Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)[O:9][N:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:14](=[O:16])[CH2:13][CH2:12][C:10]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:11]=2)[CH2:38][CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)CCc1nc(-c2ccccn2)no1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(CCc1nc(-c2ccccn2)no1)NC1CCN(Cc2ccccc2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(3-Pyridin-2-yl-[1,2,4]oxadiazol-5-yl)-propionic acid (1 g) in tetrahydrofuran (5 ml), was added carbonyldiimidazole (0.74 g). The mixture was stirred for 10 minutes before addition of 1-benzyl-piperidin-4-ylamine (1 ml) in tetrahydrofuran (5 ml). The reaction mixture was stirred for 15 minutes then partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, dried (MgSO4) and solvent removed by evaporation. Purification by Biotage® 40S eluting 3%MeOH/0.5% 880 ammonia/dichloromethane gave the title compound (0.93 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]([CH2:22][CH3:23])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:22]([N:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=1)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:23]
Reactant: CCOC(=O)CN(CC)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CN(CC)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.6 %

Procedure:
To a solution of ethyl 2-((3-(benzyloxy)phenyl)(ethyl)amino)acetate (960 mg) in methanol (30 mL) was added 10% palladium-activated carbon (300 mg) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (360 mg) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Cl[CH2:34][C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=2[CH:50]=1>>[CH3:49][O:48][CH2:47][CH2:46][CH2:45][N:40]1[C:39]2[CH:50]=[C:35]([CH2:34][O:1][CH:2]3[CH:7]([C:8]4[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]5[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=5)=[CH:12][CH:13]=4)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]3)[CH:36]=[CH:37][C:38]=2[O:43][CH2:42][C:41]1=[O:44]
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: Cc1cccc(OCCCOc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3O)cc2)c1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cccc(C)c4)cc3)cc21

Procedure:
Analogously to Method D, 1.10 g of tert-butyl 3-hydroxy-4-[4-(3-m-tolyloxypropoxy)phenyl]piperidine-1-carboxylate and 0.693 g 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a colourless oil. Rf=0.60 (1:1 EtOAc-heptane); Rt=6.14.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[CH:12].[CH2:13]([N:15]([CH2:25][CH3:26])[C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1I)[CH3:14].C1(NC2CCCCC2)CCCCC1.C(#N)C>CCOCC.[Cu]I>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:16]([N:15]([CH2:13][CH3:14])[CH2:25][CH3:26])=[O:24]
Reactant: C#CCCOCCCCCCBr
Reactant: CCN(CC)C(=O)c1ccccc1I
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccccc1CCCCOCCCCCCBr
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 38 %

Procedure:
A mixture of CuI (20 mg), 1-bromo-6-[(3-butynyl)oxy]hexane (3.04 g), N,N-diethyl-2-iodobenzamide (3.95 g), BTPC (200 mg), N,N-dicyclohexylamine (2.60 g) and acetonitrile (20 ml) was stirred under nitrogen at room temperature for 4.5 h, diluted with ether (200 ml) and filtered. The filtrate was evaporated in vacuo, the residue in ethanol (100 ml) was treated with charcoal and the solvent evaporated in vacuo. The residual oil (5.32 g) in absolute ethanol (190 ml) was hydrogenated over pre-reduced 10% PDO-C (50% paste in water, 1.25 g) in absolute ethanol (20 ml), filtered through hyflo and evaporated in vacuo to give an oil. Purification by FCC eluting with T-EA-triethylamine (95:5:1) followed by FCC eluting with CX-EA (2:1) gave the title compound as a yellow oil (2.04 g). T.l.c. (T-ET-A-40:10:1) Rf 0.14.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:14]=4[N:15]=3)[C:6]=2[CH:23]=1.[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.CC(C)([O-])C.[Na+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][C:17]1([CH3:22])[CH2:16][C:14]2[N:15]=[C:11]([N:7]3[C:6]4[CH:23]=[C:2]([NH:24][C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)[S:12][C:13]=2[C:19](=[O:20])[CH2:18]1
Reactant: Nc1cccnc1
Reactant: CC1(C)CC(=O)c2sc(N3CCOc4ccc(Cl)cc43)nc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: CC1(C)CC(=O)c2sc(N3CCOc4ccc(Nc5cccnc5)cc43)nc2C1
Temperature: 25 °C
Yield: 8.8 %

Procedure:
A mixture of Example 7 (50 mg, 0.14 mmol), 3-aminopyridine (0.171 g, 1.8 mmol), sodium tert-butoxide (0.041 g, 0.43 mmol), palladium(II) acetate (0.158 g, 0.70 mmol) and (But)3PBF4 (0.225 g, 0.78 mmol) in THF (3 mL) was heated to 140° C. under microwave irradiation for 80 min. After cooling to r.t., the mixture was concentrated in vacuo. The crude material was purified by prep HPLC to give the title compound as an off-white solid (5 mg, 8.7%). δH (CDCl3) 1.16 (6H, s), 2.44 (2H, s), 2.78 (2H, s), 4.12-4.22 (2H, m), 4.31-4.41 (2H, m), 5.75 (1H, br s), 6.84-6.89 (1H, m), 6.92-6.96 (1H, m), 7.20 (1H, dd, J 8.7, 5.1 Hz), 7.37-7.44 (1H, m), 7.87 (1H, d, J 2.6 Hz), 8.14 (1H, d, J 4.7 Hz), 8.33 (1H, d, J 2.8 Hz). LCMS (ES+) 407.0 (M+H)+.
Reaction SMILES: [CH:1]1([CH:5]([OH:17])[C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.O.O.[OH-].[Li+]>CO>[CH:1]1([CH:5]([OH:17])[C:6]2[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(C(O)C2CCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(O)C2CCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
To a flask containing ethyl 4-(cyclobutyl(hydroxy)methyl)benzoate (530 mg, 2.26 mmol) was added tetrahydrofuran (5.60 mL), water (5.60 mL), and methanol (5.60 mL). Lithium hydroxide monohydrate (475 mg, 11.3 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 490 mg of crude material. Purification by silica gel flash chromatography (0-20% ethyl acetate in heptane) afforded 4-(cyclobutyl(hydroxy)methyl)benzoic acid (360 mg, 77%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.2 Hz, 2H), 7.43 (dd, J=8.0, 1.0 Hz, 2H), 4.67 (d, J=7.6 Hz, 1H), 2.62 (d, J=8.0 Hz, 1H), 2.09-1.98 (m, 2H), 1.91-1.80 (m, 4H). MS (M−1): 205.2.
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]#[N:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[CH2:14][CH2:15][CH2:16]Br.[OH-].[K+].Cl>CCOCC.CS(C)=O>[S:1]1[C:5]([C:6]2([C:7]#[N:8])[CH2:16][CH2:15][CH2:14]2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: BrCCCBr
Reactant: N#CCc1cc2ccccc2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CC1(c2cc3ccccc3s2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of benzo[b]thiophen-2-acetonitrile (8.05 g) and 1,3-dibromopropane (5.2 ml) in ether (50 ml) was added dropwise under nitrogen over 1 hour to a stirred, ice-cold suspension of finely-powdered potassium hydroxide (13.53 g) in dimethyl sulphoxide (100 ml). When the addition was complete, the mixture was stirred at ambient temperature for 4 hours, then it was added to ice-cold water (200 ml). The resulting mixture was acidified to pH4 by the addition of concentrated hydrochloric acid, then the product was extracted into ether (3×200 ml). The combined extracts were washed with water (500 ml), dried (MgSO4), and the solvent was removed in vacuo to give 1-(benzo[b]thiophen-2-yl)cyclobutanecarbonitrile as a red oil (8.16 g) which was used without purification.
Reaction SMILES: O=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[NH:3]1.O.[OH-].[NH4+].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[N:3]=[C:4]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1cccnc1-c1cc2cccnc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1cccnc1-c1cc2cccnc2c(Cl)n1
Temperature: 0 °C

Procedure:
Heat a mixture of 8-oxo-6-(3-methyl-2-pyridinyl)-1,7-naphthyridine (16.4 g, 69.1 mmol) in phosphorus oxychloride (200 mL) on a steam bath for 3 hours. Remove excess phosphorus oxychloride under reduced pressure, cool in an ice-water bath and add ice (100 g) and water (100 mL). Add concentrated ammonium hydroxide to neutralize the solution, while maintaining the temperature below 10° C. Filter the resultant mixture, air dry the solids and triturate with boiling benzene (1 L). Concentrate the mixture, filter and crystallize the isolated solid from benzene to obtain the title compound, mp 130-1° C.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:69]/[O:70][CH3:71])/[C:27]([NH:29][CH:30]2[C:67](=[O:68])[N:32]3[C:33]([C:51]([O:53]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:52])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N:40]4[C:44]5[CH:45]=[C:46]([OH:50])[C:47]([OH:49])=[CH:48][C:43]=5[N:42]=[CH:41]4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(OC(C)C)(C)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:69]/[O:70][CH3:71])/[C:27]([NH:29][CH:30]2[C:67](=[O:68])[N:32]3[C:33]([C:51]([OH:53])=[O:52])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N:40]4[C:44]5[CH:45]=[C:46]([OH:50])[C:47]([OH:49])=[CH:48][C:43]=5[N:42]=[CH:41]4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cn3cnc4cc(O)c(O)cc43)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(/C=C/Cn3cnc4cc(O)c(O)cc43)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-3-(5,6-dihydroxybenzimidazol-1-yl)-1-propen-1-yl]-3-cephem-4-carboxylate (XIn) (171 mg, 0.175 mmol), anisole (0.5 ml) and TFA (4 ml) was stirred for an hour at room temperature. The mixture was diluted with isopropyl ether to precipitate a crude product. The product was chromatographed on a column of Prep C18 (Waters, 20×300 mm), and the column was eluted successively with 10% MeOH/H2O, 15% MeOH/H2O and 25% MeOH/H2O. The eluate was monitored by UV absorption at 254 nm and the fractions showing UV absorption were further checked by HPLC.*The fractions containing the desired product were combined and concentrated in vacuo. The concentrate was freeze-dried to give 52 mg (52% yield) of the title product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([CH3:39])[CH3:38])[CH:32]=2)[CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].O.C1(C)C=CC=CC=1>[CH:37]([C:33]1[CH:32]=[C:31]([C:29]2[CH:30]=[CH:25][N:26]=[C:27]([C:14]3[C:9]4[O:8][C:6]5[C:5]([C:10]=4[CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=5)[CH:28]=2)[CH:36]=[CH:35][CH:34]=1)([CH3:39])[CH3:38]
Reactant: Cc1ccc2c(n1)oc1c(B3OC(C)(C)C(C)(C)O3)cccc12
Reactant: CC(C)c1cccc(-c2ccnc(Cl)c2)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(n1)oc1c(-c3cc(-c4cccc(C(C)C)c4)ccn3)cccc12
Yield: 57 %

Procedure:
A mixture of 2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuro[2,3-b]pyridine (3.15 g, 10.2 mmol), 2-chloro-4-(3-isopropylphenyl)pyridine (2.60 g, 11.2 mmol), Pd2(dba)3 (0.187 g 0.204 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.335 g, 0.815 mmol), potassium phosphate (7.57 g, 35.7 mmol), toluene (90 mL) and water (9 mL) was degassed with nitrogen and then refluxed overnight. The toluene layer was dried on Na2SO4 and then further purified by column chromatography using dichloromethane in hexanes and then vacuum distilled to give 8-(4-(3-Isopropylphenyl)pyridine-2-yl)-2-methylbenzofuro[2,3-b]pyridine (2.2 g, 57% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](OCC)=[O:16].CC[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[C:15]([OH:16])[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=2[C:12]([F:11])([F:24])[F:25])[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccccc1C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC(=C(O)c1ccccc1C(F)(F)F)c1ccc(Cl)cc1
Yield: 50.9 %

Procedure:
5.8 g of 4-chlorobenzyl cyanide, 10 g of ethyl 2-trifluoromethylbenzoate and 2.9 g of sodium ethylate were added to 100 ml of toluene and then reacted for 8 hours under reflux. The reaction mixture was returned to room temperature and extracted by an addition of 200 ml of water. The aqueous phase was adjusted to pH 6 to 7 with 6N hydrochloric acid and then extracted by an addition of 400 ml of methylene chloride. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.3 g of the desired product. The NMR spectrum data of this product were the same as in Reference Preparation Example 3.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[CH2:5][CH2:6][OH:7].[Cl:9][C:10]1[CH:11]=[C:12]([N:17]=[C:18]=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>O1CCCC1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:19])[O:7][CH2:6][CH2:5][CH:3]2[CH2:4][C:2]2([F:8])[F:1])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: OCCC1CC1(F)F
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)OCCC1CC1(F)F

Procedure:
2 g (16 mmol) 2-(2,2-Difluorocyclopropyl)ethanol, dissolved in 5 ml tetrahydrofuran (THF) was treated with 3 g (16 mmol) of 3,4-dichlorophenyl isocyanate. After 6 hours reaction time at room temperature, the mixture was concentrated in vacuo and the residue recrystallised from cyclohexane. A sample was analysed by thin layer chromatography (hexane:ethyl acetate=1:1) (Rf=0.54).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl[CH2:30][C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([O:14][CH2:30][C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OCC(=O)N(CC)CC)n1Cc1ccccc1Cl
Temperature: 70 °C

Procedure:
A solution of (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid (Example 1) (5 mmol) in dry dimethylformamide (10 mL) was treated with 2-chloro-N,N-diethyl-acetamide (5.51 mmol) followed by powdered potassium carbonate. This mixture was heated at 70° C. for 7 hours, diluted with water and extracted with ethyl acetate. The water-washed, dried, concentrated product solidifies and after trituration with ether/hexane affords the title ester; mp 139°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[C:11]([C:13](=[CH:22]OCC)[C:14]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])#[N:12]>C(O)C>[C:11]([C:13](=[CH:22][NH:4][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:5]=1[Cl:10])[C:14]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])#[N:12]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1c(Cl)cc(Cl)cc1Cl

Procedure:
2,4,6-Trichloroaniline (0.04 mol) is reacted with α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (0.04 mol) by heating at reflux in ethanol to yield α-cyano-β-(2,4,6-trichloroanilino)-N-ethoxycarbonylacrylamide, which is cyclized by heating at reflux in 1,2-dichlorobenzene to yield crude product which is chromatographed on silica eluting with chloroform/acetone (3/1) to 5-cyano-1-(2,4,6-trichlorophenyl)uracil, pale yellow crystals, m.p. 245°-247°.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:11]C)[CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(F)c(F)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
A solution of 5.8 g (33.7 mmol) of 4,5-difluoro-2-methoxybenzaldehyde in 400 ml of anhydrous dichloromethane was treated dropwise at -70° while stirring over a period of 10 minutes with 37 ml (37 mmol) of a 1 M boron tribromide solution in dichloromethane. Subsequently, the mixture was stirred at room temperature for 16 hours, poured on to 400 ml of ice-water and the phases were separated. The aqueous phase was extracted once with 400 ml of dichloromethane and the combined organic phases were washed once with 200 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (hexane/ethyl acetate 4:1). There were obtained 5.05 g (94%) of 4,5-difluoro-2-hydroxybenzaldehyde as a white solid with m.p. 64°.
Reaction SMILES: C[O:2][C:3](=O)[C@@:4]([O:12][C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[C:15]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[N:14]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5]>CC(O)=O.[Fe]>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:15]1[CH:16]=[CH:17][C:18]2[NH:19][C:3](=[O:2])[C@:4]([CH3:5])([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[O:12][C:13]=2[N:14]=1
Reactant: COC(=O)[C@@](C)(Oc1nc(NCc2ccc(OC)cc2OC)ccc1[N+](=O)[O-])c1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc3c(n2)O[C@@](C)(c2ccccc2)C(=O)N3)c(OC)c1
Temperature: 60 °C
Yield: 76.3 %

Procedure:
To (S)-2-[6-(2,4-dimethoxy-benzylamino)-3-nitro-pyridin-2-yloxy]-2-phenyl-propionic acid methyl ester (253 mg, 0.54 mmol) in AcOH (7 mL) was added Fe-powder (242 mg, 4.32 mmol). The mixture was heated at 60° C. for 3 hours and then allowed to cool. The mixture was evaporated in vacuo and then the residue was purified using SiO2 chromatography (1-1.5% MeOH/CH2Cl2) to give (S)-6-(2,4-dimethoxy-benzylamino)-3-methyl-3-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2-one (167 mg) as a beige solid. MS: [M+H]+=406.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]#[N:43])[CH:37]=3)=[CH:32][C:31]=2[C:44]2[C:45]([N+:55]([O-:57])=[O:56])=[N:46][N:47](C3CCCCO3)[CH:48]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.O1CCOCC1>Cl>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]#[N:43])[CH:37]=3)=[CH:32][C:31]=2[C:44]2[C:45]([N+:55]([O-:57])=[O:56])=[N:46][NH:47][CH:48]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4cccc(C#N)c4)cc3-c3cn(C4CCCCO4)nc3[N+](=O)[O-])cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc(Oc3cc(F)c(S(=O)(=O)Nc4nncs4)cc3Cl)c(-c3c[nH]nc3[N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.5 %

Procedure:
5-Chloro-4-(3′-cyano-3-(3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)biphenyl-4-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 63, 447 mg, 0.537 mmol) was dissolved in a 4M solution of HCl in 1,4-dioxane (2.7 mL, 10.74 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was purified by reverse phase chromatography on the ISCO™ system to afford the title compound (204 mg, 64%) as a white solid.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Br)[N:18]=1.O>CN(C=O)C>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:3]3[CH2:7][CH2:6][CH2:5][CH2:4]3)=[CH:14][CH:13]=2)[N:18]=1
Reactant: Oc1ccc(CN2CCCC2)cc1
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(Oc2ccc(CN3CCCC3)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of NaH (2.6 g, 108.5 mmol) in DMF (300 mL) at 0° C., under N2, a solution of 4-pyrrolidin-1-ylmethylphenol (16 g, 90.4 mmol) was added slowly. After stirring at 0° C. for 30 min, 2,6-dibromopyridine (23.6 g, 99.4 mmol) was added and the resulting mixture was heated at 95° C. for 20 h. After cooling to RT, 200 mL of H2O was added and the mixture was extracted with EtOAc (3×300 mL). The combined organic layer was washed with brine (3×400 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as an amber solid. This was used crude in the next step. MS m/z: 333 (M+1). Calc'd for C16H17BrN2O-333.2