Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10](O)[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.S(Cl)([Cl:19])=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:19][CH:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:16][C:6]=2[C:7]=1[CH3:15])[CH:11]([CH3:13])[CH3:12]
Reactant: Cc1c(C(O)C(C)C)oc2ccc(F)cc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(Cl)C(C)C)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(5-fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-ol (1.128 g) obtained in Example A192(2) in tetrahydrofuran (10 mL) was added thionyl chloride (0.45 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give a crude 2-(1-chloro-2-methylpropyl)-5-fluoro-3-methyl-1-benzofuran (1.10 g). To the obtained 2-(1-chloro-2-methylpropyl)-5-fluoro-3-methyl-1-benzofuran (485 mg) were added ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (500 mg) obtained in Example 1(2), sodium iodide (599 mg), sodium carbonate (424 mg) and N,N-dimethylformamide (5 mL) and the mixture was stirred at 80° C. for 13 hr. 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 magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-50:50, v/v) to give a colorless amorphous compound (123 mg). The obtained amorphous compound (123 mg) was dissolved in ethanol (2.0 mL) and tetrahydrofuran (2.0 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, water (4 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (1.0 mL) under ice-cooling and the mixture was stirred for 20 min. The resulting precipitate was collected by filtration, and dried to give the title compound (97 mg, 11%) as a yellow amorphous compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].Br[CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].CCN(C(C)C)C(C)C>C(#N)C>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:4][C:3]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: Nc1cc(F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(Nc1cc(F)ccc1F)c1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
2,5-Difluoroaniline (0.19 mL, 1.85 mmol), ethyl 2-bromo-2-phenylacetate (0.22 mL, 1.23 mmol), and DIPEA (0.32 mL, 1.85 mmol) are dissolved in acetonitrile (3 mL) and heated under MW irradiation at 100° C. for 6 hours and then at 110° C. for 4 hours. Acetonitrile is evaporated and the crude is purified by flash chromatography (Petroleum ether/EtOAc=97/3) to obtain intermediate I104 as a white solid (240 mg, 67% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]([F:49])([F:48])[C:37]1[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[NH2:40].CC(C)([O-])C.[Na+].C(P(C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:31])[F:32])[CH:24]=2)[CH:12]=[C:13]([NH:40][C:39]2[CH:38]=[C:37]([C:36]([F:48])([F:49])[F:35])[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 45.8 %

Procedure:
A mixture of 2-(4′-chloro-5-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (48 mg, 0.10 mmol), 3,5-bis-(trifluoromethyl)-aniline (18 μL, 0.12 mmol), sodium tert-butoxide (9.8 mg, 0.10 mmol), Pd(OAc)2 (2.5 mg, 0.01 mmol), 2-(di-tert-butylphoshino-1,1′-binaphthyl (3.5 mg, 0.01 mmol) and toluene (1 mL) was stirred under microwave irradiation at 130° C. for 3×10 min. The mixture was diluted with toluene (9 mL), washed with 1M HCl (2×10 mL) and brine (10 mL), dried (MgSO4), concentrated in vacuo and purified by flash column chromatography (diethylether-petroleum ether) to afford the title product as a colourless powder (28 mg, 44%). Mass spectrum (ESI, m/z): 610, 612 (M−H).
Reaction SMILES: [C:1]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19](S(O)(=O)=O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]=1[CH2:7][C:6]1[CH2:26][C:16]2[C:21]([C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)C1C=Cc2ccccc21
Agent: C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)C1=C(CC2=C(C(C)(C)C)c3ccccc3C2)Cc2ccccc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 216.4 %

Procedure:
In a 500 mL flask equipped with magnetic stirring bar were introduced 12.35 g (0.072 moles) of 1-t-butyl-indene, 1.43 g (0.048 moles) of para-formaldehyde and 2.73 g (0.014 moles) of para-toluenesulphonic acid in 200 ml of toluene; the mixture was heated to 80° C. and was maintained under stirring for 6 hours at 80° C. Then the reaction was quenched with water/NaHCO3; the conversion, measured by gas chromatographic analysis, was 79.15%. The organic layer was separated, washed with water and brought to dryness under reduced pressure. The crude product crystallized upon standing at room temperature, and then was further purified by washing with MeOH, thus isolating 10.8 g bis(3-t-butyl-2-indenyl)methane (purity of 90.9 by G.C.; yield=76.81%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:21][NH:22][O:23][CH3:24]>ClCCl>[CH:1]1([CH2:4][C:5]([N:22]([O:23][CH3:24])[CH3:21])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CC1CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)CC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-cyclopropylacetic acid (C62) (30 g, 300 mmol) in dichloromethane (800 mL) was added 1,1′-carbonyldiimidazole (54 g, 333 mmol) portion-wise, not allowing the temperature to exceed 25° C. The mixture was stirred at room temperature for 2 hours. N,O-Dimethylhydroxylamine hydrochloride (30 g, 308 mmol) was added in one portion and stirred at room temperature for 18 hours. The mixture was washed with water (2×200 mL) and saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate and concentrated to give crude product as a yellow oil, which was directly used in the next step. Yield: 48 g, 336 mmol, 112%. 1H NMR (400 MHz, CDCl3) δ 3.62 (s, 3H), 3.12 (s, 3H), 2.30 (d, J=7.2 Hz, 2H), 1.03-1.06 (m, 1H), 0.48-0.52 (m, 2H), 0.11-0.13 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[Cl:8][C:9]1[N:14]=[CH:13][C:12](O)=[CH:11][N:10]=1>>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])=[CH:11][N:10]=1
Reactant: OCCC(F)(F)F
Reactant: Oc1cnc(Cl)nc1
Product: FC(F)(F)CCOc1cnc(Cl)nc1
Yield: 92 %

Procedure:
Reactions similar to those of Reference Example 28 were performed except for using 3,3,3-trifluoro-1-propanol instead of 1-methyl-4-piperidinol, and from 100 mg (0.693 mmol) of 2-chloro-5-hydroxypyrimidine, 144 mg of the title compound as a colorless oil (yield: 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=O.[CH2:11]([NH:13][NH2:14])[CH3:12]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1/[CH:8]=[N:14]/[NH:13][CH2:11][CH3:12]
Reactant: CCNN
Reactant: O=Cc1c(Br)cncc1Br
Product: CCN/N=C/c1c(Br)cncc1Br
Temperature: 100 °C
Yield: 100 %

Procedure:
In analogy to GP 1, 2.65 g of 3,5-dibromo-pyridine-4-carbaldehyde (10 mmol, 1 eq; commercially available or prepared as described in U.S. Pat. No. 6,232,320 or WO2005110410) were dissolved in 32 mL 1-propyl alkohol, treated with 2.25 g N-ethyl hydrazine (oxalate salt; 15 mmol, 1.5 eq.) and heated to 100° C. for 30 min (employing a Biotage Initiator® microwave oven in batch mode). The reaction mixture was concentrated, the residue partitioned between conc. aq. sodium bicarbonate solution and ethyl acetate, the aqueous layer reextracted with ethyl acetate, the combined organic layers dried and concentrated in vacuo to yield 3.08 g of the desired product (10 mmol, quantitative yield), which was used in the subsequent cyclization without further purification steps.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9](=[O:21])[C:8]=1[Br:22])(=O)=O.[K+].[Br-:26]>CN(C)C(=O)C>[Br:22][C:8]1[C:9](=[O:21])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:11]=[CH:12][C:7]=1[Br:26]
Reactant: O=c1c(Br)c(OS(=O)(=O)C(F)(F)F)ccn1Cc1cccc(F)c1
Reactant: [Br-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=c1c(Br)c(Br)ccn1Cc1cccc(F)c1
Yield: 50.6 %

Procedure:
3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (2.00 g, 4.65 mmol), KBr (5.53 g, 46.49 mmol), and 18-Crown-6-(0.10 g, 0.38 mmol) were dissolved in N,N-dimethylacetamide (26 mL). The reaction mixture was then heated at reflux for 16 hours. The reaction was concentrated and the resulting residue was partition between water (50 mL) and ethyl acetate (3×50 mL). The combined organics were washed with H2O (2×30 mL), brine (50 mL), dried over MgSO4, concentrated, and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexane) to afford a brown solid (0.850 g, 51%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[CH3:42][NH:43][CH2:44][CH2:45][CH3:46]>C(Cl)Cl.CN(C=O)C>[CH3:42][N:43]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:34])[F:35])[C:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1)[CH2:44][CH2:45][CH3:46]
Reactant: CCCNC
Reactant: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCN(C)Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 286) (255 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with methyl-propyl-amine in DMF according to the general procedure of example 288. Obtained as an off-white solid (207 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.C12(C)C(C)(C)C(CC1)CC2=O.C.[O-]S([O-])(=O)=O.[Mg+2]>O>[CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC=C(C)CC1
Agent: CC12CCC(CC1=O)C2(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Product: C=C(C)[C@H]1CC=C(C)CC1
Temperature: 220 °C

Procedure:
Product analysis and other analytical methods--An in situ bioassay was developed to evaluate functional expression of (-)-limonene hydroxylase activity. Expression cultures were incubated in the presence of ~300 μM (-)-(4S)-limonene, which was added to the culture medium immediately following infection. At zero and various time intervals, 50-100 ml culture samples were removed and cells were harvested by centrifugation, washed, and resuspended in 3-6 ml of sodium phosphate buffer as described above. Resuspended cell suspensions were chilled on ice and extracted twice with 3 ml portions of ice cold ether after the addition of 25 nmol camphor as internal standard. The extract was decolorized with activated charcoal, backwashed with water, and the organic phase containing the products was passed through a short column of anhydrous MgSO4 and activated silica. The purified extracts were then concentrated to ~500 μl under N2 and analyzed by capillary GLC (Hewlett-Packard 5890). GLC was performed on 0.25 mm i.d.×30 m of fused silica capillary columns coated with superox FA or AT-1000 using "on column" injection and flame ionization detection with H2 as carrier gas at 13.5 psi (programmed from 45° C. (5 min) to 220° C. at 10° C. per min). The identities of the products, (-)-trans-carveol from C-6 hydroxylation and (-)-trans-isopiperitenol from C-3 hydroxlyation, were confirmed by coincidence of retention times with the corresponding authentic standard. Peak quantitation was by electronic integration based on the internal standard.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[N:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[CH2:17][C:16]([F:30])([F:29])[CH2:15]2)[N:6]=1.CC1(C)C(C)(C)OB([C:49]2[N:54]=[C:53]([C:55]#[N:56])[CH:52]=[CH:51][CH:50]=2)O1>>[NH2:33][C:4]1[S:3][C:2]([C:49]2[CH:50]=[CH:51][CH:52]=[C:53]([C:55]#[N:56])[N:54]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[N:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[CH2:17][C:16]([F:30])([F:29])[CH2:15]1)=[O:32]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CC[C@@H](NC(=O)OC(C)(C)C)CC(F)(F)C1
Reactant: CC1(C)OB(c2cccc(C#N)n2)OC1(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(C#N)n3)sc2N)c1N1CC[C@@H](N)CC(F)(F)C1

Procedure:
Following the procedures in Example 428, tert-butyl N-[2-bromo-4-[[5-[(5R)-5-(tert-butoxycarbonylamino)-3,3-difluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate was reacted with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile to give 461. LCMS (ES+) m/z 474 (M+1)
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6](Cl)[N:5]=[C:4]([CH3:14])[N:3]=1.C(C1C=C(O)C=CC=1)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH3:31][NH:32][CH3:33]>CN(C)C=O.O>[CH3:31][N:32]([CH3:33])[N:5]1[CH:6]=[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:2]=[N:3][CH:4]1[CH3:14]
Reactant: CNC
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1Cl
Agent: CC(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC1=CN(N(C)C)C(C)N=C1
Reaction time: 16 h

Procedure:
Methyl 4,6-dichloro-2-methyl-pyrimidin-5-yl-acetate (23.5 g, 0.1 mol), 3-isopropylphenol (13.6 g, 0.1 mol) and potassium carbonate (20.7 g, 0.15 mol) are heated in dimethylformamide (30 ml) at 100° C. for 45 minutes. The mixture is cooled and an aqueous solution of dimethylamine (50 ml of a 40% solution) is added. Stirring is continued for 16 hours at room temperature. Addition of water, filtering and drying gives the methyl 1-dimethylamino-2-methyl-pyrimidin-5-yl-acetate as a brownish solid (28 g).
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[CH:27]=[C:26]([C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[S:44]([CH3:47])(=[O:46])=[O:45])[N:25]=1.[F:48][C:49]1[CH:50]=[C:51]([NH:64][C:65]([NH:67][CH2:68][CH2:69][OH:70])=[O:66])[CH:52]=[CH:53][C:54]=1B1OC(C)(C)C(C)(C)O1>CO.Cl>[F:48][C:49]1[CH:50]=[C:51]([NH:64][C:65]([NH:67][CH2:68][CH2:69][OH:70])=[O:66])[CH:52]=[CH:53][C:54]=1[C:24]1[N:25]=[C:26]([C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[S:44]([CH3:47])(=[O:46])=[O:45])[CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[N:29]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(Cl)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Agent: Cl
Solvent: CO
Product: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(-c2ccc(NC(=O)NCCO)cc2F)n1
Temperature: 90 °C

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 10) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxyethyl)urea (intermediate 13). Material was purified by prep HPLC (high pH) followed by purification by prep HPLC (low pH). Due to partial byproduct formation by reaction with formic acid the resulting material was taken up in MeOH (0.5 mL) along with 2 drops of 2M HCl and heated in the microwave for 20 minutes at 90° C. Reaction mixture was purified using a TsOH cartridge (100 mg) to afford a white solid, (12 mg, 8%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=2[CH:20]=1.[CH:21]1([C:27]2[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([C:27]2[CH:28]=[CH:29][C:30]([S:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:9]=[CH:10][C:11]4[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=4[CH:20]=3)=[CH:31][CH:32]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCBr)cc21
Reactant: Sc1ccc(C2CCCCC2)cc1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCCSc3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(5-bromopentoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-cyclohexyl-thiophenol.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)=[N:25][N:24]=1>>[N+:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[NH:32][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[O:27][C:23]([CH3:22])=[N:24][N:25]=2)=[CH:34][CH:33]=1)([O-:21])=[O:20]
Reactant: Cc1nnc(-c2ccc(N)cc2)o1
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Product: Cc1nnc(-c2ccc(Nc3ccc4ccccc4c3[N+](=O)[O-])cc2)o1
Yield: 70.5 %

Procedure:
1-Nitronaphthalen-2-yl triflate (1.67 g, 5.2 mmol) and 4-(5-methyl-[1,3,4]oxadiazol-2-yl)aniline (0.91 g, 5.2 mmol) were used in a process similar to Example 1(1) to give the titled compound (1.27 g, yield 71%).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[Br:24][CH2:25][CH2:26][CH2:27]Br.O>O1CCCC1>[Br:24][CH2:25][CH2:26][CH2:27][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][C:9]1[CH:18]=[CH:19][C:6]([C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:20][CH3:21])=[CH:7][CH:8]=1
Reactant: BrCCCBr
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCCCBr)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
2-(4-Diethylcarbamoylbenzyl)phenol (100 mg) was dissolved in tetrahydrofuran (2 ml), added with sodium hydride (60%, in oil, 21 mg) and stirred at 60° C. for 1.5 hours. The reaction mixture was added with 1,3-dibromopropane (0.18 ml) and stirred at the same temperature for 3 hours. After the reaction mixture was added with water (10 ml) and the layers were separated, the aqueous layer was extracted with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=3:1) to obtain 99 mg of the title compound. Yield: 69%.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:5][C:4](=[O:15])[C:3]=1[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24].C(N(CC)CC)C.[CH2:32]([O:35][CH2:36]Cl)[C:33]#[CH:34]>C(OCC)(=O)C>[CH3:8][C:7]1[C:2]([O:1][CH2:36][O:35][CH2:32][C:33]#[CH:34])=[C:3]([C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[C:4](=[O:15])[O:5][C:6]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: C#CCOCCl
Reactant: Cc1cc(C)c(-c2c(O)c(C)c(-c3ccccn3)oc2=O)c(C)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOCOc1c(C)c(-c2ccccn2)oc(=O)c1-c1c(C)cc(C)cc1C
Temperature: 20 °C
Reaction time: 20 h
Yield: 82.2 %

Procedure:
6.4 g (20 mmol) of 4-hydroxy-5-methyl-6-(2-pyridyl)-3-(2,4,6-trimethylphenyl)-2-pyrone in 50 ml of ethyl acetate are introduced in the absence of moisture. 2.02 g (20 mmol) of triethylamine are added thereto at 20° C. and a solution of 2.1 g (20 mmol) of propargyloxychloromethane in 20 ml of ethyl acetate is added dropwise at 0° C. with cooling. The mixture is further stirred for 20 h at 20° C. and the reaction is followed by thin-layer chromatography. The solution is filtered off from the precipitated triethylamine hydrochloride with suction and washed with ethyl acetate. The combined mother liquors are washed twice, each time with 50 ml of half-saturated common salt solution, dried over magnesium sulfate and evaporated in vacuo. 8 g of crude product are obtained. 6.4 g (82% of theory) of 5-methyl-6-(2-pyridyl)-4-propargyloxymethoxy-3-(2,4,6-trimethylphenyl)-2-pyrone are obtained as an oil by flash chromatography on 500 g of silica gel 60 (35-70 μm) using toluene:acetone 20:1 as mobile phase.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:18][C@H:19]1[O:24][C@@H:23]([CH3:25])[CH2:22][NH:21][CH2:20]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:21]2[CH2:20][C@H:19]([CH3:18])[O:24][C@H:23]([CH3:25])[CH2:22]2)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2cccc([C@H](C)NC(=O)OC(C)(C)C)c2)C[C@H](C)O1
Yield: 38 %

Procedure:
A solution of (S)-[1-(3-bromophenyl)ethyl]carbamic acid tert-butyl ester (5 g, 16.7 mmol), cis-2,6-dimethylmorpholine (5.75 g, 3eq.), palladium acetate (5 mol %, 187 mg), 2-(di-t-butylphosphino) biphenyl (10 mol %, 498 mg), and sodium tert-butoxide (1.68 g, 1.05eq) in toluene (33 ml) was stirred at 80° C. for 1.5 hours. The solution was filtered through Celite Pad and washed with ethyl acetate. The filtrate was concentrated under vacuum and purified by flash chromatography with gradient of 20% ethyl acetate/hexane to 30% ethyl acetate/hexane over 20 minutes. The product was obtained as a yellow solid (2.12 g, 38% yield).