Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])=[N:27][CH:28]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[C:66]([O:69][CH2:70][CH3:71])(=[O:68])[CH3:67]>O>[C:31]([C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[C:26]1[N:27]=[CH:28][C:23]([CH2:22][C:19]2[C:20](=[O:21])[N:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([O:8][CH2:67][C:66]([O:69][CH2:70][CH3:71])=[O:68])[CH2:10][CH2:11]3)[C:16]3[N:17]([N:40]=[CH:41][N:42]=3)[C:18]=2[CH2:37][CH2:38][CH3:39])=[CH:24][CH:25]=1)#[N:32]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)c2ncnn12
Reactant: CCOC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(5-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}pyridin-2-yl)benzonitrile (0.42 g), tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 1.1 mL) and tetrahydrofuran (20 mL) was stirred at 70° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetonitrile (20 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.31 g) was added, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL), sodium borohydride (0.016 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution (10 mL) of the obtained residue in toluene was added dropwise ethyl diazoacetate (0.14 mL) in the presence of rhodium(I) acetate (0.0012 g) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.06 g, 15%).
Reaction SMILES: [I-:1].[CH2:2]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][N+](C)(C)C)[CH3:3].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[I-:1].[CH2:2]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:3]
Reactant: CCn1cccc1C[N+](C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: CC#N
Product: CCn1cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 81.3 %

Procedure:
Subsequently, to a suspension of (1-ethylpyrrol-2-yl)methyl trimethylammonium iodide (20 g, 68.0 mmol) obtained above in acetonitrile (200 ml) was added triphenylphosphine (22.0 g, 83.9 mmol), and the resulting mixture was stirred at 80° C. for 9 hours. After cooling, the reaction mixture was concentrated to about one-half of its initial volume, to which was added ethyl acetate (1.00 ml). The crystals precipitated were collected by filtration, washed with ethyl acetate and dried in vacuo to afford the title compound (27.5 g, yield: 81%).
Reaction SMILES: C([O:5][C:6](=[O:14])[C@@H:7]1[CH2:11][CH:10]([O:12][CH3:13])[CH2:9][NH:8]1)(C)(C)C.COC1CN[C@H](C(O)=O)C1.N1CCC[C@H]1C(O)=O.C(OC(=O)[C@@H]1CCCN1)(C)(C)C.C([S:48][CH2:49][CH2:50][C:51](Cl)=[O:52])(=O)C.C(SCC(C)C(Cl)=O)(=O)C>>[SH:48][CH2:49][CH2:50][C:51]([N:8]1[CH2:9][CH:10]([O:12][CH3:13])[CH:11]=[C:7]1[C:6]([OH:5])=[O:14])=[O:52]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: COC1CN[C@H](C(=O)OC(C)(C)C)C1
Agent: CC(=O)SCC(C)C(=O)Cl
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: COC1CN[C@H](C(=O)O)C1
Product: COC1C=C(C(=O)O)N(C(=O)CCS)C1

Procedure:
By substituting 4-methoxy-L-proline tertbutyl ester [prepared from 4-methoxy-L-proline by the procedure described in J. Am. Chem. Soc., 82, 3359 (1960) for L-proline] for the L-proline tert-butyl ester and 3-acetylthiopropanoyl chloride for the 3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1, and then submitting the product to the procedure of Example 2, 4,5-dihydro-1-(3-mercapto-1-oxopropyl)-4-methoxy-1H-pyrrole-2-carboxylic acid is obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([OH:42])[CH:29]([NH2:41])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]([OH:42])[CH:29]([NH:41][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)=[O:13])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
To a solution of 4-quinolinecarboxylic acid (111 mg, 0.64 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (63 mg, 32%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:3]=1.[Br:26][C:27]1[C:28](B(O)O)=[N:29][CH:30]=[CH:31][CH:32]=1.BrC1C=NC=C(Br)C=1>>[Br:26][C:27]1[CH:32]=[C:31]([C:6]2[CH:5]=[C:4]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=3)[CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:30]=[N:29][CH:28]=1
Reactant: OB(O)c1ncccc1Br
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(OS(=O)(=O)C(F)(F)F)n1
Agent: Brc1cncc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(Br)c2)n1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.32) (2.0 g, 5.2 mmol) and commercially available 3-bromo-pyridine-boronic acid [CAS-No. 452972-09-07] (alternatively prepared from commercially available 3,5-dibromopyridine according to Tetrahedron 2002, 58(17), 3323 or Synthesis 2003, (7), 1035) (1.152 g, 5.7 mmol) according to the general procedure IVb. Obtained as a white solid (1.70 g, 83%). MS (ISP) 393.0 [(M+H)+] and 395.0 [(M+2+H)+].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+].Cl>[OH-].[K+]>[OH:16][CH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1
Reactant: N#Cc1ccc(C2CCC(C=O)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Product: N#Cc1ccc([C@H]2CC[C@H](CO)CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4.0 g of 4-(p-cyanophenyl)cyclohexanecarboxaldehyde (prepared according to Example 1) were dissolved in 50 ml of 0.1N methanolic potassium hydroxide solution while gassing with argon in a sulphonation flask provided with a thermometer and the solution was treated portionwise at 0° C. within 20 minutes with 711 mg of sodium borohydride. The mixture was stirred at 0° C. for a further 10 minutes, neutralized with 1N hydrochloric acid and concentrated on a rotary evaporator. The residue was taken up in 200 ml of water and extracted three times with 100 ml of methylene chloride each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. A single crystallization of the residue (4.2 g) from 90 ml of ethyl acetate/petroleum ether (vol. 1:2) at 0° C. gave 3.27 g (77%) of p-[trans-4-(hydroxymethyl)cyclohexyl]benzonitrile as colourless crystals of melting point 109.8° C.; purity 99.4%.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:22][CH3:23])[CH2:12][C:13](=[O:21])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:7]=1.O>C(O)(=O)C>[Cl:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:22][CH2:23][N:1]=[O:3])[CH2:12][C:13](=[O:21])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:7]=1
Reactant: CNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NCNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium nitrite, 21.26 g (0.308 m) was added over a period of 20 min to a stirred solution of 71 g (0.237 m) of 7-chloro-3,5-dihydro-2-methylamino-5-phenyl-4H-1,5-benzodiazepin-4-one in 500 ml of acetic acid. Following the addition, the mixture was stirred for 1 hr at room temperature and was then diluted with 1.5 l. of water. The precipitated product was collected, washed with water and dissolved in methylene chloride. The solution was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue was crystallized from ether to yield yellow crystals with mp 121°-124°. A second crop was obtained from the mother liquor.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[F:36][C:32]1[C:24]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]3[CH2:11][C@@H:10]([C:37]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13]3)=[O:20])=[N:22][C:23]=2[CH:35]=[CH:34][CH:33]=1
Reactant: C1CCNC1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCCC3)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (1.65 g), pyrrolidine (500 μl), HOBt (270 mg) and triethylamine (1.27 ml) were dissolved in DMF (50 ml), WSC.HCl (1.15 g) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95)-ethyl acetate-ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object product (170 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([OH:12])=O)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([Cl:15])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1cncc(Br)c1
Product: O=C(Cl)C=Cc1cncc(Br)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
3-(5-Bromo-pyridin-3-yl)-acrylic acid (26.2 g, 114.7 mmol) prepared in Step 1 was added to thionyl chloride (100.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 3-(5-bromo-pyridin-3-yl)-acryloyl chloride as an unpurified dark brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=O)[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:13]4[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45]>C(O)C>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45].[CH2:17]([N:14]1[C:13]2[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=2[O:11][C:10]2=[C:5]3[C:6](=[N:8][C:9]2=[C:15]1[N:38]1[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]1)[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4]3)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1CCNCC1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c2Oc2ccccc2N1Cc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: CN1CCN(C2=C3N=c4cc(Cl)ccc4=C3Oc3ccccc3N2Cc2ccccc2)CC1

Procedure:
In the same way as described in example 1, 3-chloro-7-benzyl-7H-indolo[3,2-b][1,5]benzoxazepine-6(5H)-one, phosphorous pentachloride and N-methyl piperazine were reacted. The product was purified by chromatography on neutral alumina and elution with 3% ethanol in ether. The yellow oil thus obtained was reacted with fumaric acid in hot ethanol and the salt recrystallized from ethanol for analysis, mp. 217°-8°.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.Br[CH:14]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH3:15]>>[I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[N:9]([CH:14]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[CH3:15])[C:4]=2[CH:3]=1
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: CC(Br)c1cc(F)c(F)cc1F
Product: CC(c1cc(F)c(F)cc1F)N1C(=O)CNc2ncc(I)cc21

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (297 mg) was alkylated with 1-(1-bromoethyl)-2,4,5-trifluorobenzene as in General Procedure 1 to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].ClN1C(=[O:19])CCC1=O>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:19])[NH:8]2)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Solvent: ClC(Cl)Cl
Product: O=C1Cc2c(cccc2[N+](=O)[O-])N1
Temperature: 70 °C

Procedure:
A mixture of 4-nitroindole (12.2 g, 75.2 mmol) and N-chlorosuccinimide (6.07 g, 30.1 mmol) in CHCl3 (500 mL) was heated at reflux for 30 h, then concentrated to dryness under reduced pressure. The residue was dissolved in AcOH (200 mL) and the resulting solution was warmed to 70° C., then 85% H3PO4 (80 mL) was added over 2 min. The mixture was heated to reflux for 90 min then cooled on ice. The cooled mixture was adjusted to pH 6 by addition of 10 N NaOH (450 mL), followed by aqueous NaHCO3, keeping the temperature below 30° C. The mixture was extracted with EtOAc (3×1 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 0:100, and then triturated with MeOH to give the title compound. MS: m/z=179 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)(O)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][C:32]1[CH:51]=[CH:50][C:35]([N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1.FC(F)(F)S(O)(=O)=O>ClCCl>[C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:47]5[CH:48]=[CH:49][C:44]([N:36]([C:35]6[CH:34]=[CH:33][C:32]([CH3:31])=[CH:51][CH:50]=6)[C:37]6[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=6)=[CH:45][CH:46]=5)([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1(c2ccccc2)c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Reactant: Cc1ccc(N(c2ccccc2)c2ccc(C)cc2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C3(c4ccccc4)c4ccccc4-c4nc5ccccc5c(-c5ccccc5)c43)cc2)cc1
Yield: 89.7 %

Procedure:
In an embodiment, the starting material 10,11-diphenyl-11H-indeno[1,2-b]quinolin-11-ol (385 mg, 1.00 mmol) and 4-methyl-N-phenyl-N-(p-tolyl)aniline (328 mg, 1.20 mmol) are placed in a round bottom flask and then dissolved in 10 ml of dichloromethane. Subsequently, trifluoromethanesulfonic acid (0.13 ml, 1.50 mmol) is slowly dripped into the flask to promote reaction. After 12 hours of reaction at 140° C., the crude product is extracted with 50 ml of Ethyl acetate and sodium bicarbonate for three times. Finally, an organic layer of the crude product is dehydrated with magnesium sulfate and concentrated to be sublimated and purified to obtain 575 mg of 4-(10,11-diphenyl-11H-indeno[1,2-b]quinolin-11-yl)-N,N-di-p-tolylaniline. The percentage yield is 89.7%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:5][C:6]=1[CH3:7].[Cl:14]N1C(=O)CCC1=O>C(#N)C>[Cl:14][CH2:1][C:2]1[N:3]=[C:4]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[S:5][C:6]=1[CH3:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nc(N2CCOCC2)sc1C
Solvent: CC#N
Product: Cc1sc(N2CCOCC2)nc1CCl
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 4-(4,5-dimethyl-1,3-thiazol-2-yl)morpholine (5.0 g) in acetonitrile (100 mL) was added N-chlorosuccinimide (3.36 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)morpholine as colorless crystals (2.06 g, 35%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 110-111° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[O:7]([C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([C:19]#[N:20])=[N:17]O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(OC)(OC)(=O)=O>CC(C)=O>[O:7]([C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([C:19]#[N:20])=[N:17][O:4][CH3:1])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: N#CC(=NO)c1ccccc1Oc1ccccc1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CON=C(C#N)c1ccccc1Oc1ccccc1
Reaction time: 0.08 h
Yield: 108.2 %

Procedure:
Potassium carbonate (3.11 g, 0.023 mol) and acetone (60 ml) were added to 2-phenoxy-α-hydroxyiminobenzyl cyanide (E/Z=11/89)(7.15 g, 0.03 mol). The mixture was stirred for 5 minutes. Then dimethyl sulfate (5.68 g, 0.045 mol) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the resulting insoluble materials were removed. To the residue obtained after concentration under reduced pressure, toluene (60 ml) and 1N aqueous sodium hydroxide solution (60 ml) were added. The mixture was stirred at room temperature for 1 hour. After stirring, water (60 ml) was added. The mixture was extracted with toluene (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromarography (ethyl acetate/n-hexane) to give 2-phenoxy-α-methoxyiminobenzyl cyanide (6.28 g, Yield: 83.0%, E/Z=7/93).
Reaction SMILES: [CH2:1]([N:8]1[C:13]([CH2:15][OH:16])([CH3:14])[CH2:12][O:11][CH2:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].[Br-].CC1(C)N([O])C(C)(C)CCC1.[O-]Cl.[Na+].Cl.[O-:35]Cl=O.[Na+]>O>[CH2:1]([N:8]1[C:9](=[O:17])[CH2:10][O:11][CH2:12][C:13]1([CH3:14])[C:15]([OH:35])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: CC1(CO)COCC(=O)N1Cc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: [Br-]
Solvent: O
Product: CC1(C(=O)O)COCC(=O)N1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Combine 4-benzyl-5-(hydroxymethyl)-5-methylmorpholin-3-one (11.75 g, 0.05 mol) ethyl acetate (75 ml), and KBr in water (0.5 M, 10 ml), followed by addition of 2,2,6,6-tetramethylpiperidine-1-oxyl (0.16 g, 1 mmol). Add solution of 12% NaClO in water (39 g, 62.5 mmol) dropwise to the mixture over 30 minutes at 5° C. at pH of 8.0-10.0. After 30 minutes, adjust the pH to 5.0 by addition of 35% hydrochloric acid, followed by addition of 25% NaClO2 in water (22.7 g, 62.5 mmol) over 30 minutes. Stirring continues for 3 hours at ambient temperature. Recover the product by extraction with ethyl acetate, washed with brine, to give 4-benzyl-3-methyl-5-oxomorpholine-3-carboxylic acid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:70][NH:71][C:72]1[CH:73]=[C:74]2[C:79](=[CH:80][CH:81]=1)[N:78]=[CH:77][CH:76]=[CH:75]2>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[S:3][C:2]([N:71]([CH3:70])[C:72]3[CH:73]=[C:74]4[C:79](=[CH:80][CH:81]=3)[N:78]=[CH:77][CH:76]=[CH:75]4)=[N:6][C:5]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:21])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1nc(Br)sc1NC(=O)c1ccc(F)cc1
Reactant: CNc1ccc2ncccc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(N(C)c2ccc3ncccc3c2)sc1NC(=O)c1ccc(F)cc1
Temperature: 110 °C

Procedure:
To a solution of ethyl 2-bromo-5-(4-fluorobenzamido)-thiazole-4-carboxylate (0.2 g, 0.50 mmol) in toluene (10 mL) was added Xantphos (0.061 g, 0.10 mmol) and Pd2(dba)3 (0.048 g, 0.040 mmol) under argon gas. To this suspension, cesium carbonate (0.344 g, 0.90 mmol) and N-methylquinolin-6-amine (0.084 g, 0.53 mmol) were added, and the mixture was heated at 110° C. for 16 h. The reaction mixture was filtered through a bed of Celite, and the celite pad was washed with ethyl acetate (3×5 mL). The filtrate was concentrated, and the crude residue was purified by silica gel column chromatography eluted with 50% EtOAc in hexane to give 0.14 g (58% yiled) of the titled compound.