Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1>>[CH:22]1[N:21]2[CH:24]=[CH:25][CH:26]=[C:20]2[CH:19]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][C:14]([O:17][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)=[CH:13][CH:12]=3)[N:23]=1
Reactant: FC(F)(F)c1cccc(CCBr)c1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCc3cccc(C(F)(F)F)c3)cc12

Procedure:
2-Pyrrolo[1,2-c]pyrimidin-3-yl-6-[2-(3-trifluoromethyl-phenyl)-ethoxy]-chromen-4-one oxime was prepared in 22% overall yield using the method described in example 85, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and 1-(2-Bromo-ethyl)-3-trifluoromethyl-benzene.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.Cl[C:11]1[N:16]=[N:15][C:14]([S:17][CH:18](C)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1>CCCCO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:16]2[N:15]=[C:14]([S:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[CH:12][C:11]2=[N:9][N:8]=1
Reactant: CCOC(=O)C(C)Sc1ccc(Cl)nn1
Reactant: NNC(=O)c1cccs1
Solvent: CCCCO
Product: CCOC(=O)CSc1ccc2nnc(-c3cccs3)n2n1
Temperature: 142.5 °C

Procedure:
To 2-thiophenecarbohydrazide (215 mg, 1.5 mmol) dissolved in n-BuOH (3 mL) was added ethyl 2-((6-chloropyridazin-3-yl)thio)propanoate (232 mg, 1 mmol), and the whole was heated for 5 h in a 140-145° C. oil bath. The reaction mixture was then cooled to room temperature (˜25° C.), and the solid residue removed by filtration. The filtrate was then diluted with methylene chloride (50 mL), and washed with saturated with NaHCO3 (˜15 mL). The combined aqueous layers were washed twice with methylene chloride, and the organic layers were then combined, washed with brine, dried over MgSO4, filtered, and evaporated. The resulting solid was then recrystallized from EtOH to give ethyl 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[O:12][CH2:11][CH2:10][CH:9]=[CH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCC=Cc1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cccc(C=CCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
To a solution of 0.17 g of 4-(3-fluorophenyl)-3-buten-1-ol, 0.30 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol and 0.27 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.20 ml of N,N-diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After the stirring was continued at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.38 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-fluorophenyl)-3-butenyloxy)benzene (84% yield), nD25.5 1.5857.
Reaction SMILES: [CH:1]1([C:4]([CH3:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:9][C:10]1[C:11]([C:17](OCC)=[O:18])=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.Cl>C(OCC)C>[CH:1]1([C:4](=[O:5])[CH2:6][C:17]([C:11]2[C:10]([Cl:9])=[CH:15][C:14]([Cl:16])=[CH:13][N:12]=2)=[O:18])[CH2:3][CH2:2]1
Reactant: CC(=O)C1CC1
Reactant: CCOC(=O)c1ncc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)C1CC1)c1ncc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
Methyl cyclopropyl ketone (1.65 g) was added to a stirred suspension of sodium hydride (80% dispersion in oil; 0.6 g) in dry diethyl ether at 0° C. under an inert atmosphere. The mixture was stirred at 0° C. for one hour. Ethyl 3,5-dichloropyridine-2-carboxylate (2.16 g) was added and the mixture was stirred at 0° C. for 1 hour and then at room temperature overnight. Hydrochloric acid (2N) was added and the mixture was extracted with diethyl ether. The organic extracts were washed with water, dried (anthydrous magnesium sulphate), filtered and evaporated to give a brown gum which was purified by column chromatography on silica eluted with a mixture of ethyl acetate and hexane to yield 3-cyclopropyl-1-(3,5-dichloropyridin-2-yl)propan1,3-dione (1.35 g) as a colourless solid, m.p. 50.2°-52.7° C.
Reaction SMILES: CO[C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3[CH:13]=[CH:14][CH2:15][S:16][C:6]=3[C:5]=2[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:21]([SH:23])[CH3:22].Cl>C(Cl)Cl>[CH2:21]([S:23][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3[CH:13]=[CH:14][CH2:15][S:16][C:6]=3[C:5]=2[CH:4]=1)[CH3:22]
Reactant: COc1ccc2c(c1)c1c(n2C)C=CCS1
Reactant: CCS
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCSc1ccc2c(c1)c1c(n2C)C=CCS1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
500 mg (1.9 mmol) of the compound obtained in Example 24, predissolved in 5cm3 of methylene chloride distilled over phosphorus pentoxide are added dropwise to a mixture, cooled to 0° C., of 380 mg (2.84 mmol)of aluminum chloride and 2.3 g (37.9 mmol) of ethanethiol. After stirring at 0° C. for 1 h, 1.5 eq. of aluminum chloride and 20 eq. of ethanethiol are added again. The mixture is stirred again for 1 h at 0° C. and then poured onto ice, treated with 1N hydrochloric acid and then extracted with dichloromethane. After treatment of the organic phase and purification of the crude product by chromatography on a silica column the expected compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:23]#[N:24])([CH3:22])[CH3:21])[N:15]=2)[CH:3]=1.CO.[NH3:27]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:27])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:23]#[N:24])([CH3:22])[CH3:21])[N:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)C#N)n1
Reactant: N
Solvent: CO
Product: CC(C)(C#N)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
In a 50 mL round bottom flask, ethyl 6-chloro-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate (792 mg, 2.29 mmol) was suspended in ammonia 7M in methanol (7.87 g, 10.0 mL, 70.0 mmol). Sealed and stirred at room temperature for 18 h. The abundant solid formed during the reaction was separated by filtration, filter cake rinsed with fresh methanol and dried in high vacuum to give clean 6-chloro-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (581 mg, 80.1% yield) as an off-white solid. 1H NMR (DMSO-d6) δ: 12.14 (s, 1H), 9.22 (s, 1H), 8.89 (s, 1H), 8.23 (s, 1H), 7.87 (t, J=7.9 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 1.73 (s, 6H); LC-MS 316.9 [M+H]+.
Reaction SMILES: C[N+]1([O-])CCOCC1.[Cl:9][CH2:10][CH2:11][CH:12]1[O:16][CH2:15][CH:14]([OH:17])[CH2:13]1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:9][CH2:10][CH2:11][CH:12]1[O:16][CH2:15][C:14](=[O:17])[CH2:13]1
Reactant: OC1COC(CCCl)C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C1COC(CCCl)C1
Reaction time: 0.5 h

Procedure:
A solution of 4-(benzyloxy)-2-(2-chloroethyl)tetrahydrofuran (2.47 g, 10.26 mmol) in ethyl acetate (50 mL) was deoxygenated for 5 min by bubbling N2 through. 10% Pd/C (0.145 g, 1.363 mmol) was added the flask evacuated then placed under 1 atm H2 for 4 h. The reaction was filtered and concentrated to give a colorless oil (1.74 g) which was used in the next step without purification. A solution of 4-methylmorpholine N-oxide (1.803 g, 15.39 mmol) in CH2Cl2 (50 mL), intermediate 5-(2-chloroethyl)tetrahydrofuran-3-ol and 4 Å powdered molecular sieves (4 g) was stirred for 30 min. To this mixture was added tetrapropylammonium perruthenate (0.036 g, 0.103 mmol) and stirring continued for 24 h at room temperature. The reaction was concentrated, then diluted with Et2O (100 mL) and filtered through a plug of CELITE®. The filtrate was concentrated to afford 5-(2-chloroethyl)dihydrofuran-3(2H)-one as viscous colorless oil. To a stirred mixture of 5-(2-chloroethyl)dihydrofuran-3(2H)-one, aqueous ammonia (5 mL) and 1N HCl (10 mL) in methanol 20 mL was added NaCN (0.43 g, 8.77 mmol) at room temperature. The yellow solution was stirred for 42 h and concentrated. The solution was made basic with sat. Na2CO3 (20 mL) and extracted with CH2Cl2 (3×25 mL). To the combined CH2Cl2 extracts was added sat. Na2CO3 (10 mL), and the mixture cooled to 0° C. with an ice bath and treated with benzyl chloroformate (1.465 mL, 10.26 mmol). After 1 h, the ice bath was removed and the reaction was stirred at room temperature for 4 h. The organic layer was separated, dried (Na2SO4), filtered, concentrated and purified by flash column chromatography on silica gel column using 10, 20, 30 and 40% ethyl acetate/hexane to afford the title compound benzyl 5-(2-chloroethyl)-3-cyanotetrahydrofuran-3-ylcarbamate (0.863 g, 2.80 mmol, 27% yield), viscous pale yellow oil. 1H NMR (500 MHz, CDCl3) δ: 7.12-7.42 (5 H, m), 5.16 (2 H, s), 4.40 (0.2 H, d, J=9.8 Hz), 4.25-4.33 (0.8 H, m), 4.10-4.19 (1 H, m), 3.95 (0.2 H, d, J=9.8 Hz), 3.56-3.68 (1.8 H, m), 2.86 (1 H, dd, J=13.4, 7.0 Hz), 2.53-2.62 (1 H, m), 2.27 (1 H, dd, J=13.4, 8.9 Hz), 1.94-2.17 (2 H, m). LCMS (M+H) calcd for C15H18ClN2O3: 309.10; found: 309.10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[NH:33][C:34]([NH:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)=[O:35].[CH:42]1([CH2:45][C:46](O)=[O:47])[CH2:44][CH2:43]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:42]1([CH2:45][C:46]([N:39]2[CH2:40][CH2:41][C@@H:37]([NH:36][C:34]([NH:33][C:3]3[CH:4]=[CH:5][C:6]([C:8]([N:10]4[CH2:11][CH2:12][N:13]([CH2:16][C:17]5[CH:18]=[CH:19][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:21][CH:22]=5)[CH2:14][CH2:15]4)=[O:9])=[CH:7][C:2]=3[F:1])=[O:35])[CH2:38]2)=[O:47])[CH2:44][CH2:43]1
Reactant: O=C(Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F)N[C@@H]1CCNC1
Reactant: O=C(O)CC1CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F)N[C@@H]1CCN(C(=O)CC2CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a stirring solution of (R)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(pyrrolidin-3-yl)urea (0.123 mmol, 73 mg), 2-cyclopropylacetic acid (0.123 mmol, 12.4 mg) and triethylamine (0.370 mmol, 35.5 mg) in dichloromethane (2 mL) was added 1-propanephosphonic acid cyclic anhydride (0.370 mmol, 118 mg; 50% solution in ethyl acetate). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (2 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (3 mL). The organic phase was concentrated and the resulting residue was purified by HPLC and then treated with strong cation exchange column chromatography to afford the title compound (28 mg). MS (ESI) m/z 674.3 [M+H]+
Reaction SMILES: [CH3:1][OH:2].[Na].Cl[C:5]1[N:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:17]=[C:13]2[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1>C(O)(=O)C>[CH3:1][O:2][C:5]1[N:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:17]=[C:13]2[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1
Reactant: CO
Reactant: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3
Agent: [Na]
Solvent: CC(=O)O
Product: COc1nc2c(c3nc(-c4ccccc4F)cn13)CCCC2

Procedure:
To 10 mL anhydrous methanol was added 100 mg of sodium, and the mixture was stirred to ensure all the sodium had dissolved. Next, 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (200 mg) was added and the mixture refluxed for 1 h. To this mixture was added 2 mL of acetic acid and the solvent was then removed under reduced pressure. The resulting solid was recrystallized from ethanol and collected to yield 5-Methoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 37), m.p. 160°-161° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:21]3[C:22]4[C:27]([O:28][C:29](=[O:30])[C:20]=3[N:19]3[C:10]=2[C:11]2[C:16]([CH2:17][CH2:18]3)=[C:15]([O:34][CH3:35])[C:14]([O:36][CH3:37])=[C:13]([O:38][CH3:39])[CH:12]=2)=[CH:26][C:25]([OH:31])=[C:24]([O:32][CH3:33])[CH:23]=4)=[CH:5][C:4]=1[OH:40]>C(OC(=O)C)(=O)C.N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:4][C:3]([O:40][C:4]1[CH:5]=[C:6]([C:9]2[C:21]3[C:22]4[C:27]([O:28][C:29](=[O:30])[C:20]=3[N:19]3[C:10]=2[C:11]2[C:16]([CH2:17][CH2:18]3)=[C:15]([O:34][CH3:35])[C:14]([O:36][CH3:37])=[C:13]([O:38][CH3:39])[CH:12]=2)=[CH:26][C:25]([O:31][C:27]([CH3:26])=[O:28])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:2]
Reactant: COc1ccc(-c2c3n(c4c(=O)oc5cc(O)c(OC)cc5c24)CCc2c-3cc(OC)c(OC)c2OC)cc1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c3n(c4c(=O)oc5cc(OC(C)=O)c(OC)cc5c24)CCc2c-3cc(OC)c(OC)c2OC)cc1OC(C)=O
Temperature: 18 °C
Reaction time: 26 h
Yield: 169.7 %

Procedure:
Lamellarin T (48 mg, 0.088 mmol) was dissolved in a solution of acetic anhydride (1.0 mL) and pyridine (1.0 mL) containing DMAP (several crystals) and the solution stirred at 18° C. for 26 h. The solution was then diluted with ethyl acetate (15 mL) and washed with NaHCO3 (a saturated solution in H2O, 20 mL) and citric acid (10% in H2O, 20 mL) dried over (MgSO4) and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (sequential elution with 2:1, 1:1 hexane/ethyl acetate) the relevant fractions (Rf 0.42 1:1 hexane/ethyl acetate) were concentrated giving the title compound (47 mg, 83%) as a white solid mp 251-2° C. IR (KBr disc, cm−1) 2937, 2840, 1769, 1718, 1603, 1545, 1507, 1475, 1456, 1414, 1295, 1266, 1201, 1141, 1117, 1036. 1H NMR (300 MHz, CDCl3) δ7.31 (dd, J=2.1, 8.4 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 7.14 (d, J=8.7 Hz, 11H), 7.07 (s, 11), 4.90 (m, 1H), 4.60 (m, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.45 (s, 3H), 3.39 (s, 3H), 3.13 (m, 2H), 2.30 (s, 6H). 13C NMR+APT (75.5 MHz, CDCl3) δ168.7 (C), 168.4 (C), 155.0 (C), 151.9 (C), 147.5 (C), 144.8 (C), 142.2 (C), 140.6 (C), 138.7 (C), 135.6 (C), 129.5 (CH), 127.6 (C), 127.2 (C), 125.4 (CH), 122.6 (C), 119.8 (C), 116.1 (C), 114.8 (C), 114.4 (C), 112.9 (CH), 111.7 (CH), 105.4 (CH), 105.0 (CH), 60.9 (CH3), 60.8 (CH3), 56.2 (CH3), 55.5 (CH3), 55.2 (CH3), 42.1 (CH2), 21.7 (CH2), 20.4 (CH3). MS (70 eV) m/z (%): 629 (53, M+•), 587 (100, M•−CH2CO); HRMS calcd for C34H3, NO11 629.1897. Found 629.1907.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:28])([F:27])[F:26])=[N:10]2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH3:31]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:30]([CH3:31])[CH3:29])=[NH:23])[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:26])([F:27])[F:28])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC#N)CC3)cc1
Reactant: CNC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC(=N)N(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
5-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-pentanenitrile (0.050 g, 0.127 mmol) was dissolved in 1:1 MeOH/CHCl3 (15 mL). Hydrogen chloride gas was bubbled through the solution for 15 min. The reaction was tightly capped and sealed, stirred overnight at rt, and concentrated to dryness. The crude intermediate was dissolved in methanol (15 mL), and 2M dimethylamine (0.45 mL, 0.892 mmol) was added. The reaction was tightly capped and sealed and stirred overnight at rt, concentrated, and purified by reverse phase HPLC freeze-dried to afford the title compound (0.050 g, 89%): 1H NMR (CHCl3) δ9.30 (bs, 0.5H), 8.76 (bs, 0.5H), 7.42 (d, j=9.1 Hz, 2H), 6.96 (d, j=8.8 Hz, 2H), 3.84 (s, 3H), 3.68 (t, j=6.8 Hz, 2H), 3.51 (t, j=6.3 Hz, 2H), 3.14 (s, 3H), 3.10(s, 3H), 3.01 (t, j=6.8 Hz, 2H), 2.66–2.62 (m, 2H), 1.72–1.60(m, 4H) ppm; Mass Spec 438.3(M+H)+.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=[O:39].[Na+].[K+]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C@H:6]3[CH2:7][CH2:8][C@H:3]([CH:1]=[O:39])[CH2:4][CH2:5]3)=[CH:16][CH:15]=2)=[CH:22][CH:21]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCc1ccc(-c2ccc(CC[C@H]3CC[C@H](C#N)CC3)cc2)cc1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2ccc(CC[C@H]3CC[C@H](C=O)CC3)cc2)cc1
Temperature: -78 °C
Reaction time: 4.5 h

Procedure:
A solution of 2.6 g of 4-[2-(trans-4-cyanocyclohexyl)ethyl]-4'-pentylbiphenyl in 100 ml of methylene chloride was placed at -78° C. in a sulphonation flask under argon gasification and treated within 5 minutes with 9.5 ml of a 1.5N soution of diisobutylaluminium hydride in toluene. The mixture was subsequently stirred at -78° C. for a further 4.5 hours, then poured into 100 ml of 10% potassium sodium tartrate solution and extracted three times with 100 ml of methylene chloride each time. The organic phases were washed once with 100 ml of 10% potassium sodium tartrate solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (2.93 g) on silica gel with ethyl acetate as the eluant gave 2.33 g (89%) of trans-4-[2-(4'-pentyl-4-biphenylyl)ethyl]cyclohexanecarboxaldehyde as colourless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:19]4/[C:20](=[O:28])[NH:21][C:22]5[C:27]/4=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1.[CH3:29]C1C=C2C(=CC=1)NC(=O)C2>>[CH3:29][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:28])/[C:19]/2=[CH:18]/[C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Reactant: Cc1ccc2c(c1)CC(=O)N2
Product: Cc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2
Yield: 26 %

Procedure:
According to procedure for the synthesis of (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one, except substituting 5-methyloxindole (9 mg, 0.06 mmol) to give the title compound as an orange solid (5.9 mg, 26%). 1H NMR (400 MHz, d6-DMSO) δ 13.58 (br s, 1H), 10.53 (br s, 1H), 8.57 (br s, 2H), 8.36 (d, J=8.0 Hz, 1H), 7.93-7.46 (m, 8H), 7.06 (d, J=8.0 Hz, 1H), 6.79 (d, J=5.8 Hz, 1H), 2.16 (s, 3H); MS ESI 379.2 [M+H]+, calcd for [C24H18N4O+H]+ 379.15.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Cl)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of 4,6-dichloro-2-methylpyrimidine (Aldrich) (1.45 g, 8.90 mmol), 4-methoxybenzylamine (Alfa Aesar) (1.278 mL, 9.78 mmol), and triethylamine (1.488 mL, 10.67 mmol) in DMF (10.0 mL) was stirred at 25° C. for 18 h. The resulting mixture was partitioned between EtOAc (300 mL) and half-saturated aqueous NaHCO3 (80 mL). The organic layer was separated, sequentially washed with water (2×80 mL) and brine (80 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (ISCO, 120 g, 0 to100% EtOAc/Hexanes) furnished 6-chloro-N-(4-methoxybenzyl)-2-methylpyrimidin-4-amine (2.30 g, 8.72 mmol, 98% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8.41 Hz, 2H); 6.89 (d, J=8.61 Hz, 2H); 6.18 (s, 1H); 4.42 (br. s., 2H); 3.81 (s, 3H); 2.50 (s, 3H). m/z (ESI, +ve ion) 264.1 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C.C(OCC)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Br:7])[CH:9]=1)[CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cccc(Br)c1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 91.7 %

Procedure:
Cesium carbonate (57.8 g, 177.4 mmol) was added to a solution of 3-bromophenol (10.23 g, 59.1 mmol) in anhydrous DMF (500 mL) at room temperature under an atmosphere of nitrogen. After five minutes, ethyl 2-bromopropionate (7.7 mL, 59.1 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir at 90° C. for 18 h. The reaction mixture was diluted with diethyl ether and extracted twice with 1N HCl and three times with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (25% ether in hexanes) to provide the titled compound (14.8 g, 97%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.13-7.07 (m, 3H), 7.02-7.13 (m, 1H), 6.79 (dt, 1H, J=7.63 Hz, 2.35 Hz), 4.70 (q, 1H, J=6.75 Hz), 4.23 (q, 2H, J=3.52 Hz), 1.60 (d, 3H, J=7.04 Hz), 1.24 (t, 3H, J=7.04 Hz). Rf=0.36 in 25% ether in hexanes.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:11]=2[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([CH2:23][CH2:24][C:25](Cl)=[O:26])([O:21][CH3:22])=[O:20].CCOCC.Cl>N1C=CC=CC=1.O>[C:19]([CH2:23][CH2:24][C:25]([O:12][C:11]1[CH:10]=[C:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:26])([O:21][CH3:22])=[O:20]
Reactant: Oc1cc(-c2ccccc2)sc1-c1ccccc1
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)CCC(=O)Oc1cc(-c2ccccc2)sc1-c1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred, ice-cooled solution of 2,5-diphenyl-3-hydroxythiophene (0.12 g, 0.5 mmol) in dried pyridine (5.0 ml) under a nitrogen atmosphere was added 3-carbomethoxypropionyl chloride (0.1 g, 0.66 mmol) over ca. 20 seconds. The mixture was allowed to stir cold for 15 minutes and then at ambient temperatures for 4 hours. The mixture was added in portions to a stirred mixture of ether, ice, water, and 2N hydrochloric acid (40 ml), the ether layer washed 2 times with water, dried over sodium sulfate, filtered and concentrated to 0.18 g of oily (I). M.S.: M+ =366; NMR: consistent. ##STR26##