Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH2:26])=[CH:21][CH:20]=[CH:19]2.CC[N:29]([CH:33](C)C)[CH:30]([CH3:32])[CH3:31].C1([O:42]C(Cl)=O)C=CC=CC=1.C1(N)CC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH:26][C:33]([NH:29][CH:30]1[CH2:31][CH2:32]1)=[O:42])=[CH:21][CH:20]=[CH:19]2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Agent: NC1CC1
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc4c(NC(=O)NC5CC5)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)naphthalen-1-amine (80 mg, 0.231 mmol) was suspended in THF (1 mL), then added Hunig's base (33 mg, 0.254 mmol) and a solution of phenylchloroformate (36 mg, 0.231 mmol) in THF (0.5 mL). The reaction was stirred at RT for 16 h. A solution of cyclopropylamine (26 mg, 0.462 mmol) in THF (0.6 mL) was added to the mixture and the reaction was heated at 50° C. for 4 h. A precipitate formed and was collected on a glass frit, washed with THF then CH2Cl2. The tan solid was purified by preparative thin layer chromatography (8% MeOH in CH2Cl2) to give N-(6-((6,7-bis(methoxy)-4-quinolinyl)oxy)-1-naphthalenyl)-N′-cyclopropylurea as a white solid. MS (ESI, pos. ion) m/z: 430.2 (M+1). Mass Calc'd for C25H23N3O4: 429.47
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18]([OH:20])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[O:20])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (33 mg, 0.0841 mmol) was dissolved in methylene chloride (3 ml), then p-anisidine (21 mg, 0.1707 mmol), triethylamine (34 mg, 0.3366 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (57 mg, 0.3372 mmol) were added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:1) to give the title compound (28 mg, 0.0563 mmol, 67%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[O:17][CH3:18].[N:19]([O-:21])=[O:20].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[CH3:18][O:17][C:8]1[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[C:10]([CH:9]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(OCCCCCl)c(OC)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1cc(OC)c(OCCCCCl)cc1[N+](=O)[O-]
Temperature: 40 °C
Yield: 934.8 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 10.1 g (36.7 mmol) of methyl 4-(4-chlorobutoxy)-3-methoxybenzoate (purity: 98%) obtained in Example II-18, 0.25 g (3.67 mmol) of sodium nitrite, and 12.5 mL of acetic acid. The resulting mixture was heated to 40° C. under stirring. To the reaction mixture was dropwise added slowly 115.4 g (146.8 mmol) of nitric acid (60 wt. %), and the mixture was heated at 40-50° C. for 5 hours. After the reaction was complete, 20 mL of water was added to the reaction mixture, and the aqueous mixture was cooled to 20° C., precipitating a crystalline product. The crystalline product was collected by filtration, washed successively with 30 mL of water and 30 mL of n-heptane, and dried under reduced pressure, to give 10.9 g (isolated yield: 92.0%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of methyl 5-methoxy-4-(4-chlorobutoxy)-2-nitrobenzoate as a white crystalline product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[CH:10]=[C:11]1[CH2:16][CH:15]([CH3:17])[O:14][C:12]1=[O:13].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:26][C@H:27]1[O:29][CH2:28]1)(=O)=O.[CH:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1[CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>CO.CN(C)C=O>[OH:29][CH:27]([CH2:28][N:52]1[CH2:53][CH2:54][CH:49]([C:40]2[CH:41]=[CH:42][C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:39]=2)[CH2:50][CH2:51]1)[CH2:26][O:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[CH:10]=[C:11]1[CH2:16][C@H:15]([CH3:17])[O:14][C:12]1=[O:13]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: CC1CC(=Cc2ccccc2O)C(=O)O1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@H]1CC(=Cc2ccccc2OCC(O)CN2CCC(c3ccc4ccccc4c3)CC2)C(=O)O1
Temperature: 40 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
Dimethylformamide (70 ml) and potassium carbonate (9.5 g) were added to α-(2′-hydroxybenzylidene)-γ-valerolactone (7 g) and (S)-glycidyl nosylate (8.9 g) was added. The mixture was stirred at 40° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. (7.5 g). By the reaction using this product (1.0 g) and 4-(naphthalen-2-yl)piperidine (1.0 g) in methanol (50 ml) in the same manner as in Example 307, an oily title compound (0.8 g) was obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[F:12])([CH3:3])[CH3:2].C([Li])CCC.[C:18](=[O:20])=[O:19]>C1COCC1.CCCCCCC>[F:12][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])[C:18]([OH:20])=[O:19]
Reactant: O=C=O
Reactant: CC(C)Oc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)Oc1ccc(C(=O)O)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of 639 mg (2.74 mmol) 1-isopropyloxy-2-fluoro-4-bromobenzene (from Step A) in 10 mL of THF at −78° C. was treated with 1.64 mL of 2.0 M n-butyllithium in heptane. After stirring at −78° C. for 30 min, the mixture was poured onto 300 g of crushed dry ice and allowed to warm up to rt. The mixture was partitioned between 100 mL of 2.0 N NaOH and 100 mL of Et2O. The aqueous layer was separated, acidified using 5.0 N HCl to pH 2, and extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried over MgSO4, and concentrated to afford 380 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.41 (d, J=6.2, 6H), 4.65-4.73 (m, 1H), 7.00 (t, J=8.5, 1H), 7.79-7.87 (m, 2H).
Reaction SMILES: [K].P(=O)(O)(O)[OH:3].[CH3:7][C:8]1[O:12][C:11]([CH:13]([CH:15]([CH3:18])[CH:16]=[CH2:17])O)=[CH:10][CH:9]=1.[Cl-].[Na+]>O>[CH3:18][CH:15]([C:13]1[C:11](=[O:12])[CH2:10][CH:9]([OH:3])[C:8]=1[CH3:7])[CH:16]=[CH2:17]
Reactant: C=CC(C)C(O)c1ccc(C)o1
Reactant: O=P(O)(O)O
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: O
Product: C=CC(C)C1=C(C)C(O)CC1=O
Reaction time: 0.92 h

Procedure:
A buffer solution was prepared by dissolving potassium secondary phosphate (4 g) in water (800 ml) and adjusting the pH value to 7.5 (25° C.) with phosphoric acid. In a reaction vessel, 5-methyl-2-furyl-(α-methylallyl)-carbinol (20 g) and the entire amount of the buffer solution as prepared above were charged, and the temperature was elevated up to 180° C. in 55 minutes while stirring. The mixture was stirred at the same temperature for 5 hours, the inner pressure at this time being 9 kg/cm2. After ice-cooling, sodium chloride (100 g) was added thereto, and the mixture was extracted with methyl isobutyl ketone (200 ml) four times. The extract was concentrated at 60° C. under reduced pressure to remove methyl isobutyl ketone, and the resultant residue was subjected to distillation (112°-117° C./0.3 mmHg) to obtain 2-(α-methylallyl)-3-methyl-4-hydroxy-2-cyclopentenone (15.3 g). Yield, 76.5%. NMR spectrum (CDCl3 internal standard; TMS, δppm, 60 MHz): 5.99 (complex m, 1H, ##STR8## 5.08 (m, 1H, ##STR9## 4.84 (m, 1H, ##STR10## 4.63 (broad d, 1H, 4-H); 3.33 (m, 2H, 4-OH and ##STR11## 2.73 (dd, 1H, 5-H); 2.21 (dd, 1H, 5-H); 2.08 (s, 3H, 3-CH3); 1.21 (d, 3H, ##STR12##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[C:27]([CH:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[C:27]([CH:31]1[CH2:32][CH2:33][CH:34]([NH:37][C:17]([C:16]2[CH:20]=[CH:21][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:14][CH:15]=2)=[O:19])[CH2:35][CH2:36]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(C(C)(C)C)CC4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.6 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.154 g, 0.409 mmol), N,N-dimethylpyridin-4-amine (0.00499 g, 0.0409 mmol), and 4-tert-butylcyclohexanamine (0.0875 ml, 0.490 mmol) in DMF (2 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0940 g, 0.490 mmol), and the reaction was stirred at ambient temperature for 16 hours. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP1 system eluting with a linear gradient of 5-70% EtOAc in hexanes to yield 37 mg of the title compound (18% yield).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([CH2:29][C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[CH:35][CH:34]=[CH:33]5)=[CH:27][N:28]=3)[N:25]=2)[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].Cl.[NH2:41][C@@H:42]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(#N)C>[F:10][C:11]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([CH2:29][C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[CH:35][CH:34]=[CH:33]5)=[CH:27][N:28]=3)[N:25]=2)[CH:17]=[CH:16][C:12]=1[C:13]([NH:41][C@@H:42]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[O:14]
Reactant: O=C(O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
N,N-Diisopropylethylamine (160 μL, 0.90 mmol) was added to the mixture of 2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoic acid (90.0 mg, 0.225 mmol), tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (63 mg, 0.281 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (150 mg, 0.34 mmol) in N,N-dimethylformamide (2.0 mL) at 0° C. The mixture was stirred overnight at RT and was added to aqueous acetonitrile. The precipitates were filtered, dried to give the desired product (0.093 g, 72%). LCMS: (M+H)=569.5.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]1([CH:18]=[CH:17][CH:16]=[C:14]([OH:15])[CH2:13]1)O.[NH2:19]/[C:20](/[CH3:28])=[CH:21]\[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>C(O)(C)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:13]2[C:14](=[O:15])[CH2:16][CH2:17][CH2:18][C:11]=2[NH:19][C:20]([CH3:28])=[C:21]1[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]
Reactant: OC1=CC=CC(O)C1
Reactant: C/C(N)=C/C(=O)OC(C)C
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: CC(C)O
Product: CC1=C(C(=O)OC(C)C)C(c2cccc(Cl)c2Cl)C2=C(CCCC2=O)N1
Temperature: 25 °C

Procedure:
3.50 g (20 mmol) of 2,3-dichlorobenzaldehyde, 2.24 g (20 mmol) of dihydroresorcinol and 2.86 g (20 mmol) of isopropyl 3-aminocrotonate are dissolved in 100 ml of isopropanol and stirred under reflux for 5 h. The product precipitates. The mixture is treated with 50 ml of water and cooled to RT. The product is filtered off with suction and washed successively with isopropanol, ethanol and ether. 5.8 g (74% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([O:17]C(=O)C)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:21])[CH3:6])[CH3:2].N1CCOCC1>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:21])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc(OC(C)=O)cc21
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(O)cc21
Temperature: 25 °C

Procedure:
To a solution of the crude 2-(6-acetoxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester in THF (80 mL) was added morpholine (5.5 mL, 63 mmol) and the mixture was heated to reflux overnight. The reaction mixture was cooled to ambient temperature and diluted with EtOAc (100 mL). The mixture was washed with brine (30 mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatograph on silica gel (eluting with 10% EtOAc in petroleum ether) to give 2-(6-hydroxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as a white solid (3.2 g, 57% over two steps). 1H NMR (CDCl3, 400 MHz): δ 6.88 (d, J=8.8 Hz, 1H), 6.47 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 6.39 (d, J=2.8 Hz, 1H), 5.24 (q, J=6.8 Hz, 1H), 4.54 (d, J=14.8 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 1.62 (d, J=6.8 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H). The phenol OH was not observed in CDCl3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6]OCC)[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4](=[O:14])[C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[S:10]([CH3:13])(=[O:11])=[O:12])=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCOC=C(C(=O)OCC)S(C)(=O)=O
Reactant: Nc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(C(=O)OCC)cc1)S(C)(=O)=O
Temperature: 145 °C
Reaction time: 2 h

Procedure:
The compound of 3-ethoxy-2-methanesulfonyl-acrylic acid ethyl ester (example 61c, 52 g, 0.234 mol) and aniline (38.65 g, 0.234 mol) was mixed and heated at 140-150° C. under stirring for two hours. After cooling the reaction to room temperature, solvent was removed to give 4-(2-ethoxycarbonyl-2-methanesulfonyl-vinylamino)-benzoic acid ethyl ester. The crude compound was used in the following reaction without further purification. LC-MS m/e 342 (MH+).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:66](O)(=[O:70])[C@H:67]([CH3:69])[OH:68]>CN(C=O)C>[OH:68][C@@H:67]([CH3:69])[C:66]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:7][CH:8]=3)[N:14]=[C:15]([N:23]([CH2:24][CH2:25][OH:26])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH2:22]1)=[O:70]
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: C[C@H](O)C(=O)O
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: C[C@H](O)C(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (100 mg, 0.23 mmol, Example 1) was dissolved in DMF (5 mL). N-Ethyldiisopropylamine (0.081 mL, 0.47 mmol) was added followed by O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (115 mg, 0.30 mmol) and L-lactic acid (21.02 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, the crude dissolved in MeOH and acetonitrile, filtered and purified by preparative HPLC yielding (S)-2-hydroxy-1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)propan-1-one (30.0 mg, 26%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].Cl[C:12]1[C:21]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[O:23])=[C:20]([CH3:33])[C:19]2[C:14](=[CH:15][C:16]([C:34]([F:37])([F:36])[F:35])=[CH:17][CH:18]=2)[N:13]=1.CCCCCC>CN(C=O)C.O>[F:32][C:28]1[CH:27]=[C:26]([CH2:25][NH:24][C:22]([C:21]2[C:12]([S:10][CH2:7][CH2:8][CH3:9])=[N:13][C:14]3[C:19]([C:20]=2[CH3:33])=[CH:18][CH:17]=[C:16]([C:34]([F:37])([F:36])[F:35])[CH:15]=3)=[O:23])[CH:31]=[CH:30][CH:29]=1
Reactant: Cc1c(C(=O)NCc2cccc(F)c2)c(Cl)nc2cc(C(F)(F)F)ccc12
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1cccc(F)c1
Temperature: 40 °C
Yield: 66 %

Procedure:
209 mg (1.5 mmol) K2CO3 and 137 μl (1.5 mmol) propanethiol were added to a solution of 200 mg (0.5 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxamide (VVV17) in DMF (4 ml) and the mixture was heated in a closed vessel for 72 h at 40° C. After cooling to RT the mixture was diluted with water and extracted with EE. The organic phase was washed with water and brine, dried over MgSO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 3:1) of the residue yielded 146 mg (0.33 mmol, 67%) N-[(3-fluorophenyl)-methyl]-4-methyl-2-(propylsulfanyl)-7-(trifluoromethyl)-quinoline-3-carboxamide. MS: m/z 437.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:5][C:3]=1[NH2:4].[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:4][C:3]1[CH:5]=[C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=[CH:8][C:2]=1[Cl:1])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1ccnc(-c2ccc(Cl)c(N)c2)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc(-c2ccc(Cl)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 16 h
Yield: 42.9 %

Procedure:
To a suspension of 2-chloro-5-(4-methoxypyridin-2-yl)aniline (165 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (233 mg) and diisopropylethylamine (0.28 ml) in dichloromethane (7 ml) was added 1-methyl-2-chloropyridinium iodide (232 mg), and the mixture was stirred for 16 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane:ethyl acetate=2:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(2-chloro-5-(4-methoxypyridin-2-yl)phenyl)guanidine (144 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Li+].CC([N-]C(C)C)C.Br[CH2:24][C:25]([C:27]1[CH:36]=[CH:35][C:30]2[C:31](=[O:34])[O:32][CH2:33][C:29]=2[C:28]=1[CH3:37])=[O:26]>C1COCC1>[CH3:37][C:28]1[C:29]2[CH2:33][O:32][C:31](=[O:34])[C:30]=2[CH:35]=[CH:36][C:27]=1[C:25](=[O:26])[CH2:24][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Cc1c(C(=O)CBr)ccc2c1COC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2=O)ccc2c1COC2=O
Reaction time: 0.25 h

Procedure:
To a THF solution of tert-Butyl 3-oxopiperazine-1-carboxylate (164 mg, 0.82 mmol) was dropped LDA (0.37 ml, 0.74 mmol) at −78° C. After stirring the solution for 15 minutes, a THF solution of 5-(bromoacetyl)-4-methyl-2-benzofuran-1(3H)-one (200 mg, 0.74 mmol) was added into the reaction. TLC showed formation of a new spot right away. LC confirmed the desired alkylation product. The product was purified by MPLC to afford tert-Butyl 4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-oxoethyl]-3-oxopiperazine-1-carboxylate. LC-MS (IE, m/z): 389 [M+1]+. The resulting solid was further treated with TFA to remove the BOC group. The crude material was dissolved in aqueous sodium bicarbonate, extracted with Chloroform-IPA (3:1) three times, dried over sodium sulfate, and concentrated to furnish the free base of 1-[2-(4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-oxoethyl]piperazin-2-one.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[OH:10][CH2:11][CH2:12][NH:13][NH2:14]>CCO>[NH2:6][C:5]1[N:13]([CH2:12][CH2:11][OH:10])[N:14]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNCCO
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(CCO)n1

Procedure:
A solution of 4,4-dimethyl-3-oxopentanenitrile (125 mg, 1.0 mmol) and 2-hydroxyethyl hydrazine (75 mg, 1.0 mmol) in EtOH was heated to 100° C. for 18 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (SiO2, 0% to 10% MeOH containing 1% NH4OH/CH2Cl2) to afford the desired amino-pyrazole.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([CH:16]([NH:23]P([O-])=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C(N)C2C=CC=CC=2)C=CC=CC=1.[PH2:41]([OH:43])=[O:42]>O1CCOCC1.C(O)C.O>[C:17]1([CH:16]([NH:23][CH:8]([P:41]([OH:43])[OH:42])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[PH]([O-])NC(c1ccccc1)c1ccccc1
Reactant: O=CCc1ccccc1
Reactant: O=[PH2]O
Agent: NC(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: OP(O)C(Cc1ccccc1)NC(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 17.59 g (0.124 mol) of phenyl acetaldehyde in 20 ml of dioxane is slowly added dropwise to a suspension, which is heated at 100° C. under argon, of 31.85 g (0.124 mol) of diphenylmethylaminohypophosphite in 350 ml of dioxane, prepared by mixing equimolar quantities of diphenylmethylamine and hypophosphorous acid (100%) in ethanol. The reaction solution is stirred at this temperature for 1 h. The water of reaction which has formed is removed by azeotropic distillation using 280 ml of dioxane. Once the reaction solution has been cooled down and diluted with 150 ml of ethanol, the product, which slowly precipitates out, is filtered off with suction, washed with ethanol/diethyl ether and dried over P2O5. Yield: 9.84 g (22.5%); m.p.: 209°-211° C.; MS: 352 (M+H)+ ; 286; 167.