Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[S:17][C:16]([S:18][CH3:19])=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[C:21]1([CH2:27][C:28]([N:30]=[C:31]=[S:32])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:31]([NH:30][C:28](=[O:29])[CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[S:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[S:17][C:16]([S:18][CH3:19])=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CSc1cc2ncnc(Oc3ccc(N)cc3F)c2s1
Solvent: C1CCOC1
Product: CSc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 2 h
Yield: 51.6 %

Procedure:
A mixture of 282 (248 mg, 0.80 mmol) and 2-phenylacetyl isothiocyanate (214 mg, 1.20 mmol) in THF (8 mL) was stirred for 2 hours, and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (3:7), to afford title compound 283 (200 mg, 52% yield) as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 12.42 (s, 1H), 11.80(s, 1H), 8.63 (s, 1H), 7.85(d, 1H), 7.54-7.44 (m, 3H), 7.35 (m, 4H), 7.30 (m, 1H), 3.81 (s, 2H), MS (m/z): 485.1 (M+H) (found).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:21])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.N.C[N:29](C)C=O>>[NH2:29][C:9]1[C:10]([F:21])=[C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]2)[CH:12]=[C:13]2[C:8]=1[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: CC1CN(c2cc3c(c(F)c2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Reactant: CN(C)C=O
Agent: N
Product: CC1CN(c2cc3c(c(N)c2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1

Procedure:
In a sealed tube, 1-cyclopropyl-5,6-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was aminated with ammonia/dimethylformamide as in Example 13 to give 5-amino-1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 181°-183° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:16][OH:17])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CO.O=[Mn]=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]=[O:17])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1O
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-benzyloxy-2-hydroxymethylphenol (2.39 g, 10.4 mmol) in CH2Cl2 (52 mL) and MeOH (5 mL) is added MnO2 (9.05 g, 104 mmol). The suspension is stirred at ambient temperature overnight. The mixture is filtered and the solvent removed under reduced pressure. The crude material is purified by flash chromatography using CH2Cl2 to afford 4-benzyloxy-2-hydroxybenzaldehyde as a pale yellow solid: 1H NMR (CDCl3) δ 11.45 (s, 1H), 9.70 (s, 1H), 7.43-7.39 (m, 6H), 6.59 (dd, J=2.28 Hz), 6.50 (d, J=2.27 Hz, 1H), 5.10 (s, 2H); (M+H)+=229.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[N:7]=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1.S(Cl)([Cl:26])=O>>[O:1]=[C:2]1[C:6]2[N:7]=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([Cl:26])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Temperature: 25 °C

Procedure:
Thionyl chloride (90 ml) was added to 4-(3-oxo-1,3-dihydro-2H-pyrazolo-[4,3-c]cinnolin-2-yl)benzoic acid (2.36 g, 7.70 mmol). The mixture was heated to reflux for 2 h under nitrogen atmosphere. A dark red solution was obtained, cooled to room temperature and excess thionyl chloride was removed under vacuum. Toluene (30 ml) was added to the residues and the mixture was stirred at room temperature under nitrogen atmosphere until precipitation was complete. The solids were collected by filtration and washed with toluene (2×30 ml). The title compound was isolated as a red solid (2.20 g, 6.77 mmol, 88%) LCMS: m/z 321 [M+H]+ (methyl ester resulting from sample make-up in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:15](=O)[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)[C:11]([O:13][CH3:14])=[O:12].Cl.[F:25][C:26]1[C:27]([C:33](=[NH:35])[NH2:34])=[N:28][CH:29]=[C:30]([F:32])[CH:31]=1.C([O-])(=O)C.[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][S:20][CH2:19]2)[NH:35][C:33]([C:27]2[C:26]([F:25])=[CH:31][C:30]([F:32])=[CH:29][N:28]=2)=[N:34]1
Reactant: N=C(N)c1ncc(F)cc1F
Reactant: COC(=O)C(=Cc1ccc(F)cc1Cl)C(=O)CCN1CCSC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)C1=C(CCN2CCSC2)NC(c2ncc(F)cc2F)=NC1c1ccc(F)cc1Cl

Procedure:
A solution of 0.20 g (0.56 mmol) of the compound from Example IX in 5 ml of isopropanol is heated together with 0.11 g (0.56 mmol) of the compound from Example VI and 0.06 g (0.67 mmol) of sodium acetate under reflux for 2 hours. The reaction mixture is concentrated, and the residue is taken up in ethyl acetate and extracted with dilute hydrochloric acid. The aqueous phase is made alkaline with dilute sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate (5:1→3:1) as mobile phase.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>ClCCl>[CH3:23][S:20]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(OS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
To a stirred solution of ethyl 3-hydroxybenzoate (3.32 g, 20 mmol) in dichloromethane (20 mL) cooled to 0° C. was added triethylamine (4.17 mL, 30 mmol). To this was added mesyl chloride (1.94 mL, 25 mmol) dropwise over 15 min. The reaction was stirred at 0° C. for 15 min then quenched with water and the phases separated. The aqueous layer was extracted with dichloromethane and the combined organics were dried over MgSO4 and concentrated in vacuo. The crude material was purified via the Biotage SP4 (silica-packed 25+M; 0-50% EtOAc/hexanes) to provide the title compound as a white solid (2.698 g, 55%). 1H NMR (300 MHz, CDCl3) δ: 7.98 (m, 1H), 7.89 (s, 1H), 7.47 (m, 2H), 4.35 (q, J=7.0 Hz, 2H), 3.16 (s, 3H), 1.37 (t, J=7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 165.3, 149.3, 132.9, 130.3, 128.7, 126.9, 123.2, 61.8, 37.8, 14.5 ppm. IR (neat, cm−1): 1721, 1384, 1369, 1268, 1194, 1168, 1098, 936, 840, 798.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].P(Cl)(Cl)(Cl)(Cl)Cl.II.[Br:21]Br>C(Cl)(Cl)Cl>[Br:21][CH:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][C:2]1=[O:12]
Reactant: BrBr
Reactant: O=C1CCCc2ccccc2N1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccccc2CCC1Br

Procedure:
To a solution of 2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (2.5 g) in chloroform (30 ml), phosphorus pentachloride (3.2 g) was added in portions, while maintaining the temperature at 0°-5°. When the addition was complete, iodine (30 mg) was added followed by bromine (2.5 g), which was added dropwise over 5 minutes. The mixture was then refluxed for 4 hours. The chloroform solution was evaporated and the residue was partitioned between ice-water (30 ml) and dichloromethane (75 ml). The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The crude residue was purified by chromatography over silica gel, eluting with ether and hexane (7:3). Concentration of the appropriate fractions yielded 3-bromo-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one, m.p. 146°-148°.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@@H:11]([OH:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:14]([C:17]1[CH:22]=[CH:21][C:20]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)=[CH:19][C:18]=1[O:32][CH3:33])=[C:15]=[O:16]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:33][O:32][C:18]1[CH:19]=[C:20]([B:23]2[O:27][C:26]([CH3:28])([CH3:29])[C:25]([CH3:30])([CH3:31])[O:24]2)[CH:21]=[CH:22][C:17]=1[NH:14][C:15](=[O:16])[O:13][C@H:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:12]
Reactant: C[C@H](O)CCO[Si](C)(C)C(C)(C)C
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)O[C@@H](C)CCO[Si](C)(C)C(C)(C)C
Temperature: 40 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
To (S)-4-(tert-butyldimethylsilyloxy)butan-2-ol (1.649 mmol, 337 mg) in dichloromethane (4 ml) were added mol sieves (4A), 2-(4-isocyanato-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.374 mmol, 378 mg) and 4-dimethylaminopyridine (0.275 mmol, 33.6 mg) were added and the mixture was stirred at 40° C. (oil bath temperature) for 18 hours. The mol sieves were removed by filtration and the filtrate washed with water, dried (sodium sulfate) and concentrated in vacuo to give a crude product which was purified by column chromatography (silica gel, heptanes with gradient 10% to 50% of ethyl acetate) to afford (S)-4-(tert-butyldimethylsilyloxy)butan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (443 mg). Tetrabutylammonium fluoride (1M in tetrahydrofuran, 1.22 mmol, 1.22 ml) was added to (S)-4-(tert-butyldimethylsilyloxy)butan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (240 mg) in tetrahydrofuran (1 ml) at room temperature. After 20 hours water was added to the reaction mixture, extracted with dichloromethane, the organic extract dried (sodium sulfate) and concentration in vacuo to yield (S)-4-hydroxybutan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (268 mg) which was used in the next step without further purification.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][CH2:19][C:20]2[C:21]([C:27]([O:29][CH3:30])=[O:28])=[N:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.[CH3:33][N:34]1[C:38]([CH2:39][CH:40]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)O)=[CH:37][N:36]=[CH:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH2:19][C:20]2[C:21]([C:27]([O:29][CH3:30])=[O:28])=[N:22][C:23]([O:26][CH:40]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)[CH2:39][C:38]3[N:34]([CH3:33])[CH:35]=[N:36][CH:37]=3)=[CH:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1nc(O)ccc1CCc1ccc(F)cc1
Reactant: Cn1cncc1CC(O)c1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nc(OC(Cc2cncn2C)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Reaction time: 16 h
Yield: 89.9 %

Procedure:
DEAD (0.85 ml) was added dropwise over 2 minutes to a stirred suspension of methyl 3-(4-fluorophenethyl)-6-hydroxypyridin-2-carboxylate (1.0 g), 2-(1-methylimidazol-5-yl)-1-(4-fluorophenyl)ethanol (0.80 g) and triphenylphosphine (1.43 g) in THF (70 ml) under an inert atmosphere at ambient temperature. After stirring for 16 hours the solution was concentrated under reduced pressure and loaded directly onto a silica flash column eluting with methanol/dichloromethane (1:20) to give methyl 3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyridin-2-carboxylate as a colourless oil (1.56 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][CH2:32][Cl:33].O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][Cl:33])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(O)cc23)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCCl)cc23)c1
Temperature: 40 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a suspension of 4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-ol (5.59 g), K2CO3 (7.06 g) in DMF (60 mL) was added 1-bromo-3-chloropropane (6.06 mL) at rt, the mixture was stirred at 40° C. for 6 h. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as a white solid (5.80 g, 77.00%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[N:23]=[C:9]2[CH:10]=[C:11]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:13]([C:14](=[S:16])[NH2:15])[N:8]2[N:7]=1)[CH3:2].Br[CH2:26][C:27](=O)[CH2:28][CH3:29]>CCO>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[N:23]=[C:9]2[CH:10]=[C:11]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:13]([C:14]3[S:16][CH:26]=[C:27]([CH2:28][CH3:29])[N:15]=3)[N:8]2[N:7]=1)=[O:24])[CH3:2]
Reactant: CCC(=O)CBr
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(N)=S)n2n1
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3nc(CC)cs3)n2n1

Procedure:
A mixture of the product of Step 1 (0.5 g, 1.47 mmol) and 1-bromo-2-butanone (0.22 g, 1.47 mmol) in EtOH (10 mL) was heated to reflux for 3 h. The solvent was removed under reduced pressure; the resulting yellow solid was dissolved in MeOH/CHCl3, and dried onto silica gel. The slurry was then purified by column chromatography on silica gel using 1-4% MeOH/CHCl3 as eluent, to afford 1-ethyl-3-[5-(4-ethyl-thiazol-2-yl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea as a solid. LCMS (APCI+) 394.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11]C)=[C:5]([CH3:13])[C:4]=1[CH:14]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C(=O)(O)[O-].[Na+]>Br>[CH3:13][C:5]1[C:6](=[O:11])[C:7]([CH3:10])=[C:8]([CH3:9])[C:3](=[O:2])[C:4]=1[CH:14]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: COc1c(C)c(C)c(OC)c(C(CCCCCC(=O)O)c2cccnc2)c1C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2cccnc2)=C(C)C1=O
Yield: 86.6 %

Procedure:
7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-(3-pyridyl)heptanoic acid (1.0 g, 2.6 mmol) prepared in the Reference Example 11 was dissolved in 47% aqueous hydrogen bromide (5 ml) and the solution was heated at a reflux temperature for 2 hours. After the reaction was completed, the reaction mixture was cooled. The solution was made alkaline with sodium bicarbonate and the product was extracted with ethylacetate. The extract was washed with water, dried, and evaporated in vacuo. The resulting hydroquinone was oxidized with air and the solvent was evaporated to yield 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-(3-pyridyl)heptanoic acid (0.8 g, 86.8%) after crystallization from ethylacetate, m.p. 126°-127° C.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Cl:7][CH2:8][C:9]([CH2:11]Cl)=O>>[Cl:7][CH2:8][C:9]1[N:6]=[C:1]([CH:2]=[CH:3][CH3:4])[O:5][CH:11]=1
Reactant: C/C=C/C(N)=O
Reactant: O=C(CCl)CCl
Product: CC=Cc1nc(CCl)co1
Yield: 10 %

Procedure:
In substantially the same manner as in Reference Example 47, crotonamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(1-propenyl)oxazole. The yield is 10%. Oily substance.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].C[O:26][C:27]([C:29]1[NH:30]N=C(OCC2C(C3C=CC=CC=3)=NOC=2C)C=1)=O>>[OH:26][CH2:27][CH2:29][NH:30][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NCCO)[nH]n1
Yield: 49 %

Procedure:
As described for example 6, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.21 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted to the title compound (37 mg, 49%) which was obtained as a white solid. MS: m/e=362.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[O-]CC.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([CH:37]=[CH:38][C:39](OCC)=[O:40])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)[C:21]([OH:23])=[O:22])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1>C(O)C>[CH3:18][O:17][C:15]1[CH:14]=[C:13]([CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([CH:37]=[CH:38][C:39](=[O:40])[NH:1][C:2]([NH2:4])=[O:3])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)[C:21]([OH:23])=[O:22])[CH:12]=[C:11]([O:10][CH3:9])[CH:16]=1
Reactant: CCOC(=O)C=Cc1ccc(Oc2ccc(C(=Cc3cc(OC)cc(OC)c3)C(=O)O)cc2)cc1
Reactant: NC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccc(C=CC(=O)NC(N)=O)cc3)cc2)cc(OC)c1

Procedure:
Urea (0.21 g, 3.58 mmol) was dissolved in sodium ethoxide (2.7 M, 2.2 mL, 5.92 mmol) at 80° C. under argon, and to this a solution of 4 (1.14 g, 2.37 mmol) in anhydrous ethanol (15 mL) was added and heated at this temperature for 13 hr. Ethanol was evaporated under reduced pressure, water (20 mL) was added, acidified to pH 1 by 5% aqueous HCl and extracted with ethyl acetate (50 mL). The organic layer was washed with water (2×25 mL), brine (2×20 mL), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by silica gel chromatography and eluted with hexane-ethyl acetate (3:7) containing acetic acid (1%), followed by recrystallization from ethanol. Yield: 167 mg, 14.4%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:3]=1.[CH2:22]([NH:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[CH:9]([O:8][C:6]1[N:7]=[C:2]([N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:23][CH2:24][CH3:25])[N:3]=[C:4]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1nc(Cl)nc(N2C(C)(C)CCCC2(C)C)n1
Reactant: CCCCNCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCN(CCCC)c1nc(OC(C)C)nc(N2C(C)(C)CCCC2(C)C)n1
Reaction time: 16 h

Procedure:
12.5 g of 2-chloro-4-isopropyloxy-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine and 5.5 g of dibutylamine are dissolved in 100 ml of xylene. After addition of a solution of 1.8 g of sodium hydroxide in 10 ml of water, the water is slowly removed by distillation in a water separator under a weak flow of nitrogen. The contents of the flask are subsequently stirred at 135° for about 16 hours. The mixture is allowed to cool somewhat, 50 ml of water are added to the contents of the flask and the mixture is stirred vigorously for 10 minutes. The aqueous phase is separated off and the organic layer is washed four times, each with 50 ml of water, dried over sodium sulfate and completely evaporated in vacuo. The 2-isopropyloxy-4-dibutylamino-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine obtained is a weakly yellowish resin.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH2:40]([N:42]([CH2:47][CH3:48])[CH2:43][CH2:44][CH2:45][NH2:46])[CH3:41]>C1COCC1>[CH2:40]([N:42]([CH2:47][CH3:48])[CH2:43][CH2:44][CH2:45][NH:46][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:39])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH3:41]
Reactant: CCN(CC)CCCN
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 63 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (20 mg, 0.036 mmol) in THF (3 mL) was added N,N-diethyl-1,3-propanediamine (0.030 mL, 0.19 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (14 mg, 62%). LC-MS m/z 619 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 6H), 1.55 (m, 2H), 2.38 (s, 3H), 2.55 (m, 6H), 3.10 (m, 2H), 4.11 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:23])[NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)=[CH:8][C:9]=1[CH3:10])=[O:4].O[Li].O>C1COCC1.O>[NH:18]1[C:19]2[C:15](=[C:14]([CH2:13][NH:12][C:11]([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH3:10])[CH:8]=3)=[O:23])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)NCc2cccc3[nH]ccc23)sc1C(=O)O
Yield: 114.5 %

Procedure:
A solution of 5-[(1H-indol-4-ylmethyl)-carbamoyl]-3-methyl-thiophene-2-carboxylic acid methyl ester (115 mg, 0.35 mmol) in THF/water (6 ml/3 ml) was treated with LiOH.H2O (157 mg, 3.5 mmol) at rt for 24 h. The reaction mixture was quenched with 1N HCl and extracted with EtOAc. The layers were separated. The organic layer was successively washed with water and brine, then dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (126 mg, 100% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[C:15](=O)[CH2:16][CH2:17][CH2:18][C:19]=3[N:20]2[CH3:23])=[CH:12][CH:11]=1>CCO.O>[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[C:15](=[N:2][OH:3])[CH2:16][CH2:17][CH2:18][C:19]=3[N:20]2[CH3:23])=[CH:12][CH:11]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)C(=O)CCC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c2c(c3ccc(Br)cc31)C(=NO)CCC2
Temperature: 40 °C
Yield: 69.7 %

Procedure:
Hydroxylamine hydrochloride (3.21 g, 46.5 mmol) and sodium acetate (3.81 g, 46.5 mmol) were added to a suspension of 7-bromo-9-methyl-2,3-dihydro-1H-carbazol-4(9H)-one (8.61 g, 30.9 mmol) in EtOH (79.0 mL) and H2O (27.0 mL), and the resulting suspension was heated at reflux for 20 h. The reaction was cooled to ˜40° C., and the solids were collected by filtration. The solids were washed with H2O and EtOH. The solids were divided into two batches of 3.93 g and 4.08 g and recrystallized in CH3CN (500 mL per batch). The material was allowed to crystallize for two days the resulting crystals were collected by filtration to afford the title compound (6.31 g, 70%) as an off-white crystalline solid: 1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.0, 1.5 Hz, 1H), 3.66 (s, 3H), 2.81 (t, J=6.0 Hz, 2H), 2.66 (t, J=6.0 Hz, 2H), 1.94-1.91 (m, 2H). Additional material was obtained by concentrating the filtrate to 200 mL and collecting the resulting solids to afford the title compound (1.22 g, 13%) as an off-white powder.