Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].[NH2:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][CH2:32][CH:28]([NH2:27])[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: NC1CCNC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Product: Nc1c(F)c(N2CCC(N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 71 %

Procedure:
The condensation of 5-amino-1-(2′,4′-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 3-aminopyrrolidine was carried out in a similar manner as described in example 1, gave the titled product. Yield 71%, m.p 268° C. (d), C20H16F4N4O3, m/z 437 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:22]C)[CH:21]=1)[C:5]([N:7]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:6].B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:5]([N:7]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:6]
Reactant: CCCN(C(=O)c1cc(Cl)cc(OC)c1)c1cc(F)cc(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCCN(C(=O)c1cc(O)cc(Cl)c1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirred solution of 3-chloro-N-(3,5-difluoro-phenyl)-5-methoxy-N-propyl-benzamide (0.164 g) in anhydrous dichloromethane (5 ml) at −78° C. was added 1M boron tribromide solution in dichloromethane (3.5 ml). The reaction mixture was stirred at this temperature for 15 min. The reaction was allowed to warm to room temperature, and after 3.5 h the reaction was cooled to −78° C. and methanol (6 ml) added. The reaction was allowed to rewarm to room temperature and the solvent removed in vacuo. The residue was purified by flash column chromatography eluting with cyclohexane:ethyl acetate (3:1 v/v) to give the title compound as a colourless oil (0.110 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24]([O:26]CC)=[O:25])[N:20]=[CH:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24]([OH:26])=[O:25])[N:20]=[CH:21]3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C(=O)O)ncc3c2)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
A mixture of ethyl 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)isoquinoline-3-carboxylate (385 mg, 1 mmol) and NaOH (2M) (5 mL) in EtOH (15 mL) and THF (15 mL) was stirred at 60° C. for 5 h. The mixture was concentrated to a residue, to which was added aq.sat. citric acid (10 mL). The solution was extracted with EA (25 ml×2), separated, dried, filtered and concentrated to yield 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)isoquinoline-3-carboxylic acid (303 mg, 85%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[O:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15](OCC)=[O:16])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[O:10][C:11]=2[CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nccn1-c1nc(-c2ccc(Cl)s2)c(CCCCO)o1
Reaction time: 1 h

Procedure:
Ethyl 4-(5-chloro-2-thienyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanoate (1.80 g) was dissolved in 20 ml of tetrahydrofuran, to which was added gradually lithium aluminum hydride (210 mg) under ice-cooling. The resulting mixture was stirred for 1 hour. Water (0.5 ml) was carefully added to the reaction mixture, the resulting mixture was filtered, and the residue on the filter paper was washed with ethyl acetate. The filtrate was concentrated to give crystals of 4-(5-chloro-2-thienyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol. Recrystallization from hexane-ethyl acetate gave pale yellow prisms (497 mg, 31%). Melting point 77-79° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][CH:8]1[CH2:12][CH2:11]C(C)O1.[OH-].[Na+]>C(O)(=O)C>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[N:1]1[CH:11]=[CH:12][CH:8]=[CH:7]1
Reactant: CC1CCC(C)O1
Reactant: Nc1nccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1ccn(-c2nccs2)c1

Procedure:
A mixture of 55.5 g (0.5 mole) 2-aminothiazole (90% pure) and 66 g (0.5 mole) 2,5-dimethyltetrahydrofuran is placed in a 1-liter 3-neck flask equipped with a stirrer, addition funnel, thermometer, and condenser, and 200 ml glacial acetic acid is added dropwise with stirring while maintaining the temperature below 20°C. After stirring for an additional 15 minutes, the reaction mixture is refluxed for 30 minutes and then cooled, made basic (pH 9-10) with 375 ml 30% sodium hydroxide, and steam-distilled to yield 1500 ml distillate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[C:15](Cl)=[CH:14][C:13]([NH2:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O>[Cl:9][C:10]1[C:15]([S:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=2)=[CH:14][C:13]([NH2:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Cc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(Sc2cc(N)c([N+](=O)[O-])cc2Cl)c1
Temperature: 90 °C
Yield: 80.8 %

Procedure:
A mixture of 3-methyl-benzenethiol (2.30 mL, 19.3 mmol), 4,5-dichloro-2-nitro-phenylamine (2.00 g, 9.66 mmol), potassium carbonate (2.67 g, 19.3 mmol), and DMF (48 mL) was heated at 90° C. for 16 h. The reaction mixture was cooled to 23° C. EtOAc was added and the organic layer was washed with saturated aqueous NaHCO3 (2×80 mL) and brine (1×80 mL). The aqueous layers were extracted with EtOAc (3×80 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-100% EtOAc/hexanes) to yield the titled compound (2.30 g, 81%). 1H NMR (400 MHz, CDCl3): 8.12 (s, 1H), 7.41-7.36 (m, 3H), 7.34-7.30 (m, 1H), 5.95 (s, 1H), 5.88 (br s, 2H), 2.41 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:13][C:14](=[CH:16][CH2:17][CH2:18]/[C:19](=[CH:21]/[CH2:22]O)/[CH3:20])[CH3:15].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:22]/[CH:21]=[C:19](\[CH3:20])/[CH2:18][CH2:17][CH:16]=[C:14]([CH3:15])[CH3:13])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1C(=O)O
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccccc1C(=O)OC/C=C(\C)CCC=C(C)C
Reaction time: 75 h
Yield: 77.5 %

Procedure:
A solution of 6.49 g (39.0 mmol) 2-acetylbenzoic acid, 3.81 g (31.2 mmol) DMAP and 12.32 g (80.0 mmol) geraniol in 60 ml dichloromethane was cooled in an ice bath before adding a solution of 8.84 g (42.9 mmol) DCC in 40 ml dichloromethane for 5 min. The reaction mixture was maintained with stirring at 40° for 75 h. The precipitate formed during the reaction was filtered and the filtrate washed with HCl (10%, 2×) and with a saturated Na2CO3 solution (2×). The organic phase was dried (Na2SO4) and concentrated. The excess geraniol was distilled, and the residue chromatographed (SiO2, 9:1 toluene/ethyl acetate) to give 9.08 g (78%) of the desired compound in the form of a slightly yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]1.[C:17]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26](O)=[O:27])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:12][C:10]1([CH3:11])[C:13]([CH3:15])([CH3:14])[O:16][B:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:26]([C@@H:25]2[CH2:29][CH2:30][CH2:31][N:24]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:27])[O:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Temperature: 60 °C

Procedure:
To 2-aminophenylboronic acid pinacol ester a (3.0 g, 0.014 mol) and N-Boc-L-proline b (3.0 g, 0.014 mol) in N,N-dimethylformamide (15 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.6 g, 0.014 mol), 1-hydrozybenzotriazole (1.9 g, 0.014 mol), and then N,N-diisopropylethylamine (2.4 mL, 0.014 mol). The reaction was heated to 60° C., stirred several days, cooled to room temperature, and then quenched by the addition of a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude residue was purified by ISCO chromatography (80 g column, 0 to 80% EtOAc/Hexanes) to give (S)-tert-butyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamoyl)pyrrolidine-1-carboxylate c (2.87 g, 49%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:5]([O:4][C:2]([NH:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC1CCC(C(=O)O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NC1CCC(C(=O)O)CC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
Benzyl chloroformate (2.2 mL, 15.4 mmol) was added to a solution of 4-amino-cyclohexanecarboxylic acid (2 g, 14.0 mmol) in a mixture of 1,4-dioxane (5 mL) and saturated sodium bicarbonate aqueous solution (5 mL). The mixture was stirred at 0° C. for 3 hours. Dioxane was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate solution was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 2.3 g (59%) of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid as yellow oil. MS (ESP−) m/z 276.39 (M−1). 1H NMR (300 MHz, CDCl3) δ 7.34 (m, 5H), 5.09 (s, 2H), 2.24 (m, 1H), 2.04 (m, 2H), 1.83 (m, 2H), 1.44 (m, 3H), 0.97 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]1[CH2:11][O:10][C:9](=[O:12])[NH:8]1.[H-].[Na+].[Br:15][C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][C:20]=12.O>CN(C=O)C>[Br:15][C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][C:22]([N:8]3[C@@H:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:11][O:10][C:9]3=[O:12])=[N:21][C:20]=12
Reactant: Clc1ccn2ncc(Br)c2n1
Reactant: O=C1N[C@@H](c2ccccn2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OC[C@H](c2ccccn2)N1c1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a solution of (S)-4-(pyridin-2-yl)oxazolidin-2-one (0.20 g, 1.2 mmol) in DMF (20 mL) was added sodium hydride (0.049 g, 1.2 mmol) and the reaction was stirred at ambient temperature for 1 hour. 3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (0.28 g, 1.2 mmol) was added and the reaction stirred for an additional 1 hour. The reaction was then poured into water (100 mL) and extracted into ether (200 mL). The organic layer was washed with water (100 mL), dried over MgSO4 and concentrated in vacuo. The crude material was chromatographed using 100% DCM to 15% EtOAc/DCM as eluent to yield (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (0.25 g, 56.8%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][CH:12]([C:44](OC)=[O:45])[C@H:13]([NH:24][C:25]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C1COCC1>[OH:45][CH2:44][C@@H:12]([CH3:11])[C@H:13]([NH:24][C:25]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: COC(=O)C(C)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@H](CO)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 20 h
Yield: 34.6 %

Procedure:
Diisobutylaluminum hydride (20.57 ml of 1.0 M in hexanes, 20.57 mmol) was added drop-wise over 10 min to a cooled (−78° C.) THF (120 mL) solution of (2S)-1-benzyl 4-methyl 3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.37 g, 6.86 mmol) prepared above, and stirred at −78° C. for 20 hr. The reaction mixture was removed from the cooling bath and rapidly poured into ˜1M H3PO4/H2O (250 mL) with stirring, and the mixture was extracted with ether (100 mL, 2×). The combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. A silica gel mesh of the crude material was prepared and submitted to chromatography (25% EtOAc/hexanes; gravity elution) to afford 1.1 g of (2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate, contaminated with benzyl alcohol, as a colorless viscous oil and (2S,3R)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate containing the (2S,3R) stereoisomer as an impurity. The later sample was resubmitted to the same column chromatography purification conditions to afford 750 mg of purified material as a white foam. [Note: the (2S,3S) isomer elutes before the (2S,3R) isomer under the above condition]. (2S,3S) isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.81 (m, 2H), 7.39-7.08 (m, 16H), 4.67 (d, J=12.3, 1H), 4.43 (d, J=12.4, 1H), 4.21 (app t, J=5.2, OH), 3.22 (d, J=10.1, NH), 3.17 (m, 1H), 3.08 (m, 1H), ˜2.5 (m, 1H, overlapped with the solvent signal), 1.58 (m, 1H), 0.88 (d, J=6.8, 3H). LC (Cond. 1): RT=2.00 min; LC/MS: Anal. Calcd. for [M+H]+ C31H30NO3: 464.45. found 464.22. (2S,3R) isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.81 (d, J=7.5, 2H), 7.39-7.10 (m, 16H), 4.63 (d, J=12.1, 1H), 4.50 (app t, J=4.9, 1H), 4.32 (d, J=12.1, 1H), 3.59-3.53 (m, 2H), 3.23 (m, 1H), 2.44 (dd, J=9.0, 8.3, 1H), 1.70 (m, 1H), 0.57 (d, J=6.8, 3H). LC (Cond. 1): RT=1.92 min; LC/MS: Anal. Calcd. for [M+H]+ C31H30NO3: 464.45. found 464.52.
Reaction SMILES: [F:1][C:2]([F:24])([C:20]([F:23])([F:22])[F:21])[C:3]([F:19])([F:18])[C:4]([F:17])([F:16])[C:5]([F:15])([F:14])[C:6]([F:13])([F:12])[C:7]([CH2:10][OH:11])([F:9])[F:8].C(N(CC)CC)C.[F:32][C:33]([F:39])([F:38])[S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[F:1][C:2]([F:24])([C:20]([F:21])([F:22])[F:23])[C:3]([F:18])([F:19])[C:4]([F:16])([F:17])[C:5]([F:15])([F:14])[C:6]([F:13])([F:12])[C:7]([CH2:10][O:11][S:34]([C:33]([F:39])([F:38])[F:32])(=[O:36])=[O:35])([F:9])[F:8]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 40 g of (pentadecafluoroheptyl)methanol, 11 g. of triethylamine, and 200 ml. of methylene chloride is stirred at -20° C. while a solution of 18 g. of trifluoromethanesulfonyl chloride in 50 ml. of methylene chloride is added. The solution is stirred for one hour at room temperature and then washed with ice-cold 10% hydrochloric acid, saturated aqueous sodium bicarbonate solution, and water; dried over anhydrous magnesium sulfate; and evaporated. The residual brown liquid is distilled to yield the product as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([NH:13][NH2:14])=[O:12])[O:8][C:7]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[CH:27]=1.[C:28](Cl)(Cl)=[O:29]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]3[O:12][C:28](=[O:29])[NH:14][N:13]=3)[O:8][C:7]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[CH:27]=1
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=c1[nH]nc(C2Oc3ccc(Cl)cc3C(C3CCCCC3)(C3CCCCC3)O2)o1
Temperature: 25 °C

Procedure:
To a solution of 300 mg 6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carboxylic acid hydrazide in 4.3 ml toluene was added 4 ml of a 1.9M solution of phosgene in toluene. The reaction mixture was heated to reflux for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine and dried with MgSO4. Then the solvent was removed in vacuo and the crude product purified by preparative HPLC (C18 reverse phase column, elution with water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a solid. Yield: 180 mg.
Reaction SMILES: [C:1]12([C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8]1)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.C(O)C.[BH4-].[Na+]>O>[OH:12][CH:11]1[C:1]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]1=2
Reactant: O=C1c2ccccc2OC12CCCCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1c2ccccc2OC12CCCCCC2
Temperature: 25 °C
Reaction time: 23 h
Yield: 89.4 %

Procedure:
A mixture of 7.48 g of spiro[benzofuran-2(3H),1'-cycloheptan]-3-one, 175 ml of denatured ethanol and 1.31 g of sodium borohydride was stirred for 23 hours at room temperature under nitrogen. After addition of 250 ml of distilled water and 10-15 minutes of stirring, the mixture was partitioned between 250 ml of distilled water and 250 ml of ether. The phases were separated and the aqueous phase extracted with additional ether (2×250 ml). The combined organic extracts were washed with distilled water (250 ml) and saturated sodium chloride solution (250 ml) and thereafter dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded a solid which was triturated, filtered and washed with hexane. The filtrate was concentrated in vacuo to afford a second crop. Trituration and washing with hexane were repeated to afford in two crops 6.75 g of a crystalline solid, m.p. 104°-107° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[CH3:14][O-:15].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([O:15][CH3:14])[CH:6]=[CH:5]2
Reactant: Cc1cc(Br)cc2ccc(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cc(Br)cc(C)c2n1

Procedure:
A solution of 6-bromo-2-chloro-8-methylquinoline (10.7 g) in methanol (80 cm3) was heated under reflux with a solution of sodium methoxide [made from sodium (2.76 g) in methanol (50 cm3)] for 24 hours. The cooled solution was then evaporated in vacuo and the residue was partitioned between chloroform (100 cm3) and water (50 cm3). The aqueous phase was further extracted with chloroform (2×50 cm3) and the combined and dried (MgSO4) organic phases were evaporated in vacuo to give a solid which was recrystallised from ethyl acetate:hexane, 1:9, to afford 6-bromo-2-methoxy-8-methylquinoline, m.p. 89°-91° (8.3 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][O:22][N:23]=[C:24]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)\[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:38][CH:39]=1
Reactant: CCOC(=O)CCC(=NOCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl 4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-pyridyl)butyrate (670 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-pyridyl)butyric acid (475 mg, yield 75%) as colorless crystals. m.p. 161-162° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][N:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7]2.C(Cl)CCl.[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[O:18][C:17](=[O:19])[CH2:16][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH3:2])[CH:5]=2)[CH2:10]1
Reactant: COc1cc2c(cc1OC)CN(CC(=O)O)CC2
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc2c(cc1OC)CN(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirred suspension of 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid hydrochloride (822 mg, 2.86 mmol) in anhydrous DCM (30 ml), DMAP (523 mg, 4.28 mmol) and EDC (712 mg, 3.71 mmol) were added. The mixture was stirred at room temperature for 1 hour and then (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1.200 g, 2.86 mmol) was added. The mixture was stirred at room temperature for 48 hours, then diluted with DCM and washed with 1N HCl, dried over Na2SO4 and evaporated. The desired product was first purified by flash chromatography on silica gel (DCM:MeOH 10:0.2) followed by preparative HPLC (Method 2). The title compound was obtained (1.354 g, 73% yield). MS/ESI+ 653.18 [MH]+; [αD]=−43.91, c=0.69 in MeOH); 1H NMR (300 MHz, DMSO-d6) δ ppm 8.60 (s, 2H) 7.20 (d, 1H) 7.13 (d, 1H) 7.01 (dd, 1H) 7.07 (t, 1H) 6.64 (s, 1H) 6.58 (s, 1H) 6.10 (dd, 1H) 3.81-3.99 (m, 2H) 3.70 (s, 3H) 3.71 (s, 3H) 3.35-3.56 (m, 4H) 3.19-3.28 (m, 2H) 2.57-2.81 (m, 4H) 1.11-1.34 (m, 1H) 0.49-0.67 (m, 2H) 0.16-0.44 (m, 2H).