Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH2:6][CH:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[O:4][N:3]=1.[F:20][CH:21]([F:31])[O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1>CO>[F:20][CH:21]([F:31])[O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][NH:30][C:2]2[CH2:6][CH:5]([CH2:7][O:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]4)[O:4][N:3]=2)=[CH:27][CH:28]=1
Reactant: NCc1ccc(OC(F)F)cc1
Reactant: O=C1CCc2cc(OCC3CC(Br)=NO3)ccc2N1
Solvent: CO
Product: O=C1CCc2cc(OCC3CC(NCc4ccc(OC(F)F)cc4)=NO3)ccc2N1
Yield: 11.7 %

Procedure:
6-((3-bromo-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (0.1 g, 0.308 mmol) and (4-(difluoromethoxy)phenyl)methanamine (0.149 g, 0.923 mmol) were heated at 160° C. for 30 min. The reaction mixture was dissolved in methanol, concentrated, and the crude product purified by preparative HPLC on a Kromasil C4 column (250×20 mm) using a 0-100% gradient of ACN in 0.1% TFA to give 6-((3-(4-(difluoromethoxy)benzylamino)-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as a white solid (0.015 g, 23%). 1H NMR 400 MHz, DMSO-d6: δ 2.41 (q, J=7.20 Hz, 2H), 2.78-2.85 (m, 3H), 3.08 (q, J=9.60 Hz, 1H), 3.89-3.97 (m, 2H), 4.18 (d, J=6.00 Hz, 2H), 4.62-4.65 (m, 1H), 6.62 (t, J=6.00 Hz, 1H), 6.72-6.78 (m, 2H), 6.81 (d, J=2.00 Hz, 1H), 7.02-7.39 (m, 5H), 9.91 (s, 1H). LCMS: RT 1.501 min; LCMS (ES-API), m/z 418.2 (M+H).
Reaction SMILES: C(O[C:4](=[O:18])/[CH:5]=[C:6](\[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[C:11]([O:16][CH3:17])[CH:10]=1)/[CH3:7])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:16][CH3:17])[N:8]=[C:6]([CH3:7])[CH:5]=[C:4]2[OH:18]
Reactant: CCOC(=O)/C=C(/C)Nc1ccc(Br)c(OC)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COc1cc2nc(C)cc(O)c2cc1Br
Temperature: 220 °C
Reaction time: 7.5 h
Yield: 83.5 %

Procedure:
A suspension of 6.6 g (21 mmol) of (Z)-3-(4-bromo-3-methoxy-phenylamino)-but-2-enoic acid ethyl ester in 40 ml of Dowtherm A were heated under stirring at 220° C. for 7.5 h after which time TLC analysis indicated completion of the reaction. The mixture was cooled to RT under stirring and the solvent was decanted off. The remaining solid residue was triturated with hexane, filtered off by suction and dried in a high vacuum to give 4.7 g (84%) of the 6-bromo-7-methoxy-2-methyl-quinolin-4-ol as a dark brown solid. EI mass spectrum, m/e: 269 (M calculated for C11H10BrNO2: 269).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([O:16][CH3:17])[CH:4]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([O:16][CH3:17])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1Sc1ccccc1
Solvent: ClCCl
Product: COc1cc(CCl)ccc1Sc1ccccc1
Reaction time: 1 h

Procedure:
The 1-hydroxymethyl-3-methoxy-4-phenylthiobenzene obtained above is dissolved in methylene chloride (372 ml), and thereto is added with strring thionyl chloride (9.12 ml) under ice cooling. The mixture is stirred for one hour, and the reaction mixture is washed with ice water (500 ml×2), and thereto is added ethyl acetate (500 ml). The mixture is washed in order with 5% aqueous sodium hydrogen carbonate solution (20 ml), water (200 ml) and saturated aqueous sodium chloride solution (200 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-chloromethyl-3-methoxy-4-phenylthiobenzene.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH:7]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH:7]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)=[CH2:1]
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of methyl triphenylphosphonium bromide (5.05 g, 14.1 mmol) in tetrahydrofuran (80 mL) was added potassium tert-butoxide (1 M in tetrahydrofuran, 14.1 mL, 14.1 mmol) and the reaction stirred for 45 minutes at room temperature. Next a prepared solution of 7-formylindole (1.00 g, 6.89 mmol) in tetrahydrofuran (10 mL) was added and the reaction stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with an 8:1 mixture of water and 1 N hydrochloric acid (2×100 mL), saturated aqueous sodium chloride (100 mL), and dried over sodium sulfate. The solution was filtered and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography. Fractions containing product were combined and concentrated under reduced pressure to provide the desired compound as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(S(F)(F)[F:19])CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:19][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCF)cc1
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-nitrophenyl)ethanol (835 mg) in methylene chloride (30 mL) was stirred at −78° C. under a nitrogen atomosphere. To this solution, diethylaminosulfur trifluoride (1.98 mL) in methylene chloride (20 mL) was added dropwise over 10 minutes. With stirring, the temperature of the reaction mixture was allowed to rise back to room temperature. After 30 minutes, the reaction was stopped by the addition of saturated aqueous sodium hydrogen carbonate solution (50 mL) in an ice bath. The methylene chloride solution was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL). After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel (25 g) column using hexane:ethyl acetate (7:2) as the eluant to give 1-fluoro-2-(4-nitrophenyl)ethane (359 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@H:4]([O:12][C:13]1[C:18]([Br:19])=[CH:17][C:16]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([OH:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:15][C:14]=1[Br:38])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[CH3:44][O:45][C:46](=[O:49])[CH2:47]Br.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:39])[CH:4]([O:12][C:13]1[C:18]([Br:19])=[CH:17][C:16]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([O:37][CH2:47][C:46]([O:45][CH3:44])=[O:49])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:15][C:14]=1[Br:38])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(O)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1c2ccccc2c(-c2cc(Br)c(OC(Cc3ccccc3)C(=O)OC)c(Br)c2)c2c1sc1ccccc12
Reaction time: 24 h
Yield: 74.1 %

Procedure:
To a solution of (R)-2-[2,6-dibromo-4-(6-hydroxy-benzo[b]naphtho[2,3-d ]thiophen-11-yl)-phenoxy]-3-phenyl-propionic acid methyl ester (0.60 g, 0.906 mmol) in anhydrous N,N-dimethylformamide was added potassuim carbonate (0.376 g, 2.72 mmol, 3 eq) and methylbromoacetate (0.26 mL, 2.72 mmol, 3 eq) at room temperature under a dry nitrogen atmosphere. After stirring for 24 hours the reaction mixture was combined with water (60 mL) the organics were extracted with diethyl ether (2×100 mL). The extracts were combined and washed with water (2×100 mL) and brine (100 mL). Silica gel was added and the solvents removed. The adsorbate was twice flash chromatographed (eluent 88/12 petroleum ether/ethyl acetate and 85/15 ethyl ether/ethyl acetate) to provide the title compound as a white solid (0.493 g, 73%): NMR (CDCl3); δ8.38 (d, J=8 Hz, 1 H), 7.81 (d, J =Hz, 1 H), 7.64-7.59 (m, 3 H), 7.55 (d, J=8 Hz, 1 H), 7.48 (ddd, J=8, 7, 1 Hz, 1 H), 7.43-7.26 (m, 6 H), 7.16 (ddd, J=8,7,1 Hz, 1 H), 6.79 (d, J=8 Hz, 1 H), 5.25 (dd, J=8, 6 Hz, 1 H), 4.94 (s, 2 H), 3.92 (s, 3 H), 3.76 (s, 3 H), 3.57 (septet, J=7 Hz, 2 H); MS (EI): [M+], 2 bromine isotope pattern, 732 (1.8%), 734 (4%), 736 (0.8%); Anal. Calc. for C35H26Br2O6S:, 57.24, H, 3.57, N, 0.00. Found: C, 57.01, H, 3.42, N, -0.07.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[O-:17]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CC(C)(C)NO
Product: COc1ccc(C=[N+]([O-])C(C)(C)C)c(O)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-hydroxy-4-methoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 72.9% yield as a pale yellow crystalline solid, m.p. 115.2-116.0° C. (Rf=0.49 on a silica gel plate using 1:1 EtOAc/hexanes as an eluant).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C(#N)C>[C:13]1([S:19]([NH:1][C:2]2[C:3]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCCc1ncccc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: N#CCCCc1ncccc1NS(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 3-amino-2-(3-cyanopropyl)pyridine* (5 g, 0.031 mole) in acetonitrile (50 ml) was treated with benzenesulphonyl chloride (4 ml) and pyridine (6 ml). The solution was allowed to stand at room temperature overnight when the solvent was removed in vacuo. The residue was dissolved in dilute sodium hydroxide (100 ml) and was extracted with chloroform (4×100 ml) the chloroform extracts being discarded. The aqueous layer was adjusted to pH=4 and extracted with chloroform (3×100 ml). The combined chloroform extracts were dried over magnesium sulphate, the solvent was removed to give the title compound (7.12 g) as a cream coloured solid. m.p. 80°-81° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc(S(C)(=O)=O)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and (3-methylsulfonylphenyl)boronic acid (Combi-Blocks, San Diego, USA, 26 mg, 0.127 mmol) to give the title compound as a white solid. (HPLC: tR 2.45 min (Method A); M+H=448 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.19-8.11 (m, 2H), 8.02-7.97 (m, 1H), 7.95-7.86 (m, 3H), 7.80-7.74 (m, 1H), 7.64-7.60 (m, 1H), 3.93 (s, 3H), 3.59 (s, 3H), 3.33-3.30 (3H), 1.94 (s, 3H))
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.Cl.[F:37][CH:38]([F:41])[CH2:39][NH2:40].C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:40][CH2:39][CH:38]([F:41])[F:37])[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: NCC(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1c(NCC(F)F)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
140 mg (0.260 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), 61 mg (0.519 mmol) of 2,2-difluoroethylamine hydrochloride and 67 mg (0.519 mmol) of N,N-diisopropylethylamine were dissolved in 2 ml of tetrahydrofuran and stirred at room temperature overnight. Without further work-up, the reaction mixture was purified by preparative HPLC. 77 mg (yield: 51% of theory) of the target compound were obtained.
Reaction SMILES: OC[C:3]([CH3:7])([CH2:5][OH:6])[CH3:4].[Cl:8][CH2:9][C:10]([CH2:12][Cl:13])=[O:11].C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:8][CH2:9][C:10]1([CH2:12][Cl:13])[O:6][CH2:5][C:3]([CH3:4])([CH3:7])[O:11]1
Reactant: CC(C)(CO)CO
Reactant: O=C(CCl)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)COC(CCl)(CCl)O1
Reaction time: 8 h
Yield: 34.6 %

Procedure:
This compound was synthesized by substantially following the procedure of the above-mentioned article by Isaka, Ejiri, and Nakamura. 69 grams of neopentyl glycol, 76 grams of 1,3-dichloroacetone, 50 ml of benzene, and 2.3 g of p-toluenesulfonic acid were refluxed through a Dean-Stark water separator for 8 hours whereon the reaction was diluted with hexanes and neutralized with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo yielding 41.2 g of 2,2-bis-chloromethyl-5,5-dimethyl-1,3-dioxolane, a pale yellow liquid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:17]=2[CH2:18][CH2:19][CH:20]2[O:22][CH:21]23)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(OCC)C.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:17]3[CH2:18][CH2:19][C:20](=[O:22])[CH2:21][C:23]=3[CH:24]=[CH:25][CH:26]=2)[C:10](=[O:15])[C:11]([F:12])([F:14])[F:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC2OC32)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC(=O)C3)cc1
Temperature: 25 °C
Yield: 41.9 %

Procedure:
A solution of N-(4-cyanophenyl)-2,2,2-trifluoro-N-(1a,2,3,7b-tetrahydronaphth[1,2-b]oxiren-4-yl)acetamide (2.8 g, 7.8 mmol) in diethyl ether (80 ml) was treated with BF3.Et2O (2.0 ml, 16 mmol) and the resulting suspension was stirred at room temperature. The suspension was diluted with methylene chloride after 1 and 3 hours (80 and 40 ml) and additional BF3.Et2O (2×1.0 ml, 16 mmol) was added at 2 and 4 hour intervals. The reaction mixture was stirred overnight, then saturated NaHCO3 solution (70 ml) slowly added. The aqueous phase was separated and extracted with methylene chloride (40 ml). The organic solutions were dried (K2CO3), concentrated in vacuo, and the residue purified by chromatography on silica gel with diethyl ether:hexane (2:3 to 1:1) to give N-(4-cyanophenyl)-2,2,2-trifluoro-N-(5,6,7,8-tetrahydro-6-oxo-1-naphthyl)acetamide (1.17 g). 1H NMR (CDCl3, 200 MHz) δ: 2.44 (t, J=7 Hz, 2H, CH2), 2.69 (dt, J=16,7 Hz, 1H, CH2), 3.03 (dt, J=16,6 Hz, 1H, CH2), 3.63 (strongly coupled AB pair, 2H, C5H2), 7.25-7.45 (m, 5H, Ar), 7.67 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C19H13F3N2O2 : C, 63.69; H, 3.66; N, 7.82. Found: C, 63.75; H, 3.72; H, 7.74.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([O:14]C(C2CC2)=O)[C:10]2[C:5](=[CH:6][C:7]([F:21])=[C:8]([F:20])[CH:9]=2)[N:4]=1)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([OH:14])[C:10]2[C:5](=[CH:6][C:7]([F:21])=[C:8]([F:20])[CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2cc(F)c(F)cc2c(O)c1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 121 %

Procedure:
2-Ethyl-3-methyl-4-cyclopropanecarbonyloxy-6,7-difluoroquinoline (5.5 g) prepared as described in Example 1 was dissolved in 50 ml of methanol. A solution of 2.5 g of sodium hydroxide in 50 ml of water was added to this solution, and the mixture was stirred at 50° C. for 3 hr. The reaction solution was allowed to stand for cooling and was then poured into 50 ml of water. The mixture was neutralized with 1N hydrochloric acid, and the precipitate was then collected by filtration to give 5.1 g of 2-ethyl-3-methyl-4-hydroxy-6,7-difluoroquinoline. In 20 ml of tetrahydrofuran was suspended 96 mg of 60% sodium hydride. Separately, 446 mg of the 2-ethyl-3-methyl-4-hydroxy-6,7-difluoroquinoline (starting material 1) was suspended in 10 ml of tetrahydrofuran, and this suspension of starting material 1 was added dropwise to the above suspension under ice cooling. The mixture was stirred for 1 hr, and 188.4 mg of acetyl chloride (starting material 2) was then added thereto. The mixture was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 168.6 mg of 2-ethyl-3-methyl-4-acetyloxy-6,7-difluoroquinoline (compound 3). 1H-NMR data are shown in Table 3.
Reaction SMILES: [N:1]#[C:2][NH2:3].[F:4][C:5]1[CH:6]=[C:7]([N:18]2[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]2=[O:28])[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.C1C=CC=CC=1>O>[C:2]([N:3]=[C:14]1[CH2:15][CH2:16][N:11]([C:10]2[CH:9]=[CH:8][C:7]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:6][C:5]=2[F:4])[CH2:12][CH2:13]1)#[N:1]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: N#CN
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=NC#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
Cyanamide (601 mg) and 500 mg of the (S)-N-{3-[3-fluoro-4-(4-oxo-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (Compound No. 7) which was synthesized in Example 3 were added to benzene (70 ml), and the mixture was heated under reflux for 2 h, with water being removed continuously by means of a water separator. The reaction mixture was cooled to room temperature and the resulting crystal was collected by filtration. After being washed with water, the crystal was dried overnight at 40° C. under vacuum to afford the title compound (423 mg) in a yield of 79%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[S:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[CH3:2].[F:24][C:25]([F:45])([F:44])[C:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27]>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[S:16][C:17]1[CH:18]=[C:19]([NH:20][C:35]([NH:34][C:31]2[CH:30]=[C:29]([C:26]([CH3:28])([CH3:27])[C:25]([F:45])([F:44])[F:24])[O:33][N:32]=2)=[O:36])[CH:21]=[CH:22][CH:23]=1)[CH3:2]
Reactant: CCOc1cc2c(Sc3cccc(N)c3)ncnc2cc1OC
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3)ncnc2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 21 %

Procedure:
To a stirred solution of 3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)aniline (100 mg, 0.305 mmol) and phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 260A (144 mg, 0.458 mmol) in anhydrous THF (5 mL), was added 4-(dimethylamino)pyridine (6 mg, 0.0492 mmol) and the mixture was stirred at rt for 15 h. Concentration in vacuo followed by purification via silica gel column chromatography (eluted with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate), afforded 1-(3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (35 mg, 21%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.74 (brs, 1H), 9.02 (s, 1H), 8.69 (s, 1H), 7.85 (m, 1H), 7.28-7.51 (m, 5H), 6.88 (s, 1H), 4.23 (q, J=7 Hz, 2H), 3.99 (s, 3H), 1.54 (s, 6H), 1.45 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 548 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:34])[C:10]1[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]2[C:25]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:26][CH:27]=[CH:28][C:12]=2[N:11]=1>O1CCCC1.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:10]1[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]2[C:25]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:26][CH:27]=[CH:28][C:12]=2[N:11]=1)=[O:34]
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCNC(=O)OC(C)(C)C)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCNC(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
A mixture of tert-butyl (2-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}ethyl)carbamate (500 mg, 0.985 mmol) and manganese(IV) oxide (856 mg, 9.85 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 4 h, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give a yellow amorphous solid (404 mg, 0.800 mmol, 81%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29](O)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([CH3:45])[CH2:42][C@H:41]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:49]([O:48][C:47]([NH:46][C@H:41]1[CH2:42][C@@H:43]([CH3:45])[CH2:44][N:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH:32][C:29]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:40]1)=[O:53])([CH3:50])([CH3:51])[CH3:52]
Reactant: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxylic acid (0.014 g, 0.034 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.013 g, 0.041 mmol) and HATU (0.033 g, 0.086 mmol) in DMF (0.14 mL), DIPEA (0.018 mL, 0.10 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous phase was further extracted with EtOAc. The combined organic phases were concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the sub-title compound. LCMS calc. for C39H49N8O5 [M+H]+: m/z=709.4. found: 709.5.