Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][N:48]([CH3:64])[C:49]([C:51]1[N:52]=[C:53]([C:60]([F:63])([F:62])[F:61])[N:54]2[CH2:59][CH2:58][NH:57][CH2:56][C:55]=12)=[O:50].C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:57]1[CH2:58][CH2:59][N:54]2[C:53]([C:60]([F:63])([F:61])[F:62])=[N:52][C:51]([C:49]([N:48]([CH3:64])[CH3:47])=[O:50])=[C:55]2[CH2:56]1)=[O:6]
Reactant: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CNCC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 10.4 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), N,N-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 22c (200 mg, 0.80 mmol) and N,N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-N,N-dimethyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 22 (45 mg, yield 11.0%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:29])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:27]#[N:28])=[N:19]3)[C@@H:12]([CH3:30])[CH2:11]2)=[C:4]([F:31])[CH:3]=1.[NH2:32][OH:33].Cl>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:29])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:27]([NH:32][OH:33])=[NH:28])=[N:19]3)[CH:12]([CH3:30])[CH2:11]2)=[C:4]([F:31])[CH:3]=1
Reactant: NO
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(C#N)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Agent: Cl
Solvent: CCO
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(=N)NO)c4cccnc43)C(C)C2)c(F)cc1Cl
Temperature: 65 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (1.6 g, 3.6 mmol, 1 eq), NH2OH.HCl (0.84 g, 10.8 mmol, 3 eq), TEA (1.5 ml), and ethanol (10 ml) was stirred at 65° C. overnight. The reaction solution was concentrated in vacuo, and dissolved in ethyl acetate, washed with brine, and concentrated to provide 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-oxo-ethyl}-N-hydroxy-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine (1.2 g).
Reaction SMILES: [CH:1]1([S:7][C:8](=[S:14])[NH:9][CH2:10][C:11]([Cl:13])=[CH2:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:15]Br>C(#N)C>[BrH:15].[Br:15][CH2:12][C:11]1([Cl:13])[S:14][C:8]([S:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[N:9][CH2:10]1.[BrH:15]
Reactant: C=C(Cl)CNC(=S)SC1CCCCC1
Reactant: BrBr
Solvent: CC#N
Product: Br
Product: ClC1(CBr)CN=C(SC2CCCCC2)S1
Temperature: 0.5 °C
Reaction time: 0.33 h

Procedure:
Under a slight stream of nitrogen, 19.0 g of (2-chloro-allyl)-dithiocarbamic acid cyclohexyl ester are placed in 100 ml of acetonitrile and cooled to 0-1° C. Before and during the addition of bromine, the apparatus is flushed thoroughly with nitrogen. Then 14.0 g of bromine are added in the course of 70 minutes in such a manner that the temperature can be maintained at 0-10° C. When the addition is complete, stirring is carried out for about 20 minutes. The reaction mixture is concentrated in vacuo at 20-25° C. 50 ml of hexane are added to the crude product, and the product is filtered off with suction at 20-25° C., washed twice with 45 ml of hexane and dried in vacuo at room temperature. The title product is obtained in the form of the hydrobromide (compound 2.3).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCOCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
To 133 g (1.31 mol) of tetrahydropyran-4-ol in pyridine (1.5 L) are added 373 g (1.95 mol) of p-toluenesulfonylchloride portionwise at 10° C. After complete addition the reaction is allowed to warm to RT and stirred for 18 h. The reaction is poured onto a stirred mixture of aq. HCl/ice. The resulting precipitate is isolated by filtration and dissolved in DCM (1 L). The organic layer is washed with 1 M aq. HCl solution (1 L), followed by sat. aq. NaHCO3 solution (1 L) and is then dried over Na2SO4. Filtration and concentration of the filtrate under reduced pressure gives 300 g of toluene-4-sulfonic acid tetrahydropyran-4-yl ester. Yield: 90%; ESI-MS: 257 [M+H]+
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[N:5].BrCC1C=CC=C(C#N)C=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2([C:28]3=[CH:29][C:30]4[O:34][CH2:33][O:32][C:31]=4[CH:35]=[C:27]3[O:26][CH2:25]2)[C:17]1=[O:36].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:36]=[C:17]1[C:18]2([C:28]3=[CH:29][C:30]4[O:34][CH2:33][O:32][C:31]=4[CH:35]=[C:27]3[O:26][CH2:25]2)[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]1[CH2:2][CH2:3][C:4]#[N:5]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: N#CCCBr
Agent: N#Cc1cccc(CBr)c1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 44 and making non-critical variations using 3-bromopropionitrile to replace α-bromo-m-tolunitrile, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propanenitrile was obtained (86%) as a colorless solid: mp 200-202° C.; 1H NMR (300 MHz, DMSO-d6) δ7.32 (ddd, J=7.6, 7.4, 1.2 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.15 (d, J=6.7 Hz, 1H), 7.04 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.66 (s, 1H), 6.24 (s, 1H), 5.89 (d, J=2.2 Hz, 2H), 4.69 (ABq, J=9.3 Hz, 2H), 4.10-3.88 (m, 2H), 2.95 (t, J=6.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.1, 155.8, 148.8, 142.2, 141.9, 132.3, 129.3, 124.1, 123.7, 120.1, 119.1, 109.8 103.6, 101.9, 93.7, 80.3, 57.9, 35.9, 16.2; MS (ES+) m/z 335.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:29]([C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)(=[O:31])=[O:30])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Clc1nc(N2CCOCC2)c2cc(CN3CCNCC3)sc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cccs1)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C

Procedure:
To 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[2,3-d]pyrimidine (150 mg) in anhydrous DCM (4 ml) and triethylamine (90 ul) was added 2-thiophenesulfonyl chloride (101 ul) at 0° C. The reaction mixture was allowed to warm up to room temperature over 4 hours. Aqueous work-up and purification on silica gave 2-chloro-4-morpholin-4-yl-6-[4-(thiophene-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[2,3-d]pyrimidine (208 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=2[C:5]([F:19])=[C:4](Cl)[N:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(N(C(C)C)CC)(C)C>CS(C)=O.CC(O)C>[C:31]([O:30][C:29]([NH:28][C@@H:23]1[C@H:22]([NH:21][C:4]2[N:3]=[C:2]([Cl:1])[C:7]3[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=3[C:5]=2[F:19])[CH2:27][CH2:26][O:25][CH2:24]1)=[O:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: CC(C)(C)OC(=O)N1Cc2c(F)c(Cl)nc(Cl)c2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 100 °C
Yield: 85.6 %

Procedure:
A mixture of tert-butyl 4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (1.42 g, 4.43 mmol), tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (1.15 g, 5.52 mmol), diisopropylethylamine (3.87 mL, 22.16 mmol) in DMSO (10 mL) and 2-propanol (40 mL) were heated to 100° C. in an oil bath for 20 h. The solution was then concentrated and the resulting oil was dissolved in water (50 mL) and heated in an oil bath to 50° C. for 1 h then allowed to cool to RT. The solution was subsequently heated to 50° C. for 15 min, allowed to cool to RT, again heated to 50° C. for 15 min, and allowed to cool to RT. The resulting precipitate was filtered and rinsed with water to give the title compound as a pale pinkish-white solid (1.90 g, 86%, 4:1 mixture with regioisomer) which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 9H), 1.50 (s, 3H), 1.59-1.61 (m, 1H), 1.97-1.99 (m, 1H), 1.97-1.99 (m, 1H), 3.46-3.49 (m, 2H), 3.80-3.83 (m, 3H), 4.31-4.33 (m, 1H), 4.73 (s, 1H), 6.59 (d, J=7.30 Hz, 1H), 7.43 (d, J=7.30 Hz, 1H). [M+H] calc'd for C22H30ClFN4O6, 501. found, 501.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:11][C:10]=1[F:33])[C:2]1[CH:7]=[CH:6]C=CC=1.[F:34]C1(CO)CC1>>[F:33][C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[CH:22]=[CH:21][C:19]=3[N:20]=2)[CH:13]=[C:14]([F:15])[C:9]=1[O:8][CH2:1][C:2]1([F:34])[CH2:7][CH2:6]1
Reactant: OCC1(F)CC1
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCc4ccccc4)c(F)c3)oc2c1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCC4(F)CC4)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3,5-difluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and (1-fluorocyclopropyl)methanol, and in the same manner as in Step A and Step B of Example 4, the title compound was obtained.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][CH:14]=[C:15](I)[C:16](=[O:17])[N:11]2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>C(N(CC)CC)C.O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][CH:14]=[C:15]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16](=[O:17])[N:11]2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCCCSc1nn2c(=O)c(I)cnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCSc1nn2c(=O)c(C#C[Si](C)(C)C)cnc2s1
Reaction time: 1 h
Yield: 80 %

Procedure:
In a mixture of 50 ml of triethylamine and 100 ml of tetrahydrofurane, 8.0 g of the thus obtained 2-heptylthio-6-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved. To this solution, 0.68 g of bis(triphenylphosphine)palladium(II) chloride and 0.2 g of cuprous iodide were added as catalysts. To this mixture, a solution of 3.9 g of ethynyltrimethylsilane in 20 ml of triethylamine was added dropwise. The mixture was warmed to 60°~80° C. and stirred for 1 hour. Thereafter, further the same amounts as above of the catalysts and ethynyltrimethylsilane were added, and the mixture was stirred at 60°~70° C. for 3 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent, and 5.9 g of 2-heptylthio-6-trimethylsilylethynyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [Na].[C:2]([CH2:7][C:8]1[N:12]=[C:11]([SH:13])[NH:10][N:9]=1)([O:4][CH2:5][CH3:6])=[O:3].CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O>>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:13][C:11]3[N:12]=[C:8]([CH2:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])[NH:9][N:10]=3)[CH2:28][S:27][C@H:22]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCOC(=O)Cc1n[nH]c(S)n1
Agent: [Na]
Product: CCOC(=O)Cc1nc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n[nH]1

Procedure:
Reaction of 3-carbethoxymethyl-1,2,4-triazole-5-thiol sodium salt, prepared as described in Example 8, and 7-aminocephalosporanic acid according to the procedure described in Example 8 gives the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:18][CH2:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:25]=2[CH2:24][CH2:23]1)=[O:21])[CH2:8][CH:9]1[CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:50](I)([CH3:52])[CH3:51]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:18][CH2:19][C:20]([N:22]1[CH2:23][CH2:24][C:25]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[CH:29][C:26]=2[CH2:27][CH2:28]1)=[O:21])[CH2:8][CH:9]1[CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:17][CH:50]([CH3:52])[CH3:51])[CH:14]=2)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)I
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(CC1Cc3cc(O)ccc31)C(=O)OC(C)(C)C)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CCN(C(=O)CCN(CC1Cc3cc(OC(C)C)ccc31)C(=O)OC(C)(C)C)CC2
Reaction time: 24 h

Procedure:
1.4 g (2.7 mmoles) of the product of Step 1 are dissolved in 15 mL of DMF. There are then added 740 mg (2 equivalents) of potassium carbonate, 160 mg (0.18 equivalent) of caesium carbonate and 0.54 mL (2 equivalents) of isopropyl iodide. Heating is then carried out at 40° C. for 24 hours. The DMF is evaporated off using a rotary evaporator. The residue obtained is then diluted with water and extracted with CH2Cl2. The organic phase is then dried over MgSO4, filtered and evaporated to dryness. An oil is obtained which is purified by flash chromatography over 100 g of silica (eluant: CH2Cl2/ethyl acetate: 80/20) to yield the expected product in the form of a sticky meringue.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:13][CH:12]=2)=O)CCC.[NH2:30][CH2:31][C:32]([OH:34])=[O:33]>>[C:22]1([S:19]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[C:10]([C:28]#[N:29])=[N:9][C:8]([C:6]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:5])=[C:17]3[OH:18])(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(S(=O)(=O)c3ccccc3)cc2c1O
Reactant: NCC(=O)O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(S(=O)(=O)c3ccccc3)ccc12

Procedure:
Prepared from 6-benzenesulfonyl-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 28e (56% yield). MS-(+)-ion: M+1=412.26.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18](O)[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.CCN(S(F)(F)[F:34])CC>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18]([F:34])[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)CC(CNc2nc(Cl)cc3nccnc23)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)CC(CNc2nc(Cl)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-5-hydroxypiperidine-1-carboxylate (1.97 g, 5.0 mmol) in dichloromethane was added DAST (4.03 g, 25 mmol). The reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by chromatography to give the title compound. MS (m/z): 396 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][O:30][CH2:31][CH2:32][N:33]=[C:34]=S.C(Cl)CCl>C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[C:34]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COCCN=C=S
Reactant: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Solvent: ClCCCl
Solvent: CCO
Product: COCCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1Cc1ccccn1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-(pyridin-2-ylmethyl)quinoline-3,4-diamine (35 mg, 0.093 mmol) was dissolved in ethanol (5 ml) and 2-methoxyethyl isothiocyanate (22 mg, 0.186 mmol) was added, then the solution was heated at 60° C. for 3 h, cooled and evaporated in vacuo. The residue was dissolved in THF (5.0 ml) and EDC (35.7 mg, 0.186 mmol) was added, then the solution was heated at 60° C. for 3 h, cooled and evaporated in vacuo and the residue purified by MDAP (formate) to give 7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-N-(2-methoxyethyl)-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-amine (25 mg, 0.055 mmol, 58.5% yield) as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:14])=O)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O>O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=3)[C:12]#[N:14])[O:8][C:4]=2[CH:3]=1
Reactant: NC(=O)c1cccc(-c2nc3ccc(Br)cc3o2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 92.3 %

Procedure:
To a mixture of 3-(6-bromobenzoxazol-2-yl)benzamide (Compound of Example 253) (1.09 g), pyridine (0.41 g) and N,N-dimethyl formamide (20 ml) was added dropwise oxalyl chloride (0.52 g) at 0° C., and the mixture was stirred at 0° C. for 50 minutes. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, successively, and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain 3-(6-bromobenzoxazol-2-yl)benzonitrile (949 mg, 92%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1.C(O)(=O)C>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:14])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)(=[O:7])[O:5][CH3:6]
Reactant: COC(=O)Cc1cccc(Cl)c1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)Cc1cccc(Cl)c1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a solution of dimethyl methylphosphonate (17.93 g, 144 mmol) in THF (270 mL) at −78° C. was slowly added n-BuLi (2.5M, 64.2 mL, 160.6 mmol). The reaction mixture was stirred for 1 h and (3-chloro-phenyl)-acetic acid methyl ester (26.93 g, 146 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and was stirred for 24 h. Acetic acid (15 mL) was added and the volatiles were removed in vacuo. The residue was diluted with CH2Cl2 and the organic solution was washed carefully with saturated aqueous NaHCO3 (3 times). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography (20% EtOAc in hexanes to EtOAc) provided the title compound (9.28 g).
Reaction SMILES: O.C(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH:15]=[O:16])=[O:14])CCC.[CH3:17][C:18]([NH2:31])([CH3:30])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1>CS(C)=O>[CH3:30][C:18]([N:31]=[C:15]([O:16][CH2:12][CH2:7][CH2:8][CH3:9])[C:13]([C:8]1[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])([CH3:17])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1
Reactant: COc1ccc(CC(C)(C)N)cc1OC
Reactant: CCCCOc1ccccc1C(=O)C=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCOC(=NC(C)(C)Cc1ccc(OC)c(OC)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 g of 2-n-butoxyphenylglyoxal hydrate are dissolved in 2.5 ml of dimethylsulfoxide, and a solution of 1.83 g of α,α-dimethyl-3,4-dimethoxyphenethylamine in one ml of dimethylsulfoxide is added thereto. The mixture is stirred at 25° C. for 30 minutes, whereby a solution of α-(α,α-dimethyl-3,4-dimethoxyphenethylimino)-2-n-butoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: O[C@H:2]1[CH2:11][N:10]2[C@H:4]([CH2:5][O:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]2=[O:12])[CH2:3]1.C(N(S(F)(F)[F:23])CC)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[F:23][C@@H:2]1[CH2:11][N:10]2[C@H:4]([CH2:5][O:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]2=[O:12])[CH2:3]1
Reactant: O=C1c2ccccc2OC[C@@H]2C[C@@H](O)CN12
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2OC[C@@H]2C[C@H](F)CN12
Temperature: 25 °C
Yield: 29.8 %

Procedure:
A solution of the material prepared in Example 25 (200 mg; 0.91 mmol) in dry ethyl acetate (10 ml) was cooled to −50° C. and (diethylamino)sulphur trifluoride (191 mg; 1.19 mmol) was added dropwise. The resultant solution was stirred at −50° C. for 1 h and then allowed to slowly warm to room temperature over a period of 3 h. The mixture was then poured onto a saturated aqueous NaHCO3 solution (50 ml) and further ethyl acetate (50 ml) added. After thorough mixing the organic layer was separated, washed sequentially with water (50 ml) and brine (50 ml), and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography to give the title compound as a pale yellow crystalline solid (60 mg). 1H NMR (CDCl3) δ 2.13 to 2.48 (m, 2H), 3.79 (qd, 1H), 4.09 (t, 1H), 4.25 to 4.35 (m, 2H), 4.43-4.49 (m, 1H), 5.333 (d, 1H), 7.04 (d, 1H) 7.15 (t, 1H), 7.41 (dd, 1H), 7.88 (dd, 1H); EIMS: m/z=222.2 [M+H]+