Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].C([O:18][C:19](=O)[C:20](Br)([CH3:22])[CH3:21])C>CC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:19](=[O:18])[C:20]([CH3:22])([CH3:21])[O:9][C:3]=2[CH:4]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)Oc2cc(Br)ccc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
5.0 g 2-Amino-5-bromophenol were dissolved in 100 ml acetone. Then 11.0 g potassium carbonate and 6.74 g ethyl-2-bromoisobutyrate were added. The reaction mixture was stirred at room temperature overnight and refluxed overnight. The cooled reaction mixture was then filtrated and the filtrate concentrated in vacuo. The resulting residue was purified by chromatography on silica gel to obtain 4.6 g 7-Bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one as a yellow solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9](=[O:22])[C:10]1C(=[CH:15][CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])C(O)=O>C(Cl)Cl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:22])[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: COC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(C(=O)Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Oxalyl chloride (5.4 mL, 62.4 mmol) was added to a suspension of 3-nitro-phthalic acid 2-methyl ester (11.7 g, 52.0 mmol, Step A) in 150 mL of anhydrous CH2Cl2 at RT. A few drops of DMF were added, then the mixture was heated to reflux for 2 h, and cooled to RT. The mixture was washed with NaHCO3 (aq), brine, dried over MgSO4, filtered, and condensed to give the titled compound as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH3:30])([CH3:29])[C:23]=4[CH:31]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:32]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH3:29])([CH3:30])[C:23]=4[CH:31]=3)=[O:32])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-cyclohexyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:9]=1.C(Cl)(=O)C(Cl)=O.[CH:29]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:31])[CH3:30]>C(Cl)Cl.CN(C=O)C>[CH2:33]([N:32]([CH:29]([CH3:31])[CH3:30])[C:14]([C:13]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9][C:10]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:11][CH:12]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)NCc1ccccc1
Reactant: O=C(O)c1cnc(N2CCOCC2)nc1-c1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccccc1)C(=O)c1cnc(N2CCOCC2)nc1-c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (4.321 g, 14.25 mmol) in CH2Cl2 (100 mL) and DMF (2 drops) was added oxalyl chloride (1.5 mL, 2.21 g, 17.5 mmol) dropwise. Most solids dissolved at first, later a precipitate formed. The suspension was stirred for 1 hour at 0° C., and then allowed to warm to room temperature (all solids dissolved). The solution was concentrated to a dark oil, which crystallized upon standing. The crude acid chloride was taken up in toluene (50 mL, distilled, dried over Na2SO4) and cooled in ice. N-Isopropylbenzylamine (9.5 mL, 8.5 g, 56.8 mmol) was added. The resulting suspension was stirred at room temperature for 90 minutes, washed with water and a saturated aqueous NaCl solution, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (400 mL silica, EtOAc/heptanes 1:1). All fractions containing the product were combined and concentrated. Some of the excess amine eluted with the product. A solution of the mixture in CH2Cl2 (50 mL) was washed with a 10% aqueous citric acid solution (2×25 mL), water (25 mL), and saturated aqueous NaCl solution (25 mL), dried over Na2SO4, and concentrated to give pure 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide as a yellowish foam (5.685 g, 13.08 mmol, 92%).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:34]3[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=3[NH:32][C:31](=O)[C@H:30]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[N:29]=2)=[CH:24][CH:23]=1>ClCCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:34]3[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=3[NH:32][C:31](=[S:2])[C@H:30]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[N:29]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2NC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2NC1=S
Temperature: 70 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A suspension of P4S10 (36.1 g, 81.1 mmol) and Na2CO3 (8.6 g, 81.1 mmol) in 1,2-DCE (700 ml) at room temperature was stirred for 2 h before methyl [(3S)-5-(4-chlorophenyl)-7-(methyloxy)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]acetate (for a preparation see Reference compound D) (16.8 g, 45.1 mmol) was added. The resulting mixture was stirred at 70° C. for 2 h before being cooled and filtered. The solid was washed twice with DCM and the filtrate washed with sat. Sodium hydrogen carbonate and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash-chromatography on silica gel (DOM/MeOH: 99/1) to afford the title compound (17.2 g, 98% yield) as a yellowish solid. LC/MS (Method D): m/z 389 [M(35Cl)+H]+, Rt 2.64 min
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=[N+]([O-])c1ccccc1NCc1cccnc1
Yield: 23 %

Procedure:
A mixture of 65 parts of 3-pyridinemethanamine, 94 parts of 1-chloro-2-nitrobenzene, 80 parts of sodium carbonate and 800 parts of 1-butanol is stirred and refluxed over week-end. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 33 parts (23%) of N-(2-nitrophenyl)-3-pyridinemethanamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:20])/[CH2:18]O)[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:20])/[CH2:18][N:44]2[C:40](=[O:50])[C:41]3[C:42](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:43]2=[O:45])[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C/C(=C\c1cc(F)c(Oc2ccccc2)c(F)c1)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C/C(=C\c1cc(F)c(Oc2ccccc2)c(F)c1)CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (E)-3-(3,5-difluoro-4-phenoxyphenyl)-2-methylprop-2-en-1-ol (Intermediate 93.1) (410 mg, 1.49 mmol) in dry toluene (7.45 mL) under N2 was added PPh3 and phthalimide. The resulting solution was cooled to 0° C. and diethyl azodicarboxylate (DEAD, 0.748 mL) was added dropwise over several minutes. The reaction was allowed to warm to room temperature and stirred overnight. After diluting with EtOAc (20 mL), the organic layer was washed with water (2×30 mL), brine (30 mL) and dried over Na2SO4. After removal of solvent, the resulting residue was applied to a silica gel column (15% EtOAc in hexanes) to yield 385 mg of the title compound (63%) as an oil.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.Br[CH:27]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[CH:20]3[CH2:25][CH2:24][N:23]([CH:27]([CH2:32][O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: COC(=O)C(Br)COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(COCc1ccccc1)N1CCC(N(Cc2cc3c(cn2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 36.7 %

Procedure:
A mixture of 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)4-piperidinylcarbamate (1.087 g, 3.11 mmol) (for a synthesis see WO2004/058144 Example 99(h)), methyl 2-bromo-3-[(phenylmethyl)oxy]propanoate (1.0 g, 3.66 mmol) and potassium carbonate (0.860 g, 6.22 mmol) in DMF (50 ml) was heated to 80° C. and stirred under argon for 2.5 h. The solvents were removed under reduced pressure and the residue treated with saturated aqueous sodium bicarbonate. The aqueous was extracted with DCM (5×100 ml) dried MgSO4, filtered and concentrated under reduced pressure. The crude product was chromatographed, eluting with 0-100% EtOAc/40-60 petroleum ether. Appropriate fractions were combined and evaporated under reduced pressure. The residue was then dissolved in DCM (50 ml) and washed with water (20 ml). The organic layer was separated, dried MgSO4 and evaporated under reduced pressure to afford product (618 mg, 35% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[N-:19]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>C(Cl)Cl>[Br:1][C:2]1[C:3]([OH:18])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:17])(=[NH:19])=[O:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)c1ccc(Nc2ncc(Br)c(O)n2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=N)(=O)c1ccc(Nc2ncc(Br)c(O)n2)cc1
Temperature: 40 °C
Reaction time: 36 h

Procedure:
324 mg of (RS)-5-bromo-2-[4-(methylsulfinyl)phenylamino]pyrimidin-4-ol and 128 mg of sodium azide are suspended in 6 ml of methylene chloride and mixed drop by drop with 0.3 ml of concentrated sulfuric acid while being cooled with ice. The mixture is stirred for 36 hours at 40° C. The organic phase is decanted off, and the residue is stirred with ice water. The solid is suctioned off, washed twice with water and once with ethanol and dried. 266 mg (78.2% of theory) of the product with a melting point of 230° C. (decomposition) is obtained.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH:2]=C.[BH4-].[Na+].C(Cl)Cl.C[OH:36]>C(=O)=O.CC(C)=O>[OH:36][CH2:2][CH2:1][O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C=CCOCc1cccc(-c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)c1
Reactant: CO
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(-c2cccc(COCCO)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
3-(3′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (260 mg, 0.664 mmol) was dissolved in DCM/methanol (4:1, 7.5 mL) and was cooled to −78° C. in dry ice-acetone bath. O3 was bubbled through the solution for 15 min. Thin layer chromatography (TLC) confirmed the completion of the reaction at this stage. The DCM was evaporated in vacuo; ethanol (5 mL) was added and the solution was cooled in ice-water bath to 0° C. NaBH4 (175 mg, 7 eq.) was added and the reaction was stirred at the temperature of 0˜5° C. for one hour then at room temperature for 1.5 hour. The reaction mixture was quenched with saturated NaHCO3 aqueous solution. The aqueous phase was extracted with DCM (3×8 mL), the combined organic phases were washed with brine (5 mL), dried over sodium sulfate and concentrated. The crude residue was purified on silica gel eluting with 20˜50% ethyl acetate in hexane to give the product (134 mg, 51%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.59 (d, 3H), 7.52 (d, 1H), 7.41 (t, 1H), 7.32 (d, 3H), 4.85 (s, 2H), 4.45 (s, 2H), 3.77 (br, 2H), 3.62 (t, 2H), 3.12 (s, 2H), 2.48 (br, 1H), 1.72 (m, 4H), 1.5 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[S:32]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:37][C:34]2[CH:35]=[CH:36][S:32][CH:33]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: BrCc1ccsc1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccsc3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.193 g, 0.44 mmol), prepared as described in EXAMPLE 43, part A, and thiophen-3-ylmethyl bromide (0.30 g, 1.68 mmol). The crude product is triturated with hexane/ether and used without further purification (0.25 g, 0.48 mmol).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[NH2:25]>[N+](C1C=CC=CC=1)([O-])=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]3[NH:25][C:24]4[CH:23]=[CH:22][N:21]=[CH:20][C:19]=4[N:18]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: Nc1ccncc1N
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Solvent: O=[N+]([O-])c1ccccc1
Product: CCn1c2ccccc2c2cc(-c3nc4cnccc4[nH]3)ccc21
Temperature: 145 °C
Yield: 15.1 %

Procedure:
A mixture of 9-ethyl-9H-carbazole-3-carbaldehyde (444 mg, 1.99 mmol) and 3,4-diaminopyridine (217 mg, 1.99 mmol) in nitrobenzene (1.5 ml) was heated at 145° C. for 24 hours. The reaction mixture was cooled to room temperature and purified directly by flash column chromatography (0.1% ammonium hydroxide/5% methanol/dichloromethane) to afford the title compound 5A (94 mg):
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1](=[N:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1cccc(N=C(c2ccccc2)c2ccccc2)c1
Reactant: O=C1C=C(Cl)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1C=C(Oc2cccc(N=C(c3ccccc3)c3ccccc3)c2)CCC1

Procedure:
A suspension of the 3-(benzhydrylidene-amino)-phenol (10.47 g, 38.3 mmol), 3-chloro-cyclohex-2-enone (5.00 g, 38.3 mmol) and potassium carbonate (5.82,42.1 mmol) in 150 mL of acetone was heated at reflux overnight. The cooled reaction mixture was filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1). In this manner, 3-[3-(benzhydrylidene-amino)-phenoxy]-cyclohex-2-enone was obtained as a yellow solid, (8.82 g, 63%): 1H NMR (CDCl3) δ 7.78 (d, 2H, J=7.0 Hz), 7.50 (d, 1H, J=7.1 Hz), 7.45 (d, 2H, J=7.7 Hz), 7.34-7.10 (m, 6H), 6.69 (d, 1H, J=8.0 Hz), 6.61 (d, 1H, J=8.0 Hz), 6.38 (s, 1H), 4.89 (s, 1H), 2.55 (t, 2H, J=6.2 Hz), 2.34 (t, 2H, J=6.2 Hz), 2.06 (m, 2H). Anal. Calc. for C25H21NO2.0.2H2O: C, 80.92; H, 5.81; N, 3.78. Found: C, 81.12; H, 5.81; N, 3.72.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C.[Cl-].[Na+]>C1COCC1>[CH:20]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1)=[O:21]
Reactant: COc1cc(Br)ccc1C#N
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1C#N
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-bromo-2-methoxybenzonitrile (1.0 g, 4.7 mmol) in 30 mL of anhydrous THF was added BuLi (1.6 M, 3.3 mL, 5.2 mmol) dropwise at −78° C. under nitrogen atmosphere. After the addition, the pale red solution was stirred for 5 min at −78° C. and dry DMF (0.6 mL) then added dropwise. After 20 min, the reaction mixture was poured onto a saturated solution of sodium chloride (50 mL). The organic phase was separated, extracted with diethyl ether (100 mL), dried over Na2SO4 and distilled off the solvent to afford 4-formyl-2-methoxybenzonitrile. MS m/z: 162 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:1][CH2:2][CH2:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCN1c2ccccc2COc2ccccc21
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.99 g (4.1 mmol) of 5,11-dihydro-5-(2-hydroxyethyl) dibenzo[b,e][1,4]oxazepine was dissolved in 6 ml of anhydrous pyridine. 0.94 g (4.9 mmol) of p-toluenesulfonyl chloride was added to the obtained solution, and they were stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane. The obtained solution was washed with 5% aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution successively. After drying, the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with ethyl acetate and hexane (1:3). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain 5,11-dihydro-5-[2-(4-methylphenylsulfonyl)oxyethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (1.25 g, 76.6%).
Reaction SMILES: [Na+].[Cl-].[CH3:3][C:4]([CH3:25])=[CH:5][CH2:6]C1C(O)=CC(O)=CC=1C1OC2C=C(O)C=CC=2C=1.CC(C)=CC[C:30]1[CH:31]=[C:32]([C:37]2O[C:46]3[CH:45]=[C:44]([OH:48])[CH:43]=[C:42]([OH:49])[C:41]=3[C:39](=[O:40])[C:38]=2O)[CH:33]=[CH:34][C:35]=1[OH:36]>CO>[CH3:3][C:4]([CH3:25])=[CH:5][CH2:6][C:45]1[CH:46]=[C:41]([C:39](/[CH:38]=[CH:37]/[C:32]2[CH:33]=[CH:34][C:35]([OH:36])=[CH:30][CH:31]=2)=[O:40])[C:42]([OH:49])=[CH:43][C:44]=1[OH:48]
Reactant: CC(C)=CCc1c(O)cc(O)cc1-c1cc2ccc(O)cc2o1
Reactant: CC(C)=CCc1cc(-c2oc3cc(O)cc(O)c3c(=O)c2O)ccc1O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCc1cc(C(=O)/C=C/c2ccc(O)cc2)c(O)cc1O

Procedure:
Yellow powder; mp 157-158° C.; UV (MeOH) λmax (log ε) 373 (4.23), 205 (4.43) nm; IR (NaCl) γmax 3350, 2923, 1645, 1558, 1508 cm−1; 1H NMR (CD3OD, 500 MHz) δ 1.75 (3H, s, H-4″), 1.76 (3H, s, H-5″), 3.27 (2H, d, J=7.2 Hz, H-1″), 5.34 (1H, m, H-2″), 6.29 (1H, s, H-3′), 6.85 (2H, d, J=8.5 Hz, H-3), 7.54 (1H, d, J=15.4 Hz, H-a), 7.59 (2H, d, J=8.5 Hz, H-2), 7.72 (1H, s, H-6′), 7.76 (1H, d, J=15.3 Hz, H-β); 13C NMR (CD3OD, 125 MHz) δ 17.8 (C-4″), 26.0 (C-5″), 28.9 (C-1″), 103.4 (C-3′), 114.4 (C-1′), 117.0 (C-3), 118.6 (C-o), 122.2 (C-5′), 124.2 (C-2″), 127.4 (C-1), 131.9 (C-2), 132.4 (C-6′), 133.1 (C-3″), 145.4 (C-β), 161.5 (C-4), 164.6 (C-4′), 165.5 (C-2′), 193.4 (CO); EIMS m/z 324 (M+, 100), 231 (10), 205 (77), 147 (12).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37]OS(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[CH3:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:37][CH2:36][C:34]2[N:35]=[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:32][C:33]=2[CH3:49])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)cc1C

Procedure:
The representative parallel synthesis procedure (B) was used to prepare the title compound from 2-(3,4-dimethyl-phenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyloxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.01-7.99 (m, 2H), 7.48-7.46 (m, 3H), 7.18 (d, 2H, J=8.8 Hz), 6.99 (d, 1H, J=8.4 Hz), 6.82 (d, 2H, J=8.4 Hz), 6.70 (d, 1H, J=2.0 Hz), 6.63 (dd, 1H, J=8.4, 2.0 Hz), 6.28 (bs, 1H), 4.22 (t, 2H, J=6.4 Hz), 3.22 and 3.11 (d of Abq, 2H, J=13.6 Hz), 3.06 (t, 2H, J=6.4 Hz), 2.42 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 1.39 (s, 3H). IR (KBr) 3100, 2950, 1772, 1611, 1512, 1177 cm−1. HRMS (ES+) m/z exact mass calcd for C30H32NO5 486.2280, found 486.2295.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH:3]=[CH:4][C:5]([OH:7])=[O:6].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[CH:3]=[CH:4][C:5]([O:7][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: C[Si](C)(C)C=CC(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[Si](C)(C)C=CC(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 94.3 %

Procedure:
A solution of 3-trimethylsilylacrylic acid (510 mg, 3.54 mmol) [J. Org. Chem., 56, pp. 4766-4772, 1991] in dichloromethane (8 ml) was added successively with benzyl alcohol (0.59 ml, 5.71 mmol), dicyclohexylcarbodiimide (DCC, 914 mg, 4.44 mmol) and 4-dimethylaminopyridine (4-DMAP, 43 mg, 0.352 mmol) under ice cooling, the mixture was stirred for 5 minutes, and then stirring was further continued at room temperature for 16 hours. The reaction mixture was cooled on ice, and then added with aqueous hydrochloric acid (1 N, 5 ml), the mixture was filtered under reduced pressure, and the resulting urea was washed with ethyl acetate. After the layers were separated, the organic layer was washed with saturated aqueous sodium hydrogencarbonate and water, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography [hexane/ethyl acetate (24:1)] to obtain benzyl 3-trimethylsilylacrylate (782 mg, 94%) mentioned in the title as colorless oil.