Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[ClH:27].[Cl:27][CH2:2][C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1cc(CO)n(Cc2ccccc2)cc1OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=c1cc(CCl)n(Cc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
A suspension of 3.21 g (10 mmol) of 2-(hydroxymethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone in 20 ml of chloroform was cooled to 0° C., and 4.65 ml (64 mmol) of thionylchloride was added dropwise. The mixture was stirred for ten minutes at 0° C. and then heated to reflux for one hour. The solvent was evaporated in vacuo and the residue washed with petroleum ether and dried.in vacuo, yielding 3.66 g of the title compound, melting point 85° C., dec.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[NH:15][C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=3[N:12]=2)[CH2:6]1.[CH:28](=O)[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:45]C(Cl)C>C(=O)(O)[O-].[Na+]>[ClH:45].[ClH:45].[CH2:28]([N:10]1[CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[NH:15][C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=3[N:12]=2)[CH2:6][C@@H:5]1[CH2:4][CH2:3][O:2][CH3:1])[CH3:29]
Reactant: CC(Cl)Cl
Reactant: CC=O
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN1CCN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)C[C@@H]1CCOC
Product: Cl
Yield: 71 %

Procedure:
Combine (S)-10-[3-(2-methoxyethyl)piperazin-1-yl]-2-isopropyl 4H-3-thia-1,4,9-triazabenzo[f]azulene (0.103 g, 0.267 mmol), acetaldehyde (30 μL, 0.534 mmol), and sodium triacetoxyborohydride (0.085 g, 0.401 mmol) in dichloroethane (7 mL) and stir, at room temperature for 6 hours. Dilute the mixture with saturated aqueous sodium bicarbonate and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the crude product. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane, gives the free base of the title compound (0.79 g, 71%) as a yellow foam: mass spectrum (APCI): m/z=414.2 (M+1). Isolate clean product as the corresponding dihydrochloride in the manner described in Example 319. Exact Mass, Calc: 414.2328; Found: 414.2326.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([OH:13])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[SH:26]>>[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[SH:26])=[O:13]
Reactant: O=C(O)c1c(Br)sc2c1CCCC2
Reactant: Cc1ccc(N)c(S)c1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(NC(=O)c2c(Br)sc3c2CCCC3)c(S)c1

Procedure:
In the same manner as in Starting Material Synthesis Example 60 and using 2-bromo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid, thionyl chloride and 2-amino-5-methylthiophenol, 2-bromo-4,5,6,7-tetrahydro-N-(2-mercapto-4-methylphenyl)-benzo[b]thiophene-3-carboxamide is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](Cl)=[N:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([NH2:31])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13]([NH:31][C:19]4[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)=[C:17]([Cl:16])[CH:18]=4)=[N:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: Clc1ncnc2sc3cc(Br)ccc3c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Clc1cc(Nc2ncnc3sc4cc(Br)ccc4c23)ccc1OCc1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
A mixture of 7-Bromo-4-chloro[1]benzothieno[2,3-d]pyrimidine (4.85 g, 16.2 mmol), 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (4.73 g, 18.1 mmol, 1.12 equiv), and HCl in dioxane (4.0 M, 7.25 mL) in IPA (100 mL) was heated to reflux for 3 days. The suspension was filtered and washed with IPA (3×20 mL) to collect a light tan solid. The solid was triturated with ether to give a yellow solid. The yellow solid was added to a saturated NaHCO3 solution in a few portions to adjust pH to 7. The suspension was stirred at rt for 5 min then filtered and washed with water and methanol to give a yellow solid. The solid was placed under vacuum oven at 35° C. for 60 h to yield 6.48 g (76%) of product. 1H-NMR (CD3OD) δ 8.81 (d, J=5.4 Hz, 1H), 8.59 (s, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.37 (t, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.87 (d, J=2.7 Hz, 1H), 7.81 (m, 1H), 7.80 (dd, J=2.1, 8.9 Hz, 1H), 7.63 (dd, J=2.1, 8.9 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 5.51 (s, 2H); LCMS RT=3.43 min, [M+H]+=499.0
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O.CCCCCC>N1C=CC=CC=1>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:18])[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide (0.85 g), prepared in a similar manner to that described in Example 11, in pyridine (85 ml) was stirred at ambient temperature for 3 days. The mixture was added to hexane (180 ml) and the solid collected by filtration was dried at 50° in vacuo to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p.234°-235° (0.49 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21].[OH-].[Na+].C(O)(=O)C>O.C(O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[N:20][OH:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2ccc(C=O)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(COc2ccc(C=NO)cc2)cc1
Temperature: 88 °C
Yield: 84.1 %

Procedure:
To a suspension of 4-(4-methoxy-benzyloxy)-benzaldehyde (26.5 g, 110 mmol) in water/ethanol (260 mL, 9:1) was added hydroxylamine hydrochloride (9.06 g, 131 mmol) followed by dropwise addition of a 3.2M NaOH solution in ethanol/water (88 mL; 262 mmol). After addition was complete, the reaction mixture was heated to 88° C. for 4.5 h and then cooled to rt. The pH of the reaction mixture was adjusted to 5.5 with glacial acetic acid. 4-(4-methoxy-benzyloxy)-benzaldehyde oxime (23.8 g, 84%) was isolated as a white solid by filtration and air drying.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[H-].[Na+].[CH2:11](I)[CH2:12][CH3:13]>C1COCC1.CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][CH3:13])[CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1
Reactant: Cc1nc(C=O)c[nH]1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCn1cc(C=O)nc1C
Reaction time: 0.08 h

Procedure:
2-Methyl-1H-imidazole-4-carbaldehyde (940 mg, 8.5 mmol) was dissolved in THF (40 ml) with DMF (5 ml). NaH (380 mg of a 60% dispersion in mineral oil) was added carefully and the reaction mixture was allowed to stir 5 minutes under nitrogen. Propyl iodide (1.65 g, 9.7 mmol) was added and it was allowed to stir for 1 h, at which time the reaction was judged complete. The solvent was removed under vacuum, and the crude was purified on silica eluted with 100% ethyl acetate −1% MeOH/ethyl acetate to yield the title product as the main isomer (390 mg (30%), 2.6 mmol). 1H NMR (DMSO-d6): δ=9.68 (s, 1H), 8.02 (s, 1H), 3.97 (t, J=7.3 Hz, 2H), 2.31 (s, 3H), 1.71 (sextet, J=7.3 Hz, 2H), 0.85 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Br:22]N1C(=O)CCC1=O>C(Cl)Cl>[Br:22][C:20]1[C:16]([C:14]2[S:15][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)=[CH:12][CH:13]=2)=[N:17][N:18]([CH3:21])[CH:19]=1
Reactant: Cn1ccc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cn1cc(Br)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Yield: 79.6 %

Procedure:
To a stirred solution of 3-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1-methyl-1H-pyrazole (0.10 g, 0.31 mmol) in DCM (3 mL, anhyd) was added N-bromosuccinimide (NBS) (56 mg, 0.31 mmol). After 22 h additional NBS (56 mg) was added and stirring was continued at ambient temperature. After 46 h (total) the reaction mixture was concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 20:80 to 40:60) to give the title compound (98 mg, 79%) as a white solid. 1H-NMR (CD2Cl2): δ 8.17 (1H, m), 7.91 (1H, m), 7.82 (1H, m), 7.72 (1H, d), 7.61 (1H, m), 7.50 (1H, s), 7.44 (1H, d), 3.91 (3H, s), 3.08 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[O:23][CH2:25][C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: Oc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Product: O=C(COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1)N1CCOCC1

Procedure:
By conducting reactions and treatments in the same manner as in Examples 1-6, using 3-(4-fluorophenyl)-1-(3-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine and 4-chloroacetylmorpholine, there was obtained 4-{3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]phenoxyacetyl}morpholine, m.p. 141°-143° C.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]2([CH3:15])[CH2:14][CH2:13]2)=[CH:11]/1)=[O:5].[CH3:31][C:32]([OH:37])([CH3:36])[CH2:33][CH2:34][OH:35].CC([O-])(C)C.[Na+]>C1COCC1.O>[OH:37][C:32]([CH3:36])([CH3:31])[CH2:33][CH2:34][O:35][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]2([CH3:15])[CH2:13][CH2:14]2)=[CH:11]/1)=[O:5]
Reactant: Cn1c(C2(C)CC2)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2F)n1C[C@H]1CCCO1
Reactant: CC(C)(O)CCO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C2(C)CC2)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)O)n1C[C@H]1CCCO1
Yield: 54.4 %

Procedure:
A mixture of Example 68D (600 mg, 1.41 mmol), 3-methylbutane-1,3-diol (294 mg, 2.82 mmol) and sodium 2-methylpropan-2-olate (271 mg, 2.82 mmol) in THF (30 mL) was heated at 40° C. for 12 hours. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) to afford 391 mg (54%) of the title compound. 1H NMR (500 MHz, chloroform-d) δ ppm 0.76-0.83 (m, 2H) 0.89-0.98 (m, 2H) 1.31 (s, 6H) 1.34 (s, 3H) 1.69-1.82 (m, 2H) 1.81-1.90 (m, 1H) 1.96-2.11 (m, 3H) 3.66-3.80 (m, 2H) 3.83 (s, 3H) 4.15-4.32 (m, 4H) 4.52 (dd, J=14.49, 2.59 Hz, 1H) 5.62 (s, 1H) 6.98 (d, J=8.54 Hz, 1H) 7.03 (s, 1H) 7.53 (dd, J=8.54, 2.14 Hz, 1H) 8.30 (d, J=2.14 Hz, 1H); MS (DCI/NH3) m/z 510 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[C:14](=[O:25])[N:15]([C:18]4[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:26]([F:29])([F:28])[F:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].N[CH:31]1[CH2:36][CH2:35][CH2:34]C[CH:32]1[NH2:37].[O-:38]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Cu]I.C(OC(=O)C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[C:14](=[O:25])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:37]5[CH2:34][CH2:35][CH2:36][CH2:31][C:32]5=[O:38])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:26]([F:29])([F:28])[F:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC1CCCCC1N
Reactant: O=C1c2c(c(C(F)(F)F)nn2-c2ccc(F)c(Cl)c2)CCN1c1ccc(I)cc1
Reactant: O=P([O-])([O-])[O-]
Agent: [Cu]I
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1CCCCN1c1ccc(N2CCc3c(C(F)(F)F)nn(-c4ccc(F)c(Cl)c4)c3C2=O)cc1
Temperature: 110 °C
Reaction time: 48 h
Yield: 808.9 %

Procedure:
Part B. 1-(3-chloro-4-fluorophenyl)-6-[4-iodophenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one (0.54 g, 1.0 mmol), 8-valerolactam (0.12 g, 1.2 mmol), 1,2-diaminocyclohexane (11.4 mg, 0.1 mmol), K3PO4 (0.42 g, 2 mmol) and CuI (2 mg, 0.01 mmol) were added to 5 mL of 1,4-dioxane. The mixture was degassed under argon and stirred at 110° C. under N2 for 48 h. The mixture was then cooled to rt. The dioxane was removed. The residue was dissolved in EtOAc (100 mL), washed with HCl (1N, 30 mL), water (50 mL×2), and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified via flash chromatography on silica gel using 1:2 hexane:ethylacetate to give the desired product (0.41 g, 80% yield). LRMS (ES+): 507.1 (M+H)+. 1H NMR (CDCl3) δ 7.68-7.65 (m, 1H), 7.50-7.45 (m, 1H), 7.36-7.16 (m, 5H), 4.16 (t, 2H), 3.64-3.62 (m, 2H), 3.47 (br, 3H), 3.17 (t, 2H), 2.62 (t, 2H), 1.98-1.96 (m, 3H).
Reaction SMILES: [OH2:1].[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:16](=O)[CH:17]=NO)[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13].O>C(O)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:16](=[N:2][NH2:3])[CH:17]=[O:1])[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13]
Reactant: COc1cc(C(=O)C=NO)cc(OC)c1OC
Reactant: O
Reactant: NN
Solvent: CCO
Product: COc1cc(C(C=O)=NN)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Hydrazine hydrate (10 g, 0.2 mol) was added to a solution of 1-(3,4,5-trimethoxyphenyl)-1,2-ethanedione 2-oxime (24 g, 0.1 mol) in ethanol (100 ml) and the reaction mixture was stirred at room temperature for 5 hours. Water was added; the precipitated solid was filtered off, washed with water and dried. Yield 10.8 g (43%). δH (DMSO-d6): 3.65 (s, 3H), 3.81 (s, 6H), 6.81 (s, 2H), 8.32 (s, 1H), 8.94 (s, 2H), 11.6 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][CH2:9][CH:10]1[O:15][CH:14]([C:16]2[O:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:13]2=[C:22]3[N:34]([CH3:35])[C:33](=[O:36])[N:32]([CH3:37])[C:31](=[O:38])[C:23]3=[C:24]([C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)[N:12]2[CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][CH2:9][CH:10]1[O:15][CH:14]([C:16]2[O:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:13]2=[C:22]3[N:34]([CH3:35])[C:33](=[O:36])[N:32]([CH3:37])[C:31](=[O:38])[C:23]3=[C:24]([C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)[N:12]2[CH2:11]1)=[O:6]
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN)OC3c2ccc(Cl)o2)n1
Reactant: O=C(Cl)CCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CNC(=O)CCCBr)OC3c2ccc(Cl)o2)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
4-Bromobutyryl chloride (29.4 mg, 0.158 mmol) was added to a solution of 8-(aminomethyl)-10-(5-chlorofuran-2-yl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazine-2,4(3H,10H)-dione (61 mg, 0.132 mmol) and triethylamine (0.022 mL, 0.158 mmol) in DCM (4 mL). The mixture was stirred at room temperature for 3.5 hours, then diluted with DCM (30 ml) and washed with saturated NaHCO3(aq) (30 ml). The organic phase was passed through a hydrophobic frit and evaporated under vacuum to afford the title compound as a crude material which was used directly
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)=[CH:3][CH:2]=1.[I:16]N1C(=O)CCC1=O>CC(C)=O>[I:16][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:8]=2)[NH:13][CH:14]=1
Reactant: c1cc(-c2cnc3[nH]ccc3n2)ccn1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Product: Ic1c[nH]c2ncc(-c3ccncc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of 22 (0.35 g) and acetone (20 mL) of acetone was added in one portion N-iodosuccinimide (0.44 g). The mixture was stirred at RT for 30 min and then concentrated to afford 0.8 g of crude material. The crude product was purified by SiO2 chromatography eluting with and EtOH/EtOAc gradient (1 to 15% over 15 minutes) to afford 0.36 g of pure 7-iodo-2-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine (24).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]O)=O.COC1(C2C(C)[C:27]34C[CH:24]([O:25][C:26]3=[CH:33][C:32](=O)[C:31]([O:35]C)=[CH:30]4)C2)C=CC=C(OC)C1.CCCCCC.C(OCC)(=O)C>ClCCl.C(OCC)(=O)C>[CH2:5]([O:7][C:33]1[CH:32]=[C:31]([OH:35])[CH:30]=[CH:27][C:26]=1[O:25][CH3:24])[C:4]1[CH:3]=[CH:2][CH:11]=[CH:10][CH:9]=1
Reactant: COC1=CC=CC(OC)(C2CC3CC4(C=C(OC)C(=O)C=C4O3)C2C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(O)cc1OCc1ccccc1

Procedure:
3-chloroperoxybenzoic acid (9.9 g, 0.0343 mols), in small portions, is added to a stirred solution of 3-benzyloxy-4-methoxybenzaldehyde (201, prepared as described in Example 66) (7.57 g, 0.0313 mols) in dicloromethane (100 ml) over a thirty minute period With vigorous shirring. The reaction flask is fitted with a condensor and the contents is heated to reflux for six hours and monitored by TLC using 2:1 hexane-ethyl acetate as eluant. The reaction is filtered off the 3-chlorobenzoic acid (which precipitates out of solution) and the filtrate is washed with saturated sodium bicarbonate followed by water and dried in vacuo to an oil which eventually solidifies. The solid is subsequently dissolved in distilled methanol (80 ml) and heated to reflux under nitrogen. TLC using hexane-ethyl acetate as the eluant shows almost complete conversion after two hours and forty five minutes. The solvent is removed in vacuo no produce a dark oil which is redissolved in a small amount of ethyl acetate and purified by column chromatography on silica gel (2:1 hexane-ethyl acetate as eluant). The major fraction from the column is combined and concentrated in vacuo to a solid (4.68 g, 64.9%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH:11]([NH:13][NH2:14])=[O:12].[C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:26][C:27]([CH3:45])([C:29]2[N:33]([CH3:34])[C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:44])([F:43])[F:42])=[N:31][N:30]=2)[CH3:28])=[C:21]([CH:25]=1)[C:22](O)=O)#[N:16].O>CN(C=O)C>[CH3:45][C:27]([C:29]1[N:33]([CH3:34])[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:43])([F:44])[F:42])=[N:31][N:30]=1)([O:26][C:20]1[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:25][C:21]=1[C:22]1[O:12][CH:11]=[N:13][N:14]=1)[CH3:28]
Reactant: NNC=O
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C#N)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C#N)cc1-c1nnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
WSC•monohydrochloride (81 mg), HOBt (57 mg) and formic hydrazide (30 mg) were sequentially added to a solution of 5-cyano-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (140 mg) in DMF (2 ml), followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid (130 mg) was dissolved in dichloromethane (2 ml) and pyridine (0.090 ml) was added thereto, followed by cooling to −78° C. Trifluoromethanesulfonic acid (0.090 ml) was added to the reaction solution and was elevated to room temperature, followed by stirring for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1). The resulting solid was washed with diisopropylether to obtain, as a white solid, 4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)-3-(1,3,4-oxadiazol-2-yl)benzonitrile (65 mg).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([Cl:15])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[N:3]=1.[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26].[K]>>[Cl:15][C:6]1[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[N:3]=[C:2]([NH:37][S:34]([C:31]2[CH:30]=[CH:29][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:33][N:32]=2)(=[O:36])=[O:35])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)c1ccc(S(N)(=O)=O)nc1
Reactant: COc1cccc(Cc2nc(Cl)c(Oc3ccccc3)c(Cl)n2)c1
Agent: [K]
Product: COc1cccc(Cc2nc(Cl)c(Oc3ccccc3)c(NS(=O)(=O)c3ccc(C(C)C)cn3)n2)c1

Procedure:
In analogy to Example 45, by reacting 4,6-dichloro-2-(3-methoxy-benzyl)-5-phenoxy-pyrimidine with potassium 5-isopropyl-pyridine-2-sulphonamide there was obtained 5-isopropyl-pyridine-2-sulphonic acid [6-chloro-2-(3-methoxy-benzyl)-5-phenoxy-pyrimidin-4-yl]-amide as a yellow foam. MS: 523 (M-H)
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]([OH:8])[CH2:4][N+:5]([O-:7])=[O:6].[C:13](OCC)(=[O:15])[CH3:14]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:13]([O:8][CH:3]([CH:2]([CH3:1])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:4][N+:5]([O-:7])=[O:6])(=[O:15])[CH3:14]
Reactant: CCOC(C)=O
Reactant: CC(C)CC(C)C(O)C[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C[N+](=O)[O-])C(C)CC(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.3 %

Procedure:
After dissolving 7.8 g of 3,5-dimethyl-1-nitro-2-hexanol in 30 ml of pyridine, 10 ml of acetic anhydride were added thereto, and the solution was stirred at room temperature for 2.5 hours. Ethyl acetate was added to the solution, and the organic layer was washed with 1 mol/l of aqueous hydrochloric acid and saturated saline. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 8.4 g of 3,5-dimethyl-1-nitrohex-2-yl acetate (yield: 87.3%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([Cl:24])[C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:12][C:13]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([Cl:24])[C:14]=1[CH2:15][O:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Reactant: Cc1cn2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
A mixture of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (207 mg), 2,6-dichloro-3-nitrobenzyl bromide (400 mg) and potassium carbonate (580 mg) in N,N-dimethylformamide (8 ml) was stirred for 2 hours at 60° C. The mixture was cooled and diluted with water. The separated oil was extracted with dichloromethane. The organic layer was washed with water, dried, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give 8-(2,6-dichloro-3-nitrobenzyloxy)-2-methylimidazo[1,2-a]pyridine (120 mg) as crystals.