Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
To a solution of 1-t-butoxycarbonyl-3-hydroxyazetidine (3.24 g, 18.7 mmol) (obtained as described in Reference Example 31(1)) in methylene chloride (160 ml) were added methanesulfonyl chloride (1.59 ml, 20.6 mmol) and triethylamine (2.89 ml, 20.6 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1→1:2) as the eluant to afford 1-t-butoxycarbonyl-3-(methanesulfonyloxy)azetidine (4.71 mg, yield 100%) as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].O.Cl>CO>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:9]=1
Reactant: COC(=O)c1ncc(C(F)(F)F)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc(C(F)(F)F)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a stirring solution of 3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A3) (1 g, 4.54 mmol) in MeOH (20 ml) was added 2M NaOH (0.182 g, 4.54 mmol). The orange solution was stirred at RT for 1 minute and then into water (10 ml). The solution was acidified to pH1 with the addition of 1M HCl and the product was extracted with EtOAc (150 ml). The organic portions were combined, washed with brine (50 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound as an orange solid; LC-MS Rt=0.82 mins [M+H]+ 207.1 (Method 2 minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 13.9 (1H, broad hump), 8.11 (1H, s), 7.59 (1H, s), 7.08 (2H, broad hump) (trace of EtOAc present but correlates to proposed structure).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)C1C(=CC=CC=1)C(N)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1C(=O)NCCCCBr
Reactant: Fc1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Product: NCCCCn1cnc(-c2ccc(F)cc2)c1
Yield: 81.8 %

Procedure:
Using the procedure of Stage A of Example 1, 10 g of the product of Stage A, 1.95 g of sodium hydride and 11.80 g of N-4-bromobutyl-phthalamide were reacted to obtain 7.53 g of the expected product melting at 138°-140° C.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:12]1(=[O:29])[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[S:23])[NH2:22])[C:15](=[O:24])[C:14]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:13]12>>[C:15]1(=[O:24])[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[S:23][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:22]=2)[C:12](=[O:29])[C:13]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:14]12
Reactant: O=C1c2ccccc2CC1Br
Reactant: NC(=S)CCCCN1C(=O)c2ccccc2C1=O
Product: O=C1c2ccccc2C(=O)N1CCCCc1nc2c(s1)Cc1ccccc1-2

Procedure:
2-Bromo-1-indanone, 5-phthalimidopentanethioamide
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:13])C(O)=O)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)(=O)[C:15]([Cl:17])=[O:16]>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:13][C:15]([Cl:17])=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)c1ccc(F)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCc1ccc(F)c(F)c1
Reaction time: 24 h
Yield: 99.8 %

Procedure:
To a dichloromethane solution (200 mL) containing 3,4-difluorophenyl propionic acid (30.45 g, 163.6 mmol) and 2 drops of dimethylformamide was added oxalyl chloride (41.4 g, 327.1 mmol) over 20 min. The resulting solution was stirred for 24 hours at which time the solvent was removed in vacuo. The residual oil was then evaporated with toluene (˜100 mL) yielding 33.4 g of 3-(3,4-difluorophenyl)propanoyl chloride as a yellow liquid, which was taken directly into the next step.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:19])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12](=[O:18])[NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH3:4].[CH2:20]1[S:22][CH2:21]1>O1CCCC1>[CH2:1]([NH:5][C:6](=[O:19])[CH2:7][CH2:8][N:9]([CH2:10][CH2:11][C:12](=[O:18])[NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:20][CH2:21][SH:22])[CH2:2][CH2:3][CH3:4]
Reactant: C1CS1
Reactant: CCCCNC(=O)CCNCCC(=O)NCCCC
Solvent: C1CCOC1
Product: CCCCNC(=O)CCN(CCS)CCC(=O)NCCCC

Procedure:
Dissolve N-butyl-3-(2-butylcarbamoyl-ethylamino)-propionamide (10 mmol) prepared in Scheme VI, step D in tetrahydrofuran (50 mL) and add dropwise ethylene sulfide (22 mmol). Heat the reaction to reflux for 4 hours. After cooling, concentrate the reaction under vacuum and purify the residue by flash chromatography (silica gel, methanol/methylene chloride) to provide N-butyl-3-[(2-butylcarbamoyl-ethyl)-(2-mercapto-ethyl)amino]-propionamide.
Reaction SMILES: C1[O:14][C:4]([CH3:13])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)OC1.[O-]CC.[Na+].Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[CH:21]=1.Cl>C(O)C.CO>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:14])[CH3:13])=[CH:11][CH:10]=2)[CH:21]=1
Reactant: ClCc1cccnc1
Reactant: CC1(Cc2ccc(O)cc2)OCCO1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(=O)Cc1ccc(OCc2cccnc2)cc1

Procedure:
A solution of (4-hydroxyphenyl)propan-2-one ethylene ketal (5 g) in ethanol (20 ml) was added to a stirred solution of sodium ethoxide in ethanol (1.26 g sodium in 50 ml). A suspension of 3-picolyl chloride hydrochloride (4.5 g) in ethanol (40 ml) was added, the mixture boiled for 41/2 hr, cooled and filtered. After evaporation of the solvent the residue was chromatographed on alumina. Elution with 10% methanol in dichloromethane gave a dark oil which was dissolved in methanol (50 ml) and boiled with 2M hydrochloric acid (40 ml) for 3 hours. Neutralisation with 2M sodium hydroxide solution followed by extraction into dichloromethane yielded an oil which was purified by bulb to bulb distillation at 70° C./0.4 mm to give [4-(3-pyridylmethyloxy)phenyl]propan-2-one.
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:22]=N[CH:24]=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)[N:6]=[CH:5]1.B.[CH3:41]O>C1COCC1>[ClH:1].[C:27]([N:13]1[CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[CH:41][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[N:10]([CH2:9][C:7]2[N:6]=[CH:5][NH:4][CH:8]=2)[CH2:11][C@H:12]1[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:28]
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Reactant: CO
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of Compound B (150 mg, 0.42 mmol) in THF (10 mL) was added borane (1 M in THF, 3 mL, 3 mmol). The solution was refluxed for 3 h and cooled to room temperature. Methanol (5 mL) was added and the solution was concentrated. 5 N HCl (10 mL) was added and the mixture was refluxed for 4 h, cooled to room temperature, neutralized to pH 6 with 50% NaOH and extracted with methylene chloride (3×50 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and concentrated to yield compound C as a slightly yellow glass (70 mg, 50%). MS (M+H)+ 330.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:45]2[CH:46]=[CH:47][C:42]([O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:43][CH:44]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Triphenylphosphine (917 mg) was added to a solution of N-tert-butoxycarbonyl-4-hydroxypiperidine (A, 704 mg), 4-benzyloxyphenol (700 mg) and diethyl azodicarboxylate (609 mg) in tetrahydrofuran (20 mL) at room temperature. After stirring at room temperature for 14 hr, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, v/v) to give the titled compound (703 mg) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 1.72 (m, 2H), 1.88 (m, 2H), 3.29 (ddd, J=3.9, 7.8, 12.5 Hz, 2H), 3.70 (m, 2H), 4.32 (quintet, J=3.9 Hz, 1H), 5.01 (s, 2H), 6.84-6.91 (m, 4H), and 7.32-7.43 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:21][C@H:22]1[C@H:27](O)[C:26]2[CH:29]=[C:30]([C:33]#[N:34])[CH:31]=[CH:32][C:25]=2[O:24][C:23]1([CH3:36])[CH3:35]>C(Cl)(Cl)Cl>[Br:21][C@H:22]1[C@H:27]([O:16][C:15](=[O:17])[C@@H:14]2[CH2:18][CH2:19][CH2:20][N:13]2[S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:11])=[O:12])[C:26]2[CH:29]=[C:30]([C:33]#[N:34])[CH:31]=[CH:32][C:25]=2[O:24][C:23]1([CH3:36])[CH3:35]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)[C@@H]1Br
Yield: 41.4 %

Procedure:
A similar procedure as in Example 1(1) was performed by using 6.7 g of N-4-nitrobenzenesulfonyl-L-proline and 5.7 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-ol to give 4.72 g of trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-(N-4-nitrobenzenesulfonyl-L-prolyloxy)-2H-1-benzopyran as a sparingly soluble diastereomer compound, melting at 226.5°-227° C. with decomposition, [α]23D =+44.7° (c=1, CHCl3) and 5.01 g of the corresponding readily soluble diastereomer compound, melting at 177°-180° C., [α]23D =-93.2° (c=1, CHCl3), respectively.
Reaction SMILES: N([O-])=O.[Na+].[CH:5]([C:8]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=1N)([CH3:7])[CH3:6].[BrH:18]>O>[CH:5]([C:8]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=1[Br:18])([CH3:7])[CH3:6]
Reactant: Br
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 7.5 g of sodium nitrite in 20 ml of water was added at -20° C. to 0° C. over 20 minutes to a suspension of 18.5 g of the product of Step C, 120 ml of a 48% hydrobromic acid solution and 80 ml of water and the mixture was stirred at 0° C. for 15 minutes and kept thereafter at 0° C. A solution of 22 g of cuprous bromide in 80 ml of 48% hydrobromic acid solution was heated with stirring to 50°-55° C. and the previous solution was then added thereto. The mixture was stirred at 55°-60° C. for one hour, was cooled and poured into water. The mixture was extracted with methylene chloride and the combined organic phases were washed with N sodium hydroxide solution, with water, dried and evaporated to dryness under reduced pressure at 50° C. The residue was rectified under reduced pressure to obtain 20.4 g of 3-isopropyl-4-bromo-nitrobenzene with a boiling point of 150°-152° C. at 8 mm Hg and having a refractive index of nD22 =1.5775.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([C:22]3[C:23](=[O:29])[NH:24][C:25](=[O:28])[NH:26][CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Cl:30][C:31]1[N:32]=[N:33][C:34](Cl)=[CH:35][CH:36]=1>CS(C)=O>[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([C:22]3[C:23](=[O:29])[NH:24][C:25](=[O:28])[N:26]([C:34]4[N:33]=[N:32][C:31]([Cl:30])=[CH:36][CH:35]=4)[CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n(-c2ccc(Cl)nn2)cc1C1c2ccccc2C=Cc2ccccc21
Temperature: 80 °C

Procedure:
Cesium carbonate (2.15 g) was added to a stirred solution of the product of example 1 step (iv) (2 g) in dimethylsulphoxide (20 ml). After 5 minutes 3,6-dichloropyridazine (1 g) was added and the mixture heated at 80° C. for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with 50% ethyl acetate in isohexane. Yield 1.8 g.
Reaction SMILES: N([O-])=O.[Na+].[N+:5]([C:8]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:9]=1N)([O-:7])=[O:6].[BrH:16]>O>[N+:5]([C:8]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:9]=1[Br:16])([O-:7])=[O:6]
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 10 g of sodium nitrite in 30 ml of water were added with stirring at 0° C. to a suspension of 21.6 g of the product of Step B, 69 ml of 48% hydrobromic acid and 138 ml of water and the mixture was stirred at 0° C. for 10 minutes and then added with stirring to a solution of 30 g of cuprous bromide in 105 ml of 48% hydrobromic acid at 60° C. The mixture was stirred at 55°-60° C. for one hour and was poured into ice water. The mixture was extracted with isopropyl ether and the combined organic phases were dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with methylene chloride. The solution was evaporated to dryness and the residue was dried under reduced pressure to obtain 20.2 g of 2-nitro-4-fluoro-bromobenzene melting at 40°-41° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:26])[N:10]3[CH2:17][C@H:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:15][C@H:11]3[C:12](=[O:14])[NH:13][C:7]=2[CH:6]=[CH:5][C:4]=1[O:27][CH3:28].[H-].[Na+].[CH3:31][Si:32]([CH2:35][CH2:36][O:37][CH2:38]Cl)([CH3:34])[CH3:33].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:26])[N:10]3[CH2:17][C@H:16]([O:18][Si:19]([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:20])[CH3:21])[CH2:15][C@H:11]3[C:12](=[O:14])[N:13]([CH2:38][O:37][CH2:36][CH2:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:27][CH3:28]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A solution of 171 (6.50 g, 15.99 mmol) in anhydrous DMF (27.5 mL) was added dropwise to a stirred suspension of NaH (0.422 g, 0.704 g of a 60% dispersion in mineral oil, 18.34 mmol) at 0° C. and the reaction mixture was allowed to stir for 30 minutes. A solution of SEM chloride (3.11 mL, 2.93 g, 17.59 mmol) in anhydrous DMF (5 mL) was added dropwise to the stirred reaction mixture at 0° C. and allowed to stir at room temperature for 16 h. The reaction mixture was poured into water (200 mL) to afford a white precipitate, which was extracted with diethyl ether (4×300 mL). The organic layer was washed with water (2×50 mL), brine (2×50 mL) and dried over anhydrous MgSO4. Filtration and evaporation of the solvent in vacuo afforded the crude product, which was purified by flash column chromatography using an 80:20 mixture of petroleum ether:EtOAc as eluent. Pure fractions were combined and evaporated in vacuo to afford the product (172) as a yellow oil (7.01 g, 13.1 mmol, 82%). 1H NMR (270 MHz, CDCl3) δ 7.35 (s, 1H, ArH), 7.24 (s, 1H, ArH), 5.52 (d, 2H, J=9.89 Hz, SEM amino acetal CH2), 4.65 (d, 2H, J=9.90 Hz, SEM amino acetal CH2), 4.61-4.56 (m, 1H, 2), 4.23 (dd, 1H, J=4.40 Hz, 8.24 Hz, 11a), 3.94 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.68 (m, 4H, SEM 1′ CH, +3), 2.86 (m, 1H, 1), 2.02 (m, 1H, 1), 0.98 (t, 2H, J=8.25 Hz, SEM 2′ CH3), 0.88 (s, 9H, TBDMS t-Bu CH2), 0.10 (s, 6H, 2×TBDMS SiCH3), 0.03 (s, 9H, 3×SEM SiCH3); 1° C. NMR (67.8 MHz, CDCl3) δ 170.0, 165.6, 151.8, 147.1, 133.9, 121.5, 111.2, 105.5, 78.1, 69.6, 67.0, 56.5, 56.2, 56.1, 53.6, 35.5, 25.7, 18.4, −1.3, −4.8.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:21]2[CH2:22][CH2:23][C@@H:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]([F:11])([F:24])[F:25])[CH2:20]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: FC(F)(F)c1ccccc1[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1cccc(Br)n1)N1CC[C@@H](c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
After 6-bromopicolinic acid (430 mg, 2.13 mmol) was suspended in acetonitrile (25 ml), (S)-3-(2-(trifluoromethyl)phenyl)pyrrolidine (503 mg, 2.34 mmol), N,N-diisopropylethylamine (0.56 ml, 3.20 mmol), and HBTU (969 mg, 2.56 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (40% EtOAc/Hexanes), to obtain 765 mg of white solid (90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[C:41](=O)[O:40][C:39]3([CH3:47])[CH3:46])[CH2:30][CH2:29]1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:41]1[C:42]2[C:38](=[CH:37][C:36]([CH2:35][CH2:34][N:31]3[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]3)=[CH:44][CH:43]=2)[C:39]([CH3:47])([CH3:46])[O:40]1
Reactant: CC1(C)OC(=O)c2ccc(CCN3CCC(O)CC3)cc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)OC(=C2C(=O)Nc3ccc(F)cc32)c2ccc(CCN3CCC(O)CC3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
To a stirred solution of 5-fluorooxindole (7.86 g, 52 mmol) in anhydrous THF (60 ml) under nitrogen was added 1.0M LiHMDS/THF solution (104 ml, 104 mmol). The mixture was stirred at room temperature for 15 minutes, and then 5-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-3,3-dimethyl-3H-isobenzofuran-1-one (5.0 g, 17.3 mmol) was added. After stirring at room temperature for 2 hours, the mixture was quenched with 50 ml of 2.5M H2SO4, heated at 65° C. for 30 minutes and poured into 500 ml of water. The mixture was basified with 5M NaOH to about pH=9 and continuously stirred at room temperature for 16 hours. The resulting solids were filtered, rinsed with water, dried under vacuum to give the title compound as a yellow solid (4.74 g, 65%).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[O:4]=[C:2]1[N:20]([CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)[C@@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]2[NH:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N[C@@H]2CCCC[C@H]2N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)N[C@@H]3CCCC[C@H]32)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 141.8 %

Procedure:
A solution of triphosgene (7.2 g, 24.2 mmol) in dichloromethane (300 mL) was added with a solution of tert-butyl 4-{[(1R,2R)-2-aminocyclohexyl]amino}piperidine-1-carboxylate (18 g, 60 mmol) and triethylamine in dichloromethane (600 mL) drop wise over a period of 1 h and stirred at room temperature for 22 h. An additional amount of triphosgene (8 g) and triethylamine (13 mL) were added and stirred at room temperature for another 22 h. An aqueous solution of sodium hydroxide (0.5N 200 mL) was added to the reaction mixture, layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the crude product which was triturated with diethylether (80 mL) to give the title compound as white solid (11.1 g, 56%). 1H NMR (300 MHz, METHANOL-D4): δ ppm 4.25-4.05 (m, 2H), 3.80-3.65 (m, 1H), 3.10-2.90 (m, 2H), 2.85-2.65 (m, 2H), 2.20-1.90 (m, 2H), 1.90-1.55 (m, 4H), 1.55-1.30 (m, 11H)
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]#[C:3][CH3:4].C(N(CC)CC)C.[OH:16]/[N:17]=[C:18](\Cl)/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25]>C(O)C>[CH2:7]([O:6][C:1]([C:2]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[N:17][O:16][C:3]=1[CH3:4])=[O:5])[CH3:8]
Reactant: O/N=C(\Cl)c1ccccc1F
Reactant: CC#CC(=O)OCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccccc2F)noc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.5 %

Procedure:
To a solution of ethyl 2-butynoate (65.5 mL, 562 mmol) and triethylamine (80.7 mL, 576 mmol) in ethanol (600 mL) was added, at 0-4° C. over 2 h, 500 mL of a solution of (E)- and/or (Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride (83.3 g 480 mmol) in ethanol (900 mL). Ethyl 2-butynoate (44.6 ml, 383 mmol) in ethanol (125 mL) was added at 0° C., then the remaining 400 ml of the (E)- and/or (Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride solution were added over a 1 h period. The resulting mixture was then stirred for 48 h at room temperature and evaporated. The mixture was then poured onto HCl (1.2 L), and extracted with tert-butyl methyl ether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 9:1) afforded the title product (73.6 g, 62%) which was obtained as a yellow oil, MS: m/e=250.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=2)[C:10]1=[O:19].[CH2:20]([O:22]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:21]>>[C:20]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=2)[C:10]1=[O:19])(=[O:22])[CH3:21]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc2c(c1)CC(Cc1ccncc1Br)C2=O
Product: CC(=O)c1cnccc1CC1Cc2cc(C)ccc2C1=O

Procedure:
The title compound 114 is prepared according to the procedure reported in Example 36.5 with compound 105 (750 mg, 2.38 mmol) and (1-ethoxyvinyl)tri(n-butyl)stannane (0.8 mL, 238 mmol) as reactants. White solid. (Yield 398.8 mg, 60%).