Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:22][CH:21]=3)=[N:15][CH:16]=2)[N:11]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41]OS(C)(=O)=O)[CH:35]=2)[C:10]1=[O:47].[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12.[K]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[CH:24][CH:25]=3)=[N:15][CH:16]=2)[N:11]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][N:52]3[C:48](=[O:58])[C:49]4=[CH:57][CH:56]=[CH:55][CH:54]=[C:50]4[C:51]3=[O:53])[CH:35]=2)[C:10]1=[O:47]
Reactant: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCOS(C)(=O)=O)c2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCN4C(=O)c5ccccc5C4=O)c2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Temperature: 90 °C
Yield: 95.2 %

Procedure:
A solution of 50 mg (0.07 mmol) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino) ethoxy]anilino]-3,4-dihydro-1-[3-(2-methanesulfonyloxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 5 ml of dimethylformamide was treated with 17 mg (0.09 mmol) of potassium phthalimide and the mixture was heated at 90° C. for 1 hour. The mixture was cooled and evaporated. The residue was partitioned between 20 ml of ethyl acetate and 20 ml of water. The organic phase was dried over magnesium sulfate and evaporated to yield 50 mg (95%) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =750].
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH2:11])([CH3:10])[CH3:9].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([O:20][CH3:21])=[C:15]([Cl:22])[N:14]=1>CC(CC)=O>[CH:8]([NH:11][C:17]1[C:16]([O:20][CH3:21])=[C:15]([Cl:22])[N:14]=[C:13]([Cl:12])[N:18]=1)([CH3:10])[CH3:9]
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: COc1c(Cl)nc(Cl)nc1NC(C)C

Procedure:
42 ml of triethylamine, 25 ml of isopropylamine, 250 ml of methylethylketone and 32 g of 2,4,6-trichloro-5-methoxypyrimidine (prepared as indicated by Budesinsky et Coll., Ceskoslov. Farm. 10, 241-247, 1961) were stirred together at 20° C. for 6 hours. The reaction mixture was then evaporated under reduced pressure and the residue fixed on a silica gel column. This was followed by elution with a 95/5 toluene-diethylamine mixture. In this way were isolated 20.2 g of 4-isopropylamino-2,6-dichloro-5-methoxypyrimidine.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccnc2ccccc12
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1ccnc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
A mixture of 4-hydroxyquinoline (0.44 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.75 g, 90% yield) as a white solid.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:24][C:25]([F:34])([F:33])[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]([F:24])([F:33])[F:34])=[CH:27][CH:28]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: COC(=O)C(Oc1ccc(C(F)(F)F)cc1)c1ccc(OCCOc2ccc(Cl)cc2)cc1

Procedure:
As described in Example 44, 8.0 g of methyl bromo{p-[2-(p-chlorophenoxy)ethoxy]phenyl}acetate is reacted with p-trifluoromethylphenol to give 7.4 g of product as white crystals. Recrystallization from methanol gives white crystals, mp 95°-97° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([Si](C)(C)C)([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][C:9]1([CH3:16])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:12]([CH:13]([OH:14])[C:18]([F:20])([F:19])[F:17])[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](C(O)C(F)(F)F)COC1(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 92.7 %

Procedure:
To a mixture of (S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.0 g, 4.36 mmol), (trifluoromethyl)trimethylsilane (2.0 M solution in THF, 2.6 mL, 5.20 mmol) in THF (10 mL) was added tetrabutylammonium fluoride (1.0 M solution in THF, 0.1 mL, 0.10 mmol) at 0° C. After addition, the mixture was stirred at room temperature for 60 h. Then, tetrabutylammonium fluoride (1.0 M solution in THF, 9 mL, 9.0 mmol) was added and the mixture stirred for another 6 h and subsequently quenched by adding saturated aq. NaHCO3 solution, extracted with EtOAc. The extracts were washed with saturated aq. NaHCO3 solution, water, brine and dried over Na2SO4. Concentration and purification gave (S)-tert-butyl 2,2-dimethyl-4-(2,2,2-trifluoro-1-hydroxyethyl)oxazolidine-3-carboxylate (1.21 g, 92%), which showed a complicated NMR spectrum because of the different comformers.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][CH:13]=2)[N:4]=1.C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[Cl:33][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:21])([F:20])[F:1])=[N:4]2)=[CH:13][CH:14]=1
Reactant: OCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To a solution of {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanol (Example 30, 1.23 g, 4.16 mmol) in dichloromethane (20 ml) under an atmosphere of argon was added triethylamine (0.75 ml, 5.4 mmol) and the mixture stirred at room temperature for 10 minutes. Methanesulfonyl chloride (0.42 ml, 5.4 mmol) was added dropwise over 5 minutes and the whole mix stirred at room temperature for 18 hours. The reaction mixture was then washed twice with water followed by saturated sodium bicarbonate. The organic layer dried over sodium sulphate and the solvent removed by rotary evaporation to give the title compound as a brown oil (1.24 g, 94%)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[S:16]([N:19]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH3:31])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17].[Li]CCCC.[C:37](=[O:39])=[O:38]>O1CCCC1>[CH3:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:16]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][C:2]=1[C:37]([OH:39])=[O:38])(=[O:18])=[O:17]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2Br)c(C)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2C(=O)O)c(C)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-bromo-N-(2,4-dimethylphenyl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (50 mg, 0.098 mmol) in tetrahydrofuran (THF) at −78° C. was added nBuLi 1.6 M in hexanes (92 μL, 0.147 mmol) and the reaction stirred for 1 hour. After this time carbon dioxide (small pellet) was added and the reaction mixture stirred at −78° C. for 30 minutes, then warmed to 20° C. and stirred for a further 1 hour. The reaction was quenched with saturated ammonium chloride solution and the mixture concentrated in vacuo. The residue was then taken up in ethyl acetate (20 mL) and the organic phase was washed with saturated ammonium chloride solution (2×25 mL), the organics were dried using a hydrophobic frit and evaporated in vacuo to give the crude product as a colourless gum, 40 mg. LCMS [LCMS2] Rt 0.97 min, m/z (ES+) 476 (M+H).
Reaction SMILES: Br.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[SH:13][C:14]1[NH:15][C:16]2[C:17](=[CH:19][S:20][CH:21]=2)[N:18]=1.CC(C)=O>CC(N(C)C)=O>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:13][C:14]1[NH:18][C:17]2=[CH:19][S:20][CH:21]=[C:16]2[N:15]=1
Reactant: CN(C)c1ccccc1CBr
Reactant: Sc1nc2cscc2[nH]1
Agent: Br
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: CN(C)c1ccccc1CSc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.9 g of 2-dimethylaminobenzyl bromide hydrobromide are added to a solution of 1.56 g of 2-mercaptothieno[3,4-d]imidazole in 20 ml of anhydrous dimethylacetamide. A crystalline precipitate separates out in a weakly exothermic reaction. The mixture is stirred at room temperature for one hour, acetone is added, and the crystals are filtered off and dried in a stream of air. The crystalline solid is then introduced into saturated aqueous NaHCO3 solution, the mixture is heated briefly on a steam bath and, after stirring at room temperature, the crystals are filtered off. Treatment with active charcoal in ethanol and concentration is followed by solution being induced to crystallize with a little acetone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[NH:12]([C:14]([NH2:16])=[O:15])[NH2:13].C([O-])(=O)C.[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:13]/[NH:12][C:14]([NH2:16])=[O:15])/[CH3:9])=[CH:4][CH:3]=1
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc(F)cc1
Yield: 108 %

Procedure:
To a solution of 1-(4-fluorophenyl)ethan-1-one (27.6 g, 199.80 mmol, 1.00 equiv) and hydrazinecarboxamide hydrochloride (22 g, 197.25 mmol, 0.99 equiv) in methanol (200 mL) was added a solution of sodium acetate (16.8 g, 204.79 mmol, 1.02 equiv) in water (80 mL) dropwise with stirring. The resulting solution was stirred at room temperature for 2 h. The solid was collected by filtration then air-dried to give 41.6 g of crude (E)-2-(1-(4-fluorophenyl)ethylidene)hydrazinecarboxamide as a white solid. LCMS (method A, ESI): RT=1.22 min, m/z=196.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:3].[C:11]([O:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[CH3:1][C:2]([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])([CH2:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])[CH3:3]
Reactant: CC(C)=CC(=O)C=C(C)C
Reactant: CC(C)(C)OO
Product: CC(C)(C)OOC(C)(C)CC(=O)CC(C)(C)OOC(C)(C)C

Procedure:
A mixture of 47.0 g. (0.34 mole) of phorone and 157 g (1.36 mole) of 78% t-butyl hydroperoxide was stirred with 34 g. of dry Amberlyst 15® sulfonic acid type ion exchange resin in a 500 ml flask equipped with a condenser and thermometer for forty-eight hours at 40° C. and one hour at 50° C. The ion exchange resin was separated by filtration and the product diluted with pentane. The pentane solution was washed with water, sodium bisulfite solution, 5% sodium hydroxide solution and water. After drying over anhydrous magnesium sulfate, the pentane was removed under reduced pressure. The recovered product weighed 74.2 g. (68.5% of the calculated amount). A GLC scan showed a large major peak for the expected product. In the infrared spectrum, small bands for hydroxyl and olefin were observed but the band in the 880 cm-1 region usually associated with t-butyl peroxy groups was strong. By active oxygen assay, the purity of the products was estimated at 83%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([OH:7])=O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:7]
Reactant: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: C1COCCN1
Product: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)N2CCOCC2)c1I

Procedure:
4-[3-Amino-2,4,6-triiodo-5-(N-methylacetamido)benzoyl]morpholine [C; Ro is CH3CON(CH3), Q is H, Z is morpholino] was prepared from the acid chloride of 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid and morpholine according to the procedure described in Example 45, part (a). The product obtained was used directly in the procedure described in part (b) below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[O:29]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:39]3[CH:40]=[CH:41][C:36]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:37][CH:38]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3ccc(Oc4ccccc4)cc3)C2=O)cc1
Yield: 42 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-phenoxyphenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (42%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].ClCCCl.[Cl-].[Al+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.C[O:21][C:22]1[N:23]=[N:24][C:25]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:26][C:27]=1[C:28]1[NH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2>>[C:1]([C:36]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][C:28]=1[C:27]1[C:22](=[O:21])[NH:23][N:24]=[C:25]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)c1c(-c2cc(-c3ccncc3)n[nH]c2=O)[nH]c2ccccc12
Temperature: 0 °C
Yield: 48.1 %

Procedure:
4 mg acetyl chloride are added at 0° C. to a suspension of 80 mg aluminum chloride 1,2-Dichloroethane, followed by 208 mg 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-1H-indole Trifluoroacetate. The reaction mixture is stirred for 4 h at room temperature and for 3h at 50° C. It is worked up pouring into an ice/water mixture and filtration. The layers are separated, the organic is layer washed with water, dried over MgSO4 and the solvent removed. Reverse phase HPLC chromatography yielded 8.1 mg 4-(3-Acetyl-1H-indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[NH3:18].C(O)(C)C>O>[NH2:18][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2cnc(Cl)nn2)cc1
Reactant: N
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(-c2cnc(N)nn2)cc1

Procedure:
A solution of methyl 4-(3-chloro-1,2,4-triazin-6-yl)benzoate (180 mg, 0.721 mmol) and 2M of ammonia in isopropyl alcohol (5 ml, 10 mmol) was stirred at 25° C. for 3 h. The reaction was diluted with water, and the precipitate was filtered to give the desired product. LCMS: (M+H2O+H)=249.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.ClC1C(C2C=CC=CC=2)=NN=C2N(CC(NC)=O)N=C(C3C=CC=CC=3)C=12.[N+:54]([C:57]1[C:62]2=[N:63][O:64][N:65]=[C:61]2[C:60]([NH:66][CH2:67][CH2:68][CH2:69][NH2:70])=[CH:59][CH:58]=1)([O-:56])=[O:55]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([NH:70][CH2:69][CH2:68][CH2:67][NH:66][C:60]3[C:61]4[C:62](=[N:63][O:64][N:65]=4)[C:57]([N+:54]([O-:56])=[O:55])=[CH:58][CH:59]=3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: NCCCNc1ccc([N+](=O)[O-])c2nonc12
Agent: CNC(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)NCCCNc1ccc([N+](=O)[O-])c2nonc12

Procedure:
Compound 6 was synthesised from 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid following a similar procedure outlined in Example 16 (Compound 5), using N1-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)propane-1,3-diamine instead of methylamine hydrochloride in the final step.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][N:8]=2)=[C:4]([CH3:17])[CH:3]=1.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].ClC1C=CC=C(Cl)C=1C(N(C1C=NC(OC2C=CC(Cl)=CC=2C)=CC=1)C)=O>>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([N:13]([C:10]1[CH:9]=[N:8][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:17])=[CH:12][CH:11]=1)[CH3:14])=[O:22]
Reactant: CNc1ccc(Oc2ccc(Cl)cc2C)nc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cc1cc(Cl)ccc1Oc1ccc(N(C)C(=O)c2c(Cl)cccc2Cl)cn1
Product: Cc1cc(Cl)ccc1Oc1ccc(N(C)C(=O)c2ccccc2C)cn1

Procedure:
2-Methyl-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide was prepared from 2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine and 2-methylbenzoyl chloride in the same manner as 2,6-Dichloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide was prepared.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25]O)[CH2:20][CH2:19]2)[CH:5]=1.C([N:36](CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.N>CO.C1COCC1>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25][NH2:36])[CH2:20][CH2:19]2)[CH:5]=1
Reactant: CCN(CC)CC
Reactant: OCC(c1ccc(F)cc1)N1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NCC(c1ccc(F)cc1)N1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Yield: 53.6 %

Procedure:
In the same way as that described in Example 6 using 1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]-4-[1-(4-fluorophenyl)-2-hydroxyethyl]piperazine (113 mg, 0.25 mmol), triethylamine (70 μL, 0.50 mmol), methanesulphonyl chloride (39 μL, 0.50 mmol) and THF (5 mL). The crude mesylate was converted to the amine in the same manner as that used in Example 6, using ammonia (2.5 mL of a 2M solution in MeOH, 5.0 mmol). The amine (60 mg, 53%) was isolated as a pale yellow foam. 1H NMR (250 MHz, CDCl3) δ1.89-2.01 (2H, m), 2.27-2.85 (14H, m), 4.10 (1H, dd, J=10.1 and 3.8 Hz), 7.00 (2H, dd, JHA-HB =8.7 Hz and JHA-F =8.7 Hz), 7.13-7.16 (2H, m), 7.34 (2H, dd, JHB-HA =8.7 Hz and JHB-F =5.5 Hz), 7.47 (1H, d, J=8.6 Hz), 7.57 (1H, d, J=1.9 Hz), 8.37 (1H, br s), 8.47 (2H, s). MS (ES+) (448, M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[O:9][CH2:11][C:12]#[N:13]
Reactant: N#CCBr
Reactant: Oc1cc(I)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#CCOc1cc(I)ccc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
A mixture of 2,5-diiodo-phenol (3.9 g, 11.28 mmol), bromoacetonitrile (2.03 g, 16.91 mmol) and potassium carbonate (3.11 g, 22.55 mmol) in 7 mL acetonitrile was sealed in a stoppered flask and stirred at room temperature for 18 hours. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chomatographed on silica gel (30%-70% CH2Cl2/hexanes) to give 2.78 g of (2,5-Diiodo-phenoxy)-acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.[C:13](OC)(OC)([O:15][CH3:16])[CH3:14].C(OC(=O)C)(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[C:8](=[C:13](/[O:15][CH3:16])\[CH3:14])/[C:9]#[N:10])=[O:7])=[CH:11][CH:12]=1
Reactant: COC(C)(OC)OC
Reactant: N#CCC(=O)c1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Product: CO/C(C)=C(\C#N)C(=O)c1ccc(F)cc1

Procedure:
A solution containing 55.8 g. (0.34 mole) of p-fluorobenzoylacetonitrile, 41 g. (0.34 mole) of trimethyl orthoacetate, and 90 g. (0.88 mole) of acetic anhydride is heated to reflux for 5 hours. The excess solvent and volatile by-products are then removed by vacuum distillation and the residue is recrystallized from diethyl ether. Alternatively, the distillation residue may be distilled over on a Kugelrohr apparatus at 160° C./0.25 mm. to provide a viscous oil which may be crystallized from diethyl ether to provide the pure title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C@H:7]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C:9](=[CH:21][CH2:22]P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH3:44][C@@H:45]([CH2:51][CH2:52][CH2:53][C:54]([CH3:61])([O:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH3:55])[CH2:46][CH2:47][CH2:48][CH:49]=O>C1COCC1>[C:1]([Si:5]([CH3:37])([CH3:38])[O:6][C@H:7]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:15])[CH3:16])[CH2:10][C:9](=[CH:21][CH:22]=[CH:49][CH2:48][CH2:47][CH2:46][C@@H:45]([CH3:44])[CH2:51][CH2:52][CH2:53][C:54]([CH3:61])([O:56][Si:57]([CH3:58])([CH3:60])[CH3:59])[CH3:55])[CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=CCP(=O)(c2ccccc2)c2ccccc2)C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: C[C@H](CCCC=O)CCCC(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](CCCC=CC=C1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C1)CCCC(C)(C)O[Si](C)(C)C
Reaction time: 0.33 h

Procedure:
8.55 g of carefully dried (3R,5R)-[2-[3,5-bis-(t-butyldimethyl-silanyloxy)-cyclohexylidene]-ethyl]-diphenyl-phosphine oxide (Tetrahedron Lett. 32, 7663 (1991)) was dissolved in 90 ml of abs. THF and treated at -78° with 10.9 ml of nBuLi (1.6M, hexane). After 20 minutes, 2.27 g of (S)-5,9-dimethyl-9-trimethylsilanyloxy-decanal, dissolved in a small amount of THF, was added dropwise to the deep red solution. The mixture was kept for 0.5 h at -78° and for 4 h at ambient temperature. After quenching with crushed ice/ KH2PO4, the product was extracted twice with ether, washed with water and brine, dried over sodium sulfate and the solvents removed i.V. Flash chromatography (SiO2, hexane/ AcOEt) yielded in the less polar fractions 3.840 g of (R)-1-[(3R,5R)-3,5-bis-(tert-butyldimethyl-silanyloxy)-cyclohexylidene]-7,11-dimethyl-11-trimethylsilanyloxy-dodec-2-ene, as colorless oil, which was deprotected as described in the following paragraph. 2.40 g of phosphine oxide, which had been used in excess, were recovered in the more polar fractions.