Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13]([NH2:15])=[O:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[C:37]([N:17]1[C:18]([CH3:27])([CH3:26])[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]1=[C:12]([N:11]=[N:10][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=1)[C:13]([NH2:15])=[O:14])(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc(N=NC(C(N)=O)=C2NC(C)(C)Cc3ccccc32)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(N=NC(C(N)=O)=C2c3ccccc3CC(C)(C)N2C(C)=O)cc1
Temperature: 0 °C

Procedure:
2-(4-acetyl-phenylazo)-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene)-acetamide (Asinex Corp., Russia) and dimethylaminopyridine are dissolved in pyridine on the ice bath, and acetic anhydride is added. After the reaction is stopped, the solvent after the reaction as described above is poured on ice water to extract the reaction product by adding dichloromethane. The reaction product is dried by using anhydrous sodium sulfate and filtered and, then, the solvent is removed by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([CH:8]1[O:10][CH2:9]1)Cl.C(N(CC)CC)C>C(O)(C)C>[C:1]([N:5]1[CH2:9][CH:8]([OH:10])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: ClCC1CO1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)N1CC(O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of tert-butylamine (10 mmol) in isopropylalcohol (20 mL) was added dropwise epichlorohydrine (10 mmol). The mixture was stirred at 25° C. for 16 h. After concentration, the residue was re-dissolved in acetonitrile (20 mL) and triethylamine (20 mmol) was added. The mixture was heated at 100° C. for 24 h, cooled to rt and filtered. The filtrate was concentrated providing 1-tert-butyl-azetidin-3-ol (1.1 g). MS (ESI): mass calcd. for C7H15NO, 129.1; m/z found, 130.1 [M+H]+. 1H NMR (CDCl3): 6.15-5.70 (br s, 1H), 4.84-4.72 (m, 1H), 4.24-4.12 (m, 2H), 4.03-3.87 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[N+:19]([O-:21])=[O:20])[C:3]=1[C:22]([O:24][CH3:25])=[O:23].[H-].[Na+].CI.[C:30](OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1[N:7]([CH3:30])[C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(C)=O
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)N(C)C(C)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]

Procedure:
12 g nifedipine was introduced into a 100-mL three-neck flask and dissolved in 50 mL tetrahydrofuran under nitrogen. 1.66 g of a 60% dispersion of sodium hydride in oil was then added with stirring. After stirring for a short period of time, 10 mL methyl iodide was added and the reaction was stirred for 1 hour at 38° C. 200 mL ethyl acetate was then added, and the organic layer was thereafter washed several times with water and dried over sodium sulfate. The sodium sulfate was subsequently filtered off and the solvent was then pulled off from the filtrate on a rotary evaporator. The obtained solid was dissolved in 200 mL MIBK, and the addition of hexane to this solution then yielded 8.9 g N-methylnifedipine as yellow crystals. mp=184°-187° C.
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6](I)[C:5]([NH2:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19]>O1CCOCC1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:9][C:5]1[C:6](/[CH:19]=[CH:18]/[C:17]([O:21][CH2:22][CH3:23])=[O:20])=[N:7][C:2]([I:1])=[N:3][CH:4]=1
Reactant: Nc1cnc(I)nc1I
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1nc(I)ncc1N
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A 3-necked roundbottom flask was purged and maintained under an atmosphere of nitrogen. 2,4-Diiodopyrimidin-5-amine (135 g, 389.4 mmol) in dioxane (1400 ml) was added followed by palladium(II) acetate (4.8 g, 19.63 mmol), triethylamine (157 g, 1.55 mol), ethyl acrylate (390 g, 3.90 mol), and tetrabutylammonium chloride (108 g, 389.9 mmol). The resulting solution was allowed to react, with stirring, for 16 hours while the temperature was maintained at 90° C. Upon completion, the mixture was concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with 1:4 to 1:1 ethyl acetate/petroleum ether to afford the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:13]=[C:14]([CH2:21][OH:22])[C:15]([CH2:19][OH:20])=[CH:16][C:17]=1[CH3:18].C(N(CC)CC)C>ClCCl.ClCCl.CS(C)=O>[CH3:18][C:17]1[CH:16]=[C:15]([CH:19]=[O:20])[C:14](=[CH:13][C:12]=1[CH3:11])[CH:21]=[O:22]
Reactant: Cc1cc(CO)c(CO)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cc(C=O)c(C=O)cc1C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
To a solution of oxalyl chloride 2M in dichloromethane (DCM) (26.5 mL, 53.0 mmol, 2.2 molar equivalents) cooled to −78° C. was added dropwise a solution of dimethylsulfoxide (DMSO) (7.5 mL, 105.8 mmol; 4.4 molar equivalents) in DCM (10 ml). The solution was stirred at −78° C. for 5 min and 4,5-dimethylbenzene-1,2-dimethanol (4.0 g, 24.1 mmol, 1.0 molar equivalent) dissolved in a mixture of DCM-DMSO (2 ml-4 ml) was added dropwise. The solution was stirred for 1 h at −78° C. and triethylamine (20 mL) was slowly added at −78° C. The reaction mixture was stirred 10 minutes at −78° C. and slowly warmed up to room temperature. Ice-cold water (100 ml) was added to the reaction mixture and the aqueous layer extracted with DCM (3×100 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated in vacuum to give a brown oil. Purification by column chromatography on silica gel (eluent: hexane-ethyl acetate 8/2) gave the title compound as white needles (3.2 g, 82%). 1H NMR (300.13 MHz, CDCl3) (ppm) 2.42 (s, 6H) 7.73 (s, 2H) 10.50 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([CH2:45][CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([CH2:45][CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(CCCN2CCCCC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(CCCN2CCCCC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 35 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (120 mg, 0.24 mmol), 2-(methyloxy)-4-[3-(1-piperidinyl)propyl]aniline (Example 139, step D) (55 mg, 0.22 mmol), and p-toluenesulfonic acid (111 mg, 0.59 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 40 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (54 mg, 0.077 mmol, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.36 (s, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.63 (s, 1H), 7.34-7.45 (m, J=17.58 Hz, 2H), 7.27 (s, 1H), 7.12-7.21 (m, 2H), 6.91-6.98 (m, 2H), 6.74 (s, 1H), 6.59 (s, 1H), 3.97 (s, 3H), 3.81 (s, 3H), 2.51-2.59 (m, 2H), 2.19-2.31 (m, 6H), 1.67-1.77 (m, 2H), 1.42-1.50 (m, 4H), 1.30-1.39 (m, 2H). MS (ESI): 704 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=3[Cl:21])[N:10]=[C:6]2[C:5]([F:22])=[CH:4][N:3]=1.[Br:23][Si](C)(C)C>C(#N)CC>[Br:23][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=3[Cl:21])[N:10]=[C:6]2[C:5]([F:22])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)Br
Reactant: O=[N+]([O-])c1cc(Cl)c(-n2cc3c(Cl)ncc(F)c3n2)c(Cl)c1
Solvent: CCC#N
Product: O=[N+]([O-])c1cc(Cl)c(-n2cc3c(Br)ncc(F)c3n2)c(Cl)c1
Temperature: 105 °C
Yield: 102.9 %

Procedure:
4-Chloro-2-(2,6-dichloro-4-nitrophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (1.78 g, 4.93 mmol) was suspended in propionitrile (30 mL), under an atmosphere of nitrogen and bromo trimethylsilane (5.1 mL, 38.3 mmol) was added. The reaction mixture was heated at 105° C. overnight. The resultant mixture was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was further extracted with ethyl acetate (×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with pentane and the solid obtained was dried under reduced pressure to afford the title compound as a pale yellow solid (2.06 g, quantitative yield). 1H NMR (300 MHz, CDCl3): δ 8.44 (s, 2H), 8.33 (d, J=2.2 Hz, 1H), 8.05 (d, J=3.0 Hz, 1H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Br:11][C:12]1[CH:13]=[C:14]([C:17](=[O:19])[CH3:18])[O:15][CH:16]=1.C([O:27][C:28](=O)[C:29]([F:33])([F:32])[CH2:30][CH3:31])C1C=CC=CC=1>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([C:17](=[O:19])[CH2:18][C:28](=[O:27])[C:29]([F:33])([F:32])[CH2:30][CH3:31])[O:15][CH:16]=1
Reactant: CC(=O)c1cc(Br)co1
Reactant: CCC(F)(F)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(F)(F)C(=O)CC(=O)c1cc(Br)co1
Temperature: -78 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
A solution of lithium hexamethyldisilazide (2.4 mL of a 1.0M solution in THF, 2.4 mmol) was diluted with THF (2 mL) and cooled in a −78° C. bath. To this cold solution was added 1-(4-bromo-furan-2-yl)-ethanone (317 mg, 1.68 mmol) dropwise as a solution in THF (4 mL), followed by a THF (1 mL) rinse of the vial and syringe to insure complete transfer. After ˜2 minutes the resulting red enolate solution was treated with a solution of 2,2-difluoro-butyric acid benzyl ester (357 mg, 1.67 mmol) in THF (4 mL), followed by a THF (1 mL) rinse of the vial and syringe to insure complete transfer. After the completion of the addition, the cooling bath was removed and the reaction was allowed to warm to ambient temperature. After stirring for 16 hrs at ambient temperature, the reaction was quenched by the addition of H2O (10 mL), and diluted with ether (50 mL). Phosphoric acid (2M, aqueous) was added to the mixture to bring the pH below 3. The layers were separated and the aqueous was extracted with ether (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a dark brown oil. The crude material was purified by flash chromatography eluting with a gradient from 0% to 30% ethyl acetate/hexane to afford 1-(4-bromo-furan-2-yl)-4,4-difluoro-hexane-1,3-dione (224 mg, 46% yield) as a red oil. The compound exists primarily in its' enolic form. 1H-NMR (400 MHz, CDCl3): δ 14.77 (1H, br s), 7.62 (1H, s), 7.27 (2H, s), 6.45 (1H, s), 2.12 (2H, t of q, JH-H=7.6 Hz, JH-F=16.7 Hz), 1.05 (3H, t, J=7.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][C:27](O)=[O:28]>>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:27](=[O:28])[CH2:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17]
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: COc1ccccc1CCC(=O)O
Product: COc1ccccc1CCC(=O)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 62 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 3-(2-methoxyphenyl) propionic acid in 62% yield following procedure 1. The product was crystallized from acetonitrile. 96% Purity by LC/MS (TIC, DAD), Mass-spec [M+H+]=371, 1H NMR (MeOH-d4): 2.62 t, 7.5 Hz (2H), 2.97 t, 7.5 Hz (2H), 3.74 s (3H, OMe), 6.40 s (1H), 6.81 t, 7 Hz (1H), 6.88 d, 8 Hz (1H), 7.03 t, 8 Hz (1H), 7.10–7.14 m (2H), 7.17 t, 8 Hz (1H), 7.27 t, 7 Hz (1H), 7.33 td, 7.5, 1 Hz (1H), 7.40 d, 8 Hz (1H), 7.54 d, 8 Hz (1H), 7.57 dd, 7.1 Hz (1H), 7.76 d, 8 Hz (1H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:16]=[C:17]([C:21]4([C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)[N:3]=1>C(O)(=O)C>[CH3:1][C:2]1[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4([C:27]5[O:28][C:31]([CH3:32])=[CH:30][N:29]=5)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:16]=3)=[CH:10][CH:9]=2)[N:3]=1
Reactant: C#CCNC(=O)C1(c2cccc(Sc3ccc(-n4nc(C)[nH]c4=O)cc3)c2)CCOCC1
Solvent: CC(=O)O
Product: Cc1nn(-c2ccc(Sc3cccc(C4(c5ncc(C)o5)CCOCC4)c3)cc2)c(=O)[nH]1

Procedure:
A solution of 4-(3-{[4-(3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)-N-prop-2-yn-1-yltetrahydro-2H-pyran-4-carboxamide (1.0 mmol) (example 16) and mercuric acetate (0.11 mmol) in acetic acid is heated at reflux for about 3 hours. All the volatiles are removed under reduced pressure and an aqueous solution of saturated potassium carbonate is added to the residue. The mixture is then extracted with dichloromethane, and the organic layer is dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue is then purified by column chromatography over silica gel to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:19]([F:21])[F:20].O>CN(C)C=O>[F:20][CH:19]([F:21])[O:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: FC(F)Cl
Reactant: COC(=O)c1cc(O)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OC(F)F)n(C)n1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
67.6 g (0.43 mol) 5-Hydroxy-3-methoxycarbonyl-1-methyl-pyrazole and 299.2 g (2.17 mol) potassium carbonate was dissolved in 1500 ml dimethylformamide and heated to 70° C. At this temperature chlorodifluoromethane was introduced over 2 hours and the mixture stirred at 80° C. for 1.5 hours. The reaction mixture was added to water and extracted 6 times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The reaction solution was concentrated.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.C1(C=CC(O)=CC=1)O.[C:23]([N:31]1[CH2:40][CH2:39][C:38]2[CH:33]([CH2:34][CH2:35][C:36](=[O:41])[CH:37]=2)[CH2:32]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>[Cu]I.O.O1CCCC1>[C:23]([N:31]1[CH2:40][CH2:39][C@@:38]2([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=3)[C@H:33]([CH2:34][CH2:35][C:36](=[O:41])[CH2:37]2)[CH2:32]1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C1C=C2CCN(C(=O)c3ccccc3)CC2CC1
Agent: [Cu]I
Agent: O=S(=O)([O-])[O-]
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc([C@]23CCN(C(=O)c4ccccc4)C[C@H]2CCC(=O)C3)c1
Reaction time: 0.5 h

Procedure:
278 ml. of 2.2 N butyl lithium solution (612 mmol) are added to a mixture of 600 ml of absolute tetrahydrofuran, 112.2 g (600 mmol) of 3-bromoanisole and 661 mg (6 mmol) of hydroquinone at -65° under nitrogen. The resulting mixture is kept at -50° for 30 minutes, treated with 57.13 g (0.3 mol) of copper (I) iodide, stirred for 1 hour at -43°, and treated with 51.06 g (0.2 mol) of 1,3,4,7,8,8a-hexahydro-2-benzoyl-6(2H)-isoquinolinone. The mixture is allowed to warm to 0° over 2 hours and kept at 0° for 16 hours. 1.2 liters of water and 79.28 g (0.6 mol) of ammonium sulphate are added to the mixture which is then extracted with toluene. The organic extracts are evaporated to yield an oil which is chromatographed on silicagel using ethyl acetate as eluant. The product, 2-benzoyl-octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-iso-quinolinone is obtained as colourless crystals from methanol; M.Pt. 78°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]([C:20](OC)=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:20][OH:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CO)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice-cold solution of methyl O-benzyl-N-(tert-butoxycarbonyl)homoserinate (6 g, 18.6 mmol) in absolute ethanol (100 mL) is added sodium borohydride (2.8 g, 74.2 mmol), and the reaction is refluxed 2 h. The solution is cooled, excess saturated potassium carbonate added, and stirred 16 h at room temperature. The ethanol is removed under reduced pressure, and the aqueous solution is extracted with chloroform. The organic layer is washed with saturated sodium bicarbonate, saturated sodium sulfate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give the title compound. ESI MS m/z 296.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[C:14]([CH3:34])=[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:16]3[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:21]([N:16]1[C:17]2[C:13](=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[CH:7][CH:8]=3)[CH:20]=[CH:19][CH:18]=2)[C:14]([CH3:34])=[C:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(-c2cccc3c2c(C)c(-c2ccccc2)n3Cc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(OCC(=O)O)cc3)c12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(1-benzyl-3-methyl-2-phenyl-1H-indol-4-yl)-phenoxy]-acetic acid methyl ester (0.263 g, 0.570 mmol) was reacted with 1N KOH (1.1 ml) in THF/MeOH (3 ml/2 ml) to give the product (0.198 g, 0.442 mmol, 78%) as a white foam, mp 82-86° C. 1H NMR (DMSO-d6) δ 1.72 (s, 3H), 4.70 (s, 2H), 5.29 (m, 2H), 6.84 (d, J=7.2 Hz, 1H), 6.88 (d, J=7.3 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 7.11 (t, J=7.5 Hz, 1H), 7.16 (t, J=7.0 Hz, 1H), 7.22 (t, J=7.0 Hz, 2H), 7.31-7.34 (m, 5H), 7.40 (t, J=7.0 Hz, 1H), 7.45 (t, J=6.7 Hz, 2H); IR (solid) 3030, 2910, 1730, 1605, 1520, 1480, 1430, 1210, and 1180 cm−1; [ESI(+)], m/z 448 (M+H)+; Anal. Calcd. for C30H25NO3.0.33H2O: C, 80.51; H, 5.63; N, 3.13; Found: C, 79.30; H, 5.78; N, 3.00.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH3:35][C@@H:36]1[CH2:41][CH2:40][CH2:39][NH:38][C@@H:37]1[CH2:42][N:43]1[C:51](=[O:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]1=[O:53]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[C:4]([N:38]1[CH2:39][CH2:40][CH2:41][C@@H:36]([CH3:35])[C@H:37]1[CH2:42][N:43]1[C:51](=[O:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]1=[O:53])=[O:6]
Reactant: O=C(O)c1c(F)cccc1-c1ncccn1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 15.5 %

Procedure:
A solution of 2-fluoro-6-(pyrimidin-2-yl)benzoic acid (366 mg, 1.67 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (292 mg, 1.67 mmol), and N-methylmorpholine (421 mg, 4.18 mmol) in anhydrous 1,4-dioxane (10 mL) was stirred at rt under nitrogen for 1.5 h. A solution of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (359 mg, 1.39 mmol) in anhydrous 1,4-dioxane (3 mL) was added at rt. After the addition was completed, the reaction was heated to 80° C. under nitrogen for 5 h. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL), subsequently washed with 0.1 N HCl (100 mL), 0.1 N NaOH (100 mL), and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes) to afford the title compound as a white foam (99 mg, 15%). ESI MS (M+H) 459.
Reaction SMILES: O.[OH-].[Li+].[OH:4][C@H:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][C:7]([O:9]C)=[O:8].Cl>C1COCC1.O.C(OCC)C>[OH:4][C@H:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCC[C@@H](O)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Lithium hydroxide monohydrate (1.98 g, 47.2 mmol) was added to a solution of (R)-methyl 3-hydroxytetradecanoate (42, 8.17 g, 31.5 mmol) in THF (66 mL) and water (66 mL) and stirred at room temperature for 2 h. The mixture was then diluted with diethyl ether (1 L) and the pH adjusted to ˜3 with a solution of hydrochloric acid (1 N). The solution was then extracted with diethyl ether (200 mL), and the organic fractions were combined and dried over Na2SO4. Na2SO4 was removed by filtration and the filtrate was concentrated in vacuo to provide (R)-3-hydroxytetradecanoic acid (36, 7.59 g, 98%) as an off-white solid. 1H NMR (CDCl3) δ 3.99-3.94 (m, 1H), 2.45-2.39 (m, 2H), 1.47 (br s, 3H), 1.29 (br s, 17H), 0.89 (t, J=7.0 Hz, 3H).