Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1ccccc1Br
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1OCC1CCCCC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
5.00 ml of 2-bromophenol was dissolved in 90 ml of N,N-dimethylformamide, 7.21 ml of (bromomethyl)cyclohexane and 7.15 g of potassium carbonate were added thereto, and the mixture was stirred at 100° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with n-hexane. The organic layer was washed with water, 5N-sodium hydroxide and brine, and then dried over anhydrous magnesium sulfate. The mixture was filtered through alumina, and the solvent was evaporated, to give 10.47 g of the title compound as a slight yellow oil.
Reaction SMILES: [CH:1](=[N:8][NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[C:12]([Cl:33])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][CH:36]([O:41][CH3:42])[CH2:37][N:38]=[C:39]=[O:40]>C(#N)C>[CH:1](=[N:8][N:9]([C:10]1[CH:11]=[C:12]([Cl:33])[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[CH:20][CH:19]=2)=[C:14]([Cl:16])[CH:15]=1)[C:39]([NH:38][CH2:37][CH:36]([O:41][CH3:42])[O:35][CH3:34])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN=C=O)OC
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cc2c(Cl)cc(NN=Cc3ccccc3)cc2Cl)cc1
Solvent: CC#N
Product: COC(CNC(=O)N(N=Cc1ccccc1)c1cc(Cl)c(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1)OC
Yield: 75 %

Procedure:
In 15 ml of acetonitrile was suspended 1.00 g of 1-benzylidene-2-{4-[4-(4-chlorobenzoyl)benzyl]-3,5-dichlorophenyl}hydrazine, and 0.40 g of 2,2-dimethoxyethyl isocyanate was added, and then 15 ml of DBU(1,8-diazabicyclo[5.4.0]undec-7-ene) was added. The mixture was reacted at 20 to 25° C. for 1 hour, and precipitated crystals were collected by filtration to give the above-identified compound as colorless crystals (yield: 75%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20](=[O:22])[N:21]=3)[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][S:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20](=[O:22])[N:21]=3)[CH:13]=[CH:12][CH:11]=2)=[O:35])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1nc(-c2cccc(SCCc3ccccc3)n2)sc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=c1nc(-c2cccc(S(=O)CCc3ccccc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
2-[6-(Phenylethylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.18 g, 0.48 mmol) was dissolved in chloroform (30 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.11 g, 0.48 mmol) in chloroform (10 ml) was added dropwise thereto. The reaction mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.14 g, 75%) as pale yellow crystals.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[C:21]([C:22]#[C:23][Si](C)(C)C)=[CH:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:22]([C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:12][CH:11]=3)[N:14]=2)[NH:19][CH:20]=1)#[CH:23]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#C[Si](C)(C)C)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1c[nH]c2ncc(-c3ccc(S(=O)(=O)C(C)C)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.9 %

Procedure:
2-[2-(4-Isopropylsulfonylphenyl)-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazin-7-yl]ethynyl-trimethyl-silane (248 mg, 0.4495 mmol) in THF (5 mL) was treated with 1M tetrabutylammonium fluoride trihydrate (674.3 μL, 0.6743 mmol) and the reaction mixture allowed to stir at ambient temperature for 16 hours. A further portion of 1M tetrabutylammonium fluoride trihydrate (449.5 μL, 0.4495 mmol) was added and the reaction mixture warmed to 40° C. for 6 hours. The reaction was cooled to ambient temperature and added dropwise to a mixture of EtOAc/ice water and the layers separated. The organic layer was washed with 2M NaOH (×2), brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column silica gel chromatography eluting with 15-20% EtOAc/DCM to give the sub-title compound as colourless crystals (89 mg, 61% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.20 (d, 6H), 3.40-3.50 (m, 1H), 4.20 (s, 1H), 8.00 (d, 2H), 8.33 (s, 1H), 8.44 (d, 2H), 9.06 (s, 1H) and 12.70 (s, 1H) ppm; MS (ES+) 326.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>[OH-].[Na+].CC(C)=O.O>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
7.6 g 4-Aminophenylacetic acid are dissolved in 50 ml 2 N aqueous sodium hydroxide solution and 50 ml acetone. A solution of 8.8 g 4-chlorobenzoyl chloride in 10 ml acetone is added dropwise thereto at 0° C. The reaction mixture is further stirred for 3 hours at ambient temperature, then diluted with water, filtered and the filtrate acidified with dilute hydrochloric acid. The precipitate obtained is reprecipitated via its sodium salt and recrystallized from ethanol. There are obtained 4.2 g (29% of theory) 4-(4-chlorobenzamido)-phenylacetic acid; m.p. 252° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C@H:18]([CH3:29])[C:19]([O:21]CC2C=CC=CC=2)=[O:20])(=[O:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO>[CH2:1]([C@@:18]([CH3:29])([CH2:17][S:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])[C:19]([OH:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](CS(=O)(=O)N1CCN(Cc2ccccc2)CC1)C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C[C@](Cc1ccccc1)(CS(=O)(=O)N1CCN(Cc2ccccc2)CC1)C(=O)O
Reaction time: 2 h
Yield: 36.7 %

Procedure:
A 100 mL round bottom flask equipped with magnetic stirring bar and N2 inlet was charged with 3.0 g benzyl 3-(4-benzylpiperizin-1-ylsulfonyl)-2(R)-methylpropionate, 1.2 g LiOH (4 eq.) in 20 mL 50% aqueous methanol. After 2 hours HPLC analysis showed no starting material. The reaction was concentrated to half volume and partitioned between Et2O and H2O. The aqueous layer was acidified to pH 5 and extracted with 2×75 mL ethyl acetate. The combined organics were dried, and concentrated in vacuo to yield 550 mg (25%) white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])[C@:20]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])([C:30]#[N:31])[C@H:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]2)=[O:16])[CH2:10][CH2:9]1.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(N(CC)CC)C>C(Cl)Cl>[C:45]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])[C:20]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])([C:30]#[N:31])[CH:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]2)=[O:16])[CH2:12][CH2:13]1)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCNCC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NC2CCN(C(=O)c3ccccc3)CC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), benzoyl chloride (21 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the mixture was stirred at rt for 1 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crude which was chromatographed on an ISCO machine (0-10% EtOAc/CH2Cl2) to give a white solid. 36 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OB(O)c1ccncc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a 25 mL round bottom flask is added 1-bromo-4-nitrobenzene (404 mg, 2.0 mmol), 4-pyridinylboronic acid (248 mg, 2.0 mmol), Na2CO3 (424 mg, 4.0 mmol) and Pd(PPh3)4 (100 mg, 0.087 mmol), DME (10 mL) and H2O (3 mL). The mixture is degassed and heated at reflux for 14 h. TLC is used to establish the completion of starting bromide, the mixture is allowed to cool to room temperature. EtOAc is added, and the EtOAc layer is washed with H2O (15 mL) and brine (10 mL) and dried over MgSO4. After removal of EtOAc, the resulting residue is subjected to flash chromatography with CH2Cl2/EtOAc (3:1) as eluent to provide the coupling product 4-(4-nitro-phenyl)-pyridine (288 mg, 72%). 1H NMR (400 MHz, CDCl3) ∂ 8.75 (2H, dd, J=6.0 and 2.8 Hz), 8.36 (2H, dd, J=9.6 and 3.2 Hz), 7.80 (2H, dd, J=8.8 and 2.4 Hz), 7.54 (2H, dd, J=5.6 and 2.0 Hz).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:15])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:2]1[N:3]=[CH:4][C:5]([NH2:15])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1
Reactant: Nc1cnc(Br)c(-c2cccc(F)c2)n1
Reactant: OB(O)c1ccncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Nc1cnc(-c2ccncc2Cl)c(-c2cccc(F)c2)n1
Temperature: 150 °C
Yield: 25.2 %

Procedure:
A microwave oven reactor was charged with 5-bromo-6-(3-fluorophenyl)pyrazin-2-amine (Preparation 1, 0.3 g, 1.11 mmol), (3-chloropyridin-4-yl)boronic acid (212 mg, 1.03 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (1:1) (39 mg, 0.047 mmol), dioxane (8 mL) and a 1.2M aqueous solution of cesium carbonate was added (1.9 mL, 2.39 mmol). The mixture was heated to 150° C. for 10 min in the microwave oven, then cooled, partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. Flash chromatography (dichloromethane to dichloromethane/methanol 90:10) furnished the title compound as a yellowish solid (78 mg, 39%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1.[CH:16](=O)[CH2:17][CH2:18][CH3:19]>>[CH2:16]([N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCC=O
Reactant: O=C1Nc2ccccc2C12CCCNC2
Product: CCCCN1CCCC2(C1)C(=O)Nc1ccccc12

Procedure:
The compound was prepared according to PROCEDURE 1, Method A by reaction with spiro[indoline-3,3′-piperidin]-2-one and butyraldehyde (10 equiv.). 13C NMR (CDCl3): δ 14.1, 20.6, 21.7, 29.1, 32.0, 49.0, 53.8, 58.5, 58.9, 109.9, 121.9, 126.4, 127.6, 134.9, 140.2, 182.4; MS (TSP): m/z (rel. int.) 260/259 (M+, 25/100).
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:3]=1[OH:4].[CH2:11]([OH:13])C.C=O>Cl.O>[CH3:1][C:2]1([CH:11]=[O:13])[C:8]([OH:9])=[CH:7][C:6]([CH3:10])=[CH:5][CH:3]1[OH:4]
Reactant: CCO
Reactant: Cc1cc(O)c(C)c(O)c1
Agent: C=O
Agent: Cl
Solvent: O
Product: CC1=CC(O)C(C)(C=O)C(O)=C1

Procedure:
To a solution of 691 g. of 2,5-dimethylresorcinol in 1 l. of ethanol were added 348 g. of a 37% aqueous solution of formaldehyde and 0.5 ml. of 35% conc. hydrochloric acid as a catalyst. The resulting mixture was heated in the same manner as in the Synthesis example 1 and poured into 5 l. of a cold water to give a pale brown powdery resin.
Reaction SMILES: [H-].[Na+].CS(C)=O.[CH2:7]([OH:9])[CH3:8].Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH2:22][NH:23][CH:24]([CH3:26])[CH3:25])(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[ClH:11].[CH2:7]([O:9][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH2:22][NH:23][CH:24]([CH3:26])[CH3:25])(=[O:19])=[O:20])=[CH:14][CH:13]=1)[CH3:8]
Reactant: CCO
Reactant: CC(C)NCCS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOc1ccc(S(=O)(=O)CCNC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6.6 g of a 60% dispersion of sodium hydride in oil (0.165 mole) in 300 mole of dimethyl sulfoxide was added 7.5 g (0.163 mole) of absolute ethanol. The mixture was stirred at room temperature for 0.5 hr, and 20.8 g (0.080 mole) of N-[2-(4-chlorophenylsulfonyl)ethyl]-2-propanamine hydrochloride (obtained in Preparation 23) was added as a solid. The mixture was heated at 120°-140° C. for 1 hr, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent removed in vacuo. The residue was dissolved in methanol, an excess of ethereal hydrogen chloride was added, and ether was added. A white solid precipitated in amount of 14.92 g (69.2%), m.p. 168°-170° C.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:7][C:6]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:5][C:4]=1[S:12][CH3:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:13][S:12][C:4]1[CH:5]=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[S:7][CH:3]=1
Reactant: CSc1cc(S(N)(=O)=O)sc1[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1csc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a solution of 5-trimethylsilyl-4-methylsulfanylthiophene-2-sulfonamide (660 mg, 2.34 mmol) in THF (10 mL) is added a solution of tetra-butylammonium fluoride (14.0 mL of 1 M in THF, 14.0 mmol). The reaction mixture is stirred at room temperature for 3 hr. The THF is removed under reduced pressure and the residue is dissolved in EtOAc (200 mL). The organic layer is washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The crude product is chromatographed on silica gel, eluting with Hex:EtOAc (2:1) to afford the title compound (400 mg, 82%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[CH2:10]([O:13][CH:14]([CH3:19])[C:15]([O:17]C)=O)[CH:11]=[CH2:12].O>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:15](=[O:17])[CH:14]([O:13][CH2:10][CH:11]=[CH2:12])[CH3:19]
Reactant: C=CCOC(C)C(=O)OC
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C=CCOC(C)C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of N-methyl-O-methyl hydroxylamine hydrochloride (10.0 g, 104 mmol, 2 equiv) in dichloromethane (100 mL) was treated with trimethylaluminum (52.0 mL, 104 mmol, 2 equiv) at 0° C. After stirring for 1 hour at 0° C., a dichloromethane (50 mL) solution of (±)-methyl 2-(prop-2-en-1-yloxy)propanoate (7.50 g, 52.0 mmol) was added over 15 minutes. The mixture was warmed to ambient temperature and stirred for an additional 14 hours. The mixture was treated with water (500 mL) and extracted with dichloromethane (2×300 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo to provide the titled compound.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH3:57])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:56])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@H:26]2[C@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[F:38])[C@:29]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[F:48])([C:39]#[N:40])[C@H:28]([CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[NH:27]2)=[O:25])=[C:19]([O:54][CH3:55])[CH:18]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:9]([CH3:57])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:56])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@H:26]2[C@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[F:38])[C@:29]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[F:48])([C:39]#[N:40])[C@H:28]([CH2:49][C:50]([CH3:52])([CH3:53])[CH3:51])[NH:27]2)=[O:25])=[C:19]([O:54][CH3:55])[CH:18]=1)=[O:11]
Reactant: COc1cc(C(=O)OCCOC(=O)[C@@H](C)NC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)OCCOC(=O)[C@@H](C)N)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 4, chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-((R)-2-tert-butoxycarbonylamino-propionyloxy)-ethyl ester (Example 5, 112 mg, 0.135 mmol) in methylene chloride (2 mL) was treated with trifluoroacetic acid (2 mL) to give chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-((R)-2-amino-propionyloxy)-ethyl ester as a white solid. MS (ES+) m/z calcd. for C36H39Cl2F2N4O6 [(M+H)+]: 731. found: 731.
Reaction SMILES: [OH:1][CH:2]1[C:7]2([C:12](=O)[NH:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][N:5]([CH3:14])[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[H][H].[OH-].[Na+]>O1CCCC1.O>[CH3:14][N:5]1[CH2:4][CH2:3][CH:2]([OH:1])[C:7]2([CH2:8][CH2:9][CH2:10][NH:11][CH2:12]2)[CH2:6]1
Reactant: CN1CCC(O)C2(CCCNC2=O)C1
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(O)C2(CCCNC2)C1
Temperature: 25 °C

Procedure:
Of the 11-hydroxy-8-methyl-2,8-diaza-spiro[5.5]undecan-1-one obtained, 2 g are taken up in 20 ml of absolute tetrahydrofuran; this solution is added dropwise, with stirring, to 1 g of LiAlH4 in 50 ml of absolute tetrahydrofuran. The temperature rises to 36° C., while hydrogen is given off in copious amounts. After another 3 hours at ambient temperature the mixture is refluxed for 10 hours. The reaction is stopped by the addition of 2 ml of water and 2 ml 1N aqueous sodium hydroxide solution while cooling with ice. The product is extracted with ethyl acetate and the solvent is eliminated in vacuo. Then the amine is precipitated from absolute ethanol with HCl gas, in the form of the hydrochloride. Yield 1.44 g.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].Cl(O)(=O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:32][C:33]([CH3:35])=O>>[NH2:20][C:4]1[N:3]=[C:2]([I:1])[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]2[C@H:12]([O:13][C:33]([CH3:35])([CH3:32])[O:11]2)[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: CC(C)=O
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(N)nc(I)nc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 93 %

Procedure:
To a suspension of 2-iodoadenosine 1 (10.0 g, 25.4 mmol) in acetone (200 ml) cooled to 0° C. was added dropwise 70% perchloric acid (4.0 mL), resulting in an exotherm of about 5° C. The resultant colorless solution was allowed to warm to room temperature over 30 minutes, then stirred for a further 45 minutes. 1M Na2CO3 (50 mL) was added, resulting in solids precipitating. This was followed by the careful portionwise addition of water (300 mL) with stirring until all solids had dissolved. The mixture was extracted with three portions of CH2Cl2. The combined organics were washed with brine, dried (Na2SO4), filtered, and evaporated to afford Compound 2 (10.26 g, 93%) as a colorless solid. 1H-NMR (600 MHz, DMSO d6): 1.32 (s, 3H), 1.54 (s, 3H), 3.54 (m, 2H), 4.19 (m, 1H), 4.93 (dd, 1H), 5.05 (t, 1H), 5.27 (dd, 1H), 6.05 (d, 1H), 7.74 (bs, 2H), 8.28 (s, 1H); 13C-NMR (150 MHz, DMSO d6): 25.45, 27.08, 85.69, 86.09, 88.44, 92.59, 114.92, 120.39, 142.47, 151.08, 157.20, 173.14. LRMS (ES): m/z=434.0 (M+H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:14]([N:17]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22](Br)=[C:21]([O:26][CH2:27][CH3:28])[CH:20]=1)([CH3:16])[CH3:15].Cl>N1C(C)=CC(C)=CC=1C>[CH:30]1([N:17]([CH:14]([CH3:15])[CH3:16])[C:18](=[O:29])[C:19]2[CH:24]=[CH:23][C:22]([O:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:21]([O:26][CH2:27][CH3:28])[CH:20]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCOc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Br
Reactant: COc1cc(O)cc(OC)c1OC
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Oc1cc(OC)c(OC)c(OC)c1
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and 4-bromo-3-ethoxybenzoic acid N-isopropyl-N-cyclohexyl amide (1.47 g, 4.0 mmol) in 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound.