Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[O:26][CH2:27][C:28]([O:30]CC)=[O:29].O.[OH-].[Li+]>O1CCCC1.O>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[O:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To a stirred solution of ethyl {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetate (0.46 g, 0.98 mmol) in a mixture of tetrahydrofuran (30 mL) and water (15 mL) was added lithium hydroxide monohydrate (0.32 g, 2.3 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 16 h. The mixture was concentrated in vacuo to a small volume, diluted with water (15 mL), washed with diethyl ether (60 mL), and acidified with 37% hydrochloric acid to pH 1. A white precipitate was formed. The mixture was extracted with ethyl acetate (3×60 mL). The combined organic solution was washed with water (30 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetic acid (0.41 g, 95%): mp 95-96° C.; 1H NMR (300 MHz, CDCl3) 7.33-7.14 (m, 3H), 7.07-6.97 (m, 2H), 6.92 (br s, 1H), 6.88-6.77 (m, 2H), 6.48 (s, 1H), 6.42 (s, 1H), 5.08-4.95 (m, 2H), 4.88-4.79 (m, 1H), 4.74-4.67 (m, 1H), 4.63 (s, 2H), 4.57-4.48 (m, 2H), 3.09-2.89 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.2, 172.6, 161.8, 161.3, 157.9, 141.9, 137.6, 132.6, 130.1, 128.8, 123.9, 123.6, 120.9, 120.0, 118.9, 113.9, 113.7, 113.7, 109.3, 93.2, 80.5, 72.4, 64.7, 57.8, 44.0, 29.0; MS (ES+) m/z 444.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:2].S(Cl)([Cl:18])(=O)=O>C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][C:12]=1[Cl:18])[CH3:2]
Reactant: CCOC(=O)CCc1cccc(O)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)CCc1cc(O)ccc1Cl
Reaction time: 2.5 h

Procedure:
To a 0 ° C. solution of 3-(3-hydroxy-phenyl)-propionic acid ethyl ester (1.0 g, 5.15 mmol) in diethyl ether (50 ml) was added sulfuryl chloride (0.493 mL, 6.18 mmol). After 2.5 h at 0° C., the reaction was quenched with sat. sodium carbonate (50 ml). The aqueous layer was extracted with ethyl acetate. The organic portions were combined and dried with magnesium sulfate. The solvent was removed in vacuo to afford crude product, which was purified by column chromatography (10% ethyl acetate/hexanes). The title compound was obtained as colorless oil (0.73 g, yield 62%): 1H NMR (CDCl3) δ 6.96 (d, J=10.1 Hz, 1H); 6.54( d, J=2.97 Hz,1H); 6.46 (dd, J=8.6, 3.0 Hz,1H); 3.96 (dd, J=12.5 5.3 Hz, 2H); 2.82-2.78 (m, 2H); 1.08-1.00 (m, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[N:4][CH:3]=[N:2]1.[CH2:9]=[O:10]>>[OH:10][CH2:9][C:5]1[N:1]([CH2:6][CH2:7][OH:8])[N:2]=[CH:3][N:4]=1
Reactant: OCCn1cncn1
Reactant: C=O
Product: OCCn1ncnc1CO
Temperature: 135 °C
Yield: 68 %

Procedure:
A solution of 2-(1,2,4-triazol-1yl)ethanol (5.0 g, 44 mmol) in 38% w/v aqueous formaldehyde (25 ml) was stirred and heated at 135° C. in a sealed tube for 18 hours. Upon cooling the volatiles were removed in vacuo (azeotroping with ethanol). The residue was purified by chromatography on silica gel, eluting with 5→10→15% methanol-dichloromethane to give the title compound (4.3 g, 68%) as a thick oil. 1H NMR (360 MHz, d6-DMSO) δ 3.69-3.74 (2H, m), 4.24 (2H, t, J=5.7 Hz), 4.60 (2H, d, J=5.7 Hz), 4.96 (1H, t, J=5.3 Hz), 5.51 (1H, t, J=5.8 Hz), 7.84 (1H, s); MS (ES+) m/e 144 [MH]+.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2cccc3c2c2ccccc2n3Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(Cn2c3ccccc3c3c(OCCN4CCNCC4)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture of tert-Butyl 4-{2-[(9-Benzyl-9H-carbazol-4-yl)oxy]ethyl}-1-piperazinecarboxylate (0.0450 g, 0.0927 mmol), trifluoroacetic acid (2.5 mL), and CH2Cl2 (2.5 mL) is stirred at room temperature for 1 h. Trifluoroacetic acid and CH2Cl2 are then removed in vacuo and the residue is partitioned between CH2Cl2 and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and taken to dryness to give 0.0326 g (91%) of the title compound; IR (drift) 2935, 2821, 1584, 1456, 1353, 1342, 1332, 1271, 1245, 1154, 1145, 1112, 783, 750, 715 cm−1; 1H NMR (CDCl3) δ2.70, 2.95, 3.04, 4.41, 5.50, 6.69, 6.99, 7.12, 7.2-7.4, 8.39. Anal. Calcd for C25H27N3O: C, 77.89; H, 7.06; N, 10.90. Found: C, 76.35; H, 7.20; N, 10.30.
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:13])[C@H:8]2[CH2:9][C@@H:4]1[CH2:5][CH2:6][C@H:7]2[CH2:10][CH2:11]Cl.Cl.[CH2:15]([OH:20])[CH2:16][CH2:17][CH2:18][OH:19]>>[CH3:2][C:3]1([CH3:13])[C@H:8]2[CH2:9][C@@H:4]1[CH2:5][CH2:6][C@H:7]2[CH2:10][CH2:11][O:19][CH2:18][CH2:17][CH2:16][CH2:15][OH:20]
Reactant: OCCCCO
Reactant: CC1(C)[C@H]2CC[C@@H](CCCl)[C@@H]1C2
Agent: Cl
Agent: [Na]
Product: CC1(C)[C@H]2CC[C@@H](CCOCCCCO)[C@@H]1C2
Temperature: 130 °C

Procedure:
12.2 g elemental sodium were dissolved in portions spread over 12 hours in 320 ml 1,4-butanediol at a temperature of 90° C. Then 80 g 2-((1S,2S,5S)-6,6dimethylbicyclo[3,1,1]hept-2-yl)-ethyl chloride were added in drops to this solution, and the reaction mixture was heated to 130° C. for 15 hours. In order to work up the reaction mixture it was cooled to room temperature, then 300 ml of a 5% aqueous hydrochloric acid solution were added, and the mixture was extracted with ether. After evaporation of the ether extract, 95.2 g crude 4-[2-((1S,2S,5S)-6,6dimethylbicyclo[3,1,1]hept-2-yl)-ethoxy]-butanol were obtained.
Reaction SMILES: [CH2:1]1COCC1.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH:10]=[O:11].C[Mg]Br>CCOCC>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]([OH:11])[CH3:1])[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: O=Cc1cc(F)cc(Br)c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc(F)cc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into the THF (8 ml) solution of 3-bromo-5-fluorobenzaldehyde (374 mg, 1.84 mmol) which was cooled in ice/water bath was added methylmagnesium bromide in Et2O (3.0 M, 0.92 ml) dropwise under an atmosphere of nitrogen. The combined mixture was stirred at 0° C. for 1 h and then at rt for 1 h. After that time, the mixture was quenched with saturated NH4Cl (10 ml) followed by water (10 ml), extracted with EtOAc (2×25 ml). The extracts were washed with water (2×15 ml), brine (15 ml), dried over MgSO4, filtered and concentrated in vacuo to give a beige oil. It was purified by chromatography on silica gel (15 g) eluting with 10% (100 ml), 15% (100 ml), 20% (100 ml) and 25% (100 ml) EtOAc/hexane to give the title compound. 1H NMR (400 MHz, CDCl3): δ=1.47 (d, J=6.4 Hz, 3H), 1.87 (d, J=3.6 Hz, 1H), 4.83-4.90 (m, 1H), 7.02-7.06 (m, 1H), 7.14 (td, J=2.0 & 8.0 Hz, 1H), 7.31 (t, J=1.6 Hz, 1H). MS (ES+): m/z 201.22/203.18 [MH+−H2O]. HPLC: tR=3.07 min (polar—5 min, ZQ3).
Reaction SMILES: ClC(Cl)C.[CH3:5][N:6]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([NH:15][C:14](=[O:17])[C:13]3=[O:18])=[C:8]2[CH2:7]1.[CH2:27](O)[CH2:28][OH:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:17]=[C:14]1[CH:13]2[O:18][CH2:27][CH2:28][O:29][C:11]3=[C:12]2[C:16](=[C:8]2[CH2:7][N:6]([CH3:5])[CH2:20][CH:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:9]2=[CH:10]3)[NH:15]1
Reactant: CN1Cc2c(ccc3c2NC(=O)C3=O)C(c2ccccc2)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(Cl)Cl
Product: CN1Cc2c(cc3c4c2NC(=O)C4OCCO3)C(c2ccccc2)C1

Procedure:
100 ml of dichloroethane are added to 20.6 g (0.0624 mol) of 8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole-2,3-dione, 21 ml (0.374 mol) of ethylene glycol and 0.336 g (0.00176 mol) of toluene-4-sulphonic acid monohydrate, with stirring, and the mixture is heated under reflux for 3.5 hours, using a water separator. Ice is added to the reaction mixture and the mixture is brought to pH 6.8 with aqueous KHCO3 solution. The mixture is extracted with CH2Cl2, the CH2Cl2 phase is washed with H2O and dried over Na2SO4 and the solvent is stripped off in a rotary evaporator. The residue is chromatographed on Al2O3 (aluminum oxide from E. Merck, Darmstadt) using an eluent mixture of ethyl acetate and MeOH (20:0.2). After trituration with ethyl acetate/petroleum ether, the substance becomes crystalline. It is dried over P2O5 at 80° C. in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:15]3[S:14][CH:13]=[CH:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:17][CH:16]=3)[C:15]=2[S:14][CH:13]=1
Reactant: Cc1ccc(Cc2cccc3ccsc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1ccc(Cc2cccc3c(Br)csc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
An acetonitrile (30 mL) solution of 7-(4-methylbenzyl)-1-benzothiophene (1.24 g, 5.20 mmol) was added with N-bromosuccinimide (1.01 g, 5.72 mmol) and stirred at room temperature for two hours. The solvent was evaporated under reduced pressure and diluted with ethyl acetate. After washed with 20 wt % sodium thiosulfate aqueous solution and brine, the organic phase was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=100:1-50:1) to obtain a colorless powdered title compound (0.92 g, 56%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH2:9]1)C1C=CC=CC=1.CCN(CC)CC.C(Cl)(=O)OC(Cl)C>C(Cl)Cl>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[N:14][CH:15]=1
Reactant: Cc1ccc(C2CCN(Cc3ccccc3)C2)nc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C2CCNC2)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 117 %

Procedure:
To a stirred solution of 2-(1-benzylpyrrolidin-3-yl)-5-methylpyridine (200 mg, 0.79 mmol) in dry CH2Cl2 (3 mL) were added Et3N (80 mg, 0.79 mmol) and 1-chloroethyl carbonochloridate (225 mg, 1.6 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated under vacuum and dissolved in CH2Cl2 (5 mL). The organic solution was washed with water (20 mL×3), and the combined aqueous layers were concentrated to give crude 5-methyl-2-(pyrrolidin-3-yl)pyridine (150 mg, 82%) as a solid, which was used for next step without purification.
Reaction SMILES: C(OC(=O)[C@@H]([N:10]1[C@H:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)[C@@H:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:13][C@@:12]([CH2:31][C:32](O)=O)([CH3:30])[C:11]1=[O:35])CC)(C)(C)C.[C:37](O)(C(F)(F)F)=O>>[CH2:31]([C@@:12]1([CH3:30])[CH2:13][C@H:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C@@H:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)[NH:10][C:11]1=[O:35])[CH:32]=[CH2:37]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)NC1=O
Temperature: 25 °C

Procedure:
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one (3.6 g, 6.85 mmol, mixture of C-3 epimers, Example 124, Step B) was dissolved in TFA (26.4 mL, 343 mmol) and the reaction was heated to 70° for 1.5 h. It was then cooled to ambient temperature and the TFA was removed by concentration under reduced pressure. The product was azeotroped with heptanes, dissolved in DCM and the organic layer was washed with sat. aq. NaHCO3 solution and sat. NaCl solution. Purification by flash chromatography on silica gel (eluent: 35 to 45% EtOAc/hexanes which had been NH3 sparged, gradient elution) provided the title compound as the more polar isomer as a white solid: (Rf in 75% EtOAc/Hexanes=0.44).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[Si:61]([O:68][C@H:69]1[CH2:73][N:72]([CH3:74])[C@H:71]([CH:75]=O)[CH2:70]1)([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:63])[CH3:62]>O1CCCC1>[Si:61]([O:68][C@H:69]1[CH2:73][N:72]([CH3:74])[C@H:71](/[CH:75]=[CH:29]/[C:28]([NH:27][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][C:23]=2[O:39][CH2:40][CH3:41])[N:20]=[CH:19][C:18]([C:42]#[N:43])=[C:17]3[NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[C:2]([Cl:1])[CH:3]=2)=[O:38])[CH2:70]1)([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:62])[CH3:63]
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Reactant: CN1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.1 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (418 mg, 0.67 mmol) was dissolved in 2.5 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (1 mL, 1 mmol). After the mixture was stirred for 45 minutes, a solution of (2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidine-2-carbaldehyde 3e (326 mg, 1.34 mmol) in 2.5 mL of tetrahydrofuran was added, and stirred for another 1 hour, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-3-[(2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidin-2-yl]-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]prop-2-enamide 3f (292 mg, yield 61.2%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1(O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)(Cl)Cl.CO>[CH:30]1([O:24][C:23]([C:18]2([C:20]([O:22][CH:30]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OC1CCCCCCC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OC1CCCCCCC1)(C(=O)OC1CCCCCCC1)O2)NC[C@H](O)c1cccc(Cl)c1
Yield: 84 %

Procedure:
The title compound was prepared as a white gum from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclooctanol according to the procedure of Example 1; yield 84%; Rf =0.30 (10/1 CHCl3 /MeOH); 1H NMR (300 MHz, CDCl3): δ 1.30-1.39 (brd, 3H), 1.40-1.92 (m, 28H), 2.72-2.87 (m, 1H), 3.06-3.30 (m, 2H), 3.39-3.52 (m, 2H), 3.80-3.91 (m, 1H), 5.02-5.13 (m, 1H), 5.40-5.80 (m, 1H), 6.71-6.89 (m, 4H), 7.21-7.37 (m, 2H), 7.44 (s, 1H), 8.73 (brs, 1H), 10.11 (brs, 1H); MS (ES) m/z (relative intensity): 679 (M+, 100).
Reaction SMILES: O.[OH-].[Li+].[C:4]1([C:10]2[N:15]=[CH:14][C:13]([C:16]3([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO.O>[C:4]1([C:10]2[N:15]=[CH:14][C:13]([C:16]3([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccccc3)nc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2ccc(-c3ccccc3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide, monohydrate (0.016 g, 0.37 mmol) was added to ethyl 1-(6-phenylpyridin-3-yl)cyclopropanecarboxylate (50.0 mg, 0.19 mmol) in methanol (1.5 mL) and water (0.5 mL). The mixture was stirred at room temperature for overnight, then was adjusted to be acidic (pH=5) with 1N HCl aqueous solution, and then was concentrated to give a crude product which was directly used in the reaction of the next step without further purification.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][C:34]([C:38](O)=[O:39])=[CH:35][CH:36]=3)[C:31]([CH3:41])=[C:30]2[CH3:42])=[CH:24][CH:23]=1)=[O:15])(C)(C)C>>[CH2:1]([NH:8][C:38]([C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:17]3[C:16]([C:14]([OH:15])=[O:13])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:27][CH:26]=1)[C:30]([CH3:42])=[C:31]2[CH3:41])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1ccccc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using benzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[K+]>CN(C=O)C>[CH2:19]([O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.2 %

Procedure:
Methyl 2,4-dihydroxybenzoate (20.0 g, 0.119 mol) was dissolved in DMF (400 mL) and potassium carbonate (17.2 g, 0.125 mol) and benzyl bromide (21.4 g, 0.125 mol) were added using additional DMF (400 mL) to aid the transfer. Potassium iodide (3.0 g) was added, and the reaction was stirred at room temperature under nitrogen for 48 h. The DMF was removed in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried, and the solvent was removed in vacuo to give a white solid which was recrystallized from ethyl acetate:hexane to yield 17.9 g (61.1%) of a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[I:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].C(N(CC)CC)C>ClCCl>[I:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH:9][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: Nc1ccccc1I
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1I
Reaction time: 1.5 h
Yield: 75.4 %

Procedure:
Methanesulfonyl chloride (4.4 mL, 57 mmol) was added to a 0° C. dichloromethane (200 mL) solution containing 2-iodoaniline (5.0 g, 23 mmol) and triethylamine (9.6 mL, 69 mmol). The resulting mixture was stirred for 90 minutes, washed with HCl (0.5 M). The organics were separated then dried over sodium sulfate and concentrated in vacuo. The residue was then treated with potassium hydroxide (2.0 M in 1:1 methanol:water, 75 mL) for 30 min. This material was then diluted with dichloromethane and washed with HCl (1.0 N, 300 mL). The organics were separated then dried over sodium sulfate and concentrated to provide the title compound (5.15 g) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>C1(C)C=CC=CC=1.N1CCCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:12](\[C:10]#[N:11])/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C#N)=C/c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a solution of 4-bromobenzaldehyde (106 g, 573 mmol) in toluene (1000 mL) were added ethyl 2-cyanoacetate (71.3 g, 630 mmol) and piperidine (976 mg, 11.5 mmol) and the clear, light brown solution was heated at reflux for 5 h in a 4-neck flask equipped with a Dean-Stark trap, then stirred overnight at room temperature. After cooling the reaction mixture was evaporated, the residue suspended in heptane (500 mL), homogenized in an ultrasound bath for min, stirred for 20 min at 50° C., then the precipitate was collected by filtration. This was dissolved in ethyl acetate (1000 mL) and heptane (500 mL), then slowly concentrated at 50° C. to a volume of approximately 300 mL of solvent. This solution started to crystallize upon standing. The precipitate (96 g) was collected by filtration and washed with heptane/ethyl acetate 9:1 (300 mL). The mother liquor was concentrated at 50° C. until crystallization started. The product was allowed to precipitate over 1 h at room temperature, then collected by filtration to produce a second crop of product (44 g). Total yield: 140 g (87%). Light yellow solid, MS: 299.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:13]1([NH:16][CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([C:18](=[CH:17][NH:16][CH:13]1[CH2:14][CH2:15]1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:5]
Reactant: CCOC(=O)C=CNC1CC1
Reactant: O=C(Cl)c1cc(F)c(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)nc1Cl

Procedure:
In dry dioxane, 2,6-dichloro-5-fluoronicotinoyl chloride, prepared in Reference Example 10-(2), was allowed to react with ethyl β-cyclopropylaminoacrylate in the presence of triethylamine to give ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-cyclopropylaminoacrylate, m.p. 129°-130° C.