Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][CH2:12][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:3]1=2.Cl[CH2:20][C:21]1[CH:22]=[C:23]([O:27][CH3:28])[CH:24]=[CH:25][CH:26]=1.[Cl-].[Na+]>C(N(CC)CC)C>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([CH2:20][N:16]2[CH2:17][CH2:18][C:13]3([C:3]4[N:2]([CH3:1])[C:10]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[C:4]=4[CH2:11][CH2:12]3)[CH2:14][CH2:15]2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(CCl)c1
Reactant: Cn1c2c(c3ccccc31)CCC21CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: COc1cccc(CN2CCC3(CCc4c3n(C)c3ccccc43)CC2)c1
Yield: 34.7 %

Procedure:
A solution of 1,4-dihydro4-methylspiro[cyclopent[b]indole-3(2H), 4′-piperidine] (2.5 g) and triethylamine (2.9 ml) in dichloromethanc (100 ml) and 3-(chloromethyl)anisole (1.95 g) was stirred overnight at ambient temperature, under nitrogen. Saturated sodium chloride solution was added and the mixture was extracted with dichloromethane. The extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flashed chromatographed (silica gel), eluting with 10% anhydrous acetone/dichloromethane. The appropriate fractions were collected and concentrated to give 1.3 g (35%) of product, mp 100-101° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32].C(N(CC)C(C)C)(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[Cl:24])(=[O:33])=[O:32])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3ccccc3Cl)CC2)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 108 mg, 0.34 mmol) and 2-chlorobenzenesulfonyl chloride (145 mg, 0.69 mmol) in THF (6 mL) was added excess N,N-diisopropylethylamine (179 μL, 1.0 mmol) at 0° C. under a nitrogen atmosphere. The resulting light brown solution was allowed to warm slowly to room temperature over 2 hours, was and then stirred for 15 hours at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with water and brine solution and the organic compound was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration and concentration gave a crude brown oil which was purified by flash chromatography (40 g ISCO column, eluting with 0-60% ethyl acetate/hexanes) to give {4-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (110 mg, 65%) as an off-white solid. MS cald. for C25H26ClFNO4S [(M+H)+] 490, obsd. 490.0.
Reaction SMILES: ClC1C=CC(N2CCN(S(N)(=O)=O)CC2)=CC=1.Cl[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[C:27]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[S:38](=[O:40])(=[O:39])[NH:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1>>[C:27]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:28]=[CH:29][C:30]([CH2:33][N:34]2[S:38](=[O:40])(=[O:39])[N:37]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:36][CH2:35]2)=[CH:31][CH:32]=1
Reactant: O=S1(=O)NCCN1Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CCl
Agent: NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Product: CC(C)(C)OC(=O)CN1CCN(Cc2ccc(-c3ccccc3)cc2)S1(=O)=O

Procedure:
Proceeding as described in Example 7, Step 2 above, but substituting potassium tert-butoxide and [4-(4-chlorophenyl)piperazine-1-sulfonyl]amine with tert-butyl chloroacetate and 5-(biphenyl4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine gave tert-butyl 5-(biphenyl-4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-acetate.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.N(OC(C)(C)C)=O.[ClH:25].CO>C(#N)C.[Cu](Cl)Cl>[Cl:25][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: N#Cc1ccc(-c2cc(N)cc(CO)c2)cc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CO
Solvent: CC#N
Product: N#Cc1ccc(-c2cc(Cl)cc(CO)c2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A solution of 3′-amino-5′-(hydroxymethyl)biphenyl-4-carbonitrile (120 mg, 0.54 mmol) in dry acetonitrile (1 mL) was added dropwise to a solution of copper (II) chloride (86 mg, 0.64 mmol) and tert-butyl nitrite (91 μL, 0.78 mmol) in acetonitrile (2 mL) at 65° C. After stirring for 30 min at 65° C., the reaction mixture was cooled to room temperature, poured into a 1 N hydrochloric acid solution, and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) afforded 46 mg (35%). LC/MS: tR=2.54 min, 244.03 (MH)+. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][S:25]([NH2:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)[CH:11]=1)#[N:9].[H][H]>O1CCOCC1.CCO.[Pd]>[NH2:9][CH2:8][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][S:25]([NH2:28])(=[O:27])=[O:26])=[CH:22][CH:23]=2)[CH:11]=1
Reactant: [H][H]
Reactant: Cc1nc(C#N)cc(Oc2ccc(CS(N)(=O)=O)cc2)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1nc(CN)cc(Oc2ccc(CS(N)(=O)=O)cc2)n1
Temperature: 22 °C
Yield: 77 %

Procedure:
Combine triethylamine (117.83 mL) and palladium 10% on charcoal (20.10 g) to a solution of [4-(6-cyano-2-methyl-pyrimidin-4-yl)oxyphenyl]methanesulfonamide (67 g, 211.35 mmoles) in a mixture of 1,4-dioxane (469 mL) and EtOH (201 mL; 159.05 g) in a PARR reactor. Maintain the mixture at 22° C. Seal the reactor and pressurize it with hydrogen (400 PSI). Shake the reactor for 18 h while maintaining it at 22° C. Thereafter open the reactor and filter of the solids. Rinse the solid residue with MeOH (1 L), a mixture of dioxane/MeOH 1:1 (1 L), and MeOH (3×1 L). Collect and concentrate the filtrate to provide a solid, Collect and dry the solid in a vacuum oven, (45° C., 15 mbar) to provide the title compound as yellow solid, 62.41 g, 77% yield. MS (m/z): 309 (M+1).
Reaction SMILES: [P:1]([O-])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[P:1]([Cl:23])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of dibenzyl phosphate (3.76 g, 13.5 mmol) in CH2Cl2 (10 mL) was treated with oxalyl chloride (1.17, 13.5 mmol) and DMF (0.5 mL). The mixture was stirred at room temperature for 1 h, the solvent was removed by rotary evaporation and the residue was dried in vacuo for 2 h to afford dibenzyl chlorophosphate as a yellowish solid. The residue was suspended in CH2Cl2 (5 mL), cooled to 0° C., treated with a solution of benzylic alcohol M (1.7 g, 6.7 mmol) in CH2Cl2 (5 mL) then DBU (2.02 mL, 13.5 mmol, added dropwise). The mixture was stirred at room temperature for 1 h30, and the solvent was removed by rotary evaporation. The residue was purified by column chromatography over silica gel using a gradient of 0-10% EtOAc/hexane as eluent.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)[N:3]=1.[F:18][C:19]1[C:20]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23]>>[F:18][C:19]1[C:20]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)=[C:21]([C:22]([N:14]2[CH2:13][CH:12]3[CH:16]([CH2:17][N:10]([C:4]4[N:5]=[C:6]([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[N:3]=4)[CH2:11]3)[CH2:15]2)=[O:23])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Reactant: Cc1nc(N2CC3CNCC3C2)nc(C)c1C
Product: Cc1nc(N2CC3CN(C(=O)c4cccc(F)c4-n4nccn4)CC3C2)nc(C)c1C

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 42 and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass calculated for C22H24FN7O, 421.20; m/z found 422.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.82-7.77 (m, 2H), 7.51-7.44 (m, 1H), 7.31 (ddd, J=9.8, 8.4, 1.3, 1H), 7.25-7.20 (m, 1H), 3.86-3.60 (m, 3H), 3.59-3.42 (m, 4H), 3.14 (dd, J=10.9, 5.3, 1H), 2.94 (dd, J=10.9, 7.1, 2H), 2.38-2.27 (m, 6H), 2.07 (d, J=7.2, 3H).
Reaction SMILES: O[C:2]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=1)=[O:3].[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C1C2C(=CC=CC=2)C=CC=1C(O)=O.IC1C=CC(N)=CC=1>>[CH:8]([C:7]1[CH:11]=[CH:12][C:4]([C:2]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:3])=[CH:5][CH:6]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: Nc1cccnc1
Agent: Nc1ccc(I)cc1
Agent: O=C(O)c1ccc2ccccc2c1
Product: CC(C)c1ccc(C(=O)Nc2cccnc2)cc1

Procedure:
This compound was synthesized by the same procedure as for Example 15 except cuminic acid and 3-aminopyridine were used instead of 2-napthoic acid and 4-iodoaniline. White needles. M+241.3
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3F)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\[OH:10])[CH:5]=[CH:4][N:3]=1.[F:29]C1C=CC(F)=CC=1S(NC1C=C(C=CC=1)C(OC)=O)(=O)=O.ClC1N=C(C)C=CN=1>>[Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:22]=[C:23]([F:29])[CH:24]=[CH:25][C:26]=3[F:27])(=[O:19])=[O:20])[CH:14]=[CH:15][CH:16]=2)\[OH:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1
Agent: Cc1ccnc(Cl)n1
Product: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1cc(F)ccc1F
Yield: 85.3 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 5, Step B using methyl 3-(2,5-difluorophenylsulfonamido)benzoate (20.5 g, 62.7 mmol) and 2-chloro-4-methylpyrimidine (8.8 g, 68.9 mmol) the title compound was obtained (22.6 g, 85.3% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.40-13.50 (br s), 10.95-11.12 (br s), 8.72-8.80 (m), 8.57-8.63 (m), 7.77-7.82 (m), 7.36-7.72 (m), 7.22-7.30 (m), 6.43 (s), 4.52 (s); m/z (ES+): 424 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH2:13])=[N:2]1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([C:27](O)=[O:28])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:27]([CH:23]2[CH2:24][CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22]2)=[O:28])=[N:2]1
Reactant: NCCNc1nsc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NCCNc2nsc3ccccc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N1-(benzo[d]isothiazol-3-yl)ethane-1,2-diamine (600 mg, 3.11 mmol), 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (854 mg, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (585 mg, 3.7 mmol) and triethylamine (577 μL, 3.7 mmol) in dichloromethane (40 mL) was allowed to stir at room temperature overnight. The reaction mixture was washed successively with 1N aqueous hydrochloric acid, saturated sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by flash column chromatography, on silica gel, eluting with a mixture of 25% ethyl acetate in hexanes gave fractions that were combined and concentrated under reduced pressure to yield tert-butyl 3-(2-(benzo[d]isothiazol-3-ylamino)ethylcarbamoyl)piperidine-1-carboxylate as a white solid, (325 mg). 1H NMR (300 MHz, DMSO-d6): 8.1 (m, 2H), 7.92 (m, 3H), 7.9 (d, 1H), 7.5 (m, 1H), 7.3 (m, 1H), 3.9 (m, 2H), 3.5 (m, 2H), 3.3 (m, 2H), 2.8 (m, 2H), 2.2 (m, 1H), 1.8 (m, 1H), 1.6 (m, 3H), 1.3 ppm (s, 9H). MW=405 confirmed by LC-MS, tr=3.81 min (Method B) MH+=406.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH:13]=[CH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])[CH:6]=[CH:5]2.[CH:23]([Mg]Br)=[CH2:24]>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH:13]=[CH:14][C:15]1[CH:16]=[C:17]([CH:18]([OH:19])[CH:23]=[CH2:24])[CH:20]=[CH:21][CH:22]=1)[CH:6]=[CH:5]2
Reactant: O=Cc1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC(O)c1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
The aldehyde of Step 2 (35.93 g, 122 mmol) was suspended in 360 mL of toluene and cooled to 0° C. 1.0 M Vinylmagnesium bromide in THF (135 mL) was added into the addition funnel and the whole system was degassed by applying vacuum and flushed with nitrogen 3 times. The Grignard reagent was then added slowly at 0° C. and the mixture was stirred at 0° C. for 15 min. Cold 25% aq. NH4OAc was then added and the product was extracted in hot toluene, washed with brine, and dried over Na2SO4. The cloudy solution was filtered through celite, concentrated, and filtered through silica with EtOAc: toluene 10:90 to afford 32.04 g (81%) of the title product.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35].C(Cl)Cl.CO>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH:38]=[CH2:39])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: C=CCOC(=O)Cl
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: C=CCOC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmol) were dissolved in 6 ml dichloromethane. 85 μl (2 molar equivalents) triethylamine and 65 μl (2 molar equivalents) of allyl chloroformate were added. The reaction mixture was stirred at 20° C. for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 95/5 volume ratio) to provide 70 mg (yield=51%) of the desired product (formula below) as an orange powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([CH3:24])[O:21][C:20]=3[CH3:25])/[CH3:18])/[C:9]2=[O:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>ClCCl>[C:34]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([CH3:24])[O:21][C:20]=3[CH3:25])/[CH3:18])/[C:9]2=[O:26])=[CH:4][CH:3]=1)(=[O:37])[CH:35]=[CH2:36]
Reactant: CC(C)=C1C(=O)N(c2ccc(O)cc2)C(=O)/C1=C(\C)c1cc(C)oc1C
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Oc1ccc(N2C(=O)C(=C(C)C)/C(=C(/C)c3cc(C)oc3C)C2=O)cc1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution obtained by dissolving 211 mg of N-(4-hydroxyphenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)ethylidene]-3-isopropylidenesuccinimide obtained in Example 5 in 5 ml of dichloromethane, 72 mg of triethylamine was added, followed by dropwise addition of 66 mg of acryloyl chloride in 10 minutes. The reaction was carried out at room temperature for 30 minutes with stirring. After the reaction, the reaction solution was well washed with water, dried over anhydrous magnesium sulfate, and subjected to removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give pale red crystals of N-(4-acryloyloxyphenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)ethylidene]-3-isopropylidenesuccinimide in yield of 44.0%.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(Nc2ccccc2)n1
Temperature: 0 °C
Yield: 94.2 %

Procedure:
To a suspension of cyanuric chloride (20 g, 108 mmol) in acetone (120 mL) and ice (50 mL) at 0° C. was added dropwise a solution of aniline (10 g, 107 mmol) in acetone (45 mL). At the end of the addition, the pH of the solution was adjusted from 1 to 7 with 5% aqueous sodium bicarbonate (150 mL). The precipitate was filtered, washed several times with water and dried in vacuo. This gave 2,4-dichloro-6-phenylamino-1,3,5-triazine as an off-white solid (24.3 g, 93% yield). The product was used in the next step without further purification. To a solution of the dichlorotriazine (6.2 g, 25.7 mmol) in THF (300 mL) at room temperature was added a solution of 2-(4-hydroxyphenyl)ethylamine (3.6 g, 25.9 mmol) in acetone (100 mL) and water (100 mL), followed by 5% aqueous sodium bicarbonate (50 mL). After 20 h reaction at room temperature, the solution was diluted with water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layers were washed with brine (150 mL), dried over anhydrous sodium sulphate, filtered and evaporated to dryness. This gave 2-chloro-4-(2-[4-hydroxyphenyl]ethylamino)-6-phenylamino-1,3,5-triazine as an off-white solid (8.5 g, 97% yield). The product was used for the next step without further purification. This triazine derivative (384 mg, 1.1 mmol) was dissolved in THF (11 mL) at room temperature. To this solution was added ethylenediamine (68 μL, 1.0 mmol) followed by diisopropylethylamine (355 μL, 2.0 mmol). After 20 h at 50° C., the solution was diluted with methanol (10 mL) and concentrated under reduced pressure. The crude residue was purified on a Biotage™ 25S column (silica, hexane/AcOEt 9:1 to 0:1) to yield compound 1 as a white solid. Yield of product: 267 mg (78%); 1H NMR (300 MHz, CD3OD) δ 7.63 (m, 4H), 7.21 (t, 4H, J=7.6 Hz), 6.98 (m, 6H), 6.68 (d, 4H, J=7.9 Hz), 3.48 (m, 8H), 2.84 (m, 4H); LRMS (FAB+): m/z 672.0 (MH+); HRMS: Calc. for MH+ C36H39N12O2, 671.33191; found 671.33060; HPLC (method 1): 8.0 min.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:8]=[CH:7][C:6]=1[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][O:31][C:30]2=[O:39])[CH2:25][CH2:24]1)=[O:22].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:41][C:2]([F:1])([F:40])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:8]=[CH:7][C:6]=1[CH2:20][C:21]([N:23]1[CH2:24][CH2:25][CH:26]([N:29]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][O:31][C:30]2=[O:39])[CH2:27][CH2:28]1)=[O:22]
Reactant: CC(C)(C)OC(=O)COc1ccc(CC(=O)N2CCC(N3C(=O)OCc4ccccc43)CC2)c(OCC(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc(CC(=O)N2CCC(N3C(=O)OCc4ccccc43)CC2)c(OCC(F)(F)F)c1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(1-(2-(2,2,2-trifluoroethoxy)-4-(tert-butyloxycarbonylmethoxy)-phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one (0.72 mg, 1.2 mmol) from Step 1 above in CH2Cl2 (20 mL) was added TFA (20 mL). After standing at ambient temperature for 1.5 h the solvents were removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a H2O:CH3CN gradient containing 0.1% TFA. The product-containing fractions were combined and lyophilized to give the title compound as an amorphous powder.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCCCC1>C(Cl)Cl>[Br:17][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CBr)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 1,1-dimethylethyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate (30.0 g, 139 mmol) and carbon tetrabromide (72.0 g, 217 mmol) in methylene chloride (150 mL) was added dropwise a solution of triphenyl phosphine (42.4 g, 162 mmol) in methylene chloride (150 mL). An ice-bath was used to maintain an internal temperature between 20 and 25° C. during the addition. After stirring the mixture at ambient temperature for 1 h, cyclohexane (500 mL) was added. Approximately one-half of the solvent was removed under reduced pressure. The remaining solution was cooled in an ice bath and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and the residue subjected to flash chromatography (0% to 25% ethyl acetate/hexanes, silica gel) to give 35.1 g (91% yield) of the desired product as a solid. MS (ES+) m/z 278 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[C:2]#[CH:3].[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15]Br>>[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15][O:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:1][C:2]#[CH:3])=[CH:11][CH:10]=1
Reactant: CC(C)=CCBr
Reactant: C#CCOc1ccc(O)cc1
Product: C#CCOc1ccc(OCC=C(C)C)cc1

Procedure:
By utilizing the procedure of Example 1, by reacting hydroquinone monopropargyl ether with 3-methyl-2-butenyl bromide, there is obtained 1-[(3-methyl-2-butenyl)oxy]-4-propargyloxy-benzene; B.P. 145°-148° C/1 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[C:22]2[O:21][CH2:20][CH2:19][NH:18][C:17]=2[CH:16]=[C:15]([CH3:23])[CH:14]=1.N1C=CC=CC=1.O>ClCCl>[Br:12][C:13]1[C:22]2[O:21][CH2:20][CH2:19][N:18]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[C:17]=2[CH:16]=[C:15]([CH3:23])[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)c2c(c1)NCCO2
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(Br)c2c(c1)N(S(=O)(=O)c1ccc(Cl)cc1)CCO2
Temperature: 0 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
4-Chloro-benzenesulfonyl chloride (560 mg, 2.65 mmol) was added in small portions under nitrogen to an ice-cold solution of 8-bromo-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (550 mg, 2.41 mmol) and pyridine (381 mg, 4.82 mmol) in dichloromethane (20 mL). After 12 hours at ambient temperature, water was added. The layers were separated. The organic phase was washed with saturated aqueous solution of sodium bicarbonate (20 mL), dried (Na2SO4) and concentrated to give the title compound as a solid (820 mg, 84%). A sample was recrystallized from ethanol. MS: M+=401. M.p. 143.0-145.1° C.