Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][N:8]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[CH:22][CH:21]=3)=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[I-].[CH3:37][N+:38](=[CH2:40])[CH3:39]>O1CCCC1.CCOCC>[CH:3]1[C:13]2[CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][N:8]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N:26]([CH2:37][N:38]([CH3:40])[CH3:39])[C:27](=[O:35])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[CH:22][CH:21]=3)=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C=[N+](C)C
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccccc1C(=O)N(CN(C)C)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a suspension of 14 mg of 60% sodium hydride in oil, in 2 ml of tetrahydrofuran is added 0.13 g of N-[4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2-methylbenzamide. The reactants are stirred for 1 hour and 62 mg of N,N-dimethyl-methylene ammonium iodide added followed by stirring for 2 hours. The mixture is diluted with 10 ml of ether and filtered. The filtrate is evaporated in vacuo to a residue which is stirred with hexanes to give 0.13 g of the desired product as a white solid, m.p. 131°-133° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(COc2ccc(OC[C@H]3CCCN3C(=O)OC(C)(C)C)cc2)c1
Yield: 53.2 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 3-methoxy-benzyl bromide (120 mg, 0.6 mmol) to afford the title product (110 mg, 53% yield); LCMS; 100% APCI+, Calcd: 413.56. Found m/z: 414.29 (M+1). 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.28-3.46 (m, 2H), 3.69-3.91 (m, 1H), 3.82 (s, 3H), 4.02-4.18 (m 2H), 4.99 (s, 2H), 6.82-6.90 (m, 5H), 6.96-7.05 (m, 2H), 7.26-7.30 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C)=[O:29])=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C1COCC1.CO>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:25][CH:26]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC(Oc1ccc(CC(=O)OC)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(CC(=O)O)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.3 %

Procedure:
A solution of methyl {4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetate (329 mg, 0.72 mmol) in THF (9.5 mL) and methanol (9.5 mL) was treated with aqueous NaOH (2M, 9.5 mL) drop-wise and the resulting solution stirred at rt for 17 hours. The volatile solvents were then removed under vacuum and the resulting aqueous mixture acidified with aqueous HCl (2M, 15 mL), diluted with water (100 mL) and the product extracted with DCM (2×100 mL). The combined organic layers were then washed with brine (100 mL), dried (MgSO4), filtered and then reduced under vacuum to give the title compound as a pale yellow foam (314 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1>>[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]=[O:12])[CH:14]=1
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2ccc3[nH]cc(C=O)c3c2)c1
Yield: 85 %

Procedure:
5-Bromo-1H-indole-3-carbaldehye was reacted with m-tolylboronic acid as described for 3-6 and 3-7. Yield: 85%; 1H NMR (300 MHz, CDCl3): δ 9.91 (s, 1 H), 8.43 (s, 1 H), 7.66 (s, 1 H), 7.36 (d, J=7.5 Hz, 1 H), 7.20 (d, J=8.7, 1 H), 4.11 (t, J=7.2 Hz, 2 H), 1.85 (t, J=6.3 Hz, 2 H), 1.30-1.24 (m, 10 H), 0.86 (t, J=6 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ 184.1, 138.7, 135.8, 126.8, 126.8, 124.7, 117.3, 116.4, 111.4, 47.4, 32.7, 31.6, 29.6, 29.0, 26.7, 22.5, 14.0.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)(=[O:31])=[O:30])[C:9]1[CH:28]=[CH:27][C:12]2[N:13]([CH3:26])[C:14]([CH2:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[NH:22])=[CH:19][CH:18]=3)=[N:15][C:11]=2[CH:10]=1)=[O:6])[CH3:3].Cl[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>CC(C)=O.O>[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)(=[O:30])=[O:31])[C:9]1[CH:28]=[CH:27][C:12]2[N:13]([CH3:26])[C:14]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:23])=[N:22][C:43]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[O:44])=[CH:24][CH:25]=3)=[N:15][C:11]=2[CH:10]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OCc3ccccc3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-ethyloxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and benzyl chloroformate in acetone/water.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[N:5][N:4]=[N:3]1>[OH-].[OH-].[Pd+2].CO.CCOC(C)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1nnnc1-c1ccc(N)cc1
Yield: 95.4 %

Procedure:
1-Methyl-5-(4-nitro-phenyl)-1H-tetrazole (470 mg), 20% Pd(OH)2 (94 mg), and 1:1 MeOH/EtOAc (25 ml), were hydrogenated at 50 PSI for 1 hour. The reaction was filtered through fiberglass filter paper under nitrogen. The filtrate was stripped to yield 383 mg of yellow solids as product. Mass Spec detects 176 (M+H). NMR (300 MHz, CDCl3) δ 7.57 (d, 2H, J=7 Hz), 6.80 (d, 2H, J=7 Hz), 4.14 (s, 3H), 4.03 (M, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=O)(C)(C)C>C(Cl)Cl.Cl.O1CCOCC1>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[C@@H:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1)[CH3:31]
Reactant: CCOC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(Cl)cc1[C@H]1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (790 mg, 1.77 mmol, 1.0 eq.) in DCM (3 mL), 4M HCl in dioxane (7.4 mL) was added. The resulting solution was stirred at r.t. for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was coevaporated with EtOH (3×). To a solution of the residue in EtOH (2 mL), conc. H2SO4 (0.18 mL) was added. The solution was stirred at r.t. for 18 hours. Water and 5% aq. NaOH soln. were added and the mixture was extracted with Et2O (3×10 mL). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[F:27][C:14]([F:13])([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-(trifluoromethoxy)benzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (29.1 mg) with purity >90%. MS (pos) m/z 411.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([C@@H:17]([CH3:19])[OH:18])[NH:5][C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([C@@H:17]([CH3:19])[O:18][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[NH:5][C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](NC(=O)COc1ccc(Cl)cc1)[C@@H](C)O
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NC(=O)COc1ccc(Cl)cc1)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
After the reaction was completed, the mixture was extracted twice with ethyl ether to eliminate unreacted p-chlorophenoxychloride, and the extracted aqueous phase was acidified with hydrochloric acid to precipitate a product which was then extracted three times with ethyl acetate. The extract was evaporated to dryness, and the residue was recrystallized from ethyl acetate/benzene/hexane to obtain a color-less crystal of N-(p-chlorophenoxy)acetyl-L-threonine. To a solution of 5 m moles of N-(p-chlorophenoxy)acetyl-L-threonine in ethyl ether, a solution of an excess amount of diazomethane in ethyl ether was added, and the mixture was allowed to stand for 30 minutes at a room temperature. The mixture was evaporated to dryness under a reduced pressure to obtain N-(p-chlorophenoxyacetyl)-L-threonine methyl ester. 3.4 m moles of N-(p-chlorophenoxyacetyl)-L-threonine methyl ester was dissolved in dried pyridine, and the resulting solution was added with 3.6 m moles of p-toluenesulfonyl chloride, stirred at 0° C. for two hours and at a room temperature for two hours. The reaction mixture was then partitioned between water and ethyl acetate, and organic phase was washed with 1N hydrochloric acid and water, and dried on anhydrous sodium sulfate. The solution was evaporated to dryness, and the resulting residue was purified by a middle pressure column chromatography with silica gel to obtain N-(p-chlorophenoxyacetyl)-O-(p-toluenesulfonyl)-L-threonine methyl ester. 0.5 m moles of N-(p-chlorophenoxyacetyl)-O-(p-toluenesulfonyl)-L-threonine methyl ester was then dissolved in 10 ml of methanol, the resulting solution was added with 1.5 ml of 1N sodium hydroxide and stirred for 20 minutes at a room temperature, and methanol was distilled off. The residue was acidified with 1N hydrochloric acid, and extracted with ethyl ether, and an organic phase was dried on anhydrous magnesium sulfate. Solvent was distilled off from the mixture to obtain a residue. The residue was then chromatographically purified to obtain the title compound N-(p-chlorophenoxyacetyl)-α,β-dehydrohomoalanine.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[C:38]([F:46])=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]([C:50]1[CH:51]=[C:52]([C:55](O)=[O:56])[S:53][CH:54]=1)([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[F:46][C:38]1[C:39]([CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:52]3[S:53][CH:54]=[C:50]([CH:47]([CH3:49])[CH3:48])[CH:51]=3)=[O:56])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: CC(C)c1csc(C(=O)O)c1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1csc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.2 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.13 g), 4-isopropylthiophene-2-carboxylic acid (example 74, step b) (0.07 g) and triethylamine (0.23 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic layer was washed with brine (2×100 mL), dried over sodium sulphate, filtered and evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.23 g.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:13](=O)([O-:16])[O:14]C.[Mg+2].COC(=O)[O-].Cl>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:13]([OH:16])=[O:14]
Reactant: Oc1cccc2c(O)cccc12
Reactant: COC(=O)[O-]
Agent: Cl
Agent: [Mg+2]
Product: O=C(O)c1ccc2c(O)cccc2c1O
Temperature: 0 °C

Procedure:
1,5-dihydroxy-naphthalene (5.04 g, 31.4 mmol) and magnesium methyl carbonate (2 M in DMF, 34.0 mL), 273 g of ice, 2M HCl (85.0 mL)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([NH2:10])=[CH:7][CH:6]=1)=[O:4].[OH:11][C:12](=[C:17]1C(=O)OC(C)(C)[O:19][C:18]1=O)[CH2:13][C:14](=O)[CH3:15].CS(O)(=O)=O>O1CCOCC1.C1(C)C=CC=CC=1>[OH:11][C:12]1[CH:13]=[C:14]([CH3:15])[N:10]([C:8]2[O:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[C:18](=[O:19])[CH:17]=1
Reactant: CC(=O)CC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: COC(=O)c1ccc(N)o1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-n2c(C)cc(O)cc2=O)o1
Temperature: 98 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
To a room temperature solution of methyl-2-amino-5-furoate (4.85 g, 34.4 mmol) in 1,4 dioxane (28.0 mL) was added 5-(1-hydroxy-3-oxobutylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.16 g, 44.3 mmol). The reaction was stirred vigorously and heated quickly (within 8 minutes) to an internal temperature of 98° C. Upon reaching temperature, the reaction was maintained for 1.0 hour. At this time, the reaction was cooled to room temperature rapidly using an ice-bath and methane sulfonic acid (3.30 g, 34.4 mmol) was added. The reaction mixture was once again brought to an internal temperature of approximately 100° C. After 1.0 hour the reaction was diluted with 10 mL of toluene and allowed to cool to room temperature on its own accord. A solid formed after 3.0 hours that was collected and subsequently recrystallized from methanol/ethyl acetate (1:1). The developing crystals were allowed to form and stand for 12.0 hours prior to collection to furnish the desired product as a solid (3.78 g, 44%). 1H NMR (400 MHz, d7-DMF) δ 11.34 (s, 1H), 7.43 (app d, J=3.6 Hz, 1H), 6.79 (app d, J=3.6 Hz, 1H), 6.01 (s, 1H), 5.63 (d, J=2.0 Hz, 1H), 3.87 (s, 3H), 2.02 (s, 3H); LC/MS C-18 column, tr=1.47 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 250 (M+H). ES-HRMS m/z 250.0696 (M+H calcd for C12H12NO5 requires 250.0710). Step 2: Preparation of methyl 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-furoate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([NH:9][NH2:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH:18]=O.C(O)C>S(=O)(=O)(O)O.O>[F:13][C:14]([F:27])([F:28])[C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=1)[CH:18]=[N:10][NH:9][C:7](=[O:8])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=1)[OH:12]
Reactant: NNC(=O)c1cc(Cl)ccc1O
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: O=C(NN=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A mixture of 5-chlorosalicylhydrazide (213.9 mg, 1.2 mmol), 3,5-bis(trifluoromethyl)benzaldehyde (190 μL, 1.2 mmol), concentrated sulfuric acid (3 drops) and ethanol (5 mL) was refluxed for 30 minutes. 3,5-Bis(trifluoromethyl)benzaldehyde (100 μL, 0.61 mmol) was added and the mixture was refluxed for further 1 hour. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→2:1) and washed with n-hexane under suspension to give the title compound (362.6 mg, 76.8%) as a white powder.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].C(O[CH:12](OCC)[N:13]([CH3:15])[CH3:14])C.C(O)C.C>C(OCC)C>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:4][C:2](=[O:3])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)=O
Reactant: CCOC(OCC)N(C)C
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)C=CN(C)C
Temperature: 5 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
Ethyl pyruvate (1,500 g) is added in the course of 2 hours, while the temperature is maintained at approximately 5° C., to N,N-dimethylformamide diethyl acetal (2,100 g) cooled to a temperature in the region of 5° C. The mixture is then stirred for 3 hours at a temperature in the region of 20° C. The reaction ethanol is evaporated off to dryness and the residue obtained is pounded with diethyl ether (12 liters) and charcoal 3S (30 g) and then filtered on supercel. The filtrate is taken up with water (500 cc), and the organic phase is decanted and the aqueous phase is extracted with dichloromethane (3×2000 cc). The organic phases are mixed, dried over sodium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The oil obtained is purified by distillation (b.p.0.1 mm Hg 146°-149° C.). Ethyl 4-dimethylamino-2-oxo-3-butenoate (695 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][NH2:14])=[CH:8][CH2:7][CH2:6]2>C(O)(=O)C>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][NH2:14])[CH2:8][CH2:7][CH2:6]2
Reactant: NCC1=CCCc2cc(F)ccc21
Agent: Cl
Solvent: CC(=O)O
Product: NCC1CCCc2cc(F)ccc21

Procedure:
The product from Example 74 was reduced as in Example 2 but replacing the NH3 with acetic acid and afforded the desired compound, m.p. 236°-38° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[C:10]([F:13])([F:12])[F:11].[NH3:14]>O1CCCC1>[NH2:14][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: Fc1cc(F)c(C(F)(F)F)c(F)c1
Reactant: N
Solvent: C1CCOC1
Product: Nc1cc(F)cc(F)c1C(F)(F)F
Temperature: 120 °C

Procedure:
In a stainless steel autoclave, 200 ml of tetrahydrofuran and 50 g of 2,4,6-trifluorobenzotrifluoride are introduced, and 30 ml of liquid ammonia are pressed on. The mixture is then heated at 120° C. for 6 hours, with stirring. The reaction mixture is cooled, the pressure is released, and the mixture is subjected to fractional distillation. At a boiling point of 57° to 58° C. at 12 mbar, 15 g of 2-amino-4,6-difluoro-benzotrifluoride are obtained. After a small intermediate cut, 32 g of 2,6-difluoro-4-amino-benzotrifluoride distil over at a boiling point of 103° to 105° C. at 16 mbar. Melting point of the resultant 2,6-difluoro-4-amino-benzotrifluoride: 66° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.CN(C)C1C=CC=CC=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1)=[O:27]
Reactant: O=C(Cl)CCCCCBr
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Solvent: CN(C)c1ccccc1
Product: O=C(CCCCCBr)Nc1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
was prepared in 89% yield from 24.4 g (0.14 mol) of 4-amino-2,6-dichlorophenol, 18.1 g (0.15 mol) of N,N-dimethylaniline and 28.8 g (0.14 mol) of 6-bromohexanoyl chloride according to the procedure of Example 6, part a, except that the reaction was cooled on ice during the addition and was stirred at room temperature rather than refluxed. The product was crystallized from ethanol-water, mp 113°-114° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][C:6]([C:17]([F:20])([F:19])[F:18])=[CH:5][N:4]=1)#[N:2].[CH3:21][N:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=[O:24]>>[C:1]([C:3]1[C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:23](=[O:24])[N:22]([CH3:21])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:14][CH:15]=2)=[CH:7][C:6]([C:17]([F:20])([F:18])[F:19])=[CH:5][N:4]=1)#[N:2]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: N#Cc1ncc(C(F)(F)F)cc1Oc1ccc(O)cc1
Product: CN(C(=O)Oc1ccc(Oc2cc(C(F)(F)F)cnc2C#N)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(2-cyano-5-trifluoromethyl-pyridin-3-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (74%, colourless oil). HPLC-MS m/z=414.1 (M+1), Rt: 4.8 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1)=C.O.I([O-])(=O)(=O)=[O:23].[Na+]>C1COCC1.[Os](=O)(=O)(=O)=O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1)=[O:23]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1nnc2ccc(C=O)nn12
Reaction time: 0.08 h
Yield: 72 %

Procedure:
Tert-butyl (6-vinyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (485 mg, 1.76 mmol) was dissolved in 5 mL of THF and 5 mL of water then osmium tetroxide (0.687 mL (4% water solution), 0.0176 mmol) was added and stirred for 5 min. Sodium periodate was added (141, 3.53 mmol) and the reaction was stirred for 2 h. The reaction was then extracted with dichloromethane (3×10 mL), dried over Na2SO4 and concentrated. Purification via MPLC (DCM/MeOH+1% NH4OH) afforded title compound as a tan solid (350 mg, 72% yield).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])Cl.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]#[C:15][CH3:16].C(N(CC)CC)C>C(OCC)C>[CH2:19]([O:18][C:13]([C:14]1[C:4]([C:3]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:2]=2[F:1])=[N:6][O:7][C:15]=1[CH3:16])=[O:17])[CH3:20]
Reactant: CC#CC(=O)OCC
Reactant: ON=C(Cl)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2ccc(F)cc2F)noc1C
Yield: 58.3 %

Procedure:
In a fashion similar to that for preparation 15, 2,4-difluorobenzoyl chloride oxime (2.00 g, 10.4 mmol), ethyl 2-butynoate (1.76 g, 15.7 mmol), triethyl amine (2.9 ml, 21 mmol) in diethyl ether (10 ml), and diethyl ether 30 ml) gave 4-ethoxycarbonyl-5-methyl-3-(2,4-difluorophenyl)isoxazole (1.62 g, 58%) after column chromatography (silica gel, hexanes/diethyl ether gradient).