Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:19]([N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](Cl)=[O:23])[CH3:20]>>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:22](=[O:23])[N:21]([CH2:19][CH3:20])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CCN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Product: CCN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-trifluoromethyl-phenoxy)-phenol and N-ethyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (ethyl
Reaction SMILES: COC([CH:5]1[C:13](=[O:14])[CH2:12][C@H:11]2[N:7]([CH2:8][CH2:9][CH2:10]2)[C:6]1=[O:15])=O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:10]1[C@@H:11]2[N:7]([C:6](=[O:15])[CH2:5][C:13](=[O:14])[CH2:12]2)[CH2:8][CH2:9]1
Reactant: COC(=O)C1C(=O)C[C@@H]2CCCN2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CC(=O)N2CCC[C@H]2C1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
(8aS)-6-Methoxycarbonyl-1,2,3,5,6,7,8,8a-octahydroindolizin-5,7-dione (183 mg (0.87 mmol), prepared as described in 2)) was dissolved in an aqueous solution of 10% acetic acid (2 ml). The resulting mixture was stirred at 110° C. for 30 minutes, and then cooled to room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate and the mixture was made alkaline. The mixture was extracted with a solution of dichloromethane and isopropanol (4:1). The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure, to give the title compound (117 mg) as a pale brown oil (yield 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:11][C@@H:12]([OH:29])[CH2:13][O:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:16].N1C=CN=C1.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40].C(OCC)(=O)C>CN(C)C=O>[Si:43]([O:29][C@H:12]([CH2:11][N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[CH2:5][C:4]1[CH:30]=[CH:31][C:32]([CH3:33])=[C:2]([F:1])[CH:3]=1)[CH2:13][O:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:16])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44]
Reactant: COC(=O)CCc1ccccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of methyl 3-{2-[(1R)-1-({(2R)-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]-2-hydroxypropyl}oxy)ethyl]phenyl}propanoate (596 mg, 1.30 mmol) which had been obtained in Example 2 (2a), in N,N-dimethyl formamide was added with imidazole (221 mg, 3.25 mmol) and tert-butyl(chloro)dimethylsilane (294 mg, 1.95 mmol), and stirred at room temperature. After stirring for 24 hours, the reaction solution was added with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=85/15) to give the title compound as a pale yellow oily substance (676 mg, yield 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][C:14]([C:17]([N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[CH3:20])=[O:18])=[CH:13][C:12]=23)=[CH:4][CH:3]=1.C(OC([NH:36][CH2:37][C:38](O)=[O:39])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:36][CH2:37][C:38]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][C:14]([C:17]([N:19]([C:21]4[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=4)[CH3:20])=[O:18])=[CH:13][C:12]=23)=[CH:4][CH:3]=1)=[O:39]
Reactant: CN(C(=O)c1ccn2ncc(-c3ccc(N)cc3)c2c1)c1ccc(C#N)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1ccn2ncc(-c3ccc(NC(=O)CN)cc3)c2c1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 42 (1.0 equiv.) in CH2Cl2 (˜0.1 M) was treated with 2-((tert-butoxycarbonyl)amino)acetic acid (1.2 equiv.), followed by HATU (1.1 equiv(2.5 equiv.). The resulting mixture was allowed to stir at rt for two hours, and then was filtered and treated with one volume of TFA. The resulting solution was allowed to stir at rt for 30 minutes, and the solvents were removed under reduced pressure. The residue was purified by mass-triggered HPLC to provide the desired product. ESI-MS (m/z): [M+H]+ 425.1, RT 1.1033 min.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:39])[CH:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])=[CH:25][C:24]=2[C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])[CH2:20][CH3:21])=[CH:12][C:11]=1[OH:40])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:41]([O-:43])=[O:42].[Na+]>C(O)(=O)C.CN(C)C=O.O>[N+:41]([C:12]1[C:13]([NH:17][C:18](=[O:39])[CH:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])=[CH:25][C:24]=2[C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])[CH2:20][CH3:21])=[C:14]([Cl:16])[CH:15]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:11]=1[OH:40])([O-:43])=[O:42]
Reactant: O=N[O-]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1c(Cl)cc(NC(=O)c2ccccc2)c(O)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
In 100 ml of acetic acid and 100 ml of dimethylformamide was dissolved 20 g (35×10-3 mole) of 2-benzamido-4-chloro-5-{2-(2,4-di-t-amylphenoxy)butanamido}phenol. To the solution was added dropwise slowly a solution of 2.7 g of sodium nitrite dissolved in 5 ml of a distilled water at room temperature, and then the mixture was stirred for 2 hours. The reaction mixture was poured into ice-cold water, and precipitated yellow solids were collected by filtration and washed with water. Yield: 21 g.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[CH2:18][CH2:17]1.Cl>C(O)C>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)[CH2:20][CH2:21]1
Reactant: Cn1c(OC2CCN(CCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: CCO
Product: Cn1c(OC2CCN(CCC3CCNCC3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of tert-butyl 4-{2-[4-(1-methyl-6-oxo-1,6-dihydro-[4,4]bipyrimidinyl-2-yloxy)piperidin-1-yl]ethyl}piperidine-1-carboxylate (326 mg, 0.654 mmol) in ethanol (6.54 ml) was added 2N hydrogen chloride in ethanol (9.81 ml, 19.6 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the residue was dissolved into water. The aqueous solution was washed with ethyl acetate and basified with potassium carbonate. Extraction with chloroform was performed three times. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 1-methyl-2-[1-(2-piperidin-4-yl-ethyl)piperidin-4-yloxy]-1H-[4,4′]bipyrimidinyl-6-one as pale yellow solid (207 mg, 0.519 mmol, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5](Cl)[C:3]=1[NH2:4].[N+](C1C=CC(N)=CC=1)([O-])=O.ClCl.Cl>O.[N+]([O-])(O)=O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: ClCl
Agent: Nc1ccc([N+](=O)[O-])cc1
Solvent: O=[N+]([O-])O
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1Cl
Yield: 90 %

Procedure:
Process for the preparation of 2,6-dichloro-4-nitroaniline by chlorination of 4-nitroaniline with chlorine bleaching liquor in water using acids, which comprises chlorinating 1 mole of 4-nitroaniline in 3-6 moles of hydrochloric acid (HCl) or nitric acid (HNO3) in the form of a dilute, aqueous acid in the presence of a dispersing agent which is stable under the reaction conditions, the chlorination initially being carried out at 5° to 10° C. and then at 15°-20° C. and, finally, after 90-95% of the 2-chloro-4-nitroaniline intermediately formed has been converted into 2,6-dichloro-4-nitroaniline, the temperature of the aqueous suspension being increased from 15°-20° C. to 70° C., without further addition of chlorine bleaching liquor, and then by post-chlorinating, by renewed addition of chlorine bleaching liquor, at temperatures between 20° and 70° C., bringing the pH of the aqueous suspension to 9.0 and filtering off the 2,6-dichloro-4-nitroaniline formed and washing it with dilute mineral acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-(4-chloro-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.4 step 2a and 2b) (13.96 g, 32.96 mmol), trimethylsilylacetylene (5.5 mL, 39.72 mmol) and Et3N (9.2 mL, 67.9 mmol) in dry DMF (33 mL) was stirred for 10 min at 23° C. while being purged with Argon, then PdCl2(PPh3)2 (116 mg, 0.5 mol %), PPh3 (43 mg, 0.5 mol %) and Cul (19 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4 h. The react mixture was then cooled to 23° C., diluted with EtOAc, washed water (twice) and brine, dried over Na2SO4. Removal of the solvent left an orange solid (13.30 g, 102%). MS (ISP) 394.1 [(M+H)+] and 396.1 [(M+2+H)+]; mp 198° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH2:22][OH:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@@H:10]([CH2:21][CH2:22][O:23][CH3:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CCO
Product: COCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
A solution of 4-benzyl-1-tert-butoxycarbonyl-2(S)-(2-hydroxyethyl)piperazine (0.322 g, 1.00 mmol) in dry, degassed dimethylformamide (4 mL) was cooled under nitrogen to 0° C. Sodium hydride was added (0.052 g, 60% dispersion in oil, 1.30 mmol) followed by methyl iodide (0.88 mL, 1.41 mmol). After 3 h, the reaction was quenched with saturated ammonium chloride. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The ethyl acetate was washed with water, saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was chromatographed on silica gel with 40% ethyl acetate in hexane to obtain the title compound as a clear oil (280 mg). NMR (CD3OD, 300 MHz) δ 7.3 (5H, m), 4.19 (1H, m), 3.85 (1H, dm, J=13 Hz), 3.56 (1H, d, J=13 Hz), 3.16 (1H, d, J=13 Hz), 3.28 (2H, m, partially obscured by solvent), 3.23 (3H, s), 3.08 (1H, t, J=13 Hz), 2.80 (1H, d, J=11 Hz), 2.70 (1H, d, J=11 Hz), 2.03 (3H, m), 1.86, (1H, sextet, J=6 Hz), 1.45 (9H, s).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[NH2:60][C:61]1[N:70]=[C:69]([NH:71][C@@H:72]2[CH2:77][CH2:76][CH2:75][CH2:74][C@@H:73]2[NH:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[C:68]([F:86])=[CH:67][C:62]=1[C:63]([O:65][CH3:66])=[O:64]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.O1CCOCC1>[C:82]([O:81][C:79]([NH:78][C@H:73]1[CH2:74][CH2:75][CH2:76][CH2:77][C@H:72]1[NH:71][C:69]1[C:68]([F:86])=[CH:67][C:62]([C:63]([O:65][CH3:66])=[O:64])=[C:61]([NH:60][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][CH:3]=2)[N:70]=1)=[O:80])([CH3:85])([CH3:83])[CH3:84]
Reactant: Brc1cncc2ccccc12
Reactant: COC(=O)c1cc(F)c(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(F)c(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cncc2ccccc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
4-bromoisoquinoline (65 mg), cesium carbonate (170 mg), Pd2(dba)3 (29 mg), and Xantphos (36 mg) were added to a 1,4-dioxane (2.1 ml) solution containing methyl 2-amino-6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoronicotinate (80 mg), followed by stirring at 100° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. Insoluble matter was removed by filtration, and the filter cake was washed with water and ethyl acetate. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 to 1:2), diisopropylether was added, solid matter was collected by filtration, and a light yellow solid of methyl 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoro-2-(isoquinoline 4-ylamino)nicotinate (77 mg) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH3:17])[C:7]2[CH:18]=[CH:19][C:20]([C:22]3[CH:26]=[CH:25][NH:24][CH:23]=3)=[N:21][C:6]1=2)[CH3:4].[CH3:27]I.O>CN(C=O)C>[CH2:3]([N:5]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH3:17])[C:7]2[CH:18]=[CH:19][C:20]([C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[CH:23]=3)=[N:21][C:6]1=2)[CH3:4]
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cc[nH]c3)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3ccn(C)c3)nc21
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.008 g, 60% in oil) was added to a solution of 5,11-dihydro-11-ethyl-5-methyl-2-(3-pyrrolyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.065 g) in dry DMF (3 mL) and stirred for 30 min. Methyl iodide (0.2 mL) was added and the reaction mixture was stirred for an additional 2 h. Water was added and the product was extracted with CH2Cl2, dried (anhyd Na2SO4), filtered, and evaporated. The residue was chromatographed over silica gel (ethyl acetate/hexanes, 1:1) and was further purified by preparative plate chromatography (ethyl acetate/hexanes, 1:1) to give 0.040 g of the title compound, mp 187°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([O:27][C:18]3[C:17]4[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=4)[N:21]=[CH:20][CH:19]=3)=[CH:29][C:30]=2[CH3:35])=[S:12])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 56%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C@@H:8]([CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:9](O)=[O:10]>C1COCC1>[NH2:7][C@@H:8]([CH2:12][S:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH2:9][OH:10]
Reactant: N[C@@H](CSCc1ccc(F)cc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N[C@H](CO)CSCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
A 1000 mL 3-neck round bottom flask fitted with a mechanical stirrer, reflux condenser, addition port, and nitrogen inlet was charged with a 1.0 M solution of lithium aluminum hydride (200 mL) in THF and anhydrous THF (200 mL). The solution was cooled in an ice/water bath and 2(R)-amino-3-(4-fluorobenzylsulfanyl)-propionic acid (24.08 g) was added with rapid stirring in small portions over 15 min. The ice bath was removed and the reaction mixture was heated to reflux overnight. After cooling the reaction mixture to room temperature, saturated aqueous potassium carbonate (50 mL) was added dropwise over 1 h. The solids were filtered off and the filter cake was washed with THF. The combined filtrate was dried over anhydrous MgSO4 and concentrated to give 2(R)-amino-3-(4-fluoro-benzylsulfanyl)-propan-1-ol (16.16 g) as a pale amber resin.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(O)C>[ClH:1].[CH:9](=[C:4]1[C:5](=[O:8])[C:6](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][NH:2][CH2:3]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CNCC1=Cc1ccccc1
Reaction time: 16 h
Yield: 94.3 %

Procedure:
A stirred solution of 10 g of 4-piperidone, hydrochloride, hydrate and 14 g of benzaldehyde in 50 ml of ethanol is cooled to 10° C and treated dropwise with 25 ml of concentrated hydrochloric acid (temperature maintained at less than 25° C during the addition) and refluxed for 4 hours; the product begins to separate soon after refluxing begins. After standing at room temperature for about 16 hours, the resulting solid is filtered, washed with cold ethanol and with ether, and air-dried yielding 19.4 g of material, melting point 272°-274° C, dec.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:12]1[C:21]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]=2[CH:15]=[CH:14][C:13]=1[C:22]([O:24][CH3:25])=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([NH:8][C:9]([N:18]1[CH2:19][CH2:20][C:21]2[N:12]=[C:13]([C:22]([O:24][CH3:25])=[O:23])[CH:14]=[CH:15][C:16]=2[CH2:17]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(n1)CCNC2
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(n1)CCN(C(=O)NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a vial containing benzyl isocyanate (0.0166 g, 0.125 mmol), was added methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride (0.0220 g, 0.0962 mmol), DIPEA (0.0586 mL, 0.337 mmol) and DMF (2 mL). The resulting solution was then shaken at rt for 13 h and then concentrated to give methyl 6-(benzylcarbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([O:7]C)=[O:6].[ClH:18]>>[ClH:18].[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(CN2CCCC2)c(C)c1
Agent: Cl
Product: Cc1cc(C(=O)O)ccc1CN1CCCC1
Temperature: 25 °C

Procedure:
A solution of methyl 3-methyl-4-[(1-pyrrolidinyl)methyl]benzoate (16 g, 68.6 mmol) in 250 mL of 1 N HCl was heated at reflux overnight (13 hr). After cooling to ambient temperature, the aqueous solution was extracted with EtOAc (150 mL). The aqueous layer was concentrated by rotary evaporation to give 16.8 g (65.7 mmol; 96%) of the title acid as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH2:10]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:11]=[CH2:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:13]1([CH2:10]/[CH:11]=[CH:12]/[C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C=CCC1CCCCC1
Reactant: Nc1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1ccc(/C=C/CC2CCCCC2)cc1F
Yield: 69 %

Procedure:
Toluene (5 mL) was added to 4-bromo-2-fluoroaniline (950 mg, 5.00 mmol), allylcyclohexane (1.15 mL, 7.50 mmol), palladium acetate (112 mg, 0.50 mmol), tris(2-methylphenyl)phosphine (457 mg, 1.50 mmol) and triethylamine (2.09 mL, 15.0 mmol), and the mixture was stirred, followed by heating to reflux for 10 hr. After cooling, ethyl acetate was added thereto, the mixture was filtered through Celite (registered trademark), and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=9:1) to afford the title compound as a pale yellow oil (805 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][OH:37]>CN(C=O)C.O>[OH:37][CH2:36][CH2:35][N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(CCO)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (1) (0.68 mmol) in DMF (8 mL) was added potassium carbonate (0.68 mmol) and 2-bromoethanol (0.68 mmol). The resulting solution was stirred at room temperature overnight. Then, the mixture was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 2. The material was purified by flash chromatography on silica gel, eluting with 50% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2. The product was further purified by reverse-phase chromatography, eluting with 10% to 90% CH3CN in H2O, to afford the title compound (0.025 g, 9%). 1H NMR (300 MHz, DMSO-d6): δ 11.45 (s, 1H), 8.08 (d, J=8.9 Hz, 2H), 7.00 (d, J=9.1 Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 4.30-4.55 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.43-3.67 (m, 2H), 3.10-3.43 (m, 7H), 2.77-3.04 (m, 1H), 2.31-2.64 (m, 2H). ESI MS m/z 411 [M+H]+.