 1H), 2.36 (s, 3H), 1.44 (t, J=7.03 Hz, 3H), 1.23 (s, 3H), 1.21 (s, 3H); MS (m/z) 496.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:22])[CH2:9][NH:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:13])[CH:5]=[CH:6][CH:7]=1.[O:23](C(OC(C)(C)C)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=O.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C1COCC1.CN(C1C=CN=CC=1)C>[C:27]([O:26][C:24](=[O:23])[N:10]([CH2:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:22])[CH2:11][C:12](=[O:13])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1ccccc1NC(=O)CNCC(O)c1cccc(Br)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)CN(CC(O)c1cccc(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.2 %

Procedure:
To 2-[2-(3-bromo-phenyl)-2-hydroxy-ethylamino]-N-o-tolyl-acetamide (4 g) in THF (100 mL) was added DMAP (134 mg) and (BOC)2O (2.89 g) in THF (100 mL) at 0° C. The mixture was stirred at room temperature for 2 h. An aqueous solution of NaHCO3 and ethyl acetate was added, the phases were separated and the inorganic one was extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2, n-heptane/ethyl acetate 1:1,) yielded [2-(3-bromo-phenyl)-2-hydroxy-ethyl]-(o-tolylcarbamoyl-methyl)-carbamic acid tert-butyl ester (0.88 g, 88%) as a colorless oil, MS: 463.1 (M+H, 1Br)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([Cl:18])=[O:17])[CH2:9]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O1CCOCC1>CN(C=O)C>[ClH:18].[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:16]([C@@H:10]3[CH:11]4[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]4)[CH2:9]3)=[O:17])=[CH:21][CH:22]=2)=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Reactant: Nc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)[C@H]1CN2CCC1CC2
Temperature: 100 °C
Reaction time: 18 h

Procedure:
480 mg (3.50 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 490 mg (2.33 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 250 mg (1.17 mmol) of 4-amino-4′-nitrobiphenyl in 11 ml of a 10:1 mixture of dioxane and DMF. The reaction mixture is stirred at 100° C. for 18 h and then concentrated. The residue is suspended in methanol and filtered. The filtration residue is washed with water, mixed with 20 ml of a 3:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. The above filtrate is purified by preparative HPLC. The product fractions are concentrated, taken up in 5 ml of a 3:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 291 mg (61.7% of theory) of the title compound are obtained from the filtration residue, and a further 65 mg (12.4% of theory) are obtained from the filtrate, in this way.
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[C:6]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)([Br:28])=O.CN(C=O)C>C1(C)C=CC=CC=1>[Br:28][C:11]1[C:10]2[C:5](=[C:6]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:25])([F:1])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=2)[N:12]=1
Reactant: COC(=O)c1cccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc12
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c(Br)nc(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (30 g, 85.9 mmol), POBr3 (3.7 g, 429.5 mmol), TEA (43.5 g, 429.5 mmol) and DMF (0.1 mL) in toluene (300 mL) was heated with stirring at 100° C. for 4 h. The mixture was concentrated and the residue was suspended in water (1 L) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water (2×50 mL) and brine, and then concentrated at 35° C. under reduced pressure until a solid began to precipitate. The mixture was allowed to cool, and the solid was collected by filtration and washed with a small quantity of cold EtOAc to afford methyl 4-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline-8-carboxylate (23 g, 65%). LC-MS (ESI) m/z 412.7, 414.7 (M+H+). The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with EtOAc/hexanes to afford additional methyl 4-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline-8-carboxylate (3.0 g, 8%).
Reaction SMILES: [F:1][C:2](I)([F:13])[C:3](F)([F:11])[C:4]([F:10])(F)[C:5]([F:8])([F:7])[F:6].[F:15]C(F)=C(F)F>>[C:3](/[F:11])(\[C:2]([F:1])([F:13])[F:15])=[C:4](\[F:10])/[C:5]([F:6])([F:7])[F:8]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: FC(F)=C(F)F
Product: F/C(=C(/F)C(F)(F)F)C(F)(F)F
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A 240 mL Hastelloy shaker tube was flushed with nitrogen, then loaded with 5 g of aluminum chlorofluoride catalyst, cooled to -78° C., evacuated and loaded with 20 g (0.06 mole) of perfluorobutyl iodide and 50 g (0.5 mole) of tetrafluoroethylene. The reaction vessel was allowed to warm and kept on a shaker at 25-30° C. at autogenous pressure. Significant pressure drop (approximately 150 psi) was observed in the first 2 hours. After 18 hours, the pressure tube was unloaded. The product, 40 g, was collected in a -78° C. cold trap. According to 19F NMR, it was a mixture of 90% of perfluorobutene-2, mixture of cis and trans isomers in a 3:2 ratio and 10% of perfluoroethyl iodide. The calculated yield of perfluorobutene-2 based on converted perfluorobutyl iodide was 72%. According to 19F NMR, the main component (about 70%) of the residue (15 g) was a mixture of perfluorohexene-2, (minor) and perfluorohexene-3.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[CH2:15][O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OCCCl)=O>ClCCl>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]2[C:11]3([O:14][CH2:15][C:16]=2[CH:21]=1)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3
Reactant: Clc1ccc2c(c1)COC21CCN(Cc2ccccc2)CC1
Agent: O=C(Cl)OCCCl
Solvent: ClCCl
Product: Clc1ccc2c(c1)COC21CCNCC1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 44.4 %

Procedure:
To a solution of 1′-benzyl-5-chloro-3H-spiro[2-benzofuran-1,4′-piperidine] (950 mg, 3.02 mmol) in dichloromethane (CH2Cl2) (6 mL) was added chloroethyl chloroformate (560.6 mg, 3.92 mmol) slowly at 0° C. After addition was complete the reaction mixture was kept on stirring at 0° C. for 25 min. The volatiles were removed in vacuo, the residue was dissolved in methanol (6 mL) and kept at reflux for 40 min. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-5% methanol in dichloromethane, 0.2% ammonium hydroxide, NH4OH) to give the titled compound (300 mg) and 1′-benzyl-5-chloro-3H-spiro[2-benzofuran-1,4′-piperidin] was recovered (320 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH2:25][CH3:26]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCC1NCCc2c(F)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CCC1c2cccc(F)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[N:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])=[N:14]2)[N:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2nc(Cn3ccc(N)n3)cs2)OCCO1
Product: CC(=O)c1nc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)cs1

Procedure:
Following general procedure B followed by C, starting from 1-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-4-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.0 min; [M+H]+=394.25.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C:11]([CH2:12][NH:13][C:14](=[O:44])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:28][C@H:27]4[N:24]([C:25](=[O:36])[C@@H:26]4[C@H:29]([O:31][Si](C)(C)C)[CH3:30])[C:23]=3[C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])=[CH:18][C:17]=2[Cl:43])=[CH:10][N:9]=[CH:8]1)=[O:6])[CH:2]=[CH2:3].Cl.C(=O)(O)[O-]>C1COCC1.O.[Cl-].[Na+].O>[CH2:1]([O:4][C:5]([N:7]1[C:11]([CH2:12][NH:13][C:14](=[O:44])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:28][C@H:27]4[N:24]([C:25](=[O:36])[C@@H:26]4[C@H:29]([OH:31])[CH3:30])[C:23]=3[C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])=[CH:18][C:17]=2[Cl:43])=[CH:10][N:9]=[CH:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(c2ccc(CC(=O)NCc3cncn3C(=O)OCC=C)c(Cl)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C1=C(c2ccc(CC(=O)NCc3cncn3C(=O)OCC=C)c(Cl)c2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 77.8 %

Procedure:
Allyl (5R,6S)-3-(4-{2-[({1-[(allyloxy)carbonyl]-1H-imidazol-5-yl}methyl)amino]-2-oxoethyl}-3-chlorophenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.78 g, 1.22 mmol) prepared by step c) was dissolved in THF (23 ml) and water (11 ml), and the solution was cooled in a water bath. Thereto was gradually dropped using a pH meter, 0.1N hydrochloric acid to adjust pH to 3.0. Fifteen minutes later, pH of the solution was adjusted 6.8 by gradually dropping saturated bicarbonate solution thereto, and then saturated brine (50 ml) was added. The solution was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give allyl (5R,6S)-3-(4-{2-[({1-[(allyloxy)carbonyl]-1H-imidazol-5-yl}methyl)amino]-2-oxoethyl}-3-chlorophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.54 g, yield 78%) as a pale yellow amorphous.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.[CH2:23]([O:27]C1N=C(C(O)=O)C=CC=1)[CH2:24][CH2:25][CH3:26].S(Cl)(Cl)=O>C(O)CCC>[CH2:23]([O:27][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1)[CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)c1cccc(Cl)n1
Reactant: CCCCOc1cccc(C(=O)O)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: O=S(Cl)Cl
Product: CCCCOc1cccc(C(=O)OC)n1
Temperature: 25 °C
Yield: 78 %

Procedure:
To methyl 6-chloro-pyridine-2-carboxylate (2.58 g, 15.0 mmol, obtained from Example 17(a)) was added 1-butanol (35 mL) followed by sodium bis(trimethylsilyl)amide (5.51 g, 30.1 mmol). The suspension was warmed to 130° C. for 24 h after which more sodium bis(trimethylsilyl)amide (5.51 g, 30.1 mmol) was added. After another 24 h at reflux, the solution was cooled to r.t. and was poured into 200 mL 1N HCl in an ice bath. The aqueous solution was extracted twice with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo resulting in 3.79 g of crude 6-butoxy-pyridine-2-carboxylic acid. To the crude 6-butoxy-pyridine-2-carboxylic acid was added thionyl chloride (100 mL) and after 1 h the resulting solution was concentrated in vacuo. To the residue was slowly added anhydrous methanol (100 mL) and after stirring o.n., the solvents were removed in vacuo. The resulting 3.73 g of crude material was purified by silica gel column chromatography (hexanes/ethyl acetate, 8:1) resulting in 2.46 g of the title compound as a colourless oil (78% yield, 11.7 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH:4][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Solvent: Cc1ccccc1C
Product: CS(=O)(=O)Nc1cc(Cl)c(Cl)cc1Cl

Procedure:
A mixture of 2,4,5-trichloroaniline (39.3 g.), methane sulfonyl chloride (22.9 g. ) and 100 ml. of xylene were heated together under reflux conditions for 18 hours. The mixture was then allowed to cool, which formed a brown precipitate. The product was worked up in the same manner as set forth in Example 1 to yield 24.0 g. of product, m.p. 144°-145° C.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32].[CH3:41][C:42]1[S:43][C:44]([CH:48]=O)=[C:45]([CH3:47])[N:46]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32])=[CH:48]/[C:44]1[S:43][C:42]([CH3:41])=[N:46][C:45]=1[CH3:47]
Reactant: COC(=O)C(NC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: Cc1nc(C)c(C=O)s1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
1,1,3,3-Tetramethylguanidine (60 μL, 0.48 mmol) was added to a solution of rac.-(E)-N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 135; 116 mg, 0.24 mmol) in tetrahydrofuran (5 mL) at −20° C. After 10 min, 2,4-dimethylthiazole-5-carboxaldehyde (Example 43; 36 mg, 0.255 mmol) was added and the solution was stirred at room temperature for 16 h. The solvent was evaporated and ethyl acetate (10 mL) was added. The solution was washed with saturated sodium bicarbonate solution (10 mL) and brine (10 mL). Each aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were dried, filtered, evaporated and chromatographed (60% ethyl acetate/hexanes) to give rac.-(Z)-2-[[2-chloro-4-[(E)-1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (101 mg, 84% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5].[F:33][C:34]1[C:35](I)=[N:36][CH:37]=[CH:38][CH:39]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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]>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:35]2[C:34]([F:33])=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2ccc(Cl)c(C(=O)Nc3cc(C#N)nn3-c3ccccc3)c2)OC1(C)C
Reactant: Fc1cccnc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 100 °C
Yield: 48.8 %

Procedure:
To a degassed solution of 2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Preparation 7, 223 mg, 0.49 mmol) in dioxane (2 mL) was added 3-fluoro-2-iodopyridine (167 mg, 0.75 mmol), Pd(dppf)Cl2 (36 mg, 0.049 mmol), K2CO3 (206 mg, 1.49 mmol) and water (1 mL). The reaction was heated at 100° C. for 18 hours before cooling and concentrating in vacuo. The residue was suspended in DCM (20 mL) and filtered through a pad of celite. The filtrate was purified directly by silica gel column chromatography eluting with 0-80% EtOAc in heptanes to afford the title compound as a brown solid (100 mg, 48%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10])(=[O:3])[CH3:2].BrBr>C(Cl)(Cl)Cl>[CH2:14]([O:13][C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][O:3]2)=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(N)=O)c1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cc(C2CO2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
5-Acetyl-2-(phenylmethoxy)benzamide (10.0 g, 37.1 mmol) was dissolved in chloroform and brought to reflux. Bromine (1.98 g, 12.4 mmol) was added. The solution was allowed to cool to room temperature. After 10 minutes the bromine color had disappeared and a second portion of bromine was added. A third portion of bromine was added after the color had again discharged and the solution refluxed for a further 10 minutes. The flask was allowed to cool and placed in the freezer overnight. The solvent was removed in vacuo and the residue crystallized from ethanol to provide the title compound (11.3 g, 32.4 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4](Cl)[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: N#Cc1cc(I)c(N)cc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(I)c(N)cc1N1CCOCC1
Temperature: 100 °C
Reaction time: 40 h

Procedure:
To a flask containing 4-amino-2-chloro-5-iodobenzonitrile (1 g, 3.6 mmol) in DMSO (5.0 mL) was added morpholine (1.0 mL, 11.5 mmol) dropwise. Upon complete addition, the mixture was warmed to 100° C. After 40 h, the reaction mixture was cooled to rt, then an additional 2 mL of morpholine was added to the mixture. The reaction was re-heated to 100° C. and monitored with LC-MS. After 17 h, the reaction was cooled to rt, then 1 g of potassium carbonate was added in portions. The reaction was re-heated to 100° C. and monitored with LC-MS. After 13 days, the reaction was diluted with water then subsequently extracted five times with EtOAc. The organic extractions were then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-35% EtOAc in hexanes) to afford a pale brown solid as 4-amino-5-iodo-2-morpholinobenzonitrile. 1H NMR (500 MHz, CDCl3) δ ppm 7.80 (1H, m), 6.27 (1H, s), 4.57 (2H, br. s.), 3.92 (4H, m), 3.20 (4H, m). Mass Spectrum (pos.) m/e: 330.0 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[N:8]1([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:25]([OH:27])=[O:26])=[CH:21][NH:20][C:18]=3[N:19]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>C(O)=O>[CH:1]([N:11]1[CH2:10][CH2:9][N:8]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:25]([OH:27])=[O:26])=[CH:21][NH:20][C:18]=3[N:19]=2)[CH2:13][CH2:12]1)=[O:3]
Reactant: O=C(O)c1c[nH]c2nc(N3CCNCC3)ncc2c1=O
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN1CCN(c2ncc3c(=O)c(C(=O)O)c[nH]c3n2)CC1
Temperature: 50 °C

Procedure:
Formic acid (140 ml) was added dropwise to acetic anhydride (200 ml) cooled on an ice bath. The solution was heated at 50° C. for 15 minutes and then cooled to 5° C. To the solution, 5,8-dihydro-2-(1-piperazinyl)-5-oxopyrido[2,3-d] pyrimidine-6-carboxylic acid (70 g) was added. The mixture was heated at 80° C. for 3 hours and then cooled. The crystals precipitated were collected by filtration and washed with ethyl ether to give 5,8-dihydro-2-(4-formyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (72.5 g). m.p. above 300° C.