Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc(Cl)c1
Product: O=C(Cc1cccc(Cl)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3-chlorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.47-7.45 (m, 1H), 7.39-7.42 (m, 1H), 7.33-7.37 (m, 2H), 3.78-3.87 (m, 4H), 3.70 (s, 2H), 3.08-3.14 (m, 4H); MS (ESI−) M/Z 397 (M−H)−.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([O:36]C(C)(C)C)=[O:35])=[N:32][CH:33]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([OH:36])=[O:35])=[N:32][CH:33]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of compound 61b (200 mg, 0.371 mmol) in 5 mL of DCM at rt was added TFA (2.00 mL, 26.1 mmol). After stirring at rt for 6 h, the mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0:1-1:9 MeOH-DCM) to afford the title compound 107 (with 1 eq of TFA) as a bright yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 8.97 (br. s., 1H), 8.35 (br. s., 2H), 7.88-8.05 (m, 2H), 7.65-7.79 (m, 2H), 7.51-7.65 (m, 1H), 6.16 (d, J=5.6 Hz, 1H), 4.09 (br. s., 4H), 3.90-4.03 (m, 4H), 3.19 (br. s., 2H), 2.84 (br. s., 2H), 1.93 (br. s., 2H), 1.78-1.89 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C27H26N6O3, 483.5 (M+H). found 483.4.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[NH:13][C:12]([CH3:14])=[N:11][C:10]=1[N+:15]([O-])=O.[C:19]([CH:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24])(=O)[CH3:20]>C(O)C.C(O)(=O)C.[Fe]>[OH:25][CH2:26][CH2:27][C:22]1[C:19]([CH3:20])=[N:15][C:10]2[N:11]([C:12]([CH3:14])=[N:13][C:9]=2[C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:18])[C:23]=1[OH:24]
Reactant: Cc1cc(C)c(-c2[nH]c(C)nc2[N+](=O)[O-])c(C)c1
Reactant: CC(=O)C1CCOC1=O
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)c(-c2nc(C)n3c(O)c(CCO)c(C)nc23)c(C)c1
Yield: 34.1 %

Procedure:
A solution of 5-mesityl-2-methyl-4-nitro-1H-imidazole (2.1 g, 8.56 mmol), α-acetyl-γ-butyrolactone (1.21 g, 9.42 mmol), and iron powder (2.39 g, 42.8 mmol) in ethanol (40 mL) and acetic acid (10 mL) was stirred at 80° C. for one day. The mixture was filtered through Celite and evaporated. The resulting crystals were washed with ethyl acetate, to give the title compound (0.95 g) as white crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: CC(C)(C)O
Product: CC(C)(C)OC(=O)CCCCCBr
Reaction time: 8 h
Yield: 85.8 %

Procedure:
6-Bromohexanoyl chloride (2 g, 9.37 mmol) was added to t-butanol (6.98 g, 93.7 mmol) under an inert atmosphere. The reaction mixture was stirred overnight and then was concentrated in vacuo, dissolved in ethyl acetate (150 ml), washed with saturated aqueous sodium bicarbonate and 10% aqueous citric acid, and dried over magnesium sulfate to yield t-butyl 6-bromohexanoate (2.02 g, 80% yield).
Reaction SMILES: [O:1]=[O+][O-].[C:4]([O:8][C:9](=[O:28])[CH2:10][N:11]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:12][CH:13]=C(C)C)([CH3:7])([CH3:6])[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CO>[C:4]([O:8][C:9](=[O:28])[CH2:10][N:11]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH2:12][CH:13]=[O:1])([CH3:5])([CH3:6])[CH3:7]
Reactant: O=[O+][O-]
Reactant: COc1ccc(S(=O)(=O)N(CC=C(C)C)CC(=O)OC(C)(C)C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(CC=O)CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ozone is passed through a solution of [(4-methoxybenzenesulfonyl)-(3-methyl-but-2-enyl)-amino]-acetic acid t-butyl ester (2.0 grams, 5.4 mmol) in methylene chloride-methanol (50 mL, ca. 1:1) at -78° C. until a blue color persisted. Triphenylphosphine (4.24 grams, 16.2 mmol) is added and the resulting solution is stirred at room temperature for 3 hours. Concentration provided the crude product which is purified by silica gel chromatography (elution with 1:1 ethyl acetate-hexanes) to provide [(4-methoxybenzenesulfonyl)-(2-oxo-ethyl)-amino]-acetic acid t-butyl ester.
Reaction SMILES: C1(C)C=CC(S([CH2:9][CH2:10][C:11]2[N:29]=[C:14]3[CH:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:16][CH2:17][CH2:18][N:13]3[N:12]=2)=O)=CC=1>C1(C)C=CC=CC=1>[F:28][C:25]([F:26])([F:27])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:15]1[CH2:16][CH2:17][CH2:18][N:13]2[N:12]=[C:11]([CH:10]=[CH2:9])[N:29]=[C:14]12
Reactant: Cc1ccc(S(=O)CCc2nc3n(n2)CCCC3c2ccccc2C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: C=Cc1nc2n(n1)CCCC2c1ccccc1C(F)(F)F
Yield: 71.2 %

Procedure:
2-[2-(Toluene-4-sulfinyl)ethyl]-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (8.87 g) was dissolved in toluene (300 ml), and the reaction solution was heated under reflux for three days. After leaving to cool, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (4.27 g). The property values of the compound are as follows.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[CH:9](OC)=[O:10].[OH-].[Na+]>ClCCl>[CH:9]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1)=[O:10]
Reactant: OCC1CCNCC1
Reactant: COC=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=CN1CCC(CO)CC1
Reaction time: 1.5 h

Procedure:
4-Piperidinemethanol (10 g, 87 mmol) was dissolved in methyl formate (7 mL, 113 mmol) 0° C., and maintained at that temperature for 30 min, then allowed to reach 20° C. and stirred 90 min. Solid sodium hydroxide was added (0.87 g, pellets) and the mixture was left overnight. Dichloromethane was added, the NaOH removed by filtration and the solution treated with 1M HCl in ether (10 mL). The mixture was filtered through Celite and the solvent was removed under reduced pressure to afford the crude title compound. 1H NMR (400 MHz, CDCl3): 0.85-1.1 (2H, m); 1.55-1.85 (3H, m); 2.5-2.7 (1H, m); 2.95-3.1 (1H, m); 3.3 (2H, d, J 7 Hz); 3.6-3.7 (1H, m); 4.1-4.3 (1H, m); 8 (1H, s).
Reaction SMILES: [N:1](=[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:4]=[N:5][OH:6])[NH2:2].[CH:13](OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:7]1([C:3]2[N:1]=[N:2][CH:13]=[N+:5]([O-:6])[CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(OCC)OCC
Reactant: NN=C(C=NO)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: [O-][n+]1cnnc(-c2ccccc2)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a mixture of hydrazono-phenyl-acetaldehyde oxime (30 g, 184 mmol) and triethyl orthoformate (30.6 ml, 184 mmol) was added 4-toluenesulphonic acid monohydrate (3.5 g, 18.4 mmol). The reaction mixture was heated at 110° C. with stirring for 30 min. The cooled reaction mixture was recrystallised from CH2Cl2/hexane to give 27 g (156 mmol, 85%) of 6-phenyl-[1,2,4]triazine-4-oxide as a pale yellow solid. δH (400 MHz; CDCl3) 7.55-7.63 (3H, m, aromatics), 8.01 (2H, dd, J 8.1 and 1.7, aromatics), 8.52 (1H, d, J 1.7, triazine H5), 9.27 (1H, d, J 1.7, triazine H3); m/z (ES+) 174 (M++H, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12]S(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Br:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:23])[CH:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cccc(Br)c2)C1
Temperature: 80 °C
Yield: 84.9 %

Procedure:
To 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (0.795 g, 3.16 mmol) and Cs2CO3 (1.13 g, 3.48 mmol) in DMF (30 mL) was added 3-bromophenol (0.547 g, 3.16 mmol). The reaction was heated to 80° C. for 18 h, then cooled to rt. Brine was added and the mixture extracted with Et2O (2×). The combined organics were washed with brine and dried. Silica gel chromatography (0-40% EtOAc in hexanes) gave 0.881 g (85%) of the title compound. MS (ESI): mass calcd. for C14H18BrNO3, 327.05; m/z found, 272.0 [M-56]+. 1H NMR (CDCl3): 7.17-7.11 (m, 2H), 6.90-6.88 (m, 1H), 6.70-6.66 (m, 1H), 4.89-4.82 (m, 1H), 4.30 (ddd, J=9.7, 6.4, 0.9 Hz, 2H), 3.99 (dd, J=10.3, 4.1 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]=[C:2]1[S:6]/[C:5](=[N:7]\[C:8](=[O:10])[CH3:9])/[N:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:3]1.[C:21]([OH:24])(=[O:23])[CH3:22].ICl.C([O-])(=O)C.[K+]>ClCCl>[C:21]([O:24][CH2:1][C:2]1[S:6]/[C:5](=[N:7]\[C:8](=[O:10])[CH3:9])/[N:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:3]=1)(=[O:23])[CH3:22]
Reactant: C=C1CN(c2ccc(C(F)(F)F)cc2)/C(=N/C(C)=O)S1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: ClI
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)/N=c1\sc(COC(C)=O)cn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N-{(2Z)-5-Methylene-3-[4-(trifluoromethyl)phenyl]-1,3-thiazolidin-2-ylidene}acetamide (4.51 g, 15.0 mmol, Intermediate A6) was dissolved into acetic acid (60 mL) and treated with 1 M iodine monochloride in dichloromethane (30 mL) over three minutes. After about 15 minutes more iodine monochloride solution (0.8 mL) was added, and after another ten minutes the solution was partially concentrated, and then concentrated twice from toluene. The residue was triturated with 20% ethyl acetate/toluene and the allyl chloride was collected by filtration. The filtrate was concentrated and redissolved into acetic acid (20 mL), treated with potassium acetate (2.95 g, 30 mmol), stirred 6 hours at room temperature, and concentrated thrice from ethyl acetate. The residue was mixed with a little ethyl acetate and filtered through basic alumina with a 2% methanol/ethyl acetate rinse. The filtrate was concentrated and chromatographed on silica (ethyl acetate/dichloromethane/hexanes) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:21])[N:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[CH:28][CH:27]=4)[CH:3]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cncc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cncc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 5′-bromo-4-(4-chloro-phenyl)-6-methyl-[2,3′]bipyridinyl (example E.31) (0.600 g, 1.6 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.404 g, 1.8 mmol) according to the general procedure VI. Obtained as a white solid (0.180 g, 29%). MS (ISP) 373.2 [(M+H)+] and 375 [(M+2+H)+];mp 188-192° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1B(O)O>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Reactant: COc1ccc(OC)c(B(O)O)c1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cc(OC)ccc2OC)cc1

Procedure:
The colourless oil, (E)-ethyl 3-(2′,5′-dimethoxy-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (example 50a) and 2,5-dimethoxyphenyl boronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:30]I>CN(C=O)C>[C:1]([N:4]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:7][CH:6]=1)[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Br)cc3)CC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(C(=O)N2CCN(CCc3ccc(Br)cc3)CC2)cc1

Procedure:
In a manner analogous to that described in Example 5, 1.6 g of 1-(4-acetylaminobenzoyl)-4-[2-(4-bromophenyl)ethyl]-piperazine, dissolved in 15 ml DMF, are treated first with 0.2 g NaH in 10 ml DMF and then with 0.6 g methyl iodide in 5 ml DMF. The crude product is crystallised from ether. Thus 1-[4-(N-acetyl-N-methylamino)benzoyl]-4-[2-(4-bromophenyl)ethyl]-piperazine is obtained, m.p. 161°-162°.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]([NH:16][NH2:17])=[O:15])[N:6]=1.[CH3:22][OH:23]>>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]2[O:15][C:22](=[O:23])[NH:17][N:16]=2)[N:6]=1
Reactant: NNC(=O)c1nc(Cc2ccccc2F)n2ccccc12
Reactant: CO
Product: O=c1[nH]nc(-c2nc(Cc3ccccc3F)n3ccccc23)o1

Procedure:
155 mg (0.55 mmol) of 3-(2-fluorobenzyl)imidazo[1,5-a]pyridine-1-carbohydrazide from example 16A are dissolved in 3 ml of methanol. 106 mg (0.65 mmol) of N,N′-carbonyldiimidazole are added, and the mixture is heated to reflux for 2 h. It is then purified directly by preparative HPLC to result in 98 mg (58% of theory) of the desired compound as a pale beige solid.
Reaction SMILES: CC1(C)OC(=O)[CH:5]([C:9](=[O:20])[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4](=O)[O:3]1.CO>C(OCC)(=O)C.C(Cl)Cl>[O:3]=[C:4]1[CH2:5][C:9](=[O:20])[CH2:10][CH2:11][N:12]1[C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19]
Reactant: CC(C)(C)OC(=O)NCCC(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1=O
Temperature: 105 °C
Yield: 82.8 %

Procedure:
Tert-butyl 3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-oxopropylcarbamate (I-59b: 50 g, 158.57 mmol) was dissolved in ethyl acetate (500 mL) at room temperature under nitrogen atmosphere and the resulting reaction mass was heated at 105° C. for 20 hours. The reaction was monitored by TLC (10% methanol in DCM). The reaction mass was cooled to room temperature and concentrated under reduced pressure to afford the crude product. Purification by ether-wash afforded 28 g of the product (83% yield).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:45])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])=[CH:9][C:8]=1[F:44].[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:45])=[O:4])=[C:8]([F:44])[CH:9]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:39])([C:35]([F:36])([F:37])[F:38])[C:31]([F:33])([F:34])[F:32])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(F)c2)c(C)c1
Reaction time: 4 h
Yield: 101.1 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.11 mL) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 106-(1); 21.9 mg, 0.0357 mmol) in methanol (0.3 mL), and the mixture was stirred for four hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (21.6 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:35][C:36]([OH:38])=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:10]=2[C:9]1=[O:34].[BH4-].[Na+]>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:35][C:36]([OH:38])=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:16]([OH:17])[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][C:30]([F:32])([F:33])[F:31])[C:10]=2[C:9]1=[O:34]
Reactant: O=C(O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC(F)(F)F)C2=O)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC(F)(F)F)C2O)c(Cl)c1
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
To a solution of (3-chloro-4-{1,3-dioxo-4,9-bis[(2,2,2-trifluoroethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetic acid (0.250 g, 0.45 mmol) in ethanol (10 ml) and tetrahydrofuran (20 ml), was added sodium borohydride (0.059 g, 1.56 mmol) in portions. A further addition of sodium borohydride (0.059 g, 1.56 mmol) was made and stirring continued for 10 minutes. The mixture was evaporated and then quenched with aqueous saturated ammonium chloride solution until the mixture was pH 7. This was extracted ×2 with ethyl acetate, washed with brine, dried over magnesium sulphate and evaporated to give the crude product (0.235 g, 0.42 mmol). LC/MS: Rt=3.28, [MH]+564.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5](OC)=O.O1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:10]1[C:4]2[C:5](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: C1CCOC1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: c1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
Procedure 2 is illustrated with the conversion of diol (S)-28 to diester (S)-29. To a solution of optically pure (S)-28 (5.8 g., 10.5 mmol) in 250 ml. of tetrahydrofuran was added sodium hydride as a 50% suspension in oil (2.4 g., 50 mmol), and the mixture was stirred at 25° for 2 hr. Methyl bromoacetate (7.6 g., 50 mmol) was added to the above suspension, and the mixture was heated to reflux for 6.5 hours. The reaction mixture was cooled, filtered, and the filter cake was washed with tetrahydrofuran. The combined filtrate was evaporated to an oil that was chromatographed on 150 g. of silica gel. Elution of the column with 1.4 l. of dichloromethane gave non-naphthalene containing products (pmr). Elution with 3.5 l. of 2% methanol-ether gave (S)-29. The eluate was evaporated to give 3.2 g. (44%) of a glass, which was dried at 165° under 0.07 mm for 1 hour, [α]54625 -25.7° (C 1.0, (CH2)4O). The 70 ev mass spectrum of the material gave a parent ion at m/e 692. A 100 MHz pmr spectrum in CDCl3 gave the following signals: δ 7.7-8.05 (m, ArH, 4H), 7.0-7.5 (m, ArH, 6H), 5.0 (s, ArCH2O, 4H), 4.35 (s, OCH2CO2, 4H), 3.80 (s, OCH3, 6H), 2.8-3.8 (m, OCH2CH2O, 2OH). Table I records the analysis. ##STR93##
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:13][Br:21])=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(F)cc(Br)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)cc(Br)c1CBr
Temperature: 0 °C

Procedure:
A suspension of (E4), NBS (1.2 eq.) and benzoyl peroxide (0.1 eq.) in CCl4 (0.28 M) was heated to reflux for 4.5 h. Afterwards, the reaction mixture was cooled down to 0° C. and the solid filtered off. The solid was washed with Et2O and the filtrate was washed sequentially with 1 M Na2S2O3, brine and dried (Na2SO4). Evaporation of the solvent under reduced pressure afforded the title compound that was used without further purification in the next step. 1H NMR (400 MHz, CDCl3, 300 K) δ 7.63 (1H, dd, J=8.6 and 2.8 Hz), 7.52 (1H, dd, J=7.4 and 2.8 Hz), 5.10 (2H, s), 3.97 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8](I)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[CH:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([C:27]3[CH:28]=[CH:29][C:24]([CH:22]=[O:23])=[CH:25][CH:26]=3)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(C=O)cc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a degassed solution of 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (400 mg, 0.82 mmol), (4-formylphenyl) boronic acid (110 mg, 0.74 mmol) and Na2CO3 (174 mg, 1.6 mmol) in DMF (4 mL) was added Pd(dppf)Cl2 (20 mg) under N2, and the mixture was stirred at 100° C. for 2 h. After the solvent was removed, the residue was purified by column chromatography (DCM:EtOAc=10:1) to give the product of 5-bromo-2-(4-formylphenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (200 mg, yield: 52%). 1H-NMR (CDCl3, 400 MHz) δ 10.09 (s, 1H), 8.09˜8.15 (m, 3H), 8.02 (s, 2H), 7.75 (s, 1H), 5.90 (br s., 1H), 3.36 (s, 3H), 3.11 (s, 3H), 3.05 (d, J=4.8 Hz, 3H). MS (M+H)+: 465/467.