Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([NH:21][C@H:22]1[CH2:47][CH2:46][C@:24]2([O:28][CH2:27][C@H:26]([C:29]3[CH:34]=[C:33]([N:35]4[CH:39]=[CH:38][N:37]=[C:36]4[C:40]([F:43])([F:42])[F:41])[CH:32]=[CH:31][C:30]=3[O:44][CH3:45])[CH2:25]2)[C@@H:23]1[C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1)=O)C1C=CC=CC=1.IC.[C:57]([O:60][CH2:61][CH3:62])(=[O:59])[CH3:58]>C1COCC1>[CH2:61]([O:60][C:57]([CH2:58][NH:21][C@H:22]1[CH2:47][CH2:46][C@:24]2([O:28][CH2:27][C@H:26]([C:29]3[CH:34]=[C:33]([N:35]4[CH:39]=[CH:38][N:37]=[C:36]4[C:40]([F:42])([F:43])[F:41])[CH:32]=[CH:31][C:30]=3[O:44][CH3:45])[CH2:25]2)[C@@H:23]1[C:48]1[CH:49]=[CH:50][C:51]([F:54])=[CH:52][CH:53]=1)=[O:59])[C:62]1[CH:46]=[CH:47][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(-n2ccnc2C(F)(F)F)cc1[C@H]1CO[C@]2(CC[C@H](NC(=O)OCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(-n2ccnc2C(F)(F)F)cc1[C@H]1CO[C@]2(CC[C@H](NCC(=O)OCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A THF solution of sodium bis(trimethylsily)amide (0.059 mL, 1.0M, 0.059 mmol) was added to an ice-cooled solution of (3S,5R,6R,7S)-7-(benzyloxycarbonylamino)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]nonane (30 mg, 0.049 mmol) in 0.50 mL of dry THF. After stirring for 15 minutes at 0° C., iodomethane (0.0037 mL, 8.4 mg, 0.059 mmol) was added. The mixture was stirred at 0° C., then allowed to warm up to RT for 3 h. The reaction was diluted in 20 mL of ethyl acetate and washed with 10 mL of saturated aqueous sodium bicarbonate, followed by 10 mL of brine. Drying over sodium sulfate and concentration afforded the crude product. Purification by preparative TLC, eluting with 30% ethyl ether in 1:1 toluene/hexane, yielded 7.5 mg of pure title compound and 15 mg of a mixture containing the title compound and recovered starting material. Mass spectrum (NH3/CI): m/z=624.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[NH2:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22]>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([NH:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22])=[O:8]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: NC(CO)CO
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NC(CO)CO)c1I
Yield: 95 %

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride was reacted with serinol according to the conditions in Example 24 g. The product was isolated in 95% yield.
Reaction SMILES: CC1C=CC(C(O[C@H]([C@@H](OC(=O)C2C=CC(C)=CC=2)C(O)=O)C(O)=O)=O)=CC=1.[F:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([N:40]1[CH2:45][CH2:44][N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=3)[CH2:42][CH2:41]1)[N:36]([C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[CH:56][C:55]=1[O:64][CH3:65])[CH:35]2[CH2:66][C:67]([O:69]C)=[O:68].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([N:40]1[CH2:41][CH2:42][N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=3)[CH2:44][CH2:45]1)[N:36]([C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[CH:56][C:55]=1[O:64][CH3:65])[C@@H:35]2[CH2:66][C:67]([OH:69])=[O:68]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: Cc1ccc(C(=O)O[C@@H](C(=O)O)[C@@H](OC(=O)c2ccc(C)cc2)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cccc(N2CCN(C3=Nc4c(F)cccc4[C@@H](CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
(2R,3R)-2,3-Bis [(4-methylbenzoyl)oxy]succinic acid-methyl {8-fluoro-2-[4-(3-methoxyphenyl)-piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (1:1 salt) (170 g) are suspended in ethyl acetate (850 ml) and shaken with saturated aqueous sodium bicarbonate solution (850 ml) until both phases are clear (ca. 5 min.). The phases are separated, and the solvent of the organic phase is replaced at normal pressure with 1,4-dioxane up to a final temperature of 99° C. (a total of 2.55 l of solvent is distilled off and 2.55 l of 1,4-dioxane are employed in portions). The mixture is cooled to room temperature and stirred at room temperature for 18 h with 1N sodium hydroxide solution (525 ml). Subsequently, the pH is adjusted to 7.5 using concentrated hydrochloric acid (ca. 35 ml), MIBK (850 ml) is added, then the pH is readjusted to 7.0 using concentrated hydrochloric acid (ca. 10 ml). The phases are separated, and the organic phase is dried over sodium sulphate and concentrated. The residue is dissolved in ethanol (350 ml) and concentrated, then again dissolved in ethanol (350 ml) and concentrated at 50° C. A total of 91.6 g of (R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid are thus obtained as an amorphous solid, corresponding to 91.6% of theory.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:18][CH:19]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC(=O)C(=CNc1ccc(CO)cc1)C(=O)OCC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)C(=CNc1ccc(COC(=O)c2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
A solution of ethyl 2-butyryl-3-(4-hydroxymethylphenylamino)acrylate (49.5 g, 0.17 mol) and pyridine (50 ml) in chloroform (250 ml) was stirred at 0°-5° (ice-bath). Benzoyl chloride (22 ml, 0.19 mol) in chloroform (250 ml) was added dropwise keeping the reaction temperature below 10° C. Cooling was removed and the mixture was stirred overnight at room temperature. The mixture was washed with 2M HCl, sodium hydrogen carbonate solution and brine, dried (anhyd. MgSO4), filtered and evaporated to an oil which crystallized on standing. The product was slurried with petroleum ether, filtered off and washed with petroleum ether to give ethyl 2-butyryl-3-(4-benzoyloxymethylphenylamino)acrylate as white crystals (61.8 g, 92%), m.p. 73°-5° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][NH2:1])[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(C)Cn1c(CN=[N+]=[N-])nc2c(N)nc3ccccc3c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cn1c(CN)nc2c(N)nc3ccccc3c21

Procedure:
2-Azidomethyl-1(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.2 g, 0.0108 mol, Example 11) was added to ethanol (300 mL) and 5% Pd/C (about 1 g) was added to the mixture. The mixture was hydrogenated on a Parr apparatus until hydrogen uptake stopped. Hydrogen was removed and the mixture was flushed with hydrogen to regenerate the catalyst. Hydrogenation was resumed. This procedure was repeated until no more hydrogen was absorbed. The catalyst was filtered from the mixture and the filtrate was evaporated. The residue was recrystallized several times from ethanol to give yellowish crystals m.p. 287-291° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=O.[ClH:7].[N:8]1([CH2:14][CH:15]=[CH:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl.CN(C)C=O>[ClH:4].[ClH:7].[N:8]1([CH2:14][CH:15]=[CH:16][C:17]([O:19][C:1](=[O:5])[CH:2]=[CH:15][CH2:14][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(O)C=CCN1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(C=CCN1CCCCC1)OC(=O)C=CCN1CCCCC1
Reaction time: 1 h

Procedure:
Oxalyl chloride (4.2 ml) was added to a stirred solution of 4-(piperidin-1-yl)-but-2-enoic acid hydrochloride (10 g) in dichloromethane (200 ml). Dimethylformamide (2 drops) was then added. The resultant suspension was stirred for 4 h and then concentrated to ˜25 ml. The slurry obtained was stirred a further 1 h and then filtered. The filter pad was washed with dichloromethan (50 ml) and dired in vacuo to give the title compound as a white solid (4.95 g). M.p. 120-124° C. (decomposition).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[Cl:2][CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:24]=[O:26])=[CH:8][CH:7]=1)[CH2:13][CH2:14][Cl:15]
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C=Nc1ccc(N(CCCl)CCCl)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride 18 (1.22 g, 4 mmol) in dry chloroform (50 mL) was added triethylamine (0.72 mL) at room temperature. The clear solution obtained was then cooled to −10° C. and a solution of triphosgene (0.712 g, 2.4 mmole) in dry chloroform (10 mL) was added dropwise into a reaction mixture at 0° C. After being stirred for 30 min, the reaction mixture was evaporated to dryness under reduced pressure. The solid residue was triturated with dry THF (100 ml), filtered, and washed with small amount of THF. The combined filtrate and washings was evaporated to dryness to give the crude isocyanate 19, which was then dissolved in dry DMF (5 mL) and added dropwise to a solution of N1-(6-methoxy-2-methylquinolin-4-yl)benzene-1,3-diamine (0.56 g, 2 mmol) in dry DMF (10 mL) containing Et3N (1 mL). After being stirred for 5 h at room temperature, the solid separated was filtered and washed with dry DMF. The filtrate was evaporated to dryness in vacuo. The residue was purified by column chromatography using CHCl3/MeOH (100:3 v/v) as an eluent. The fractions containing the main product were combined and evaporated to dryness and the residue was recrystallized from CHCl3 to give BO-1547 (0.87 g, 81%); mp 225-227° C.; 1H NMR (DMSO-d6) δ 2.58 (3H, s, Me), 3.68-3.70 (8H, m, CH2), 3.97 (3H, s, OMe), 6.73-6.69 (3H, m, Ar—H), 7.03 (1H, d, J=7.6 Hz, Ar—H), 7.28 (2H, d, J=9.0 Hz, Ar—H), 7.35 (1H, d, J=7.7 Hz, Ar—H), 7.44 (1H, t, J=8.0 Hz, Ar—H), 7.64-7.62 (1H, m, Ar—H), 7.71 (1H, s, Ar—H), 7.93 (1H, d, J=9.1 Hz, Ar—H), 8.09 (1H, s, Ar—H), 8.84 (1H, s, NH, Exchangeable), 9.31 (1H, s, NH, Exchangeable), 10.49 (1H, s, NH, Exchangeable); ESI-HRMS calcd for C28H29Cl2N5O2 m/z 538.4682 (M+H). found 538.2451 (M+H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[O:5][CH2:4][C@@H:3]1[NH:10][C:11](=[O:19])[O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>ClCCl>[CH3:30][S:27]([O:1][C@@H:2]1[C@@H:3]([NH:10][C:11]([O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])=[O:19])[CH2:4][O:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)C[C@H](O)[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C[C@H](OS(C)(=O)=O)[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 124.4 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (3S,4S)-4-hydroxy-6,6-dimethyl-tetrahydro-2H-pyran-3-ylcarbamate (1.0 g, 3.5 mmol) and triethylamine (1.4 mL, 10 mmol) in dichloromethane (10 mL) at 0° C. was dropwise added mesyl chloride (600 mg, 5.20 mmol). The reaction mixture was stirred at room temperature for 4 hours and then diluted with dichloromethane (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (1.6 g, crude) as a yellow oil which was directly used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][C@H:14]([CH3:18])[CH2:13]1)=[CH:8][C:7]2=[O:19].C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.Cl>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:29]([C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][C@H:14]([CH3:18])[CH2:13]1)=[CH:8][C:7]2=[O:19])(=[O:31])[CH3:30]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Br)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(C)=O)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (1.45 g, 3.79 mmol), bis(triphenylphosphine) palladium(II) chloride (0.107 g, 0.15 mmol) and tributyl(1-ethoxyvinyl)stannane (1.346 mL, 3.98 mmol) in 1,4-dioxane (20 mL) were degassed, purged with argon and heated to 90° C. for 4 hrs. After cooling to RT, HCl 2N (1.9 mL, 3.79 mmol) was added and the mixture was left to stir for 1 h. The reaction mixture was concentrated, suspended in water, neutralised with NaHCO3 and extracted with DCM. The combined organic phases were washed with water, brine, dried over magnesium sulfate and concentrated. The crude product was triturated with n-heptane, filtered and retriturated with ether, filtered and dried to give methyl 8-acetyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (1.15 g, 88%) as a grey solid.
Reaction SMILES: [CH2:1]([C:3]1([CH3:20])[C:7](=[O:8])[C:6](I)=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[O:4]1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])[CH3:28]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([C:30]1[CH:35]=[CH:34][C:33]([C:6]2[C:7](=[O:8])[C:3]([CH2:1][CH3:2])([CH3:20])[O:4][C:5]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:32][CH:31]=1)(=[O:29])[CH3:28]
Reactant: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(I)C1=O
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc(C(C)=O)cc2)C1=O
Temperature: 95 °C
Reaction time: 12 h
Yield: 61.2 %

Procedure:
To a stirred solution of 2-ethyl-4-iodo-2-methy-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (200 mg) in 15 ml toluene and 5 ml ethanol, were added 34 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2M aqueous sodium carbonate solution and 120 mg of 4-acetylbenzeneboronic acid. Then the reaction solution was stirred at 95° C. for 12 hours. The reaction solvent was evaporated off under reduced pressure and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). Then the organic layer was concentrated in vacuo and the resulting crude product was purified by column chromatography (hexane/ethylacetate) to afford 120 mg of 4-(4-acetylphenyl)-2-ethyl-2-methyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 147-148° C. NMR: δ0.97 (t, J=7.5 Hz, 3H), 1.56 (s, 3H), 1.99 (m, 2H), 2.62 (s, 3H), 3.08 (s, 3H), 7.39 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 7.97 (m, 2H). IR (cm−1): 2929, 1684, 1410, 1317, 1149, 1016, 769, 552.
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[C:4]([CH3:16])([CH3:15])[CH2:3]1.[N:17]([Na])=[N+:18]=[N-:19]>CN(C=O)C>[N:17]([CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[C:4]([CH3:16])([CH3:15])[CH2:3]1)=[N+:18]=[N-:19]
Reactant: COc1ccc2c(c1)C(Br)CC(C)(C)C2=O
Reactant: [N-]=[N+]=N[Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(N=[N+]=[N-])CC(C)(C)C2=O
Temperature: 60 °C
Yield: 88.8 %

Procedure:
4-Bromo-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one (3.9 g, 14 mmol) was added to DMF (10 mL) followed by azidosodium (3.6 g, 55 mmol). The mixture was heated to 60° C. overnight. The reaction was cooled to RT and quenched with water (25 mL). The aqueous layer was extracted with Et2O (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and the residue was purified by column chromatography (0-50% EtOAc/Hexane to provide the title compound as a white solid (3.05 g, 90% yield). MS m/z: 268.2 (M+Na).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[O:23][CH3:24])=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:29])=O.CN(C)C=O>ClCCl>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([Cl:29])=[O:19])=[CH:16][C:15]=2[O:23][CH3:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1cc(C(=O)O)ccc1OCCCCCOc1ccc(C#N)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)ccc1OCCCCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid (3600 g, 10.13 mol) is suspended in dichloromethane (36 L) and to this is added thionyl chloride (1345 g, 11.30 mol) dropwise over 20 minutes followed by dimethylformamide (74.4 g, 10.0 mmol). The reaction mixture is stirred at room temperature for 21 hours; after 6 hours a complete solution is obtained. The solution is concentrated in vacuo (50° C, 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoyl chloride as a solid, which is then redissolved in dichloromethane (36 L) without further purification and cooled to 5° C. with an ice bath. Diisopropylamine (3077 g, 30.40 mmol) is added dropwise over a period of 1 hour. The reaction mixture is stirred at 20° C. for 3 hours and then, N,N-dimethylethylenediamine (80.3 g, 0.91 mmol) is added. The reaction is followed by TLC (2:1 ethyl acetate/hexanes, silica plates) until no more byproduct (bis-anhydride of 4-[5-(4-cyanophenoxy)pentoxy]3-methoxybenzoic acid) is detected. The reaction mixture is then stirred overnight at room temperature. Water (18 L) is added,stirred and the layers separated. The organic layer is washed with hydrochloric acid (1.0 N, 23 L), water (18 L), ammonium hydroxide (0.5 N, 2×23 L), water (18 L) and brine solution (18 L). The separated dichloromethane solution is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo (50° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)- benzamide as a solid. The solid is dissolved in 2 B ethanol (21.5 L) by warming and to the solution is added water (8.6 L). The product is allowed to crystallize overnight in an ice bath. The product is filtered, washed with EtOH/H2O (5:2, 2×2 L) and dried in vacuo (54° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)- benzamide, mp 90°-92° C. HPLC indicates a purity of >99.7%.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[OH:12]S(O)(=O)=O.N([O-])=O.[Na+].C(OCC)(=O)C>O>[OH:12][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C#N)c1cccc(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C#N)c1cccc(O)c1
Temperature: 4 °C
Reaction time: 0.33 h

Procedure:
2-(3-aminophenyl)propionitrile (1.0 g, 6.75 mmol), was suspended in water (12 mL), then under vigorous stirring, H2SO4 (1.5 ml, 27 mmol) was added dropwise. After stirring 20 min, the mixture was cooled to 4° C., a solution of NaNO2 (0.466 g, 6.75 mmol) in water (5 mL) was added dropwise and the resulting solution was left stirring at reflux 1 h. After cooling at room temperature, ethyl acetate (10 mL) was added to the mixture, the crude was extracted and the organic phase washed with water (3×10 mL) and brine (3×10 mL). After drying over Na2SO4 and solvent evaporation under reduced pressure 2-(3-hydroxyphenyl)propionitrile was obtained as yellow oil in nearly quantitative yield.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=1.C([O:19][CH2:20][CH3:21])(=O)C>O1CCCC1>[CH3:15][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:13])[NH:14][C:21]2([NH:14][C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=3)=[O:13])[C:9]3[C:8](=[CH:7][CH:6]=[CH:5][CH:10]=3)[NH:11][C:20]2=[O:19])=[CH:7][CH:6]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(NC(N)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NC2(NC(=O)Nc3ccc(C)cc3)C(=O)Nc3ccccc32)cc1
Yield: 36 %

Procedure:
To a solution of 12.0 g of anhydrous aluminum chloride in 150 ml of dry tetrahydrofuran were added successively a solution of 5.79 g of isatin-3,3-dimethylacetal in 150 ml of dry tetrahydrofuran and 9.0 g of p-tolylurea at 0° C. under a nitrogen atmosphere, and the mixture was heated under reflux for 40 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed twice with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, followed by concentration. To the residue was added 150 ml of ethyl ether, and insoluble matter was removed by filtration. The filtrate was concentrated and recrystallized from acetone to yield 4.61 g (36%) of the title compound as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]([OH:17])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:19]=[CH2:20]>>[F:24][C:23]([F:26])([F:25])[C:22]([NH:21][CH2:18]/[CH:19]=[CH:20]/[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:10]([OH:17])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:3]=1)=[O:27]
Reactant: CCCC(O)(C#Cc1cccc(Br)c1)CCC
Reactant: C=CCNC(=O)C(F)(F)F
Product: CCCC(O)(C#Cc1cccc(/C=C/CNC(=O)C(F)(F)F)c1)CCC

Procedure:
4-((3-bromophenyl)ethynyl)heptan-4-ol was coupled with N-allyl-2,2,2-trifluoroacetamide following the procedure described in Example 123 to give (E)-2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)allyl)acetamide as a pale yellow oil. Yield (0.082 g, 10%): 1H NMR (400 MHz, DMSO-d6) δ 9.68 (t, J=5.4 Hz, 1H), 7.42-7.39 (m, 2H), 7.30 (t, J=8.0 Hz, 1H), 7.23 (dt, J=7.6, 1.4 Hz, 1H), 6.51 (d, J=16.0 Hz, 1H), 6.29 (dt, J=16.0, 6.0 Hz, 1H), 5.13 (s, 1H), 3.95 (t, J=5.4 Hz, 2H), 1.60-1.40 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).