Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O[N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34]>CN(C=O)C.C(Cl)Cl>[NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:11])[C@H:2]([C:7]([O:9][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Fmoc-L-Leu-OH (10 g,28.32 mmol) was dissolved in a mixture of DMF (10 ml)-CH2Cl2 (70 ml) and cooled in an ice-bath. N-Hydroxysuccinimide (3.58 g, 31.14 mmol, 1.1 equiv.) and dicyclohexylcarbodiimiide (6.06 g, 31.14 mmol, 1.1 equiv.) were added and the mixture was stirred at 0° C. for 1 hour and 25° C. for 14 hour. The reaction mixture was cooled in an ice-bath, filtered and the precipitate washed with CH2Cl2 (40 ml). The filtrate was evaporated to dryness and the residue dissolved in a mixture of dioxane (80 ml)-H2O (10 ml) to form a solution of Fmoc-Leu-OSu. A solution of anhydrous L-asparagine (5.606 g, 42.48 mmol, 1.5 equiv.) in 60 ml of Na2CO3 (2.50 g, 42.28 mmol, 1.5 equiv.) was added to the above solution of Fmoc-Leu-OSu. An additional 10 ml of dioxane was added and the reaction mixture was stirred at 25° C. for 2 hours. Ethyl acetate (200 ml) was added to the reaction mixture and the pH adjusted to about 2 by the addition of 5% aqueous HCl with stirring. The EtOAc layer was separated and the aqueous layer was extracted 4 more times with 100 ml each. The combined EtOAc extract was washed with saturated NaCl (100 ml), H2O (3×100 ml), dried over anhydrous Na2SO4, filtered and evporated to dryness. The residue was dissolved in DMF (60 ml) with warming (40-45° C.) and H2O added to the cloud point. The product crystallized after standing overnight. It was filtered, washed with ether and recrystallized from DMF-H2O. Lyophilization from dioxane gave 9.45 g (71.3%) of product. NMR and FAB mass spectroscopy confirmed the molecular formula C25H29N3O6 with an observed mass for (M+H)+, 468.3. The product Fmoc-Leu-Asn-OH was shown to be >95% pure by analytical HPLC. HPLC conditions were: column: Lichrosorb RP-8 (5μ); eluant: (A) 0.1M NaClO4 (pH 2.5)-(B) CH3CN; gradient: 40%-80% (B) in 20 minutes; flow 1 ml/l minute.; and detection: 210 nm.
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].S(=O)(=O)(O)O>C(O)CCC>[CH2:10]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([S:11](=[O:13])(=[O:14])[NH2:12])[C:2]([Cl:1])=[C:3]([N+:15]([O-:17])=[O:16])[CH:4]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)c1cc([N+](=O)[O-])c(Cl)c(S(N)(=O)=O)c1

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (10 g), n-butanol (100 ml), and conc. sulphuric acid (2 ml) was refluxed for 4 hours, during which 50 ml of the solvent were distilled off slowly. After cooling, the n-butyl-4-chloro-3-nitro-5-sulphamyl-benzoate was isolated by filtration and recrystallized from n-butanol. The compound was obtained with a melting point of 140°-141°C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CO.[Br:14]Br.Cl>[OH-].[Na+]>[Br:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: BrBr
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2[nH]nc(Br)c2c1
Temperature: 40 °C
Yield: 47 %

Procedure:
A 2-L round bottomed flask was charged with 1H-indazole-5-carbonitrile (17.6 g, 123 mmol), 333 mL methanol (MeOH), 333 mL of 2.0 M aq. NaOH, and a solution of bromine (Br2, 54.7 g, 344 mmol, 2.80 equiv.) in 166 mL of 2.0 M aq. NaOH. The mixture was warmed on an oil bath to 40° C. (external temperature) for 6 h, and then cooled to room temperature in a water bath. The pH of the solution adjusted to ca. 5.5 with 103 mL of 4.0 M aq. HCl. The resulting precipitate was collected by filtration, washed with 200 mL of H2O, and dried. The product was purified by chromatography on 265 g of silica gel using 30–40% EtOAc in hexanes. This afforded the title compound (12.83 g, 47% yield): ES-MS (m/z) 222 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][CH2:19][O:20][C:21]1[N:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[N:22][C:21]([O:20][CH2:19][F:18])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1cnc(OCF)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCF)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-fluoromethoxy-pyrazine-2-carboxylic acid (CAS 1174321-00-6) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=396.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:18])=[O:17].[Br:25]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:3]([Br:25])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:18])=[O:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1[nH]c2ccc(N)cc2c1S(=O)(=O)N1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccc(N)c(Br)c2c1S(=O)(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Ethyl 5-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (189 mg, 0.53 mmol, 1.0 equiv) was dissolved in 4 mL of dimethylformamide and cooled to 0° C. N-bromosuccinimide (95 mg, 0.54 mmol, 1.0 equiv) was added and the reaction was stirred for 15 minutes. The reaction mixture was partitioned between dichloromethane and aqueous saturated NaHCO3, which was extracted three times with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 50% ethyl acetate/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 432.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[CH2:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[K+]>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6][NH:17][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:4]([F:11])[CH:3]=1
Reactant: CC(C)CCN
Reactant: O=Cc1c(F)cc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [K+]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)CCNCc1c(F)cc(Br)cc1F
Reaction time: 2 h

Procedure:
4-Bromo-2,6-difluoro-benzaldehyde (I-1a: 30 g) and isoamyl amine (13 g) were combined in dichloroethane (1 L) at ambient temperature. After stirring for 2 hours, sodium triacetoxyborohydride (144 g) was added to the reaction mixture. After stirring overnight, the reaction mixture was treated with a 2 M aqueous potassium hydroxide solution. The layers were separated and the organic phase dried over magnesium sulfate before being filtered and concentrated with a rotary evaporator to provide the title compound (I-1b) as an oil, which was used in the subsequent transformation without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH3:25][O:24][C:19]1[CH:18]=[C:17]([O:26][CH3:27])[CH:16]=[C:15]2[C:20]=1[C:21](=[O:23])[NH:22][C:13]([C:7]1[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=1)=[N:14]2
Reactant: C1CCNC1
Reactant: COc1cc(OCCBr)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Solvent: C1CCOC1
Product: COc1cc(OCCN2CCCC2)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-[3-(2-bromo-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (7.10 g, 16.0 mmol) in THF (20 mL) was added pyrrolidine (11.38 g, 160.0 mmol) and the reaction mixture was stirred at room temperature for 15 hours. THF was removed under reduced pressure, the residue was purified by column chromatography (silica gel 230-400 mesh; eluting with 5% 2.0 M ammonia in methanol solution in dichloromethane) to give the title compound as a white solid. Yield: 3.2 g (47%). MP 159-160° C. 1H NMR (400 MHz, CDCl3): δ 10.66 (s, 1H), 7.25 (m, 2H), 6.84 (d, J=2.0 Hz, 1H), 6.67 (t, J=2.4 Hz, 1H), 6.45 (d, J=2.0 Hz, 1H), 4.21 (t, J=6.0 Hz, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 2.93 (t, J=6.0 Hz, 2H), 2.64 (m, 4H), 1.80 (m, 4H). MS (ES+) m/z: 426.20 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[C:26](O)([CH3:29])([CH3:28])[CH3:27]>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 76 %

Procedure:
4-Amino-5-chloro-2-methoxybenzoic acid (1.0 g, 4.96 mmol) was dissolved in t-butanol (20 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g, 5.46 mmol) was added with stirring at room temperature, and the mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was washed with hexane. The resulting filtrate was recrystallized with ethanol to give the title compound (0.97 g; yield, 76%) as a white solid.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:21]=[C:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[S:20][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Product: OC12N=C(c3ccccc3)SC1Cc1cc(Cl)ccc12

Procedure:
This compound is prepared analogously to the process described in Example 6b using 2-bromo-5-chloroindan-1-one and thiobenzamide; melting point: 155° C.
Reaction SMILES: [CH3:1][C:2]([CH3:24])=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[CH3:24][C:2]1([CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=2)[NH:6][C:4](=[O:5])[CH2:3]1
Reactant: CCCCCC(C(=O)OCC)c1ccc(NC(=O)C=C(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCCCC(C(=O)OCC)c1ccc2c(c1)C(C)(C)CC(=O)N2

Procedure:
1 g of (RS)-ethyl 2-[4-(3,3-dimethylacrylamido)-phenyl]-heptanoate was dissolved in 10 ml of methylene chloride and treated with 1.2 g of aluminium chloride. The mixture was heated to reflux for 6 hours. The mixture was poured onto 25 ml of iced water and then was extracted with two portions of 25 ml of methylene chloride. The combined extracts were washed with two portion of 25 ml of saturated aqueous sodium bicarbonate solution and one portion of 25 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes). 1H NMR (CDCl3): 8.92 (br. s, 1H), 7.21 (d, J=1.9 Hz, 1H), 7.13 (dd, J=8.1, 1.9 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 4.20-4.00 (m, 2H), 3.48 (t, J=7.7 Hz, 1H), 2.48 (s, 2H), 2.10-1.90 (m, 1H), 1.80-1.65 (m, 1H), 1.35-1.15 (m, 6H), 1.33 (s, 3H), 1.32 (s, 3H), 1.22 (t, J=7.1 Hz, 3H), 0.86 (t, J=6.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[O:16][C:15]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:27]1[N:36]=[C:35]2[C:30]([C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33][N:34]2[CH:37]2[CH2:39][CH2:38]2)=[CH:29][C:28]=1[F:44]>>[CH:37]1([N:34]2[C:35]3[C:30](=[CH:29][C:28]([F:44])=[C:27]([N:11]4[CH2:12][CH2:13][N:8]([C:7]5[CH:6]=[CH:5][C:4]([N:14]6[CH2:18][C@H:17]([CH2:19][NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[O:16][C:15]6=[O:25])=[CH:3][C:2]=5[F:1])[CH2:9][CH2:10]4)[N:36]=3)[C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33]2)[CH2:38][CH2:39]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CS(=O)(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Product: CS(=O)(=O)NC[C@H]1CN(c2ccc(N3CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
This compound was synthesized in analogy to the procedure described in Example 10 using 0.082 g N-[(5R)-3-(3-fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-methansulfonamide (0.22 mmol) and 0.067 g 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (0.22 mmol).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:23])[C:3]=1[O:24]CC1C=CC=CC=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[OH:24][C:3]1[C:4](=[O:23])[O:5][C:6]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH:20]([CH3:21])[CH3:22])=[CH:17][CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[OH:1]
Reactant: CC(C)Cc1ccc(C2(c3ccccc3)OC(=O)C(OCc3ccccc3)=C2O)cc1
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CC(C)Cc1ccc(C2(c3ccccc3)OC(=O)C(O)=C2O)cc1
Yield: 51.4 %

Procedure:
Hydrogenolysis of 500 mg (1.2 mmol) of 4-hydroxy-5-(4-isobutylphenyl)-5-phenyl-3-phenylmethoxy-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide 200 mg (51% yield) of 3,4-dihydroxy-5-(4-isobutylphenyl)-5-phenyl-2(5H)-furanone as a white powder: mp 138-139° C. (CHCl3 /hexanes). 1H NMR (acetone-d6) δ 7.40-7.15 (m, 9H), 2.49 (d, J=7.1 Hz, 2H), 1.94-1.74 (m, 1H), 0.89 (d, J=6.5 Hz, 6H). Anal Calcd for C20H20O4 : C, 74.1; H, 6.2. Found: C, 73.7; H, 6.3.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[CH2:14]([OH:16])[CH3:15]>>[ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[C:6](=[NH:7])[O:16][CH2:14][CH3:15]
Reactant: CCO
Reactant: COc1ccc(C#N)c(OC)c1
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 57 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2,4-dimethoxy-benzonitrile (5.20 g, 32 mmol) in anhydrous ethanol (200 mL) at 0° C. After 7 h, hydrogen chloride gas was stopped and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was triturated in diethyl ether to afford ethyl 2,4-dimethoxy-benzimidate hydrochloride (4.5 g, 57%). It was used without further purification.
Reaction SMILES: CN(C)C([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][O:13][Si](C)(C)C)[N:7]=[CH:6]1)=O.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1>C(#N)C.Cl>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:7]2[C:8]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:9][N:5]=[CH:6]2)=[CH:22][CH:23]=1)#[N:28]
Reactant: CN(C)C(=O)n1cnc(CCCO[Si](C)(C)C)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2CCCO)cc1
Reaction time: 0.25 h

Procedure:
A solution of 97.0 g of 1-dimethylcarbamoyl-4-trimethylsilyloxypropyl-1H-imidazole and 72.0 g of 1-bromomethyl-4-cyanobenzene in 500 ml of acetonitrile is refluxed for 10 hours. The solution is cooled to 0° in an ice bath and ammonia gas is bubbled in for a few minutes. The mixture is then evaporated in vacuo to give a semi-solid which is dissolved in 500 ml of 1N hydrochloric acid. The solution is allowed to stand at room temperature for 15 minutes and then is extracted with ether. The pH of the aqueous phase is adjusted to 9 with 50% sodium hydroxide solution and the mixture is then extracted with methylene chloride. The methylene chloride extracts are washed with water, dried over sodium sulfate and evaporated to give a semi-solid which is triturated with cold acetone to yield the title compound (b) as a white solid, m.p. 121°-123°.
Reaction SMILES: [CH2:1]([CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1)[CH3:2].C([Li])CCC.[F:14][C:15]([F:22])([F:21])[C:16]([O:18]CC)=O>>[F:22][C:15]([F:14])([F:21])[C:16]([C:3]1([CH2:1][CH3:2])[S:8][CH2:7][CH2:6][CH2:5][S:4]1)=[O:18]
Reactant: CCC1SCCCS1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Product: CCC1(C(=O)C(F)(F)F)SCCCS1
Yield: 34.9 %

Procedure:
The same operation as in Example (36a) was performed using 2-ethyl-1,3-dithiane obtained in Example (39a) (3.51 g, 23.7 mmol), n-butyllithium (1.58 M solution in hexane, 18 mL, 28.3 mmol) and ethyl trifluoroacetate (4 mL, 33.6 mmol), to obtain 2.02 g of the title compound as a pale yellow oily substance (35%).
Reaction SMILES: C([CH:3]([C:22]([OH:24])=[O:23])[N:4]([C:12](OCC1C=CC=CC=1)=O)[CH2:5][P:6]([CH2:10][CH3:11])([CH2:8][CH3:9])=[S:7])C.Br.[CH3:26]COCC>C(O)(=O)C>[CH2:12]([N:4]([CH2:5][P:6]([CH2:10][CH3:11])([CH2:8][CH3:9])=[S:7])[CH2:3][C:22]([OH:24])=[O:23])[CH3:26]
Reactant: CCC(C(=O)O)N(CP(=S)(CC)CC)C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(=S)(CC)CC
Reaction time: 1 h

Procedure:
Ethyl N-carbobenzoxy-N-(diethylthiophosphinylmethyl)glycine (1 g., 0.0024 mole) was dissolved in 5 ml. of 30% hydrogen bromide in glacial acetic acid at 0° C. The mixture was stirred for one hour. Ether was added and the oily precipitate was isolated by decanting the ether layer. The oil was washed with ether twice, then suspended in benzene and treated with propylene oxide. The solution was concentrated in vacuo to yield ethyl N-(diethylthiophosphinylmethyl)glycine (0.15 g., 0.0005 mole) as an oil, ND25 =1.4960.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1/[CH:10]=[C:11](\[CH3:17])/[C:12]([O:14]CC)=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH3:33])[C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>CN(C=O)C>[F:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([O:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([N:25]([CH3:33])[CH3:24])[CH:27]=2)[C:3]=1/[CH:10]=[C:11](\[CH3:17])/[C:12]([OH:14])=[O:13]
Reactant: CN(C)c1cccc(O)c1
Reactant: CCOC(=O)/C(C)=C/c1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\c1c(F)cc(F)cc1Oc1cccc(N(C)C)c1)C(=O)O

Procedure:
11 b/12 b) The ester from 11 a/12 ma, 3 eq. of potassium carbonate and 1.1 eq. of 3-dimethylaminophenol were stirred in DMF at 150° C. for 3 hours. An isomer mixture of the ethyl esters of E-3-[2,6-difluoro-4-(3-dimethylaminophenoxy)]-2-methyl-propenoic acid and E-3-[2,4-difluoro-6-(3-dimethylaminophenoxy)-phenyl]-2-methyl-propenoic acid was isolated.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][CH2:34][CH2:35]Br>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:35][CH2:34][O:33][CH3:32])[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Reactant: COCCBr
Solvent: CC#N
Solvent: O
Product: COCCn1ccc2c(-c3ccc4c(c3C)CCCO4)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c21

Procedure:
The title compound was prepared in a manner similar to that described in example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 2-bromoethyl methyl ether and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29-7.36 (m, 1H) 6.97-7.12 (m, 1H) 6.69-6.82 (m, 1H) 5.71-5.81 (m, 1H) 5.18-5.49 (m, 1H) 4.82-4.90 (m, 1H) 4.72-4.79 (m, 1H) 4.57-4.67 (m, 1H) 4.16-4.28 (m, 2H) 3.75-3.85 (m, 2H) 3.69-3.72 (m, 3H) 3.51 (s, 2H) 3.34 (s, 3H) 2.63-2.76 (m, 2H) 2.06-2.16 (m, 2H) 1.93-2.06 (m, 3H) 1.01-1.21 (m, 9H); LCMS (m/z) ES+=483 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH:14][CH2:15][CH2:16][S:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O=P(Cl)(Cl)Cl.[BH4-].[Na+].O>CC#N.C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][CH:12]1[C:23]2[CH:22]=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=2[S:17][CH2:16][CH2:15][NH:14]1
Reactant: COc1ccc(CC(=O)NCCSc2ccc(OC)c(OC)c2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(CC2NCCSc3cc(OC)c(OC)cc32)cc1OC
Temperature: 0 °C
Yield: 30.4 %

Procedure:
To a stirred solution of 2-(3,4-dimethoxy-phenyl)-N-[2-(3,4-dimethoxy-phenylsulfanyl)-ethyl]-acetamide (4.0 g, 10.0 mmol) in dry CH3CN (21 ml), was added POCl3 (2.80 ml, 30.0 mmol). The resulting mixture was stirred at reflux for 3 h under nitrogen. After cooling, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (85 ml). The solution was cooled to 0° C. and NaBH4 (2.7 g, 69.0 mmol) was added portionwise, the resulting pale yellow suspension was stirred at RT for 16 h under nitrogen. The reaction mixture was poured into H2O and extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2Cl2/MeOH: 9/1) gave the title product (1.14 g, 27%) as a viscous brown oil.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C([C:10]1[C:15]([OH:16])=[C:14](C(C)(C)C)[CH:13]=[C:12](C)[CH:11]=1)(C)(C)C>>[C:1]([O:5][CH2:14][CH:15]([OH:16])[CH2:10][O:16][C:15]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)O
Product: C=CC(=O)OCC(O)COc1ccccc1

Procedure:
3-Phenoxy-2-hydroxypropyl acrylate was prepared as described in Example 17 except that the acrylic acid was added over 1 hour at 100°, 2,6-di-tert. butyl-p-cresol was used in place of hydroquinone, and the mixture was heated for 4 hours at 100° after the acrylic acid had been added.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[CH:19]=[C:18]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[CH:19]=[C:18]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N2CCc3ccccc32)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-(4-fluoroanilino)-4-(indolin-1-yl)benzoate, and it was stirred at room temperature for 2 hours and 10 minutes. The solvent was removed under reduced pressure, ethyl acetate and water were added to the obtained residue, and it was adjusted to pH6.5 with saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with water and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue, solid matter was filtrated to give 2-(4-fluoroanilino)-4-(indolin-1-yl)benzoic acid 22 mg of a white solid.