Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:10][CH2:9][S:8][CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[O:20][CH:29]([CH3:31])[CH3:30])[CH2:6][CH2:7][S:8][CH2:9][CH2:10]1)=[O:4]
Reactant: CC(C)Br
Reactant: COC(=O)C1(NC(=O)c2cccc(C)c2O)CCSCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)CCSCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a suspension of 4-(2-hydroxy-3-methyl-benzoylamino)-tetrahydro-thiopyran-4-carboxylic acid methyl ester (27) (98 mg, 0.32 mmol), anhydrous Cs2CO3 (208 mg, 0.64 mmol), and KI (11 mg, 0.06 mmol) in DMF (5 mL) is added 2-bromopropane (150 μL, 1.6 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (20 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (80 g silica gel, gradient elution: 5-40% EtOAc in heptane) to give a pure product (28) as white solid (92 mg, 81%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)([CH3:3])[CH3:2].O.[O:18]1CCOCC1>O1CCOCC1>[CH:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:18])([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: COc1ccc2c(c1OC(C)C)CCCC2
Solvent: O
Product: COc1ccc2c(c1OC(C)C)CCCC2=O
Reaction time: 12 h
Yield: 71 %

Procedure:
34 (120 mg, 0.55 mmol) was weighed in a 100 mL round bottom flask and a solution of 5 mL of water:dioxane (5:95) was added and the reaction was set up under nitrogen. A solution of 2,4-dichloro-5,6-dicyanobenzoquinone (0.25 g, 1.09 mmol) dissolved in 5 mL of dioxane was added dropwise to the reaction mixture. The reaction mixture was stirred for 12 h. The solid separated was filtered and washed with ethylacetate. The filtrate was concentrated under reduced pressure and 10 mL of saturated sodium bicarbonate solution was added and the resulting reaction mixture was extracted with ether (3×20 mL) and the combined organic phases dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. Purification by flash column chromatography (silica gel, 30:70 EtOAc:Hexanes) yielded 90 mg (71%) of 35. Rf value: 0.458 (40:60 EtOAc:Hexanes).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[ClH:20].[CH3:21]O>>[ClH:20].[CH3:21][O:10][C:9](=[O:11])[CH:8]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CO
Reactant: O=C(O)C(NCc1ccccc1)c1ccc(F)cc1
Agent: Cl
Product: COC(=O)C(NCc1ccccc1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
4-Fluoro-α- [(phenylmethyl)amino]benzeneacetic acid (12.2 kg, 47.1 moles) was slurried in methanol (37 L), then hydrogen chloride gas was passed over the mixture. The resulting slurry was stirred at 35-45° C. for 3 hours, then concentrated to 30-35 L by distillation. Methyl-t-butyl ether (20 L) was added and the batch was seeded with 4-Fluoro-α-[(phenylmethyl)amino]benzeneacetic acid methyl ester hydrochloride. Upon development of the seed-bed, methyl-t-butyl ether (20 L) was added. The slurry was aged for 1 hour, then filtered. The filter cake was washed with methyl-t-butyl ether:methanol (95:5, 8.0 L), then dried under vacuum at 30° C. to give 12.2 kg (84% yield) of 4-fluoro-α-[(phenylmethyl)amino]-benzeneacetic acid methyl ester hydrochloride.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:16]([C:17]2C=CN[N:18]=2)=[CH:15][N:14]=[C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:12]=1.[N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2NC=1C(=CN(C)C)C(C1C=CC([Cl:53])=CC=1Cl)=O>>[ClH:3].[ClH:53].[N:18]1[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[NH:35][C:17]=1[C:16]1[C:11]([C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])=[N:12][C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)=[N:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3cc[nH]n3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1nc2ccccc2[nH]1
Agent: Cl
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3nc4ccccc4[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
Made using the same procedure as for [4-(2,4-dichlorophenyl)-5-pyrazolylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine dihydrochloride except that 2-benzimidazolyl-1-(2,4-dichlorophenyl)-3-(dimethylamino)prop-2-en-1-one (XIV, 468 mg, 1.3 mmol) was used and the crude product was purified by recrystallization (CH2Cl2/Et2O/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14]([B-](F)(F)F)=[CH2:15].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:12]=[C:11]([CH:14]=[CH2:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(Br)cc1Cl
Reactant: C=C[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=Cc1ccc(C(=O)OCC)c(Cl)c1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
To a stirred solution of ethyl 2-chloro-4-bromobenzoate (2 g, 7.63 mmol) in dimethylsulfoxide (20 mL) was added potassium vinyltrifluoroborate (3.06 g, 22.9 mmol) and potassium carbonate (3.16 g, 22.9 mmol). The reaction mixture was degassed with argon for 30 min Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.27 g, 0.38 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×50 mL), washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the compound as brown gummy material (1.1 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.70 (dd, J=17.6, 11.2 Hz, 1H), 5.87 (d, J=17.6 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 211.22 ([M+H]+); IR (thin film) 1729, 886 cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22]O)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCOC.[CH2:30]([Al](CC(C)C)CC(C)C)[CH:31](C)[CH3:32].[OH-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH:31]([CH3:32])[CH3:30])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(C)Cc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a solution of 2.0 g (5.43 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) in 50 ml 1,2-dimethoxyethane 0.75 g (0.65 mmol) tetrakis(triphenylphosphine)palladium was added. After 20 min, 16.3 ml (16.3 mmol) triisobutylaluminium (1M solution in n-hexane) was added and the reaction mixture was heated under reflux for 66 h. After cooling to room temperature another 8.1 ml (8.1 mmol) triisobutylaluminium (1M solution in n-hexane) was added and the reaction again heated under reflux. After 5 h the reaction was poured onto 1M aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:3) as eluant to afford the desired compound as a light brown oil (76.2%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=O)[CH:16]=[CH:17][CH:18]=1.[H][H]>C(OCC)(=O)C.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1ccc(C(=O)C=Cc2cccc(OCc3ccc4ccccc4n3)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CCCc2cccc(OCc3ccc4ccccc4n3)c2)cc1

Procedure:
A solution of 4-(3-(3-(2-quinolinylmethyloxy)phenyl)-1-oxo-2-propen-1-yl)benzonitrile (0.008 mol) in ethyl acetate (150 ml) is shaken under 50 psi of hydrogen gas in the presence of 10% palladium an carbon catalyst (1.0 g). The reaction is filtered through a celite pad and evaporated to give 4-(3-(3-(2-quinolinylmethyloxy)phenyl)propyl)benzonitrile.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].[C:25]1(=O)[CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH:25]1([N:22]2[CH2:23][CH2:24][CH:19]([C@@H:17]([NH:16][C:12]3[N:11]=[C:10]([N:5]4[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]4=[O:9])[CH:15]=[CH:14][N:13]=3)[CH3:18])[CH2:20][CH2:21]2)[CH2:28][CH2:27][CH2:26]1
Reactant: O=C1CCC1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCNCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCN(C3CCC3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.4 %

Procedure:
A solution of (S)-4-Isopropyl-3-[2-((S)-1-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-oxazolidin-2-one (28 mg, 0.084 mmol) in THF (2 mL) was added cyclobutanone (14 mg, 0.20 mmol) and sodium triacetoxyborohydride (28 mg, 0.13 mmol). The reaction was stirred at room temperature for 18 hours. The solvent is then removed under vacuum. The crude material was then purified using reverse phase C18 ODB column water-acetonitrile 0.1% TFA modifier to give (S)-3-{2-[(S)-1-(1-Cyclobutyl-piperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-4-isopropyl-oxazolidin-2-one (20 mg) in 62% yield.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C([NH+](CC)CC)C.[N:32]1([CH2:41][C:42]([O-:44])=O)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[CH:33]1.CN1CCOCC1.[CH2:52]([NH2:59])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]>C(#N)C>[N:32]1([CH2:41][C:42]([NH:59][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:44])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[CH:33]1
Reactant: O=C([O-])Cn1cnc2ccccc21
Reactant: CCCCCCCN
Agent: CC[NH+](CC)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCCCCCCNC(=O)Cn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
O-(7-Azabenzotriazol1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (80 mg, 0.21 mmol) was added under stirring to a solution of 1H-benzoimidazol-1-ylacetic acid triethylammonium salt (55.5 mg, 0.2 mmol) and N-methyl morpholine (66 μL, 0.6 mmol) in acetonitrile (1 mL). After 5 min 1-heptylamine (30 μL, 0.2 mmol) was added and mixture was stirred at ambient temperature for 3 h. The solvent was evaporated, the residue was dissolved in ethyl acetate (15 mL) and extracted with saturated aqueous NaHCO3 (5 mL) and brine (5 mL) then dried over anhydrous Na2SO4 and concentrated. Purification of the crude product was performed by preparative HPLC (XTerra C8 column 19×300 mm, 0.1 M NH4OAc/CH3CN). Product-containing fractions were pooled and lyophilised affording the title compound (43.7 mg, 80%). Calculated for C16H23N3O m/z: 273.18, found 274.03 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (m, 3H), 1.26 (m, 8 H), 1.41 (m, 2H), 3.07 (m, 2H), 4.88 (s, 2H), 7.20 (m, 2H), 7.42 (m, 1H), 7.64 (m, 1H), 8.14 (s, 1H), 8.27 (t, J=5.6 Hz, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH2:17][CH3:18])[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2.[Al+3].[Cl-].[Cl-].[Cl-].CCS>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH2:17][CH3:18])[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2
Reactant: CC[C@H](C(=O)OC)[C@@H]1CCc2cc(OC)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CC[C@H](C(=O)OC)[C@@H]1CCc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a cold solution (ice water bath) of the compound prepared in Example 22 (233 g, 0.94 mol) in CH2Cl2 (2.5 L), was added AlCl3 (630 g, 4.7 mol) slowly under argon. The internal temperature was kept below 20° C., and the color of the reaction turned purple. EtSH (345 mL, 4.7 mol) was added slowly via an addition funnel maintaining the internal temperature below 15° C. After 2 h of stirring at a temperature below 20° C., the reaction was completed and was slowly poured into ice-water (2.5 L) with strong agitation. The organic phase was separated, and the aqueous phases was extracted with CH2Cl2 (1 L) The combined organic phases were washed with water (4×1 L) until a pH of 6.0-7.0 was reached, and then dried over Na2SO4, filtered, concentrated under reduced pressure and then dried under vacuum to provide the title compound (216 g, 98%) as a white solid. 1H NMR (300 MHz), (DMSO-d6) δ 9.10 (s, 1H), 6.78 (d, 1H), 6.58 (d, 1H), 6.50 (dd, 1H), 3.60 (s, 3H), 3.20 (q, 1H), 2.70 (m, 2H), 2.40 (m, 1H), 2.08 (m, 1H), 1.80 (m, 1H), 1.50 (m, 2H), 0.80 (t, 3H).
Reaction SMILES: O.NN.[C:4]([C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH3:36])[N:29]=2)=[CH:15]\[CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]>C(O)C.[Cl-].[Na+].O>[C:4]([C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH3:36])[N:29]=2)=[CH:15]\[CH2:16][NH2:17])=[CH:10][CH:9]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: COc1nc(/C(=C/CN2C(=O)c3ccccc3C2=O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(/C(=C/CN)c2ccc(C(C)(C)C)cc2)ccc1Cl

Procedure:
Hydrazine monohydrate (13 μL) was added to a solution of 2-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-yl]-1H-isoindole-1,3(2H)-dione (98 mg) in ethanol. Thereafter, the mixture was stirred with heating under reflux for three hours and then stirred at room temperature overnight. Brine was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure to give a crude product of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-amine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Cl)=[N:15][C:14]([Cl:19])=[CH:13][CH:12]=2)=[O:7])(=[O:3])[CH3:2].[CH3:20][N:21]([CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1)[CH3:22]>>[C:1]([O:4][CH2:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([CH2:23][N:21]([CH3:22])[CH3:20])[CH2:25][CH2:26]1)=[N:15][C:14]([Cl:19])=[CH:13][CH:12]=2)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Product: CC(=O)OCC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure I, 2-(4,6-dichloro-1,5-naphthyridin-3-yl)-2-oxoethyl acetate (101 mg, 0.33 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexan amine (67 mg, 0.43 mmol) to afford the desired product (90 mg, 65%) as an off-white solid. ESI MS m/z 419 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][N:9]2[CH:18]=1)([O:3]CC)=[O:2].[OH-].[K+]>CO.O>[OH2:2].[CH:7]1[C:6]([C:1]([OH:3])=[O:2])=[CH:18][N:9]2[C:8]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[CH:10]2.[CH:7]1[C:6]([C:1]([OH:3])=[O:2])=[CH:18][N:9]2[C:8]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[CH:10]2
Reactant: CCOC(=O)c1cc2c3ccccc3ncn2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c3ccccc3ncn2c1

Procedure:
A solution of the product of Example II (2.0 g, 0.008 m) and KOH (2.0 g, 0.036 m) in MeOH (20 ml) and H2O (20 ml) was refluxed for 1 hr. The methanol was removed under vacuum and the resulting aqueous solution was acidified with HCl (10% aqueous). When the solution became acidic, a white solid formed. It was filtered and washed well with H2O and dried, to yield 1.23 g of crude product. Crystallization from MeOH afforded the product as an off-white solid; m.p. 323°-325° C.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([C:7]([OH:9])=O)[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]>>[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:7]([C:5]3[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[N:6]=3)=[O:9])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: Cn1nc(C(=O)O)c(C(F)(F)F)n1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3nn(C)nc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-methyl-5-trifluoromethyl-2H-[1,2,3]triazole-4-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (15% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.05, 7.83, 7.00, 4.28, 3.97-3.67, 3.51-3.45, 1.75-1.68, 1.49, 0.92. MS (ES+) m/z 455.2 (M+1).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]([O:20]C)=[O:19])[C:12]([CH3:22])=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:9]=3)[N:13]([CH2:17][C:18]([OH:20])=[O:19])[C:12]=2[CH3:22])=[CH:25][CH:26]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(N)ccc21
Product: CCS(=O)(=O)Nc1ccc2c(c1)c(Oc1ccc(Cl)cc1)c(C)n2CC(=O)O

Procedure:
The title compound was prepared by the method of example 7 step (iii) using ethanesulfonyl chloride and the product from example 7 step (ii). Yield 155 mg
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[Cl:17][C:18]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](O)=O>>[Cl:17][C:18]1[C:19]([C:20]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:23][CH:24]=[C:25]([Cl:27])[N:26]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2Cl)o1
Yield: 35 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (400 mg, 1.84 mmol) was converted using 2,6-dichloronicotinic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=80:20 to 40:60, 240 mg, 35%) which was obtained as a white solid. MS: m/e=373.0/375.0 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([C:8]1[CH:13]=[C:12]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26][N:27]([CH2:29][CH3:30])[CH3:28])[CH:20]=3)[O:16][N:15]=2)[CH:11]=[C:10]([CH3:31])[C:9]=1[OH:32])[CH3:7].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:6]([C:8]1[CH:13]=[C:12]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26][N:27]([CH2:29][CH3:30])[CH3:28])[CH:20]=3)[O:16][N:15]=2)[CH:11]=[C:10]([CH3:31])[C:9]=1[O:32][CH2:2][CH2:3][CH2:4][OH:5])[CH3:7]
Reactant: OCCCBr
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1OCCCO
Temperature: 60 °C
Reaction time: 3 h

Procedure:
3-bromo-1-propanol (55 mg, 398 μmol) was added to a suspension of 2-ethyl-4-(5-{3-[(ethyl-methyl-amino)-methyl]-5-methyl-phenyl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenol (97 mg, 265 μmol) and K2CO3 (88 mg, 637 μmol) in DMF (2 mL). The mixture was stirred at 60° C. for 3 h before it was filtered. The filtrate was separated by prep. HPLC (XBridge 30×75 mm, eluting with a gradient of MeCN in water containing 0.5% of sat. aq. ammonia) to give the title compound as a colourless resin (67 mg). LC-MS**: tR=0.61 min; [M+1]+=424.25; 1H NMR (D6-DMSO): δ 1.06 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.3 Hz, 3H), 1.90-1.98 (m, 2H), 2.15 (s, 3H), 2.34 (s, 3H), 2.41-2.49 (m, 5H), 2.71 (q, J=7.3 Hz, 2H), 3.55 (s, 2H), 3.65 (q, J=5.8 Hz, 2H), 3.90 (t, J=6.0 Hz, 2H), 4.55 (t, J=4.8 Hz, 1H), 7.47 (s, 1H), 7.80 (s, 2H), 7.90 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[OH:14])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:5]=1[OH:14]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(F)(F)F)c1O
Reaction time: 4 h
Yield: 71.5 %

Procedure:
2-Nitro-6-trifluoromethyl-phenol (1.8 g) (J. Org. Chem. 1962, 27, 4660-4662) was dissolved in MeOH (20 ml) prior to the addition of 10% Pd/C (1.0 g). The reaction was placed on a Parr aparatus under hydrogen at 60 psi for 4 h. The palladium was filtered off and the solution was concentrated to give 2-amino-6-trifluoromethyl-phenol (1.1 g): 1H NMR (CD3OD, δ ppm, 300 mHz) 6.78 (m, 2H), 6.90 (d, 1H).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[OH:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=O)=[CH:31][CH:30]=1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:33]([C:32]3[CH:36]=[CH:37][C:29]([CH2:28][OH:27])=[CH:30][CH:31]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)c1ccc(CO)cc1
Product: CON=C1C[C@@H](c2noc(-c3ccc(CO)cc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 4-(hydroxymethyl)benzoic acid, the title compound was obtained in 54% purity by HPLC. MS(ESI+): m/z=469.4.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:29][CH2:28][CH2:27][C:22]2[C:23]([CH3:26])=[N:24][O:25][C:21]=2[C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Reactant: Clc1ccc(CBr)cc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCOCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-bromomethyl-4-chloro-benzene.