Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[CH3:23][S:24]([O:27][CH:28]([CH2:38][CH2:39][CH2:40][OH:41])[CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:26])=[O:25].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:23][S:24]([O:27][CH:28]([CH2:38][CH2:39][CH:40]=[O:41])[CH2:29][O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)OC(CCCO)COCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCC=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
440 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one (Dess-Martin Periodinane) was added to a solution of 200 mg of 1-benzyloxy-5-hydroxypentan-2-yl methanesulfonate in 2 mL of dichloromethane, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 100 mg of Dess-Martin Periodinane was added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the reaction mixture was added to a mixture of 50 mL of ethyl acetate and 30 mL of a saturated sodium hydrogen carbonate aqueous solution, and the obtained mixture was then filtrated with Celite. The organic layer was fractionated. The obtained organic layer was washed with 30 mL of a sodium thiosulfate aqueous solution twice, and then with 30 mL of a saturated sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/2 to 1/1), so as to obtain 141 mg of 1-benzyloxy-5-oxopentan-2-yl methanesulfonate in the form of a colorless oily product.
Reaction SMILES: [CH3:1][S-:2].[Na+].[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C@@H:16]2[CH2:18][O:17]2)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].O>C1COCC1>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C@@H:16]([OH:17])[CH2:18][S:2][CH3:1])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H]2CO2)C1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
Sodium methyl mercaptide (296 mg, 4.2 mmol) was dissolved in THF (1.0 mL), and the mixture was stirred for 10 minutes at room temperature. (S)—(R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (300 mg, 1.41 mmol) was dissolved in THF (0.4 mL) and added to the mixture. The resulting solution was placed in a microwave reactor for 30 minutes at 100° C., then cooled to room temperature. Hexanes (3×10 mL) was added, followed by water (10 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in hexanes) to yield the title compound as a clear oil (207 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[NH:8][C:7](=O)[CH:6]=[CH:5]2.P(Br)(Br)[Br:14]>C(=O)([O-])[O-].[Na+].[Na+]>[Br:14][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][N:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: BrP(Br)Br
Reactant: O=c1ccc2cc(Cl)ncc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1cc2ccc(Br)nc2cn1
Temperature: 130 °C
Yield: 50 %

Procedure:
A mixture of 6-chloro-1,7-naphthyridin-2(1H)-one (1.0 g, 5.5 mmol) and phosphorus tribromide (10 mL) was heated in a sealed tube at 130° C. for 20 hours. The cooled reaction mixture was poured onto ice, diluted with saturated aqueous sodium carbonate solution (100 mL), and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-80% ethyl acetate in heptane) to afford the title compound as a white solid (700 mg, 50%). 1H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 8.38 (d, J=8.7 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J=8.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:51])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30](Cl)[C:29]([CH3:33])=[CH:28][C:27]=5[O:34][C@H:35]([CH2:37][CH:38]=[CH2:39])[CH3:36])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:40])[C:12]=2[C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44]C)=[O:43])[CH2:7][CH2:6]1)C=C.C(OC1(C)CC[N:59](C2N3N=C(C4C=C(C5C(O[C@H](CC=C)C)=CC=C(Cl)C=5C)C=CC=4)C=C3N=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C.BrC1C=C(Cl)C(C)=CC=1O[C@H](CC=C)C.BrC1C(C)=C(Cl)C=CC=1O[C@H](CC=C)C>>[C:47]([O:46][C@@H:41]([C:12]1[C:13]([CH3:40])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:51])([O:4][CH2:1][CH2:39][CH2:38][CH2:37][C@H:35]([CH3:36])[O:34][C:27]2[CH:28]=[C:29]([C:33]#[N:59])[CH:30]=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)[C:42]([OH:44])=[O:43])([CH3:48])([CH3:49])[CH3:50]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5c(O[C@@H](C)CC=C)ccc(Cl)c5C)c4)nn23)CC1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(Cl)c(C)cc5O[C@@H](C)CC=C)c4)nn23)CC1
Agent: C=CC[C@H](C)Oc1cc(C)c(Cl)cc1Br
Agent: C=CC[C@H](C)Oc1ccc(Cl)c(C)c1Br
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C#N)ccc1-c1cccc-3c1

Procedure:
(S)-Methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-chloro-4′-methyl-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate and (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3′-chloro-2′-methyl-6′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate: Prepared from a 2:1 mixture of (S)-1-bromo-5-chloro-4-methyl-2-(pent-4-en-2-yloxy)benzene and (S)-2-bromo-4-chloro-3-methyl-1-(pent-4-en-2-yloxy)benzene using the same procedures as intermediate 182 and 168 to provide an inseperable mixture of the products in 98% yield and 2:1 ratio. (S)-Methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-chloro-4′-methyl-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate. LCMS (M+1)=715.4. (S)-Methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3′-chloro-2′-methyl-6′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate. LCMS (M+1)=715.4.
Reaction SMILES: CS(O[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=O)=O.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[F:17][C:18]([F:26])([F:27])[C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cccc(OS(C)(=O)=O)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cccc(Nc2ccc(C(F)(F)F)cc2)c1
Temperature: 110 °C
Yield: 93.1 %

Procedure:
Following general procedure A, a mixture of ethyl 3-(methylsulfonyloxy)benzoate (122 mg, 0.5 mmol), 4-(trifluoromethyl)aniline (75 μL, 0.6 mmol), K2CO3 (97 mg, 0.7 mmol), 10 (4 mg, 1 mol %), 1 (2.5 mg, 1 mol %), and t-BuOH (6 mL) was heated to 110° C. for 16 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-30% EtOAc/hexanes) to provide the title compound as a white solid (144 mg, 93%), mp 106-108° C. 1H NMR (300 MHz, CDCl3) δ: 7.81 (s, 1H), 7.71 (d, J=7.0 Hz, 1H), 7.49 (d, J=8.5 Hz, 2H), 7.36 (m, 2H), 7.07 (d, J=8.5 Hz, 2H), 6.13 (s 1H), 4.38 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 166.7, 146.3, 141.8, 132.1, 130.1, 129.8, 127.1, 127.0, 127.0, 126.9, 126.6, 123.8, 123.8, 123.0, 122.6, 122.2, 120.6, 116.0, 61.5, 14.5 ppm. IR (neat, cm−1): 3358, 1701, 1620, 1543, 1333, 1158, 1108, 1070, 751. Anal. Calcd. for C16H14F3O2N: C, 62.13; H, 4.56. Found: C, 61.97; H, 4.46.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]2[O:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][NH:18][CH3:19]>C(O)C>[CH3:17][N:18]([CH3:19])[CH2:9][CH:8]([OH:10])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C(c2ccccc2)C2CO2)cc1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
1,1-Diphenyl-2,3-epoxy-propane prepared as described in Example 21, was further reacted with dimethylamine in ethanol by the procedure described in Example 8 to give 3-dimethylamino-1,1-diphenyl-propan-2-ol (90%) m.p. 72° - 73°
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][OH:6])[CH2:3][OH:4].C([Sn](=O)CCCC)CCC.CN1C=CN=C1.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>C1(C)C=CC=CC=1.O>[C:29]1([CH3:30])[CH:31]=[CH:32][C:26]([S:23]([O:4][CH2:3][C:2](=[CH2:1])[CH2:5][OH:6])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C(CO)CO
Agent: CCCC[Sn](=O)CCCC
Agent: Cn1ccnc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(CO)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.4 %

Procedure:
2-Methylene-1,3-propanediol (480 mg) and dibutyltinoxide (1,7 g) were dissolved in toluene (30 ml) and the resulting suspension was refluxed for 1 hour eliminating water with the help of a Dean-Stark apparatus. The flask was cooled down to room temperature and then, N-methyl-imidazol (797 ml) and tosyl chloride (1,56 g) were added. After 15 minutes stirring, the reaction crude was directly purified by column chromatography (hexane-ethyl acetate v/v from 7:1 to 1:1). The title compound (428 mg) was obtained as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][N:29]2[CH2:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][C:34]=2[O:43][CH3:44])=[CH:25][CH:24]=1>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([CH2:6][C:7]([NH:22][C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[CH:28][N:29]3[CH2:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][C:34]=3[O:43][CH3:44])=[CH:25][CH:24]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(Cn2ccc3ccc(N)cc32)c(OC)c1
Reactant: O=C(O)CC1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2ccc3ccc(NC(=O)CC4CCCC4)cc32)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of cyclopentylacetic acid (0.24 ml) and 1,1'-carbonyldiimidazole (0.34 g) in methylene chloride (3 ml) was heated under reflux for 30 minutes and then treated with a solution of ester (B) (0.5 g) in methylene chloride (3 ml). The mixture was heated under reflux for 30 minutes, stirred at room temperature for 24 hours, and then diluted with ethyl acetate. This organic solution was washed sequentially with 10% v/v hydrochloric acid, water, and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on a 6×18 cm silica gel column using 99:1 v/v ethyl acetate:toluene as the eluent followed by recrystallization from hexane/ethyl acetate to give methyl 4-[6-(2-cyclopentylacetamido)indol-1-ylmethyl]-3-methoxybenzoate (P) as a solid; partial NMR: 2.0-2.5(br m, 3H, CH2CH), 3.9(s, 3H, OCH3), 4.0(s, 3H, OCH3), 5.3(s, 2H, NCH2).
Reaction SMILES: [C:1]([O:8][C:9]([C:12]([CH2:15][CH2:16]I)([F:14])[F:13])([F:11])[F:10])([C:4]([F:7])([F:6])[F:5])([F:3])[F:2].CN1CCCC1=[O:24]>O>[C:1]([O:8][C:9]([C:12]([CH2:15][CH2:16][OH:24])([F:14])[F:13])([F:11])[F:10])([C:4]([F:7])([F:6])[F:5])([F:3])[F:2]
Reactant: CN1CCCC1=O
Reactant: FC(F)(F)C(F)(F)OC(F)(F)C(F)(F)CCI
Solvent: O
Product: OCCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Yield: 52 %

Procedure:
The flask was charged with 130 g of C2F5OCF2CF2CH2CH2I, 643 mL of the N-methyl pyrrolidone and 48 mL of deionized (DI) water. The reaction mixture was heated to 132 C for 20 hours. DI water was added and the lower layer was separated. The lower layer was dissolved in ether, washed with saturated sodium sulfite, and dried over anhydrous sodium sulfate. After rotary vaporization, 48 g of C2F5OCF2CF2CH2CH2OH (compound B3) was obtained by distillation in 52% yield. The boiling point was 70˜72° C. at 60 mm Hg pressure (7980 Pa).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)ccc1Oc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 60 h
Yield: 84.4 %

Procedure:
Methyl 5-fluoro-2-hydroxybenzoate (2.65 g, 15.6 mmo.) and 1-fluoro-2-nitrobenzene (2.02 g, 14.2 mmol) were dissolved in acetonitrile (30 mL) and cesium carbonate (6.10 g, 18.7 mmol) was added. The reaction mixture was stirred at 80° C. for 60 hours. The mixture was cooled down to room temperature and poured into ethyl acetate. This organic mixture was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography with 10-20% ethyl acetate in hexanes and triturated in ethanol to afford the title compound 18 (3.49 g, 84%) as white solid. LRMS (ESI): (calc) 291.05. (found) 292.2 (MS)+.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[Na].Cl[CH2:13][C:14](=[N:16][OH:17])[NH2:15]>C(O)C>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:13][C:14](=[N:16][OH:17])[NH2:15]
Reactant: NC(CCl)=NO
Reactant: CN(C)c1ccccc1S
Agent: [Na]
Solvent: CCO
Product: CN(C)c1ccccc1SCC(N)=NO
Reaction time: 2 h

Procedure:
2-Dimethylaminobenzenethiol (4.6 g; 3×10-2 mol) was added dropwise to a solution of sodium (0.69 g; 3×10-2 mol) in absolute ethanol (50 ml) at 25°. Immediately chloroacetamidoxime was added. Stirring at 25° was continued for 2 hours, sodium chloride was removed by filtration and the filtrate evaporated under reduced pressure. Re-crystallisation of the residue from isopropanol gave 2-(2-dimethylaminophenylthio)acetamidoxime, m.p. 133°.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C@H:9]([O:11][C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH2:8][NH:7][C@@H:6]1[C:19]([OH:21])=O)=[O:4].[C:22]1([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:22]1([C:28]2[CH2:33][CH2:32][N:31]([C:19]([C@@H:6]3[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][C@H:9]([O:11][C:12]([N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)=[O:13])[CH2:8][NH:7]3)=[O:21])[CH2:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)[C@H]1C[C@H](OC(=O)N2CCCC2)CN[C@@H]1C(=O)O
Reactant: C1=C(c2ccccc2)CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](OC(=O)N2CCCC2)CN[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2S,3S,5S)-3-(methoxycarbonyl)-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-2-carboxylic acid (90.1 mg, 0.000300 mol) and 4-phenyl-1,2,3,6-tetrahydropyridine (64.6 mg, 0.000330 mol) HCl salt, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (146 mg, 0.000330 mol) in N,N-dimethylformamide (0.44 mL, 0.0057 mol) was added N,N-diisopropylethylamine (0.115 mL, 0.000660 mol) at rt. The mixture was stirred at rt overnight, then quenched with aq. sodium bicarbonate. After separation of the organic layers, the aq. layer was extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to dry. The crude material was used directly in next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[C:19]([O:11][CH2:10][CH2:9][CH:8]([C:6]1[CH:5]=[CH:4][C:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:2]([F:1])[CH:7]=1)[CH3:12])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(CCO)c1ccc(-c2ccccc2)c(F)c1
Reactant: O=C(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CCOC(=O)c1ccccc1)c1ccc(-c2ccccc2)c(F)c1

Procedure:
Using a procedure analogous to that described in Example 3, 5.85 gm (67% of theory) of the ester of the formula ##EQU28## having a boiling point of 181°-185°C at 0.05 mm Hg were obtained by refluxing a mixture consisting of 6.11 gm (0.025 mol) of 3-(2-fluoro-4-biphenylyl)-1-butanol, 6.20 gm (0.051 mol) of benzoic acid, 0.5 gm of p-toluene-sulfonic acid and 40 ml of toluene until no more water separated out.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([OH:17])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH3:35])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([N:20]([C:21]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:27])[C:28](=[O:29])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a solution of tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (250 mg, 0.521 mmol, 1.00 equiv) in CH2Cl2 (5.2 mL, 0.1 M) at 0° C. (ice water bath) were added proton sponge (335 mg, 1.56 mmol, 3.00 equiv) and trimethyloxonium tetrafluoroborate (116 mg, 0.782 mmol, 1.50 equiv). The resulting white suspension was stirred at 0° C. for 30 minutes (min), removed from the cold bath and stirred at room temperature for 5 h, and then poured into ½ sat'd NaHCO3 solution (20 mL). The mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic phases were washed with 1N HCl (20 mL), dried over Na2SO4, filtered, and concentrated to provide an oil. Purification by automated silica gel column chromatography provided tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-8-methoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (220 mg, 85%) as a colorless, sticky solid: IR (ATR) 2979, 2935, 2831, 1742, 1706, 1455, 1293, 1254, 1170, 1144, 1121, 1098, 1057, 913, 853, 732 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.32-7.24 (m, 2H), 7.22-7.15 (dd, J=5.1, 2.6 Hz, 3H), 5.18-5.06 (dd, J=8.6, 6.3 Hz, 1H), 4.94-4.79 (dq, J=9.1, 6.3 Hz, 1H), 4.16-4.01 (dd, J=11.8, 6.3 Hz, 1H), 3.94-3.76 (dd, J=11.8, 8.7 Hz, 1H), 3.59-3.50 (d, J=10.5 Hz, 1H), 3.50-3.45 (s, 3H), 1.50-1.45 (m, 21H), 3.42-3.32 (dd, J=10.8, 6.2 Hz, 1H), 3.14-3.01 (m, 2H), 2.47-2.31 (t, J=12.4 Hz, 1H), 2.08-1.89 (s, 1H), 1.53-1.43 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 169.94, 152.62, 139.87, 129.25, 128.33, 126.03, 86.42, 83.03, 75.09, 70.91, 59.58, 57.42, 46.62, 35.15, 27.92, 18.92; HRMS-ESI (m/z) [M+Na]+ calc'd for C26H39NO8Na, 516.2568. found, 516.2572.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH2:30][CH3:31]>C1COCC1.C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([O:19][CH2:30][CH3:31])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCI
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1c(C#N)ncc2c1c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (120 mg, 0.28 mmol) in anhydrous THF (5 mL) was cooled to 0° C. and treated with sodium hydride (60% dispersion in mineral oil; 12 mg, 0.30 mmol). After gas evolution had ceased, iodoethane (424 μL, 4.10 mmol) was added and the mixture stirred at ambient temperature overnight then heated at 60° C. for 5 h. The reaction was then allowed to cool, diluted with toluene and concentrated in vacuo. The residue was purified by column chromatography (silica, 2 g column, Si II SPE, 10-100% ethyl acetate in DCM) to afford the title compound as a yellow solid (30 mg, 23%). 1H NMR (DMSO-D6, 400 MHz): 8.86 (s, 1H), 8.77 (s, 2H), 8.24-8.22 (m, 1H), 8.22-8.20 (m, 1H), 7.81-7.75 (m, 1H), 7.68-7.61 (m, 2H), 4.75 (q, J=7.2 Hz, 2H), 1.64 (t, J=7.2 Hz, 3H). LCMS (Method B): RT=3.30 min, M+H+=457/459.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:45])[CH2:35][CH2:36][N:37]([CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[CH3:38])=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:45])[CH2:35][CH2:36][N:37]([CH2:39][CH2:40][CH2:41][N:42]([CH3:43])[CH3:44])[CH3:38])=[CH:17][N:16]=1
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Reactant: COc1cc(-c2csc3c(NC(=O)CCN(C)CCCN(C)C)cnc(N)c23)ccc1N
Product: COc1cc(-c2csc3c(NC(=O)CCN(C)CCCN(C)C)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using 1-methyl-1H-indole-2-carbonyl chloride, N-[4-Amino-3-(4-amino-3-methoxyphenyl)-thieno[3,2-c]pyridin-7-yl]-3-[(3-dimethylaminopropyl)methylamino]propionamide, and the procedure described in General Procedure F. m/z (M+H)+ 614.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].[CH:20]1([CH2:23][N:24]([C:31]2[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=2)[C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:22][CH2:21]1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:34]1[CH:35]=[CH:36][C:31]([N:24]([CH2:23][CH:20]2[CH2:21][CH2:22]2)[C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:30]=2)=[CH:32][CH:33]=1
Reactant: Ic1ccc(N(CC2CC2)c2ncccn2)cc1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(CC2CC2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 69.1 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (139 mg) was reacted with N-(cyclopropylmethyl)-N-(4-iodophenyl)pyrimidin-2-amine (162 mg) to obtain (E)-5-[4-(cyclopropylmethyl-pyrimidin-2-ylamino)phenyl]-2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (167 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=1/1) was used for purification.