Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl-].[In+3].[Cl-].[Cl-].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([CH:23]1[CH2:25][CH:24]1[C:26]#[N:27])(O)[CH3:21].[CH3:28][S:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2>ClCCl>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([CH:23]1[CH2:25][CH:24]1[C:26]#[N:27])([C:36]1[C:35]2[C:39](=[C:31]([CH2:30][S:29][CH3:28])[CH:32]=[CH:33][CH:34]=2)[NH:38][CH:37]=1)[CH3:21]
Reactant: CC(O)(c1ccc(F)cc1F)C1CC1C#N
Reactant: CSCc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc(F)cc3F)C3CC3C#N)c[nH]c12

Procedure:
0.08 ml (1.08 mmol) of trifluoroacetic acid and 218 mg (0.99 mmol) of indium(III) chloride were added to 200 mg (0.90 mmol) of the compound from Example 133A and 318 mg (1.79 mmol) of the compound from Example 8A in 8 ml of dichloromethane at RT, and the mixture was heated under reflux overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 128 mg (37% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[CH:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]#[CH:15])=[CH:17]1
Reactant: C=Cc1c[nH]c2ccccc12
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c2ccccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (4.79 g) in dimethylformamide (25 ml) was added 3-ethenylindole (2.9 g) and potassium carbonate (2.84 g), the mixture was heated at 90° C. for 3 hours under an atmosphere of nitrogen and then left to stir overnight at room temperature. The reaction was diluted with water (100 ml) and extracted with hexane (2×100ml). The organic fractions were separated, combined, evaporated to dryness and purified by column chromatography on silica gel (300 g) eluted with hexane:ethylacetate (97:3) to give the title compound as a white solid (1.3 g), m.p. 120-122 ° C.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O.C(O)C>CS(C)=O>[CH3:1][N:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[C:5](=[O:7])[N:14]2[CH2:21][CH2:20][CH2:19][CH:15]2[C:8]1=[O:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: CCO
Solvent: CS(C)=O
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
The N-methyl isatoic anhydride (I) and L-proline (II) are reacted in a solvent such as ethanol or dimethyl sulfoxide at 25° to 200° C. for a period of 1 to 24 hours to produce the dextrorotatory isomer of the 1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[CH3:24][CH2:25][O:26][C:27]([CH2:29]Br)=[O:28]>O.C1COCC1>[CH3:1][C:2]1[N:3]([CH2:29][C:27]([O:26][CH2:25][CH3:24])=[O:28])[C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:10])([F:8])[F:9])[N:6]=1
Reactant: C=Cc1[nH]c(C)nc1C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1c(C(F)(F)F)nc(C)n1CC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of 2-methyl-4-(trifluoromethyl)-5-vinyl-1H-imidazole (911 mg, 5.17 mmol) was added DMF (7 mL) and THF (3 mL), followed by K2CO3 (1.43 g, 10.35 mmol) and ethyl bromo acetate (687 mL, 6.2 mmol). The resulting mixture was then stirred overnight at room temperature. Water (50 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined EtOAc layers were dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (SiO2, 60% EtOAc/hexanes) to obtain the desired ethyl 2-[2-methyl-4-(trifluoromethyl)-5-vinyl-imidazol-1-yl]acetate (796 mg, 3.03 mmol, 59% yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14][OH:15])=[CH:13][C:8]=3[O:7][C:6]=2[CH:16]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(N(CC)CC)C.C(OCC)C>C1COCC1.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14][O:15][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:13][C:8]=3[O:7][C:6]=2[CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc2c(c1)oc1cc(Br)ccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)oc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.6 %

Procedure:
To a solution of 3-bromo-7-hydroxymethyl-dibenzofuran 3 (2.74 g, 9.9 mmol) and t-butyldimethylsilyl chloride (1.93 g, 12.8 mmol) in THF (60 ml) was added triethylamine (1.95 ml, 13.8 mmol) followed by 4-dimethylaminopyridine (120.7 mg, 0.99 mmol). After stirring at room temperature for 20 hours, the solution was poured into ethyl ether (180 ml) and washed successively with saturated NH4Cl, saturated NaHCO3, H2O, and brine. Drying (MgSO4) and evaporation gave a brown solid which was purified by flash chromatography through 100 g silica gel (10% CH2Cl2 hexane) to yield 3.2 g (82%) of the title compound as a pale yellow solid.
Reaction SMILES: [BH4-].[Li+].[Br:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:7]([C:8](OC)=[O:9])=[CH:6][C:5]=1[O:16][CH3:17].C(OCC)(=O)C>O1CCCC1>[Br:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[O:16][CH3:17]
Reactant: COC(=O)c1cc(OC)c(Br)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CO)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
Lithium borohydride (20.8 g) was slowly added to a solution of methyl 4-bromo-3,5-dimethoxybenzoate (133.2 g) in tetrahydrofuran (500 mL) at room temperature, and the mixture was stirred for 3 hours while heating to reflux. The reaction mixture was cooled to room temperature, ice water (1.5 L) was added, and then ethyl acetate (1.2 L) was further added for extraction. The obtained organic extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to afford the title compound (118.8 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CSC.CO>C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[OH:11]
Reactant: Cc1cccc2c1CCC2=O
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1cccc2c1CC[C@H]2O
Temperature: -30 °C
Reaction time: 0.83 h

Procedure:
To a solution of 4-methyl-indan-1-one (5.00 g, 34.20 mmole) and (S)-2-methyl-CBS-oxazaborolidine (5.00 mL, 1.0 M in THF, 5.00 mmol) in THF at −20° C. was added borane-methylsulfide (12.00 mL, 1.0 M in THF, 12.00 mmol) over 20 minutes. The resulting mixture was then stirred for 50 minutes and cooled to −30° C. Methanol (40.00 mL) was added and the resulting mixture was gradually warmed to room temperature and concentrated to give the crude alcohol.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[CH:12]=[CH:11][N:10](C(=O)C(C)(C)C)[CH:9]=[C:8]1[CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])([CH3:4])([CH3:3])[CH3:2].[S]>C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCCC1C1=CN(C(=O)C(C)(C)C)C=CC1COC(C)(C)C
Agent: [S]
Solvent: Cc1ccccc1
Product: CN1CCCC1c1cnccc1COC(C)(C)C
Yield: 73.3 %

Procedure:
A solution of 1-[4-tert-butoxymethyl-3-(1-methylpyrrolidin-2-yl)-4H-pyridin-1-yl]-2,2-dimethyl-propan-1-one (0.194 g, 0.5 mmol), sulfur (0.02 g, 0.5 mmol) and toluene (5 mL) was refluxed for 1 day. After filtration of the mixture through a pad of Celite and evaporation of the solvent under reduced pressure, the crude material was purified by radial PLC (hexanes) to afford 0.091 g (54%) of 4-tert-butoxymethyl-3-(1-methylpyrrolidin-2-yl)-pyridine as a yellow oil. IR (thin film, neat, NaCl) 2970, 2778, 1594, 1362, 1193, 1088 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.72 (s, 1H), 8.45 (d, 1H, J 6.4 Hz), 7.40 (d, 1H, J=6.4 Hz), 4.52 (s, 2H), 3.32–3.20 (m, 3H), 2.32–2.22 (m, 2H), 2.18 (s, 3H), 1.96–1.66 (m, 4H), 1.29 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 148.3, 147.7, 146.2, 135.3, 121.4, 73.4, 65.2, 59.6, 56.5, 40.2, 33.7, 27.20, 22.4; HRMS Calcd for C15H24N2O: 249.1967 [M+H]+. Found: 249.1964 [M+H]+. [α]D28−108.2 (c 3.4, CH2Cl2).
Reaction SMILES: [CH3:1][O-].[Na+].[C:4]([O:13][CH3:14])(=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[SH:7].IC>CO>[CH3:14][O:13][C:4](=[O:12])[C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[S:7][CH3:1]
Reactant: COC(=O)c1ccccc1S
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COC(=O)c1ccccc1SC
Yield: 388 %

Procedure:
To a solution of 160 mg (2.97 mmol) of sodium methoxide in 10 mL of methanol was added at 0°, 0.4 mL (2.97 mmol) of methyl thiosalicylate, 0.37 mL (5.97 mmol) of iodomethane and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, taken up in ethyl acetate, washed with water, brine, dried over sodium sulfate, and concentrated in vacuo to give 2.10 g of the title compound.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[N:10][C:11]3[C:16]([C:17]=2O)=[CH:15][CH:14]=[CH:13][C:12]=3[C:19]([F:22])([F:21])[F:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=N[C:27]2[C:32](C=1O)=[CH:31][CH:30]=[CH:29][C:28]=2C(F)(F)F.C1(S)C=CC=CC=1.[Na].O>CN(C=O)C>[C:27]1([C:17]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Oc1c(Br)cnc2c(C(F)(F)F)cccc12
Reactant: Oc1c(Sc2ccccc2)cnc2c(C(F)(F)F)cccc12
Agent: Sc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(Sc3ccccc3)cnc12
Temperature: 120 °C
Yield: 57 %

Procedure:
3-(phenylthio)-8-(trifluoromethyl)quinolin-4-ol: A solution of 3-bromo-8-(trifluoromethyl)quinolin-4-ol (0.240 g, 0.830 mmol), sodium thiophenol (0.293 g, 45.1 mmol), is dissolved in DMF and heated in a microwave reactor for 10 min at 120° C. After which, the reaction is poured into water and extracted with ethyl acetate. The combined extracts are washed with sat aq NaHCO3, water, brine, and dried with magnesium sulfate. The extracts are concentrated and the residue is chromatographed with 1:9 ethyl acetate:hexanes to afford the title compound as a white solid (0.151 g, 57%). mp 153-155° C.; MS (ESI) m/z 322; MS (ESI) m/z 320; HRMS: calcd for C16H10NF3OS+H, 322.05134; found (ESI, [M+H]+), 322.0486.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])(C)C)=[O:2].[CH3:17][N:18]([O:27][CH3:28])[C:19](=[O:26])[C@H:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH2:21].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:13][CH:11]([CH2:10][C@H:9]([NH:8][C:1]([O:3][CH2:4][C:7]1[CH:24]=[CH:23][CH:22]=[CH:20][CH:19]=1)=[O:2])[C:14]([OH:16])=[O:15])[CH3:12].[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12].[CH3:17][N:18]([O:27][CH3:28])[C:19](=[O:26])[C@H:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH2:21]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CON(C)C(=O)[C@@H](N)CC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-Boc-L-leucine-L-leucine N,O-dimethylhydroxylamide (923 mg) and trifluoroacetic acid (10 mL) in methylene chloride (20 mL) was stirred at 0° C. for 3 hours. The solvent was evaporated under reduced pressure and the residue was dried under vacuum. A portion of this product (488 mg) was transferred to another flask and was combined with Z-L-leucine (451 mg), 1-hydroxybenzotriazole monohydrate (276 mg), N-methylmorpholine (0.22 mL), and DMF (15 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (357 mg) was then added at 0° C. The mixture was stirred at 0° C. for 2 h, then at room temperature for 42 h. The reaction was quenched with water (50 mL) and the mixture was extracted with EtOAc (3×60 mL). The combined organic layers were washed with aqueous 10% HCl, saturated NaHCO3, and brine, then dried over anhydrous MgSO4, filtered, and evaporated to afford the product as a white solid. This was further purified by silica gel chromatography (hexane/acetone 80:20, 70:30) to give the title compound (546 mg) as a white solid.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[CH2:17]([O:19][C:20](=[O:31])/[C:21](/[CH3:30])=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH3:18].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:17]([O:19][C:20]([C:21]1([CH3:30])[CH:22]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5]1)=[O:31])[CH3:18]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C(C)=C/c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (1.55 g, 6.54 mmol) in CH2Cl2 (5 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-3-(4-Chloro-phenyl)-2-methyl-acrylic acid ethyl ester (1.00 g, 4.45 mmol; preparation described in J. Org. Chem. 1966, 31: 4043-4047) and trifluoroacetic acid (0.034 mL, 0.44 mmol) in CH2Cl2 (10 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 24 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:8) afforded 0.85 g (54%) of the title compound as a colorless oil. ES-MS m/e: 358.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:9](Br)=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)[NH:25][C@H:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]#[CH:33])[C:27]1=[O:34])C1C=CC=CC=1>>[C:1]([O:5][C:6]([N:7]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:33]=[C:32]1[CH2:31][N:28]1[CH2:29][CH2:30][C@H:26]([NH2:25])[C:27]1=[O:34])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Br
Reactant: C#CCN1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Product: CC(C)(C)OC(=O)n1c(CN2CC[C@H](N)C2=O)cc2ncccc21

Procedure:
The title compound is prepared from (2-bromo-pyridin-3-yl)-carbamic acid tert-butyl ester (1.6 g, 5.9 mmol) and (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl carbamic acid benzyl ester (1.6 g, 5.9 mmol) according to the methods described in EXAMPLE 59, Parts C,D and E. The title compound was obtained as a white solid (0.29 g, 0.88 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH3:16])[N:9]=1.CO>C(=O)=O>[CH3:29][C:2]1([CH3:1])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH3:16])[N:9]=1.[CH3:29][C:2]1([CH3:1])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH3:16])[N:9]=1
Reactant: CC(Nc1nccc(N2C(=O)OCC2(C)C)n1)c1ccc(N2CCCCC2)cc1
Agent: O=C=O
Solvent: CO
Product: C[C@@H](Nc1nccc(N2C(=O)OCC2(C)C)n1)c1ccc(N2CCCCC2)cc1
Product: C[C@H](Nc1nccc(N2C(=O)OCC2(C)C)n1)c1ccc(N2CCCCC2)cc1

Procedure:
4,4-dimethyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (example 183, 70 mg) was resolved on a column (IA 4.6×100 mm) using 40% MeOH in CO2 to give (S)-4,4-dimethyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4,4-dimethyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=O)[C:10](OC)=[O:11])=[CH:5][CH:4]=1.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1.CS(O)(=O)=O>O(C1C=CC=CC=1)C1C=CC=CC=1>[OH:11][C:10]1[C:35]2[C:25](=[CH:26][CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:34]=2)[N:24]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COC(=O)C(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CS(=O)(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)c(O)c2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
Methyl 2,3-bis(4-methoxyphenyl)-3-oxopropanoate (1.3 g, 4.14 mmol, 1.00 equiv), ethyl 4-aminobenzoate (680 mg, 4.12 mmol, 1.00 equiv), CH3SO3H (118 mg, 1.23 mmol, 0.30 equiv), and Ph2O (20 mL) were placed in a 100-mL round-bottom flask stirred for 1 h at 90° C., then at 180° C. for 3 h, in an oil bath. Upon cooling, 100 ml of petroleum ether was added. The resulting solid was collected by filtration and dried in a vacuum oven, affording 1.1 g (crude) of ethyl 4-hydroxy-2,3-bis(4-methoxyphenyl)quinoline-6-carboxylate as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:31][CH2:32][CH2:33]O)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:31][CH2:32][CH2:33][NH:44][S:41]([CH3:40])(=[O:43])=[O:42])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: CS(=O)(=O)Cl
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one by treatment with (i) MeSO2Cl and (ii) MeSO2NH2. LC-MS Method 2 tR=1.02 min, m/z=542.3; 1H NMR (CDCl3) 1.35 (m, 1H), 1.53 (d, 3H), 1.69 (m, 1H), 1.89 (m, 1H), 2.00 (m, 1H), 2.17-2.33 (m, 3H), 2.89 (s, 3H), 2.97 (m, 1H), 3.06 (m, 2H), 3.66 (s, 3H), 4.38 (s, 1H), 5.67 (m, 1H), 6.82 (d, 1H), 6.99 (m, 4H), 7.15 (m, 2H), 7.22 (m, 2H), 7.47 (s, 1H), 7.63 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:19]CC4C=CC(OC)=CC=4)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:29]#[N:30])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][N:15]=1)[N:12]=[CH:11][C:10]([C:29]#[N:30])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COc1ccc(CNc2cc3c(Nc4cccc(Br)c4)c(C#N)cnc3cn2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc2cnc(N)cc2c1Nc1cccc(Br)c1
Reaction time: 20 h
Yield: 84.6 %

Procedure:
To 400 mg of 4-(3-bromo-phenylamino)-6-(4-methoxy-benzylamino)-[1,7]naphthyridine-3-carbonitrile in 10 mL of methylene chloride was added 10 mL of trifluoroacetic acid. After stirring under an inert atmosphere for 20 hours, 10 mL of toluene was added and the solvents were stripped on a rotary evaporator. The product was purified by flash chromatography with a gradient of 0-5% methanol/chloroform to give 250 mg of 6-amino-4-(3-bromo-phenylamino)-[1,7]naphthyridine-3-carbonitrile as an off-white solid: melting point 185-190° C. (decomposed); mass spectrum (m/e): M+H 340.0, 342.1.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]=2[N:3]=1.[Cl:19]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[Cl:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]=2[N:3]=1
Reactant: Oc1nc2c3ccccc3sc2c2ccccc12
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Product: Clc1nc2c3ccccc3sc2c2ccccc12

Procedure:
The procedure was similar to step S19C, while the starting material was 23B in stead of 19B.
Reaction SMILES: [F-:1].[Cs+].S([O:8][CH3:9])(OC)(=O)=O.FC1(F)[C:16]([F:18])([F:17])[C:15]([F:20])([F:19])[C:14]([F:22])([F:21])[C:13]([F:24])([F:23])C1=O>COCCOCCOC.O>[C:16]([O:8][CH3:9])([C:15]([C:14]([C:13]([F:23])([F:24])[F:1])([F:21])[F:22])([F:19])[F:20])([F:17])[F:18]
Reactant: COS(=O)(=O)OC
Reactant: [F-]
Reactant: O=C1C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Agent: [Cs+]
Solvent: COCCOCCOC
Solvent: O
Product: COC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 18 h

Procedure:
A 500 ml, 3-necked round bottom flask equipped with an overhead stirrer, an addition funnel, and a condenser was charged with anhydrous cesium fluoride (27.4 g, 0.18 mole), anhydrous diethylene glycol dimethyl ether (258 g, hereinafter diglyme), and dimethyl sulfate (22.7 g, 0.18 mole). Perfluorocyclohexanone (50 g, 0.18 mole) was then added dropwise to the resulting stirred mixture, and stirring was continued for 18 hours after the addition. Water (approximately 200 ml) was added to the resulting mixture, and the lower fluorochemical phase of the mixture was separated from the upper phase and washed once with saturated aqueous sodium chloride solution. Since the fluorochemical phase still contained about 12% diglyme, water was added to it, and the resulting product was azeotropically distilled to yield 32.8 g of c-C6F11OCH3 (b.p.=100° C.), which was free of diglyme. The product identity was confirmed by IR, GCMS, and 1H and 19F NMR.
Reaction SMILES: [Mg].[F:2][C:3]([F:16])([F:15])[C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[CH3:17][C:18]([CH3:20])=[O:19].[Cl-].[NH4+]>C(OCC)C>[F:2][C:3]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([C:18]([OH:19])([CH3:20])[CH3:17])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: CC(C)=O
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 99.2 %

Procedure:
16.10 g (0.659 mol) of magnesium turnings was treated under argon in 450 ml of diethyl ether with 150 g (0.507 mol) of 3,5-bis-trifluoromethylbromobenzene at 33° C. for 1.5 h. Then a solution of 56.0 ml (0.763 mol) of acetone in 100 ml of diethylether was added at 16-22° C. under stirring. 110 ml of 25% Ammonium chloride solution was added at ca. 20° C. after 1.5 h to the reaction mixture and the suspension stirred for 1 h. The organic phase was dried over sodium sulfate, rotary evaporated and finally dried at 35° C. and 10 mbar, affording 136.96 g of 2-(3,5-bis-trifluoromethyl-phenyl)-propan-2-ol, which had a 99.2% purity according to GC analysis. Light yellow crystals, m.p. 59-60° C.