Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[O:2]=[C:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N:18]1[CH:23]=NC=N[CH:19]=1>C(O)C>[CH2:11]([C:10]1[C:3](=[O:2])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:23][NH:18][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ncncn1
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1c[nH]cc(Cc2ccccc2)c1=O
Reaction time: 8 h
Yield: 71.2 %

Procedure:
To a solution of sodium (0.5835 g, 25.4 mmol) in ethanol (18 ml) under nitrogen, was added ethyl 3-oxo-5-phenylpentanoate (5.5752 g, 25.3 mmol) in ethanol (5 ml) and 1,3,5-triazine (2.0544 g, 25.3 mmol). The mixture was heated at reflux for 1 h, then allowed to cool. The solvent was removed in vacuo, and water (15 ml) was added to the residue. The pH was brought to 4 by the addition of concd HCl (3 ml) and the mixture was left overnight. The resulting solid was collected by filtration, washed with ethanol and dried under vacuum at 60° C. to yield 4.6324 g (71%) of the title compound as a buff solid; 1H NMR (360 MHz, DMSO-d6) δ1.24 (3H, t, J 7.1 Hz), 3.64 (2H, s), 4.16 (2H, q, J 7.1 Hz), 7.15-7.28 (5H, m), 7.53 (1H, s), 8.18 (1H, s), 11.64 (1H, br s).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:11][C:12]1[CH:13]=[C:14](O)[CH:15]=[CH:16][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[I:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=1
Reactant: OCCCc1ccccc1
Reactant: Oc1cccc(I)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1cccc(OCCCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
In a 100 mL round-bottom flask was placed 3-phenyl-1-propanol (2.00 g, 14.7 mmol, 1.5 equiv.), 3-iodophenol (2.16 g, 9.82 mmol) , triphenylphosphine (3.85 g, 14.7 mmol, 1.5 equiv.) and THF (40 mL). The mixture was stirred in a small ice bath. Neat diethyl azodicarboxylate (2.30 mL, 14.6 mmol, 1.5 equiv.) was added over a period of 30 min. The mixture was stirred in the ice bath for 20 h, then the bath was removed, and stirring was continued for 24 h at room temperature. The resulting mixture was concentrated under vacuum and diluted with EtOAc (200 mL). The solution was washed with brine (60 mL) and dried over Na2SO4. After evaporation, the residue was chromatographed on silica gel with EtOAc/petroleum ether 1:50. This resulted in 3.30 g (99%) of 1-iodo-3-(3-phenylpropoxy)benzene as light-yellow oil. 1H NMR (CDCl3, TMS, 300 MHz) δ 7.34-7.25 (m, 7H), 6.98 (t, 1H, J=8.0 Hz), 6.84 (dd, 1H, J=2.0, 8.2 Hz), 3.92 (t, 2H, J=6.5 Hz), 2.79 (t, 2H, J=7.7 Hz), 2.08 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:27]Br>>[F:22][C:23]([F:36])([F:37])[C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=1)[CH2:27][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 49.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-bis(trifluoromethyl)benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (255 mg, yield: 49.8%).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[F:23][C:24]([F:31])([F:30])[C:25]1[NH:29][N:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([N:28]4[CH:27]=[CH:26][C:25]([C:24]([F:31])([F:30])[F:23])=[N:29]4)[C:3]3=[O:22])[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(F)cc1
Reactant: FC(F)(F)c1ccn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(N2CCC(n3ccc(C(F)(F)F)n3)C2=O)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 81 %

Procedure:
A mixture of 3-bromo-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.015 g, 0.041 mmol), 5-(trifluoromethyl)-1H-pyrazole (0.030 g, 0.22 mmol) and K2CO3 (0.030 g, 0.22 mmol) in DMF (0.5 mL) was stirred at 60° C. for 40 min. The mixture was then cooled to room temperature, quenched with water (30 mL), extracted with EtOAc (50 mL), and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to yield the title compound (0.014 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J=1.6 Hz, 1H), 7.57 (s, 1H), 7.38 (dd, J=8.8, 4.8 Hz, 2H), 7.18 (dd, J=8.4, 8.4 Hz, 2H), 6.58 (d, J=2.4 Hz, 1H), 5.07 (dd, J=8.8, 7.2 Hz, 1H), 4.03 (m, 1H), 3.82 (m, 1H), 2.97 (heptet, J=7.6 Hz, 1H), 2.84 (m, 2H), 1.20 (d, J=7.2 Hz, 3H), 1.12 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C20H19F4N5O [M+H]+ 422.1. found 422.1.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:13]([N:16]1[CH2:24][CH2:23][CH:19]([C:20](Cl)=[O:21])[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>C(=S)=S>[C:13]([N:16]1[CH2:17][CH2:18][CH:19]([C:20](=[O:21])[C:8]2[CH:9]=[CH:10][C:5]([O:11][CH3:12])=[CH:6][CH:7]=2)[CH2:23][CH2:24]1)(=[O:15])[CH3:14]
Reactant: COc1ccccc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)cc1
Yield: 58.9 %

Procedure:
To a suspension of aluminum trichloride (3.40 g, 25.7 mmol) in CS2 (15 mL) were added anisole (1.90 mL, 17.6 mmol) and, portionwise, N-acetylisonipecotoyl chloride (2.40 g, 11.7 mmol). After the addition was complete, the mixture was refluxed for 1 h. The solvent was decanted and the red residue was dissolved in 5% HCl (50 mL) and was extracted with EtOAc (4×30 mL). The combined organic phase was dried and was concentrated under reduced pressure to afford the title compound as a colorless solid (1.8 g, 60%): mp 102-105° C.; 1H NMR (CDCl3) d 1.50-1.75 (m, 1H), 1.70-2.00 (m, 3H), 2.10 (s, 3H), 2.70-2.90 (m, 1H), 3.15-3.30 (m, 1H), 3.40-3.53 (m, 1H), 3.86 (s, 3H), 3.85-4.00 (m, 1H), 4.56 (d, J=13.2 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.92 (d, J=9.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=S)[NH:13][S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[N:4]=1.CC(C)=[O:26]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:13][S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[O:26])[N:4]=1
Reactant: CC(C)=O
Reactant: COc1nc(NC(=S)NS(=O)(=O)c2cccnc2)nc(OC)n1
Product: COc1nc(NC(=O)NS(=O)(=O)c2cccnc2)nc(OC)n1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture containing 2.7 g of N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)aminothioxomethyl]-3-pyridinesulfonamide, 2.98 g of mercuric oxide and 75 ml of acetone was stirred at ambient temperature for 60 hours and then filtered. Evaporation of the filtrate in vacuo yielded the desired product as a residual white solid of m.p. 182°-185° dec.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2
Reactant: O=C1Cc2c(cccc2[N+](=O)[O-])N1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1CC(=O)N2
Reaction time: 3 h
Yield: 75.5 %

Procedure:
A catalytic amount of 10% palladium-on-carbon is added to a solution of 4-nitrooxindole (0.889 g, 4.99 mmol) in methanol (100 mL). The suspension is degassed three times and placed under an atmosphere of hydrogen for 3 hours. The suspension is filtered through a pad of Celite and the Celite is washed several times with methanol. The methanol from the filtrate is removed by rotary evaporation. The resulting residue is purified via silica gel column chromatography using 3% methanol/methylene chloride as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.558 g of 4-aminooxindole as a light orange solid (76%).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]5[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=5[F:37])[CH:28]=4)[N:23](C(OC(C)(C)C)=O)[CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:37][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:30]=1[C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[C:19]1[N:20]=[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10]2)[CH:16]=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCCN(c2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 5-(2,6-difluorophenyl)-3-iodo-1H-indole-1-carboxylate (350 mg, 0.769 mmol), tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-3-ylcarbamate (436 mg, 0.769 mmol), Pd(PPh3)4 (89 mg, 0.077 mmol), and CuI (15 mg, 0.077 mmol) in DMF (6 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 30 min. The mixture was diluted with DCM and water. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated to give the crude product, tert-butyl 3-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate. MS (ESI, pos. ion) m/z: 606 (M+1). To a solution of tert-butyl 3-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate (466 mg, 0.769 mmol) in DCM (6 mL) was added TFA (4 mL) and the reaction was stirred at RT for 3 h, then solvent was removed. The residue was diluted with DCM and washed with saturated NaHCO3 aqueous solution twice. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified with RP-HPLC to give 1-(6-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-3-amine as a light brown solid. MS (ESI, pos. ion) m/z: 406 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][CH:8]=[C:9]([S:10](Cl)(=[O:12])=[O:11])[C:5]=2[CH:4]=1.[NH3:16]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][CH:8]=[C:9]([S:10]([NH2:16])(=[O:12])=[O:11])[C:5]=2[CH:4]=1
Reactant: COc1ccc2scc(S(=O)(=O)Cl)c2c1
Reactant: N
Solvent: C1CCOC1
Product: COc1ccc2scc(S(N)(=O)=O)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-methoxy-benzo[b]thiophene-3-sulfonyl chloride(0.80 g, 3.08 mmol) in THF (20 mL) was added ammonia gas until saturation at ca. 10° C., then the flask was stoppered, and the reaction mixture was stirred at rt for 4 h. The reaction mixture was then quenched with water; the organic solvent was slowly evaporated under vacuum. The precipitate formed was filtered off, washed with water and dried over P2O5 under high vacuum to obtain the desired compound (0.64 g) as a yellowish solid. MS (ISN): m/e 239.4 (M−H)−
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:22][C:17]1[CH:16]=[C:15]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH:20]=[CH:19][C:18]=1[OH:21]
Reactant: Oc1ccc(Br)cc1F
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)c(F)c2)cc1
Yield: 61.4 %

Procedure:
3-Fluoro-4′-(methylsulfonyl)-4-biphenylol (0.42 g, 62%) was prepared as an off-white solid from [4-(methylsulfonyl)phenyl]boronic acid (0.58 g, 2.82 mmol), 4-bromo-2-fluorophenol (0.5 g, 2.57 mmol), 2M Na2CO3 (15 mL) and Pd(PPh3)4 (30 mg 0.03 mmol) in DME (15 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 2H, J=8.6 Hz), 7.70 (d, 2H, J=8.5 Hz), 7.40-7.30 (m, 2H), 7.11 (t, 1H, J=8.6 Hz), 5.22 (d, 1H, J=4.1 Hz), 3.08 (s, 3H); LRMS (APCI), m/z 267 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:11]([CH2:12][OH:13])=[CH:10]2
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Reactant: C1COCCN1
Product: Cc1cccc2cc(CO)c(N3CCOCC3)nc12
Yield: 80 %

Procedure:
Following the procedure described for Intermediate 60, (2-chloro-8-methyl-quinolin-3-yl)methanol (200 mg, 0.97 mmol) and morpholine (2 mL) gave the title compound (200 mg, 80%). δH (CDCl3) 7.99 (1H, s), 7.57 (1H, d, J=8.1 Hz), 7.48 (1H, d, J=7.0 Hz), 7.35-7.26 (1H, m), 4.87 (2H, s), 3.93 (4H, t, J=4.6 Hz), 3.58 (1H, s), 3.35 (4H, t, J=4.6 Hz), 2.72 (3H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][CH:24]=2)([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=2)[CH2:10][C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1)=[CH2:2].[OH-].[Li+].Cl>O1CCOCC1>[CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:8][CH:7]=2)([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=2)[CH2:10][C:11]([OH:13])=[O:12])=[CH:28][CH:27]=1)=[CH2:30]
Reactant: C=Cc1ccc(C(CC(=O)OC)(c2ccc(C=C)cc2)c2ccc(C=C)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=Cc1ccc(C(CC(=O)O)(c2ccc(C=C)cc2)c2ccc(C=C)cc2)cc1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
Fifty-four (54) mg of methyl 3,3,3-tris(4-vinylphenyl)-propionate was suspended in 0.5 ml of dioxane, and to the suspension 0.5 ml of 4N aqueous lithium hydroxide solution was added at room temperature, followed by 17 hours' stirring at 90° C. under heating. The reaction liquid was made acidic by addition of 1N hydrochloric acid, extracted with chloroform and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 52.5 mg of the title compound was obtained.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[C:7]([O:15][C:16]1[CH:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(C)=O>[C:7]([O:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][C:17]=1[O:24][CH3:25])[C:22]([OH:2])=[O:23])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(C=O)cc1OC(=O)c1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)O)cc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of potassium permanganate (28 g) in acetone (200 mL) is treated with 2-methoxy-5-formylphenyl benzoate (35.2 g; that is prepared as described in Reference Example 8), and the resulting vigorously reacting mixture is cooled in an ice bath. It is then stirred at room temperature for 3 hours. The mixture is then concentrated and the residue is treated with saturated aqueous sodium metabisulfite solution (300 mL). The resulting white solid is filtered off, washed well with water (200 mL), and dried, to give 3-benzoyloxy-4-methoxy-benzoic acid (29.3 g), m.p. 180-183° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].S(Cl)([Cl:13])(=O)=O>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Cl:13][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: CCc1ccc(O)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1ccc(O)c(Cl)c1
Temperature: 70 °C
Yield: 76.3 %

Procedure:
A solution of 4-ethylphenol (25.4 g, 0.21 mol) and sulfuryl chloride (18.5 ml, 0.23 mol) in carbon tetrachloride (40 ml) was stirred under heating at 70° C. for 3 hr. The reaction mixture was diluted with chloroform and washed with water. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2-chloro-4-ethylphenol (25.1 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[O:24][C:23]([C:25]5([NH:33]C(=O)OC(C)(C)C)[CH2:30][O:29]C(C)(C)[O:27][CH2:26]5)=[CH:22][C:21]=4[CH:41]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].CCO>C(Cl)Cl>[NH2:33][C:25]([C:23]1[O:24][C:20]2[CH:19]=[CH:18][C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH3:11])=[C:2]([Cl:1])[CH:3]=4)[O:16][N:15]=3)=[CH:41][C:21]=2[CH:22]=1)([CH2:26][OH:27])[CH2:30][OH:29]
Reactant: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCOc1ccc(-c2nc(-c3ccc4oc(C(N)(CO)CO)cc4c3)no2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a stirred solution of product of Step D (0.1 g, 0.17 mmol) in CH2Cl2 (0.5 ml) TFA (1 ml) was added. After stirring for 1 h at room temperature, EtOH (2 ml) was added and stirring was continued for additional 1 h. The mixture was evaporated to dryness and the residue was purified by FCC (SiO2, CH2Cl2 saturated with concentrated NH4OH/MeOH; 98:2) to give the title product (0.035 g, 46%) as colourless solid. 1H-NMR (DMSO-d6) 8.3 (d, 1H, J=1.11 Hz); 8.15 (d, 1H, J=2.01 Hz); 8.09 (dd, 1H, J=8.67, 2.04 Hz); 7.94 (dd, 1H, J=8.58, 1.53 Hz); 7.68 (d, 1H, J=8.61 Hz); 7.37 (d, 1H, J=8.76 Hz); 6.92 (s, 1H); 4.91 (b, 2H); 4.14 (t, 2H, J=6.36 Hz); 3.69 (d, 2H, J=10.6 Hz); 3.59 (d, 2H, J=10.6 Hz); 1.83-1.72 (m, 2H); 0.97 (t, 3H, J=7.41 Hz).
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:12][CH2:11][C@@H:6]2[CH2:7][O:8][CH2:9][CH2:10][N:5]2[CH2:4]1.[C:13]([O-:16])(=[O:15])[CH3:14].[K+]>CN(C=O)C>[C:13]([O:16][CH2:2][CH:3]1[O:12][CH2:11][CH:6]2[CH2:7][O:8][CH2:9][CH2:10][N:5]2[CH2:4]1)(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: ClC[C@H]1CN2CCOC[C@H]2CO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCC1CN2CCOCC2CO1
Temperature: 140 °C
Reaction time: 16 h
Yield: 41.5 %

Procedure:
A suspension of (3R,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine (1.97 g, 10.3 mmol) and potassium acetate (10.1 g, 102 mmol) in DMF (20.0 mL) was stirred at 140° C. for 16 h, and then at 150° C. for another 12 h. The reaction mixture was partitioned between water (250 mL) and ethyl acetate (250 mL), the organic layer was washed with 5% lithium chloride (2×100 mL) and brine (100 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. Column chromatography (SiO2, 1:1 hexane:ethyl acetate, then 100% ethyl acetate) afforded 0.92 g (42%) of hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate as a yellow oil. Distinct diastereomers as described above were converted in this step to give: (3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate: 1H NMR (400 MHz, CDCl3): 4.18 (dd, 1H), 4.00 (m, 1H), 3.80 (dd, 1H), 3.68 (dt, 1H), 3.60 (dd, 1H), 3.46 (m, 2H), 3.22 (t, 1H), 2.64 (dd, 1H), 2.53 (m, 2H), 2.43-2.35 (m, 2H), 2.10 (s, 3H), and (3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate: 1H NMR (400 MHz, CDCl3): 4.09 (d, 2H), 3.90-3.82 (m, 2H), 3.75-3.64 (m, 3H), 3.27 (t, 1H), 3.18 (t, 1H), 2.69 (dd, 1H), 2.63 (m, 1H), 2.46-2.33 (m, 2H), 2.16 (t, 1H), 2.10 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[C:7](=O)([O:10]C)[O:8][CH3:9]>C[O-].[Na+].CO>[C:7](=[O:10])([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[O:8][CH3:9]
Reactant: COC(=O)OC
Reactant: OCC(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)OCC(F)(F)F
Temperature: 100 °C
Yield: 32.8 %

Procedure:
In a flask (3-liter volume) equipped with 10 distillation columns, 2,2,2-trifluoroethanol (790 g, 7.9 ml), dimethyl carbonate (2140 g, 23.7 mol) and a 28% sodium methoxide/methanol solution (15.3 g) were charged. The flask was heated to 100° C. to allow the starting materials to react for 30 hours while removing the methanol from the distillation columns by evaporation. After allowing the mixture to cool to room temperature, an aqueous solution of ammonium chloride was added to the mixture and the mixture was shaken to remove the sodium methoxide. The organic layer was washed with water, dried and distilled to give methyl 2,2,2-trifluoroethyl carbonate as a colorless liquid (410 g, yield 33%). The chemical structure of the produced compound was determined based on the IR and NMR absorbance spectra shown in FIG. 3 and FIG. 4 respectively and the mass spectrometry spectrum (M/e=158).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C(C)(C)C)=[C:5]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH:4]=1.C(=O)(O)[O-].[Na+]>C(COC)OC>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][C:5]=1[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ccc(Cl)cc1C(=O)C(F)(F)F

Procedure:
6N Hydrochloric acid (6.0M, 257 mmol) was added to N-[4-chloro-2-(trifluoroacetyl)phenyl]-2,2-dimethylpropanamide (3.3 g, 10.7 mmol) in anhydrous dimethoxyethane (40 ml) at room temperature and mixture was heated to reflux conditions for two hours until no starting material was observed by LC/MS. After cooling reaction to 0° C., reaction was basified to pH 9 by adding solid sodium bicarbonate in portions. Reaction was extracted with ethyl acetate (3×150 ml), and combined organic extracts were dried over MgSO4 and Na2SO4. After filtering mixture, the collected filtrate was concentrated in vacuo to give a crude yellow solid. Flash chromatography of the crude solid on silica gel (0-25% ethyl acetate/hexanes) afforded 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.70 (m, 1H), 7.32 (dd, J=2.4 and 9.2 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.46 (s, 2H). MS (Electrospray): m/z 223.9 (M+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[C:5]2[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH2:35])[CH:29]=1>C1(C)C=CC=CC=1.C(O)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[C:5]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:35][CH2:34][C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[CH:3]=2)[N:8]=1
Reactant: NCc1cccnc1
Reactant: COc1ccccc1CNc1cc(-c2cccnc2)c2cc(Cl)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COc1ccccc1CNc1cc(-c2cccnc2)c2cc(NCc3cccnc3)ccc2n1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
(6-Chloro-4-pyridin-3-yl-quinolin-2-yl)-(2-methoxy-benzyl)-amine (185 mg, 0.492 mmol) was dissolved in 5 mL toluene and 1 mL tert. butanol. Argon was bubbled through the solution for 2 minutes to remove oxygen. 3-Picolylamine (160 mg, 1.48 mmol), sodium tert.-butylate (95 mg, 0.99 mmol), palladium acetate (6 mg, 0.027 mmol) and 2-dicyclohexyl-phosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos, 23 mg, 0.05 mmol) were added. The reaction mixture was stirred in a sealed tube at 130° C. for 16 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The title compound was obtained as a yellow foam (105 mg, 47%), MS: m/e=448.3 (M+H+).