Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.[CH3:13][N:14]([CH3:32])[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][C:22]2[C:23]([CH3:31])=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][N:26]=[CH:25]3)[CH2:17][CH2:16]1>CN(C)C=O.O>[C:8]([N:27]1[C:28]2[C:24](=[C:23]([CH3:31])[C:22]([O:21][C@H:18]3[CH2:17][CH2:16][C@H:15]([N:14]([CH3:32])[CH3:13])[CH2:20][CH2:19]3)=[CH:30][CH:29]=2)[CH:25]=[N:26]1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: Cc1c(O[C@H]2CC[C@H](N(C)C)CC2)ccc2[nH]ncc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)n1ncc2c(C)c(O[C@H]3CC[C@H](N(C)C)CC3)ccc21
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, triethylamine (112 μl, 0.807 mmol) and acetyl chloride (25.2 μl, 0.355 mmol) were added to a solution of monohydrochloride (100 mg, 0.323 mmol) of the trans-N,N-dimethyl-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine obtained in Example 412 in N,N-dimethylformamide (2 ml) at room temperature. After 1 hour, triethylamine (0.420 mmol) and acetyl chloride (0.355 mmol) were further added thereto. After 2 hours, the reaction solution was poured into water and extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol) to obtain trans-N-{4-[(1-acetyl-4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylamine (20.1 mg, 20%).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH3:6][O:7][C:8]1[C:9]([CH3:27])=[C:10]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]=[O:26])=[CH:17][N:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1>>[CH3:6][O:7][C:8]1[C:9]([CH3:27])=[C:10]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]([OH:26])[CH2:1][CH2:2][CH3:3])=[CH:17][N:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1
Reactant: CCC[Mg]Cl
Reactant: COc1ccc(C)c(-c2ncc(C=O)c3ccccc23)c1C
Product: CCCC(O)c1cnc(-c2c(C)ccc(OC)c2C)c2ccccc12
Temperature: 25 °C
Yield: 66.6 %

Procedure:
n-PrMgCl (4.7 ml of 2M solution in THF, 9.36 mmol) is added to a solution of 1-(3-methoxy-2,6-dimethyl-phenyl)-isoquinoline-4-carbaldehyde (2.48 g, 8.51 mmol) dropwise at −78 C and the mixture is allowed to warm to room temperature. After quenching with saturated NH4Cl, the mixture is extracted with EtOAc. The combined extracts are washed with saturated brine, dried over Na2SO4, and concentrated. The residue is chromatographed on silica gel to give 1.9 g of 1-[1-(3-methoxy-2,6-dimethyl-phenyl)-isoquinolin-4-yl]-butan-1-ol as a white foam.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]([Cl:11])[CH2:9][CH:8]([CH2:12][CH3:13])[CH2:7][C:5]=2[N:6]=1.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>N1C=CC=CC=1>[CH2:12]([CH:8]1[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:15](=[O:16])[O:17][CH2:18][CH3:19])[S:3][C:4]=2[CH:10]([Cl:11])[CH2:9]1)[CH3:13]
Reactant: CCOC(=O)Cl
Reactant: CCC1Cc2nc(N)sc2C(Cl)C1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2c(s1)C(Cl)CC(CC)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-5-ethyl-7-chloro-4,5,6,7-tetrahydrobenzothiazole (0.10 mol) dissolved in pyridine (125 ml.) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. Ethyl chloroformate (0.12 mol) is then added dropwise to the reaction mixture with stirring and cooling. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is poured into ice water to form a precipitate. The precipitate is recovered by filtration, is dried and recrystallized to yield the desired product ethyl N-(5-ethyl-7-chloro-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=1)[CH:19]=O>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH2:19][C:10]2[S:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Fc1ccccc1-c1cccs1
Product: Fc1ccc(Br)cc1Cc1ccc(-c2ccccc2F)s1

Procedure:
2-(2-Fluorophenyl)thiophene obtained in Reference Example 66-(1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 365/367 (M+H)
Reaction SMILES: [CH:1]1([CH2:7][C:8]2([O:25][CH3:26])[CH2:13][CH2:12][N:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1>[CH:1]1([CH2:7][C:8]2([O:25][CH3:26])[CH2:13][CH2:12][N:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc(N2CCC(CC3CCCCC3)(OC)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC1(CC2CCCCC2)CCN(c2ccc(C(=O)O)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of Example 1G (300 mg) in dioxane (5 mL) was treated with 1N NaOH (2 mL), stirred overnight, acidified with 1N HCl, extracted with ethyl acetate (3×), dried (MgSO4), and filtered. Concentration of the filtrate gave the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:4][N:3]=1
Reactant: C1CCNCC1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCCCC3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and piperidine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:10][CH2:11][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[CH:5][CH:4]=1)#[N:2]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=2)[CH2:10][CH2:11][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=CCc2c[nH]cn2)c2ccc(C(F)(F)F)cc2)cc1
Solvent: CCO
Product: N#Cc1ccc(C(CCc2c[nH]cn2)c2ccc(C(F)(F)F)cc2)cc1

Procedure:
4-[3-(4-cyanophenyl)-3-(4-trifiuoromethylphenyl)-2-propenyl]-1H-imidazole is hydrogenated in ethanol using 10% Pd/C as a catalyst to give the product.
Reaction SMILES: [Na+:1].C([N:4]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([O-:19])=[O:18])[CH2:12][CH2:11][N:10]([CH2:20][C:21]([O-:23])=[O:22])[CH2:9][CH2:8][N:7]([CH2:24][C:25]([O-:27])=[O:26])[CH2:6][CH2:5]1)=O.[Na+].[Na+].[OH-].[Na+]>>[Na+:1].[N:7]1([CH2:24][C:25]([O-:27])=[O:26])[CH2:6][CH2:5][NH:4][CH2:15][CH2:14][N:13]([CH2:16][C:17]([O-:19])=[O:18])[CH2:12][CH2:11][N:10]([CH2:20][C:21]([O-:23])=[O:22])[CH2:9][CH2:8]1.[Na+:1].[Na+:1]
Reactant: O=CN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])CCN(CC(=O)[O-])CC1
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])CN1CCNCCN(CC(=O)[O-])CCN(CC(=O)[O-])CC1
Temperature: 70 °C

Procedure:
The mixture from step B) is then added with 77.3 kg of 30% w/w NaOH and heated to 70° C. for 9 h. The resulting aqueous solution contains 0.131 kmol of the desired compound (content determined by HPLC), as a trisodium salt.
Reaction SMILES: [Cl:1][Si:2](Cl)([CH3:7])[Si:3]([Cl:6])([CH3:5])[CH3:4].[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[Co](Cl)Cl.C(OCC)C>[Cl:1][Si:2]([CH3:7])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[Si:3]([Cl:6])([CH3:5])[CH3:4]
Reactant: C[Si](C)(Cl)[Si](C)(Cl)Cl
Reactant: Br[Mg]c1ccccc1
Agent: Cl[Co]Cl
Solvent: CCOCC
Product: C[Si](C)(Cl)[Si](C)(Cl)c1ccccc1
Reaction time: 3 h
Yield: 83 %

Procedure:
1,1,2-trichloro-1,2,2-trimethyl disilane 103.8 g (0.5 mole), cobalt chloride 6.5 g (0.05 mole) and diethyl ether 200 g were placed in the same type of reaction apparatus as used in the above Comparative Example, and a diethyl ether solution of phenyl magnesium bromide 90.5 g (0.5 mole) was dropwise added thereto for 3 hours while stirring at the reaction temperature of 25° to 30° C. After the dropwise addition, the stirring was continued for 2 hours at 25° to 30° C. to complete the reaction. In order to identify the reaction product, the product obtained by separating the by-produced magnesium salt by filtration was subjected to 1H-NMR spectrum (C6D6) analysis in the same manner as in the above Comparative Example. As this result, it was proved that 1,2-dichloro-1,2,2-trimethyl-1-phenyl disilane could be produced at a favourable selectivity. The reaction product was then purified by a normal purification method to obtain 1,2-dichloro-1,2,2-trimethyl-1-phenyl disilane 103.5 g at the yield of 83%.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10]/[C:11](=[CH:21]\[F:22])/[CH2:12][NH:13]C(=O)OC(C)(C)C)=[CH:7][CH:6]=1)=[O:4].FC(F)(F)C(O)=O.[ClH:33]>C(Cl)Cl>[ClH:33].[NH2:13][CH2:12]/[C:11](=[CH:21]/[F:22])/[CH2:10][O:9][C:8]1[CH:23]=[CH:24][C:5]([C:3]([N:2]([CH3:25])[CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)c1ccc(OC/C(=C\F)CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(OC/C(=C\F)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a stirring solution of (Z)-tert-butyl 2-((4-(dimethylcarbarnoyl)-phenoxy)methyl)-3-fluoroallylcarbamate (520.0 mg, 1.48 mmol) in CH2Cl2 (8.0 mL) at room temperature was added trifluoroacetic acid (2.0 mL). The resulting mixture was stirred at room temperature for 30 min. All volatiles were removed in vacuo and the residue was co-evaporated with CH2Cl2 (2×20 mL) to remove trifluoroacetic acid. The resulting oil was taken up in ethyl acetate (3.0 mL) and then ethereal HCl (2.0 M in diethyl ether; 1.0 mL, 2.0 mmol) was added. The precipitate formed was isolated and dried under reduced pressure to afford (Z)-4-(2-(aminomethyl)-3-fluoroallyloxy)-N,N-dimethylbenzamide hydrochloride (301 mg, 71%) as a pale yellow solid; m.p.=135-137° C.; 1H-NMR (300 MHz; MeOD) δ ppm: 3.06 (3H, br s), 3.10 (3H, br s), 3.71 (2H, d, J 3.0 Hz), 4.88 (2H, dd, J 2.8, 0.8 Hz), 7.11 (2H, d, J 8.9 Hz), 7.13 (1H, d, J 80.8 Hz), 7.45 (2H, d, J 8.9 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][N:3]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.ClCl.[C:36]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47]O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl.C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:36]([C:40]1[CH:41]=[CH:42][C:43]([CH2:46][CH2:47][O:1][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][N:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:44][CH:45]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)c1ccc(CCO)cc1
Reactant: Oc1ncnc2nccnc12
Agent: ClCl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CCOc2ncnc3nccnc23)cc1
Temperature: -17.5 °C

Procedure:
To a suspension of 2 g of 4-hydroxypteridine in 20 mL of CH2Cl2 under nitrogen was added 1.2 g of 25 pyridine. The mixture was cooled to -30° C and over a 15 minute period a solution of 4.82 g of triphenyl phosphite in CH2Cl2 was added simultaneously with addition of chlorine gas. The mixture was stirred for one and one half hours while maintaining the temperature at -15 to -20° C. The mixture was then allowed to warm to 10° C., and a solution of 2.67 g of 2-[4-(t-butyl)phenyl]ethanol in CH2Cl2 was added. The resulting mixture was refluxed for 45 minutes, then cooled and diluted into toluene. The toluene solution was washed with dilute base, then filtered through phase separating paper and concentrated in vacuo. The resulting bluish oil was adsorbed onto silica gel and chromatographed (silica gel, CH2Cl2 →80% CH2Cl2, 20% EtOAc). Fractions containing the major product were combined. The product was then recrystallized from petroleum ether/CH2Cl2. Yield 60 mg. M.P. 149° C.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@H:17]2[CH2:25][CH2:24][C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[C:35]1(=O)[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@H:17]2[CH2:25][CH2:24][C@@H:23]3[C@@H:19]([CH2:20][N:21]([C:35]4[CH2:39][CH2:38][C:37](=[O:40])[CH:36]=4)[CH2:22]3)[C@@H:18]2[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: C[C@@H](O[C@H]1CC[C@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of 12.3 mg (0.26 mmol) of (3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}4-(4-fluorophenyl)octahydro-1H-isoindole (Example 2) in ˜2 mL dry toluene was added 2.7 mg (0.028 mmol) cyclopentane-1,3-dione and a catalytic amount (˜0.5 mg) of PTSA. The resulting mixture was heated at reflux for 16 hr. The solvent was removed vacuum and the residue was purified by prep TLC eluting with EtOAc/MeOH (95/5) to afford the title compound. 1H-NMR (CDCl3): δ: 7.73 (1 H, s), 7.20 (2 H, s), 7.03-6.90 (2 H, m), 4.98, 4.80 (1 H, s), 4.50 (1 H, m), 3.62-3.18 (2 H, m), 3.30-3.18 (3 H, m), 3.15, 2.97 (1 H, d, J=11.2 Hz), 2.68 (2 H, m), 2.55-2.40 (4 H, m), 2.17 (1 H, m), 2.20 (1 H, m), 2.00 (1 H, m), 1.85 (1 H, m), 1.62 (1 H, m), 1.33 (3 H, d, J=6.2 Hz). MS: (MH)+ 556.0.
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]1[C:24]2[C:19](=[C:20]([O:27]C)[N:21]=[C:22]([CH2:25][CH3:26])[CH:23]=2)[N:18]([CH3:29])[CH:17]=1.Cl.O1CCOCC1>>[F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:16]1[C:24]2[CH:23]=[C:22]([CH2:25][CH3:26])[NH:21][C:20](=[O:27])[C:19]=2[N:18]([CH3:29])[CH:17]=1
Reactant: CCc1cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c2c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c2c(=O)[nH]1
Temperature: 70 °C
Yield: 90.3 %

Procedure:
The product from Example 92B (0.04 g, 0.082 mmol) and 4M hydrogen chloride in dioxane (5 mL, 20.00 mmol) were combined, heated at 70° C. for 3 hours, cooled and concentrated. Purification by chromatography (silica gel, 0-4% methanol in dichloromethane) afforded the title compound (0.035 g, 90%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.87 (s, 1H) 7.58 (d, J=2.03 Hz, 1H) 7.49 (s, 1H) 7.41-7.52 (m, 1H) 7.17-7.28 (m, 2H) 7.05-7.14 (m, 1H) 6.82 (d, J=8.14 Hz, 1H) 6.38 (s, 1H) 4.51 (s, 2H) 4.07 (s, 3H) 2.94 (s, 3H) 2.43 (q, J=7.63 Hz, 2H) 1.14 (t, J=7.46 Hz, 3H). MS (ESI+) m/z 473 (M+H)+.
Reaction SMILES: Cl[CH:2]1[NH:6][C:5]2=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][C:10]([F:11])=[C:4]2[O:3]1.[N+:16](C1C=CC=CC=1O)([O-])=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH2:16][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][C:10]=2[F:11])[N:6]=1
Reactant: COC(=O)c1ccc(F)c2c1NC(Cl)O2
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c2oc(N)nc12
Yield: 26.2 %

Procedure:
A mixture of methyl 2-chloro-7-fluoro-2,3-dihydrobenzoxazole-4-carboxylate (720 mg, 3.14 mmol), o-nitrophenol (660 mg, 4.71 mmol) and K2CO3 (0.96 g, 7.0 mmol), in THF (10 mL), was stirred at ambient for 2.5 h. The reaction mixture was filtered and gaseous ammonia was bubbled through the mother liquor for 10 min. The precipitate formed was filtered and washed with THF (20 mL). The combined THF fractions were concentrated, and the resulting residue crystallized from methanol to afford methyl 2-amino-7-fluorobenzoxazole-4-carboxylate (173 mg, 26%) as a pale yellow solid. 1H NMR and MS consistent.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[C:8]2[C:33](O)=[O:34])(=[O:4])=[O:3].[F:36][C:37]([F:47])([F:46])[C@H:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(OCC)(=O)C.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:27][CH2:28][C:29](=[O:32])[CH2:30][CH2:31]1)=[C:8]2[C:33]([NH:45][C@H:38]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:37]([F:46])([F:47])[F:36])=[O:34])(=[O:3])=[O:4]
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(=O)CC3)c(C(=O)O)c2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(=O)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
A mixture of 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.977 g, 1.929 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.449 g, 2.12 mmol), N,N-diisopropylethylamine (0.404 mL, 2.315 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (1.705 mL of a 50% solution in ethyl acetate, 2.89 mmol) in dichloromethane (19.29 mL) was stirred at 0° C. for 2 h, warmed to room temperature, and stirred at room temperature overnight. The mixture was diluted with 10% Na2CO3, and extracted with methylene chloride (four times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 40 g silica, 5-100% ethyl acetate hexanes) to afford 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.570 g, 31% yield). MS (m/z) 664.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH2:24][CH2:23][CH2:22]2>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:25]2[C:26]3[C:21](=[CH:20][C:19]([CH3:18])=[CH:28][CH:27]=3)[CH2:22][CH2:23][CH2:24]2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Cc1ccc2c(c1)CCCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)CCCN2c1ncnc(Cl)n1
Temperature: 0 °C

Procedure:
2,4-Dichloro-1,3,5-triazine (1.95 g, 13 mmol) was dissolved in DMF (50 mL) under N2 and cooled to 0° C. DIEA (1.68 g, 13 mmol) was added, followed by the addition of 6-methyl-1,2,3,4-tetrahydroquinoline (1.91 g, 13 mmol). The reaction was stirred with gradual warming to RT. The reaction was quenched after 3 h with water, which caused a sticky precipitate to form. The mixture was extracted 3 times with EtOAc. The EtOAc extracts were washed brine, combined, dried over Na2SO4, filtered, and concentrated, then dried under high vacuum to remove residual traces of DMF. The recovered material was purified by silica gel chromatography (5%, 10%, 20% and 40% EtOAc/Hexane step gradient) giving 1-(4-chloro-[1,3,5]triazin-2-yl)-6-methyl-1,2,3,4-tetrahydro-quinoline as a white solid.
Reaction SMILES: [O+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7]([O-:11])(=[O:10])(=[O:9])=[O:8].[O+]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl([O-])(=O)(=O)=O.[CH3:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[O+:27]=[C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=1>>[Cl:7]([O-:11])(=[O:10])(=[O:9])=[O:8].[O:1]1[C:6]2[CH:23]=[CH:24][CH:25]=[CH:26][C:5]=2[C:4](=[CH:13][C:14]([C:15]2[CH:33]=[CH:28][CH:29]=[CH:17][CH:16]=2)=[CH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[O+:27]=[C:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:25]=2)[CH:3]=[CH:2]1
Reactant: c1cc[o+]cc1
Reactant: Cc1cc(-c2ccccc2)[o+]c2ccccc12
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: C1=CC(=CC(=Cc2cc(-c3ccccc3)[o+]c3ccccc23)c2ccccc2)c2ccccc2O1

Procedure:
This pyrylium salt was made in a manner identical to that set forth in Example 1 above, except the pyrylium perchlorate salt starting material of Example 1 was replaced with 4-methylflavylium perchlorate. The pyrylium salt product was identified as the above-noted salt having a melting point of 298°-299° C. and an empirical formula of C39H27ClO6.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2S(C)(=O)=O)[CH2:3][CH2:2]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C.CCOCC.[Mg+2].[Br-].[Br-]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1c(N2CCOCC2)n(C2CC2)c2cc(F)c(F)cc2c1=O
Yield: 62.5 %

Procedure:
The ethyl 1-cyclopropyl-6,7-difluoro-2-(methylsulfonyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (140 mg, 0.377 mmol) obtained in (A) was dissolved in tetrahydrofuran (5 ml), added with morpholine (0.0395 ml, 0.452 mmol), N,N-diisopropylethylamine (0.131 ml, 0.754 mmol) and magnesium bromide diethyl etherate (389 mg, 1.51 mmol), and then the mixture was refluxed by heating for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative TLC (chloroform:methanol=100:5) to obtain the title compound (89.2 mg, 62%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:14]1[N:25]([C:24]2[CH:26]=[CH:27][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(C(F)(F)F)cc1
Yield: 78.4 %

Procedure:
A mixture of 1-(4-methylsulfonylphenyl)-1,4-pentanedione (Example 1, Step 2) (300 mg, 1.18 mmol), 4-(trifluoromethyl)aniline hydrochloride (257 mg, 1.3 mmol) and p-toluenesulfonic acid (30 mg) in toluene (80 ml) was heated to reflux for 20 hours. The reaction mixture was cooled, filtered and concentrated. The crude solid (560 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrrole (351 mg, 78%) as a white solid: mp (DSC) 130° C. Anal Calc'd. for C19H16NSO2F3 : C, 60.15; H, 4.25; N, 3.69. Found: C, 60.38; H, 4.44; N, 3.67.