Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Na+].[CH:11]([CH:13]1[CH:15]([C:16]([O:18][CH2:19][C:20]2[C:25]([F:26])=[C:24]([F:27])[C:23]([CH2:28][O:29][CH3:30])=[C:22]([F:31])[C:21]=2[F:32])=[O:17])[C:14]1([CH3:34])[CH3:33])=O.Cl.O1C[CH2:39][CH2:38][CH2:37]1>>[C:37]([C:38]([CH3:39])=[CH:11][CH:13]1[CH:15]([C:16]([O:18][CH2:19][C:20]2[C:21]([F:32])=[C:22]([F:31])[C:23]([CH2:28][O:29][CH3:30])=[C:24]([F:27])[C:25]=2[F:26])=[O:17])[C:14]1([CH3:34])[CH3:33])#[N:5]
Reactant: C1CCOC1
Reactant: COCc1c(F)c(F)c(COC(=O)C2C(C=O)C2(C)C)c(F)c1F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Product: COCc1c(F)c(F)c(COC(=O)C2C(C=C(C)C#N)C2(C)C)c(F)c1F
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 0.54 g of diethyl (1-cyanoethyl) phosphonate was dissolved in 6 ml of tetrahydrofuran and 2.8 ml of a tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (1 mol/l) were added thereto at about 0° C. The mixture was stirred for 30 minutes and 2 ml of a tetrahydrofuran solution containing 1.0 g of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 3-formyl-2,2-dimethylcyclopropanecarboxylate given by formula (7): (prepared by the method described as reference production example 1 below) was added thereto and stirred for 3 hours at room temperature. After that, the reaction mixture was poured into about 20 ml of 1% hydrochloric acid and extracted with 100 ml of ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, subsequently, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give 0.76 g of 4-methoxymethy-2,3,5,6-tetrafluorobenzyl 3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylate given by formula (8): (isomers ratio based on the double bond: Z/E=about 2/1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(NC(C)C)(C)C.[CH:15]#[C:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:15]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)#[C:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCCC
Reactant: Ic1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC#Cc1ccccn1
Temperature: 85 °C
Yield: 88.3 %

Procedure:
To a degassed solution of 2-iodopyridine (0.519 mL, 4.88 mmol), bis(triphenylphosphine)palladium(II) chloride (0.205 g, 0.293 mmol), copper(I) iodide (0.046 g, 0.244 mmol), and diisopropylamine (2.78 mL, 19.5 mmol) in N,N-dimethylformamide (20 mL) was added 1-pentyne (0.721 mL, 7.32 mmol). The reaction was heated to 85° C. for 3 hrs. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), washed with a 10% aqueous solution of lithium chloride (2×100 mL), washed with a 2M aqueous solution of ammonium hydroxide (100 mL), washed with brine (100 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (3/2) afforded 2-(pent-1-ynyl)pyridine (636 mg, 4.31 mmol). The compound had an HPLC retention time=0.982 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.2% H3PO4; Solvent B=90% MeOH—10% water—0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=146.3. 1H NMR (400 MHz, CDCl3) δ ppm 1.06 (t, 3H), 1.67 (dt, J=7.23 Hz, 2H), 2.43 (t, J=7.15 Hz, 2H), 7.18 (ddd, J=7.65, 4.89, 1.00 Hz, 1H), 7.38 (d, J=7.78 Hz, 1H), 7.62 (td, J=7.72, 1.88 Hz, 1H), and 8.55 (d, J=4.27 Hz, 1H).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([CH3:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[CH2:28][C@@H:15]3[O:16][CH:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[O:18][CH2:19][C@@H:14]3[CH2:13]2)[CH:3]=1.CCN(C(C)C)C(C)C.[C:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])#[CH:39]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:17]2[O:16][C@H:15]3[CH2:28][C@H:12]([N:4]4[C:5]5[N:6]=[CH:7][N:8]=[C:9]([CH3:11])[C:10]=5[C:2]([C:39]#[C:38][Si:40]([CH3:43])([CH3:42])[CH3:41])=[CH:3]4)[CH2:13][C@H:14]3[CH2:19][O:18]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4cc(I)c5c(C)ncnc54)C[C@@H]3O2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4cc(C#C[Si](C)(C)C)c5c(C)ncnc54)C[C@@H]3O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a suspension of 5-iodo-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (337 mg, 0.685 mmol), copper(I) iodide (26.0 mg, 0.137 mmol), dichlorobis(triphenylphosphine)-palladium(II) (48.0 mg, 0.0684 mmol) and DIPEA (0.240 mL, 1.38 mmol) in DMF (20.0 mL) was added ethynyltrimethylsilane (188 mg, 1.91 mmol) and the mixture was stirred at rt overnight. The reaction mixture was quenched via addition of saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography eluting with a gradient of 0 to 75% EtOAc in hexanes afforded the title compound (314 mg, 99%). LC/MS: Rt=2.38 min, ES+ 462 (AA standard).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1COCC1.C([Li])CCC.[CH:24]([Si:27](Cl)([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])([CH3:26])[CH3:25]>CCOCC>[CH:24]([Si:27]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([CH3:26])[CH3:25]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[Si](C(C)C)(C(C)C)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of 3.0 g (18.07 mmol) of fluorene in 50 mL of dry ether and 25 mL of freshly distilled THF was added dropwise 13 mL of 1.4M n-butyllithium. The mixture was refluxed for 3 hours, cooled to room temperature, and treated with 3 mL (14.02 mmol) of triisopropylsilyl chloride in one portion. The mixture was refluxed for 3 days, cooled to room temperature, and washed with sat'd NH4Cl (2×50 mL) and water (50 mL). The organic layer was dried over MgSO4 and the solvent was evaporated in vacuo to give an oil which was triturated with methanol to afford 3.34 g (73.8%) of the crude silane as a yellowish solid. Recrystallization from EtOH gave 2.98 g (65.9%) of 9-triisopropylsilylfluorene as white needles, m.p. 122°-123° C.; 1H NMR (CDCl3): δ 0.91 (d, 18H, Si-C-Me2), 1.09-1.42 (hept, 3H, Si-CH-Me2 , 4.26 s, 1H, ArCHAr), 7.05-8.00 (m, 8H, aryl).
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[P:5](Cl)Cl)([CH3:3])[CH3:2].[CH3:11][Si:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15].CCN(CC)CC.[CH3:25][CH2:26][O:27]CC>>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[P:5]([O:27][CH2:26][CH2:25][Si:12]([CH3:16])([CH3:13])[CH3:11])[O:15][CH2:14][CH2:13][Si:12]([CH3:17])([CH3:16])[CH3:11])([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(C)N(C(C)C)P(Cl)Cl
Reactant: C[Si](C)(C)CCO
Solvent: CCN(CC)CC
Product: CC(C)N(C(C)C)P(OCC[Si](C)(C)C)OCC[Si](C)(C)C
Temperature: -1 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A solution of diisopropylphosphoramidous dichloride (10.8 g 50.78 mmoles) in Et2O (53 mL) in 250 mL three neck flask equipped with a temperature probe and addition funnel was cooled to 0 to −2° C. under N2. A solution of 2-(trimethylsilyl)ethanol (12.6 g; 106.55 mmoles) and Et3N (15.4 g; 152.19 mmoles) in Et2O (84 mL) was added dropwise over 27-28 minutes to the stirred diisopropyl-phosphoramidous dichloride solution. A mild exotherm (+1-2° C.) accompanied the formation of a thick white suspension. After stirring overnight at 20° C., the mixture was filtered. The resultant cake was washed twice with 30 mL each of Et2O. The combined filtrates were washed 2×100 mL of saturated aqueous NaHCO3 followed by 40 mL of brine. After drying over MgSO4 and concentrating to dryness under vacuum at room temperature, bis(2-(trimethylsilyl)ethyl) diisopropylphosphoramidite (18.12 g; 49.56 mmoles; 97.60% yield) was obtained as a clear colorless liquid. 1H NMR δ (400 MHz, CDCl3): 3.90-3.78 (m, 4H), 3.77-3.68 (m, 2H), 1.31 (d, J=6.6 Hz, 12H), 1.17-1.12 (m, 4H), 0.15 (s, 18H). 13C NMR δ (100 MHz, CDCl3): δ0.7 (2, d, JC—P=19.1 Hz, 2C), 42.7 (1, d, JC—P=12.7 Hz, 2C), 24.6 (3, d, JC—P=7.6 Hz, 4C), 20.1 (2, d, JC—P=7.6 Hz, 2C), −1.4 (3, 6C). 31P NMR δ (162 MHz, CDCl3): 143.5 (s). LC/MS: m/e (M+H); 4 ml gradient; min retention.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:13])[CH3:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:25][I:26]>C(O)C>[I-:26].[C:1]([N:4]1[CH2:5][CH2:6][N+:7]([CH2:10][C:11]([NH:14][C:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:24])([CH3:13])[CH3:12])([CH3:25])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)N1CCN(CC(C)(C)NC(=O)OCc2ccccc2)CC1
Solvent: CCO
Product: CC(=O)N1CC[N+](C)(CC(C)(C)NC(=O)OCc2ccccc2)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 168 h

Procedure:
Benzyl 1-(4-acetylpiperazin-1-yl)-2-methylpropan-2-ylcarbamate (2.62 g, 7.86 mmol) was placed into a 15 mL pressure tube. Absolute ethanol (1.1 mL, 7.1 M) and methyl iodide (2.45 mL, 5 equiv, 39.3 mmol) was added to the pressure tube. A stir bar was added and the pressure tube sealed. The reaction was left to stir at room temperature for 7 days. The dark red solution was concentrated to a red oil which became a foam after drying under high vacuum. The foam was purified via Prep-LC using isocratic 95% water and 5% methanol for 5 min followed by a gradient to 95% methanol and 5% water over 16 min. Fraction were pooled to give recovered starting material (0.68 g, 20%) and product as a yellow foam (1.69 g, 45%). 1H NMR (D2O, 400 MHz): δ 1.51 (s, 6H), 2.12 (s, 3H), 3.23 (s, 3H), 3.35-3.60 (m, 5H), 3.68-3.85 (m, 4H), 3.92-4.02 (m, 1H), 5.11 (s, 2H), 7.38-7.48 (m, 5H). LRMS (ESI+) for C19H30N3O3+ (348.2); Found: 348 (M+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=O.C(N(CC)CC)C.[CH2:13]([N:16]=[C:17]=[S:18])[CH:14]=[CH2:15].Cl>O.N1C=CC=CC=1>[CH2:13]([N:16]1[C:3](=[O:5])[CH2:2][NH:1][C:17]1=[S:18])[CH:14]=[CH2:15]
Reactant: NCC(=O)O
Reactant: C=CCN=C=S
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: C=CCN1C(=O)CNC1=S
Temperature: 55 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Glycine (30 g, 0.40 mol), triethylamine (44 g, 0.44 mol), pyridine (100 mL), and water (100 mL) were mixed in a flask equipped with a magnetic stirrer and a temperature controller. Allyl isothiocyanate (44 g, 0.44 mol) was added, and the temperature was raised to 55° C. (the mixture became homogeneous at ca. 30°). When the mixture reached this temperature, it was allowed to cool to room temperature. The mixture was extracted with 3×200 mL of toluene to remove the pyridine and excess isothiocyanate and was then treated with 66 mL (0.8 mol) of concentrated hydrochloric acid. The mixture was heated at 90° C. for 2.5 hr and was then stirred rapidly while it cooled to room temperature. A solid mass of crystals formed instantaneously when the solution was seeded with a fragment of a crystal of authentic product. After the suspension stood at room temperature overnight, the product was collected and pressed with rubber dam. The filter cake was washed with 3×60 mL of water (the filter cake was pressed with rubber dam after each wash). After the material had dried to constant weight in a hood draft, it weighed 49 g (71% yield). NMR (CD3OD) δ 4.9-6.1 (m, 3H), 4.6 (s, 1H), 4.3 (d, 2H), 4.0 (s, 2H). HPLC analysis showed no other components at several wavelengths.
Reaction SMILES: C1(C)C=C[C:4]([S:7](O)(=[O:9])=[O:8])=CC=1.[CH3:12][C:13]1([CH3:32])[CH:15]([CH:16](OS(C)(=O)=O)[C:17]([C:20]([F:23])([F:22])[F:21])([Br:19])[Cl:18])[CH:14]1[C:29]([O-:31])=[O:30]>C(Cl)Cl>[CH3:32][C:13]1([CH3:12])[CH:15]([CH:16]([S:7]([CH3:4])(=[O:9])=[O:8])[C:17]([C:20]([F:21])([F:22])[F:23])([Br:19])[Cl:18])[CH:14]1[C:29]([OH:31])=[O:30]
Reactant: CC1(C)C(C(=O)[O-])C1C(OS(C)(=O)=O)C(Cl)(Br)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC1(C)C(C(=O)O)C1C(C(Cl)(Br)C(F)(F)F)S(C)(=O)=O
Temperature: 40 °C

Procedure:
30 mg of p-toluene sulfonic acid were added at 40° C. to a solution of 1 g of the product of Step B and 10 ml of methylene chloride and the reaction mixture was heated for 5 hours at 40° C., then poured on to ice, and decanted. The organic phase was washed with water, dried on sodium sulfate and evaporated to dryness under reduced pressure to obtain 860 mg of [1R-[1α-,3α-(RS*,RS*)]] 2,2-dimethyl-3-[2-trifluoromethyl-2-bromo-2-chloro-1-methylsulfonylethyl]-cyclopropane carboxylic acid melting at 138° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:34][O:35][C:36](=[O:51])[C@@H:37]([NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH2:38][NH2:39].C[Si](C)(C)NC(=O)C>ClCCl.CN(C)C=O>[CH3:34][O:35][C:36](=[O:51])[C@@H:37]([NH:40][C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[CH2:38][NH:39][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25]
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a stirred solution of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidine carboxylic acid (1.0 g) and N,N-dimethylformamide (210 μl) in dichloromethane (10 ml) was added dropwise oxalyl chloride (240 μl) at 4° C. under a nitrogen atmosphere. To an ice cooled solution of 2(S)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (940 mg) and N-(trimethylsilyl)-acetamide (2.85 g) in N,N-dimethylformamide (10 ml) was added dropwise the above solution with stirring under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature, and stirred for 2 hours, which was partitioned between a mixture of ethyl-acetate and n-hexane and water. The organic layer was separated, washed in turn with water, aqueous 5% NaHCO3 solution and brine, and dried over MgSO4. Evaporation of the solvent gave a residue, which was purified by silica-gel column chromatography eluting with n-hexane-ethyl acetate (from 1:6 to ethyl acetate only) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alanine methyl ester (0.89 g) as a foam, which is the same compound obtained in Preparation 15.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9][C:8]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:7][C:6]=2[CH:22]=1.Cl.O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9][C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:22]=1
Reactant: CCCN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.3 %

Procedure:
In ethyl acetate (80 ml) was dissolved t-butyl 7-bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (8.05 g). To the solution was added a solution of 4N hydrochloric acid in ethyl acetate (80 ml), and the mixture was stirred at room temperature for 12 hours. To the mixture was added water, and the mixture was adjusted to pH2 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue of solid was washed with hexane-ethyl acetate to give yellow crystals of 7-bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (2.61 g, 39%).
Reaction SMILES: C([O-])=O.[NH4+].[OH:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([C:9]3=O)[CH2:7]1)[CH2:13]2.C([N:19](CC)CC)C.[CH3:24][C:25]([O:28][C:29]([O:31]C(OC(C)(C)C)=O)=O)([CH3:27])[CH3:26]>CO.[Pd]>[C:25]([O:28][C:29](=[O:31])[NH:19][CH:9]1[CH:8]2[CH2:14][CH:12]3[CH2:13][C:6]([OH:5])([CH2:15][CH:10]1[CH2:11]3)[CH2:7]2)([CH3:27])([CH3:26])[CH3:24]
Reactant: CCN(CC)CC
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1C2CC3CC1CC(O)(C3)C2
Temperature: 20 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Ammonium formate (10 g, 0.15 mol) was added to a solution of 5-hydroxyadamantan-2-one (4.5 g, 0.027 mol, prepared as described in Tetrahedron 1968, 24, 5369) in MeOH (50 ml). Then 10% Pd—C (500 mg) was added carefully and the solution heated under reflux for 1 h. It was then filtered through celite and to this filtrate at 0° C. was added triethylamine (11.2 ml, 0.081 mol) and Boc anhydride (7.06 g, 0.0324 mol). The solution was stirred for 4 h at 20° C. and then concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The organic layer was dried and concentrated to give (5-hydroxyadamantan-2-yl)carbamic acid tert-butyl ester (7 g, 96%). LC-MS (m/z): 168 (M+1). 1H NMR (300 MHz, DMSO-d6): δ 6.8 (d, 1H), 6.7 (brs, 1H), 3.45 (d, 1H), 2.0 (s, 1H), 1.75-1.95 (m, 4H), 1.5-1.7 (m, 6H), 1.35 (s, 9H), 1.25 (t, 2H).
Reaction SMILES: [OH-].[Na+].[NH2:3][CH:4]([C:6]([OH:8])=[O:7])[CH3:5].[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O>[NH2:3][C:4]([CH3:5])([CH:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=Cc1ccccc1
Reactant: CC(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(N)(C(=O)O)C(O)c1ccccc1
Temperature: 5 °C

Procedure:
Sodium hydroxide (6 g, 150 mmoles) and 8.9 g (100 mmoles) of D,L-alanine are dissolved in 25 mL of water and the solution cooled to around 5° C. while stirring under a nitrogen atmosphere. To the solution is added 21.2 g (200 mmoles) benzaldehyde and the mixture stirred at 5° C. for approximately one hour. The mixture is then warmed to room temperature and maintained for approximately 20 hours. Concentrated hydrochloric acid then is added to bring the reaction mixture to pH 2.0. After stirring the acidic solution for two hours, the aqueous phase is separated, extracted with ethyl acetate and evaporated under vacuum. The resulting material is twice extracted with 80 mL hot absolute ethanol, followed by evaporation of the ethanol. The resulting material is again extracted with 40 mL of absolute ethanol, followed by removal of the ethanol. The extract then is dissolved in at least a 1:1 methanol water solution and absorbed on polymethacrylate column. The column then is eluted with the same 1:1 methanol water solution and the 30 mL fractions are combined and evaporated. Purification on the polymethacrylate column then is repeated using 95% ethanol to yield racemic 2-amino-2-methyl-3-hydroxy-3-phenylpropionic acid.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)[O:4]1.[CH3:10][C@@H:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.[CH2:20]([C:27](O)=O)[C:21](CC(O)=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[C:12]1([CH:11]([N:18]2[CH:6]3[CH2:5][CH2:27][C@@H:20]2[CH2:21][C:3](=[O:4])[CH2:7]3)[CH3:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC1CCC(OC)O1
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: C[C@@H](N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(c1ccccc1)N1C2CC[C@@H]1CC(=O)C2

Procedure:
Three drops of 5M hydrochloric acid were added to a mixture of 2,5-dimethoxytetrahydrofuran (16.5 g) and water (70 ml). A cooled mixture of (R)-a-methylbenzylamine (15.125 g) and 5M hydrochloric acid (30 ml) was then added followed by 1,3-acetonedicarboxylic acid (18.26 g) sodium acetate (10 g) and water (100 ml). After 5 days the mixture was basified with aqueous sodium carbonate solution and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2 ; ethyl acetate:hexane (10:90) to (20:80)] gave (R)-8-(1-phenylethyl)-8-azabicyclo[3.2.1]octan-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][N:6]=[CH:5]2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH:21]=O)=[CH:16][C:15]=1[F:24]>C(O)C>[F:24][C:15]1[CH:16]=[C:17]([C:20]2[CH:21]=[N:1][C:2]3[CH:3]=[C:4]4[CH:5]=[N:6][NH:7][C:8]4=[CH:9][C:10]=3[N:11]=2)[CH:18]=[CH:19][C:14]=1[O:13][CH3:12].[F:24][C:15]1[CH:16]=[C:17]([C:20]2[CH:21]=[N:11][C:10]3[CH:9]=[C:8]4[NH:7][N:6]=[CH:5][C:4]4=[CH:3][C:2]=3[N:1]=2)[CH:18]=[CH:19][C:14]=1[O:13][CH3:12]
Reactant: Nc1cc2cn[nH]c2cc1N
Reactant: COc1ccc(C(=O)C=O)cc1F
Solvent: CCO
Product: COc1ccc(-c2cnc3cc4[nH]ncc4cc3n2)cc1F
Product: COc1ccc(-c2cnc3cc4cn[nH]c4cc3n2)cc1F
Temperature: 25 °C

Procedure:
To an ice-cooled mixture of 5,6-diaminoindazole (0.5 g) in 20 ml absolute ethanol is added slowly a solution of 1-methoxy-2-fluoro-4-glyoxyloylbenzene (0.75 g) in 30 ml ethanol. The resulting mixture is stirred at room temperature over night. The solid which forms is filtered off, washed with a small amount of ethanol then with hexane and air dried to give a yellow material.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])[C:6]1[CH:27]=[CH:26][C:9]([C:10]([O:12][Sn](CCCC)(CCCC)CCCC)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.O[N:52]1[C:56](=[O:57])[CH2:55][CH2:54][C:53]1=[O:58]>C1COCC1.CC(O)=O>[CH3:35][CH2:34][CH2:33][CH2:32][Sn:5]([C:6]1[CH:27]=[CH:26][C:9]([C:10]([O:12][N:52]2[C:56](=[O:57])[CH2:55][CH2:54][C:53]2=[O:58])=[O:11])=[CH:8][CH:7]=1)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)OC(=O)c1ccc([Sn](CCCC)(CCCC)CCCC)cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.2 %

Procedure:
To a solution of 1.29 g (1.84 mmol) of tri-n-butylstannyl 4-(tri-n-butylstannyl)benzoate in 18.4 mL of anhydrous THF was added 417 mg (2.02 mmol) of dicyclohexylcarbodiimide (Sigma) and 212 mg (1.84 mmol) of N-hydroxysuccinimide (Sigma, and the mixture was stirred for 15 hours at room temperature. To the mixture was then added three drops of HOAc. The solids were removed by filtration, and the mixture was concentrated. Purification by silica gel chromatography (25% EtOAc/hexane) yielded 731 mg (78%) of N-succinimidyl 4-(tri-n-butylstannyl)benzoate: 1H NMR (CDCl3)δ 0.50-2.20 (m, 27H), 2.90 (s, 4H), 7.65 (d, J=8 Hz, 2H), 8.06 (d, J=8 Hz, 2H). IR (neat) 1780, 1750, 1190, 1055, 980 cm-1.