Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Cl[CH2:11][CH:12]([OH:35])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(Cl)Cl>CN(C=O)C.CCCCC>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH:12]([OH:35])[CH2:11][S:3][C:4]3[N:9]=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:19][CH2:18]2)=[CH:22][CH:23]=1
Reactant: OC(CCl)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: Sc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OC(CSc1ncccn1)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
To NaH (240 mg, 5 mmol, 50% in oil, prewashed with pentane) in DMF (5 mL) was added 2-mercaptopyrimidine (5 mmol, 560 mg) in portions over 5 minutes at 0° C. After 30 minutes, 1-(1-chloro-2-hydroxy-3-propanyl)-4-(4,4'-diflurobenzhydryl)piperazine (1.9 g, 5 mmol) in DMF (15 mL) was added over 10 minutes under nitrogen. After 12 days, the sodium chloride was removed by filtration and the DMF was removed in vacuo (~0.5 mm Hg, ~50° C.) to give the crude (1.82 g). Flash column chromatography over silica gel using 2% methanol:methylene chloride (2×) and subsequent washings of the product with pentane gave the pure product (380 mg, 16.7%) as a white solid, mp 75°-76° C.; DCI/MS (M+1)=456; (400 MHz) 1H NMR (CDCl3)δ: 8.55 (s, 1H), 8.50 (s, 1H), 7.35 (m, 4H), 7.0 (m, 4H), 4.2 (s, 1H) , 4.0 (m, 1H), 3.3 (m, 2H), 2.65 (m, 2H), 2.4 (m, 8H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C[O-].[Na+].C1(C)C=CC=CC=1.[C:21]1([C:27](=O)[CH:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:28]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C(c1ccccc1)C(C(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(-n2nc(-c3ccccc3)c(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.1 %

Procedure:
After this, 10.3 g (0.046 mole) of p-bromophenylhydrazine hydrochloride, 2.36 g (0.043 mole) of sodium methoxide, and 79.3 g of toluene were placed in a 300-ml four-necked flask. The mixture was then heated under reflux with stirring for three hours while distilling off methanol. To this reaction mixture was added 12.4 g (0.041 mole) of the 1,2,3-triphenylpropane-1,3-dione obtained above. After the addition, the mixture was heated under reflux with stirring for 20 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and 39.7 g of water was added in drops. The reaction mixture was transferred to a separatory funnel and an organic layer was separated. The organic layer was concentrated under reduced pressure to dryness. The residue was purified by reslurrying with methanol and a solid was separated. To the solid was added 10.0 g of toluene in drops and the solid was dissolved by heating. To the resulting solution was added methanol in drops at 65° C. over a period of 30 minutes to effect precipitation. Thereafter, the mixture was cooled to room temperature and a solid was recovered by filtration. The solid was washed with methanol and dried under reduced pressure to give 10.2 g of 1-(p-bromophenyl)-3,4,5-triphenylpyrazole.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:25][OH:26])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1C=CC=CC=1.[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1>O1CCOCC1>[CH3:1][C:2]1[NH:3][C:4]([CH2:25][O:26][C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)NC(COC(=O)CCC(=O)O)=C(C(=O)OCC)C1c1ccccc1Cl
Yield: 87.4 %

Procedure:
A mixed solution of diethyl 2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.3798 g), pyridine (0.791 g) and succinic anhydride (0.1501 g) in dioxane (5 ml) was refluxed for 4.5 hours. The resultant solution was concentrated, acidified with dilute hydrochloric acid and extracted with diethyl ether. The extract was washed with dilute hydrochloric acid and water in turn. The diethyl ether extract was back-extracted with an aqueous saturated sodium bicarbonate solution and the aqueous solution was washed with diethyl ether. The aqueous solution was acidified with dilute hydrochloric acid to precipitate crystals. The crystals were collected by filtration, washed with water and then dried to give diethyl 2-methyl-4-(2-chlorophenyl)-6-(3-carboxypropionyl)oxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (419.3 mg), m.p. 130° to 131° C.
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]1=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[O:10]=[C:2]1[N:1]([C:22]([O:24][CH3:25])=[O:23])[C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of methyl (S)-(+)-2-pyrrolidone-5-carboxylate (4.80 grams, 33.5 mmol) in tetrahydrofuran (90 mL) was added a solution of lithium bis(trimethylsilyl)amide (1 M solution in hexanes, 40.0 mL, 40.0 mmol) dropwise via syringe over 15 minutes; then methyl chloroformate (2.90 mL, 36.9 mmol) was added dropwise via syringe over 5 minutes. The resulting slurry was stirred at −78° C. for 1 hour after which the reaction was quenched with 1 M HCl (50 mL). The mixture was allowed to come to room temperature, concentrated under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and 1 M HCl (200 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic layers were dried (sodium sulfate), filtered, and concentrated to provide the titled compound. MS (DCI/NH3) m/e 202 (M+H)+; 1H NMR (300 MHz, CDCl3): δ ppm 4.70 (dd, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 2.74-2.30 (m, 3H), 2.15-2.05 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1.[H][H].F[C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][N:23]3[CH:31]=[CH:32][CH:33]=[C:22]3[CH2:21]2)=[O:19])=[C:14]([C:34]([F:37])([F:36])[F:35])[CH:13]=1>CN(C)C=O.[Cl-].[Na+].O>[CH3:3][C:4]1[N:8]=[CH:7][N:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][N:23]4[CH:31]=[CH:32][CH:33]=[C:22]4[CH2:21]3)=[O:19])=[C:14]([C:34]([F:35])([F:36])[F:37])[CH:13]=2)[N:5]=1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Reactant: [H][H]
Reactant: Cc1nc[nH]n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(C(F)(F)F)c2)n1
Temperature: 110 °C
Yield: 39.4 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.3 g) in dimethylformamide (50 ml) was added dropwise 3-methyl-1,2,4-triazole (0.45 g). After hydrogen gas evolution ceased, 4-fluoro-2-trifluoromethyl-phenyl-(5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepine-10-yl)-methanone (1.76 g) was added and the reaction mixture was heated in a sand bath at 110° C. for 18 hours. The mixture was poured onto ice, diluted with brine, and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and the residue was triturated with diethyl ether to give 0.81 g of the title compound as colorless crystals, m.p. 148-150° C., MS m/z: 438.2 (M+H)+, 875.8 (2M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][CH:10]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])=[CH:4][CH:3]=1.C[Si]([N:34]=[N+:35]=[N-:36])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][CH:10]([C:21]2[CH:28]=[CH:27][CH:26]=[C:23]([C:24]3[NH:36][N:35]=[N:34][N:25]=3)[CH:22]=2)[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(C(CC(=O)c2ccc(F)cc2)CC(=O)c2ccc(F)cc2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(CC(CC(=O)c1ccc(F)cc1)c1cccc(-c2nnn[nH]2)c1)c1ccc(F)cc1
Yield: 88.1 %

Procedure:
A mixture of 3-[3-(4-fluorophenyl)-1-[2-(4-fluorophenyl)-2-oxoethyl]-3-oxopropyl]-benzonitrile (1 g, 2.1 mmol), trimethylsilylazide (0.48 g, 4.2 mmol), and dibutyltin oxide (0.05 g) is heated under N2 in toluene (25 mL) at 100° C. for 18 hours. The toluene is removed under vacuum and the residue is dissolved in a small amount of methanol. The methanol is removed under vacuum and the residue chromatographed over SiO2 eluting with dichloromethane:2-propanol (4:1). Pure fractions are combined, concentrated, and triturated with diethyl ether to provide 0.8 g of the title compound; mp 162°-164C.
Reaction SMILES: COC1C=CC([P:9]([C:12]2C=CC(OC)=CC=2)(=[O:11])[OH:10])=CC=1.[OH-:20].[CH2:21]([N+:25]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24].C[CH:39]([OH:41])C>O>[OH:20][CH2:12][P:9]([CH2:39][OH:41])(=[O:11])[O-:10].[CH2:34]([N+:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:35][CH2:36][CH3:37]
Reactant: CC(C)O
Reactant: [OH-]
Reactant: COc1ccc(P(=O)(O)c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: O=P([O-])(CO)CO

Procedure:
To a flask were added 2.0 g bis(4-methoxyphenyl)phosphinic acid, 3.0 g of a 55-60% solution of tetrabutylammonium hydroxide in water, 2.0 g of water and 18 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 20 ml of 2-propanol were added and removed by distillation under reduced pressure. A waxy solid was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>C1COCC1>[Cl:25][C:26]1[CH:27]=[C:28]([C:29](=[O:30])[CH2:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[O:5][C:4](=[O:14])[CH:3]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cc1cc(=O)oc2ccc(C#N)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2oc(=O)cc(CC(=O)c3cccc(Cl)c3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-6-carbonitrile (180 mg, 0.92 mmol) in dry THF (33 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (1.6 mL). After 30 minutes 3-chlorobenzoylchloride (200 mg) was added into the reaction mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (15 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-60% ethyl acetate in hexanes to yield 4-[2-(3-chloro-phenyl)-2-oxo-ethyl]-2-oxo-2H-chromene-6-carbonitrile as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:33])[C:23]3=[O:34])=[CH:18][CH:17]=2)[CH2:10]1.[OH2:35].[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([OH:13])[CH2:10][CH:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:33])[C:23]2=[O:34])=[CH:18][CH:17]=1)[C:12]([OH:35])=[O:14]
Reactant: Cn1c(=O)n(-c2ccc(CC3CC(c4c(Cl)cccc4Cl)OC3=O)cc2)c(=O)c2ccccc21
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(=O)n(-c2ccc(CC(CC(O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)c2ccccc21

Procedure:
The mixture of 7 mg of 3-[4-[[5-(2,6-dichlorophenyl)-2-oxotetrahydrofuran-3-yl]methyl]phenyl]-1-methylquinazoline-2,4-dione, 0.6 mg of lithium hydroxide-monohydrate and 5 ml of tetrahydrofuran was stirred. After removing a solvent, the residue was purified by reverse phase HPLC to obtain the subject compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH2:4][CH2:3]1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([Cl:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[ClH:27].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][N:12]3[S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc3[nH]ccc23)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCN(C)CC4)cccc32)cc1
Product: Cl

Procedure:
The title compound was prepared 4-(4-methyl-1-piperazinyl)-1H-indole and p-methylbenzenesulfonyl chloride according to Method 4 (45%): 1H NMR (CD3OD) δ 7.81-6.77 (m, 9H), 3.62-3.02 (m, 8H), 2.98 (s, 3H), 2.34 (s, 3H); MS (ESI) 370.5 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: C(CC1C=CC(OC)=C([N:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]([C:33]4[CH:37]=[CH:36][O:35][N:34]=4)CC4C=CC(OC)=CC=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:38])C=1)#N.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:35]1[CH:36]=[CH:37][C:33]([NH:23][S:20]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:10][C:11](=[O:38])[CH:12]=[CH:13]3)(=[O:22])=[O:21])=[N:34]1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(CC#N)ccc3OC)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2[nH]1
Yield: 15.1 %

Procedure:
To a mixture of Xantphos (0.049 g, 0.084 mmol), Pd2(dba)3 (0.077 g, 0.084 mmol) and 1-(5-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.500 g, 0.838 mmol) in N,N-dimethylformamide (0.838 ml) was added (trimethylsilyl)acetonitrile (0.138 ml, 1.006 mmol) followed by zinc difluoride (0.061 g, 0.587 mmol). The flask was sealed under an atmosphere of nitrogen and heated at 100° C. overnight. The reaction was diluted with water and extracted with DCM (×2). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was taken up in DCM and purified via MPLC, eluting with 0-100% ethyl acetate in heptanes with a 5% DCM additive, followed by reverse-phase preparative HPLC (XBridge Prep C18 column, 10 micron OBD, 19×100 mm), 0.1% TFA in CH3CN/H2O, gradient 25% to 95% over 12 min to provide 1-(5-(cyanomethyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.092 g, 0.165 mmol, 19.72% yield) as a light-yellow solid. 1-(5-(cyanomethyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (92 mg) was taken up in 2.5 mL of DCM and 2.5 mL of TFA and was heated under microwave irradiation for 1 h at 70° C. until complete deprotection. The reaction mixture was concentrated in vacuo. The crude material was purified by reverse-phase preparative HPLC (XBridge Prep C18 column, 10 micron OBD, 19×100 mm), 0.1% TFA in CH3CN/H2O, gradient 25% to 70% over 12 min to provide 1-(5-(cyanomethyl)-2-methoxyphenyl))-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.011 g, 0.025 mmol, 3.01% yield) as a white solid. MS (ESI, pos. ion) m/z: [M+1] 437.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.68 (s, 3 H) 4.03 (s, 2 H) 6.44 (d, J=1.76 Hz, 1 H) 6.71 (d, J=9.02 Hz, 1 H) 6.79 (d, J=9.64 Hz, 1 H) 7.30 (d, J=2.28 Hz, 1 H) 7.34 (d, J=8.60 Hz, 1 H) 7.55 (dd, J=8.60, 2.28 Hz, 1 H) 7.84 (dd, J=8.97, 2.23 Hz, 1 H) 8.22 (d, J=9.74 Hz, 1 H) 8.36 (d, J=2.18 Hz, 1 H) 8.73 (d, J=1.87 Hz, 1 H) 11.64 (s, 1 H).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C@@H:7]([C:20]2[O:21][C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH2:6]1)(=O)C.C[O-].[Na+].Cl>CC#N.CO>[C:25]1([C:23]2[N:24]=[C:20]([C@H:7]3[CH2:6][C@H:5]([OH:4])[CH2:9][N:8]3[C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[O:21][C:22]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)O[C@H]1C[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@@H](O)C[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of benzyl (2R, 4S)-4-acetoxy-2-(4,5-diphenyloxazol-2-yl)pyrrolidine-1-carboxylate (1.49 g) in MeCN (15 mL) was added 28% sodium methylate in MeOH (0.72 mL) at 5° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 1N HCl (3.8 mL) under ice-cooling, and extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogen carbonate solution, water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gal column chromatography (hexane-EtOAc, 1:3 elution) to give benzyl (2R, 4S)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (980.8 mg).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH2:17][CH3:18])[CH:10]=1.C([O-])(=O)C.[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:11]([O:16][CH2:17][CH3:18])[CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: CCOc1cc(Br)ccc1O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl bromoacetate (1.04 mL) was added to a mixture of 4-bromo-2-ethoxyphenol (1.69 g) and potassium acetate (1.62 g) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over an hydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: diethyl ether/n-hexane=1/10) to afford ethyl (4-bromo-2-ethoxyphenoxy)acetate (2.26 g).
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[F:5][C:6]([F:14])([F:13])[C:7]([C:9]([F:12])([F:11])[F:10])=[O:8].COC(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O>[F:5][C:6]([F:14])([F:13])[C:7]1([C:9]([F:12])([F:11])[F:10])[O:3][CH2:2][CH2:1][O:8]1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Product: FC(F)(F)C1(C(F)(F)F)OCCO1
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
Into a 300 mL three-necked flask equipped with a gas-inlet tube, a reflux condenser, and a thermometer was charged 10.0 g (0.12 mol) of ethylene chlorohydrin beforehand, followed by cooling with ice. Then, 20.0 g (0.12 mol) of hexafluoroacetone was added through the gas-inlet tube. After completion of the addition, the whole was stirred for 15 minutes as it was and then 100 mL of t-butyl methyl ether was added. Then, 16.6 g (0.12 mol) of potassium carbonate was added portionwise over a period of 1 hour and, after completion of the addition, the whole was stirred as it was. The resulting mixture was poured into 100 mL of water and an organic layer was separated by two-layer separation in a separating funnel. The resulting organic layer was subjected to distillation under normal pressure to collect a fraction of 106° C. to 107° C. to obtain 15.8 g (purity 99%, yield 62.0%) of 2,2-bis(trifluoromethyl)-1,3-dioxolane (fluorinated acetal (E)).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:6]1.[H-].[Na+].[CH3:40][O:41][C:42](=[O:53])[CH2:43][C:44]1[C:45]([Cl:52])=[N:46][C:47]([CH3:51])=[N:48][C:49]=1Cl.O>COCCOC>[Cl:52][C:45]1[N:46]=[C:47]([CH3:51])[N:48]=[C:49]([O:1][CH2:2][CH2:3][O:4][CH:5]2[CH:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:15][CH:16]=3)[CH2:9][CH2:8][N:7]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:6]2)[C:44]=1[CH2:43][C:42]([O:41][CH3:40])=[O:53]
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1c(Cl)nc(C)nc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Reaction time: 0.5 h

Procedure:
A solution of 1.95 g of tertbutyl 3-(2-hydroxyethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 14c) in 20 ml of 1,2-dimethoxyethane is admixed in portions at 0° C. with 0.195 g of sodium hydride dispersion (60%) and stirred for 30 minutes. A solution of 0.91 g of methyl(4,6-dichloro-2-methylpyrimidin-5-yl)acetate in 5 ml of dimethoxyethane is added dropwise and the reaction mixture is stirred at room temperature over 2.5 hours. The reaction mixture is admixed with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.42 (1:1 EtOAc-heptane); Rt=6.10.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[NH:20]1[CH2:25]CSC[CH2:21]1.CN(C)C=O>O>[CH3:21][N:20]([CH3:25])[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Reactant: C1CSCCN1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc2c(=O)c(-c3nnnn3C)cn(C)c2c1
Reaction time: 5.5 h

Procedure:
A mixture of 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (10 g), thiomorpholine (10 g) and dimethylformamide (20 ml) was heated at 100° for 22 hours and then at 140° for 5.5 hours. The mixture was cooled and poured into water (220 ml). The resulting precipitate was collected and purified by high performance liquid chromatography on silica using dichloromethane:industrial methylated spirit:isopropanol 98.25:0.5:1.25 as the eluent. This gave the novel compound 7-dimethylamino-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 280°-283°.