Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([Li])[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:5](=[CH2:6])[C:2]2([CH3:4])[CH3:3].[Cl-].[Zn+2:13].[Cl-]>CCCCC.C(OCC)C>[C:1]12([Zn:13][C:1]34[CH2:10][CH:7]([CH2:8][CH2:9]3)[C:5](=[CH2:6])[C:2]4([CH3:4])[CH3:3])[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:5](=[CH2:6])[C:2]2([CH3:4])[CH3:3]
Reactant: [Zn+2]
Reactant: [Li]C12CCC(C1)C(=C)C2(C)C
Agent: [Cl-]
Solvent: CCCCC
Solvent: CCOCC
Product: C=C1C2CCC([Zn]C34CCC(C3)C(=C)C4(C)C)(C2)C1(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Thiele et al. Anorg. Allg. Chem. Chem. 1988, 561, 73. To a stirred suspension of 18.4 g 1-camphenyllithium in 250 mL n-pentane is added dropwise a solution of 9 g zincchloride in 300 mL diethylether at room temperature (keep the speed of addition in such a way that the solution is boiling smoothly). This reaction mixture is stirred for 3 h and is subsequently allowed to stand overnight. The precipitated LiCl is filtered off and the solvent of the filtrate is completely removed. The residue is solved in n-pentane and remaining LiCl is separated. The solution is the cooled to -78° C. The precipitated crystalls are filtered at low temperature and dried in vacuo. Yield: 12.5 g (60%).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[N:17]2[C:18]3[N:9]([C:10](=[O:20])[CH:11]=[N:12][C:13]=3[CH:14]=[CH:15][C:16]2=[O:19])[CH2:8]1)(=O)=O.N1C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1>C(#N)C>[O:20]=[C:10]1[CH:11]=[N:12][C:13]2=[C:18]3[N:9]1[CH2:8][C@@H:7]([CH2:6][N:27]1[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]1)[N:17]3[C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CS(=O)(=O)OC[C@@H]1Cn2c(=O)cnc3ccc(=O)n1c32
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
A solution of [(1S)-3,8-dioxo-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylen-1-yl]methyl methanesulfonate (1.05 g, 3.53 mmol) in dry acetonitrile (50 ml) at room temperature under argon was treated with pyridine (0.343 ml, 4.24 mmol), followed by 1,1-dimethylethyl 4-piperidinylcarbamate (0.884 g, 4.24 mmol). The mixture was heated at 70° C. for 1.5 h and then at 90° C. for 3 h. LCMS showed ˜25% of product. So 0.5 eq of pyridine and 0.5 eq of 1,1-dimethylethyl 4-piperidinylcarbamate were added and the reaction was heated at 90° C. overnight and then stirred at room temperature for 2 days. The reaction was complete. The solvent was evaporated and the residue partitioned between sat NaHCO3 and 20% methanol/dichloromethane (100 ml/100 ml). The layers were separated and the aqueous layer was extracted with 20% methanol/dichloromethane again (2×100 ml). The combined organic extracts were dried on magnesium sulphate, filtered and evaporated to afford 1.7 g of crude which was purified by silica chromatography using a 0-5% methanol/dichloromethane gradient to afford the product as a yellow solid (0.57 g, 40.2%).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1.Br[C:13]1[CH:20]=C(C)C(C=O)=C(C)[CH:14]=1>>[CH3:10][C:8]1[CH:9]=[C:2]([CH:13]([CH3:20])[CH3:14])[CH:3]=[C:4]([CH3:11])[C:5]=1[CH2:6][OH:7]
Reactant: Cc1cc(Br)cc(C)c1C=O
Reactant: Cc1cc(Br)cc(C)c1CO
Product: Cc1cc(C(C)C)cc(C)c1CO
Yield: 95 %

Procedure:
4-Bromo-2,6-di methylbenzyl alcohol, from 4-bromo-2,6-dimethylbenzaldehyde (Hjed, H. et al. Acta Chem. Scand. 1965, 19:2166); 95% yield, mp 1 17-119° C.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1(P([CH:24]2[CH2:29][CH2:28]CCC2)C2CCCCC2)CCCCC1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(B(O)O)CC1>O.C1(C)C=CC=CC=1>[CH:28]1([C:2]2[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:29][CH2:24]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: N#Cc1ccc(F)cc1Br
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)C1CC1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(F)cc1C1CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
500 mg commercially available 2-Bromo-4-fluorobenzonitrile, 70 mg tricyclohexylphosphine, 2.04 g tri potassium phosphate mono hydrate and 278 mg cyclopropylboronic acid placed in a reaction vessel and 11 ml toluene were added. The mixture was degassed with argon, then 561 mg palladium(II)acetate were added and the reaction mixture stirred at 100° C. for 1.5 hours. To the cooled reaction mixture was added 30 ml water and the mixture was extracted five times with portions of 30 ml ethyl acetate. The combined organic layers were dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with the eluent heptane=>n-heptane:ethyl acetate=5:1 to obtain 310 mg 2-Cyclopropyl-4-fluoro-benzonitrile as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:13]Cl>C(O)(=O)C>[Cl:13][C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9][NH:10][CH:11]=1
Reactant: ClCl
Reactant: Clc1ccc(-c2cc[nH]n2)cc1
Solvent: CC(=O)O
Product: Clc1ccc(-c2n[nH]cc2Cl)cc1
Yield: 33.3 %

Procedure:
1.0 g (0.006 mol) of 3-(4-chlorophenyl)-1H-pyrazole are dissolved, at room temperature and with stirring, in 20 ml of acetic acid. 0.5 g (0.007 mol) of chlorine is then introduced into the reaction mixture. The white precipitate formed is filtered, washed with water and heptane and then chromatographed on a silica column (eluent 70/30 heptane/ethyl acetate). 0.7 g (0.002 mol) (yield: 58%, melting point: 158° C.) of 4-chloro-3-(4-chlorophenyl)-1H-pyrazole is obtained.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].[NH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[C:26]([Cl:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2>>[Cl:38][C:26]1[CH:25]=[C:24]([NH:23][C:15]2[C:14]3[C:19](=[CH:20][CH:21]=[CH:22][C:13]=3[O:12][CH2:11][CH2:10][NH:9][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:18]=[CH:17][N:16]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CS(=O)(=O)CC(=O)O
Product: CS(=O)(=O)CC(=O)NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 51 %

Procedure:
The procedure described in Example 1 was repeated using methanesulfonylacetic acid and 5-(2-aminoethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.6, preparation of starting materials) to give the title compound in 51% yield; NMR spectrum (DMSO-d6) 2.99 (s, 3H), 3.74 (m, 2H), 4.04 (s, 2H), 4.34 (t, 2H), 5.29 (s, 2H), 7.13 (d, 1H), 7.22 (d, 1H), 7.35 (m, 2H), 7.55 (m, 2H), 7.71 (t, 1H), 7.87 (dt, 1H), 8.03 (d, 1H), 8.46 (s, 1H), 8.58 (d, 1H), 8.76 (t, 1H), 9.79 (s, 1H); Mass Spectrum MH+ 542.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C([O-])(O)=O.[Na+]>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2([CH3:16])[CH2:7][C:6]3[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=3[O:4]2)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(Cc3ccccc3)CC1)O2
Temperature: 180 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
In an autoclave, a mixture of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (0.85 g), 4-benzylpiperidine (1.1 g), and triethylamine (1.3 mL) was stirred under nitrogen gas at 180° C. for 15 hours. This reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethanol=10:1) and crystallized from hexane to provide 0.86 g of the title compound. Yield 78%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2N=N[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1)[CH3:2].[CH:26](N1CCCC1)=[CH:27][CH3:28]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:26]=[C:27]([CH3:28])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CC=CN1CCCC1
Reactant: CCOC(=O)c1nnc(-c2ccc(CC)cc2)c(-c2ccccc2)n1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccccc2)c(-c2ccc(CC)cc2)cc1C

Procedure:
Following General Procedure D, ethyl 6-(4-ethylphenyl)-5-phenyl-1,2,4-triazine-3-carboxylate (Compound 13, 200 mg, 0.60 mmol) and crude 1-propenyl-pyrrolidine (Compound 39, 2 g) in CHCl3 (10 ml) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[O:11]1CCOC[CH2:12]1.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:10][C:4]1[S:3][C:2]2[NH:1][C:12](=[O:11])[O:8][C:7](=[O:9])[C:6]=2[CH:5]=1
Reactant: Cc1cc(C(=O)O)c(N)s1
Reactant: C1COCCO1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc2c(=O)oc(=O)[nH]c2s1
Temperature: 5 °C
Yield: 100 %

Procedure:
step 2—A suspension of 60b (4.0 g, 25.5 mmol) and dioxane (65 mL) was cooled to 5° C. Phosgene (22.5 mL of a 20% solution in toluene, 45.9 mmol) was added dropwise through a septum. The flask was equipped with a condenser and the mixture was refluxed for 4 h. After cooling the solvents were evaporated in vacuo to afford 5.0 g (100%) of 6-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (61a) which was used without purification: ms [M−H]=182.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OC(=O)c2cc(O)ccc2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2cc(OCc3ccccc3)ccc2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 500 mg 6-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (2.57 mmol), 550 mg benzyl bromide (3.22 mmol), and 922 mg cesium carbonate (2.8 mmol) in 8.6 mL of anhydrous DMF were stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate, and brine solutions. The organic fraction was dried over sodium sulfate and concentrated under reduced pressure to give a crude residue which was further purified by column chromatography, eluting from silica gel with a gradient of 10 to 50% ethyl acetate in hexanes, to give the desired product as a pale yellow solid. MS: (+) m/z 285.10 (M+1)
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1.[C:30]1([C:36]2[N:37]=[C:38]([CH2:47]Br)[O:39][C:40]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:30]1([C:36]2[N:37]=[C:38]([CH2:47][NH:1][CH:2]3[CH2:11][CH2:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:3]3)[O:39][C:40]=2[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC(N)C2)(c1ccccc1)c1ccccc1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1cccc2c1CCC(NCc1nc(-c3ccccc3)c(-c3ccccc3)o1)C2)(c1ccccc1)c1ccccc1

Procedure:
A solution of 2-amino-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (0.96 g), (4,5-diphenyloxazol-2-yl)methyl bromide (0.80 g) and potassium carbonate (0.41 g) in DMF (14 ml) was stirred for 3.5 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo to give crude 2-[(4,5-diphenyloxazol-2-yl)methylamino]-1,2,3,4-tetrahydro-5-t-butyldiphenylsilyloxynaphthalene. To a solution of crude 2-[(4,5-diphenyloxazol-2-yl)methylamino]-1,2,3,4-tetrahydro-5-t-butyldiphenylsilyloxynaphthalene in THF (5 ml) was added 1M THF (3 ml) solution of tetrabutylammonium fluoride. After being stirred for 1 hour at room temperature, the mixture was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 2-[(4,5-diphenyloxazol-2-yl)methylamino]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.66 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][N:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1Br.[Cu][C:22]#[N:23].CN1CCCC1=O.Cl>[Fe](Cl)(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][N:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[C:22]#[N:23]
Reactant: N#C[Cu]
Reactant: CCCCCc1cnc(-c2cc(F)c(Br)c(F)c2)nc1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCCc1cnc(-c2cc(F)c(C#N)c(F)c2)nc1
Yield: 42.4 %

Procedure:
0.7 g of 2-(3',5'-difluoro-4'-bromophenyl)-5-pentylpyrimidine, 0.5 g of copper (I) cyanide and 3.5 ml of N-methylpyrrolidone were mixed in a flask and refluxed for 5 hours. The solution was poured into a solution including 1.7 g of iron (III) chloride, 0.4 ml of concentrated hydrochloric acid and 1.7 ml of water. The solution was extracted with chloroform and washed with water and an aqueous 10% solution of potassium hydroxide. The chloroform was distilled off. The residue was treated through a silica gel column using chloroform as the solvent and recrystallized from methanol to yield 0.25 g of 2-(3',5'-difluoro-4'-cyanophenyl)-5-pentylpyrimidine. The crystal--isotropic liquid transfer point (C-I Point) of the compound was 65.3° C.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]([O:16]CC)=[O:15])[CH:9]=[CH:10][C:11]=1[CH3:12].[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]([OH:16])=[O:15])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: CCOC(=O)Cc1ccc(C)c(OCc2c(C)cccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(CC(=O)O)cc1OCc1c(C)cccc1C
Reaction time: 3 h

Procedure:
To a stirred solution of Ethyl 2-(3-(2,6-dimethylbenzyloxy)-4-methylphenyl)acetate (Step D, 1.1 g, 3.5 mmol) in absolute ethanol (20 ml) was added 1N NaOH (7 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified to pH 3.5-4.0 by adding 1N HCl and concentrated. The residue was taken into chloroform and washed with 0.1N HCl, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)[N:4]=1.[N:19]1([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=[N:20]1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][N:15]([C:26]([C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[O:27])[CH2:16]3)[CH2:12]2)[N:4]=1
Reactant: COc1cc(OC)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1ccccc1-n1cccn1
Product: COc1cc(OC)nc(N2CC3CN(C(=O)c4ccccc4-n4cccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 39 and 2-pyrazol-1-yl-benzoic acid. MS (ESI) mass calcd. for C22H24N6O3, 420.46; m/z found, 421.1 [M+H]+. 1H NMR (CDCl3): 7.74 (d, J=2.0 Hz, 1H), 7.59-7.29 (m, 5H), 6.31 (br s, 1H), 5.32 (s, 1H), 3.90-3.64 (m, 7.8H), 3.61-3.41 (m, 2.2H), 3.40-3.05 (m, 3H), 2.95-2.65 (m, 3H).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.CN(C)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:15][S:16]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: On1nnc2ccccc21
Agent: CN(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CS(=O)(=O)On1nnc2ccccc21
Reaction time: 8 h

Procedure:
1-Hydroxy-1,2,3-benzotriazole (6.5 g) and trimethylamine (7.0 ml) are dissolved in benzene (50 ml). To the solution is added dropwise methanesulfonyl chloride (3.9 ml) with stirring under ice-cooling and the mixture is stirred for 2 hours and then allowed to stand overnight. To the reaction mixture are added water and ethyl acetate. The ethyl acetate layer is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off. The resulting crystals are washed with petroleum ether to give 1-methanesulfonyloxy-1,2,3-benzotriazole (9.2 g), melting point: 90°-92° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:17]([Cl:28])[CH:16]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38].C(=O)(O)[O-].[Na+]>CN(C=O)C.C1COCC1>[Cl:28][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:36](=[O:39])[CH:37]=[CH2:38])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][C:18]=1[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Sc2ccccc2)c(Cl)c1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Sc4ccccc4)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.9 %

Procedure:
Dissolved 1.00 g (2.48 mmol) 6-amino-4-[(3-chloro-4-thiophenoxyphenyl)amino]-3-quinolinecarbonitrile in 2.0 ml DMF and 12 ml THF and chilled to 0° C under N2. Added 380 μl (2.73 mmol) triethylamine and 227 μl (2.73 mmol) acryloyl chloride. Removed ice bath at 15 minutes and at 1.5 hours stripped solvent and slurried residue with dilute sodium bicarbonate. Collected solids and washed with water. Recrystallized from ethyl acetate and dried in vacuo, giving 293 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=457.3. 459.3.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].C([Si](C)(C)[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[CH:27]=O)(C)(C)C.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:27]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:29]=[C:30]([CH3:32])[CH:31]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(OCCO[Si](C)(C)C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)cc(OCCO)c3)nc2c1
Temperature: 120 °C

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (0.350 g, 1.78 mmol) in N,N-dimethylacetamide (20 mL) under nitrogen was added 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-benzaldehyde (0.520 g, 1.78 mmol) followed by sodium hydrogensulfite (0.270 g, 2.67 mmol), and p-toluenesulfonic acid (0.033 g, 0.18 mmol). The resulting mixture was heated at 120° C. for 24 hours, then the solvent was concentrated to 5 mL under reduced pressure, and water was added to obtain a precipitate, which was filtered off and washed with Et2O and methylene chloride. The resulting solid was dissolved in hot CH2Cl2/MeOH, and then precipitated by adding Et2O, and purified by preparative thin-layer chromatography (DC-Fertigplatten SIL G-100 UV, 9/1 methylene chloride/MeOH as eluent) to give the title compound as a yellow solid. Yield: 81 mg (13%). MP 106.9-109.1° C. 1H NMR (400 MHz, CDCl3): δ7.86 (s, 1H), 7.41 (d, 2H), 6.82 (s, 1H), 6.57 (s, 1H), 4.15-4.13 (m, 2H), 3.94-3.90 (m, 8H), 2.43 (s, 3H). MS (ES+) m/z: 357.53 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[Cl:18])[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: NCc1ccccc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccc2Cl)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-chlorobenzylamine and DBU in DME. EI-MS m/e (%): 327 (M{37Cl}+, 10), 325 (M{35Cl}+, 35), 290 ([M—Cl]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]#[N:29])[C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[C:17](C(O)=O)=[N:16]3)=[CH:11][C:10]=2OC)=[CH:4][CH:3]=1.SC[C:32](O)=[O:33]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[CH:17]=[N:16]3)=[C:13]([O:33][CH3:32])[CH:14]=2)[C:28]#[N:29])=[CH:4][CH:3]=1
Reactant: COc1cc(-n2nc(C(=O)O)c(=O)[nH]c2=O)ccc1C(C#N)c1ccc(Cl)cc1
Reactant: O=C(O)CS
Solvent: O
Product: COc1cc(C(C#N)c2ccc(Cl)cc2)ccc1-n1ncc(=O)[nH]c1=O
Temperature: 175 °C

Procedure:
A mixture of 4.2 parts of 2-[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acid and 13 parts of 2-mercaptoacetic acid is stirred and heated for 2 hours at 175° C. After cooling, 150 parts of water are added. The aqueous phase is decanted and the remaining oil is stirred in water. The whole is treated with sodium hydrogen carbonate. The product is extracted with a mixture of trichloromethane and methanol (90:10 by volume). The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated in vacuo. The residue is crystallized from 8 parts of acetonitrile. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-3-methoxybenzeneacetonitrile (intermediate 2).