Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[C:15]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)=[CH:31][CH:32]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OC4CCN(C(C)=O)CC4)cc3)nc2c1
Temperature: 115 °C

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (0.20 g, 1.0 mmol) and 4-(1-acetyl-piperidin-4-yloxy)-benzaldehyde (0.25 g, 1.0 mmol) in N,N-dimethyl acetamide (5 mL), NaHSO3 (0.20 g, 1.1 mmol) and p-TSA (20 mg, 0.10 mmol) were added and the reaction mixture was heated at 115° C. for 16 hours. The reaction mixture was cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water and the solid was collected; the crude product was purified by column chromatography on silica gel (230-400 mesh), using 5% methanol in CH2Cl2 as eluent, to give the title compound. Yield: 0.2 g (47%). MP 275-277° C. 1H NMR (400 Hz, CDCl3): δ 11.94 (s, 1H), 8.16 (d, 2H), 7.10 (d, 2H), 6.70 (d, 1H), 6.50 (d, 1H), 4.76 (m, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.70 (m, 1H), 3.30 (m, 2H), 3.20 (m, 1H), 2.04 (s, 3H), 1.95 (m, 2H), 1.64 (m, 1H), 1.52 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.CN(C)CCN(C)C.C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([B:24]([OH:29])[OH:25])=[CH:7][C:6]=2[CH:10]=1
Reactant: Clc1ccc2occc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cc2cc(Cl)ccc2o1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
To a solution of 5-chlorobenzofuran (14 g, crude) in dry tetrahydrofuran (250 mL) were added tetramethylethylenediamine (12.82 g, 110 mmol). The solution was kept below −60° C. under argon, while the solution of butyllithium in hexane (44 ml, 2.5 M) was added dropwise. It was warmed to −10° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of triisopropyl borate (51.88 g, 276 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (70 ml, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3×80 ml). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give 5-chlorobenzofuran-2-ylboronic acid (7.5 g) which was used for the next step without further purification.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)=[CH:3][CH:2]=1.[Br:27]C1CC(=O)NC1=O>C(Cl)(Cl)Cl>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14][C:15]3[CH:16]=[C:17]([Br:27])[CH:18]=[CH:19][C:20]2=3)=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccc(N3c4ccccc4Cc4ccccc43)cc2)cc1
Reactant: O=C1CC(Br)C(=O)N1
Solvent: ClC(Cl)Cl
Product: Brc1ccc2c(c1)Cc1ccccc1N2c1ccc(-c2ccccc2)cc1
Yield: 77.7 %

Procedure:
The obtained 10-(biphenyl-4-yl)-9,10-dihydroacridine (15.3 g, 45.9 mmol) was added with chloroform (500 ml), and then with bromosuccinimide (9.8 g, 55.1 mmol). The resultant solution was stirred at room temperature for 2 hours. After the reaction was completed, the resultant solution was washed with distilled water. Then, an organic layer was extracted and dried with sodium sulfate so as to remove the solvent. The residue was purified by silica gel column chromatography (methylene chloride/n-hexane (1/20)) to obtain 10-(biphenyl-4-yl)-2-bromo-9,10-dihydroacridine compound (white solid, 14.7 g, yield 77%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](C#N)=[CH:7][C:6]=1[F:13].[C:14](=[O:17])(O)[O-:15].[Na+]>O.S(=O)(=O)(O)O>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:14]([OH:15])=[O:17])=[CH:7][C:6]=1[F:13]
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(OCCBr)c(F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(OCCBr)c(F)c1
Yield: 65 %

Procedure:
4-(2-Bromoethoxy)-3-fluorobenzonitrile (3.78 g, 15.5 mmol) in water (18 mL) and concentrated sulfuric acid (18 mL) was heated at 110° C. for 12 hours. The solution was then cooled to room temperature and neutralized with solid sodium bicarbonate. Acidification with glacial acetic acid leads to a white solid precipitate, which was collected by filtration and dissolved in dichloromethane. The resulting solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give the product as a beige-colored solid (2.65 g, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.00 (brs, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.69 (d, J=12.0 Hz, 1H), 7.29 (dd, J=8.8 Hz, 8.4 Hz, 1H), 4.48 (t, J=5.2 Hz, 2H), 3.85 (t, J=5.2 Hz, 2H).
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[N:6]([C:15]1[C:23]2[S:22][C:21]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:20][C:19]=2[C:18]([O:33][CH3:34])=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1>C(O)(=O)C.[Zn]>[CH3:34][O:33][C:18]1[C:19]2[N:20]=[C:21]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:22][C:23]=2[C:15]([NH:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(N(Cc2ccc(C)cc2)C(=O)OCC(Cl)(Cl)Cl)c2sc(NC(=O)c3ccccc3)nc12
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(NCc2ccc(C)cc2)c2sc(NC(=O)c3ccccc3)nc12
Temperature: 80 °C
Yield: 21.5 %

Procedure:
To a stirred solution of 100 mg (01.17 mmol) (2-benzoylamino-4-methoxy-benzothiazol-7-yl)-(4-methyl-benzyl)-carbamic acid 2,2,2-trichloro-ethyl ester in 3 ml acetic acid at room temperature was added 90 mg (1.34 mmol) activated zinc powder and the mixture was heated at 80° C. for 16 hours. The mixture was then filtered and the filtrate concentrated in vacuo. Flash chromatography (ethyl acetate/hexane) afforded 15 mg (21%) N-[4-methoxy-7-(4-methyl-benzylamino)-benzothiazol-2-yl]-benzamide as a yellow crystalline solid, ES-MS m/e (%): 426 (M+Na+, 27), 404 (M+H+, 100), and 10 mg (13%) N-{7-[acetyl-(4-methyl-benzyl)-amino]-4-methoxy-benzothiazol-2-yl}-benzamide as a yellow crystalline solid, ES-MS m/e (%): 468 (M+Na+, 12), 446 (M+H+, 100).
Reaction SMILES: C(O[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[C:6](=[O:8])[CH3:7])C.[CH3:12][NH:13][N:14]=[C:15]([CH3:17])[CH3:16]>CCOCC>[CH3:12][N:13]([CH:4]=[C:5]([C:6](=[O:8])[CH3:7])[C:9](=[O:11])[CH3:10])[N:14]=[C:15]([CH3:17])[CH3:16]
Reactant: CNN=C(C)C
Reactant: CCOC=C(C(C)=O)C(C)=O
Solvent: CCOCC
Product: CC(=O)C(=CN(C)N=C(C)C)C(C)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-(ethoxymethylene)pentane-2,4-dione (Preparation 2, 8.6 g) was dissolved in Ether (30 mL) and cooled to 0° C. The reaction solution was then slowly treated with 1-methyl-2-(propan-2-ylidene)hydrazine (Preparation 1, 4.8 g) dropwise over 5 minutes, and then warmed and stirred at room temperature overnight. The reaction solution was purified directly by flash column chromatography (Biotage Quad 25; Eluent: 20% EtOH in EtOAc) to afford the title compound as a light red solid. (9.1 g, 84.0%).
Reaction SMILES: [OH-].[Na+].S(OC)(O[CH3:7])(=O)=O.[OH:10][C:11]1[C:20]([CH3:21])=[C:19]2[C:14]([C:15](=[O:24])[CH2:16][C:17]([CH3:23])([CH3:22])[O:18]2)=[CH:13][CH:12]=1>O>[CH3:7][O:10][C:11]1[C:20]([CH3:21])=[C:19]2[C:14]([C:15](=[O:24])[CH2:16][C:17]([CH3:22])([CH3:23])[O:18]2)=[CH:13][CH:12]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1c(O)ccc2c1OC(C)(C)CC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1C)OC(C)(C)CC2=O
Reaction time: 2 h
Yield: 78 %

Procedure:
The reaction is carried out under nitrogen. In 50 ml of a 10% sodium hydroxide solution 4.9 g (20 millimoles) of 7-hydroxy-2,2,8-trimethyl-4-chromanone are dissolved, 2.6 g (2 ml, 21 millimoles) of dimethyl sulfate are added and the reaction mixture is vigorously stirred for 2 hours. The reaction mixture is diluted with 100 ml of icecold water and extracted three times with 50 ml of carbon tetrachloride each. The organic phase is washed twice with 50 ml of water each, dried over sodium sulfate, the solvent is removed and the residue crystallized from 90% methanol. Thus 3.4 g of the desired compound are obtained, yield 78%. Mp.: 105°-107° C.
Reaction SMILES: C(OC([N:6]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)[C:8]2([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][C:11](=[O:20])[NH:10][CH:9]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:7]1=[O:35])=O)C.[OH-].[Na+]>CO>[Cl:34][C:31]1[CH:32]=[C:33]2[NH:6][C:7](=[O:35])[C:8]3([CH:13]([CH:14]4[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]4)[CH2:12][C:11](=[O:20])[NH:10][CH:9]3[C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[C:28]2=[CH:29][CH:30]=1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1ccc(Cl)cc1)NC(=O)CC2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(C2CCCCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2ccc(Cl)cc2)N1
Yield: 43.4 %

Procedure:
In a manner similar to the method described in example 4d, racemic (2′S,3S,4′R)-6-chloro-2′-(4-chlorophenyl)-4′-cyclohexyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.4 g, 0.78 mmol) was reacted with NaOH (56 mg, 1.4 mmol) in methanol to give racemic (2′S,3S,4′R)-6-chloro-2′-(4-chlorophenyl)-4′-cyclohexylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.15 g, 44%).
Reaction SMILES: C(OC([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:15])[CH3:14])=[CH:9][CH:8]=1)C)C>C(O)(=O)C.O1CCOCC1.O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:15])[CH3:14])=[CH:9][CH:8]=1
Reactant: CCOC(C)Oc1ccc(C(C)O)cc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 700 ml of a mixed solvent of acetic acid/dioxane/water (10/5/5) was dissolved 0.35 mole of a each R-form of fatty acid ester of 1-(4-(1-ethoxyethoxy)phenyl)ethanol, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled under reduced pressure to give an R-form of fatty acid ester of 1-(4-hydroxyphenyl)ethanol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)=[C:6]([O:20][CH3:21])[CH:5]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:21][O:20][C:6]1[CH:5]=[C:4]([CH2:3][CH:2]=[O:1])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCO)cc2OC)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(CC=O)cc2OC)cc1
Reaction time: 1.5 h

Procedure:
A solution of Example 491B (2.47 g, 8.63 mmol) in dichloromethane (25 mL) at room temperature was treated with Dess-Martin periodinane (4.03 g, 9.49 mmol), stirred for 90 minutes, and concentrated The concentrate was purified by flash column chromatography on silica gel with 1:1 ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[S:24][C:25]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:17][CH:16]=1>>[CH2:1]([N:5]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]2[S:24][C:25]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc2nc(/C=C/c3ccc(OCCCCl)cc3)sc2c1
Reactant: CCCCNCCCC
Product: CCCCN(CCCC)CCCOc1ccc(/C=C/c2nc3ccc(OC)cc3s2)cc1
Yield: 52 %

Procedure:
Reaction of this product (2.0 g, 5.6 mmol) with dibutylamine produced 1.3 g (52% yield) of the named compound as the HCl salt, mp 190°-200° C. IR(KBr); 1600 cm-1. MS: 453(MH+). 1H NMR (CDCl3): δ 7.41-6.88 (m, 9H), 4.13 (t, 2H), 3.91 (s, 3H), 3.09 (m, 6H), 2.41-0.88 (m, 16H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[C:15]([O:18][C:19](=O)C)(=O)C>>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([C:6](=[CH:15][O:18][CH3:19])[C:7]#[N:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: N#CCC(=O)c1cc(F)c(Cl)cc1Cl
Product: COC=C(C#N)C(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 150 °C
Yield: 98.8 %

Procedure:
A mixture of 21 g of 2,4-dichloro-5-fluorobenzoyl-acetonitrile, 19.2 g of methyl o-formate and 23.1 g of acetic anhydride is refluxed at a bath temperature of 150° C. for 3 hours. The volatile constituents are then distilled off under a waterpump vacuum and finally under a fine vacuum at a bath temperature of 120° C. 24.5 g (99%) of 2-(2,4-dichloro-5-fluorobenzoyl)-3-methoxy-acrylonitrile are obtained. A sample recrystallized from toluene gives colorless crystals of melting point 159° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:34][CH3:35])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:16]([C:18]1[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17])=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+]>CO.O>[CH2:34]([N:7]1[C:8]2[C:13](=[CH:12][C:11]([NH:15][C:16]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=4)=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3])[CH3:35]
Reactant: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1CC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21

Procedure:
1-Ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid ethyl ester (4.5 g, 9.37 mmol) was added to MeOH/H2O (110 mL, 10/1). Lithium hydroxide monohydrate (1.5 g, 35.7 mmol) was added to the above mixture. The mixture which resulted was heated to reflux overnight. The solvent was removed under reduced pressure and the residue was dissolved in H2O (500 mL). The solution was acidified with 6N HCl to pH 2. The solid was collected by filtration and dried under vacuum (4.0 g, 94.5%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)nc2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cn1

Procedure:
A solution of 81.7 mg (0.194 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-methyl-5-pyridyl)-2-naphthalenyl)ethynyl]benzoate (Compound 12) and 40.7 mg (0.969 mmol) of LiOH—H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 8.41 (IH, d, J=1.9 Hz), 7.90 (2H, d, J=8.3 Hz), 7.63 (1H, dd, J =2.3, 7.9 Hz), 7.59 (2H, d, J=8.3 Hz), 7.49 (2H, m), 7.33 (1H, d, J=7.8 Hz), 6.95 (1H, s), 6.11 (1H, t, J=4.5 Hz), 2.52 (3H, s), 2.37 (2H, d, J=4.6 Hz), 1.31 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18]N3C(=O)C4C(=CC=CC=4)C3=O)[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[H-].[Na+].COC1C=CC(C2N=CNC=2C)=CN=1.BrCCCC[N:51]1[C:55](=[O:56])[C:54]2=[CH:57][CH:58]=[CH:59][CH:60]=[C:53]2[C:52]1=[O:61]>CN(C=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:57]3[CH:58]=[CH:59][CH:60]=[C:53]4[C:54]=3[C:55](=[O:56])[NH:51][C:52]4=[O:61])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(CCCCN3C(=O)c4ccccc4C3=O)[nH]c2C)cn1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: COc1ccc(-c2nc[nH]c2C)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CCCCc3cccc4c3C(=O)NC4=O)[nH]c2C)cn1
Reaction time: 22 h
Yield: 24 %

Procedure:
2-{4-[4-(6-methoxy(3-pyridyl))-5-methylimidazolyl]butyl}-isoindole-1,3-dione. To a solution of sodium hydride, 60% dispersion (1.8 g, 44.75 mmoles) in DMF (9 ml) at 0° C. was added a solution of 2-methoxy-5-(5-methylimidazol-4-yl)pyridine (3.4 g, 17.9+mmoles) in DMF (18 ml) dropwise. A solution of N-(4-bromobutyl)phthalimide (7.6 g, 26.9 mmoles) in DMF (12 ml) was than added. The reaction was held at 0° C. for 22 hours, at which time it was dumped onto ice (400 g). The precipitate was filtered and the solid was dissolved in DCM. The organic solution was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using a solvent gradient of 0-1-3% MeOH in CH2Cl2 with 0.1% TEA to yield 2-{4-[4-(6-methoxy(3-pyridyl))-5-methylimidazolyl]butyl-isoindole-1,3-dione (1.6 g, 24%). MH+(391)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[NH:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[CH2:6]1.C(=[NH:29])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[O-].[Na+].[ClH:79]>O>[ClH:79].[CH3:1][O:2][C:3](=[O:15])[NH:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:29])[CH:11]=2)[CH2:6]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)N[C@@H]1Cc2ccc(Br)cc2C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)N[C@@H]1Cc2ccc(N)cc2C1
Temperature: 72.5 °C

Procedure:
A mixture of 94.55 g of (R)-(5-bromo-indan-2-yl)-carbamic acid methyl ester, 69.78 g of benzophenone imine, 2.32 g of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 26.47 g of sodium methoxide, and 1.60 g of tris(dibenzylideneacetone)dipaladium(0) in 875 mL of deoxygenated and dry toluene is stirred under nitrogen and heated to an internal temperature of 70-75° C. over a period of 15 minutes. The mixture is stirred at this temperature for 16 hours, and cooled to 30-35° C. over a period of 30 minutes. Isopropyl acetate (875 mL) is added over a period of about 15 minutes and the mixture is further cooled to 20-25° C. Water (875 mL) is added over a period of about 15 minutes and the suspension is stirred for an additional 10 minutes. The solid is collected and washed with 175 mL of toluene followed by 263 mL of water to obtain crude (R)-[5-(diphenylmethylene)amino-indan-2-yl]-carbamic acid methyl ester as a yellow solid. The reaction flask, Buchner funnel, and filtration flask are washed with about 400 mL of isopropyl acetate and this is combined with the filtrate. The organic layer is separated and washed with a solution of 43.75 g of citric acid in 831 mL of water to afford a solution of additional crude (R)-[5-(diphenylmethylene)amino-indan-2-yl]-carbamic acid methyl ester which is added to the above crude product. 2 N Hydrochloric acid (170 mL) is added and the mixture is stirred at an internal temperature of 20-25° C. for 16 hours. Water (350 mL) is then added and the biphasic solution is stirred for an additional 10 minutes. The mixture is filtered, the aqueous layer is separated and washed with a total of 1750 mL of isopropyl acetate in two equal portions to yield about 2200 mL of a solution of (R)-(5-amino-indan-2-yl)-carbamic acid methyl ester hydrochloride. The solution is cooled to 0-5° C. over a period of 15 minutes. 2 N sodium hydroxide (2175 mL) is added to adjust the pH to 8-9 in 45 minutes while maintaining an internal temperature below 18° C. A solution of 93.5 g of sodium chloride in 267 mL of water is added and the resulting suspension is stirred at this temperature for an additional 30 minutes. The solid is collected by filtration and washed with 438 mL of water in two equal portions. The solid is dried at 55-60° C. under vacuum (10-30 torr) with nitrogen bleeding to obtain crude (R)-(5-amino-indan-2-yl)-carbamic acid methyl ester as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[F:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][NH:20][C:21]([C:23]2[S:27][C:26]([N:28]3[CH2:32][CH2:31][CH2:30][C:29]3=[O:33])=[N:25][C:24]=2[CH3:34])=[O:22])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][NH:20][C:21]([C:23]2[S:27][C:26]([N:28]3[CH2:32][CH2:31][CH:30]([CH2:2][C:3]4[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=4)[C:29]3=[O:33])=[N:25][C:24]=2[CH3:34])=[O:22])=[CH:17][CH:16]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccc(F)cc1
Product: Cc1nc(N2CCC(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 26 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use 1-(bromomethyl)-4-(trifluoromethoxy)benzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene to react with N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 26% yield: mp 165-166° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.34-7.16 (m, 4H), 7.12 (d, J=8.6 Hz, 2H), 7.01 (t, J=8.6 Hz, 2H), 6.02 (t, J=5.6 Hz, 1H), 4.52 (d, J=5.6 Hz, 2H), 4.09-4.02 (m, 1H), 3.93-3.79 (m, 1H), 3.29-3.20 (m, 1H), 3.05-2.95 (m, 1H), 2.85-2.75 (m, 1H), 2.60 (s, 3H), 2.35-2.19 (m, 1H), 1.99-1.81 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.6, 162.3, 155.4, 152.8, 148.1, 136.9, 133.7, 131.6, 130.3, 129.6, 121.2, 118.6, 115.7, 45.9, 44.3, 43.4, 35.7, 24.3, 17.2; MS (ES+) m/z 508.3 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][CH2:13][O:14][CH3:15])=[CH:7][C:6]=1Br.CCCCCC.C([Li])CCC.CN([CH:31]=[O:32])C>C(OCC)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](=[CH:7][C:8]([CH2:11][O:12][CH2:13][O:14][CH3:15])=[CH:9][CH:10]=1)[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: COCOCc1ccc(OCOC)c(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COCOCc1ccc(OCOC)c(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-4-methoxymethoxymethylphenol methoxymethyl ether (11.18 g) in diethyl ether (400 ml) was cooled to -78° C. To the solution was added dropwise a 1.6M n-butyl lithium hexane solution (28 ml) under argon atmosphere. The mixture was stirred for one hour while maintaining the temperature, to which was added dropwise DMF (5 ml), followed by raising the temperature up to room temperature and stirring overnight. The reaction mixture was subjected to extraction with the addition of water and ethyl acetate. The organic layer was washed (a saturated aqueous saline solution) and dried (anhydrous magnesium sulfate). Then, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 5-methoxymethoxymethyl salicylaldehyde methoxymethyl ether (7.23 g) (Compound B-23). The physical properties are shown in Table 7.