Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[N:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[H-].[Na+].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[O:26]>CN(C=O)C>[CH3:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([N:10]=[C:2]2[N:3]([CH2:24][C:25](=[O:26])[C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1]2)(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Cc1ccc(S(=O)(=O)N=c2[nH]c3ccccc3s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cn2c(=NS(=O)(=O)c3ccc(C)cc3)sc3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a solution of 20 (930 mg, 3.01 mmol) in DMF (15 mL) at room temperature was added NaH. After the effervescence subsided, 2-bromo-4′-methylacetophenone (775 mg, 3.36 mmol) was added. The reaction was first stirred at room temperature for an hour and then heated at 80° C. until completion (by TLC). The mixture was allowed to cool before being poured on ice (400 mL). A precipitate dropped out. It was filtered and washed with cold water and dried to give a pale yellow powder in quantitative yield: mp 180-182° C.; 1H-NMR (DMSO-d6) 2.35 (s, 3H), 2.43 (s, 3H), 5.86 (s, 2H), 7.33 (m, 3H), 7.42 (m, 3H), 7.57 (d, 1H), 7.64 (d, 2H), 7.91 (d, 1H), 7.97 (d, 2H); Anal. (C23H20N2O3S2) C, H, N.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([O:13][CH2:14][CH:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[CH2:6]([O:13][CH2:14][CH:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:16][N:17]([C:3](=[O:4])[CH2:2][Br:1])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)NC(CNCc1ccc(F)cc1)COCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(COCc1ccccc1)CN(Cc1ccc(F)cc1)C(=O)CBr
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Bromoacetyl bromide (588 μL, 6.75 mmol) was added slowly to a stirred solution of tert-butyl 2-(benzyloxy)-1-{[(4-fluorobenzyl)amino]-methyl}ethylcarbamate (2.39 g, 6.14 mmol) and triethylamine (941 μL, 6.75 mmol) in anhydrous THF (12 mL) at 0° C. under inert atmosphere. After stirring for 20 min, the reaction was poured into ice water and extracted twice with diethyl ether. The combined organic layers were washed twice with brine, dried over Na2SO4, and concentrated in vacuo. The resulting orange/brown oil was purified by silica gel chromatography (10% to 40% EtOAc/hexanes) to afford the title compound as a red-orange oil. 1H NMR (500 MHz, CDCl3) δ 7.40-7.21 (m, 6H), 7.16-6.96 (m, 3H), 5.20 (d, J=8.0 Hz, 1H), 5.01 (d, J=9.0 Hz, 1H), 4.75-4.66 (m, 1H), 4.59-4.48 (m, 2H), 4.39 (d, J=15.0 Hz, 1H), 4.04-3.92 (m, 2H), 3.87-3.28 (m, 4H), 1.43 (s, 9H). ES MS (M+1−100, for loss of BOC group)=409.4.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH2:9]([NH2:11])[CH3:10]>CCOCC>[CH2:9]([NH:11][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH3:10]
Reactant: CCN
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCOCC
Product: CCNS(=O)(=O)CCCCl
Yield: 100 %

Procedure:
To a solution of 3-chloropropylsulfonyl chloride 1(6.1 g,34.5mmol) in ether (25 ml) was added dropwise ethylamine (a 70% aqueous solution,4.4 g,68.3 mmol) with stirring under ice-cooling over 15 minutes. The resultant mixture was stirred for one hour at room temperature and concentrated in vacuo. Benzene (100 ml) was added to the residue and the solvent was distilled off in vacuo. To the residue was added ether (150 ml) and filtered to remove the insoluble material. The liltrate was distilled in vacuo to remove ether and 6.96 g (yield, about 100%) of crude N-ethyl-3-chloro propylsulfonamide (intermediate 3a) was obtained as colorless crystals (m.p.=30°-32° C.). To a solution of this intermediate 3a (6.96 g,34.5 mmol) in THF (50 ml) was slowly added sodium hydride (60% in oil,1.52 g,38.0 mmol) with stirring under ice-cooling over 15 minutes. The reaction mixture was stirred for another 30 minutes at room temperature. After the addition of ether (50 ml), the mixture was filtered to remove insoluble material and the filtrate was distilled in vacuo to remove solvent and to give 4.93 g (96%) of the objective compound 4a as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:15]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:10])[CH2:16]2)=[N:4][C:3]=1[CH3:9]
Reactant: Cc1nc(Cl)ccc1Br
Reactant: C[C@@H]1CNCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN[C@H](C)C2)ccc1Br
Temperature: 165 °C
Yield: 35.6 %

Procedure:
In a 10 mL microwave vial equipped with a magnetic stir bar were mixed 3-bromo-6-chloro-2-methylpyridine (515 mg, 2.496 mmol), (R)-2-methylpiperazine (250 mg, 2.496 mmol), and Et3N (1.044 mL, 7.49 mmol) in DMF (4 mL). The resulting yellow suspension was heated in a microwave reactor to 165° C. for 4 hours. The reaction mixture was subsequently partitioned between 0.25N HCl (40 mL) and EtOAc (40 mL). The phases were separated and the aqueous layer was back-extracted with EtOAc (40 mL). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified using flash chromatography (12 g column) eluting with a gradient of 0-100% EtOAc in heptanes and then 0-20% MeOH in DCM. The pure fractions were combined and concentrated to give the title compound as a clear syrup (240 mg, 35.6%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>O1CCOCC1>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: NC1CCOCC1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(NC3CCOCC3)n2)c1F)c1ccoc1

Procedure:
Following a procedure analogous to the procedure described in example 300 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol), 4-aminotetrahydropyrane (107 mg, 1.056 mmol) in 1,4-dioxane (2 mL), the title compound was obtained as a brown foam (20 mg, 0.032 mmol, 15%). 1H NMR (400 MHz, DMSO-d6) ppm 1.33-1.63 (m, 2H), 1.75 (qd, J=11.96, 4.29 Hz, 4H), 1.99-2.05 (m, 2H), 3.19-3.39 (m, 5H), 3.47 (td, J=11.62, 1.77 Hz, 2H), 3.78-3.90 (m, 2H), 3.90-3.98 (m, 2H), 6.66 (d, J=1.26 Hz, 1H), 7.23-7.38 (m, 3H), 7.45 (t, J=6.95 Hz, 1H), 7.82 (t, J=1.77 Hz, 1H), 8.11 (d, J=4.55 Hz, 1H), 8.28 (s, 1H), 10.32 (s, 1H); MS (ESI): 586.0 [M+H]+.
Reaction SMILES: C([O:8][C:9](=[O:23])[C:10]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)([CH3:12])[CH3:11])C1C=CC=CC=1>C(O)C.[Pd]>[CH3:12][C:10]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)([CH3:11])[C:9]([OH:23])=[O:8]
Reactant: CC(C)(C(=O)OCc1ccccc1)c1ccc2ccccc2c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc2ccccc2c1
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 2,2-dimethyl-(2-naphthyl)acetic acid benzyl ester (0.46 g, 1.5 mmol) and 10% Pd/C (0.040 g) in ethanol (5 mL) was hydrogenated at 1 atmosphere for 16 hours. The catalyst was removed by filtration, and the solvent was evaporated to give 2,2-dimethyl-(2-naphthyl)acetic acid (0.33 g, 1.5 mmol, 100%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH2:18][CH2:17]3)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>C(O)CCC>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]3)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Clc1ccncc1
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CCN3)CC1
Agent: Cl
Solvent: CCCCO
Product: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CCN3c2ccncc2)CC1
Reaction time: 3 h
Yield: 69.7 %

Procedure:
A mixed solution of 3-(1-acetyl-4-piperidinyl)-1-(2,3-dihydroindol-5-yl)-1-propanone (0.4 g, 1.33 mmol) and 4-chloropyridine hydrochloride (0.2 g, 1.33 mmol) in 1-butanol (4 ml) was heated and stirred for 3 hours. The solvent was then distilled off and the residue was dissolved in 5% sodium hydroxide/H2O-ethyl acetate and extracted with ethyl acetate. The extract was washed with saturated NaCl/H2O and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=10:1) to provide the title compound (0.35 g) as colorless powders melting at 157-158° C.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12].Cl>[Cu].ClCCl>[F:10][C:8]1[CH:7]=[CH:6][C:5]([C:11](=[O:13])[CH3:12])=[C:4]([NH:2][CH3:1])[CH:9]=1
Reactant: CN
Reactant: CC(=O)c1ccc(F)cc1Cl
Agent: [Cu]
Agent: Cl
Solvent: ClCCl
Product: CNc1cc(F)ccc1C(C)=O
Reaction time: 2 h

Procedure:
A mixture of a solution of methylamine in industrial methylated spirit (33% w/w; 315.8 ml), industrial methylated spirit (291.6 ml), 2'-chloro-4'-fluoroacetophenone (203.4 g) and copper powder (2.8 g) was heated to 80° in a glass autoclave over a period of 1 hour. The mixture was stirred at 80° for a further 2 hours and then allowed to cool to 45° over a period of 1 hour. The mixture was transferred to a second vessel and the autoclave rinsed with industrial methylated spirit (50 ml) which was then added to the second vessel. The mixture was heated to 50°. A solution of sodium sulphide nonahydrate (11.2 g) in water (117 ml) was added and the mixture was heated at 50° for a further 15 minutes. The mixture was filtered and the residue washed with industrial methylated spirit (100 ml). The filtrate and washings were combined and evaporated to give a brown oil. The brown oil was stirred with hydrochloric acid (5M; 800 ml) for 2.5 hours and then dichloromethane (600 ml) added. The layers were separated and the aqueous phase further extracted with dichloromethane (2×300 ml). The organic phases were combined and evaporated to give 4'-fluoro-2'-(methylamino)-acetophenone as a brown oil which solidified at ambient temperature.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:35][C:36]1[CH:37]=[C:38]([C:43](=O)[C:44]([F:47])([F:46])[F:45])[CH:39]=[C:40]([Cl:42])[CH:41]=1.O>C1(C)C=CC=CC=1>[C:11]1([S:10][CH:9]=[C:43]([C:38]2[CH:39]=[C:40]([Cl:42])[CH:41]=[C:36]([Cl:35])[CH:37]=2)[C:44]([F:47])([F:46])[F:45])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(SC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)C(=CSc1ccccc1)c1cc(Cl)cc(Cl)c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
Triphenyl[(phenylsulfanyl)methyl]phosphonium chloride (50.0 g, 116 mmol) and potassium carbonate (32.2 g, purity 98%, 233 mmol) were suspended in toluene (1 L) under an inert gas atmosphere (argon) and cooled to 5° C. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanone (29.5 g, purity 96%, 116 mmol) and polyethyleneglycole (MW 1500, 8.76 g, 5.82 mmol) were added and the reaction mixture was stirred for five and a half hours at 5° C. and after warming to room temperature stirred for additional two hours. Water (500 mL) was added and the phases were separated. The water phase was extracted with toluene and the combined organic phases were washed with water (2x) and brine. After drying over sodium sulfate, filtration and evaporation the crude mixture was treated with n-heptane (250 mL) and left in the freezer overnight. The solid was filtered off and the solvents of the filtrate were evaporated. This material was again taken up in n-heptane (100 mL) and kept in the freezer for three days. Filtration and evaporation of the solvent gave 2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfide (41.6 g, 96% purity, 99% yield; E/Z=94/6—determined by GC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:12])=[C:6]([CH:11]=1)[CH2:7][NH:8][CH2:9][CH3:10].[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:12])=[C:6]([CH:11]=1)[CH2:7][N:8]([CH2:9][CH3:10])[C:16]([CH:13]1[CH2:15][CH2:14]1)=[O:17]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(Br)ccc1I
Product: CCN(Cc1cc(Br)ccc1I)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (5-bromo-2-iodo-benzyl)-ethyl-amine and cyclopropanecarbonyl chloride.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:7][O:6]1)[CH2:2][CH:3]=[CH2:4].[CH2:8]=[CH:9][CH2:10][CH2:11]CC>>[CH2:1]([CH:5]1[CH2:7][O:6]1)[CH2:2]/[CH:3]=[CH:4]/[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=CCCC1CO1
Reactant: C=CCCCC
Product: CCCC/C=C/CCC1CO1

Procedure:
2-(But-3-enyl)oxirane (1.000 g, 10.2 mmol) and hex-1-ene (9.12 g, 102 mmol) were stirred at room temperature for 24 hr in a sealed scintillation vial with Zhan Catalyst-1 (0.057 g, 0.086 mmol). Solvent was removed under reduced pressure and the residue purified by column chromatography (0-10% EtOAc/n-hexane/silica) to give (±)-(E)-2-(oct-3-enyl)oxirane as a colorless oil. 1H NMR (CDCl3): δ 5.5-5.4 (m, 2H), 3.0-2.9 (m, 1H), 2.8-2.7 (m, 1H), 2.5-2.45 (m, 1H), 2.2-2.1 (m, 2H), 1.99 (q, 2H, J=5.7), 1.65-1.55 (m, 2H), 1.35-1.25 (m, 4H), 0.95-0.85 (m, 3H). Contains ca 20% (Z)-2-(oct-3-enyl)oxirane.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:33]=[N:32][C:31]([NH2:30])=[N:36][CH:35]=3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CC(C)S(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 116. (400 MHz, CDCl3): 1.28 (6H, d (J=6.85), CH3), 2.54-2.56 (4H, m, CH2), 3.12 (1H, m, CH), 3.34-3.37 (4H, m, CH2), 3.79 (2H, s, CH2), 3.80-3.82 (4H, m, CH2), 3.94-3.97 (4H, m, CH2), 5.13 (2H, b, NH2), 7.21 (1H, s, ar), 9.21 (2H, s, ar). (M+H)+519.27
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH2:12]([O:11][C:9]([CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:10])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)Cc1cccc(O)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)Cc1cccc(OC(C)(C)C(=O)OCC)c1
Temperature: 80 °C
Reaction time: 60 h

Procedure:
Allyl 3-hydroxyphenylacetate (5.72 g, 32.9 mmol), potassium carbonate (6.82 g, 49.35 mmol), and ethyl 2-bromoisobutyrate (7.35 mL, 49.35 mmol) were dissolved in dimethylformamide (10 mL), and the mixture was stirred for 60 hours at 80° C. The reaction mixture was added to water, and the resultant mixture was extracted with diethyl ether, followed by washing sequentially with water and saturated brine, drying over magnesium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=20/1), whereby the target compound was obtained (6.40 g, 20.90 mmol, 63.5%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[N:11][CH:10]=2)=[CH:5][CH:4]=1.Cl[CH:17]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH:18]=O.C(O)CCCC>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][C:12]3[N:13]([C:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[CH:18][N:15]=3)[N:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(Cl)C=O)cc1
Reactant: Nc1ncc(-c2ccc(F)cc2)nn1
Agent: Cl
Solvent: CCCCCO
Product: COc1ccc(Cc2cnc3ncc(-c4ccc(F)cc4)nn23)cc1
Temperature: 130 °C

Procedure:
A mixture of 6-(4-fluorophenyl)-1,2,4-triazin-3-amine hydrochloride (50 mg, 0.2 mmol) and 2-chloro-3-(4-methoxyphenyl)propanal (48 mg, 0.24 mmol) in tent-amyl alcohol (1 mL) was heated at 130° C. for 4 h. After cooling, the mixture was purified by preparative HPLC to afford the desired product. (7.1 mg) LCMS: (M+H)=335.1.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Br[C:10]([CH3:17])([CH3:16])[C:11](OCC)=[O:12].C(NC(C)C)(C)C>CN(C=O)C>[CH3:16][C:10]1([CH3:17])[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:7][C:11]1=[O:12]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccccc1N
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC1(C)Nc2ccccc2NC1=O
Reaction time: 8 h

Procedure:
A mixture of 1,2-phenylenediamine (II, 7.55 g), ethyl 2-bromoisobutyrate (III, 12.8 ml), diisopropylamine (15.5 ml) and DMF (30 ml) is heated at 110° for 5 hr, after which an additional ethyl bromoisobutyrate (III, 0.5 ml) and diiopropylethylamine (0.8 ml) is added. After heating for 2 more hours, the reaction is cooled and the DMF is removed in under reduced pressure. The residue is stored overnight in the freezer and then partitioned between ethyl acetate, water, and saline. The phases are separated and the organic phase is dried over magnesium sulfate, the organic phase is removed under reduced pressure. The residue is chromatographed eluting with ethyl acetate/dichloromethane (20/80). The product crystallizes out in the column. The product is recrystallized from dichloromethane/hexane to give the title compound, mp 173°-174°; NMR (CDCl3) 1.41, 3.72, 6.67, 6.76, 6.87 and 8.50 δ.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]3)[CH2:3][CH2:2]1.[O:17]1CCOCC1>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([CH:16]=[O:17])[CH:12]=[CH:11]3)[CH2:2][CH2:3]1
Reactant: C1COCCO1
Reactant: Cc1ccc2cccc(OCC3CC3)c2n1
Solvent: O
Product: O=Cc1ccc2cccc(OCC3CC3)c2n1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 8-(cyclopropylmethoxy)-2-methylquinoline (3.00 g, 14.1 mmol) in dioxane (100 mL) and water (1.0 mL) was added SeO2 (1.87 g, 16.9 mmol). The reaction mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (1:4 hexane/DCM) to give 8-(cyclopropylmethoxy)quinoline-2-carbaldehyde (3.1 g, 97.0%) as a solid
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[C:8]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[N:9][O:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O>[C:13]([C:8]1[C:7]([NH:6][C:3](=[O:4])[CH2:2][Br:1])=[C:11]([CH3:12])[O:10][N:9]=1)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1onc(C(=O)c2ccccc2)c1N
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1onc(C(=O)c2ccccc2)c1NC(=O)CBr
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Bromoacetylbromide (40 g, 0.2 mole) was added slowly to a mixture of 20 g (0.1 mole) (4-amino-5-methylisoxazol-3-yl)-phenylmethanone of Example Ib in 500 ml dichloromethane with 200 ml of 2N sodium carbonate and 500 ml saturated sodium bicarbonate at 5° C. After stirring for 30 minutes the mixture was diluted with 400 ml dichloromethane and 400 ml water. The organics were washed with water and brine and dried (magnesium sulfate). Concentration gave 32 g of an oil which was chromatographed on high pressure liquid chromatograph (HPLC) using dichloromethane as an eluent to yield 23 g (71%) of a solid, melting point 89°-92° C.
Reaction SMILES: BrC[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:19])[CH:6]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:8]2.[C:20]([O-])(=[O:22])[CH3:21].[K+]>CN(C=O)C.O>[C:20]([C:6]1[C:5](=[O:19])[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][CH:3]=2)[O:8][C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH3:21]
Reactant: O=c1cc(-c2ccccc2)oc2cccc(CBr)c12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(-c2ccccc2)oc2ccccc2c1=O
Temperature: 100 °C
Yield: 107.2 %

Procedure:
The diketone compound (2.3 g, 6.92 mmol) was taken into a mixture of HCl (1 mL) and acetic acid (15 mL) and heated at 100° C. for 1 h. The reaction mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and concentrated to give 1.75 g of the intermediate in 80.6% yield. In a 100 mL dry round-bottomed flask fitted with condenser and magnetic stirrer were placed this intermediate (925 mg, 2.94 mmol) in CH2Cl2 (30 mL). BBr3 (2.21 g, 8.83 mmol, 1M solution in CH2Cl2) was added slowly at 0° C. The reaction mixture was stirred for 16 h at rt under nitrogen. The reaction mixture was quenched by carefully adding methanol. The solvent was removed under reduced pressure and the resulting solid was washed with water and dried to give 1.0 g of crude 3′-fluoro-4′-methoxy-5-bromo methyl flavone in 97% yield. To a solution of 5-bromomethyl flavone (1.0 g, 2.86 mmol) in DMF (20 mL), potassium acetate (845 mg, 8.60 mmol) was added. The mixture was heated at 100° C. for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give crude acetyl flavone (810 mg, 86%). To a solution of the acetyl flavone (810 mg, 2.47 mmol) in methanol (15 mL), K2CO3 (1.02 g, 7.41 mmol) was added and the reaction mixture was stirred for 2 h at rt. The solvent was removed and the product was taken in to water and neutralized by dilute HCl. The solid was separated by filtration, washed with water and dried to give 2-(3-fluoro-4-hydroxyphenyl)-6-(hydroxymethyl)-4H-chromen-4-one in 38% yield. MS (ES) m/z: 286.96 (M); Mp. 256-258° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][C:24]=1F>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:24]3[CH:23]=[CH:22][C:21]([C:26]([F:29])([F:28])[F:27])=[CH:20][C:19]=3[Cl:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Oc2ccc3c(ccn3Cc3ccccc3)c2)c(Cl)c1
Reaction time: 16 h
Yield: 68.6 %

Procedure:
A slurry of 0.413 g (1.85 mmol) 1-benzyl-5-hydroxy-1H-indole, 0.3 ml (2.2 mmol) 3-chloro-4-fluorobenzotrifluoride, and 1.0 g (3.0 mmol) Cs2Cb3 in 12 ml DMF was heated to 130° C. with stirring for 16 hr. The solution was allowed to cool and then filtered to remove Cs2CO3. The solution was concentrated under vacuum and chromatographed on silica using 5-7% EtOAc-hexane to afford 0.51 g 1-benzyl-5-(2-chloro-4-trifluoromethyl-phenoxy)-1H-indole as an oil.