Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7][CH3:8].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1B1OC(C)(C)C(C)(C)O1)[C:27]#[N:28].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:27]([C:26]1[CH:29]=[CH:30][C:31]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=3)[C:6]=2[O:7][CH3:8])=[C:24]([F:23])[CH:25]=1)#[N:28]
Reactant: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Reactant: CC1(C)OB(c2ccc(C#N)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3F)c2OC)nc1

Procedure:
Combined 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide (60 mg, 0.163 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (120 mg, 0.488 mmol), PdCl2(dppf)-CH2Cl2 adduct (19.91 mg, 0.024 mmol) and sodium bicarbonate (68.3 mg, 0.813 mmol) in dioxane (0.6 mL) and water (0.15 mL) and heated at 110° C. for 1 h in the microwave. The reaction mixture was diluted with EtOAc, concentrated onto Celite®, and purified on a 10 g NH silica gel column eluted with 0 to 80% EtOAc in hexanes to give 6-(4-(4-cyano-2-fluorophenyl)-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide as a white solid. MS m/z 410 [M+H]+.
Reaction SMILES: [S-2:1].[Na+].[Na+].CO.[C:6]([N:10]=[N:11][C:12]1(Cl)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:8])[CH3:7]>O>[C:6]([N:10]=[N:11][C:12]1([S:1][C:12]2([N:11]=[N:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)N=NC1(SC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Temperature: 15 °C
Reaction time: 0.75 h
Yield: 30 %

Procedure:
A solution of 1.56 grams (0.2 moles) of sodium sulfide in 50 ml. of 75% aqueous methanol was prepared in a 200 ml. beaker and cooled to 15°C. To this solution was added 8.2 grams (.0404 moles) of 1-t-butylazo-1-chlorocyclohexane dropwise over a 15 minute period. After the addition was complete, the reaction was stirred for 45 minutes at room temperature and poured into 100 ml. of cold water. A solid formed and was filtered off and dried. The dried material weighed 2.2 grams (30% yield). The infrared spectrum of the product was in agreement with the structure of the desired compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13])[CH:8]=2)[C:3](/[CH:16]=[CH:17]/[C:18]([O:20]C)=[O:19])=[CH:2]1.O.[OH-].[Li+].CO.Cl>O.O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:8]=2)[C:3](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:2]1
Reactant: COC(=O)/C=C/c1ccc2c(/C=C/C(=O)OC)c[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C/c1ccc2c(/C=C/C(=O)O)c[nH]c2c1
Yield: 87.7 %

Procedure:
A mixture of dimethyl E,E-indole-3,6-diacrylate (1.1 g), lithium hydroxide monohydrate (1.29 g), methanol (25 ml), tetrahydrofuran (10 ml) and water (5 ml) was stirred and heated at 55°-60° for 7 hr under an atmosphere of nitrogen. The cooled mixture was diluted with water (30 ml) and acidified to pH 4 with 6M hydrochloride acid. The yellow precipitate was isolated by filtration, washed with water and dried under vacuum to give E,E-indole-3,6-diacrylic acid (0.87 g, 88%) as a solid; mp >360°; partial NMR (250 MHz, DMSO-d6): 6.33(d, J=16.0 Hz, 1H, olefinic H), 6.49(d, J=16.0 Hz, 1H, olefinic H), 11.94(br s, 1H, NH), 12.10(br s, 1H, COOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([NH2:8])=[NH:7].Cl.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24](=O)[CH2:25][C:26]([O:28]CC)=[O:27].[I-].[K+].[OH-].[Na+]>CO.C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[NH:8][CH:23]=[C:24]([CH2:25][C:26]([OH:28])=[O:27])[N:7]=2)[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1cc(C(=N)N)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: COc1cc(-c2nc(CC(=O)O)c[nH]2)ccc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 16 h

Procedure:
7 g (60% purity, 21.519 mmol) 3-methoxy-4-nitro-benzamidine are dissolved in methanol and combined with 11 ml (44 mmol) 4 N dioxanic hydrochloric acid, the solvents are eliminated in vacuo. The residue and 6.13 g (44.384 mmol) potassium carbonate are suspended in 350 ml acetonitrile and combined with 3.24 ml (22.764 mmol) ethyl 4-chloracetoacetate and 880 mg (5.301 mmol) potassium iodide. The reaction mixture is stirred for 16 h at 45° C. The reaction mixture is diluted with water and combined with 1 N sodium hydroxide solution, and extracted with ethyl acetate. The aqueous phase is adjusted to pH 1 with 1 N HCL and saturated with sodium chloride. The product is then suction filtered.
Reaction SMILES: S(=O)(=O)(O)O.[Na].[CH2:7]([N:9]([CH2:16][CH2:17]O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8].[N-:19]=[N+:20]=[N-:21].[Na+]>>[CH2:7]([N:9]([CH2:16][CH2:17][N:19]=[N+:20]=[N-:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CCN(CCO)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [Na]
Product: CCN(CCN=[N+]=[N-])c1ccccc1

Procedure:
The coupling component of Example 25 was prepared by reaction of the sulphuric acid semi-ester (or its sodium salt) of N-ethyl-N-β-hydroxyethyl-aniline with sodium azide to form N-ethyl-N-β-azido-ethylaniline in a two-phase aqueous organic solvent system, for example in water/chlorobenzene, and reaction of the azido compound thus obtained with acetylene.
Reaction SMILES: C(O)(=O)C.[F:5][C@@H:6]1[C@H:11]([NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:10][CH2:9][C@@H:8]([C:21]([OH:23])=O)[CH2:7]1.C(=O)(O)[O-].[NH4+].O[N:30]1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[F:5][C@@H:6]1[C@H:11]([NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:10][CH2:9][C@@H:8]([C:21]([NH2:30])=[O:23])[CH2:7]1
Reactant: C[C@@H](N[C@@H]1CC[C@@H](C(=O)O)C[C@@H]1F)c1ccccc1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[C@@H](N[C@@H]1CC[C@@H](C(N)=O)C[C@@H]1F)c1ccccc1

Procedure:
A solution of (d) (75 mg) in DMF (2 mL) was treated with ammonium bicarbonate (80 mg), 1-hydroxy-7-azabenzotriazole (57 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg). After 2.5 hours the reaction mixture was evaporated and the residue partitioned between ethyl acetate/dilute brine. The organic extract was dried and evaporated. The residue was chromatographed eluting with 2-8% methanol/dichloromethane affording a white solid (52 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1

Procedure:
In analogy to the procedure described in example 409f, (2S,4R)-4-methanesulfonyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (example 409c) was reacted with trifluoroacetic acid to give the title compound as brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:11][C@@H:10]([N:12]=[N+]=[N-])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N=[N+]=[N-])C1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N)C1
Reaction time: 18 h

Procedure:
A mixture of tert-butyl(cis-3-azidocyclobutyl)carbamate (7.0 g, 33.0 mmol) and palladium 10% on activated carbon (3.51 ml, 33.0 mmol, Sigma-Aldrich Chemical Company, Inc.) in three necked 1000 mL flask was flushed with N2 and closed tightly and 2M ammonia in methanol solution (200 mL) was added. The flask was evacuated and a balloon filled with hydrogen was introduced. The mixture was stirred for 18 h, filtered, and the filtrate was evaporated under reduced pressure to give the title compound, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(phenyloxy)phenyl)methyl)propionate (5.26 g, 13.3 mmol) in methanol (40 ml) was added 2N aqueous sodium hydroxide solution (13.4 ml, 26.8 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated-brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(phenyloxy)phenyl)methyl)propionic acid (2.31 g, 47%).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:17])[C:10](=[CH2:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][NH2:19]>CO>[Si:1]([O:8][C@H:9]([CH3:17])[C@H:10]([CH2:16][NH:19][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=C(C(=O)OCC)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CN
Solvent: CO
Product: CCOC(=O)[C@@H](CNC)[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl (3R)-3-t-butyldimethylsilyloxy-2-methylidenebutanoate (130 g) in methanol (1.3 l) was added a solution of 30% methylamine in methanol (63 ml). The resulting mixture was allowed to stir at ambient temperature for 2 days. Evaporation of the solvent gave ethyl (2S,3R)-3-t-butyldimethylsilyloxy-2-(methylaminomethyl)butanoate (150.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6]C(=O)[O:8][C:9](=O)[C:4]=2[CH:3]=1.[NH4+:14].[OH-]>>[NH2:6][C:5]1[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=1[C:9]([NH2:14])=[O:8]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-Bromo-1H-benzo[d][1,3]oxazine-2,4-dione (56.0 g, 230 mmol) was suspended in 1 N aq. NH4OH (600 mL, 2.6 equivalents), and the suspension was stirred 3 d at room temperature. After filtration, the collected solid was washed with water and subsequently dissolved in tetrahydrofuran. This solution was filtered, evaporated to dryness, and dried by repeated azeotropic distillation with toluene. The solid was suspended in CH2Cl2, filtered, and washed once with CH2Cl2 yielding 35.4 g (71.2%) of 2-amino-5-bromo-benzamide.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[CH3:25][C@H:26]([NH2:29])[CH2:27][OH:28]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:29][C@@H:26]([CH3:25])[CH2:27][OH:28])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Reactant: C[C@H](N)CO
Product: C[C@@H](CO)NC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 59 %

Procedure:
As described for example 325, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (60 mg, 0.18 mmol) was converted, using S-(+)-2-amino-1-propanol instead of rac-2-amino-1-propanol, to the title compound (28 mg, 59%) which was obtained as a white solid MS: m/e=370.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O.C(OCC)(=O)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Product: Nc1ccccc1Oc1ccc(Cl)cc1Cl
Yield: 99 %

Procedure:
To a stirred solution of 2,4-dichloro-1-(2-nitro-phenoxy)-benzene (3.5 g, 12.32 mmol) in ethyl acetate (60 mL) stannous chloride dihydrate (13.89 g, 61.6 mmol) was added and the mixture was refluxed for 2 h before it was quenched with saturated sodium hydrogencarbonate solution (192 mL). The organic phase was separated and the aqueous phase was washed several times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to yield 3.1 g (99%) of the title compound as a yellowish oil: MS (EI) 255.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4](=[P:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)C(CC(=O)OC(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (triphenylphosphanylidene)-acetic acid methyl ester (2.26 g, 6.77 mmol) in methylene chloride (25 mL) is added t-butyl bromoacetate (1.32 g, 6.77 mmol) and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure and the residue is purified by column chromatography using a gradient of 80-100% heptane/EtOAc to afford 2-(triphenylphosphanylidene)-succinic acid 4-tert-butyl ester 1-methyl ester. MS 449.3 (M+1).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:28]([CH3:34])([CH3:33])[CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CC(C)(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)(C)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (85 mg, 80%), MS (ISP) m/z=427.5 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 3,3-dimethyl-butyric acid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([CH2:15][O:16][CH2:17][CH:18]=[CH2:19])([CH2:13][CH3:14])[CH2:7][O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:2]=[CH2:3].[CH2:20]([O:22][SiH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH3:21]>>[CH2:20]([O:22][Si:23]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[CH2:3][CH2:2][CH2:1][O:4][CH2:5][C:6]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][Si:23]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[O:22][CH2:20][CH3:21])([CH2:13][CH3:14])[CH2:7][O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH3:21]
Reactant: C=CCOCC(CC)(COCC=C)CO[Si](C)(C)C
Reactant: CCO[SiH](OCC)OCC
Product: CCO[Si](CCCOCC(CC)(COCCC[Si](OCC)(OCC)OCC)CO[Si](C)(C)C)(OCC)OCC
Temperature: 80 °C

Procedure:
A 1-liter, 3-neck flask equipped with magnetic stirrer, pot thermometer, addition funnel and condenser was charged with 143.2 g of 2,2-Bis(allyloxymethyl)-1-trimethylsiloxybutane. After heating to ˜80° C., 35 g of triethoxysilane was added followed by 1 ml of Karstedt catalyst containing 2% Pt. Once initiation was observed, the balance of triethoxysilane (133.4 g) was added at a rate to maintain temperature at 80-110° C. When the addition was complete, an additional 0.5 ml of Karstedt catalyst was added and temperature of 90° C. was maintained for 2 hours. A GC indicated the reaction was not complete. Two additional portions 43 g of triethoxysilane and 0.5 g of Karstedt were added, maintaining the temperature at 95-105° C. The product was purified by means of a wiped-film evaporator, removing volatiles on a first pass and then distilling crude product on a second pass. A short-path distillation produced purified product: b.p.: 200-205° C. at 0.8 mm; density: 0.980; 1HNMR(C6D6): 0.13(s, 9H), 0.77(m, 4H), 1.00(m, 3H), 1.14(t, 18H), 1.18(m, 2H), 1.85(m, 4H) 3.38(dd, 8H), 3.76(s, 2H), 3.81(q, 12H). The FTIR showed a strong absorption at 1105.1 cm−1, which is characteristic of Si—O.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].C(OC(=O)CCOCCOCCOCCOS(S(C1C=CC(C)=CC=1)(=O)=O)(=O)=O)(C)(C)C.[C:37]([O:41][C:42](=[O:57])[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][N:54]=[N+]=[N-])([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C.O.CCOC(C)=O.[Pd]>[C:37]([O:41][C:42](=[O:57])[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][NH2:54])([CH3:38])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN=[N+]=[N-]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)S(=O)(=O)OCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCN
Reaction time: 8 h

Procedure:
NaN3 (35 g, 538 mmol) was added to a stirring solution of 3-{2-[2-(2-tosylsulfonyloxy-ethoxy)-ethoxy]-ethoxy}-propionic acid tert-butyl ester (20 g, 46 mmol) in DMF (150 mL) and the reaction was stirred overnight. Reaction was diluted with water (200 mL) and extracted with EtOAc (4×100 mL). The organic layer was washed with water (100 mL) and brine (100 mL) and dried over Na2SO4. The solvent was removed in vacuo to give an oil. Column chromatography EtOAc/Hex (1:4) gave an oil which corresponds to the 3-{2-[2-(2-azido-ethoxy)-ethoxy]-ethoxy}-propionic acid tert-butyl ester, (M+1)=304. This oil was hydrogenated using Pd (5% on carbon) in EtOAc under hydrogen (1 atm.) over 3 days. The catalyst was removed by filtration and solvent removed in vacuo to give an oil corresponding to the title compound, (M+1) 278.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCCCC1.ClC(OCC)=O.Cl.[CH3:31][NH:32][O:33][CH3:34]>ClCCl>[CH3:34][O:33][N:32]([CH3:31])[C:14]([C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][CH2:11][CH2:12][CH3:13])=[O:16]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Temperature: -40 °C
Reaction time: 2.5 h
Yield: 106.3 %

Procedure:
To a stirred solution of 27.8 g (120.0 mmol) of N-Boc-L-Norleucine in 150 mL of dichloromethane at −40° C. was added a solution of 18.4 mL (151.5 mmol) of 1-methylpiperidine in 40 mL of dichloromethane over 20 min. Then, 13.9 mL (145.4 mmol) of ethyl chloroformate in 40 mL of dichloromethane was added over 30 min and the reaction mixture was stirred at −40° C. for 2.5 h. A solution of 14.2 g (145.4 mmol) of N,O-dimethylhydroxylamine hydrochloride and 18.4 mL (151.5 mmol) of 1-methylpiperidine in 90 mL of dichloromethane was added over 45 min, then the reaction mixture was allowed to slowly warm to room temperature and was stirred for 18 h. It was then washed with 100 mL of water, 100 mL of 1% hydrochloric acid (2×), 100 mL of saturated aqueous sodium bicarbonate, and dried over anhydrous magnesium sulfate. Concentration in vacuo afforded 35.0 g (quantitative yield) of crude tert-butyl (1S)-1-{[methoxy(methyl)amino]carbonyl}pentylcarbamate as a thick oil. 1H-NMR (400 MHz, DMSO-d6): δ 6.94 (d, J=8 Hz, 1H), 4.35–4.25 (m, 1H), 3.68 (s, 3H), 3.05 (s, 3H), 1.52–1.36 (m, 2H), 1.32 (s, 9H), 1.30–1.14 (m, 4H), 0.80 (t, J=6 Hz, 3H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([O:16][CH2:17][CH2:18][OH:19])(=[O:15])[CH:13]=[CH2:14]>C(N(CC)CC)C>[C:12]([O:16][CH2:17][CH2:18][O:19][C:4](=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11])(=[O:15])[CH:13]=[CH2:14]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C=CC(=O)OCCO
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCOC(=O)c1ccccc1C(=O)O
Temperature: 75 °C
Reaction time: 6 h

Procedure:
Phthalic anhydride (112.1 grams), 2-hydroxyethyl acrylate (87.9 grams), and triethylamine (0.44 grams) were mixed in a round bottom flask. A small amount of dry air was bubbled into the liquid reaction mixture. The reaction mixture was mixed and heated to 75° C. and held at that temperature for six hours. The product was cooled to room temperature. NMR was used to confirm that the product was phthalic acid mono-(2-acryloyloxy-ethyl)ester. The product partially crystallized over time. The product was mixed with 1-methoxy-2-propanol to obtain a 50 weight percent solution.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH:24]=[CH2:25])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])C.Br[O-].[Na+].[OH-].[Na+].BrBr.S([O-])([O-])(=[O:35])=S.[Na+].[Na+].Cl>O.O1CCOCC1>[CH2:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:10]1[CH:9]=[CH:8][C:13]2[C:14]3[C:6](=[CH:5][C:4]([C:1]([OH:35])=[O:3])=[CH:16][CH:15]=3)[CH2:7][C:12]=2[CH:11]=1)[CH:24]=[CH2:25]
Reactant: O=S([O-])([O-])=S
Reactant: C=CCOCCCCOc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCOCCCCOc1ccc2c(c1)Cc1cc(C(=O)O)ccc1-2
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A dioxane (380 ml) solution of 2-acetyl-7-(4-allyloxybutyloxy)fluorene 22 g was cooled to 8° C. Sodium hypobromite prepared from water 209 ml, sodium hydroxide 42.7 g and bromine 15.2 ml was dropwise added thereto, and after finishing dropwise adding, the solution was stirred at 40° C. for 15 minutes. The reaction mixture was cooled to 10° C., and then a saturated sodium thiosulfate aqueous solution was added thereto. A solid matter deposited by acidifying the solution with hydrochloric acid was filtered and then dried. The solid matter was recrystallized from acetic acid to obtain 15 g of 2-(4-allyloxybutyloxy)fluorene-7-carboxylic acid. Phase transition temperature: C164N222I.