Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([NH2:14])[CH:7]=1.[NH2:16][C:17]1([C:21](O)=O)[CH2:20][CH2:19][CH2:18]1>C(Cl)Cl.Cl.NC1(C(Cl)=O)CCC1.C(O)(=O)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:15])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]2[N:12]([CH3:13])[C:21]([C:17]3([NH2:16])[CH2:18][CH2:19][CH2:20]3)=[N:14][C:8]=2[CH:7]=1
Reactant: NC1(C(=O)O)CCC1
Reactant: CNc1ccc(/C=C/C(=O)OC)cc1N
Agent: Cl
Agent: NC1(C(=O)Cl)CCC1
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)nc(C1(N)CCC1)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(E)-3-(3-Amino-4-methylaminophenyl)acrylic acid methyl ester 2-4 from Example 2 (40 mg, 0.194 mmol) was suspended in CH2Cl2 (3 mL) and 1-aminocyclobutanecarboxylic acid chloride hydrochloride, prepared from 1-aminocyclobutanecarboxylic acid following an adaptation of the procedure described by E. S. Uffelman et al. (Org. Lett. 1999, 1, 1157), (31 mg, 0.18 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to obtain a white solid. The solid was then dissolved in acetic acid (5 mL) and heated to 60° C. for 20 hours. The reaction crude was diluted with aqueous saturated NaHCO3, extracted with CH2Cl2 (2×50 mL) and brine, the organic layer was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure to give (E)-3-[2-(1-aminocyclobutyl)-1-methyl-1H-benzoimidazol-5-yl]acrylic acid methyl ester 3-1 as a light brown foam (53 mg).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[OH-].[Na+].Cl.CC#N.O>O1CCCC1>[F:24][C:22]1[CH:21]=[CH:20][C:19]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:34])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5cccc(OC)c5)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: COc1cccc(Cc2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{(S)-6-[(R)-7-Fluoro-4-(3-methoxybenzyl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester (30 mg) is dissolved in tetrahydrofuran (4 mL) and 1 N aqueous sodium hydroxide solution (0.4 mL) is added. The mixture is stirred at room temperature overnight and then acidified with 1 N aqueous hydrochloric acid (0.4 mL). The solution is submitted to HPLC on reversed phase (MeCN/water) to give the title compound. LC (method 6): tR=0.71 min; Mass spectrum (ESI−): m/z=447 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:28])[C:12]=1[O:13][C@H:14]1[C@@H:19]3[O:20]C(=O)[O:22][C@@H:18]3[C@@H:17]([O:24][CH3:25])[C:16]([CH3:27])([CH3:26])[O:15]1)[O:9][C:8](=[O:29])[C:7]([NH:30][C:31](=[O:40])OCC1C=CC=CC=1)=[CH:6]2.CCN=C=NCCCN(C)C.[CH3:52][O:53][C:54]1[CH:55]=[C:56]([C:60]2[C:65]([O:66][CH3:67])=[CH:64][CH:63]=[C:62](C(O)=O)[CH:61]=2)[CH:57]=[CH:58][CH:59]=1.C(=O)([O-])[O-]>[Pd].C1COCC1.N1C=CC=CC=1.C(Cl)Cl.CO.C(N(CC)CC)C>[OH:20][C@@H:19]1[C@H:18]([OH:22])[C@@H:17]([O:24][CH3:25])[C:16]([CH3:27])([CH3:26])[O:15][C@H:14]1[O:13][C:12]1[C:11]([CH3:28])=[C:10]2[C:5]([CH:6]=[C:7]([NH:30][C:31]([C:62]3[CH:61]=[C:60]([C:56]4[CH:57]=[CH:58][CH:59]=[C:54]([O:53][CH3:52])[CH:55]=4)[C:65]([O:66][CH3:67])=[CH:64][CH:63]=3)=[O:40])[C:8](=[O:29])[O:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2cc(NC(=O)OCc3ccccc3)c(=O)oc2c(C)c1O[C@@H]1OC(C)(C)[C@H](OC)[C@H]2OC(=O)O[C@@H]12
Reactant: COc1cccc(-c2cc(C(=O)O)ccc2OC)c1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(-c2cc(C(=O)Nc3cc4cc(OC)c(O[C@@H]5OC(C)(C)[C@H](OC)[C@@H](O)[C@H]5O)c(C)c4oc3=O)ccc2OC)c1
Reaction time: 6.5 h
Yield: 3.5 %

Procedure:
Palladium on carbon (10%, 20.0 mg) was added to 25a (100 mg, 0.18 mmol) in anhydrous THF (5.00 mL) and the solution was placed under an atmosphere of H2. After 6.5 hours, the solution was filtered through SiO2 (1:1 CH2Cl2:Acetone) and the eluent was concentrated to afford a yellow solid, which was used without further purification (56.0 mg, 75%). EDCI (21.4 mg, 0.11 mmol) and 3′,6-dimethoxybiphenyl-3-carboxylic acid (23.1 mg, 0.089 mmol) were added to the amine (18.7 mg, 0.045 mmol) in 30% pyridine/CH2Cl2 (0.70 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford a colorless solid, which was used without further purification (10.5 mg, 36%). Triethylamine (150 μL) was added to the carbonate (10.4 mg, 0.016 mmol) in MeOH (2.50 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 20:1; CH2Cl2:MeOH) to afford 26a as a colorless amorphous solid (2.00 mg, 20%, 5% over 3 steps): 1H NMR (CDCl3, 500 MHz) 8.73 (s, 1H), 8.70 (d, J=5.4 Hz, 1H), 7.84 (td, J=6.2, 2.4 Hz, 1H), 7.82 (s, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 7.03-7.00 (m, 2H), 6.88-6.86 (m, 1H), 6.81 (s, 1H), 4.99 (d, J=6.6 Hz, 1H), 4.24 (t, J=4.2 Hz, 1H), 4.00 (dd, J=6.5, 3.7 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.80 (d, J=7.4 Hz, 1H), 3.45 (s, 3H), 3.08 (d, J=4.7 Hz, 1H), 2.67 (s, 1H), 2.42 (s, 3H), 1.28 (d, J=8.1 Hz, 3H), 1.18 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 164.6, 158.9, 158.3, 158.2, 148.2, 145.6, 142.5, 137.5, 130.1, 129.0, 128.2, 127.2, 124.9, 122.5, 122.2, 121.2, 121.0, 115.1, 144.2, 112.1, 110.0, 105.4, 101.3, 81.7, 76.8, 69.0, 68.0, 59.1, 55.3, 54.9, 54.3, 28.3, 28.2, 9.1; IR (film) νmax 2961, 2928, 1713, 1670, 1601, 1464, 1383, 1261, 1094, 1022, 798, 700 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C34H37NO11, 636.2445; found, 636.2477.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6].[C:13](O)([CH3:16])([CH3:15])[CH3:14].CCCCCC>S(=O)(=O)(O)O>[C:13]([C:11]1[CH:10]=[CH:9][C:3]([NH:4][C:5]([O:7][CH3:8])=[O:6])=[C:2]([F:1])[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)Nc1ccccc1F
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: COC(=O)Nc1ccc(C(C)(C)C)cc1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 158.7 %

Procedure:
2-Fluoro-N-methoxycarbonylaniline (150 g, 0.859 mol) was dissolved in 77.6% sulfuric acid (206 g) to prepare a solution. t-Butyl alcohol (72.9 g, 1.07 mol) was added dropwise to the solution under a nitrogen atmosphere over a period of 30 min while stirring and heating the solution at 70° C. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. t-Butyl alcohol (72.9 g, 1.07 mol) was again added dropwise thereto over a period of 30 min. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. t-Butyl alcohol (72.9 g, 1.07 mol) was again added dropwise thereto over a period of 30 min. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. The reaction solution was cooled to room temperature. n-Hexane (530 mL) was then added to the cooled reaction solution to carry out extraction for separation of the mixture into a sulfuric acid layer and an organic layer. n-Hexane (530 mL) was again added to the sulfuric acid layer to carry out extraction for separation of an organic layer. The organic layers thus obtained were combined, and the combined organic layer was washed with water and saturated brine in that order. The solvent was then removed from the organic layer by distillation to give 307 g of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline as an oily crude product (yield on weight basis 159%, purity as determined by gas chromatography 65.1%, 4-t-butyl form 5-t-butyl form=100:0).
Reaction SMILES: C([O:4][C@H:5]1[CH2:12][C@H:11]([O:13]C(=O)C)[C@@H:10]([CH3:17])[O:9][C@:6]1([NH:18][C:19](=[O:25])[CH2:20][P:21]([OH:24])([OH:23])=[O:22])[O:7][CH3:8])(=O)C.C(O[C@H]1C[C@H](OC(=O)C)[C@@H](C)O[C@]1(NC(=O)CCl)OC)(=O)C>>[P:21]([CH2:20][C:19]([NH:18][C@@:6]1([O:9][C@H:10]([CH3:17])[C@@H:11]([OH:13])[CH2:12][C@@H:5]1[OH:4])[O:7][CH3:8])=[O:25])([OH:23])([OH:24])=[O:22]
Reactant: CO[C@@]1(NC(=O)CP(=O)(O)O)O[C@H](C)[C@@H](OC(C)=O)C[C@@H]1OC(C)=O
Agent: CO[C@@]1(NC(=O)CCl)O[C@H](C)[C@@H](OC(C)=O)C[C@@H]1OC(C)=O
Product: CO[C@@]1(NC(=O)CP(=O)(O)O)O[C@H](C)[C@@H](O)C[C@@H]1O
Reaction time: 2 h

Procedure:
Synthesis of (1S,2R,8R,8aR)-1,2,8.triacetoxy-octahydro-5-oxyindolizine 14, from Methyl 2,4-di-O-acetyl-3,6-dideoxyphosphonoacetamido-alpha-D-mannopyranoside, 9. Methyl 2,4-di-O-acetyl-3,6-dideoxychloroacetamido-alpha-D-mannopyranoside, 8, 5 g (0.02 mole) and 20 mL triethylphoside were heated at 110° C. for 15 h. The solvent was removed at high vacuum and the residual oil stirred with 50 mL hexane and stored in the freezer for 2 h. The hexane was decanted to afford methyl 3,6-dideoxyphosphonoacetamido-alpha-D-mannopyranoside, 15, as a thick white oil. TLC analysis (SiO2 /CH2Cl12 -MeOH) indicated that the compound was a single spot with Rf of 0.7 staining with 12 . This compound was evaporated from MeOH, and dried at high vacuum.
Reaction SMILES: C([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][S:11][CH3:12])(OC(C)(C)C)=O.[NH2:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20].Cl>CO>[NH2:8][C@@H:9]([CH2:10][S:11][CH3:12])[C:13]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15]
Reactant: CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: Cl
Solvent: CO
Product: CSC[C@H](N)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
tert-Butyl [(R)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-(methylthio)ethyl]carbamate was obtained as an amorphous solid, MS: 445 (M+H)+, by condensing (R)-Boc-(S-methyl)cysteine (J. Chem. Soc. C 1967, 2632) and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol in an analogous manner to that described in Example 1g). Subsequent cleavage of the Boc protecting group using hydrochloric acid in methanol yielded (R)-2-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(methylthio)propionamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C@H:11]([C@H:20](OS(N2C=CN=C2)=O)[C@@H:21]([CH:37]([CH3:39])[CH3:38])[C:22]([N:24]2[C@H:28]([CH3:29])[C@H:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][C:25]2=[O:36])=[O:23])[O:10][C:9]1([CH3:49])[CH3:48])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C@H:11]([CH2:20][C@H:21]([CH:37]([CH3:38])[CH3:39])[C:22]([N:24]2[C@H:28]([CH3:29])[C@H:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:26][C:25]2=[O:36])=[O:23])[O:10][C:9]1([CH3:48])[CH3:49])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H](C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)[C@@H](OS(=O)n1ccnc1)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reaction time: 10 h
Yield: 69.1 %

Procedure:
The resultant product from Example 143 (129 mg, 0.185 mmol) was dissolved in 10 ml dry toluene and added slowly dropwise over 30 min to a refluxing solution of tri-n-butyltin hydride (93 μl, 100 mg, 0.346 mmol) in 15 ml dry toluene under a nitrogen atmosphere. Reflux was continued for an additional 10 h. The resulting solution was cooled, concentrated in vacuo, and the residue was triturated with four 10 ml portions of acetonitrile, with gentle warming. The combined acetonitrile extracts were washed with three 20 ml portions of hexane, then the combined hexane phases were back-extracted with 20 ml of acetonitrile. All acetonitrile phases were combined and concentrated in vacuo. The crude product was purified by silica gel chromatography (hexane-ethyl acetate 9:1) to give 73 mg (69%) of the desired product. 1H NMR (CDCl3) δ 0.90 (d,3H), 0.92 (d,3H), 0.9-1.1 (bm,3H), 1.06 (d,3H), 1.15-1.35 (bm,3H), 1.51 (bs,9H), 1.57-2.14 (several bm), 3.84 (m,1H), 3.97 (m,1H), 4.85 (dq,1H), 5.68 (d,1H), 7.3-7.46 (m,5H). Mass spectrum: (M+H)+ =571.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][CH:23]([CH3:26])[NH:22][C:21]=2[CH:27]=1>>[Cl:16][C:17]1[C:27]2[C:11](=[O:13])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:22]3[CH:23]([CH3:26])[CH2:24][O:25][C:20]([C:21]=23)=[CH:19][CH:18]=1
Reactant: CC1COc2ccc(Cl)cc2N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cn2c3c(ccc(Cl)c3c1=O)OCC2C

Procedure:
Using the method of Example 1, diethyl ethoxymethylene malonate is reacted with 6-chloro-3,4-dihydro-3-methyl-2H-1,4-benzoxazine and the product reacted with polyphosphoric acid to provide ethyl 8-chloro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate, m.p. 205°-206° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1.C=O.[C:28]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[S:10][CH2:11][CH2:12][N:13]([C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:23])[CH2:28][C:6]=2[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(NCCSc1ccc(OC(F)(F)F)cc1)OCc1ccccc1
Agent: C=O
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)N1CCSc2ccc(OC(F)(F)F)cc2C1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of benzyl 2-(4-(trifluoromethoxy)phenylthio)ethylcarbamate (29) (300 mg), paraformaldehyde (300 g), p-toluenesulfonic acid (100 g) in benzene (15 mL) was stirred at 80° C. for 3 days. The reaction mixture was filtered and washed with sat. NaHCO3 (2×5 mL). Removal of the solvent gave 30 as white solid. The product was purified by chromatography on SiO2 (petroleum ether/EtOAc=3/1). Yield: 235 mg, 76%.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:13]1[CH2:17][CH2:16][CH:15]=[CH:14]1)(=O)C.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.[Cl-].[Zn+2].[Cl-].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[C:1]1([CH:17]2[CH2:16][CH2:15][CH:14]=[CH:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC1C=CCC1
Reactant: Br[Mg]c1ccccc1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: C1=CC(c2ccccc2)CC1
Temperature: 40 °C

Procedure:
A solution of 8 mL of 2M phenylmagnesium bromide in THF was added dropwise to a solution of 32.2 mL (0.016 mole) of 0.5M zinc chloride in THF. A solution of 3.05g (0.024 mole) of 3-acetoxycyclopent-1-ene in 25 mL of dry THF was added, and 321 mg of 1,2-bis(diphenylphosphino)ethane and 462 mg of palladium bis(dibenzylideneacetone) added. The reaction mixture was heated at 40° C. for 18h. The reaction was cooled to room temperature and the solids filtered off. Ether was added, and the organic layer was washed sequentially with saturated ammonium chloride, water, and brine. After drying (MgSO4), the solvent was evaporated in vacuo to give 6 g of a yellow oil. Flash chromatography (SiO2) eluting with hexane gave 760 mg of an oil. Mass spectrum (Cl-NH3) m/z=145 (M+1); 300 MHz NMR (CDCl3) δ 1.68-1.78 (m, 1H); 2.32-2.6 (m, 3H); 3.85-3.96 (m, 1H); 5.72-5.82 (m, 1H); 5.92-6.01 (m, 1H); 7.12-7.38 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2.[Cl-].Cl[CH:23]=[N+:24]([CH3:26])[CH3:25].C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:23][N:24]([CH3:26])[CH3:25])[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2
Reactant: CCCc1c(O)cc2oc3cc(Cl)cn3c(=O)c2c1O
Reactant: C[N+](C)=CCl
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCc1c(O)cc2oc3cc(Cl)c(CN(C)C)n3c(=O)c2c1O
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To 60 mg (0.20 mmol) of 2-chloro-6,8-dihydroxy-7-propyl-9H-pyrrolo [2,1-b][1,3]benzoxazin-9-one in 20 mL of CH2Cl2 was added 157 mg (1.22 mmol) of chloromethylene dimethylammonium chloride and the reaction stirred for 1 hr. The mixture was concentrated, diluted with 50 mL of dry MeOH and 1.0 g (15.9 mmol) of sodium cyanoborohydride was added. After 24 hr the mixture was quenched with saturated NaHCO3 and the mixture extracted with ethylacetate which was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (Silica Gel EtOAc 100% to acetone 100%) to give 50 mg of the title compound.
Reaction SMILES: N1C(C)=CC(C)=CC=1C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[Br:24][C:25]1[CH:43]=[CH:42][C:28]2[O:29][CH2:30][CH2:31][CH:32]=[C:33]([O:34][Si](C(C)(C)C)(C)C)[C:27]=2[CH:26]=1>C1(C)C=CC=CC=1>[Br:24][C:25]1[CH:43]=[CH:42][C:28]2[O:29][CH2:30][CH:31]=[CH:32][C:33](=[O:34])[C:27]=2[CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OC1=CCCOc2ccc(Br)cc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: Cc1cc(C)nc(C)c1
Product: O=C1C=CCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 94 %

Procedure:
2,4,6-Collidine (5.6 ml), DDQ (9.0 g, 40 mmol) and (7-bromo-2,3-dihydrobenzo[b]oxepin-5-yloxy)(tert-butyl)dimethylsilane was dissolved in toluene, the mixture was stirred for 5.5 hours at room temperature. the mixture was concentrated in vacuo and then purified by column chromatography to give 7-bromobenzo[b]oxepin-5(2H)-one (4.5 g, 94%). 1H-NMR (MeOD): 4.71 (m, 2H), 6.38 (m, 1H), 6.76 (m, 1H), 6.99 (m, 1H), 7.54 (m, 1H), 8.06 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:14][CH2:15][C:16](Cl)=[O:17].OS(C(F)(F)F)(=O)=O>FC(F)(F)C(O)=O.CC(OC)(C)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]2[C:7]([C:16](=[O:17])[CH2:15][CH2:14][O:10]2)=[CH:8][CH:9]=1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: O=C(Cl)CCCl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Product: O=C1CCOc2cc(OC(F)(F)F)ccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
A solution of 3-(trifluoromethoxy)phenol (7.13 mL, 55.0 mmol) and 3-chloropropanoyl chloride (5.5 mL, 57.6 mmol) in trifluoroacetic acid (25 mL) was stirred 15 minutes at ambient temperature, and then heated at 50° C. for 90 minutes. After stirring at ambient temperature overnight, the solution was added over 5 minutes to preheated triflic acid (20 mL) at 50° C. After 20 minutes, the mixture was removed from the oil bath, then cooled in an ice water bath. Crushed ice was added, slowly at first, keeping the temperature of the orange solution below 25° C. Eventually a solid precipitate formed, and the suspension was diluted with MTBE (200 mL). The mixture was cooled in an ice water bath. It was washed with brine and then four times with water, partially dried (Na2SO4), filtered, and concentrated. After standing overnight, the yellow mixture was dissolved in ethanol (180 mL) and added slowly over 22 minutes to 1.5 M aqueous Na2CO3 (180 mL) cooled with a water ice bath (internal temp did not exceed 15° C.). The suspension was permitted to come to ambient temperature overnight, and was then diluted with 2:1 EtOAc/hexanes (300 mL) and filtered. The solids were rinsed with more 2:1 solution (105 mL), and the aqueous phase of the filtrate was separated and extracted with 1:1 EtOAc/hexanes (3×100 mL). The combined organic phases were washed once with water (200 mL), and the aqueous phase was back-extracted once with 1:1 solution (40 mL). The organic phases were combined and washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated, chromatographed on silica (gradient elution, 5-20% Et2O/hexanes) to give the title compound (4.95 g, 21.3 mmol, 39% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.90-7.85 (m, 1H), 7.08-7.01 (m, 2H), 4.61 (dd, 2H), 2.83 (dd, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])(=[O:16])=[O:15])[CH:6]=[C:5]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])(=[O:15])=[O:16])[CH3:30])[CH:6]=[C:5]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccccc3OC)c2n1COC
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3ccccc3OC)c2n1COC
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a solution of ethyl 1-(methoxymethyl)-7-{[(2-methoxyphenyl)sulfonyl]amino}-1H-indole-2-carboxylate (11.0 g) and potassium carbonate (5.9 g) in N,N-dimethylformamide (80 mL) was added methyl iodide (2.7 mL) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:2-4:1), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (10:9 g, yield: 89%) as colorless needle crystals. melting point: 124-125° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=2[O:17][CH2:18][CH2:19][OH:20])=[CH:4][CH:3]=1.[CH3:21][O:22][C:23](=[O:33])[C:24]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)=[O:25].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:21][O:22][C:23](=[O:33])[C:24](=[O:25])[C:26]1[CH:27]=[CH:28][C:29]([O:20][CH2:19][CH2:18][O:17][C:9]2[C:10]([CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: CC(C)c1cccc(-c2ccc(F)cc2)c1OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OCCOc2c(-c3ccc(F)cc3)cccc2C(C)C)cc1
Yield: 48 %

Procedure:
As in Example 15, (2-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yloxy]ethanol (0.393 g) was treated with 4-hydroxyphenylglyoxylic acid methyl ester (0.258 g) in the presence of diethyl azodicarboxylate (0.298 g) and triphenylphosphine (0.449 g) in tetrahydrofuran (25 mL). The usual work up afforded 0.6 g of crude product which was purified by flash chromatography over silica gel (60 g; ethyl acetate-hexane; 3:7) to furnish 0.3 g of 4-[2-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yloxy]ethoxy]-alpha-oxobenzeneacetic acid methyl ester. Crystallization of the ester from ethyl acetatehexane yielded the analytical specimen, mp 77°-79° C.