Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22]C(OC(C)(C)C)=O)[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClCCl>[Cl:32][C:2]([Cl:1])([Cl:33])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH2:22])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 0 °C
Reaction time: 1.17 h

Procedure:
A cooled (0° C.) solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (176.5 mg, 0.332 mmol) in dichloromethane (10 mL) was treated with trimethylsilyl-trifluoromethanesulfonate (120 μL, 0.664 mmol). After stirring at 0° C. for 70 min, the reaction was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The combined organics were filtered through a phase separator and the volatiles were removed in vacuo to provide (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester as a white solid. To the white solid was added a solution of (E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2-[1-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-methyl-but-3-enoic acid [1,2,3]triazolo[4,5-b]pyridin-1-yl ester (200.0 mg, 0.332 mmol) in anhydrous acetonitrile (10 mL) and N,N-diisopropylethylamine (120 μL, 0.664 mmol). After stirring at room temperature for 19 h, the reaction was quenched at 0° C. with hydrochloric acid (1 M, 30 mL). The aqueous layer was extracted with ethyl acetate. The combined organics were washed with a saturated solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The crude residue was combined with (S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2-[1-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-methyl-but-3-enoylamino}-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester obtained in the previous step and purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:3 to afford the title compound (305.0 mg, 55%, over 3 steps) as a white solid and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 898.5/900.5 [M+H], Tr=4.16 min.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:38])=O>>[Cl:38][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(O)ncnc2cc1OCCCN1CCOCC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Yield: 66 %

Procedure:
A solution of 4-hydroxy-6-methoxy-7-(3-morpholinopropoxy)quinazoline (2.87 g, 9 mmol) and DMF (1 ml) in thionyl chloride (35 ml) was refluxed for 45 minutes. After addition of toluene, the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH8 with 2M aqueous sodium hydroxide. The organic layer was washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The solid residue was purified by column chromatography eluting with a mixture of methylene chloride, acetonitrile and methanol (50/47.5/2.5) to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (2 g, 66%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccnc2)cc1
Temperature: 100 °C
Reaction time: 5.5 h

Procedure:
To a solution of 20 g (161.1 mmol) of p-fluorobenzaldehyde in 300 ml of DMF, 19.8 g (290.8 mmol) of imidazole and 44.5 g (322.24 mmol) of potasium carbonate are step by step added at r.t. After being stirred for 5.5 h at 100° C., the reaction mixture is cooled to r.t., diluted with ice water and then the mixture is extracted with AcOEt and CH2Cl2. The combined extracts are concentrated under reduced pressure to give 4-imidazol-1-yl-benzaldehyde as a pale yellow powder. 1H-NMR (400 MHz, CDCl3): 7.26 (s, 1H), 7.38 (2, 1H), 7.59 (d, 2H, J=8.56 Hz), 7.98 (s, 1H), 8.02 (d, 2H, J=8.56 Hz), 10.05 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Na].ClCCl.[CH3:13][OH:14]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:14][CH3:13])[N:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: Clc1cc(Cl)ncn1
Agent: [Na]
Solvent: ClCCl
Product: COc1cc(Cl)ncn1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
3 g of 4,6-dichloropyrimidine were dissolved in 30 ml of dried methanol and mixed dropwise at -10° C. with a solution of 0.46 g of sodium in 20 ml of dried methanol and stirred at -10° C. for 5 hours and at room temperature for 12 hours. The solution was rotated in, the residue taken up with 50 ml of dichloromethane and a little activated carbon was added. After filtration, rotation in to dryness took place. The initially liquid residue became crystalline solid when left to stand. 2.5 g of 4-chloro-6-methoxypyrimidine were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([C:19]#[N:20])([CH3:18])[CH3:17])[CH:11]=2)=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[S:33][C:28]2=[N:29][CH:30]=[CH:31][N:32]=[C:27]2[CH:26]=1)=[O:24].[Cu][C:35]#[N:36]>CN1C(=O)CCC1.[NH4+].[Cl-].[Cu]I>[C:35]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([C:19]#[N:20])([CH3:18])[CH3:17])[CH:11]=2)=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[S:33][C:28]2=[N:29][CH:30]=[CH:31][N:32]=[C:27]2[CH:26]=1)=[O:24])#[N:36]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c(NC(=O)c3cc4nccnc4s3)c2)c1
Reactant: N#C[Cu]
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(NC(=O)c3cc4nccnc4s3)c2)c1
Yield: 16.7 %

Procedure:
A solution of N-(2-bromo-5-(3-(2-cyanopropan-2-yl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 64 (80 mg, 0.154 mmol), copper(I) iodide (29.3 mg, 0.154 mmol) and copper(I) cyanide (13.77 mg, 0.154 mmol) in NMP (1.5 mL) was stirred 10 min in microwave at 150° C. with cooling on. The reaction mixture was poured out in NH4Cl solution and extracted with EtOAc. Organic layer was washed (3×) with water, brine, dried, and evaporated. Purification by chromatography CH2Cl2: MeOH (9:1) and then crystallization in acetonitrile gave the title compound N-(2-cyano-5-(3-(2-cyanopropan-2-yl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 65 (12 mg, 16%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 7.64 (t, d=7.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.87 (dd, J=8.6 and 1.9 Hz, 1H), 7.92-7.99 (m, 2H), 8.05 (m, 1H), 8.21 (d, J=1.9 Hz, 1H), 8.58 (s, 1H), 8.79 (d, J=2.3 Hz, 1H), 8.91 (d, J=2.3 Hz, 1H), 10.82 (s, 1H), 11.25 (s, 1H). (m/z)=467 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH3:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:5][C:4]=2[N:3]=1>[Pd].C(O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH3:23])[N:14]([CH2:15][CH:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)nc(N)c1nc(CC)n(CC3CCOCC3)c12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(c1)nc(N)c1nc(CC)n(CC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.6 %

Procedure:
A glass Parr bottle was charged with 10% palladium on carbon (0.2 g) wetted with ethanol (10 mL) and a slurry of ethyl (2E)-3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate (1.81 g, 4.4 mmol) in ethanol (250 mL). The vessel was placed on a Parr apparatus, evacuated and charged with hydrogen (55 psi). The mixture was shaken at ambient temperature for 48 hours. The reaction mixture was filtered through a 0.2 micron PTFE membrane filter and the filter was rinsed with ethanol (300 ml). The filtrate was concentrated to dryness under reduced pressure. Recrystallization from acetonitrile provided 1.51 g of ethyl 3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoate as a white crystalline solid, mp 172-173° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:3]=1[CH2:20][CH2:21][N:22]([OH:26])C(N)=O.ClC1C=C(C=CC=1)C(OO)=[O:32]>ClCCl>[NH:22]([CH2:21][CH2:20][C:3]1/[C:4](=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:19])=[O:32])=[CH:16][CH:17]=2)/[C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(/C=C2/C(CCN(O)C(N)=O)=C(C)c3ccccc32)cc1
Solvent: ClCCl
Product: CC1=C(CCNO)/C(=C/c2ccc(S(C)=O)cc2)c2ccccc21

Procedure:
To a solution of the hydroxylamine from Example 16, Step 6 (130 mg, 0.40 mmol) in dichloromethane (5 mL) at 0° C. was added in one portion 85% m-chloroperoxy benzoic acid (90 mg, 0.44 mmol, 1.1 eq.). After 45 minutes the reaction mixture was diluted with dichloromethane and washed successively with 1N aqueous sodium hydroxide, water, brine, dried over MgSO4 and evaporated to dryness. The residue was chromatographed on silica gel eluting with a 30:1 mixture of dichloromethane:methanol to yield the title compound as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=1)[CH2:6][CH2:5]2.[CH3:23][O:24][CH2:25][C:26](Cl)=[O:27]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH:22][C:26](=[O:27])[CH2:25][O:24][CH3:23])[CH:19]=[CH:18][C:16]=3[N:17]=1)[CH2:6][CH2:5]2
Reactant: COCC(=O)Cl
Reactant: Nc1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2
Product: COCC(=O)Nc1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2
Yield: 40.3 %

Procedure:
Prepared from rac-N2-(5-fluoro-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 11) (100 mg, 0.336 mmol) and methoxyacetyl chloride (34 ul, 0.370 mmol) according to the procedure described for Example 17. Obtained the title compound as a white solid (50 mg, 40%), MS (ISP) m/e=370.2 [(M+H)+].
Reaction SMILES: O[C:2]1[C:3]2[N:13]=[CH:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.P(Cl)(Cl)([Cl:16])=O.C(#N)C>CN(C)C=O>[Cl:16][C:2]1[C:3]2[N:13]=[CH:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)c2ncccc2n1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CSc1nc(Cl)c2ncccc2n1
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
A mixture of 19.0 g (98 mmol) of 4-hydroxy-2-methylthiopyrido[3,2-d]pyrimidine, 36.5 mL (60 g, 390 mmol) of phosphorus oxychloride and 200 mL of acetonitrile was prepared and heated to reflux with stirring. Since not much appeared to happen, about 1 mL of N,N-dimethylformamide was added. The solids then all went into solution in about 10 min. After about 2 hours, the volatiles were removed by evaporation under reduced pressure and the residue was diluted with dichloromethane. The resulting mixture was carefully washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was diluted with hexane and the solids were recovered by filtration and dried to obtain 17.8 g of the title compound melting at 120°-121° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1ccc(F)cc1C(=O)c1ccncc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 108 mg of (2-Amino-5-fluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.25 (s, 9H), 6.98 (dd, 1H, J=8.8 Hz, 3.2 Hz), 7.30-7.38 (m, 3H), 7.43 (m, 2H), 7.62 (m, 2H), 7.80 (dd, 1H, 9.2 Hz, 4.8 Hz), 8.82 (d, 2H, 4.8 Hz), 9.82 (s, 1H). MS: m/z 413.5 (M++1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[C:21](Br)[CH:20]=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[C:27]([Zn]C#N)#[N:28]>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:26])([F:25])[C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)(NC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21)C(F)(F)F
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CC(C)(NC(=O)c1nn(-c2cc(C#N)ccn2)c2c1C[C@H]1C[C@@H]21)C(F)(F)F
Temperature: 130 °C
Yield: 42.2 %

Procedure:
To a mixture of (1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide (35 mg, 0.082 mmol) and dicyanozinc (19.2 mg, 0.164 mmol) in DMA (2 mL) under nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (9.4 mg, 0.0081 mmol) was added. The reaction was heated in a heavy-walled sealed tube under microwave irradiation at 130° C. for 1 h. The mixture was purified by preparative HPLC to give the title compound (13 mg). LCMS m/z=376.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.44-0.47 (m, 1H), 1.26 (td, J=7.9 and 4.9 Hz, 1H), 1.72 (s, 6H), 2.25-2.32 (m, 1H), 2.76-2.82 (m, 1H), 2.92 (d, J=16.9 Hz, 1H), 3.00 (dd, J=16.7 and 6.2 Hz, 1H), 6.87 (bs, 1H), 7.42 (dd, J=5.0 and 1.4 Hz, 1H), 8.15 (s, 1H), 8.62 (d, J=5.0 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:13][CH3:14])[C:11]=1[OH:12])[C:6]([OH:8])=[O:7])[CH3:2].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:7][C:6](=[O:8])[C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:11]([OH:12])=[C:10]([CH2:13][CH3:14])[CH:9]=1
Reactant: CO
Reactant: CCc1cc(C(=O)O)cc(CC)c1O
Agent: O=S(=O)(O)O
Product: CCc1cc(C(=O)OC)cc(CC)c1O

Procedure:
A solution of 27.2 g. (0.14 mol.) of 3,5-diethyl-4-hydroxybenzoic acid in 200 ml. of methanol containing 2 ml. of sulfuric acid is refluxed for 12 hours. After cooling, excess methanol is evaporated, water is added to the residue and it is made basic with 10% aqueous sodium hydroxide. The precipitate is collected, washed with water and dried in vacuo to give 3,5-diethyl-4-hydroxybenzoic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:36][C:37]3[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=3)[C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cn1ccnc1CCl
Reactant: Cc1ccccc1N1CNC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1CN(Cc2nccn2C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=580.3 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloromethyl-1-methyl-1H-imidazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:21]#[N:22]>>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([CH:23]=[C:24]([CH3:26])[CH:25]=3)[C:21]#[N:22])=[CH:8][C:7]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: Cc1cc(Br)cc(C#N)c1
Product: Cc1cc(C#N)cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1

Procedure:
3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methyl-benzonitrile was prepared, from (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 3-bromo-5-methylbenzonitrile according to the procedure of Example 5, as a white solid: mp 256-258° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.67-7.62 (m, 3H), 6.97 (d, 1H, J=8.11 Hz), 2.42 (s, 3H), 1.68 (s, 6H); MS (APCI) m/z 293 ([M+H]+, 100%); Anal. Calc. For C18H16N2O2: C, 73.96; H, 5.52; N, 9.58. Found: C, 73.26; H, 5.46; N, 9.24.
Reaction SMILES: [CH2:1]([N:9]1[C:17]([CH2:18]O)=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:20])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Br)(Br)[Br:22]>C(Cl)Cl>[CH2:1]([N:9]1[C:17]([CH2:18][Br:22])=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:20])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ncnc2c1nc(CO)n2CCc1ccccc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1nc(CBr)n2CCc1ccccc1

Procedure:
A solution of N9-phenethyl-8-hydroxymethyladenine (1 mmol) in methylene chloride was treated with phosphorus tribromide (1 mmol) at 25° C. for 1 h. Extraction and chromatography gave N9phenethyl-8-bromomethyl-adenine as a white solid. TLC: Rf=0.31,10% MeOH—CH2Cl2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1.[CH2:20]([N:27]=[C:28]=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(=O)C.[K+]>C(O)C.O>[CH2:20]([NH:27][C:28](=[S:29])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]2[CH:18]=[CH:19][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:12][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(NNC(=O)c2ccc(Cl)cc2)cc1
Reactant: S=C=NCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(NNc1ccc(NC(=S)NCc2ccccc2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
1-(4-Chlorobenzoyl)-2-(4-aminophenyl)hydrazine hydrochloride (1.5 g, 0.005 mole) was dissolved in hot ethanol (30 ml) under a nitrogen atmosphere. Benzyl isothiocyanate (0.82 g, 0.0055 mole) and potassium acetate (0.6 g, 0.006 mole) were added and the mixture was refluxed under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (10-15 ml.) and chilled in ice. The product was filtered off, washed with ethanol and dried. Recrystallization of the product from acetonitrile gave an off-white solid. Yield 1.25 g (62%), m.p. 197°-199° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH2:5]([O:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16]O[C:14]=1[CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>CO>[CH2:5]([O:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16][N:4]([CH2:1][CH2:2][CH3:3])[C:14]=1[CH3:20])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1ccc(=O)c(OCc2ccccc2)c1C

Procedure:
The starting material can be prepared as follows: 20.64 ml of n-propylamine are added to a solution of 43.24 g of 3-benzyloxy-2-methyl-4H-pyran-4-one in 1000 ml of methanol, followed by the addition of 12.0 g of sodium hydroxide in 100 ml of methanol. The reaction mixture is refluxed for 3 hours, then concentrated by evaporation. The residue is taken up in methylene chloride and the organic solution is washed with water. The phases are clarified by addition of a saturated solution of sodium chloride in water, and the organic extract is dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue is dried under a high vacuum, giving 3-benzyloxy-2-methyl-1-n-propyl-4(1H)-pyridinone as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)ccc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)c(CBr)c1
Yield: 45 %

Procedure:
1-bromo-2-(bromomethyl)-4-chlorobenzene was prepared according to literature precedent (J. Am. Chem. Soc. 2002, 124 (7), 1354): a suspension of 1-bromo-2-methyl-4-chlorobenzene (1 eq), NBS (1 eq) and benzoyl peroxide (0.004 eq) in CCl4 (0.7 M) was heated at reflux for 4 h. The reaction was then filtered whilst hot and the volatiles reduced in vacuo. PE was added, and the resultant precipitate filtered off and dried in vacuo to afford the title compound (45%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[C:18](=[O:21])[CH:19]=[CH2:20])[CH3:2]
Reactant: CCNCc1ccncc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(CC)Cc1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
To a 0° C. solution of 0.835 ml (6.0 mmol) of 4-(ethylaminomethyl) pyridine and 1.05 ml (7.5 mmol) of triethylamine in 10 ml dichloomethane, was dropwise added 0.406 ml (5.0 mmol) of acryloyl chloride. The reaction mixture was warmed to room temperature and stilred for 18 hr. The resulting nmxture was washed with water and brne, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with 3% MeOH/CH2Cl2 as the eluant to provide 651 mg (68%) of the desired product as a yellow gum. Electrospray Mass Spec 191(M+H).
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]3[CH:33]=[CH:34][C:35](=[O:38])[NH:36][N:37]=3)=[CH:31][C:26]=2[N:25]=[CH:24]1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][C:30]([C:32]5[CH:33]=[CH:34][C:35](=[O:38])[NH:36][N:37]=5)=[CH:31][C:26]=4[N:25]=[CH:24]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Reactant: NCCn1cnc2cc(-c3ccc(=O)[nH]n3)ccc21
Product: O=c1ccc(-c2ccc3c(c2)ncn3CCNCC(O)COc2ccc(CCOCC3CCC3)cc2)n[nH]1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone.