Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]([F:13])([F:12])[CH:10]=[CH2:11].[SH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].COC(OC)(C1C=CC=CC=1)C(C1C=CC=CC=1)=O>[OH-].[Na+]>[F:8][C:9]([F:13])([F:12])[CH2:10][CH2:11][S:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCS
Reactant: C=CC(F)(F)F
Agent: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(O)CCSCCC(F)(F)F
Reaction time: 4 h

Procedure:
A 250 mL three-neck round bottomed flask was charged with toluene (81 mL) and cooled to <−50° C. with a dry ice/acetone bath. 3,3,3-Trifluoropropene (10.28 g, 107.0 mmol) was bubbled into the solvent and the ice bath was removed. 3-Mercaptopropionic acid (9.200 g, 86.70 mmol) and 2,2-dimethoxy-2-phenylacetophenone (1.070 g, 4.170 mmol) were added and the long wave light (366 nm, 4 watt UVP lamp) was turned on (Starting temperature: −24° C.). The reaction reached a temperature of 27.5° C. due to heat from the lamp. The reaction was stirred under the black light on for 4 hours. After 4 hours the black light was turned off and the reaction concentrated by rotary evaporation (41° C., 6 mm Hg) giving a pale yellow oil (18.09 g, 51:1 linear:branched isomer, 90 wt % linear isomer by GC internal standard assay, 16.26 g active, 93%). The crude material was dissolved in 10% sodium hydroxide w/w (37.35 g) and was washed with toluene (30 mL) to remove non-polar impurities. The aqueous layer was acidified to pH ˜2-3 with hydrochloric acid (2 N, 47.81 g) and was extracted with toluene (50 mL). The organic layer was washed with water (40 mL) and dried over magnesium sulfate, filtered, and concentrated by rotary evaporation giving a pale yellow oil (14.15 g, 34:1 linear:branched isomer, 94 wt % linear isomer by GC internal standard assay, 13.26 g active, 76%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:25][C@H:26]2[C@@H:31]3[O:32]C(=O)[O:34][C@@H:30]3[C@@H:29]([O:36][CH3:37])[C:28]([CH3:39])([CH3:38])[O:27]2)=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=[O:13])[C:9]([NH:14][C:15](=[O:24])OCC1C=CC=CC=1)=[CH:8]2)[CH3:2].CCN=C=NCCCN(C)C.[NH:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]1C(O)=O.C(=O)([O-])[O-]>[Pd].C1COCC1.N1C=CC=CC=1.C(Cl)Cl.CO.C(N(CC)CC)C>[OH:32][C@@H:31]1[C@H:30]([OH:34])[C@@H:29]([O:36][CH3:37])[C:28]([CH3:39])([CH3:38])[O:27][C@H:26]1[O:25][C:4]1[C:3]([CH2:1][CH3:2])=[C:12]2[C:7]([CH:8]=[C:9]([NH:14][C:15]([C:52]3[NH:51][C:59]4[C:54]([CH:53]=3)=[CH:55][CH:56]=[CH:57][CH:58]=4)=[O:24])[C:10](=[O:13])[O:11]2)=[CH:6][CH:5]=1
Reactant: CCc1c(O[C@@H]2OC(C)(C)[C@H](OC)[C@H]3OC(=O)O[C@@H]23)ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc12
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1c(O[C@@H]2OC(C)(C)[C@H](OC)[C@@H](O)[C@H]2O)ccc2cc(NC(=O)c3cc4ccccc4[nH]3)c(=O)oc12
Reaction time: 12 h
Yield: 8 %

Procedure:
Palladium on carbon (10%, 12 mg) was added to 25h (121 mg, 0.22 mmol) in anhydrous THF (5.00 mL) and the solution was placed under an atmosphere of H2. After 12 hours, the solution was filtered through SiO2 (1:1 CH2Cl2:Acetone) and the eluent was concentrated to afford a yellow solid, which was used without further purification (90.0 mg, 99%). EDCI (28.3 mg, 0.15 mmol) and 1H-indole-2-carboxylic acid (19.0 mg, 0.12 mmol) were added to the amine (24.0 mg, 0.059 mmol) in 30% pyridine/CH2Cl2 (1.63 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetdne) to afford an colorless foam, which was used without further purification (23.8 mg, 73%). Triethylamine (150 μL) was added to the carbonate (14.1 mg, 0.026 mmol) in MeOH (1.50 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford 26p as a yellow amorphous solid (5.00 mg, 37%, 27% over 3 steps): 1H NMR (CD2Cl2, 500 MHz) 8.65 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 7.13 (s, 2H), 7.07 (t, J=7.5 Hz, 1H), 5.46 (d, J=2.0 Hz, 1H), 4.07 (dd, J=9.3, 3.5 Hz, 1H), 4.04 (t, J=3.5 Hz, 1H), 3.51 (s, 3H), 3.25 (d, J=7.2 Hz, 1H), 2.78 (q, J=7.0 Hz, 2H), 1.27 (s, 3H), 1.10 (t, J=7.5 Hz, 3H), 1.06 (s, 3H); 13C NMR (CD2Cl2, 125 MHz) 158.4, 157.3, 154.2, 146.8, 135.3, 128.1, 125.5, 124.0, 123.0, 123.0, 122.8, 120.1, 119.5, 118.7, 118.2, 112.0, 110.1, 109.7, 102.4, 97.0, 82.1, 76.5, 69.3, 66.4, 26.7, 20.3, 14.3, 11.4; IR (film) νmax 3435, 3416, 2974, 2935, 2469, 2359, 2339, 1715, 1651, 1520, 1456, 1435, 1379, 1354, 1259, 1180, 1113, 1088, 1026, 997, 962, 798, 739 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C28H30N2O8, 545.1900. found, 545.1909.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[C:15]([CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:14][CH:13]=[CH:12][N:11]=1>>[N:17]1([CH2:16][C:15]2[C:10]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Brc1ncccc1Cn1ccnc1
Reactant: OB(O)c1cccs1
Product: c1csc(-c2ncccc2Cn2ccnc2)c1

Procedure:
Synthesized using 2-thiophenylboronic acid (161 mg, 1.26 mmol) and 5 (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 111 mg, 0.46 mmol, 73%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.39 (s, 2H), 6.88 (t, J=1.3 Hz, 1H), 7.13-7.15 (m, 2H), 7.17 (dd, J=7.9, 1.9 Hz, 1H), 7.20 (dd, J=7.9, 4.4 Hz, 1H), 7.23 (dd, J=3.8, 1.3 Hz, 1H), 7.50 (dd, J=5.0, 1.3 Hz, 1H), 7.51 (brs, 1H). 8.60 (dd, J=4.4, 1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.4, 119.3, 122.5, 127.2, 127.8, 128.5, 128.6, 130.3, 136.1, 137.5, 142.7, 149.0, 150.8; MS (ESI): m/z=241.79 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49].C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CS(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Benzylamino-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.9 g, 1.9 mmol) obtained in step 5 was dissolved in DMF (15 mL), 1,1′-carbonyldiimidazole (1.2 g, 7.6 mmol) was added, and the mixture was stirred at room temperature for 2 hr. Methanesulfonamide (0.9 g, 9.5 mmol) and DBU (1.4 g, 9.5 mmol) were added to the reaction mixture, and the mixture was stirred at 60° C. for 1 hr. 10% Aqueous citric acid solution (5 mL) and water (60 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, washed with water (50 mL), and purified by silica gel column chromatography (chloroform/methanol=95/5) to give compound a-1 (0.8 g, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[H-].[Na+].Cl[CH2:19][C:20](=O)[CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[C:11]2[C:20]([CH3:21])=[CH:19][O:15][C:10]=2[CH2:9]1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2ccccc2Br)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccccc1Br)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2-bromophenyl)cyclohexane-1,3-dione (mp174-175° C.; 1.07 g) in DMF (15 ml) was added 60% sodium hydride (0.18 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.36 ml), and the mixture was stirred at 150° C. overnight (13 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2-bromophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[Cl:12]N1C(=O)CCC1=O.C(OO)(C)(C)C>>[Cl:12][CH2:9][C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:11])[CH:5]=1)=[CH2:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1cc(Cl)nc(Cl)c1
Agent: CC(C)(C)OO
Product: C=C(CCl)c1cc(Cl)nc(Cl)c1
Temperature: 180 °C
Reaction time: 5 h
Yield: 31.7 %

Procedure:
A mixture of 26.3 g of 2,6-dichloro-4-isopropenylpyridine, 33.4 g of N-chlorosuccinimide, 2 g of t-butylhydroperoxide and 30 ml of carbon tetrachrolide was stirred at 180° C. for 5 hours while being irradiated with light. After the reaction mixture was cooled to room temperature, the insoluble matter was filtered out. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (eluted with ethyl acetate-n-hexane 1:20) to obtain 9.86 g of the objective compound.
Reaction SMILES: [C:1]1(=[O:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:12]=[N+]=[N-].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O.O>[C:1]1(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:12]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCCCCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCCCCCCCCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.1 %

Procedure:
Cyclodecanone (n=6) (1.0 g) in 10 mL concentrated sulfuric acid was cooled to 0° C. and 0.54 g of sodium azide was added. The reaction continued to stir at 0° C. for 1 h and warmed to room temperature where it was stirred for two h. The solution was diluted with cold water and treated with cold 10% NaOH solution until pH=9. Extraction with ether (2×), drying over magnesium sulfate and evaporation of solvent provided 1.23 g of 2-azacycloundecanone.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([NH:12][CH:13]([CH:15]1[CH2:17][CH2:16]1)[CH3:14])=[O:11].[Br:23][C:24]1[CH:28]=[C:27]([C:29](OC2C=CC=CC=2)=[O:30])[N:26]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][N:39]=2)[N:25]=1.Cl>CS(C)=O>[Br:23][C:24]1[CH:28]=[C:27]([C:29]([NH:7][C:8]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=2[C:10](=[O:11])[NH:12][CH:13]([CH:15]2[CH2:17][CH2:16]2)[CH3:14])=[O:30])[N:26]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][N:39]=2)[N:25]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1N)C1CC1
Reactant: O=C(Oc1ccccc1)c1cc(Br)nn1-c1ncccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Yield: 38.6 %

Procedure:
0.18 g of potassium tert-butoxide was added to a mixed solution comprising 0.23 g of 2-amino-5-chloro-N-(1-cyclopropylethyl)benzamide, 0.30 g of phenyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate and 5 ml of dimethyl sulfoxide, followed by reaction at room temperature for 1 hour. The reaction liquid was slowly added to diluted hydrochloric acid, the mixed liquid was subjected to extraction with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 to 7.5/2.5) to obtain 0.16 g of the desired product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH2:4][O:5][C:6]1[C:15]([CH3:16])=[C:14]2[C:9]([C:10](O)=[CH:11][C:12]([C:17]3[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=3)=[N:13]2)=[CH:8][CH:7]=1.O=P(Cl)(Cl)[Cl:30].CO.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:30][C:10]1[C:9]2[C:14](=[C:15]([CH3:16])[C:6]([O:5][CH2:4][CH:3]([O:26][CH3:27])[O:2][CH3:1])=[CH:7][CH:8]=2)[N:13]=[C:12]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)[CH:11]=1
Reactant: COC(COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C)OC
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COC(COc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1C)OC
Temperature: 80 °C

Procedure:
7-(2,2-Dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-8-methyl-quinolin-4-ol (875 mg, 2.3 mmol) was dissolved in pyridine (20 mL). POCl3 (4.2 ml, 46.0 mmol) was added slowly. The reaction was heated at 80° C. for 4 hours. The reaction was cooled to 0° C. and methanol (5 mL) was added. The reaction was neutralized with a saturated aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate (3×20 mL). The combined organics were dried with sodium sulfate, filtered and was concentrated. 4-Chloro-7-(2,2-dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-8-methyl-quinoline (410 mg, 44%) was purified by silica gel chromatography.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@H:17](O)[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@H:10]1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[C:29]1(=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:38])[NH:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl.C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([N:30]2[C:31](=[O:38])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:29]2=[O:39])[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@H:10]1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@@H](O)CC[C@H]1c1cccc(F)c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@H](N2C(=O)c3ccccc3C2=O)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 22 h

Procedure:
In an oven-dried 100 mL round-bottomed flask was dissolved tert-butyl (5S,6S,9S)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyrazin-5-ylcarbamate (35.3 mg, 0.090 mmol) (9, azeotroped with dry benzene) in methylene chloride (3 mL) to give a colorless solution. isoindoline-1,3-dione (26.5 mg, 0.180 mmol) and triphenylphosphine (47.3 mg, 0.180 mmol) were added, followed by diisopropylazodicarboxylate (0.026 mL, 0.135 mmol). The mixture was stirred at rt under nitrogen. After 22 h, the mixture was directly subject to flash column chromatography up to 50% ethyl acetate/hexane afforded one major peak. Concentration afforded the desired product as a colorless oil. 1H NMR indicated that some elimination product might also be present. This was carried onto next reaction without further purification and characterization.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30]([C:28]3[S:29][C:25]([F:24])=[CH:26][CH:27]=3)=[O:31])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1ccc(F)s1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(F)s3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 5-fluoro-thiophene-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=352.0 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]([C:9](=[O:19])[CH2:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]OC)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:9](=[O:19])[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:18][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC=C(OC(C)=O)C(=O)CC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1coc(-c2ccccc2)cc1=O

Procedure:
To a solution of 545 mg (3.5 mmol) of 1-methoxy-3-oxobut-1-en-2-yl acetate in THF (14.2 mL) at −78° C. was added LHMDS (3.45 mL of a 1 M solution in toluene) dropwise. After stirring for min at −78° C., the reaction mixture was treated with 0.4 mL (3.5 mmol) of benzoyl chloride dropwise, then removed from the cold bath and allowed to warm to room temperature and continue stirring for 18 h. The reaction was quenched with 10 mL 10% aq HCl and extracted with diethyl ether (3×10 mL). The organic fractions were combined, washed with sat. aq. NaCl, dried (Na2SO4), and concentrated under reduced pressure to provide 1-methoxy-3,5-dioxo-5-phenylpent-1-en-2-yl acetate which was used the subsequent step without further purification. To a solution of crude 1-methoxy-3,5-dioxo-5-phenylpent-1-en-2-yl acetate (3.5 mmol) in toluene (35 mL) was added pyridinium p-toluenesulfonate (130 mg, 0.5 mmol). The reaction mixture was heated at reflux under a nitrogen atmosphere for 1 h before being cooled and concentrated under reduced pressure and purified by flash chromatography (80 g SiO2, 0-100% ethyl acetate/hexanes gradient elution) to provide 4-oxo-6-phenyl-4H-pyran-3-yl acetate. LC/MS (M+H)+ 231.
Reaction SMILES: C([O:4][C:5](=[CH:7][C:8]([CH3:10])=[CH2:9])[CH3:6])(=O)C.[CH3:11][C:12]([CH3:16])=[CH:13][CH2:14]O.CC(C)=CC(O)=O>C(O)(=O)C>[CH3:6][C:5]([CH2:4][CH2:14][CH:13]=[C:12]([CH3:16])[CH3:11])=[CH:7][C:8](=[O:9])[CH3:10]
Reactant: CC(C)=CCO
Reactant: C=C(C)C=C(C)OC(C)=O
Agent: CC(C)=CC(=O)O
Solvent: CC(=O)O
Product: CC(=O)C=C(C)CCC=C(C)C
Yield: 86 %

Procedure:
110 parts of 4-methyl-2,4-pentadien-2-yl acetate and 60 parts of prenol are heated with 1.4 parts of 3,3-dimethylacrylic acid at about 180°C for 4 hours in a small pressure column at a pressure of 2 atmospheres, the acetic acid formed being distilled off continuously. Fractional distillation of the reaction product gives 61.8 parts of 4,8-dimethyl-3,7-nonadien-2-one (yield 86% of theory, conversion 62% based on prenol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].C([Li])CCC.C[O:16][B:17](OC)[O:18]C.Cl>O1CCCC1.O>[Cl:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[B:17]([OH:18])[OH:16]
Reactant: COB(OC)OC
Reactant: Clc1cccc(Br)c1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1cccc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
A solution of 1-bromo-2,3-dichlorobenzene (20 g, 0.088 mole, Aldrich) in dry tetrahydrofuran (44.24 ml) was added dropwise to a solution of n-butyllithium (1.6M in hexane, 66.36 ml, 0.11 mole) in anhydrous tetrahydrofuran (16 ml), maintaining the temperature below −65° C. The resulting pale yellow suspension was stirred at −78° C. for 75 min. Trimethylborate (13.28 ml, 12.16 g, 0.12 mole) was added dropwise maintaining the temperature below −55° C. The resulting pale yellow solution was warmed to room temperature overnight. Excess n-butyllithium was decomposed with water (30 ml) and the reaction mixture was evaporated in vacuo. The residue obtained was suspended in water and acidified with 2M hydrochloric acid (10 ml). The insoluble solid was filtered, washed well with water and dried. The solid was suspended in 60-80° C. petroleum ether, stirred at room temperature for 10 min, filtered dried in vacuo. Yield 8.42 g (50%), M.p. 235-238° C.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[N:5][C:4](Cl)=[CH:3][C:2]=1[C:9]([F:12])([F:11])[F:10].[OH-].[NH4+:14]>>[Cl:7][C:6]1[N:5]=[C:4]([NH2:14])[CH:3]=[C:2]([C:9]([F:12])([F:11])[F:10])[CH:1]=1
Reactant: [NH4+]
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Agent: [OH-]
Product: Nc1cc(C(F)(F)F)cc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 2,6-dichloro-4-(trifluoromethylpyridine) (Fluorochem, 10.0 g; 46.30 mmol; 1.0 eq.) in ammonium hydroxide (˜25% in water) (40.0 mL; 4.0 V) was heated to 180° C. for 3 h in a Parr apparatus and cooled down to rt. After this time, reaction mixture was filtered over a bed of celite, evaporated to dryness under reduced pressure, triturated with DCM and filtered. The mother liquors were concentrated under reduced pressure to give the title compound as a yellow oil that crystallized upon standing (4.83 g; 53%). HPLC, Rt: 3.58 min. (purity 96.9%). LC/MS, M+(ESI): 196.8, M−(ESI): 194.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=1)[C:5]2=O.O.[NH2:28][NH2:29]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)=[CH:7][NH:29][N:28]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: O=c1c(-c2cccc(-c3ccc(F)cc3)c2)coc2cc(O)c(Cl)cc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: Oc1cc(O)c(-c2n[nH]cc2-c2cccc(-c3ccc(F)cc3)c2)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(4′-fluoro-biphenyl-3-yl)-7-hydroxy-chromen-4-one (0.2 g, 0.54 mmol), hydrazine hydrate (2.5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give an oil which was purified by column chromatography to give 4-Chloro-6-[4-(4′-fluoro-biphenyl-3-yl)-1H-pyrazol-3-yl]-benzene-1,3-diol as an off white solid (0.13 g, 63.3%); Rf 0.2 cf SM 0.7 ethyl acetate/hexane (80/20).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccc4ccccc4c3)cc2)C(O)C1

Procedure:
In analogy to the procedure described in Example 14, by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate with 2-bromomethylnaphthalene in the presence of potassium carbonate there was obtained tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(naphthalen-2-ylmethoxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 434 (M+H)+.