Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.[CH3:14]O>>[CH3:14][O:12][C:11](=[O:13])[C@@H:8]1[CH2:7][C@@H:6]([OH:5])[CH2:10][NH:9]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Thionyl chloride (5.6 mL, 76.3 mmol) was added dropwise to dry methanol (76 mL) at −20° C., following by addition of trans-4-hydroxy-L-proline (5.0 g, 38.1 mmol). The resulting mixture was allowed to warm to rt and stirred for 20 h. The solvent was removed under reduced pressure, and the residue was further dried under high vacuum to provide trans-4-hydroxy-L-proline methyl ester 1 as a white solid: 1HNMR (300 MHz, DMSO-d6) δ 2.18-2.23 (m, 2H), 3.06 (m, 1H), 3.32-3.36 (m, 2H), 3.76 (s, 3H), 4.42 (br. s, 1H), 4.48 (dd, J=5.4, 8.1 Hz, 1H), 5.56 (br. s, 1H); EIMS m/z 146 ([M]++1).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[C:56]([O:61][Si](C(C)(C)C)(C)C)[CH:57]=4)[CH:52]=3)[CH:46]([OH:69])[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[C:56]([OH:61])[CH:57]=4)[CH:52]=3)[CH:46]([OH:69])[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O[Si](C)(C)C(C)(C)C)ccc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O)ccc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 48 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6"'-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (39.8 mg) in CH2Cl2 (1.5 mL.) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL. of a 10% w/v solution). The mixture was stirred 1.25 h at 0° C. and then 1.75 h at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted 2× with 2:1 hexanes/acetone) affording 17 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6"'-hydroxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[N:19]O)[NH2:18])=[N:15][CH:16]=1>>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]1[O:9][N:19]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][N:15]=2)[N:18]=1
Reactant: O=C(O)c1occc1Br
Reactant: NC(=NO)c1ccc(Cl)cn1
Product: Clc1ccc(-c2noc(-c3occc3Br)n2)nc1

Procedure:
The title compound was prepared from 3-bromo-furan-2-carboxylic acid (381.7 mg, 2.00 mmol) and 5-chloro-pyridine-2-amidoxime (343 mg, 2.00 mmol), similar to Example 70, and yielded 353 mg (54%) of white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23]Br>>[Br:21][CH2:22][CH2:23][O:13][C:10]1[CH:11]=[CH:12][C:4]2[O:3][C:2]([CH3:14])([CH3:1])[NH:7][C:6](=[O:8])[C:5]=2[CH:9]=1
Reactant: BrCCBr
Reactant: CC1(C)NC(=O)c2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)NC(=O)c2cc(OCCBr)ccc2O1

Procedure:
A mixture of 48.2 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one, 70 g of potassium carbonate and 250 ml of 1,2-dibromoethane is refluxed for 4 hours whilst stirring. The semi-liquid reaction mixture is extracted 3 to 4 times whilst hot with 1 liter of methanol each time; the combined methanol extracts are concentrated by evaporation and the residue is recrystallised from methanol. 6-(2-Bromoethoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one having a melting point of 190°-195° is obtained.
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4])#[C-:2].[F:15][C:16]([F:25])([F:24])[C:17]1[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:4][C:3]1[N:1]=[CH:2][O:23][C:22]=1[C:20]1[O:21][C:17]([C:16]([F:24])([F:15])[F:25])=[CH:18][CH:19]=1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(C(F)(F)F)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (0.893 g, 4.27 mmol), 5-(trifluoromethyl)furan-2-carbaldehyde (0.70 g, 4.3 mmol), and K2CO3 (1.18 g, 8.53 mmol) in MeOH (25 mL) was heated to reflux. After 2.5 hr the reaction mixture was cooled to ambient temperature and stirred overnight. The reaction mixture was extracted with EtOAc (2×200 mL) and washed with water (2×200 mL), then washed with brine and dried over Na2SO4, filtered, and concentrated to an orange solid. The crude product was chromatographed on silica gel (Analogix® SF25-40G column, 0%-25% EtOAc/hexanes, 30 mL/min) to yield 709 mg (77%) of the title compound as a light yellow solid. 1H NMR (300 MHz, MeOH-d4) δ 8.19 (s, 1H), 7.12 (m, 1H), 6.80 (dd, J=3.7, 0.6 1H), 2.41 (s, 3H). MS (DCI+) m/z 218 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([C:17]([OH:19])=O)[CH2:16][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1.[C:42]1([CH:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[NH2:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl.O>[CH:48]([NH:49][C:17]([C@@H:15]1[CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]2[CH2:16]1)=[O:19])([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](C(=O)O)C[C@H]2C1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](C(=O)NC(c3ccccc3)c3ccccc3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (7S,8aS)-2-(tert-butoxycarbonyl)octahydropyrrolo[1,2-a]pyrazine-7-carboxylic acid (80 mg, 0.296 mmol) in dichloromethane (2 mL) was added a solution of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (68.9 mg, 0.444 mmol) and hydroxybenzotriazole hydrate (40.0 mg, 0.296 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature for 1 hour and then diphenylmethanamine (54.2 mg, 0.296 mmol) was added. After stirring for three days the mixture was poured into water (10 mL). The mixture was extracted with dichloromethane (3×5 mL), the organic fractions were concentrated and the residue was purified by flash chromatography (dichloromethane/methanol=25:1) to give the title compound. MS (ESI) m/z 436 (M+H)+.
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(O)O.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc(-c2ccccn2)cc1
Yield: 90.9 %

Procedure:
To a solution of 4-boronobenzoic acid (1.66 g, 10 mmol) and 2-bromopyridine (1.72 g, 11 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) were added. The mixture was degassed and purged withed nitrogen. The mixture was stirred under reflux for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=4 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.81 g of white solid of 4-(pyridin-2-yl)benzoic acid. Yield: 91%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: C(O)C.[CH3:4][C:5]([CH3:46])([CH:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)=[CH:30][CH:29]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7].[OH-].[Na+:48]>C1COCC1>[Na+:48].[CH3:4][C:5]([CH3:46])([CH:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)=[CH:30][CH:29]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:12][CH:11]=1)[C:6]([O-:8])=[O:7]
Reactant: CC(C)(C(=O)O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C(=O)[O-])C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution in THF (10 mL) and ethanol (8 mL) of 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propionic acid (0.128 g, 0.225 mmol), prepared as in step 3, was added one equivalent of NaOH (2.3 mL, 0.1N NaOH). The reaction was stirred for 1 hour at room temperature, concentrated, and dried under high vacuum to provide 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propionic acid sodium salt as a white powder 0.13 g (99%): mp 250°-255° C. (dec); 1H NMR (300 MHz, DMSO-d6) d 0.91 (s, 6H), 4.46 (s, 1H), 5.29 (s, 4H), 6.87 (d, 4H, J=9 Hz), 7.15 (d, 4H, J=9 Hz), 7.61 (m, 2H), 7.67 (d, 4H, J=9 Hz), 7.78 (m, 2H), 8.00 (t, 4H, J=9 Hz), 8.40 (d, 2H, J=9 Hz); MS m/e (FAB+) 569 (M+H)+, (FAB-) 567 (M-H)-. Anal. Calc'd. for C37H31N2O4Na.0.5 H2O: C, 74.10; H, 5.37; N 4.67. Found C, 74.02; H, 5.24; N, 4.50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1.[O:18]1CCOCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[C:11]3=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2cc(-c3cccc(Cl)c3)ccc2N1
Reactant: C1COCCO1
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C1=O
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one (10.0 g, 41 mmol) in dioxane (200 cm3) and SeO2 (22.8 g, 205 mmol) was brought to reflux for 2 h then cooled to RT and concentrated onto Florisil. The Florisil was washed (acetone:CHCl3 1:9) and the combined organic extracts were evaporated. The residue was purified by column chromatography (SiO2, acetone:CHCl3 1:8) to afford the subtitled compound (8 g, 31 mmol, 76%) as a tan solid: m.p. 256-258° C., 1H NMR (THF-d8) δ 6.96 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.4 (dd, J=7.7, 7.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.68 (dd, J=1.84, 1.84 Hz, 1H), 7.83-7.86 (m, 2H), 10.05 (br s, 1H); 13C NMR (DMSO-d6) δ 113.30 (d), 119.08 (s), 123.44, 125.57, 126.65, 127.92, 131.41 (d), 133.88, 134.47 (s), 137.25 (d), 141.51, 150.99, 160.15, 184.83 (s); MS (EI) m/z 256 (M−H)+; Anal. (C14H8ClNO2-0.1H2O) C, H, N.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=O)[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.[SH:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCl>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:15](=[O:17])[C@H:2]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[CH:7]=2)[CH:12]=1)[CH3:1]
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: OCCCCS
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)SCCCCO)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a solution of naproxen (5.03 g, 21.9 mmol), 4-mercapto-l-butanol (2.32 g, 21.9 mmol) and N,N-dimethylaminopyridine (DMAP) (0.534 g, 4.37 mmol) in dichloromethane (200 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC) (5.03 g, 26.2 mmol) as a solid, in portions. The reaction mixture was stirred for 3 hours at room temperature, then partitioned between dichloromethane and water, and the water layer was washed with more dichloromethane. The combined organic layer was washed with water and brine, then dried over magnesium sulfate. The solution was concentrated under vacuum, and the residue was purified via column chromatography, 50% ethyl acetate/hexane. The appropriate fractions were combined, and the solvent removed by rotary evaporation to give an oil, 2.647 g, which contained 19% 4-mercapto-l-butanol by weight (product weight 2.07 g, 6.5 mmol, 30% yield): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=2.7 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.69 (d, J=1.0 Hz, 1H), 7.40 (dd, J=1.8, 8.5 Hz, 1H), 7.15 (dd, J=2.5, 8.8 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 4.02 (q, J=7.1 Hz, 1H), 3.92 (s, 3H), 3.61-3.64 (m, 2H), 2.87 (m, 2H), 1.61 (d, J=7.1 Hz, 3H), 1.59 (m, 2H), 1.41 (m, 2H); mass spectrum (API-TIS) m/z 319 (M+H+), 336 (M+18+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:14]([O:18][C:19](=[O:27])[NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1)([CH3:17])([CH3:16])[CH3:15].C(O)CCCC>>[C:14]([O:18][C:19](=[O:27])[NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:22]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Solvent: CCCCCO
Product: COc1ccc2nccc(N3CCCC(NC(=O)OC(C)(C)C)C3)c2n1

Procedure:
According to procedure F and starting from 8-bromo-2-methoxy-[1,5]naphthyridine and (RS)-piperidin-3-yl-carbamic acid tert-butyl ester (commercial) and using 1-pentanol instead of NMP as reaction solvent, the title compound was isolated as an orange oil (2.44 g, 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[O:12][CH3:13].C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.CN(CCN(C)C)C>C1(C)C=CC=CC=1>[F:11][C:5]1[C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]([B:19]([OH:24])[OH:20])=[C:3]([O:12][CH3:13])[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(F)c(C(C)C)cc1Br
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COc1cc(F)c(C(C)C)cc1B(O)O
Reaction time: 0.17 h
Yield: 83 %

Procedure:
A solution of 2-bromo-4-isopropyl-5-fluoroanisole (88 wt % in toluene, 10.44 g, 37.2 mmol) in anhydrous toluene was cooled to −10° C. under N2 atmosphere, and 2.5 M, n-butyllithium solution in hexanes (16.36 ml, 40.69 mmol) was added slowly. After stirring at the same temperature for 10 minutes, the resulting solution was transferred to a cooled solution of triisopropyl borate (14.53 ml, 61.3 mmol) and TMEDA (2.80 ml, 18.59 mmol) in toluene slowly at −20° C. After stirring for 30 minutes, the reaction mixture was quenched with 3M H2SO4 (45 ml), and the resulting mixture was worked up as described in Step 4a to provide the title compound in 83% yield (6.62 g, 98.5 wt %).
Reaction SMILES: COC1C=CC(C([O:22][C@@H:23]2[C:27]([CH2:30][OH:31])([CH2:28][OH:29])[O:26][C@@H:25]([N:32]3[CH:40]=[C:38]([CH3:39])[C:36](=[O:37])[NH:35][C:33]3=[O:34])[CH2:24]2)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>C(O)(=O)C.O>[OH:29][CH2:28][C:27]1([CH2:30][OH:31])[O:26][C@@H:25]([N:32]2[CH:40]=[C:38]([CH3:39])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[CH2:24][C@@H:23]1[OH:22]
Reactant: COc1ccc(C(O[C@H]2C[C@H](n3cc(C)c(=O)[nH]c3=O)OC2(CO)CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cn([C@H]2C[C@H](O)C(CO)(CO)O2)c(=O)[nH]c1=O
Yield: 90.8 %

Procedure:
A solution of 3′-O-(4,4′-dimethoxytrityl)-4′-C-hydroxymethylthymidine (6.32 g, 11.0 mmol) in 80% acetic acid in water (50 ml) stood at room temperature for 4 h. Solvents were removed under reduced pressure and water (200 ml) added. The resulting cloudy mixture was washed with ether (3×80 ml) and water was evaporated. The residue was dissolved in methanol and toluene and the resulting solution was concentrated. This process was repeated twice. 4′-C-hydroxymethylthymidine (2.72 g, 91%) was obtained as a foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[NH:26]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:3][C:2]([N:26]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: OC1CCNC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCC(O)C3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 39 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and 3-pyrrolidinol according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 39%; MS: m/z=419 (M+H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](O)=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2].C[N:17](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]([NH:4][C:5]1[C:10]([C:11]([NH2:17])=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CSc1ncc(C(=O)O)c(NC(C)C)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc(C(N)=O)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
4-(Isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (8.38 g, 36.9 mmol) and HATU (21.03 g, 55.3 mmol) were combined in a 250 mL round-bottomed flask followed by the addition of DMF (92 mL). After that ammonia hydrochloride (9.86 g, 184 mmol) and DIEA (32 mL, 184 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and water (150 mL) was added. The resulting suspension was filtered, washed with water and dried under high vacuum overnight to afford 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxamide (8 g, 35.4 mmol, 96% yield); MS (ESI) m/z 227.4 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[C:20]1(OB(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[N+:17]([C:3]1[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: OB(O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
tert-Butyl trans-3-(4-bromo-3-nitrophenyl)acrylate (7.07 g, 21.5 mmol) was dissolved in 1,4-dioxane (200 mL) and thereto were added phenyl boric acid (5.25 g, 42.1 mmol), cesium carbonate (56.1 g, 172.2 mmol), 1,1-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.88 g, 1.1 mmol), and purified water (50 mL). The mixture was stirred under a nitrogen flow at 80° C. for 4 hours. The reaction solution was filtered through celite, alumina, and Florisil, and, thereafter, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain tert-butyl trans-3-(3-nitro-4-phenylphenyl)acrylate (6.52 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[C:46](=O)[CH2:47][CH2:48][OH:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:51][S:52](Cl)(=[O:54])=[O:53]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][O:49][S:52]([CH3:51])(=[O:54])=[O:53])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(C(=O)CCO)CCC3)cc1
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)cc1

Procedure:
In analogy to the procedure described in example 8(b), the (3R,4R)-3-[1-(3-hydroxy-propoyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 4(a)] was treated with methanesulfonyl chloride to yield the (3R,4R)-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester, which was directly used in the next step without further characterization.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12]/[CH:13]=[CH:14]/[C:15]2[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1.[OH-].[K+]>CO.O1CCCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([CH:21]([CH3:23])[CH3:22])[C:15]=2/[CH:14]=[CH:13]/[CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:31])[C:3]([OH:32])=[O:2])=[CH:10][CH:9]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)C(=O)c1ccc(OC/C=C/c2c(-c3ccc(F)cc3)cccc2C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cccc(-c2ccc(F)cc2)c1/C=C/COc1ccc(C(=O)C(=O)O)cc1
Yield: 62 %

Procedure:
As in Example 19, (E)-4-[3-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yl]-2-propenyloxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in a mixture of methanol (4 mL) and tetrahydrofuran (2 mL) was treated with 1N potassium hydroxide (1.4 mL). The usual work up gave 0.4 g of a solid, which after crystallization from diethyl ether-hexane provided 0.3 g of (E)-4-[3-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yl]-2-propenyloxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 142°-143° C.