Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:5](=[O:21])[C:6](=[O:20])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([CH2:18][CH3:19])[CH:11]=1)C.[NH2:22][C@@H:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:24].ClCCl>C(O)C>[O:21]=[C:5]1[C:6](=[O:20])[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([CH2:18][CH3:19])[CH:11]=2)=[C:4]1[NH:22][CH:23]([CH3:24])[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOc1c(NCc2ccc(C#N)c(CC)c2)c(=O)c1=O
Reactant: C[C@@H](N)C(C)(C)C
Solvent: CCO
Solvent: ClCCl
Product: CCc1cc(CNc2c(NC(C)C(C)(C)C)c(=O)c2=O)ccc1C#N
Reaction time: 24 h

Procedure:
This compound was prepared according to the procedure described in Example 24, Step 1. From 3-ethyl-4-cyanobenzaldehyde oxime (0.88 g, 5.05 mmol), zinc powder (1.32 g, 20 mmol), glacial acetic acid (10 mL), and 3,4-diethyoxy-3-cyclobutene-1,2-dione (0.75 mL, 5.07 mmol) in absolute ethanol (100 mL) there was obtained after chromatography on silica gel (hexane:ethyl acetate (1:1), 5% methanol in dichloromethane) 0.64 g (45%) of a solid. Following the procedure described in Example 34, a portion of this solid, 3-ethoxy-4-(3-ethyl-4-cyano-benzylamino)-cyclobut-3-ene-1,2-dione (0.38 g, 1.34 mmol), (R)-2-amino-3,3-dimethylbutane (10 mL of a 0.2M solution in absolute ethanol, 2.0 mmol), and dichloromethane was allowed to stand for 24 hours at room temperature. The resulting solid was filtered, rinsed with acetonitrile (5×1 mL) and dried. This gave 0.22 g (48%) of the (R) isomer of the title compound as a white solid: mp 251°-253° C.; [α]25D =+28.48° (4.2 mg/mL, DMSO); 1H NMR (DMSO-d6) δ7.79 (d, 1H), 7.68 (br m, 1H), 7.44 (s, 1H), 7.34 (d, 1H), 7.28 (br d, 1H), 4.78 (m, 2H), 3.91 (br m, 1H), 2.79 (q, 2H), 1,21 (t, 3H), 1.10 (d, 3H), 0.85 (s, 9H) ppm. IR (KBr): 3210, 2980, 2210, 1790, 1650 cm-1 ; MS (m/z) 339 (M+).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:35][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccncc5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccncc5)cc4)CC3)n2CCS1
Yield: 86.2 %

Procedure:
A solution of the compound (174 mg, 0.34 mmol) obtained in Example 5-1) and 4 M hydrochloric acid (1,4-dioxane solution, 0.43 mL) in methanol (2 mL) was stirred at room temperature for 21 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 30:70, gradient) to obtain the title compound (115 mg, 85%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-:11]#[N:12].[K+]>CN(C)C=O>[Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: Cc1cccc(CBr)c1Br
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(CC#N)c1Br
Temperature: 90 °C
Reaction time: 20 h
Yield: 44.1 %

Procedure:
A mixture of 2-bromo-3-methylbenzylbromide (25 g, 0.095 mol) and potassium cyanide (16 g, 0.25 mol) in dimethylformamide (100 ml) was stirred at 90° C. for 20 h. The solvent was evaporated under reduced pressure and to the residue were added toluene and water. The organic layer was separated washed with water, separated and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride as eluent gave 8.8 g (44%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:17])[C:4]([O:6][CH:7]1[CH2:15][CH:14]2[CH2:16][CH:8]1[CH:9]1[CH:13]2[CH2:12][CH2:11][CH2:10]1)=[O:5].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O>[C:24]([O:1][CH2:2][C:3](=[CH2:17])[C:4]([O:6][CH:7]1[CH2:15][CH:14]2[CH2:16][CH:8]1[CH:9]1[CH:13]2[CH2:12][CH2:11][CH2:10]1)=[O:5])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(CO)C(=O)OC1CC2CC1C1CCCC21
Solvent: c1ccncc1
Solvent: O
Product: C=C(COC(C)=O)C(=O)OC1CC2CC1C1CCCC21
Reaction time: 20 h
Yield: 85.3 %

Procedure:
To a mixture of 23.6 g of 8-tricyclo[5.2.1.02,6]decyl α-(hydroxymethyl)acrylate and 15.8 g of pyridine was added 15.3 g of acetic anhydride. The mixture was stirred for 20 hours. Water was added to the reaction solution to stop the reaction, followed by conventional aqueous workup. The solvent was distilled off in vacuo. Purification by distillation (boiling point 123° C./13 Pa) gave 23.7 g (yield 90%) of 8-tricyclo[5.2.1.02,6]decyl α-(acetoxymethyl)acrylate represented by formula (12).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:29]=[CH:28][C:8]([O:9][C:10]2[CH:27]=[CH:26][C:13]([CH2:14][NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[C:17]=3[CH3:25])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:4][C:5]1[CH:29]=[CH:28][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][N:15]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[C:17]=3[CH3:25])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCOc1ccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)cc1
Product: C=CCOc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 60C and benzyl bromide was processed as described in Example 6B to provide the title compound.
Reaction SMILES: [C:1]([CH2:8][C:9]([OH:11])=[O:10])(=O)[CH2:2][CH2:3][CH2:4]CC.[C:12](Cl)(=O)[C:13]([Cl:15])=[O:14]>>[C:9]([O:11][CH2:12][C:13]([Cl:15])=[O:14])(=[O:10])[CH2:8][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC(=O)CC(=O)O
Product: CCCCCC(=O)OCC(=O)Cl
Temperature: 55 °C

Procedure:
8.7 gm (0.05 mole) of hexanoylacetic acid and 12.7 gm (0.10 mole) of oxalyl chloride were mixed together at room temperature. The reaction was heated gradually over one hour at 50-60° C. for about two hours. Excess oxalyl chloride was removed under reduced pressure to yield an oil that exhibits no --OH stretch by IR. Weight was 9.6 gm.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]#[N:14].O.[SH2:16].[Na].Cl.C(NCC)C>CN(C=O)C.O>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13](=[S:16])[NH2:14]
Reactant: N#CCCc1ccc2c(n1)NCCC2
Reactant: S
Agent: Cl
Agent: [Na]
Solvent: CCNCC
Solvent: O
Solvent: CN(C)C=O
Product: NC(=S)CCc1ccc2c(n1)NCCC2
Temperature: 55 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
Reagents 3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propanenitrile (100 mg), sodium hydrogen sulfide hydrate (360 mg), diethylamine hydrochloride (530 mg) were mixed in DMF (10 mL). The mixture was warmed to 55° C. and stirred at this temperature for about 24 h. The mixture was allowed to cool and then diluted with water (30 mL) followed by extraction with ethyl acetate (3×25 mL). The extracts were combined and washed with water (3×20 mL). The organic phase was dried (magnesium sulfate) and filtered. The solution was concentrated and column purification (CHCl3: MeOH=10:1) to yield a yellow solid 101 mg (89%). 1H NMR (DMSO-d6) δ 9.30 (d, 2H), 7.10 (d, 2H), 6.35 (m, 2H), 3.25 (m, 2H), 2.80 (m, 2H), 2.75 (m, 2H), 2.64 (m, 2H), 1.72 (m, 2H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([NH2:35])[CH2:31][CH2:32][O:33][CH3:34]>>[CH3:34][O:33][CH2:32][CH2:31][C:30]1[N:35]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:29]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 242 mg (1.640 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted Yield: 350 mg (46% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5]Br.[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5][N:15]=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cc(CBr)cc(C(Cl)=C(Cl)Cl)c1
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(F)cc(C(Cl)=C(Cl)Cl)c1

Procedure:
A solution of 3-fluoro-5-(trichlorovinyl)benzyl bromide (3.18 g) and sodium azide (0.975 g) in 25 ml of ethanol is heated at reflux for 2 hours. The reaction mixture is concentrated and the residue triturated with 50 ml of hexane. The mixture is filtered and the filtrate concentrated to give the desired azide.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([OH:21])=O)[CH2:17][C:6]=2[CH:5]=1.Cl.[C:31]1([C:37]2[NH:41][N:40]=[C:39]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](=[O:21])[N:45]3[CH2:44][CH2:43][CH:42]([C:39]4[CH:38]=[C:37]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH:41][N:40]=4)[CH2:47][CH2:46]3)[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Reactant: c1ccc(-c2cc(C3CCNCC3)n[nH]2)cc1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(c2cc(-c3ccccc3)[nH]n2)CC1
Yield: 38.2 %

Procedure:
(S)-2-(4-chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (66 mg, 0.23 mmol) and 4-(5-phenyl-1H-pyrazol-3-yl)piperidine hydrochloride (40 mg, 0.15 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound (34 mg) was obtained as white solid. MS (ESI) 594 (M+H); Rf=1.99.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([Cl:22])[CH:15]=[CH:16][C:17]=2Br)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:24]([N:26](C)C)=O>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([Cl:22])[CH:15]=[CH:16][C:17]=2[C:24]#[N:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N(C)C
Reactant: O=C(OCc1ccccc1)N1CCc2c(Br)ccc(Cl)c2C1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(Cl)c2c1CCN(C(=O)OCc1ccccc1)C2
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-8-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (381 mg, 1.00 mmol, 1.00 eq.) in DMAC (2 mL), zinc cyanide (59 mg, 0.50 mmol, 0.50 eq.), tris(dibenzylideneacetone)dipalladium(O) (20 mg, 0.02 mmol, 0.02 eq.), 1,1′-bis-(diphenylphosphino)-ferrocene (15 mg, 0.03 mmol, 0.03 eq.) and poly(methylhydrosiloxane) (20 μL) were added. The resulting mixture was stirred at 150° C. under microwave irradiation for 30 min. The mixture was allowed to cool to r.t. To the previous mixture, zinc cyanide (59 mg, 0.50 mmol, 0.50 eq.), tris(dibenzylideneacetone)dipalladium(O) (20 mg, 0.02 mmol, 0.02 eq.), 1,1′-bis-(diphenylphosphino)-ferrocene (15 mg, 0.03 mmol, 0.03 eq.) and poly(methylhydrosiloxane) (20 μL) were added. The resulting mixture was stirred at 150° C. under microwave irradiation for 30 min. The reaction mixture was diluted with AcOEt and water was added. The layers were separated and the org. layer was dried over MgSO4, filtered over celite, and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 40 fractions of 30 mL, Heptane+5% AcOEt to Heptane+30% AcOEt) to yield the title compound as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:14])=[C:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=1)=[O:4].[I-:18].[Na+].CCCCCC>COCCOC>[OH:14][C:8]1[C:9]([CH:11]([CH3:13])[CH3:12])=[CH:10][C:5]([C:3](=[O:4])[CH2:2][I:18])=[CH:6][C:7]=1[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Reactant: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CC(C)c1cc(C(=O)CI)cc(C(C)C)c1O
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 50.95 g (200 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone in 250 ml of 1,2-dimethoxyethane, a solution of 30.94 g (206 mmol) of sodium iodide in 250 ml of 1,2-dimethoxyethane is added dropwise at room temperature. After the addition, stirring is continued for 16 hours at room temperature. Then 100 ml of hexane is added and, after stirring for additional 15 minutes, the precipitated salts are removed by filtration. The obtained solution is evaporated and the resulting residue is purified by recrystallization from hexane/dichloromethane to give 48.5 g (70%) of compound 201, m.p. 127-128° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:34]O)[C:22]1[C:31]([F:32])=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([Cl:33])[CH:23]=1>>[Cl:33][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:34]=2)[C:31]([F:32])=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: COC(=O)c1cc(F)c(C(N)=NO)cc1Cl
Product: COCc1cc(-c2nc(-c3cc(Cl)c(C(=O)OC)cc3F)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (230.67 mg; 0.90 mmol) and Intermediate 55 (184.97 mg; 0.75 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1). The white solid was washed with MeOH affording the title compound as a white powder. 1H NMR (CDCl3, 300 MHz) δ 8.44-8.43 (m, 1H), 8.35 (d, J=6.1 Hz, 1H), 8.18 (dd, J=7.9, 1.8 Hz, 1H), 7.77 (d, J=10.1 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.32-7.24 (m, 3H), 7.13 (d, J=7.2 Hz, 1H), 4.27-4.18 (m, 2H), 3.99 (s, 3H), 3.34 (s, 3H), 2.08 (s, 3H). LC/MS (Method B): 467.1 (M+H)+. HPLC (Method A) Rt 6.09 min (Purity: 98.8%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)\[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)\[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:35][CH:36]=2)[N:4]=1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: COC(=O)CC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A mixture of 4-(chloromethyl)-2-(2-furyl)-5-methyloxazole (348 mg), methyl E-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyrate (507 mg, yield 67%) as a colorless oil from an ethyl acetate-hexane (1:3, v/v)-eluted fraction.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.C1C=CC=CC=1.II.S(=O)(=O)(O)O.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>[Zn].O.C1(C)C=CC=CC=1>[OH:10][C:9]([C:8]1[CH:17]=[CH:18][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: COCOc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: II
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(O)(c1ccccc1)c1ccc(OCOC)cc1
Yield: 39.9 %

Procedure:
0.485 g of 4-(methoxymethoxy)benzophenone was dissolved in 0.45 ml ethyl bromoacetate, 1.5 ml benzene and 1.5 ml toluene, mixed with 3.27 g of zinc and 50 mg of iodine, and then refluxed for 2 hours under a stream of argon. The reaction mixture was mixed with water, adjusted to pH 1 with concentrated sulfuric acid, and then extracted with benzene three times. The extract was filtrated to remove insoluble components, washed twice with water and once with brine, followed by drying over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was evaporated and purified via column chromatography on silica gel (ethyl acetate:hexane=1:5) to give ethyl 3-hydroxy-3-[4-(methoxymethoxy)phenyl]-3-phenylpropionate (263 mg, yield: 39.9%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH3:12])[C:8]2=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1>CCCCCC.C(#N)C>[N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:47]=[CH:48][C:39]=1[CH2:38][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH3:12])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CC1Cc2ccc(O)cc2C1=O
Reactant: ClCc1ccc2ccccc2n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC#N
Product: CC1Cc2ccc(OCc3ccc4ccccc4n3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.8 %

Procedure:
A mixture of the phenol (15.16 g, 93.58 mmole) of Step D, powdered anhydrous potassium carbonate (12.93 g, 93.6 mmole), 18-crown-6 (2.47 g, 9.36 mmole) and dry acetonitrile (200 mL) is stirred at room temperature under a nitrogen for 15 minutes. 2-Chloromethylquinoline (free base, freshly prepared from 18.29 g or 102.96 mmole of the hydrochloride salt) is added in one portion and the mixture is placed in an oil bath heated at 65° C. for 11 hours (TLC, dichloromethanemethanol 9:1, UV). The solvent is removed in vacuo and the residue is partitioned between ethyl acetate and water. The organic phase is washed with brine, dried (MgSO4) and evaporated to yield an oil which solidifies upon trituration with hexane (ca. 31 g). The crude product is purified by flash chromatography (on silica Merck-60, absorbed in methylene chloride, eluted with CH2Cl2 -ethyl acetate 90:10 and 85:15) to provide 5.95 g of slightly impure material together with 24.55 g of the pure title compound (pale yellow solid, 84.8%).
Reaction SMILES: [C:1]1([CH2:7][NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21](Cl)=[O:22].[OH-].[Na+]>C1COCC1.O>[CH3:12][C@H:9]1[N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21](=[O:22])[CH2:20][O:11][CH2:10]1
Reactant: O=C(Cl)CCl
Reactant: C[C@H](CO)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1COCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To (2R)-2-[(phenylmethyl)amino]-1-propanol (8.43 g, 51 mmol) in THF (50 mL) was added a solution of K2CO3 (21.15 g, 153 mmol) in water (50 mL). To the resulting mixture at 0° C. was added slowly via syringe chloroacetyl chloride (5.7 mL, 71.4 mmol) with vigorous stirring, and the reaction mixture was stirred for 1 hour at 0° C. A 50% aqueous NaOH solution was added to adjust the pH>13, and the resulting mixture was warmed up overnight to room temperature. The solution was extracted with CH2Cl2 (2×200 mL), and the organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound (100% crude yield) as a colorless oil. LC-MS (ES) m/z=206 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:18]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:27]([O:29][C:30](=O)[C:20]=2[CH:19]=1)=[O:28]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:4]3[CH:3]=[C:2]([N:1]4[C:27](=[O:28])[C:21]5[C:20](=[CH:19][CH:18]=[C:23]([C:24]([OH:26])=[O:25])[CH:22]=5)[C:30]4=[O:29])[CH:7]=[CH:6][CH:5]=3)=[N:12][C:11]=2[CH:13]=1
Reactant: Nc1cccc(-c2nc3cc(Cl)ccc3o2)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4cc(Cl)ccc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)-5-chlorobenzoxazole (34 mg, 0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (30 mg, 0.16 mmol) the title compound was obtained, 38 mg (64%). 1H NMR (DMSO) δ 8.48(dd, 1H), 8.39(bd, 2H), 8.30(dt, 1H), 8.16(d, 1H), 8.00(d, 1H), 7.88(m, 4H), 7.54(dd, 1H). MS 417 m/z (M−H)−.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH2:12]([S:16](Cl)(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]>C(Cl)Cl>[CH2:12]([S:16]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)NCCC
Reaction time: 20 h

Procedure:
6.9 ml of n-propylamine (4.9 g, 84 mmol) and 11.6 ml of triethylamine (8.5 g, 84 mmol) were dissolved at room temperature in 85 ml of methylene chloride. Likewise at room temperature 10.9 ml of n-butanesulfonyl chloride (13.1 g, 84 mmol) were added dropwise to this solution over the course of 1 h. After 20 h of stirring the reaction mixture was washed twice with 50 ml of water. The organic phase was dried over magnesium sulphate, the methylene chloride was distilled off and the oily residue which remained was dried in vacuo. This gave 13.5 g of the target compound, whose constitution was verified by NMR spectroscopy.