Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH2:21][CH:22]4[CH2:25][O:24][CH2:23]4)=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.C(NC(C1N2CCOC3C=CC([C:48]#[C:49][C@@:50]([OH:58])([C:52]4[CH:56]=[C:55]([CH3:57])[O:54][N:53]=4)[CH3:51])=CC=3C2=NC=1C(N)=O)=O)(C)(C)C.CNC1COC1.CC1ON=C([C@](O)(C#C)C)C=1>>[OH:58][C@:50]([C:52]1[CH:56]=[C:55]([CH3:57])[O:54][N:53]=1)([CH3:51])[C:49]#[C:48][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH2:21][CH:22]4[CH2:25][O:24][CH2:23]4)=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC(C)(C)C)n2CCO3)no1
Reactant: NC(=O)c1nc2n(c1C(=O)NCC1COC1)CCOc1ccc(Br)cc1-2
Agent: C#C[C@@](C)(O)c1cc(C)on1
Agent: CNC1COC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NCC4COC4)n2CCO3)no1
Yield: 2 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-N3-(oxetan-3-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide (prepared as described in the synthesis of (R)—N3-(tert-butyl)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing tert-butyl amine with 3-methylaminooxetane) was reacted with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (6.7 mg, 2%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])([O-:3])=[O:2].[C:19](=O)([O-])[O-].[K+].[K+].CI>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:18][CH3:19])([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
2-Nitro-4-phenylmethoxy-phenol is methylated by contacting it with a slight molar excess of potassium carbonate and a large molar excess of methyl iodide and tetrabutylammonium bromide (TBAB) in an inert solvent (such as acetone) and refluxed for 8 to 15 hours, preferably 12 hours. After cooling, filtration and evaporation of the solvent, the residue is purified by conventional means to give 2-nitro-4-phenylmethoxyanisole, which in turn is hydrogenated to give the corresponding aniline of Formula 12.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23]Br)[CH3:20]>CCCCCC.CCOCC>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH3:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(CC(OCC)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
A mixture of 10.6 gms (0.25 moles) sodium hydride 57% oil dispersion and 75 mL hexane was stirred under argon for 10 minutes. The hexane solvent was replaced by 125 mL of dry dimethylformamide, and to this suspension was added dropwise 40.5 gms (0.25 moles) diethyl malonate over 30 minutes. 49 gms (0.25 moles) bromoacetaldehyde diethyl acetal was then added dropwise over 20 minutes. After the addition was complete, the reaction mixture was stirred at 86 degrees Celsius for 18 hours, then cooled to room temperature and diluted with 600 mL of an ice-water mixture. The mixture was 4×200 mL ether extracted. The ether extracts were combined, washed twice with 50 mL cold 5% HCl, twice with 50 mL 5% NaHCO3 solution, twice with saturated NaCl solution, dried over magnesium sulfate, and filtered. The ether was evaporated in vacuo to give 55.2 gms of oil. The crude oil was purified by two successive vacuum distillations to finally give 18 gms of pure product, b.p. 81-83 degrees/0.1 mmHg. Elemental analysis: calculated C 56.51, H 8.75; found C 57.11, H 9.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-])=O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>ClCCl.O>[NH2:24][C:3]1[CH:4]=[C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:62]3[CH2:63][CH2:64][N:59]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[CH3:52])[CH2:60][CH2:61]3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC2CO2)C1
Reactant: Cc1ccccc1N1CCNCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(N)c3)nn2CC(O)CN2CCN(c3ccccc3C)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
A solution of 1-[3-(4-chloro-3-nitro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.754 g, 2.0 mmol) in dichloromethane (10 mL) was treated with ytterbium(III)triflate (0.25 g, 0.40 mmol) and 1-(2-methylphenyl)-piperazine (0.705 g, 4.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and diluted with dichloromethane (100 mL) and water (50 mL). The organic layer was separated, washed with water (2×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5% MeOH/CH2Cl2) to afford 0.98 g (90%) of the desired product as a light yellow solid. MS (electrospray): m/z 553.2 (553.2, calculated for C28H33ClN6O4, [M+H]+). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 8.25-8.15 (m, 1H), 7.75-7.70 (m, 1H), 7.63-7.55 (m, 1H) 7.20-7.10(m, 2H), 7.05-6.95 (m, 2H), 4.90-4.70 (m, 1H), 4.65 (s, 1H), 4.30-4.15 (m, 2H), 4.10-3.70 (m, 4H), 3.00-2.40 (m, 12H), 2.20(s, 3H), 2.15 (s, 1.5H), 2.10 (s, 1.5H).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[N+:18]([C:14]1[C:10]2[C:11](=[O:13])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:1](=[O:8])[C:9]=2[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
cyclizing said 2-benzoyl-6-nitrobenzoic acid in concentrated sulfuric acid at a temperature of 100°-110° C for a period of 1-3 hours to form 1-nitroanthraquinone and recovering the same therefrom.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[C:17]([F:24])[C:16]=2[F:25])=[CH:11][CH:10]=1)C1C=CC=CC=1>C1COCC1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[C:17]([F:24])[C:16]=2[F:25])=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)c(F)c1F
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2ccc(O)cc2)c(F)c1F
Temperature: 80 °C

Procedure:
27.0 g (79.4 mmol) of 4′-benzyloxy-2,3-difluorobiphenyl-4-boronic acid are hydrogenated to completion on palladium/active carbon catalyst in THF. The catalyst is filtered off, and the solvent is removed in vacuo. The crude product is heated to 80° C. with 110 ml of toluene/ethyl acetate (10:1) with stirring and filtered off with suction after cooling, giving 4′-hydroxy-2,3-difluorobiphenyl-4-boronic acid as a colourless solid, which is employed in the next step without further purification.
Reaction SMILES: C1[C@H](N2C3NC=NC(=O)C=3N=C2)O[C@H](COP(OP(OP(O)(O)=O)(O)=O)(O)=O)[C@H]1O.[P:31]([O:43][CH2:44][C@H:45]1[O:49][C@@H:48]([N:50]2[CH:57]=[CH:56][C:54]([NH2:55])=[N:53][C:51]2=[O:52])[CH2:47][C@@H:46]1[OH:58])([O:34]P(OP(O)(O)=O)(O)=O)(=[O:33])[OH:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[Mg+2].[Cl-].[Cl-].[Na+].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+]>>[CH2:47]1[C@H:48]([N:50]2[C:51](=[O:52])[N:53]=[C:54]([NH2:55])[CH:56]=[CH:57]2)[O:49][C@H:45]([CH2:44][O:43][P:31]([OH:33])([OH:34])=[O:32])[C@H:46]1[OH:58]
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: O=c1nc[nH]c2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1
Product: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Temperature: -20 °C
Reaction time: 7 h

Procedure:
A reaction mixture for the synthesis of poly (dI:dC) contains 3.5 μ moles each of dITP and deoxycytidine-5'-triphosphate (dCTP), 600 μ moles of potassium phosphate buffer (pH 7.4) and 30 μ moles of magnesium chloride, and 40-80 units of DNA (deoxynucleic acid) polymerase in a total volume of 10 ml. After a lag period of 2-4 hours, polymerization is complete in 6-8 hours. The course of the reaction is followed by optical density measurements at intervals. When hypochromicity at 260 mμ is at a maximum, the reaction is stopped by adjusting the mixture to 0.2M sodium chloride and 0.1M sodium citrate. Dialysis is extensively carried out against the same buffer to remove all low molecular weight material. The product is stored frozen at -20° C. until used for interferon induction.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[C:24]([O:20][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:21])[C@H:11]2[C@@:2]1([F:1])[C@:3]1([CH3:23])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:22])[CH:5]=[CH:4]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F

Procedure:
A solution of 20 g of 9-fluoro-11β-hydroxyandrosta-1,4-dien-3,17-dione, 120 ml of glacial acetic acid, 120 ml of acetic anhydride and 5 g of p-toluenesulfonic acid was stirred at room temperature under nitrogen for 20 hours. The resulting solution was quenched with 5 g of sodium acetate. The solvent was partially removed in vacuo at 35°-40° C. and the resultant slurry was diluted with chloroform. The chloroform solution was washed with water, saturated sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound. This was crystallized from ethyl acetate-hexane to give 20 g of the title compound melting point 177°-178° C.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:10]([CH2:17][NH:18][CH2:19][CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=2)[C:21]1=[O:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(OCC)C>[CH2:10]([CH2:17][NH:18][CH2:19][CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=2)[C:21]1([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1c2ccc(F)cc2CCC1CNCCc1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: OC1(c2ccccc2)c2ccc(F)cc2CCC1CNCCc1ccccc1

Procedure:
Phenylmagnesium bromide (3 M solution in diethyl ether, 9 cm3) was added to dry diethyl ether (20 cm3) under nitrogen with stirring. This was then cooled to below 0° C. (salt-ice bath) and 2-(N-benzylmethylamino)methyl-6-fluoro-3,4-dihydro-2H-naphthalene-1-one hydrochloride was added in small portions at such a rate as to maintain the temperature below 0° C. (approx. 15 mins). The reaction mixture was stirred for a further 1 h at 0° C. and then poured onto ice. Water (100 cm3) and diethyl ether (100 cm3) were added and the aqueous layer was separated and extracted with further diethyl ether (100 cm3). The combined ether layers were extracted with hydrochloric acid (5 M, 3×50 cm3). The acidic extracts were basified (K2CO3) and re-extracted with dichloromethane (3×75 cm3). The combined extracts were dried (Na2SO4) and the solvent was removed under reduced pressure to provide the title compound (1.55 g) as a brown oil which solidified on standing.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)(=O)C.[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1>>[O:7]([C:8]1[CH:9]=[CH:10][C:11]([C:32]2[C:28]([CH3:27])=[N:29][O:30][C:31]=2[CH3:36])=[CH:12][CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)cc1
Reactant: Cc1noc(C)c1B(O)O
Product: Cc1noc(C)c1-c1ccc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 63 %

Procedure:
By carrying out the operation analogously to example 29, starting from 4-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 3,5-dimethyl-4-isoxazoleboronic acid, the expected compound is obtained in the form of a white solid with a yield of 63%.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:11]C(OCC1C=CC=CC=1)=O)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:11])=[O:4]
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.3 %

Procedure:
(1R,2S)-2-Benzyloxycarbonylamino-cyclohexanecarboxylic acid methyl ester (5.78 g, 19.8 mmol) was dissolved in methanol (200 mL). 10% Palladium on charcoal (0.21 g) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 5 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford the desired product, (1R,2S)-2-amino-cyclohexanecarboxylic acid methyl ester (2.5 g, 15.9 mmol, 80%), as a clear oil. LC-MS (ESI) calcd for C8H15NO2 157.11, found 158.1 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C:11](=O)[CH2:12][C@H:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Mg].Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(Cl)Cl.C(O)C>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=2)[NH:16][C@H:13]([CH2:14][CH3:15])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](CC(=O)NC(=O)OCc1ccccc1)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC[C@@H]1C[C@H](NC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc2N1
Temperature: -12 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A clean, dry and nitrogen gas purged flask was charged with (3R)-[3-(4-trifluoromethyl-phenylamino)-pentanoyl]-carbamic acid benzyl ester (11.51 g, 29.18 mmol) and 95% ethanol (80 mL) and the solution was cooled in an ice/acetone bath (˜−12° C.). Sodium borohydride (0.773 g, 20.4 mmol) was then added to the solution. The internal temperature of the reaction was −11.5° C. To the reaction flask was slowly added a solution of MgCl2.6H2O (6.23 g, 30.6 mmol, in 13 mL H2O). The internal temperature was maintained below −5° C. by adjusting the addition rate. Once all of the magnesium solution was added, the solution temperature was raised to 0° C. and stirred for 30 minutes. The reaction was then quenched by the addition of methylene chloride (115 mL), 1N hydrochloric acid (115 mL) and citric acid (14.02 g, 72.97 mmol). This bilayer was stirred at room temperature. After 3.75 hours, the cyclization reaction was found to be complete by HPLC analysis and the phases were separated. Water (58 mL) and citric acid (8.41 g, 43.77 mmol) were added to the organic layer and the mixture was stirred at room temperature for 45 minutes. The phases were separated and g-60 Darco® activated charcoal (1.52 g) (Atlas Powder Co., Wilmington, Del.) was added to the organic layer. After stirring for 45 minutes, the solution was filtered through Celite® and washed with methylene chloride (2×15 mL). The filtrate was then displaced with hexanes (approximately 350 mL) by distillation under atmospheric pressure and concentration of the mixture to a total volume of 230 mL. The mixture was stirred at room temperature for 14 h, filtered, and dried to afford 9.0872 g (82%) of the title compound.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[Na].[CH3:9][O:10][C:11](Cl)=[O:12]>C1C=CC=CC=1>[CH3:9][O:10][C:11]([N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7])=[O:12]
Reactant: COC(=O)Cl
Reactant: O=C1CCC(=O)N1
Agent: [Na]
Solvent: c1ccccc1
Product: COC(=O)N1C(=O)CCC1=O

Procedure:
Repeating the aforedescribed procedure in the absence of benzene solvent for the sodium succinimide-methylchloroformate reaction yields similar results.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[C:33]([C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:34]([O:36][CH3:37])=[O:35])=[CH:28][CH:27]=1>C1COCC1>[CH3:12][C:11]([CH3:14])([O:10][C:8]([N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([CH:32]([C:29]2[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=2)[CH:33]([C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:34]([O:36][CH3:37])=[O:35])[C:2]1=[O:1])=[O:9])[CH3:13]
Reactant: COC(=O)C(=Cc1ccc(F)cc1)C(=O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)C(C)C)C(c1ccc(F)cc1)C1CCCN(C(=O)OC(C)(C)C)C1=O
Temperature: -30 °C
Reaction time: 0.42 h
Yield: 77.4 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 2-oxo-1-piperidinecarboxylate (10 g, 50 mmole) in anhydrous THF (50 mL) which had been cooled to −20 to −30° C. was added LiHMDS in THF (55 mL, 1M, 55 mmol) solution, maintaining the temperature between −25 to −35° C. The reaction mixture was stirred for 20-30 minutes then transferred via cannula to a cooled solution (−20° C.) of methyl 3-(4-fluorophenyl)-2-isobutyrylacrylate (12.5 g, 50 mmol) in 75 mL anhydrous THF. When the reaction was complete as judged by TLC monitoring, the reaction was quenched with 100 mL of saturated ammonium chloride and extracted with ethyl acetate (2×200 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to provide an off white solid. Recrystallization from ethyl acetate/hexanes afforded 17.4 g (77% yield) of methyl 1-[(1,1-dimethylethoxy)carbonyl]-β-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-2-oxo-3-piperidinepropanoate in as a white crystalline solid. NMR clearly shows a mixture of isomers: IR (KBr) cm−1 2979, 1758, 1755, 1745, 1714, 1671; 1H NMR (CDCl3, 400 MHz) δ 7.21-7.20 (m, 4H), 6.93-6.92 (m, 4H), 4.40 (dd, 2H), 4.09 (m, 2H), 3.66 (s, 3H), 3.58-3.33 (m, 4H), 3.32 (s, 3H), 2.80-2.48 (m, 4H), 2.02-1.60 (m, 6H), 1.47 (s, 18H), 1.43-1.51 (m, 2H), 1.08 (d, J=4 Hz, 3H), 1.05 (d, J=8 Hz, 3H), 0.85 (d, J=4 Hz, 3H), 0.71 (d, J=8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 206.9, 206.8, 171.7, 171.6, 168.4, 168.2, 162.6, 160.2, 151.9, 134.5, 134.3, 131.1, 130.0, 130.8, 130.7, 115.2, 115.1, 115, 114.9, 82.9, 61.5, 60.8, 53.0, 52.6, 48.2, 48.0, 46.3, 45.9, 45.6, 44.9, 41.9, 40.9, 28.63, 24.2, 24.0, 21.9, 21.3, 19.5, 19.0, 18.8, 18.7; HRMS (ES) calcd. for C24H32FNNaO6 (M+Na): 472.2111; found: 472.2100.
Reaction SMILES: O[C:2]([CH3:6])([CH3:5])[C:3]#[N:4].[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[NH2:4][CH2:3][C:2]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:6])[CH3:5]
Reactant: CC(C)(O)C#N
Reactant: C1CCNCC1
Product: CC(C)(CN)N1CCCCC1

Procedure:
The starting material 1-(2-amino-1,1-dimethylethyl)piperidine was prepared in a route similar to that in Example 39 from 2-hydroxy-2-methyl-propionitrile and piperidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[NH2:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:30]([CH:36]2[CH2:40][CH2:39][CH2:38][N:37]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:29](F)[CH:28]=1>C(OCC)(=O)C>[NH2:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:30]([CH:36]2[CH2:40][CH2:39][CH2:38][N:37]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:29]([O:14][C:11]2[CH:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:13][CH:12]=2)[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc([N+](=O)[O-])c(N)cc1F
Reactant: Oc1ccc(-c2ccccc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1c1cc([N+](=O)[O-])c(N)cc1Oc1ccc(-c2ccccc2F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
200 mg of 2′-fluorobiphenyl-4-ol and 184 mg of potassium carbonate were added to an N,N-dimethylformamide (3 ml) solution of 288 mg of t-butyl 2-(4-amino-2-fluoro-5-nitrophenyl)pyrrolidine-1-carboxylate, and the reaction liquid was stirred overnight at 80° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:12]C1CCCCO1)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([OH:12])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCC#CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCCCCCCC#CCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a solution of tetrahydro-2-(2-undecynyloxy)-2H-pyran in methanol (100 mL), was added p-toluenesulfonic acid (30 mg). The mixture was stirred at room temperature for 4 hours. The solvent was removed by rotary evaporation. The residue was taken up in ether (150 mL) and washed with aqueous saturated NaHCO3 (120 mL), saturated NaCl (120 mL) and water (200 mL). The organic layer was dried (MgSO4) and concentrated to yield a yellow oil. Purification by flash silica gel chromatography (90:10 hexane/EtOAc) afforded 2-undecyn-1-ol (48) (2.6 g, 77% overall) as a colorless oil: Rf 0.27 (90:10 hexane/EtOAc); IR (neat) 3300, 2925, 2855, 1437, 1110 Cm-1 ; 1H NMR (CDCl3) δ 4.18 (t, J=2.4 Hz, 2 H), 2.8 (s, 1 H), 2.14 (tt, J1 =7.2 Hz, J2 =2.4 Hz, 2 H), 1.35 (m, 12 H), 0.82 (t, J=6.9 Hz, 3 H); 13C NMR (CDCl3) δ 86.15, 78.28, 50.93, 31.76, 29.09, 29.04, 28.82, 28.56, 22.56, 18.63, 13.95. ##STR22##
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([CH:16]1[CH:20]([C@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][N:18](CC2C=CC=CC=2)[CH2:17]1)=[O:15].O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:12][O:13][C:14]([CH:16]1[CH:20]([C@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:19][N:18]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17]1)=[O:15]
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1[C@H](C)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@H](C)CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
Benzyloxycarbonyl chloride (3.25 mL, 22.8 mmol) was added to a solution of 1-benzyl-4-[(S)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]pyrrolidine-3-carboxylic acid methyl ester (2.97 g, 7.58 mmol) in dichloromethane (20 mL), and the mixture was stirred for one hour. Saturated sodium bicarbonate water was added to the reaction mixture. The organic layer was separated, dried over magnesium sulfate, and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3.1 g (96%) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.