Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH:19]([OH:20])[C:18]3[S:21][CH2:22][CH:23]([O:26][CH3:27])[CH2:24][S:25][C:17]=3[C:16]2=[O:28])=[N:13][CH:14]=1.Cl.Cl[C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32].N1C=CC=CC=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH:16]([O:28][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[C:17]3[S:25][CH2:24][CH:23]([O:26][CH3:27])[CH2:22][S:21][C:18]=3[C:19]2=[O:20])=[N:13][CH:14]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: COC1CSC2=C(SC1)C(O)N(c1ccc(Cl)cn1)C2=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1CSC2=C(SC1)C(OC(=O)N1CCN(C)CC1)N(c1ccc(Cl)cn1)C2=O
Temperature: 45 °C
Yield: 31.7 %

Procedure:
Triethylamine (42 cc) is added, at about 15° C., to a suspension of 7-(5-chloropyrid-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (7.4 g) and 1-chlorocarbonyl-4-methylpiperazine hydrochloride (43.0 g) in anhydrous methylene chloride (215 cc), and anhydrous pyridine (90 cc) is then added to the resulting mixture. The reaction mixture is heated for 10 hours at 45° C. After cooling, the mixture is diluted by adding methylene chloride (250 cc). The organic phase is washed three times with an N aqueous sodium hydroxide solution (total 300 cc) and three times with distilled water (total 750 cc), dried over anhydrous sodium sulphate and evaporated. The residue is dissolved in boiling ethanol (50 cc). After cooling the solution for 20 hours at 2° C., the resulting crystals are filtered off, washed three times with ice-cooled ethanol (total 30 cc) and dried under reduced pressure (20 mm Hg). The resulting product (5.1 g; m.p. 197° C.) is dissolved in boiling ethanol (80 cc). After filtering the boiling solution and then cooling the filtrate for 16 hours at 2° C., the resulting crystals are filtered off, washed with ice-cooled ethanol (8 cc) and dried under reduced pressure (0.2 mm Hg) at 55° C. 7-(5-Chloropyrid-2-yl)-3-methoxy-6-(4-methylpiperazin-1-yl)carbonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]-pyrrole (3.2 g), which melts at 199° C., is obtained.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH2:16][CH3:17])=[O:10])C1C=CC=CC=1>CO.[Pd]>[CH2:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])[CH3:17]
Reactant: CCN1CCCC1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCN1CCC[C@H]1C(=O)O
Reaction time: 12 h
Yield: 76 %

Procedure:
A suspension of 1-ethyl pyrrolidine-2-carboxylic acid benzyl ester (1.5 g, 6.43 mmol) and 10% Pd on charcoal in methanol (30 mL) was hydrogenated over 12 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to get title product (700 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21](O)=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.COC1C=C([NH2:35])C=CC=1N>>[NH2:35][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15]3[S:16][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:9][C:10]=3[N:11]=[CH:12]2)=[CH:19][C:20]=1[O:25][CH3:26]
Reactant: COc1cc(N)ccc1N
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N
Yield: 50 %

Procedure:
The product was prepared according to the manner of 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin4(3H)-one (the preparation of which may be found in Example K1), using 2-methoxybenzene-1,4-diamine to give the product as a yellow powder (0.19 g, 50%). LCMS m/z 384 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.00 (s, 1H), 7.95 (d, 2H), 7.60 (d, 2H), 7.00 (s, 1H), 6.80 (d, 1H), 6.75 (d, 1H), 5.05 (s, 2H), 3.80 (s, 3H), ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[O:41]=[S:37]1(=[O:40])[CH2:36][CH2:35][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:39][CH2:38]1
Reactant: O=S1(=O)CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCS(=O)(=O)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 4-((2-bromophenyl)sulfonyl)thiomorpholine 1,1-dioxide. MS (ESI): mass calcd. for C20H19FN4O4S2, 462.08; m/z found, 463.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.62-8.60 (m, 1H), 8.16-8.14 (m, 1H), 8.13-8.12 (m, 1H), 8.05 (t, J=8.1 Hz, 1H), 7.69-7.65 (m, 1H), 7.59-7.54 (m, 1H), 7.39-7.36 (m, 1H), 7.25-7.21 (m, 2H), 4.81 (s, 2H), 3.36-3.30 (m, 4H), 3.02-2.98 (m, 4H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[O:19][CH2:18]1)[C:11]([O:13]CC)=[O:12].C(O)(=O)C>[OH-].[Na+]>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[O:19][CH2:18]1)[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)[C@H](CCCCCCN)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NCCCCCC[C@H](N[C@H]1COc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
In 15 ml of 1N sodium hydroxide solution is dissolved 0.5 g of 3(S)-[7-amino-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride obtained in Example 68, and the solution is allowed to stand at room temperature for 30 minutes. Acetic acid (3.5 ml) is added to the solution and the mixture is purified by Amberlite XAD-2 column chromatography (methanol:water=1:2). The eluate is concentrated under reduced pressure and lyophilized to give 0.31 g of 3(S)-[7-amino-1(S)-carboxyheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[OH:34][C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C1COCC1.C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([C:36](=[O:37])[C:35]([OH:34])([CH3:40])[CH3:39])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)(O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (150 mg, 0.33 mmol), 2-hydroxy-2-methylpropionic acid (52 mg, 0.50 mmol), HOBt (50 mg, 0.37 mmol), NMM (81 μL, 0.74 mmol) and EDCI (96 mg, 0.50 mmol) in THF (3 mL) was allowed to stir at r.t. for 4 h. The resulting mixture was diluted with DCM and washed with sat. aq. NaHCO3, dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, THF:EtOAc, 0-50%) then triturated with Et2O/cyclohexane. The resulting solid was collected by filtration and dried in vacuo affording 811 (108 mg, 60%). LCMS (method I): RT 3.21 min, [M+H]+ 535.3. 1H NMR (DMSO, 400 MHz): δ 8.06-8.05 (1 H, m), 7.64-7.63 (1 H, m), 7.26-7.25 (2 H, m), 5.23 (1 H, s), 5.05 (1 H, d, J=10.74 Hz), 4.67 (1 H, d, J=10.76 Hz), 4.55 (1 H, d, J=10.69 Hz), 4.29 (4 H, brd s), 4.16 (1 H, d, J=10.75 Hz), 3.79 (4 H, t, J=4.62 Hz), 3.73 (3 H, s), 3.29-3.27 (2 H, m), 3.09 (3 H, s), 1.35 (3 H, t, J=7.43 Hz), 1.30 (3 H, s), 1.25 (3 H, s)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:26][C:27](=[O:29])[CH3:28])([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18]CC1C=CC=CC=1)[CH2:7][CH2:8][CH3:9])(=[O:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:4][CH2:5][C:6]([NH:26][C:27](=[O:29])[CH3:28])([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[CH2:7][CH2:8][CH3:9])(=[O:3])[CH3:2]
Reactant: CCCC(CCc1ccccc1OCc1ccccc1)(COC(C)=O)NC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCCC(CCc1ccccc1O)(COC(C)=O)NC(C)=O
Reaction time: 6 h
Yield: 93.4 %

Procedure:
To a solution of 2-acetamido-2-(2-(2-benzyloxyphenyl)ethyl)pentyl acetate (0.90 g) in ethanol (45 ml), 10% palladium-carbon (0.40 g) was added and the mixture was subjected to catalytic reduction at room temperature for 6 hours. Catalyst was filtered off from the reaction solution and the solvent was distilled away under reduced pressure to give the subject compound (0.65 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].[N+:17]([O-])([OH:19])=[O:18]>CC(O)=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([N+:17]([O-:19])=[O:18])[CH:14]=1)[C:6]#[C:7][CH3:8]
Reactant: O=[N+]([O-])O
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Solvent: CC(=O)O
Product: CC#CC(CC(=O)OC)c1ccc(O)c([N+](=O)[O-])c1
Yield: 38.3 %

Procedure:
3-(4-Hydroxy-phenyl)-hex-4-ynoic acid methyl ester (1.32 g, 6 mmol) was treated with HNO3 (0.30 mL, 7.2 mmol) in AcOH (10 mL) at 80° C. for 3 h. The solvent was concentrated in vacuo and 3-(3-nitro-4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (613 mg, 2.3 mmol) was isolated from flash chromatography. MS ESI m/e: 264.0 (M+H). The nitro group was then reduced with SnCl2 (2.62 g, 11.6 mmol) in EtOH (10 mL0 and EtOAc (10 mL) at 70° C. for 3 h. The reaction mixture was cooled to 25° C., washed with saturated aqueous Na2CO3, water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was then purified by reverse phase HPLC to give 3-(3-amino-4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (174 mg, 0.74 mmol). MS ESI m/e: 234.0 (M+H). 3-(3-amino-4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (174 mg, 0.74 mmol) and 3-bromobenzaldehyde (278 mg, 1.5 mmol) in DMF (3 mL) was treated with DDQ (204 mg, 0.9 mmol) for 2 h at 25° C. The producted was purified by reverse phase HPLC. MS ESI m/e: 398.0 (M+H). 3-[2-(3-Bromo-phenyl)-benzooxazol-5-yl]-hex-4-ynoic acid methyl ester (19.6 mg, 0.05 mmol) and trifluorophenylboronic acid (38 mg, 0.2 mmol) in DME (1 mL) and 0.2 mL of 2M solution of aqueous Na2CO3 was treated with Pd(PPh3)4 at 80° C. for 14 h. The product was isolated from flash chromatography. MS ESI m/e: 464.0 (M+H). The methyl ester (7.8 mg, 0.017 mmol) was hydrolyzed with LiOH (4 mg, 0.1 mmol) in a 1 mL of 1:1:1 mixture of MeOH, THF, and water for 2 h at 25° C. The reaction mixture was acidified with 1N HCl, extracted with CH2Cl2 and concentrated to give the pure acid (7.6 mg). MS ESI m/e: 450.1 (M+H). 1H NMR (500 MHz) (CDCl3) δ 8.52 (1H, s); 8.30 (1H, d, J=7.8 Hz); 7.91 (1H, s); 7.83 (2H, d, J=8.2 Hz); 7.82 (1H, s); 7.78 (2H, dd, J=8.0, 8.0 Hz); 7.67 (1H, dd, J=7.8, 7.8 Hz); 7.58 (2H, d, J=8.4 Hz); 7.46 (1H, dd, J=8.4, 1.5 Hz); 4.29 (1H, m); 2.94 (1H, dd, J=15.8, 8.1 Hz); 2.84 (1H, dd, J=15.8, 6.9 Hz); 1.89 (3H, d, J=2.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[Br:24]Br.C(OCC)C.C([O-])(O)=O.[Na+]>ClCCl>[Br:24][C:9]1[C:10]([C:21]([OH:23])=[O:22])=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Br
Yield: 81.2 %

Procedure:
To a magnetically stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (20.0 g, 54.5 mmol) in dichloromethane (400 ml) was slowly added bromine (5.62 ml, 109 mmol) and the resulting mixture was reacted for 16 hours at room temperature. Diethyl ether (400 ml) and excess aqueous saturated NaHCO3 solution were successively added. The organic layer was separated, twice washed with aqueous saturated NaHCO3 solution and subsequently washed with brine, dried over MgSO4, filtered and concentrated to give 4-bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (19.77 gram, 81% yield). Melting point: 222-224° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22].CO>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)=CCBr
Reactant: O=C1C=C(NCc2ccc(Cl)nc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C=C(N(CC=C(Cl)Cl)Cc2ccc(Cl)nc2)CO1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
350 mg (1.56 mmol) of 4-[[(6-chloropyridin-3-yl)methyl]amino]furan-2(5H)-one (Ia-1; cf. EP 0539588 A 1) and 124 mg (3.12 mmol) of a 60% dispersion of sodium hydride in mineral oil in 100 ml of tetrahydrofuran are heated under reflux for 3 h. After cooling to room temperature, 592 mg (3.12 mmol) of 3-bromo-1,1-dichloroprop-1-ene (cf. WO 8800183 A1) are added and the mixture is heated under reflux for a further 5 h. After cooling of the reaction mixture to room temperature and addition of methanol, the mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is then dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate: cyclohexane (2:1) gives 264 mg (50% of theory) of 4-[[(6-chloropyridin-3-yl)methyl](3,3-dichloroprop-2-en-1-yl)amino]furan-2(5H)-one.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([NH:10][C:11](=O)[O:12]C1C=CC([N+]([O-])=O)=CC=1)[C:8]#[CH:9]>ClCCl>[CH2:7]([NH:10][C:11]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:12])[C:8]#[CH:9]
Reactant: C1COCCN1
Reactant: C#CCNC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: C#CCNC(=O)N1CCOCC1
Yield: 92.6 %

Procedure:
Morpholine (510 mg, 5.86 mmol) and 4-nitrophenyl prop-2-yn-1-ylcarbamate (800 mg (80% purity), 2.91 mmol) in dichloromethane (10 ml) were stirred at room temperature for 4 hours and then the reaction solution was purified directly by chromatography on silica using ethyl acetate as eluent to give N-prop-2-yn-1-ylmorpholine-4-carboxamide (453 mg, 92%) as a pale yellow solid; NMR Spectrum: (CDCl3) 2.24 (t, 1H), 3.37 (m, 4H), 3.69 (m, 4H), 4.05 (m, 2H), 4.65 (s, 1H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:34][Si:35]([CH3:51])([CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:51][Si:35]([CH3:34])([CH2:45][CH2:46][Si:47]([CH3:48])([CH3:49])[CH3:50])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=2)=[N:32][CH:31]=1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCCCCCCO
Reactant: CCCCCCCCc1ccc(-c2ccc(O)cn2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(-c2ccc(OCCCCCCCC[Si](C)(C)CC[Si](C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethylazodicarboxylate (0.065 g, 0.375 mmol) in THF (5.0 ml) was added dropwise to a stirred solution of 6-(4-octylphenyl)-pyridin-3-ol (0.085g, 0.300 mmol), compound 17 (0.083 g, 0.300 mmol) and triphenylphosphine (0.098 g, 0.375 mmol) in THF (10 ml). The treaction mixture was stirred at room temperature for 24 h, the solvent removed in vacuo and the residues purified by column chromatography [silica gel eluted with hexane/ethyl acetate (9:1)] to yield a colorless solid that was recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>O>[Cl:12][S:13]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[C:7]([OH:9])=[O:8])(=[O:15])=[O:14]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: COc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
Solid 4-methoxy benzoic acid (45.6 g, 0.3 mol), in portions, was added to chlorosulfonic acid (139.8 g, 80 mL, 1.2 mol) at room temperature. After most of the bubbling had ceased, the reaction mixture was heated to 80° C. for 1 hr. The reaction mixture was then poured into vigorously stirring crushed-ice (500 g) and water was then added (500 mL). After 30 min, the white solid was collected, washed with water (2 L) and dried to give 50 g (66%) of the title compound.
Reaction SMILES: [CH:1]1([CH:7]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([NH:18][S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:21])=[O:20])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([NH:18][S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:21])=[O:20])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(NS(=O)(=O)c4ccccc4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(NS(=O)(=O)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
To a mixture of ethyl 3-[({4-[(cyclohexyl{3-methyl-5-[(phenylsulfonyl)amino]-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (312 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (240 mg, 80%) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:13]=[C:12]([I:14])[CH:11]=[C:6]([C:7](OC)=[O:8])[CH:5]=1.[BH4-].[Na+].Cl>C1COCC1.O>[OH:8][CH2:7][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:13]=[C:12]([I:14])[CH:11]=1
Reactant: COC(=O)c1cc(I)cc(C(=O)OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(I)cc(CO)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of dimethyl-5-iodisophthalate in 800 ml of THF was treated with with 22.2 g of CaCI2. Then, 15.2 g of NaBH4 were added portionwise. The mixture was stirred for one day at room temperature. Then, the mixture was acidified with 250 ml of 3N HCl and diluted with 2 l of H2O. The crude product was isolated by extraction and purified by crystallization from THF/hexane. There were obtained 11.2 g of (3-hydroxymethyl-5-iodo-phenyl)-methanol as white crystals.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Br:30])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33]([O:35]C)=[O:34]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:32][C:33]([OH:35])=[O:34])=[C:25]([Br:30])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Product: O=C(O)COc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3-bromo-biphenyl-4-ol, and methyl bromoacetate, in substantially the same manner, as described in Example 2 step g , and was obtained as a white solid, mp 150-152° C.; MS m/e 528 (M+);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:5]=1[CH2:12][CH2:13][CH3:14].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1ccc(OC)cc1C(=O)OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1ccc(O)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a −78° C. solution of 5-Methoxy-2-propyl-benzoic acid methyl ester (350 mg, 1.68 mmol) in DCM (18 mL) is added boron tribromide (840 μL, 8.40 mmol, 1.0 M in DCM) dropwise. The reaction mixture is warmed to room temperature overnight. The reaction mixture is quenched by the dropwise addition of MeOH and is stirred at room temperature for 30 min. The reaction is concentrated and the residue is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated, and chromatographed (0% to 20% EtOAc/Hex) to yield the title compound (274 mg, 84%) 1H NMR (400 MHz, CDCl3) δ 7.34 (d, 1H, J=2.6 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.92 (dd, 1H, J=8.4, 3.1 Hz), 6.92 (dd, 1H, J=8.4, 3.1 Hz), 3.88 (s, 3H), 2.87-2.81 (m, 2H), 1.63-1.52 (m, 2H), 0.94 (t, 3H, J=7.3 Hz).