Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[CH3:21][C:19]1[O:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[C:16](=[O:15])[CH:20]=1
Reactant: Cc1cc(O)no1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(=O)n(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])o1

Procedure:
226 g of 4-chloro-3-nitrobenzotrifluoride, 129 g of 3-hydroxy-5-methylisoxazole, 336 g of sodium hydrogen carbonate, and 600 ml of dimethylsulfoxide were mixed with each other and reacted at 75° C. for 6 hours. After completion of the reaction, the reaction solution was poured into water, and the crystals which precipitated were purified using a silica gel short column chromatography and recrystallized from water-methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[N:14]=[C:13]([NH:22][C:23]3[CH:24]=[C:25]([CH2:29][CH2:30][OH:31])[CH:26]=[CH:27][CH:28]=3)[N:12]=[CH:11][C:10]=2[CH2:9]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([O:31][CH2:30][CH2:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:13]2[N:12]=[CH:11][C:10]3[CH2:9][C@@H:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15]=3[N:14]=2)[CH:24]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of (R)-2-(3-(6-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenyl)ethanol (4.59 g, 11.17 mmol) in dichloromethane (50 mL) was added triethylamine (2.33 mL, 16.75 mmol) and methanesulfonyl chloride (0.95 mL, 12.28 mmol). The mixture was stirred at room temperature for 1 h, washed with water (60 mL×3), dried over sodium sulfate and concentrated to yield the title compound as a yellow solid (5.37 g, 98% yield). 1H-NMR (DMSO-d6) δ 9.59 (s, 1 H), 8.37-8.35 (dd, 1 H), 8.33 (s, 1 H), 7.80 (s, 1 H), 7.71 (d, J=10.4 Hz, 1 H), 7.54-7.45 (m, 2 H), 7.29-7.22 (m, 3 H), 7.07-7.02 (m, 2 H), 6.82-6.78 (m, 2 H), 4.67 (t, J=6.8 Hz, 1 H), 4.45 (t, J=6.8 Hz, 2 H), 3.22-3.08 (m, 2 H), 3.13 (s, 3 H), 3.01 (t, J=6.4 Hz, 2 H). LCMS m/e 490 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[C:15](=[O:18])[NH:16][CH3:17])[CH:6]=[CH:7][C:8]([O:10]C)=[O:9].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[C:15](=[O:18])[NH:16][CH3:17])[CH:6]=[CH:7][C:8]([OH:10])=[O:9]
Reactant: CNC(=O)c1ccc(C=CC(=O)OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)c1ccc(C=CC(=O)O)cc1OC
Temperature: 50 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
To a solution of methyl 3-methoxy-4-(methylcarbamoyl)-cinnamate (300 mg) in methanol was added 1H aqueous sodium hydroxide solution (1.5 ml) at ambient temperature, and the mixture was stirred for 5 hours at 50° C. The solvent was removed, and water was added thereto. The mixture was washed with diethyl ether and adjusted to pH 4 with 1N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water to give 3-methoxy-4-(methylcarbamoyl)-cinnamic acid (250 mg).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11](O)=O)=[CH:2]1.[CH3:14][N:15]1[CH:19]=[C:18]([C:20]2[N:25]=[N:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=2)[CH:17]=[N:16]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]3[N:24]([C:11]([CH2:10][C:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:1][CH:2]=4)=[N:27][N:26]=3)[N:25]=2)[CH:17]=[N:16]1
Reactant: Cn1cc(-c2ccc(NN)nn2)cn1
Reactant: O=C(O)Cc1c[nH]c2ncccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3nnc(Cc4c[nH]c5ncccc45)n3n2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.1 %

Procedure:
To a 20 ml vial 52 mgs (0.295 mmol) of (1H-pyrrolo[2,3-b]pyridine-3-yl)-acetic acid, 1.2 eq. (0.354 mmol) of 0-(7-azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluroniumhexafluoro-phosphate, 1.5 eq. (0.443 mmol) [6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine and 4 eq. (1.18 mmol) N,N-diisopropylethylamine were added and dissolved in 4 mls of dimethyl-formamide. The reaction mixture was stirred at room temperature for 18 h. After such time the dimethylformamide was removed in vacuo and acetic acid (4 mls) was added to the residue and heated to 60° C. for 4 hours. The solvent was removed in vacuo purification via preparative HPLC eluting with dichloromethane:methanol 95:5 returned the title compound (3 mgs, 3% yield) as an off white solid. Analytical data presented in Table 1.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([O:12][CH2:13][CH2:14][OH:15])[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1C=CC=CC=1.CCCCCCC>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:15][CH2:14][CH2:13][O:12][CH:10]2[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][O:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCCOC1c2ccccc2COc2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3COc3ccccc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.7 %

Procedure:
Under a nitrogen atmosphere, 2-(6,11-dihydrodibenzo[b,e]oxepin-11-yloxy)-ethanol (256 mg, 1.0 mmol), tributylphosphine (223 mg, 1.1 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (262 mg, 1.1 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (278 mg, 1.1 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and dihydro-ADDP separated out was filtered off. After evaporation of the solvent the product was purified chromatography eluting with ethyl acetate/heptane (1:4) to give 175 mg (37%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H), 1.25 (t, 3H), 2.93 (d, 2H), 3.30-3.40 (m, 1H), 3.55-3.65 (m, 1H), 3.65-3.75 (m, 1H),3.78-3.88 (m,1 H), 3.95 (t, IH), 4.10 (t, 2H), 4.15 (q, 2H), 4.85 (d, 1H), 5.25 (s, 1H), 6.15 (d, 1H), 6.75 (d,2H), 6.85-6.95 (m, 2H), 7.10 (d, 2H), 7.15-7.40 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][C:24]([F:27])=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][C:24]([F:27])=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([OH:37])=[O:36])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Br
Yield: 59.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-fluorothiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.63 g, 1.2 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.23 g, 1.4 mmol) according to the procedure as described in Example 28 to give the title compound as a yellowish solid (0.41 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:20])[O:16][C:17]([CH3:19])=[CH2:18]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:1]1([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=2[NH:14][C:15](=[O:20])[O:16][C:17]([CH3:19])=[CH2:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(N)c(-c2ccccc2)c1
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1ccc(C)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a biphasic solution of 2-phenyl-4-methylbenzenamine (0.29 g, 1.583 mmol) in EtOAc (10 mL) and NaHCO3 (10 ml) was added prop-1-en-2-yl carbonochloridate (0.259 ml, 2.374 mmol) and mixture was stirred for 16 h at RT. The layers were separated and the aqueous layer was extracted with EtOAc (1×30 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to provide prop-1-en-2-yl 2-phenyl-4-methylphenylcarbamate as an off-white solid (0.33 g, 78% yield). 1H NMR (400 MHz, CDCl3): δ 8.00 (brs, 1H), 7.50-7.46 (m, 2H), 7.42-7.35 (m, 3H), 7.18 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.05 (s, 1H), 6.67 (brs, 1H), 4.72 (s, 1H), 4.68 (s, 1H), 2.34 (s, 3H), 1.94 (s, 3H); MS (ESI) m/z: 290.0 (M+Na+).
Reaction SMILES: O[CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>ClCCl>[Br:20][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)COc1cc(/C=C/CO)cc(OC)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)COc1cc(/C=C/CBr)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of the compound (150 mg, 0.594 mmol) of Example 16-4 in dicloromethane (2 ml) were added carbon tetrabromide (207 mg, 0.623 mmol) and triphenylphosphine (163 mg, 0.623 mmol), and the mixture was stirred for 30 minutes at room temperature. By adding ether to the reaction mixture, the resulting precipitate was filtered off. The filtrate was concentrated and the residue was purified with silica gel chromatography (hexane:ethyl acetate=2:1) to give the subject compound (141 mg, 75.3%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:2]=1.C(O)C.[CH:15](=[O:19])/[CH:16]=[CH:17]/[CH3:18]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][N:10]([CH:17]([CH3:18])[CH2:16][CH:15]=[O:19])[CH:11]=2)[CH:2]=1
Reactant: C/C=C/C=O
Reactant: c1cncc(-c2c[nH]cn2)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CC(CC=O)n1cnc(-c2cccnc2)c1

Procedure:
To a solution 4pyridin-3-yl-imidazole (10 g, 68.88 mmol) in THF (300 ml) were added ethanol (4.04 ml, 68.88 mmol) and crotonaldehyde (22.83 ml, 275.52 mmol). The resulting mixture was heated under reflux for 18 hours. At this point of time, an additional 2 equiv of crotonaldehyde was added and contiuned to reflux for another 20 hours. TLC analysis indicated the reaction was complete. Solvent was removed in vacuo and the crude aldehyde of formula 18, wherein R7 is methyl and R3 is pyridin-3-yl, which was used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].IC.CN(C)[C:37](=O)[CH3:38]>>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:37][CH3:38])[C:12]2[CH:13]=[C:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cc(C(C)C)c3c(c2)C(C)(C)CO3)cc1
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOC(=O)c1ccc(N(CC)c2cc(C(C)C)c3c(c2)C(C)(C)CO3)cc1
Yield: 75 %

Procedure:
Following general procedure G and using 4-[(3,3-dimethyl-7-isopropyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 17, 0.064 g, 0.19 mmol), potassium carbonate (0.105×2 g, 0.76×2 mmol) and iodomethane (0.24×2 g, 0.76×2 mmol) in 2 mL of anhydrous N,N-dimethylacetamide, the title compound (0.05 g, 75%) was obtained as a pale yellow oil. This reaction was performed in a sealed tube for 96 hours, with addition of a second equivalent of potassium carbonate and iodomethane to the reaction mixture after 48 hours. 1H NMR (300 MHz, CDCl3): δ 7.75 (d, 2H, J=9.0 Hz), 6.74 (d, 1H, J=2.1 Hz), 6.67 (d, 1H, J=2.1 Hz), 6.49 (d, 2H, J=9.0 Hz), 4.23 (q, 2H, J=7.1 Hz), 4.20 (s, 2H), 3.66 (q, 2H, J=7.1 Hz), 3.01 (heptet, 1H J=6.8 Hz), 1.27 (t, 3H, J=7.1 Hz), 1.25 (s, 6H), 1.19-1.13 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:32]4[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=4)[CH:3]=3)[NH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(F)cc4)c3c2)cc(OC)c1OC
Yield: 28.7 %

Procedure:
5-Bromo-3-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (37 mg, 0.083 mmol), 3,4,5-trimethoxyphenylboronic acid (21 mg, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium (II) (3 mg, 0.004 mmol) were combined in CH3CN (1.5 ml) and 1 M Na2CO3 (2 ml) and reacted in a microwave reactor for 20 min at 150° C. EtOAc was added and the mixture was washed with water, dried, evaporated and purified by silica gel chromatography using 0-2% MeOH:DCM to yield 9 mg (29%) of the title compound. MS ESI (m/z): 379.2 (M+1)+, calc. 378.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[OH:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[NH2:22][OH:23].C([O-])(=O)C.[NH4+]>O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[N:22][OH:23])[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[OH:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: COc1ccc(O)c(C(=O)C2CCN(C(C)=O)CC2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: COc1ccc(O)c(C(=NO)C2CCN(C(C)=O)CC2)c1
Yield: 17.1 %

Procedure:
A solution of 15.5 g of 1-acetyl-4-(2-hydroxy-5-methoxybenzoyl)piperidine, 7.0 g of hydroxylamine hydrochloride, 9.5 g of ammonium acetate and 75 ml of water was heated under reflux for 20 hrs. The solution was poured into water and extracted with dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give an oil. The oil was triturated with hot toluene. The toluene was decanted and the oil was triturated with ether to give a solid. The tolulene triturant, upon standing, yielded a solid. The solids were combined and recrystallized from acetonitrile to yield 2.8 g (17.4%) of product, mp, 191°-193°, as a mixture of E- and Z-isomers. The chromatogram showed 2 spots.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[CH:11]=[N:12][OH:13].[Cl:14]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:13][N:12]=[C:11]([Cl:14])[C@H:2]1[CH2:3][O:4][C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:1]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=C[C@H]1COC2(CCCCC2)O1
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (9.08 g, 49 mmol) in DMF (50 mL) was added 1-chloropyrrolidine-2,5-dione (7.20 g, 53.9 mmol) and the reaction stirred overnight at ambient temperature. The reaction was poured into water (500 mL) extracted with ether. The organics were washed with brine and dried over magnesium sulfate. The material was concentrated in vacuo to yield (R)—N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (10.4 g, 47 mmol, 96.6%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=O.Cl.[C:26]1([C@:32]2([OH:53])[CH2:40][CH2:39][C:38]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:37]3[C@H:33]2[CH2:34][NH:35][CH2:36]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl>[C:26]1([C@:32]2([OH:53])[CH2:40][CH2:39][C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C@@H:37]3[C@H:33]2[CH2:34][N:35]([C:22](=[O:24])[CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH2:36]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: O[C@@]1(c2ccccc2)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@]2(O)c1ccccc1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
0.28 g of carbonyldiimidazole is added to a solution of 0.28 g of (2-methoxyphenyl)-acetic acid in 20 cm3 of dry methylene chloride. The mixture is stirred at room temperature for I hour and a suspension of 0.7 g of (3aS,4S,7aS)-4,7,7-triphenyl-perhydroisoindol-4-ol hydrochloride in 20 cm3 of dry methylene chloride and then 0.48 cm3 of triethylamine are subsequently added in succession. The reaction mixture is stirred at room temperature for 24 hours, diluted with 100 cm3 of methylene chloride, washed with 100 cm3 of water (twice) and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 16 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting fractions of 20 cm3. Fractions 7 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised in 16 cm3 of acetonitrile. The crystals are filtered off and dried. 0.3 g of (3aS,4S,7aS)-4,7,7-triphenyl-2-[(2-methoxyphenyl)-acetyl]-perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 236° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:8])[CH2:2][CH3:3]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CCCOc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Propoxy-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Propoxy-N-(4-nitro-3-trifluromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[C:4]([N+:17]([O-])=O)[C:3]=1[CH3:20].O.[Cl-].[NH4+]>CCO.[Fe]>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]([NH2:17])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:7]=1
Reactant: Cc1c(Br)cc(Oc2ccc(F)cc2F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1c(N)cc(Oc2ccc(F)cc2F)cc1Br
Temperature: 85 °C
Yield: 113.9 %

Procedure:
1-Bromo-5-(2,4-difluoro-phenoxy)-2-methyl-3-nitro-benzene (7.31 g, 21.2 mmol) was dissolved in 145 mL EtOH and 35 mL water was added, followed by addition of ammonium chloride (3.63 g, 67.9 mmol) and powdered iron (3.56 g, 63.8 mmol). The reaction mixture was placed under nitrogen atmosphere and heated to 85° C. for 2.5 hours. The reaction mixture was cooled, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was partitioned between water and EtOAc and the organic phase was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-25% EtOAc in hexanes) to give 7.583 g of 3-bromo-5-(2,4-difluoro-phenoxy)-2-methyl-phenylamine, MS(M+H)=314.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21]OS(C)(=O)=O)[N:9]=1.[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:37][C:38]([SH:41])=[N:39][N:40]=2)=[CH:32][CH:31]=1.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][S:41][C:38]2[NH:37][C:36]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)=[N:40][N:39]=2)[N:9]=1
Reactant: Sc1nnc(-c2ccncc2)[nH]1
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCOS(C)(=O)=O)n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCSc3nnc(-c4ccncc4)[nH]3)n2)c1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
Compound 95, methanesulfonic acid 2-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-ethyl ester (50 mg., 0.12 mmol) was dissolved in tetrahydrofuran (2 mL). To the reaction mixture was added 5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (124 mg., 0.66 mmol) and sodium hydride (12 mg., 0.5 mmol) and the vessel was stirred at room temperature for sixteen hours. The solvent was removed under reduced pressure and the crude oil was purified by column chromatography to give Compound 25, N-(3-methyl-benzylidene)-N′-{6-morpholin-4-yl-2-[2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-pyrimidin-4-yl}-hydrazine (34 mg.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[O:16][C:17]([F:20])([F:19])[F:18].[C:21]([Cu])#[N:22].Cl>CN(C=O)C.O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[C:3]([O:16][C:17]([F:18])([F:19])[F:20])[CH:4]=1
Reactant: N#C[Cu]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c(OC(F)(F)F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 45.9 %

Procedure:
1,1-Dimethylethyl {4-bromo-3-[(trifluoromethyl)oxy]phenyl}carbamate (Intermediate 50, 1.0 g, 2.8 mmol) was dissolved in dry DMF (25 mL). To this solution was added CuCN (1.0 g, 11.1 mmol), and the reaction mixture was heated to reflux for 5 h. A second portion of CuCN (500 mg, 5.6 mmol) was added and heating at reflux was continued for 10 h. The reaction mixture was cooled to room temperature, and FeCl3 was added. This was followed by 1N HCl at 0° C. and the mixture was stirred for 2 hr at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (60-120 silica gel), eluting with 30% ethyl acetate/pet ether to give the title compound (260 mg).