Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].CCN(CC)CC.[C:11]([C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([CH3:14])([CH3:13])[CH3:12]>CC#N>[C:11]([C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[N:2][OH:3])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: NO
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cccc(C=NO)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.7 %

Procedure:
To a stirred solution of hydroxylamine hydrochloride (437 mg, 6.3 mmol) in CH3CN at 0° C. was added Et3N and 3-tert-butyl-2-hydroxybenzaldehyde (1.02 g, 5.7 mmol). The reaction mixture was warmed up to room temperature and stirred for 24 h. The solvent was removed and the residue was dissolved in EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure to provide 3-tert-butyl-2-hydroxybenzaldehyde oxime (1.01 g, 92%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[H-].[Na+].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>CN(C)C=O>[CH:36]1([CH2:35][N:13]([C:12]2[C:3]([O:2][CH3:1])=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:38][CH2:37]1
Reactant: BrCC1CC1
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4ccccc4nc3OC)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)N(CC3CC3)c3cc4ccccc4nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
1-[(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(106 mg, 0.25 mmol) was dissolved in dimethylformamide(15 ml) and sodium hydride(6.2 mg, 0.26 mmol) was added and the solution was stirred at room temperature for 15 min. Bromomethylcyclopropane(22 mg, 0.26 mmol) was added to the above solution. The mixture was stirred at room temperature for 16 hours and concentrated under the reduced pressure to remove dimethylformamide. The concentrate was purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@:9]2([CH2:18]O)[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11](O)[C@@H:10]2O)[C@H](O)[C@@H](O)[C@@H]1O.C(OS(C1C=CC=CC=1)(=O)=O)CCCCCCCCCCC.[Na].O.[ClH:48]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1>[Cl:48][CH2:18][C:9]1[O:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=1
Reactant: Cl
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CCl)o1
Reaction time: 3 h

Procedure:
To a three-necked flask equipped with a condenser and a stirrer were added 5 g (0.014 mole) of a commercially available D-(+)-saccharose and two kinds of surface active agent, i.e., 47.1 mg (0.00014 mole) of cetyltrimethylammonium chloride and 51.3 mg (0.00014 mole) of sodium laurylbenzenesulfonate. Then, 5 ml of water and 30 ml of toluene were added thereto and the mixture was stirred. Thereafter, a molar excess of hydrogen chloride was passed through the mixture at room temperature for about 30 minutes with thorough stirring. After the reaction was continued at room temperature for a further 3 hours, the upper toluene layer was separated from the lower aqueous layer. Thirty milli-liters of toluene and the above two surface active agents of the same amounts as above were then freshly added to the aqueous layer. After the reaction was carried out at room temperature for 3 hours, the upper toluene layer was again separated. This toluene extraction operation was repeated three times in total. All the toluene layers were combined and filtered through Celite. The filtrate was neutralized with an aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated. Thus, about 2.6 g of 5 -chloromethylfurfural was obtained as a crude product.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([C:20](=[O:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[CH3:31][O:32][C:33](=[O:42])[CH:34]([P:36]([O:40][CH3:41])([O:38][CH3:39])=[O:37])[NH2:35].COC(=O)C(P(OC)(OC)=O)NC(OCC1C=CC=CC=1)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CO.C(OCC)(=O)C>[CH3:31][O:32][C:33](=[O:42])[CH:34]([P:36]([O:38][CH3:39])([O:40][CH3:41])=[O:37])[NH:35][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([C:20](=[O:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:19][C:11]=1[Cl:10]
Reactant: COC(=O)C(N)P(=O)(OC)OC
Reactant: O=C(CCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
Diisopropylethylamine (1.05 mL, 6 mmol) was added to a solution of 2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoic acid (Example 94; 457 mg, 1.5 mmol), rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (662.5 mg, 2.0 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (597 mg, 1.6 mmol) and 1-hydroxybenzotriazole (223 mg, 1.65 mmol) in N,N-dimethylformamide (12 mL). The solution was stirred at room temperature for 17 h and then it was evaporated in vacuo to remove N,N-dimethylformamide. A solution of the residue in ethyl acetate (40 mL) was washed in turn with 0.5N hydrochloric acid solution (20 mL), brine (20 mL), saturated sodium bicarbonate solution (20 mL) and brine (20 mL). Each of the aqueous layers was extracted with ethyl acetate (20 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting oil was chromatographed over silica gel (75% ethyl acetate/hexanes, then 5% methanol/ethyl acetate) to give rac.-N-[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (450 mg, 62% yield) as an oil.
Reaction SMILES: C(O[C:4]([C:6]1([C:29]([O:31]CC)=[O:30])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])C.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)C>[C:35]1([CH2:34][N:41]([CH2:15][C:13]2[CH:14]=[CH:8][CH:9]=[CH:11][CH:12]=2)[C:4]([C:6]2([C:29]([OH:31])=[O:30])[O:10][C:9]3[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[OH:21])[CH3:17])=[CH:14][C:8]=3[O:7]2)=[O:5])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1
Reactant: NCc1ccccc1
Solvent: CCO
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)N(Cc1ccccc1)Cc1ccccc1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
A mixture of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and benzylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform:methanol (3:1). It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9:1 chloroform:methanol to yield a colorless spongy solid; mp 101; yield 2.0 g; 67%; M+H 600.
Reaction SMILES: OC1C=C2C(=CC=1)C(=O)N(C1C=C(OC)C=CC=1CCC1C=CC(OC)=CC=1)C2=O.Cl.ClCCN1CCCCC1.[CH3:41][O:42][C:43]1[CH:44]=[CH:45][C:46]([CH2:69][CH2:70][C:71]2[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=2)=[C:47]([N:49]2[C:57](=O)[C:56]3[C:51](=[CH:52][CH:53]=[C:54]([O:59][CH2:60][CH2:61][N:62]4[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]4)[CH:55]=3)[C:50]2=O)[CH:48]=1>>[CH3:41][O:42][C:43]1[CH:44]=[CH:45][C:46]([CH2:69][CH2:70][C:71]2[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=2)=[C:47]([N:49]2[CH2:57][C:56]3[C:51](=[CH:52][CH:53]=[C:54]([O:59][CH2:60][CH2:61][N:62]4[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]4)[CH:55]=3)[CH2:50]2)[CH:48]=1
Reactant: COc1ccc(CCc2ccc(OC)cc2N2C(=O)c3ccc(OCCN4CCCCC4)cc3C2=O)cc1
Agent: COc1ccc(CCc2ccc(OC)cc2N2C(=O)c3ccc(O)cc3C2=O)cc1
Agent: Cl
Agent: ClCCN1CCCCC1
Product: COc1ccc(CCc2ccc(OC)cc2N2Cc3ccc(OCCN4CCCCC4)cc3C2)cc1
Yield: 86.3 %

Procedure:
Synthesized from 5-hydroxy-2-{5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenyl}isoindole-1,3-dione and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Example 383 described below, 2-{5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenyl}-5-(2-piperidin-1-ylethoxy)isoindole-1,3-dione (772 mg) was used according to an analogous synthetic method to Example 337 to provide the title compound (630 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.C1(=O)O[CH2:15][CH2:14][O:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:15][CH2:14][OH:13])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Oc1ccc2ccncc2c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc2ccncc2c1
Temperature: 145 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A mixture of 7-hydroxyisoquinoline (1.15 g, 7.9 mmol), ethylene carbonate (0.98 g, 11.1 mmol), powdered K2CO3 (0.65 g, 4.7 mmol) in dry DMF (20 mL) was stirred at 145° C. for two hours. The reaction was quenched with MeOH (1 mL), filtered and the solvent was removed under reduced pressure. The residue was taken up between alkaline water (K2CO3) and CHCl3. Concentration of the dried (MgSO4) organic phase afforded 1.4 g (94%) of the title compound as a yellow oil that solidified upon standing. Purity 91% (HPLC). Fragmenting mass analysis supports the stated structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:23])[CH2:21][CH3:22])=[C:13]3[NH:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH2:36][CH2:35][CH2:34][CH:33]([NH:37]C(=O)OC(C)(C)C)[CH2:32]3)=[N:29][CH:30]=2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].Cl>ClCCl.C(OCC)C>[NH2:37][CH:33]1[CH2:34][CH2:35][CH2:36][N:31]([C:28]2[N:29]=[CH:30][C:25]([NH:24][C:13]3[C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:4]5[CH:5]=[C:6]([F:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=5)[CH:11]=4)[N:16]=[CH:15][C:14]=3[C:20](=[O:23])[CH2:21][CH3:22])=[CH:26][CH:27]=2)[CH2:32]1
Reactant: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(N)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
tert-butyl 1-(5-(6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-propionylquinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (32 mg, 0.051 mmol) was dissolved in dichloromethane (5 mL). To this solution was added a 2.0 M HCl solution in diethyl ether (2 mL) the mixture was stirred for 16 h at room temperature where a precipitate formed. The precipitate was filtered off, washed with dichloromethane (10 mL), dried under vacuum to obtain the desired product as the HCl salt (16 mg, 49%) as an orange solid: 1H NMR (500 MHz, MeOD) δ 9.28 (s, 1H), 8.23 (m, 2H), 8.01 (m, 2H), 7.75 (d, J=8.5 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.10 (t, J=4.9 Hz, 2H), 4.54 (s, 1H), 4.04 (d, J=13.0 Hz, 1H), 3.36 (m, 3H), 3.24 (q, J=13.3, 6.2 Hz, 1H), 2.20 (m, 1H), 1.97 (m, 1H), 1.74 (m, 2H), 1.26 (t, J=6.6 Hz, 3H); ESI MS m/z 520, [C28H27ClFN5O2+H]+; HPLC 98.7% (AUC), tR=10.05 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([CH:32]([CH3:34])[CH3:33])[C:22]=1[O:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH:18]=O)([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:18][C:17]1[CH:16]=[C:15]([CH:12]([CH3:14])[CH3:13])[C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:21]([CH:32]([CH3:34])[CH3:33])[CH:20]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1OCCN1CCOCC1
Product: CC(C)c1cc(C=C2C(=O)Nc3ccc(Cl)cc32)cc(C(C)C)c1OCCN1CCOCC1

Procedure:
5-Chloro-2-oxindole was condensed with 3,5-diisopropyl-4-(2-morpholin-4-yl-ethoxy)-benzaldehyde using method B to give 5-chloro-3-[3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-1,3-dihydroindol-2-one as a brownish-orange solid which was reduced using method E to give 1.3 g (100%) of 5-chloro-3-[3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzyl]-1,3-dihydroindol-2-one as a yellow/orange foam.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](CS([O-])(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])([CH3:26])([CH3:25])[CH3:24].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:7]([N:8]1[CH2:11][CH:10]([O:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:23]([CH3:26])([CH3:24])[CH3:25])[CH2:9]1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)([O-])CC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)c1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A stirred solution of 1-(diphenylmethyl)-3-azetidinylmethane sulfonate (12.68 g, 39.9 mmol), 2-tert-butylphenol (6.0 g, 39.9 mmol), tetrabutylammonium bromide (1.29 g, 3.99 g) and sodium hydroxide (15.0 mL of 8.0 M solution in water, 120 mmol) in toluene (40 mL) was heated at 100° C. for 5 h. Then, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and separated. The organic layer was washed with water, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 100:0 to 98:2 heptane/ethyl acetate) provided impure 1-benzhydryl-3-(2-tert-butylphenoxy)azetidine (9.10 g, 66%) as a yellow oil, which was used without further purification or characterization.
Reaction SMILES: [ClH:1].Cl.[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:13][CH2:14][N:15]1[CH2:18][CH:17]([N:19]2[CH2:24][CH2:23][N:22]3[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][CH:21]3[CH2:20]2)[CH2:16]1)[CH3:10])=[O:8].N1CC(N2CCN(C(C3CC3)=O)CC2)C1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[ClH:1].[ClH:1].[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)[CH2:13][CH2:14][N:15]1[CH2:18][CH:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24]2)[CH2:16]1)[CH3:10])=[O:8]
Reactant: CN(C[C@@H](CCN1CC(N2CCN3C(=O)CCCC3C2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C(C1CC1)N1CCN(C2CNC2)CC1
Agent: [BH3-]C#N
Solvent: CO
Product: CCCC(=O)N1CCN(C2CN(CC[C@H](CN(C)C(=O)c3cc(Br)cc(C(F)(F)F)c3)c3ccc(F)cc3)C2)CC1
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
To a solution of 3-bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 450 mg, 1.0 mmol) and 1-azetidin-3-yl-4-(cyclopropylcarbonyl)piperazine (see Method 15; ˜0.9 mmol) in methanol (50 mL) was added a solution of sodium cyano borohydride (250 mg, 4.0 mmol) and zinc chloride (270 mg, 2.0 mmol) in methanol (30 mL). The reaction mixture was stiffed at RT for 15 min and then the solvent was removed by evaporation. The residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic solution was washed with brine and then dried over Na2SO4. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate. The product was purified by means of silica gel chromatography first eluting with ethyl acetate and then with a mixture of ethyl acetate, methanol and triethylamine (9:1:1). The proper fractions were combined and concentrated on a rotavapor then the residue was co-evaporated twice using methylene chloride. The residue was dissolved in methylene chloride and to the solution was added HCl-saturated diethyl ether (1 mL). The solvent was removed by evaporation and then, the residue was co-evaporated twice with methylene chloride. There was obtained 220 mg (30%) of the title compound. 1H NMR (400 MHz, CD3OD): 0.8-1.0 (t, 3H), 1.5-1.6 (qt, 2H), 1.8-2.2 (cm, 3H), 2.4 (t, 2H), 2.6-4.6 (cm, 20H), 7.0-7.6 (cm, 6H), 7.9 (d, 1H); LCMS: m/z 642 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:27](O)=[O:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([CH3:33])=[C:24]([OH:23])[CH:25]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)c1ccc(C)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was taken 100 mg of 3-(3-chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (0.31 mmol, 1.00 eq), 52 mg of 3-hydroxy-4-methylbenzoic acid (0.31 mmol, 1.00 eq), 163 mg BOP (0.37 mmol, 1.20 eq), 171 uL (1.23 mmol, 4.00 eq), and 1.5 mL NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield N-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-3-hydroxy-N-(2-methoxy-ethyl)-4-methyl-benzamide. MS (ES) M+H expected=480.0, found=480.1.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][C:8]=2[CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[CH:15]([CH3:17])[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C2CCCCC2)c(C(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(O)ccc1C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 120.1 %

Procedure:
To 1-cyclohexyl-4-methoxy-2-isopropyl-benzene (2.09 g, 9.0 mmol) in CH2Cl2 (20 mL) was added BBr3 (1 M in CH2Cl2, 22.5 mmol) dropwise at 0° C. This mixture was stirred at 0° C. for two hours. The reaction mixture was then quenched with MeOH (5 mL), after which aqueous sodium hydrogen carbonate (10 mL) was added. The reaction mixture was stirred at room temperature for one hour and extracted with CH2Cl2 three times. The organic phase was washed with brine, dried (Na2SO4) and concentrated. Silica gel chromatography (0-2% EtOAc/heptane) provided 2.36 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[C:22]3[O:21][C:20]([F:24])([F:23])[C:19]([F:26])([F:25])[O:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(OP([CH2:35][C:36]#[N:37])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[C:22]3[O:21][C:20]([F:24])([F:23])[C:19]([F:26])([F:25])[O:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:35][C:36]#[N:37])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2cccc3c2OC(F)(F)C(F)(F)O3)c1
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2cccc3c2OC(F)(F)C(F)(F)O3)c1
Yield: 94 %

Procedure:
(3,5-Dimethoxyphenyl)-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-5-yl)methanone (0.42 g, 1.13 mmol), cyanomethylphosphonic acid diethyl ester (0.36 ml, 2.26 mmol) in anhydrous THF (10 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 2.26 ml, 2.26 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 25% EtOAc in hexane in about 30 min.) to give 3-(3,5-dimethoxy-phenyl)-3-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-acrylonitrile as an oil (0.42 g, 94%): 1HNMR (DMSO-d6) 7.70-7.35 (m, 6H, Ar), 6.86 (s, 0.32H, double bond proton of one isomer), 6.68-6.66 (m, 2H, Ar), 6.53 (d, J=2 Hz, 1.3H, Ar), 6.48 (d, J=1 Hz, 0.7H, Ar), 6.27 (s, 0.62H, double bond proton of the other isomer), 3.74 (s, 6H, 2OCH3); 13C NMR (DMSO-d6) δ 160.7, 160.5, 155.0, 153.8, 138.0, 137.3, 136.7, 133.7, 128.7, 128.7, 127.8, 127.5, 126.8, 126.7, 126.5, 119.5, 119.3, 117.1, 116.9, 106.2, 105.3, 102.5, 101.8, 101.1, 100.6, 55.4, 55.4; Anal. Calcd. For C19H13F4NO4: C, 57.73; H, 3.31; N, 3.54; F, 19.22. Found: C, 57.62; H, 3.34; N, 3.49; F, 19.17.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)SC)#[N:2].[CH3:18][NH2:19]>CO>[C:1]([NH:3][C:4]([NH:19][CH3:18])=[N:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)#[N:2]
Reactant: CN
Reactant: CSC(=NCc1ccc(CCO)cc1)NC#N
Solvent: CO
Product: CNC(=NCc1ccc(CCO)cc1)NC#N

Procedure:
A solution of 0.42 g (0.00168 mol) of N-cyano-N'-[4-(2-hydroxyethyl)benzyl]-S-methylisothiourea in 50 ml of methanol and 10 g of methylamine was stirred at room temperature overnight. Evaporation of the solvent gave the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:22][CH2:23][CH2:24][CH2:25][Cl:26])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C1COCC1>[Cl:26][CH2:25][CH2:24][CH2:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:27][CH3:28])[N:15]=[CH:14][N:13]=[C:12]2[S:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:3]
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCCl
Reactant: Nc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OCCCCl
Reaction time: 0.5 h

Procedure:
In a round bottomed flask, sodium hydride (121 mg, 3.14 mmol), a 60% dispersion in mineral oil, was suspended in 20 mL of dry THF. To this suspension 3-aminothiophenol (394 mg, 3.14 mmol) was added and the reaction stirred for 30 minutes. To this solution 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline (900 mg, 3.14 mmol) and the reaction stirred overnight. The reaction was quenched with water, concentrated, and partitioned between water and ethyl acetate. After extracting twice, the extracts were combined, dried over magnesium sulfate, filtered and concentrated to give 3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)aniline as a yellow solid and used without further purification. 1H(DMSO-d6) 8.70 (s, 1H), 7.34 (s, 1H), 7.15 (m, 1H), 6.80 (s, 1H), 6.75 (m, 2H), 4.28 (m, 2H), 3.99 (s, 3H), 3.84 (m, 2H), 2.38 (m, 2H); LCMS (ESI) m/z 376 (M+H).