Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1([CH3:25])[CH2:23][CH2:22][C:21](=O)[CH:20]=[CH:19]1.O>O1CCCC1>[CH3:17][C:18]1([CH3:25])[CH2:23][CH2:22][C:21](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:20]=[CH:19]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1C=CC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a suspension of sodium hydride (60% dispersion in oil, 2.2 g, 55 mmol) in tetrahydrofuran (100 ml) at 0° C. was added ethyl 2-(diethoxyphosphoryl)acetate (11.2 g, 50 mmol) over 30 min, and the mixture was stirred at room temperature for 1 h. To this was added 4,4-dimethyl-2-cyclohexene-1-one over 20 min and the reaction mixture was stirred for a further 1 h. Water (100 ml) was added and the mixture was extracted with ether (2×100 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (9.7 g, 100%).
Reaction SMILES: [CH:1]1([C@H:7]([NH:20][C:21]([C:23]2[C:24]([OH:34])=[N:25][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[N:27][CH:28]=2)=[O:22])[C:8]2[CH:13]=[CH:12][C:11]([P:14]([CH3:19])(=[O:18])[O:15]CC)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1>[CH:1]1([C@H:7]([NH:20][C:21]([C:23]2[C:24]([OH:34])=[N:25][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[N:27][CH:28]=2)=[O:22])[C:8]2[CH:13]=[CH:12][C:11]([P:14]([CH3:19])(=[O:15])[OH:18])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOP(C)(=O)c1ccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1ccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)C2CCCCC2)cc1
Temperature: 80 °C

Procedure:
A solution of 27-e (0.90 g, 1.86 mmol) in 30 ml of dioxane was treated with 3 ml of 3N NaOH and heated at 80° C. for 2 hour. The mixture was cooled to room temperature and then concentrated under vacuum and the residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with conc. HCl to pH=1 and resulting solids were collected via filtration to give 27-1 (400 mg 47.2%). 1H NMR (300 MHz, DMSO-d6): δ 10.06 (br, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.70 (m, 2H), 7.39 (m, 2H), 6.73 (s, 1H), 4.88 (m, 1H), 1.52 (m, 9H), 1.16 (m, 5H). (M+H)+=456.2.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC)(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[SH:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=[O:30])[N:21]=2)[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cc(C2CCCN2C(=O)c2ccccc2)ccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)N1CCCC1c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 83.8 %

Procedure:
4-(1-Benzoyl-2-pyrrolidinyl)-2-pyridinecarbonitrile (0.42 g, 1.5 mmol) and methyl thiosalicylate (1.03 g, 6.1 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 14 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (4:1, v/v) were collected and concentrated to give the titled compound (0.52 g, 82%) as amorphous crystals.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].C(=O)([O-])[O-].[Na+].[Na+].[C:17](OCC)(=[O:22])[CH2:18][C:19]([CH3:21])=O>O>[CH3:21][C:19]1[N:9]=[C:8]([S:7][CH3:6])[NH:10][C:17](=[O:22])[CH:18]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CSc1nc(C)cc(=O)[nH]1
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of 2-methyl-2-thiopseudourea sulfate (Aldrich, 58.74 g, 0.422 mol) in water (1000 mL) were added sodium carbonate (81.44 g, 0.768 mol) and ethyl acetoacetate (50 g, 0.384 mol) at room temperature. The reaction mixture was stirred overnight. After neutralizing to pH=8, the solid was collected through filtration followed by drying under vacuum overnight to afford 6-methyl-2-(methylthio)pyrimidin-4(3H)-one (57.2 g, 95% yield) of product. 1H NMR (400 MHz, DMSO-d6): δ 12.47 (bs, 1H), 5.96 (bs, 1H), 2.47 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1[OH:16])=[C:13]([Cl:17])[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[OH-].[Na+:27]>C(O)C>[CH3:2][CH2:1][N:3]([C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:17])[C:14]=2[C:15]=1[O-:16])=[O:5])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1.[Na+:27]
Reactant: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(C(=O)c1c([O-])c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 27.5 °C
Yield: 81.3 %

Procedure:
Laquinimod (2.7 gm) was taken in ethanol (13 ml) and stirred at 25-30° C. followed by the addition of sodium hydroxide solution (0.33 gm of NaOH in 0.4 ml of water). The resulting solution was stirred for 15 minutes followed by filtration through hyflow bed and washing of the bed with ethanol (7 ml). The resulting clear solution was then stirred for 16 hours at 25-30° C. The separated solid was filtered, washed with chilled ethanol (2 ml) and then dried at 60-65° C. to yield 2.33 gm of laquinimod sodium as a white solid (HPLC Purity: 99.92%).
Reaction SMILES: N[C:2]([NH2:4])=[NH:3].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([C:20](Cl)=[N:21][OH:22])[CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])([CH3:8])[CH3:7]>C(O)C>[NH2:4][C:2]1[O:22][N:21]=[C:20]([C:11]2[CH:12]=[C:13]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:14]([OH:15])=[C:9]([C:6]([CH3:8])([CH3:7])[CH3:5])[CH:10]=2)[N:3]=1
Reactant: N=C(N)N
Reactant: CC(C)(C)c1cc(C(Cl)=NO)cc(C(C)(C)C)c1O
Solvent: CCO
Product: CC(C)(C)c1cc(-c2noc(N)n2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2.6 g (0.044 mole) of guanidine in absolute ethanol (100 ml) is added dropwise a solution of 6.2 g (0.022 mole) of 3,5-bis(1,1-dimethylethyl)-N,4-dihydroxybenzenecarboximidoyl chloride in absolute ethanol (60 ml). The mixture is stirred at room temperature for 18 hours, then evaporated to dryness (vacuum). The oil is dissolved in ethyl acetate (125 ml) and poured into water (125 ml). While stirring, the solution is acidified (pH 4.0-5.0) with 1N hydrochloric acid. The organic layer is separated, washed with water (2×100 ml), and dried (anhydrous magnesium sulfate). Evaporation of the organic layer leaves 5.0 g of crude material. Purification by flash chromatography (silica gel, ethyl acetate/hexane elution) gives 1.0 g (16%) of analytically pure 4-(5-amino-1,2,4-oxadiazol-3-yl)-2,6-bis(1,1-dimethylethyl)phenol, mp 202°-204° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC=CC=3)(=O)=O)[C:9]([CH3:11])=[CH:10][C:3]=12.[Cl:21][C:22]1[CH:23]=[N:24][N:25]([CH2:52][CH3:53])[C:26]=1[C:27]([NH:29][C:30]1[CH:38]=[C:37]([Sn](C)(C)C)[CH:36]=[C:35]2[C:31]=1[CH:32]=[N:33][N:34]2S(C1C=CC=CC=1)(=O)=O)=[O:28].C1(S)C=CC=CC=1>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[N:24][N:25]([CH2:52][CH3:53])[C:26]=1[C:27]([NH:29][C:30]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][C:9]([CH3:11])=[CH:10][C:3]=23)[CH:36]=[C:35]2[C:31]=1[CH:32]=[N:33][NH:34]2)=[O:28]
Reactant: Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Reactant: CCn1ncc(Cl)c1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Agent: Sc1ccccc1
Solvent: CN(C)C=O
Product: CCn1ncc(Cl)c1C(=O)Nc1cc(-c2ccnc3[nH]c(C)cc23)cc2[nH]ncc12
Temperature: 135 °C
Reaction time: 8 h

Procedure:
4-Bromo-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (63 mg) in DMF (0.4 ml) was added to 4-chloro-1-ethyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1H-pyrazole-5-carboxamide (100 mg) in DMF (0.4 ml). Solvias catalyst (4 mg) was added and the sealed vessel was heated in the Anton Paar microwave at 135° C. for 20 min. PS-thiophenol resin was added and the reaction was stirred overnight before being filtered onto a C18SPE cartridge, pre-washed with 0.1% TFA, with acetonitrile. The cartridge was washed with 0.1% TFA in acetonitrile and the collected solvent was removed under a stream of nitrogen. The residue was dissolved in DMSO (1 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo. The residue was dissolved in isopropanol (0.3 ml), 2M sodium hydroxide (aq) (0.3 ml) was added and the reaction was left at room temperature overnight, then heated to 60° C. for 1 h. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO (0.5 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo to give title compound, 6 mg.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.CC1(C)C(C)(C)[O:15][B:14](B2OC(C)(C)C(C)(C)O2)[O:13]1.C(Cl)Cl.C([O-])(=O)C.[K+].Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([B:14]([OH:15])[OH:13])[C:3]([CH3:10])=[N:4][CH:5]=1
Reactant: COc1cnc(C)c(Br)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cnc(C)c(B(O)O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution 3-bromo-5-methoxy-2-methylpyridine (500 mg, 2.475 mmol) in dry 1,4-Dioxane (5 ml), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (691 mg, 2.72 mmol), Pd(dppf)Cl2.CH2Cl2 (606 mg, 0.742 mmol) and potassium acetate (729 mg, 7.42 mmol) were added and the solution was heated to 80° C. The reaction was stirred overnight. Then, solvent was removed and residue dissolved in THF (5.00 ml) and 12 N aqueous hydrogen chloride (4.12 ml, 49.5 mmol) was added and stirred for 3 hrs. Then, solvent was removed and the product was purified by C-18 flash chromatography (eluent ((H2O/ACN)) 95:5+0.1% HCOOH}:{(ACN/H2O) 95:5+HCOOH 0.1%} from 95:5 to 0:100 affording the title (350 mg, 2.096 mmol, 85% yield) as a white solid.
Reaction SMILES: FC1C=C(C2(C(OCC)=O)CCCC2)C=C(OCC2C=CC(N3C=CN=C3C)=CC=2)C=1.[F:32][C:33]1[CH:34]=[C:35]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([N:56]3[CH:60]=[CH:59][N:58]=[C:57]3[CH3:61])=[CH:52][CH:51]=2)[CH:36]=[C:37]([C:39]2([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43]O[CH2:41][CH2:40]2)[CH:38]=1>>[F:32][C:33]1[CH:34]=[C:35]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][C:53]([N:56]3[CH:60]=[CH:59][N:58]=[C:57]3[CH3:61])=[CH:54][CH:55]=2)[CH:36]=[C:37]([C:39]2([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43][CH2:41][CH2:40]2)[CH:38]=1
Reactant: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(N)=O)CCOCC3)c2)cc1
Agent: CCOC(=O)C1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2)CCCC1
Product: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(N)=O)CCCC3)c2)cc1

Procedure:
The desired compound was prepared from ethyl 1-[3-fluoro-5-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]cyclopentane-1-carboxylate according to the preparation of 4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (Example 5).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][N:22]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C#N)cn2)CC1
Yield: 73.3 %

Procedure:
A solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (198 mg, 0.697 mmol), 2-chloro-5-cyanopyridine (90 mg, 0.65 mmol) and diisopropylethylamine (400 μL) in dioxane (2 mL) in a sealed tube was heated to 170° C. under microwave conditions for 20 minutes. The reaction mixture was cooled, concentrated and then purified by chromatography (silica gel, eluting with 10% hexane/ethyl acetate to 60% ethyl acetate/hexane) to provide the titled compound (167 mg) as a white foam. MS (CI) m/z 380 (M+1)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.45 (s, 1H), 7.80 (dd, 1H), 7.37 (m, 5H), 7.18 (s, 1H), 6.93 (d, 1H), 5.00 (s, 2H), 4.00-3.95 (m, 2H), 3.35-3.26 (m, 2H), 2.19-2.07 (m, 2H), 1.49-1.43 (m, 2H), 1.27 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]3[N:15]([CH2:18][C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[N:25]=[CH:24][CH:23]=[CH:22]5)[N:16]=[N:17][C:12]3=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1>ClCCl.B(Br)(Br)Br>[N:25]1[C:26]2[C:21](=[CH:20][C:19]([CH2:18][N:15]3[C:13]4=[N:14][C:9]([C:5]5[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=5)=[CH:10][CH:11]=[C:12]4[N:17]=[N:16]3)=[CH:28][CH:27]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To a solution of example 2 (0.110 g, 0.299 mmol) in dichloromethane (1 ml), BBr3 (1M in dichloromethane, 0.82 ml) was added at 0° C. and the reaction mixture was warmed to RT and stirred for 1 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid (0.030 g, 28%), M.P.: 255-257° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.70 (s, 1H), 8.88 (dd, J=4.1, 2.6 Hz, 1H), 8.62 (d, J=8.7 Hz, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.04 (m, 3H), 7.83 (dd, J=8.7, 1.8 Hz, 1H), 7.64 (s, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 6.92 (dd. J=7.9, 1.4 Hz, 1H), 6.19 (s, 2H). MS (m/z): 354.02 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1)[NH2:5].C([O-])([O-])=O.[K+].[K+].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1>[Cl:20][CH2:21][C:22]([NH:5][C:4]1[C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=[C:2]([Cl:1])[C:3]=1[F:13])=[O:23]
Reactant: Nc1c(C(F)(F)F)ccc(Cl)c1F
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCl)Nc1c(C(F)(F)F)ccc(Cl)c1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 3-chloro-2-fluoro-6-(trifluoromethyl)aniline (250 mg, 1.136 mmol) in THF (2 mL) was added K2CO3 (235 mg, 1.703 mmol). The mixture was cooled to 0° C. and added 2-chloroacetyl chloride (0.099 mL, 1.249 mmol). The ice-water bath was removed and the reaction was allowed to warm to rt. After stirred at rt overnight, The reaction mixture was diluted with ether and water. The organic ether layer was separated and washed with brine, dried over MgSO4, filtered and concentrated to yield a crude white solid product, which was purified by silica gel chromatography to yield desired product (280 mg, 85%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.06 (br. s., 1H), 7.55-7.49 (m, 1H), 7.48-7.42 (m, 1H), 4.27 (s, 2H). MS (ESI) m/z: 289.9 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:1][C:6]1[C:5]([O:4][CH3:3])=[C:10]([O:11][CH3:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: CCOP(=O)(OCC)c1cc(OC)c(OC)c(OC)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)c1cc(OC)c(OC)c(OC)c1Br

Procedure:
A solution of bromine (10 mmol) in 10 mL of acetic acid is added dropwise to a solution of ester 11 (10 mmol) in 10 mL of acetic acid cooled by an ice water bath. After the red color of the resulting mixture is discharged, the mixture is poured into saturated NaHCO3 (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases are washed with 100 mL portions of 5% NaHCO3 until no further gas evolution is apparent. The organic phases are then washed with brine (100 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The mixture is purified by flash chromatography to give the product as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCc1ccc(C=O)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 8.8 g. of p-n-pentylbenzaldehyde in 100 ml. of benzene is treated with 150 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After evaporation, there remain 13.9 g. of a yellow oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-pentylbenzyliden)amino]benzonitrile which is obtained has a melting point of 45.6°-46.4°C. and a clearing point of 75.0°C. UV (ethanol): ε279 = 24400 (shoulder at 314 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[C:12]1([C:18]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:21]([CH3:29])[O:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CI.[NH4+].[Cl-]>C1COCC1>[C:12]1([C:18]2[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:21]([CH2:29][CH3:1])[O:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [Li]CCCC
Reactant: Cc1onc(-c2ccccc2)c1-c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CCc1onc(-c2ccccc2)c1-c1ccccc1
Temperature: -78 °C
Yield: 75 %

Procedure:
n-Butyllithium in hexane (2.19M, 0.213 mL, 0.4675 mmol) is added to 3,4-diphenyl-5-methylisoxazole (P10, 0.100 g, 0.425 mmol) in THF (5 mL) kept stirring at −78° C. in a nitrogen atmosphere. The reaction mixture obtained is kept stirring for 1 hour at −78° C. before adding CH3I (4.25 mmol). The reaction mixture is brought to ambient temperature and then blocked by adding an aqueous solution of NH4Cl. The two phases are separated and the aqueous phase is extracted three times with ethyl acetate. The combined organic extracts are dried over Na2SO4 and the solvent is then evaporated in a vacuum. The residue is subjected to column chromatography (silica gel, petroleum ether:ethyl acetate=10/1) and 3,4-diphenyl-5-ethylisoxazole is obtained with a yield of 75%. M.p. 85-87° C. (hexane), white crystals. FT-IR (KBr): 3029, 3005, 2923, 2848, 1625, 1596, 1493, 1467, 1437, 1410, 1327, 1282, 1210, 1011, 905, 771, 702 cm−1. 1H NMR (200 MHz, CDCl3, δ): 1.29 (t, 3H), 2.78 (q, 2H); 7.12-7.43 (m, 10H). 13C NMR (75 MHz, CDCl3, δ): 12.5, 19.7, 115.2, 127.9, 128.7, 128.9, 129.4, 129.5, 130.2, 130.7, 161.3, 171.4. GC-MS (70 eV) m/z (rel.int.): 249 [M+, 100], 234 (6), 221 (18), 220 (99), 194 (9), 193 (61), 192 (46), 165 (17), 115 (7), 103 (8), 89 (53), 77 (15), 63 (10), 51 (10).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[N:30][N:31]([CH3:33])[N:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[N:30][N:31]([CH3:33])[N:32]=4)=[CH:24][CH:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnn(C)n2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnn(C)n4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (40% EtOAc/hexanes) gave the product as a pale yellow solid (0.106 g, 29% yield). MS: m/z 513.3 [M+H]+.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].C(C=P(CCCC)(CCCC)CCCC)#N.[C:47]1([SH:53])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][S:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: Sc1ccccc1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CSc2ccccc2)C1=O
Temperature: 110 °C

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (180 mg, 0.403 mmol; Example 91, Step B) in 2 mL of toluene was added cyanomethylenetributylphosphorane (324 uL, 1.21 mmol) and benzenethiol (121 μL, 1.21 mmol) at RT. The mixture was heated to 110° C. for 2 h. The reaction was cooled down, quenched (sat. aq. NH4Cl solution), extracted (2×EtOAc), and washed with brine. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 10, 20, 40% EtOAc/hexane) provided the title compound.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[Cl:14][C:13]1[CH:12]=[CH:11][C:10]([C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH2:1])=[CH:9][C:8]=1[Cl:7]
Reactant: COc1ccc(OCC(=O)c2ccc(Cl)c(Cl)c2)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(COc1ccc(OC)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (60.3 g) in THF (800 mL) was added potassium tert-butoxide (20.7 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise a solution of 1-(3,4-dichlorophenyl)-2-(4-methoxyphenoxy)ethanone (48 g) in THF (400 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15.1 g).