Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.Br[C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:6][CH:5]=1.C([Li])CCC.[B:25](OCC)([O:29]CC)[O:26]CC>O1CCCC1>[CH3:18][N:17]([CH2:16][CH2:15][O:14][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:4]([B:25]([OH:29])[OH:26])=[CH:5][CH:6]=1)[CH3:19]
Reactant: CCOB(OCC)OCC
Reactant: CN(C)CCOc1ccc(Br)c2c1CCCC2
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(B(O)O)c2c1CCCC2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a 1 L 3N round-bottomed flask equipped with septum and N2 inlet were added 8.55 g (28.7 mmol) 4-bromo-1-(2-dimethylaminoethoxy)-5,6,7,8-tetrahydro-naphthalene and 300 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 13.8 mL (34.4 mmol) of a 2.5 M solution of butyl lithium in hexanes was added. The reaction was stirred at −70° C. for 1 h, then 5.9 mL (34.4 mmol) triethyl borate was added, and the reaction stirred at −70° C. for 2 h and warmed to room temperature overnight. The reaction was quenched with aqueous saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was triturated with hexane to a white solid, 6.3 g (83.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([Br:21])[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][N:11](CC2C=CC(OC)=CC=2)[C:10]1=[O:31].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([Br:21])[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:31]
Reactant: COc1ccc(CN2Cc3c(Br)cc(OC)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Temperature: 25 °C

Procedure:
A solution of 1-(2,6-dichlorophenyl)-3-(4-methoxyphenyl)methyl-5-bromo-7-methoxy-3,4-dihydro-2(1H)-quinazolinone (30.91 g, 0.0592 mol) (INTERMEDIATE 22) and anisole (28 ml, 0.258 mol) in 350 mL trifluoroacetic acid under a nitrogen atmosphere was refluxed for 2 h. The solution was cooled to RT and concentrated. The residue was partitioned between 500 mL NaHCO3 and 500 mL EtOAc. The organic phase was washed with water (500 mL) and brine (500 mL) and concentrated. The NaHCO3 and brine phases contained a suspension of precipitated product. This material was collected by filtration and combined with the crude. The combined crude was suspended in ethyl ether, filtered and washed with ethyl ether and hexanes to give 1-(2,6-dichlorophenyl)-5-bromo-7-methoxy-3,4-dihydro-2(1H)-quinazolinone. 1H NMR(CDCl3, 500 MHz): δ 3.68 (s, 3H), 4.64 (s, 2H), 5.46 (s, 1H), 5.62 (d, 1H, J=2.3 Hz), 6.79 (d, 1H, J=2.5 Hz), 7.36 (t, 1H, J=8.1 Hz), 7.50 (d, 2H, J=8.2 Hz). MS(ES) 401 (M+1); LC 1: 3.18 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:10]=2[CH3:26])[CH:7]=1.C[Sn](C)(C)[C:35]1[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[N:36]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:11]1[C:10]([CH3:26])=[C:9]([NH:8][C:6]2[CH:7]=[C:2]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[N:36]=3)[CH:3]=[CH:4][C:5]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: CC(=O)Nc1nccc([Sn](C)(C)C)n1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(Br)ccc1N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nccc(-c2ccc(N3CCOCC3)c(Nc3c(C)c(-c4ccccc4F)nc4ccccc34)c2)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of N-(5-bromo-2-morpholinophenyl)-2-(2-fluorophenyl)-3-methylquinolin-4-amine (100 mg, 203 μmol), N-(4-(trimethylstannyl)pyrimidin-2-yl)-acetamide (91 mg, 305 μmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 20 μmol) in toluene (4.00 mL) was purged with nitrogen and heated to gentle reflux. After 3.5 h LC-MS indicated no starting bromide remained and the reaction was removed from heat and left stirring overnight at rt before concentrating under reduced pressure. The concentrate was dissolved in 3 mL DMF and purified by reversed-phase HPLC. Mass Spectrum (ESI) m/e=549.3 (M+1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N+:8]([C:11]1[CH:12]=[C:13]([C:23]2[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O-:10])=[O:9]>C(O)(=O)C>[C:1]([N:20]1[CH2:21][CH2:22][N:17]([C:16]2[CH:15]=[CH:14][C:13]([C:23]3[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=3)=[CH:12][C:11]=2[N+:8]([O-:10])=[O:9])[CH2:18][CH2:19]1)(=[O:3])[CH3:2]
Reactant: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])CC1

Procedure:
0.57 ml (6 mmol) of acetic acid anhydride are added at room temperature to 1.27 g (4 mmol) of 6-[3-nitro-4-(1-piperazinyl)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 30 ml of acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]I.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH3:13])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
2-(4-Bromophenyl)ethanol (2.0 g) was dissolved in N,N-dimethylformamide (50 mL), and sodium hydride (60% in oil) (0.44 g) was added under ice-cooling. After gradually warming to room temperature, the mixture was stirred for 2 hr, and methyl iodide (2.1 g) was added again under ice-cooling. After gradually warming to room temperature, the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1 to 10:1) to give the title compound (1.2 g) as a colorless oil.
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1>C(Cl)CCl>[Cl:1][C:9]1[C:8]([OH:11])=[CH:7][CH:6]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:10]=1
Reactant: ClCl
Reactant: Oc1ccc(C(F)(F)F)cc1
Solvent: ClCCCl
Product: Oc1ccc(C(F)(F)F)cc1Cl
Yield: 71 %

Procedure:
Chlorine gas is passed through a flow meter into a solution of α,α,α-trifluoro-p-cresol (4.05 g. 0.025 mole) in ethylene dichloride (200 ml.) at 0° C. until the theoretical volume has been absorbed. The solvent is stripped off and the residue distilled to give 2-chloro-α,α,α-trifluoro-p-cresol (3.5 g. 71%) b.p. 80°-82° C. at 33 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Al](C)C.C[O:21][C:22]([C@H:24]1[CH2:28][C@H:27]([OH:29])[C@@H:26]([NH:30][C:31]([C:33]2[S:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[O:32])[CH2:25]1)=O.[O-]S([O-])(=O)=O.[Mg+2]>O1CCOCC1.O>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([C@@H:24]1[CH2:25][C@H:26]([NH:30][C:31]([C:33]2[S:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[O:32])[C@@H:27]([OH:29])[CH2:28]1)=[O:21]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a stirred suspension of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (296 mg; CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) at r.t. in dioxane (3 ml) under an argon atmosphere was added carefully trimethyl aluminium solution (0.72 ml; 2M in heptane). After stirring for 2 hrs at r.t., a solution of (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentane-carboxylic acid methyl ester (110 mg) in dioxane (3 ml) was added. The mixture was heated to 100° C. and stirring at that temperature was continued for 24 h. The mixture was cooled to r.t. and water (0.8 ml) was added. After 15 min stirring, MgSO4 was added and stirring was continued for another 15 min. The solids were filtered off and washed with dichloromethane. The filtrate was concentrated. The crude product was isolated by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentyl}-amide (81 mg) as light yellow solid. MS: 476.0 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10](F)(F)F)=C)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[N:26][OH:27])=[CH:21][C:20]=1[CH2:28][C:29]([F:32])([F:31])[F:30]>ClCCl.[O-]Cl.[Na+]>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:10][CH:8]([C:6]3[CH:5]=[C:4]([C:14]([F:15])([F:16])[F:17])[CH:3]=[C:2]([Cl:1])[CH:7]=3)[O:27][N:26]=2)=[CH:21][C:20]=1[CH2:28][C:29]([F:30])([F:31])[F:32]
Reactant: C=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: ON=Cc1ccc(Br)c(CC(F)(F)F)c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: FC(F)(F)Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)C2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (680 mg, 2.48 mmol, 1.00 equiv), a solution of N-[[4-bromo-3-(2,2,2-trifluoroethyl)phenyl]methylidene]hydroxylamine (700 mg, 2.48 mmol, 1.10 equiv) in dichloromethane (20 mL), NaClO (10 mL). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30-1:10). This resulted in 600 mg (50%) of 3-[4-bromo-3-(2,2,2-trifluoroethyl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazole as yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:18]([NH:25][CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]([CH2:16][C:14]1[O:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)[CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNCc1ccccc1
Reactant: CCc1cc(-c2ccc(C=O)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(CN(C)Cc3ccccc3)o2)c(C)[nH]c1=O
Yield: 53 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]furan-2-carbaldehyde is reacted with benzyl methylamine as described in Method A, Example 123 to give the title compound as a solid (53% yield). LC/MS: RT 2.08 min; m/e 337 (M+H); 1H NMR (δ, ppm): 11.6 (1H, s), 7.46 (1H, s); 7.3 (5H, m); 6.4 (2H, dd), 3.6 (2H, s), 3.55 (2H, s), 2.4 (2H, m), 2.36 (2H, s), 2.2 (3H, s), 1.05 (3H, t).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][N:14]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:15](=[O:27])[N:16]2[C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[C:11]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[CH:10]=1)(=[O:7])=[O:6].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(OCC)(=O)C>[Cl:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[C:11]1[CH:10]=[C:9]([NH:8][S:5]([CH2:4][CH2:3][CH2:2][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)(=[O:6])=[O:7])[CH:18]=[C:17]2[C:12]=1[CH2:13][N:14]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:15](=[O:27])[N:16]2[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26]
Reactant: C1COCCN1
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NS(=O)(=O)CCCCl)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NS(=O)(=O)CCCN4CCOCC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 25 °C

Procedure:
3chloro-N-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]propane-1-sulfonamide (93 mg, 0.14 mmol) in morpholine (0.25 mL) was heated at 130° C. for 45 min. The reaction mixture was cooled to rt, diluted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated under reduced pressure. The product was purified by flash chromatography on a Biotage 40S column, eluting with 60:40 hexanes-acetone to yield N-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-3-morpholin-4-ylpropane-1-sulfonamide. Mass spectrum (ESI) 729 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([C:14]([O:16]CC)=[O:15])[NH:7]2.[OH-].[Na+]>>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[NH:7]2
Reactant: CCOC(=O)c1cc(=O)c2c(Br)cc(CC)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(Br)c2c(=O)cc(C(=O)O)[nH]c2c1
Yield: 70.1 %

Procedure:
Treatment of ethyl 5-bromo-7-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.59 g) with sodium hydroxide (0.247 g). as described in Example 1a, gave 5-bromo-7-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.378 g), mp 276° C. (dec.) δ (360 MHz, DMSO-d6) 1.21 (3H, t, CH3), 2.66 (2H, q, CH2), 6.54 (1H, s, 3-H), 7.79 (1H, d, 8-H) and 11.75 (1H, bs, NH), (Found: C, 46.17; H, 3.76; N, 4.48%, C12H10BrNO3. 0.9H2O requires C, 46.14; H, 3.80; N, 4.48%).
Reaction SMILES: [I-].[Na+].C[Si](Cl)(C)C.[F:8][C:9]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20]C)[CH:15]=1)=[O:12]>C(#N)C.O>[F:8][C:9]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:31])[F:32])[C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=1)=[O:12]
Reactant: COc1cc(NC(=O)c2c(F)cc(C(F)(F)F)cc2C(F)(F)F)ccn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(Nc1cc[nH]c(=O)c1)c1c(F)cc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of sodium iodide (2.54 g, 16.95 mmol) in acetonitrile (75 mL) under nitrogen was added TMSCl (2.15 mL, 16.95 mmol) and the mixture was stirred at 25° C. for 30 min. Thereafter, anhydrous acetonitrile (130.0 ml) was added to this solution followed by 2-fluoro-N-(2-methoxy-4-pyridyl)-4,6-bis(trifluoromethyl)benzamide (1.2 g, 3.14 mmol). The resulting reaction mixture was heated with stirring at 80° C. for 5 h and at 60° C. for 12 hours. The reaction was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated to a dark yellow-orange solid. The solid was triturated with ethyl acetate/hexanes several times to remove dark red color, then with dichloromethane to remove yellow color, then finally with hexanes. The resulting solid was dried under vacuum to provide 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide (960 mg, 83%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 11.03 (s, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H), 7.37 (d, J=7.1 Hz, 1H), 6.71 (d, J=2.0 Hz, 1H), 6.31 (dd, J=7.2, 2.1 Hz, 1H) ppm. ESI-MS m/z calc. 368.04. found 369.1 (M+1)+; Retention time: 1.28 minutes (3 minutes run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=C)=[N:9][C:8]([C@@H:14]([NH:16][C:17](=[O:33])[O:18][CH2:19][CH:20]1[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:15])=[CH:7]2.[O:34]1CCOCC1>O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:34])=[N:9][C:8]([C@@H:14]([NH:16][C:17](=[O:33])[O:18][CH2:19][CH:20]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:15])=[CH:7]2
Reactant: C=Cc1nc([C@H](C)NC(=O)OCC2c3ccccc3-c3ccccc32)cc2cccc(Cl)c12
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-vinylisoquinolin-3-yl)ethylcarbamate (347) (10.6 g, 23.3 mmol, 1.0 eq) in 1,4-dioxane (200 mL) and water (100 mL), OsO4 (50 mg) was added and the resulting mixture was stirred at RT for 30 min. To this mixture, NaIO4 (15 g, 69.9 mmol, 3.0 eq) was added, and then the mixture was stirred at RT for 16 h. The mixture reaction was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5-20% ethyl acetate-petro ether) to afford (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-l-formylisoquinolin-3-yl)ethylcarbamate (348).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[C:23](Br)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH2:36]([Sn:40](Cl)([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH3:39]>O1CCCC1>[C:1]([O:5][C:6](=[O:30])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[C:23]([Sn:40]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:24][N:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(Br)n2ccnc12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c2nccn12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.8 %

Procedure:
To a cooled (−78° C.) solution of (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (2.55 g, 5.38 mmol) in tetrahydrofuran (20 mL) is added isopropylmagnesium chloride (0.829 g, 8.06 mmol). After stirring for 5 min tributyltin chloride (2.97 g, 9.14 mmol) is added and the reaction is stirred at −78 ° C. for 10 min before being allowed to warm to room temperature. After stirring at room temperature for 30 min, the mixture is concentrated. The residue is purified by silica gel flash column chromatography eluting with 5:1 petroleum ether-ethyl acetate followed by 1:1 petroleum ether-ethyl acetate to afford the product as yellow solid (2.35 g, 64%).
Reaction SMILES: FC(S(O[C:9]1[C:17]2[CH:16]=[CH:15][O:14][C:13]=2[C:12]([C:18]2[C:19](=[O:35])[N:20]([CH3:34])[C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:11][CH:10]=1)(=O)=O)(F)F.[C:36](=[NH:49])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)C>[C:36](=[N:49][C:9]1[C:17]2[CH:16]=[CH:15][O:14][C:13]=2[C:12]([C:18]2[C:19](=[O:35])[N:20]([CH3:34])[C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:11][CH:10]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2ccc(OS(=O)(=O)C(F)(F)F)c3ccoc23)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2ccc(N=C(c3ccccc3)c3ccccc3)c3ccoc23)C1=O
Temperature: 25 °C

Procedure:
Heat a mixture of 7-[1-methyl-4-(1-methylindol-3-yl)-2,5-dioxo-3-pyrrolin-3-yl]benzo[b]fur-4-yl (trifluoromethyl)sulfonate (100 mg, 0.2 mmol), benzophenone imine (0.037 ml, 0.22 mmol), tris-(benzylideneacetone)-dipalladium(0)(9 mg, 0.01 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.03 mmol), and cesium carbonate (91 mg, 0.28 mmol) in anhydrous toluene (1 ml) to 80° C. for 19 hours under a nitrogen atmosphere. Allow the reaction to cool to room temperature, dilute with diethyl ether, and filter through Celite. Wash the filtrate with water, brine, dry over magnesium sulfate, filter and concentrate. Flash chromatography over silica gel (ethyl acetate: hexanes) affords the title compound as a red oil. MS(ES+): 536.1.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[S:44][C:43]([CH3:45])=[N:42][C:41]=1[CH3:46]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[S:44][C:43]([CH3:45])=[N:42][C:41]=2[CH3:46])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1nc(C)c(CCl)s1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: Cc1nc(C)c(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)s1
Yield: 100.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 5-(chloromethyl)-2,4-dimethylthiazole (0.49 g) as starting materials, 5-benzyloxy-N-({1-[(2,4-dimethylthiazol-5-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.92 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:35][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:36][CH3:37])[N:27]=[CH:26][CH:25]=[C:24]2[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COC(=O)CCCCCCCCC(=O)c1cc(C)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COC(=O)CCCCCCCCC(=O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 10.3 %

Procedure:
Methyl 10-(2-hydroxy-5-methyl-phenyl)-10-oxo-decanoate (546 mg), 4-chloro-6,7-dimethoxyquinoline (397 mg), and 4-dimethylaminopyridine (434 mg) were suspended in o-dichlorobenzene (20 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give methyl 10-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-10-oxo-decanoate (90 mg, yield 1.0%).