Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:12][C:13]([CH3:15])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:13]([CH3:15])[CH3:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To ethylpiperidine-4-carboxylate (1 eq) in methanol was added acetone (1 eq) and acetic acid (5%) and the resulting mixture was stirred for 2 h at ambient temperature. To it was then added sodium cyanoborohydride (1 eq) and continued stirring for 16 h. The mixture was then concentrated and to it was added sodium bicarbonate and was partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate and concentrated to yield ethyl-1-(methylethyl)piperidine-4-carboxylate. To this was then added concentrated hydrochloric acid and water (2:1) and the mixture was refluxed for 5 h. The resulting 1-(methylethyl)piperidine-4-carboxylic acid was then azeotroped with toluene. MS: MH+=172.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C.C(OCC)C>O1CCCC1>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[CH:4]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(Br)c(F)cc1Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)OB(c2cc(F)c(Cl)cc2F)OC1(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
1-Bromo-4-chloro-2,5-difluorobenzene (1.11 g, 4.9 mmol) was dissolved in tetrahydrofuran (THF; 15 mL) and cooled to −10° C. A 2.0M solution of isopropyl-magnesium chloride (2.7 mL, 5.4 mmol) in THF was added dropwise via a syringe. The reaction mixture was stirred at −10° C. for 1 hour, allowed to warm toward 0° C. for 1 hour, then cooled to −10° C. again. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 5.4 mmol) in THF (1.0 mL) was then added dropwise and the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to diethyl ether and extracted with 1N sodium hydroxide twice. The aqueous phases were combined, acidified to pH 3 with concentrated HCl, and extracted with dichloromethane twice. The organic phases were combined, dried, filtered and concentrated to give the title compound (0.97 g, 72.3% yield) that was used without further purification: 1H NMR (CDCl3): δ 7.45 (dd, 1H), 7.09 dd, 1H), 1.36 (s, 12H).
Reaction SMILES: [OH:1][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:3].[C:22](O)([CH3:25])([CH3:24])[CH3:23].C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[C:22]([O:3][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[O:1])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CCC(C[PH](=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CCC(C[PH](=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of di-tert-butyl 2-[(hydroxyphosphinyl)methyl]pentane-1,5-dioate (315 g, 0.977 mol) in dichloromethane (1000 ml) cooled in an ice bath and under nitrogen were added tert-butanol (123.1 g, 1.66 mol), 4-dimethylaminopyridine (1 g, 8.2 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (281 g, 1.47 mol) . The reaction was allowed to stir overnight. Water was added to the reaction mixture and the dichloromethane layer was retained and dried, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography and the desired product was eluted with 1:1 to 2:3 hexane/ethyl acetate. The fractions containing product were concentrated under reduced pressure leaving a clear oil (260 g, 70%). 1H NMR (CDCl3): δ 1.4 (m, 27H) , 1.8 (m, 1H), 1.9 (m, 2H) 2.1 (m, 1H), 2.3 (m, 2H), 2.7-2.8 (m, 1H), 6.7 & 8.0 (d, 1H, the P-H).
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][OH:23].C(=O)(O)[O-].[Na+]>O.CC(C)=O>[C:2]1([CH2:1][O:8][C:9]([NH:19][C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][OH:23])=[O:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCO)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (23.57 g., 94.58 mmol.) was added to a solution of L-homoserine (10.24 g., 85.98 mmol.) and sodium bicarbonate (7.95 g., 94.58 mmol., 1.1 eq.) in a mixture of water (100 ml.) and acetone (100 ml.). The mixture was stirred at room temperature overnight. The acetone was removed under reduced pressure (rotovap) and the aqueous solution was washed with methylene chloride (2×75 ml.). The aqueous layer was then acidified to pH 2 by addition of 6N hydrochloric acid and extracted with ethyl acetate (2×250 ml.). The combined ethyl acetate layers were washed with water (2×100 ml.) and brine, dried over sodium sulfate, filtered, concentrated and dried in vacuo to afford 19.54 g. of title product as a white solid. TLC (ethyl acetate:n-butanol:acetic acid:water; 2:1:1:1) Rf =0.74
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:32])[N:11]([CH2:15][C:16](=[O:31])[N:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd].[Fe+3]>[OH:8][C:9]1[C:10](=[O:32])[N:11]([CH2:15][C:16](=[O:31])[N:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cn1cccc(OCc2ccccc2)c1=O)N(Cc1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Fe+3]
Agent: [Pd]
Solvent: CCO
Product: O=C(Cn1cccc(O)c1=O)N(Cc1ccccc1)c1ccccc1
Yield: 22 %

Procedure:
18 (280 mg, 0.7 mmol) was suspended in 150 mL of EtOH. 10% (w/w, 38 mg) of 10% Pd/C catalyst was added to the hydrogenation flask (500 mL Pyrex® Parr reaction bottle tested to 120 psi, max. working pressure of 60 psi). The Parr hydrogenation system located in the VanNieuwenhze lab was used for the deprotection reactions. The hydrogen pressure was set to 35 psi with agitation, and the process went on for 19 h. A white precipitate was present even after the reaction was stopped, but this white product reacted with iron(III) to give a pink product instead of no reaction as with the protected starting material. The catalyst was removed by vacuum filtration and separated from the product by dissolving the white precipitate in 100 mL hot CH2Cl2. An additional batch of product was isolated by cooling the EtOH filtrate to 0° C. for 2 h. The clear solution was concentrated by rotary evaporation to yield a white solid. The solid was washed with MeOH to remove residual DCU. Yield: 22%. 1H NMR (d6-DMSO, 400 MHz, 25° C.): δ 4.34 (d, J=6.0 Hz, 2H, —CH2—), 4.63 (s, 2H, —CH2—), 6.08 (t, J=7.2 Hz, 1H, Ar—H), 6.69 (d, J=7.2 Hz, 1H, Ar—H), 7.10 (d, J=6.4 Hz, 1H, Ar—H), 7.44 (m, 5H, Bz-H), 7.64 (m, 4H, Phenyl-H), 8.70 (t, J=5.6 Hz, 1H, —NH—), 9.02 (s, 1H, —OH). APCI-MS: m/z 334.9 [M+H]+. Anal. Calcd for C20H18N2O3: C, 71.84; H, 5.43; N, 8.38. Found: C, 71.49; H, 5.78; N, 8.52.
Reaction SMILES: [ClH:1].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[S:14]([O-:18])([O-:17])(=[O:16])=[O:15].[K+:19].[K+]>O>[Cl-:1].[K+:19].[S:14]([OH:18])([OH:17])(=[O:16])=[O:15].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5]
Reactant: O=S(=O)([O-])[O-]
Reactant: Cl
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [K+]
Solvent: O
Product: O=S(=O)(O)O
Product: [Cl-]

Procedure:
contacting glucosamine hydrochloride with potassium sulfate in the presence of water to form an aqueous solution of glucosamine sulfate potassium chloride; and
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH:16]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:22](=[O:23])[NH:21][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Reactant: O=C=NC1CCCC1
Product: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)NC1CCCC1

Procedure:
Prepared according to the procedure described in Example 19, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and cyclopentyl isocyanate.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.C([Li])CCC.[I:23]I>C1COCC1>[I:23][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:17])([CH3:16])[CH3:1])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: II
Reactant: C[Si](C)(C)CCOCn1cnc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(I)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 63.2 %

Procedure:
A solution of 1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole (5.029 g, 20.25 mmol) (see Witten et al., J. Org. Chem., 51, 1891-1894 (1986)) in THF (50 mL) was cooled to −78° C. and added dropwise over 12 min via cannula to a flask containing n-butyllithium (2.5 M in hexanes, 12.2 mL) in THF (30 mL) at −78° C. under argon. After stirring for 25 min at −78° C., the flask was warmed to 0° C. for 10 min, then cooled again to −78° C. This solution was then added via cannula to a second flask containing iodine (25.7 g, 101 mmol) in THF (50 mL) at −78° C. Once the addition was complete (−5 min), the cooling bath was removed, and stirring was continued for 30 min. The reaction mixture was partitioned between ethyl acetate (500 mL) and water (100 mL). The organic layer was washed with saturated aqueous sodium metabisulfite (2×100 mL) to remove the dark iodine color, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (10% to 50% ethyl acetate/hexanes) yielded 4.79 g (63%) of pure 2-iodo-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-benzoimidazole as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.76-7.72 (m, 1H), 7.54-7.51 (m, 1H), 7.29-7.25 (m, 2H), 5.54 (s, 2H), 3.59 (t, 2H, J=8.1 Hz), 0.92 (t, 2H, J=8.1 Hz), −0.03 (s, 9H). Anal. (C13H19IN2OS)C, H. Calculated: C, 41.71; H, 5.12; L 33.90; N, 7.48. Found: C, 41.90; H, 5.09; L 34.00; N, 7.37.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Br)[CH:11]=[CH2:12]>CC(C)=O>[CH2:12]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH:11]=[CH2:10]
Reactant: N#Cc1ccc(O)cc1
Reactant: C=CCBr
Solvent: CC(C)=O
Product: C=CCOc1ccc(C#N)cc1

Procedure:
A solution of 4-cyanophenol (50 g), allyl bromide (27.2 ml) potassium carbonate (47.8 g) in acetone (100 ml) was heated at reflux for 16 hours. The reaction mixture was evaporated, water was added to the residue and the aqueous mixture was extracted with diethyl ether. The diethyl ether extract was washed with dilute aqueous sodium hydroxide solution, dried (MgSO4) and evaporated to give 4-cyanophenyl allyl ether as a solid, m.p. 41.6° C.; microanalysis, found: C, 75.1; H, 5.8; N, 8.7%; C10H9NO2 requires: C, 75.5; H, 5-7; N, 8.8%; NMR: 4.55-4.65(2H,m), 5.2-5.4(2H,m), 5.9-6.05(1H,m), 7.0-7.1(2H,m) and 7.65-7.75(2H,m).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)=[O:4].[OH-].[Na+].O.Cl>CO>[C:10]([N:7]1[CH:8]=[N:9][C:5]([C:3]([OH:4])=[O:2])=[N:6]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
A mixture of 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid methyl ester (500 mg, 1.35 mmol) in methanol at 25° C. was treated with a 1N aqueous sodium hydroxide solution (4.0 mL). The reaction was stirred at 25° C. for 24 h. At this time, the reaction mixture was poured into water (100 mL) and acidified with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (2×150 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×150 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid (326 mg, 67%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.37 (s, 1H), 7.39 (m, 9H), 7.05 (m, 6H), 3.82 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:10][O:11][C:12](=[O:15])[CH2:13]Br.C(N(CC)CC)C>C1COCC1.O>[CH3:10][O:11][C:12](=[O:15])[CH2:13][N:6]1[CH2:7][CH2:8][C:3]([F:9])([F:2])[CH2:4][CH2:5]1
Reactant: FC1(F)CCNCC1
Reactant: COC(=O)CBr
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CN1CCC(F)(F)CC1
Yield: 96.1 %

Procedure:
To a solution of 4,4-difluoropiperidine hydrochloride (1 g, 6.3 mmol) in THF (20 mL) was added methylbromoacetate (0.63 mL, 6.6 mmol) and triethylamine (2.65 mL, 19.0 mmol). The reaction was heated at reflux for 4 h. The reaction was diluted with water (50 mL) and the product extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4,4-difluoropiperidin-1-yl)acetic acid methyl ester as a brown oil (1.17 g, 96%). MS 194 (M+H)+. To a solution of (4,4-dfluompiperidin-1-yl)acetic acid methyl ester (1.17 g, 6.1 mmol) in THF (15 mL) at 0° C. was added potion wise lithium aluminium hydride (0.46 g, 12.2 mmol). Once the effervescence had ceased the reaction was heated at 60° C. for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4,4-difluoropiperidin-1-yl)-ethanol as a brown oil (0.99 g, 99%). MS 166 (M+H)+. To a solution of diisopropylazodicarboxylate (0.36 mL, 1.82 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (728 mg, 2.18 mmol). The reaction was stirred at RT for 10 min. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (025 g, 1.21 mmol) and 2-(4,4-difluoropiperidin-1-yl)-ethanol (210 mg, 1.27 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50% tert-butyl methyl ether in n-heptane to yield 5-[2-(4,4-difluoropiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (375 mg, 88%). MS 354 (M+H)+. To a solution of 5-[2-(4,4-difluoropiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester (375 mg, 1.06 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (34 mg, 2.12 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 326 (M+H. 5.3 min) and used for coupling onto H2N-Leu-P1 without any further purification.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[C:9](O[C:12](=[O:13])[CH:2]21)=[O:10].[NH3:14]>O1CCCC1.O>[CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[C:9](=[O:10])[NH:14][C:12](=[O:13])[CH:2]21
Reactant: N
Reactant: O=C1OC(=O)C2C3CCC(CC3)C12
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC(=O)C2C3CCC(CC3)C12

Procedure:
A solution of bicyclo[2.2.2]octane-2,3dicarboxylic anhydride (3 g; 16.6 mmol) in tetrahydrofuran (9 ml) was dropwise added to a mixture of 29% aqueous ammonia (6 g; 83 mmol) in water (18 ml) while ice-cooling, and the resultant mixture was heated. The solvent was removed under atmospheric pressure, and acetic anhydride (10 ml) was added thereto, followed by refluxing for 30 minutes. The solvent was removed under reduced pressure, and the residue was combined with toluene (24 ml) and heated to dissolve. After cooling, the precipitated crystals were collected by filtration to give the objective compound. M.P., 199°-200° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[C:13]([N+:25]([O-])=O)[C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)[CH3:4].N1C2C(=CC=CC=2)C=CC=1>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:25][C:13]1[C:14](=[O:24])[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12]=1[CH2:11][CH2:10][C@@H:9]1[C@@H:19]2[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:8]1[CH2:7][CH2:6][C@@H:5]2[CH:3]([CH2:2][OH:1])[CH3:4]
Reactant: CC(CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: CC(CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h

Procedure:
A solution of 20-hydroxymethyl-4-nitropregn-4-en-3-one (2.01 g, 5.35 mM) in absolute ethanol (28 mL) is treated sequentially with Lindlar's catalyst (5% Pd on CaCO3 with 5.2% Pb, 0.81 g) and with quinoline (37) and kept under hydrogen at between 40-55 p.s.i. for 24 hours. The mixture is then filtered through celite, and the filtrate is concentrated to a yellow solid which is purified by short path chromatography to give 4-amino-20-hydroxymethylpregn- 4-en-3-one, m.p. 180°-185° C. (aqueous isopropanol). IR 3512, 3470, 3384, 1648, 1614, 1576 cm-1 MS(CI) 346(100%, M+1), 328(30%, M+l-H2O).
Reaction SMILES: Cl.C(Cl)Cl.[CH:5]([Si:8]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:9][CH:10]([C:15]1[C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:11][CH2:12]C=C)([CH3:7])[CH3:6].N#N>CCCCCC.CCOCC>[CH:23]([Si:8]([CH:26]([CH3:28])[CH3:27])([CH:5]([CH3:7])[CH3:6])[O:9][CH:10]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:20]2[CH:21]=[CH:22][CH2:12][CH2:11]1)([CH3:25])[CH3:24]
Reactant: C=CCCC(O[Si](C(C)C)(C(C)C)C(C)C)c1ncccc1C=C
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)[Si](OC1CCC=Cc2cccnc21)(C(C)C)C(C)C
Temperature: 40 °C
Yield: 70.9 %

Procedure:
Hydrogen chloride (5.64 mL, 11.28 mmol) (10 mL, 2M diethyl ether solution) was added to the CH2Cl2 (25 mL) solution of 2-(1-(triisopropylsilyloxy)pent-4-enyl)-3-vinylpyridine (3.9 g, 11.28 mmol). The solvent was removed via vacuum and the corresponding HCl salt was azeotroped by benzene twice. The reaction was charged with CH2Cl2 (500 mL) and purged with N2 for 10 min before addition of Grubb II (0.192 g, 0.226 mmol). The reaction was heat to 40° C. for 3 hours, LCMS showed no starting material left. The reaction was washed with saturated NaHCO3 solution once. The CH2Cl2 was separated, dried (Na2SO4), filtered and concentrated. Flash column by ether in hexane from 0 to 25% gave the desired product as yellow oil (2.54 g, 71% yield). MS (ESI)[M+H+]=318.35.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:51])([F:50])[F:49])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].BrC1C=CC(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(OCC)OCC)=CC=3OC)N=2)=C2C=1CN(C)[C:58]2=[O:63]>>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:50])([F:49])[F:51])=[CH:19][N:18]=2)=[C:14]([O:63][CH3:58])[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Compound 246A using diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl) pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and 4-(4,4,5,5-ttramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Tetrahedron Letters, 2000, 44, pp 3705-3708). MS (ES+): m/z 761.33 (100) [MH+]; HPLC: tR=1.56 min (UPLC, analytical).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C>C(#N)C>[S:1]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:14][S:1](=[O:4])(=[O:3])[NH2:2])(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCCCCCCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)OCCCCCCCOS(N)(=O)=O
Yield: 37 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride in acetonitrile solution prepared in (a) was reacted as in Example 12 with 10.5 g (0.0755 mole) of 1,7-heptanediol (95%), 30.3 g (0.300 mole) of triethylamine in 100 ml additional acetonitrile followed by using extracting, washing and concentration procedures of Example 12 through the first evaporation. The viscous residue which solidified on standing was purified by high pressure liquid chromatography using the Waters Associates® Prep LC/System 500A with Prep Pak 500 ® silica. Eluting solvent used was 10:1 mixture methylene chloride-acetone at a flow rate of 200 ml/min. Fractions containing the title compound were combined and the solvents were evaporated under reduced pressure to give a viscous oil which solidified on standing. The solid was recrystallized from wet methylene chloride to give 8.2 g (37% yield) of title compound as white solid, mp 88.5°-90.5° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][Cl:14])(=O)=O)=CC=1.[OH:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:14][CH2:13][CH2:12][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1OCCCl
Temperature: 45 °C
Reaction time: 12 h
Yield: 79.1 %

Procedure:
A mixture of 2-chloroethyl 4-methylbenzenesulfonate (39; 27.0 g, 0.115 mol), 2-hydroxybenzaldehyde (25; 14.0 g, 0.115 mol) and K2CO3 (31.7 g, 0.23 mol) in DMF (100 mL) was stirred at 45° C. for 12 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed saturated brine (3×50 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:ethyl acetate=10:1) to give 2-(2-chloroethoxy)benzaldehyde 40 (16.8 g, 0.091 mol, 79%) as a pale yellow solid.