Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16](/[CH:21]=[CH:22]/[S:23](Cl)(=[O:25])=[O:24])[CH:17]=[CH:18][C:19]=1[Cl:20].C(N(CC)CC)C>ClCCl>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:2]([NH:1][S:23](/[CH:22]=[CH:21]/[C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=2)(=[O:25])=[O:24])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(Cl)cc1NS(=O)(=O)/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
2-Amino-4-chlorobenzenesulfonamide (100 mg, 0.48 mmol) and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride (171 mg, 0.63 mmol) were dissolved in anhydrous dichloromethane (5 mL) and were flushed with argon. Anhydrous triethylamine (0.155 mL, 1.11 mmol) was added and the reaction was stirred at room temperature under an inert atmosphere over night. The reaction was quenched using 2 M hydrochloric acid (20 mL) and extracted with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated under vacuum to give 194 mg (91% yield) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]([CH2:9][CH2:10][C@@H:11]([OH:19])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([O-:17])=[O:16])[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:5]=1[C:33]([NH:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:34])[CH3:3].[CH3:42][CH:43]([C:45]1[N:49]([CH2:50][CH2:51][C@@H:52]([OH:60])[CH2:53][C@@H:54]([OH:59])[CH2:55][C:56]([O-:58])=[O:57])[C:48]([C:61]2[CH:62]=[CH:63][C:64]([F:67])=[CH:65][CH:66]=2)=[C:47]([C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:46]=1[C:74]([NH:76][C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1)=[O:75])[CH3:44].[Ca+2]>C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[N:8]([CH2:9][CH2:10][C@@H:11]([OH:19])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([OH:17])=[O:16])[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]=1[C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34])[CH3:1].[CH3:44][CH:43]([C:45]1[N:49]([CH2:50][CH2:51][C@@H:52]([OH:60])[CH2:53][C@@H:54]([OH:59])[CH2:55][C:56]([OH:58])=[O:57])[C:48]([C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=2)=[C:47]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:46]=1[C:74]([NH:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)=[O:75])[CH3:42]
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)[O-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Yield: 59.4 %

Procedure:
5.0 g (8.6 mmole) of atorvastatin calcium was dissolved in 300 mL ethyl acetate and washed with 300 mL 10% (w/v) aqueous sodium hydrogen sulfate solution (pH 3). The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to afford 2.85 g (5.11 mmole) of atorvastatin acid. This material was dissolved in 300 mL anhydrous toluene and heated at 60° C. for 40 hours, at which time analytical thin-layer chromatography using 4:1 methylene chloride:acetone eluent indicated near-complete conversion of the starting acid to a less polar product. The toluene was removed under reduced pressure and the reaction mixture was fractionated on 300 cc of silica gel using 4:1 methylene chloride: acetone eluent to afford, after combining, concentrating and drying of the appropriate fractions, 2.14 g (3.96 mmol, 46% overall) of atorvastatin lactone as a white foam. The 400 MHz 1H nuclear magnetic resonance (NMR) spectrum and the electrospray mass spectrum (ES-MS) were consistent with the lactone product. 1H NMR (Me2SO-d6) δ 9.80 (s, 1H), 7.49 (d, 2H), 7.25–7.15 (m, 6H), 7.05 (s, 4H), 6.99 (t, 2H), 5.15 (d, 1H), 4.46 (br s, 1H), 4.02 (s, 1H), 3.97 (m, 1H), 3.89 (m, 1H), 3.21 (q, 1H), 2.55 (dd, 1H), 2.32 (dd, 1H), 1.74 (br s, 2H), 1.6 (m, 2H), 1.36 (d, 6H). ES-MS: obsvd. m/z 541 ([MH]+).
Reaction SMILES: [O:1]([CH2:13][CH2:14][S:15][CH2:16][CH2:17][C:18]([O:20]C)=O)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].O.[NH2:23][NH2:24].C(Cl)(Cl)Cl.CO.O>C(O)C>[O:1]([CH2:13][CH2:14][S:15][CH2:16][CH2:17][C:18]([NH:23][NH2:24])=[O:20])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COC(=O)CCSCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: NN
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NNC(=O)CCSCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
2-(2-Methoxycarbonylethylthio)ethyl β-D-galactopyranoside (28) (500 mg) was dissolved in ethanol (99.5%; 2.5 ml) and hydrazine hydrate (85%; 1 ml) was added. The reaction mixture was left at room temperature over night (TLC; SiO2, chloroform/methanol/water 65:35:10, lower phase). Evaporation gave the title compound (29) as a syrup (pure by TLC and 1H-NMR) in quantitative yield. Recrystallization from ethanol gave the pure compound: mp 178°-179°; [α]D23 -2.2° (c 0.5; H2O); 1H-NMR (D2O, TMS as an external standard) δ 4.43 (d, 1H, J1,2 =7.7 Hz, H1), 4.07 (m, 1H, O--CH2 --CH2), 3.92-3.60 (m, 7H), 3.50 (dd, 1H, J2,3 =11.6 Hz, H2), 2.90, 2.86 (t, 2H each, J=7 Hz, --CH2S), 2.54 (t, 2H, CH2CO) 13C--NMR (D2O, TMS as an external standard) δ 176.1 (CO), 105.6 (C-1), 77.9, 75.4, 73.4, 71.6, 71.3 (C2-C6), 63.7 (O--CH2 --CH2), 36.5, 33.5, 29.9 (CH2S, CH2CO).
Reaction SMILES: [O:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[CH3:22])C.B(Br)(Br)Br>ClCCl>[OH:1][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:14])[F:15])[O:10]2)=[CH:5][C:4]=1[CH3:22]
Reactant: CCOC(=O)C1=Cc2cc(C)c(OC)cc2OC1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cc(C)c(O)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of ethyl 7-methoxyl-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (5.2 g, 16.4 mmol) in 30 mL of dry dichloromethane at −78° C. in a dry ice/acetone bath was added a solution of 1.0 M of boron tribromide (164 mL, 164 mmol) dropwise. After finishing adding, the dry ice/acetone bath was removed. The reaction was stirred at room temperature overnight. The reaction was then cooled to −78° C. in dry ice/acetone bath. 200 mL of ethanol was added dropwise. After finishing addition, the cooling bath was removed. The reaction was allowed to warm to room temperature. LC-MS indicated that the reaction was finished. The volatiles were removed on rotavapor. The residue was then purified on silica gel column with 1:9 EtOAc/hexane. The desired product was isolated as off-white solid, 3.2 g. m.p.=151.0-153.0° C. 1H NMR (CDCl3/CD3OD/300 MHZ):7.68(s, 1H), 6.97(s, 1H), 6.43(s, 1H), 5.65(q, J=7.2 Hz, 1H), 4.31(m, 2H), 2.17(s, 3H), 1.36(t, J=6.9 Hz, 3H). 19F NMR(CDCl3/CD3OD/300 MHz) −79.03(d, J=7.3 Hz). 13C(CDCl3/CD3OD/300 Mhz) 164.8, 159.4,153.3, 137.8, 131.8, 123.9(q, J=287.9 Hz), 119.4, 112.5, 111.8, 102.6, 70.9(q, J=32.9 Hz), 61.4, 15.3, 14.4. LC-MS(ES+): 303.1(M+1). MS(EI+): 302.0(M+, 80), 233(M−69, 100); High resolution MS: m/z calc. For C14H13F3O4: 302.0766(M+, theoretical), found: 302.0763.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[N+:39]([O-])([OH:41])=[O:40]>ClC(Cl)C.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[C:31]([N+:39]([O-:41])=[O:40])[CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)c([N+](=O)[O-])c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of compound prepared in step I (2 g, 3.64 mmol) in dichloroethane (20 mL) was added TBAB (117 mg, 0.364 mmol), 6% aqueous nitric acid (20 mmol) at 0-5° C. and stirred at room temperature for 4 h. Organic layer was separated, washed with water and brine and concentrated to furnish crude acetic acid (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-3-nitro-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester which was further purified by column chromatography (1.5 g)
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]([OH:17])[CH:5]=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([O:17][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(O)c(CCCc2ccccc2)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c(CCCc2ccccc2)c1O

Procedure:
A mixture of 6.69 g (24.7 mmol) of 1-[2,4-dihydroxy-3-(3-phenylpropyl)phenyl]ethanone, from the preceding example, 5.35 g (31.3 mmol) of benzyl bromide, 14.9 g (0.108 mol) of anhydrous potassium carbonate, 115 mL of dry N,N-dimethylformamide, and 230 mL of acetone was stirred and refluxed for 8 hr. After being cooled, the slurry was filtered with suction and the solids washed well with acetone. The filtrate and washes were combined and concentrated under reduced pressure to give a yellow oil which was chromatographed on silica gel. There was obtained 5.57 g (62.6%) of the desired monoether as a pale-yellow solid. Recrystallization of a sample from hexane-ethyl acetate gave the title compound as colorless needles, mp 115°-116° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:23]C(OCC2C=CC=CC=2)=O)[CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:11][C:10]=1[C:34]([CH3:37])([CH3:36])[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[NH2:23][CH:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:11]=1)[CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CC(C)(C)c1cc(CC(CNS(C)(=O)=O)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cc(CC(N)CNS(C)(=O)=O)ccc1OCc1ccccc1
Yield: 76 %

Procedure:
N-[3-(4-benzyloxy-3-tert-butylphenyl)-2-benzyloxycarbonylaminopropyl]methanesulfonamide (1.2 g, 2.29 mmol) was dissolved in a mixture of methanol (23 ml) and methylene chloride (5 ml), mixed with palladium hydroxide/carbon (0.60 g) and stirred for 12 hours in a hydrogen atmosphere. After filtering off insoluble material using Celite, the filtrate was concentrated to give crude N-[2-amino-3-(4-benzyloxy-3-tert-butylphenyl)propyl]methanesulfonamide (0.68 g).
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1.Cl>O>[C:2]1([S:8]([CH:13]2[CH2:14][CH2:15][CH2:16][C:11](=[O:17])[CH2:12]2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CCCC1
Reactant: O=S([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1CCCC(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
Benzenesulfinic acid sodium salt (10.25 g) was added to a solution containing 5 ml of cyclohexenone and 30 ml of water, followed by the dropwise addition of 60 ml of 1N hydrochloric acid. The reaction mixture was stirred at room temperature for 24 hours. The crystals so precipitated were filtered and then washed with water, isopropanol and cold ethyl ether. After recrystallization from isopropanol, 5.74 g of 3-(phenylsulfonyl)-cyclohexan-1-one were obtained in the form of white crystals. Yield: 97%
Reaction SMILES: [CH2:1]([O:5]/[N:6]=[N+:7](/[N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][OH:15])\[O-:8])[CH2:2][CH2:3][CH3:4].Cl[C:17]([O:19][CH:20]([Cl:22])[CH3:21])=[O:18].N1C=CC=CC=1>C(Cl)Cl>[C:17](=[O:18])([O:19][CH:20]([Cl:22])[CH3:21])[O:15][CH2:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][N:9]1/[N+:7](/[O-:8])=[N:6]/[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCCCO/N=[N+](\[O-])N1CCC[C@H]1CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCO/N=[N+](\[O-])N1CCC[C@H]1COC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {(2S)-1-[(2)-butoxy-NNO-azoxy]pyrrolidin-2-yl}methanol (Example 1, Step A) (856 mg, 3.94 mmol) in CH2Cl2 (15 mL) at rt was added 1-chloroethyl chloroformate (676 mg, 4.73 mmol) and followed by pyridine (935 mg, 11.8 mmol). After stirring at rt for 3 h, the mixture was purified by flash chromatography (Biotage 25+M) using 10-30% EtOAc/hexane gradient, affording the title compound.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[NH:4]1)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:22])([F:21])[F:20])[CH3:2].[BH3-]C#N.[Na+].C(O[CH:32](O)[C:33]([F:36])([F:35])[F:34])C>C(O)(C(F)(F)F)=O>[CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[N:4]1[CH2:32][C:33]([F:36])([F:35])[F:34])[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:21])([F:22])[F:20])[CH3:2]
Reactant: CCOC(O)C(F)(F)F
Reactant: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1CC(F)(F)F
Yield: 167.7 %

Procedure:
This compound was prepared according to General Method 5 (EXAMPLE 2) from (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.008 g, 0.024 mmol), NaCNBH3 (0.007 g, 0.118 mmol) and trifluoroacetaldehyde ethyl hemiacetal (0.028 mL, 0.235 mmol) in TFA (0.8 mL) to afford 0.017 g of (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-4-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a brown-red solid. This material (0.017 g) was carried on according to General Method 4 (EXAMPLE 1) by treatment with conc. HCl (0.3 mL) in AcOH (0.6 mL) and heated at 95° C. for 2 h to afford 0.006 g (67% for the 2 steps) of Compound 110, a yellow solid. Rf0.4 (9:1 CH2Cl2;MeOH); 1H NMR (400 MHz, CDCl3) δ 12.47 (broad s, 1H), 7.15 (s, 1H), 7.14 (d, 1H, J=8.9), 7.02 (d, 1H, J=8.9), 4.38 (d, 1H, J=10.9), 3.98 (dd, 1H, J=10.8, 2.4) 3.93–3.65 (m, 2H), 3.27–3.22 (m, 1H), 1.68–1.51 (m, 2H), 0.98 (t, 3H, J=7.5).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.ClCCl>[C:22]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc2c(ccn2C(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 117.8 %

Procedure:
Sodium hydride (58 mg) was added to a solution of benzyl 1H-indole-5-carboxylate (300 mg) in N,N-dimethylformamide (2 ml) with ice cooling, and then stirred for 30 minutes. Benzoyl chloride (202 mg) was added thereto, and the mixture was stirred for 2 hours. The reaction mixture was diluted with dichloromethane, and the organic phase was washed with 2 N hydrochloric acid, a saturated sodium bicarbonate solution and a saturated saline solution. The organic phase was dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give benzyl 1-benzoyl-1H-indole-5-carboxylate (500 mg, Y.:quant.) as pale orange crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:33]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:31]=[C:30](Br)[CH:29]=2)=[CH:20][C:19]=1[CH3:44]>CN(C=O)C.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:29]=[C:30]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][CH:4]=3)[CH:31]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:33]=2)=[CH:20][C:19]=1[CH3:44]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCCCC3)c2)cc1C
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCCCC3)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-ethynyl-4-trifluoromethyl-benzene (300 mg, 1.77 mmol), (4-{3-[3-bromo-5-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (100 mg, 0.2 mmol, example 3), Pd(PPh3)4 (22 mg, 0.02 mmol), CuI (10 mg, 0.055 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 50 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using ethyl acetate/methanol mixtures to give (2-methyl-4-{3-[3-(3-piperidin-1-yl-prop-1-ynyl)-5-(4-trifluoromethyl-phenylethynyl)-phenyl]-prop-2-ynyloxy}-phenoxy)-acetic acid methyl ester in 30 mg (26%) yield.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O[C@@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH2:38][CH2:37][CH2:36]2>ClCCl.C(OC(=O)C)C>[Cl:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]([C@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16])[CH2:38][CH2:37][CH2:36]2
Reactant: Clc1ccc2c(c1)CCCN2
Reactant: O=C1OCC[C@H]1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OCC[C@@H]1N1CCCc2cc(Cl)ccc21
Temperature: -20 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Prepared using general procedure 57. Under an N2 atmosphere at −20° C., diisopropyl ethyl amine (15.9 mL, 91.4 mmol) was added drop wise to a solution of solution of (R)-3-hydroxydihydrofuran-2(3H)-one (4.67 g, 45.7 mmol) in dichloromethane (70 mL). Then added trifluoromethanesulfonic anhydride (8.1 mL, 48.0 mmol) drop wise by maintaining internal temperature of the reaction mixture <−20° C. Upon completion of addition, the mixture was stirred at −20° C. for 1 hour. Then added at −20° C., 6-chloro-1,2,3,4-tetrahydroquinoline drop wise. The reaction was allowed to warm to RT over a period of 30 minutes and continued to stir at RT for 16 hrs. The reaction mixture was diluted with 200 mL of ethylacetate and washed with saturated sodium bicarbonate (3×50 mL). The organic layer was washed with a saturated aqueous NaCl solution (2×50 mL). The solution was dried over magnesium sulfate, filtered, and concentrated. Purification via silica gel chromatography using 5-50% ethyl acetate in hexane gave (S)-3-(6-chloro-3,4-dihyroquinolin-1(2H)-yl)dihyrofuran-2(3H)-one as a white solid (10.74 g, 93% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=252.3; tR=1.66 min. 1H NMR (400 MHz, DMSO-d6) δ 7.03-6.98 (m, 2H), 6.74 (d, J=8.9 Hz, 1H), 5.07 (t, J=10.0 Hz, 1H), 4.42 (t, J=9.5 Hz, 1H), 4.30-4.23 (m, 1H), 3.16-3.02 (m, 2H), 2.68 (t, J=6.4 Hz, 2H), 2.44-2.27 (m, 2H), 1.87-1.77 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=[C:21]([C:23]([OH:25])=O)[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:35]1[CH:39]=[C:38]([NH2:40])[CH:37]=[N:36]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[CH:20]=[C:21]([C:23](=[O:25])[NH:40][C:38]2[CH:39]=[N:35][NH:36][CH:37]=2)[CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)O)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)Nc3cn[nH]c3)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Temperature: 40 °C

Procedure:
To a solution of intermediate (1c), 2-[5-carboxy-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]indole-1-carboxylic acid tert-butyl ester, (3 g, 6.2 mmol) in tetrahydrofuran (100 mL) was added intermediate (2H), 1H-pyrazol-4-ylamine (0.62 g, 7.46 mmol), 1-hydroxybenzotriazole hydrate (1.09 g, 8.07 mmol), N,N-diisopropylethylamine (2.4 g, 3.24 mL, 18.6 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.55 g, 8.07 mmol). The reaction mixture was heated at 40° C. for 2 hours. The reaction mixture was cooled and partitioned between ethyl acetate and aqueous saturated sodium hydrogen bicarbonate solution. The ethyl acetate layer was separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—66% ethyl acetate/hexane (gradient) to afford the desired title compound as a yellow solid, 1.36 g, 40%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[CH3:12])[C:5](OC)=[O:6].[BH4-].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[C:10]([Br:13])[C:11]=1[CH3:12]
Reactant: COC(=O)c1cc(Br)c(C)c(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(Br)cc(CO)cc1Br
Yield: 72.9 %

Procedure:
A mixture of methyl 3,5-dibromo-4-methylbenzoate (15 g, 48.706 mmol), NaBH4 (5.53 g, 146.18 mmol) and absolute ethanol (175 mL) was heated to reflux for 4 h. The mixture was cooled, followed by acidification with 2N HCl. The solids were filtered through celite and rinsed with EtOAc. The filtrate was poured onto water and extracted. The organic layer was washed with brine and dried (Na2SO4). Chromatography (Hexanes/EtOAc) afforded (3,5-dibromo-4-methyl-phenyl)-methanol (9.94 g) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ: 2.48 (s, 3H), 4.45 (d, 2H), 5.38 (t, 1H), 7.57 (s, 2H) ppm.