Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].Cl.Cl.[NH2:26][C@@H:27]([CH2:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[C:44]([F:49])[CH:43]=1)[C@H:28]([OH:40])[CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH3:39])[CH:33]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C)C=O.O>[F:48][C:46]1[CH:47]=[C:42]([CH:43]=[C:44]([F:49])[CH:45]=1)[CH2:41][C@H:27]([NH:26][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:28]([OH:40])[CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH3:39])[CH:33]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nccs2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2nccs2)c1
Reaction time: 8 h
Yield: 10.8 %

Procedure:
A solution of 3-[(dipropylamino)carbonyl]-5-(1,3-thiazol-2-yl)benzoic acid (156 mg, 0.47 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (191 mg, 0.47 mmol), HOBt (64 mg, 0.47 mmol), and N-methylmorpholine (200 μL, 1.5 mmol) was stirred in dimethylformamide (2 mL) for 15 min. EDC (145 mg, 0.84 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with water, and extracted with ethyl acetate (3×25 mL). The organic layer was washed with 1 N hydrochloric acid (25 mL), saturated sodium bicarbonate (25 mL), saturated sodium chloride, dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N3,N3-dipropyl-5-(1,3-thiazol-2-yl)isophthalamide (33 mg): 1H NMR (500 MHz, CDCl3) δ 8.40 (br s, 1H, —NH), 8.15 (br s, 1H), 7.94 (br s, 1H), 7.80 (d, J=3 Hz, 1H), 7.51 (br s, 1H), 7.34 (d, J=3 Hz, 1H), 7.27-7.24 (m, 1H), 7.21-7.18 (m, 2H), 7.11-7.10 (m, 1H), 7.00 (br s, 1H), 6.62-6.58 (m, 1H), 4.23 (d, J=5 Hz, 1H), 3.91-3.85 (m, 3H), 3.57 (br s, 2H), 3.31 (br s, 2H), 3.05 (d, J=5 Hz, 4H), 2.83 (d, , J=6 Hz, 2H), 2.64 (q, J=8 Hz, 2H), 1.75 (br s, 2H), 1.44 (t, J=7 Hz, 2H), 1.22 (t, J=8 Hz, 3H) 1.04 (t, J=7 Hz, 3H), 0.65 (t, J=7 Hz, 3H); ESI MS m/z 649 [M+H]+;
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([OH:58])[CH2:45]2)[CH:7]([CH3:60])[CH:6]([OH:61])[CH2:5][C:4]1=[O:62])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:67][CH:68]=[CH2:69].FC(F)(F)S(O)(=O)=O>C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([O:58][CH2:69][CH:68]=[CH2:67])[CH2:45]2)[CH:7]([CH3:60])[CH:6]([OH:61])[CH2:5][C:4]1=[O:62])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 49.5 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (290 mg in 3.9 ml 33% methylene chloride in cyclohexane) allyl trichloroacetimidate (131 mg neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (6 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 5 days the reaction was diluted with ethyl acetate and quenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was washed with brine then dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:5)+1% methanol) gave the title compound (150 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[CH3:16].C(N(CC)CC)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[B]1OC(C)(C)C(C)(C)O1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[F:69][C:70]1[C:77](I)=[C:76]([O:79][CH3:80])[CH:75]=[CH:74][C:71]=1[CH:72]=[O:73]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:69][C:70]1[C:77]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][C:8](=[O:13])[N:9]3[CH3:12])=[CH:4][C:3]=2[CH3:16])=[C:76]([O:79][CH3:80])[CH:75]=[CH:74][C:71]=1[CH:72]=[O:73]
Reactant: COc1ccc(C=O)c(F)c1I
Reactant: Cc1cc2c(cc1Br)N(C)C(=O)CC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)O[B]OC1(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C=O)c(F)c1-c1cc2c(cc1C)C(C)(C)CC(=O)N2C
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 52 %

Procedure:
To a solution of 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro- 1H-quinoline-2-one (example 1d) (0.96 g, 3.40 mmol) in dioxane (2 mL) were added under argon, triethylamine 1.9 mL, 13.61 mmol), palladium acetate (38 mg, 0.17 mmol), 2-(dicyclohexylphosphino) biphenyl (238 mg, 0.68 mmol) and pinacolborane (1M in THF, 10.2 mL, 10.2 mmol). The mixture was stirred at 80° C. for 1 hr 45 min, then cooled to room temperature. Water (1.5 mL), barium hydroxide octahydrate (3.22 g, 10.20 mmol) and 2-Fluoro-3-iodo-4-methoxy benzaldehyde dissolved in dioxane (7 mL) were successively added and the mixture heated at 100° C. for 13 hrs. The mixture was cooled to room temperature and filtered over celite. Brine was added and the aqueous layer was extracted with dichloromethane. The organic extract was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (20% to 30% ethyl acetate in hexane) to give 0.63 g of 2-Fluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde (52%). 1H NMR (300 MHz; CDCl3): 1.33 (s, 3 H), 1.35 (s, 3 H), 2.09 (s, 3 H), 2.54 (s, 2 H), 3.35 (s, 3 H), 3.87 (s, 3 H), 6.79 (s, 1 H), 6.92 (d, J=8.7 Hz, 1 H), 7.21 (s, 1 H), 7.94 (t, J=8.7 Hz, 1 H), 10.25 (s, 1 H).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.CI.C(OCC)(=O)C>C1COCC1.CCCCCC>[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]([F:14])([F:16])[F:15])[C:12]=1[CH3:1]
Reactant: [Li]CCCC
Reactant: FC(F)(F)c1cncc(Br)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: Cc1c(Br)cncc1C(F)(F)F
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 17.9 %

Procedure:
n-Butyl Lithium (1.9 mL, 3.044 mmol) was added to a solution of DIPA (335.7 mg, 3.318 mmol) in THF (6 mL) at -78° C. The reaction mixture was stirred at -10° C. for 10 minutes. This was followed by the addition of 3-bromo-5-trifluoromethyl-pyridine (500 mg, 2.212 mmol) in THF (3 mL) at -100° C. The reaction mixture was stirred for a further 15 minutes at -90° C. and was followed by the addition of methyl iodide (557.0 mg, 3.924 mmol) in THF (2 mL) at -78° C. with stirring over a period of 30 minutes. The reaction was monitored by TLC (5% ethyl acetate in hexane). The reaction mixture was quenched with aqueous NaHCO3 solution and extracted with ethyl acetate (100 mL). The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (2% ethylacetate in hexane) afforded 95 mg of the product (17.92% yield). LCMS: m/z=239.8 (M+1)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[Cl:21])C1C=CC=CC=1.Cl>C(O)(=O)C>[ClH:21].[Cl:21][C:10]1[CH:11]=[C:12]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Clc1cc(N2CCNCC2)ccc1OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: Oc1ccc(N2CCNCC2)cc1Cl
Reaction time: 1.5 h
Yield: 207.7 %

Procedure:
To 1-(4-benzyloxy-3-chlorophenyl)piperazine (4.739 g), acetic acid (20 mL) and conc. hydrochloric acid (10 mL) were added, followed by 1.5 hours' heating under reflux. The reaction liquid was let stand to cool off, and from which the solvent was distilled off by heating under reduced pressure. The crude product was suspended in tetrahydrofuran, recovered by filtration, washed with tetrahydrofuran and dried by heating under reduced pressure to provide 2-chloro-4-(piperazin-1-yl)phenol hydrochloride (4.050 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[C:17]([F:26])[CH:16]=3)[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[O:6][N:5]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[C:17]([F:26])[CH:16]=3)[CH2:12][NH:11][CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: CCOc1noc(C2CC(c3ccc(OC(F)(F)F)c(F)c3)CN(C(=O)OC(C)(C)C)C2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1noc(C2CNCC(c3ccc(OC(F)(F)F)c(F)c3)C2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
387 mg (0.50 mmol) of tert-butyl 3-(3-ethoxy-1,2,4-oxadiazol-5-yl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]piperidine-1-carboxylate were initially charged in 30 ml of dichloromethane and admixed with 0.38 ml (567 mg, 4.97 mmol) of trifluoroacetic acid. The reaction mixture was stirred at RT for 16 hours, admixed with the same amount of trifluoroacetic acid and stirred at RT for a further 3.5 hours. The reaction mixture was concentrated under reduced pressure, taken up in ethyl acetate and washed twice with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 195 mg (96% of theory)
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]2[C:15]([C:16]([C:26]([F:29])([F:28])[F:27])=[CH:17][C:18](=[O:25])[O:19]2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[O:36]1[CH2:41][CH2:40][O:39][C:38]2[CH:42]=[C:43]([C:46]3([CH3:53])[NH:50][C:49](=[O:51])[NH:48][C:47]3=[O:52])[CH:44]=[CH:45][C:37]1=2>O>[O:36]1[CH2:41][CH2:40][O:39][C:38]2[CH:42]=[C:43]([C:46]3([CH3:53])[NH:50][C:49](=[O:51])[N:48]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]4[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]5[C:15]([C:16]([C:26]([F:29])([F:28])[F:27])=[CH:17][C:18](=[O:25])[O:19]5)=[CH:14][CH:13]=4)[C:47]3=[O:52])[CH:44]=[CH:45][C:37]1=2
Reactant: CCCc1c(OCCCCBr)ccc2c(C(F)(F)F)cc(=O)oc12
Reactant: CC1(c2ccc3c(c2)OCCO3)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCN2C(=O)NC(C)(c3ccc4c(c3)OCCO4)C2=O)ccc2c(C(F)(F)F)cc(=O)oc12
Reaction time: 8 h
Yield: 94.6 %

Procedure:
An N,N-dimethylformamide (2 mL) solution of 7-(4-bromobutoxy)-8-propyl-4-(trifluoromethyl)-2H-chromen-2-one (30 mg, 0.074 mmol) was added with potassium carbonate (20.4 mg, 0.148 mmol) and 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylimidazolidine-2,4-dione (27.4 mg, 0.111 mmol) and then stirred overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified using thin-layer silica-gel chromatography (hexane:ethyl acetate=5:2), and the title compound (40.2 mg, 95%) was obtained as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)c1ccc(F)c(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(O)c1ccc(F)c(N)c1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a solution of 1-(3-amino-4-fluorophenyl)-ethanone (3 g) in a mixture of MeOH (20 mL) and CH2Cl2 (20 mL) was added in portions NaBH4 (1520 mg) at 0° C. After stirring for 0.5 hours, the reaction mixture was quenched with saturated NH4Cl solution and most of the solvent was removed in vacuo. The residue was extracted with CH2Cl2, and the combined organic layer was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (33% ethyl acetate in hexane) to give 2.9 g of the title compound as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])C)=[O:12])[CH2:10][CH:5]2[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(Cl)(=O)O[C:40]1[CH:45]=CC=C[CH:41]=1>ClCCl.C(OCC)(=O)C.O1CCCC1>[O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]3[CH:16]=[CH:45][CH:40]=[CH:41][CH:17]=3)=[O:12])[CH2:10][CH:5]2[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OC(c3ccccc3)C2C1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Oc1ccccc1)N1CCN2C(=O)OC(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
To a solution of 1,1-dimethylethyl tetrahydro-3-oxo-1-phenyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (0.12 g, 0.38 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and then ethyl acetate was added to the residue. The resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue were added tetrahydrofuran (5 mL), triethylamine (0.10 ml, 0.75 mmol) and phenyl chlorocarbonate (88 mg, 0.56 mmol), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=9:1 to ethyl acetate) to obtain the title compound (0.10 g, yield 80%) as a diastereomer mixture. Diastereomer ratio (α:β=3:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Cl:29][CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>O1CCCC1>[Cl:29][CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([NH:9][C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:13]=[CH:12][N:11]=3)[CH:3]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CCl)cc1
Reaction time: 0.5 h
Yield: 114.4 %

Procedure:
N-(3-amino-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (11 g, 39.8 mmol) was dissolved in tetrahydrofuran (100 ml), triethylamine (8.3 ml, 59.5 mmol) was added thereto, and the mixture was stirred for 30 minutes. 4-Chloromethyl benzoyl chloride (2.03 g, 10.78 mmol) was added, and the resulting mixture was reacted under reflux for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated and crystallized from methylene chloride to give N-(5-(4-chloromethylbenzoylamino)-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (5.3 g).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:10][C:11]([CH3:13])=[O:12]>>[C:11]([C:13]1[CH:8]=[CH:9][C:4]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:5]=2)=[CH:5][CH:6]=1)(=[O:12])[CH3:10]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc(-c2cccc(-c3ccccc3)c2)cc1

Procedure:
Nitrobenzene is stripped with steam and the solid residue is dissolved into acetone. After filtration and the acetone evaporation, 400 g of crude product is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[NH:28][C:29]4[CH:39]=[CH:38][C:37]5[C:32](=[C:33]([OH:44])[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=5)[C:30]=4[N:31]=3)[CH:22]=2)[CH:17]=[CH:18][C:19]=1[CH3:20].C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[S:40]([C:35]1[CH:36]=[C:37]2[C:32](=[C:33]([OH:44])[CH:34]=1)[C:30]1[N:31]=[C:27]([C:23]3[CH:22]=[C:21]([C:16]4[CH:17]=[CH:18][C:19]([CH3:20])=[C:14]([CH3:13])[CH:15]=4)[CH:26]=[CH:25][CH:24]=3)[NH:28][C:29]=1[CH:39]=[CH:38]2)(=[O:42])=[O:41])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)Cl)cc(O)c54)[nH]3)c2)cc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)N6CCC[C@H]6C(=O)OC(C)(C)C)cc(O)c54)[nH]3)c2)cc1C
Reaction time: 15 h

Procedure:
To an agitated suspension of (S)-pyrrolidine-2-carboxylic acid tert-butyl ester (0.036 g, 0.21 mmol) in DMF (1 mL) was added 2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxyl-3H-naphtho[1,2-d]imidazole-7-sulfonyl chloride (0.064 g, 0.14 mmol) and triethyl amine (0.022 g, 0.21 mmol). After agitated for 15 hrs, the reaction mixture was concentrated under reduced pressure to give (S)-1-[2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazole-7-sulfonyl]-pyrrolidine-2-carboxylic acid tert-butyl ester. The crude product was treated with 90% trifluoroacetate acid (2 ml). After agitated for 1 hour, the mixture was concentrated under reduced pressure, then subjected to to HPLC (ODS-A, gradient 10-90% CH3CN/water 0.1% TFA) to provide the title compound (0.006 g, 8%) MS(ES) m/z 542 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:12]1[O:14][C@H:13]1[CH2:15]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C([O-])(=O)C.[NH4+].S(C1C=CC([N+]([O-])=O)=CC=1)(OCC1OC1)(=O)=O>C(#N)C.CN(C)C=O>[N:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:15][C@@H:13]3[O:14][CH2:12]3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: Oc1cccc2ncccc12
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CO2)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: c1cc(OC[C@H]2CO2)c2cccnc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A mixture of 5-hydroxyquinoline (5.60 g, 38.6 mmol), R-glycidyl nosylate (10.0 g, 38.6 mmol), powdered potassium carbonate (11.7 g, 84.9 mmol), and N,N-dimethylformamide (100 mL) was stirred at ambient temperature until HPLC analysis (40% acetonitrile/60% of a 0.5% aqueous ammonium acetate solution, 1 mL/min, wavelength=230 nm, Zorbax RX-CB 25 cm×4.6 mm column) indicated complete disappearance of glycidyl nosylate (approximately 6 hours). The reaction mixture was filtered through paper and the filter cake was washed with 200 mL of a 3:1 mixture of MTBE and methylene chloride. The filtrate was washed with 200 mL of water and the aqueous layer was extracted four times with 100 mL of 3:1 MTBE/methylene chloride. The combined organic layers were dried over 30 grams of magnesium sulfate and the dried solution was then stirred with 50 grams of basic alumina for 30 minutes. The alumina was removed by filtration and the filter cake was washed with 200 mL of 3:1 MTBE/methylene chloride. The filtrate was concentrated to a volume of 100 mL, 300 mL of MTBE were added, and the solution was again concentrated to 80 mL. After heating to 50° C., the solution was treated with 160 mL of heptane dropwise over 15 minutes, allowed to cool to 40° C., and seeded, causing the formation of a crystalline precipitate. The mixture was stirred for two hours at ambient temperature and then at 0-5° C. for an additional 2 hours. The crystals were filtered, washed with cold heptane, and dried to provide 5.68 g (73.2%) of (2R)-1-(5-quinolinyloxy)-2,3-epoxypropane as white needles.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:10](=O)[CH2:11][CH3:12])[C:6](=O)[CH2:7][CH3:8])=[O:4].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:16]=1[NH:26][NH2:27]>C(O)C>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[C:17]([Cl:25])[C:16]=1[N:26]1[C:10]([CH2:11][CH3:12])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]([CH2:7][CH3:8])=[N:27]1
Reactant: CCC(=O)C(C(=O)CC)C(=O)OC
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1C(=O)OC
Yield: 43 %

Procedure:
A solution of 7.5 g (40 mmol) of the compound of step A and 11.85 g (48 mmol) of 2,6-dichloro-4-trifluoromethylphenyl hydrazine in 50 mL of ethanol was heated at reflux for 8 hours. The ethanol was removed by evaporation and the residues were partitioned between ethyl acetate and dilute hydrogen chloride. The organic extracts were dried and evaporated to give the desired product in 43% yield as a maroon oil. 1H-NMR (CDCl3) δ1.08 (3H, t, J=7), 1.24 (3H, t, J=7), 2.22 (2H, q, J=7), 2.94 (2H, q, J=7), 3.86 (3H, s), 7.46 (2H, s).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:24])=[C:11]([NH:13][C:14]([C:16]3[S:20][C:19](B(O)O)=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=1[CH3:34]>>[C:32]([C:30]1[CH:29]=[CH:28][C:27]([CH3:34])=[C:26]([C:19]2[S:20][C:16]([C:14]([NH:13][C:11]3[CH:12]=[C:7]([C:5](=[O:6])[NH:4][CH:1]4[CH2:3][CH2:2]4)[CH:8]=[CH:9][C:10]=3[CH3:24])=[O:15])=[CH:17][CH:18]=2)[CH:31]=1)#[N:33]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(B(O)O)s1
Reactant: Cc1ccc(C#N)cc1Br
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(-c2cc(C#N)ccc2C)s1

Procedure:
The title compound was prepared by coupling 5-(5-(cyclopropylcarbamoyl)-2-methylphenylcarbamoyl)thiophen-2-ylboronic acid (Example 210, Step A) with commercially available 2-bromo-4-cyanotoluene using the method described in Step B of Example 136 to afford a white solid after purification by reverse phase preparative HPLC (Example 213). HPLC Ret time=3.36 min. LCMS [M+H]+ 416.29.
Reaction SMILES: C([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:23])[N:6]([CH3:22])[C:7]1[N:8]2[CH:13]=[N:14][C:15]=1[C:16]1[N:20]=[C:19]([CH3:21])[O:18][N:17]=1)#C.CC1ON=C(C[N+]#[C-])N=1.CN1C(=O)C2C(=CC=CC=2C#C[Si](C)(C)C)NC1=O>>[CH3:22][N:6]1[C:5](=[O:23])[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][CH:3]=2)[N:8]2[CH:13]=[N:14][C:15]([C:16]3[N:20]=[C:19]([CH3:21])[O:18][N:17]=3)=[C:7]12
Reactant: C#Cc1cccc2c1c(=O)n(C)c1c(-c3noc(C)n3)ncn21
Agent: Cn1c(=O)[nH]c2cccc(C#C[Si](C)(C)C)c2c1=O
Agent: [C-]#[N+]Cc1noc(C)n1
Product: Cc1nc(-c2ncn3c4ccccc4c(=O)n(C)c23)no1
Yield: 12 %

Procedure:
6-ethynyl-4,5-dihydro-4-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-oxo-imidazo(1,5-a)quinazoline, M.p. 202-206° C.. by reaction between 5-methyl-3-isocyanomethyl-1,2,4-oxadiazole and 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-5-trimethylsilylethynyl-quinazoline. Column chromatography(silica gel)ethyl acetate) of the crude product yielded 0.08g (12%) of 4,5-dihydro-4-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-oxo-imidazo(1,5-a)quinazoline and 0.Olg (1.9%) of 6-ethynyl-4,5-dihydro-4-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-oxo-imidazo(1,5-a)quinazoline.