Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[O:22]1CCOC[CH2:23]1>ClC(OC(Cl)(Cl)Cl)=O>[N:1]([C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])=[C:23]=[O:22]
Reactant: C1COCCO1
Reactant: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1N
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Product: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1N=C=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
6.04 g of 3-(3-amino-4-methoxyphenyl)-1-trifluoroacetyl piperidine in 120 ml of dioxane and 2.9 ml of trichloromethyl chloroformate were mixed together and stirred for 4 hours at 80° C. Then, the mixture was evaporated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of cyclohexane and ethyl acetate (7-3) to obtain 6.4 g of crude product which was used as is for the following step.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C1COCC1>[F:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:25]=1[C:26](=[O:27])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Cc1ccc(C(=O)Cl)c(F)c1
Reactant: CCOC(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1ccc(C)cc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The solution of ethyl 2-phenylacetate (5 g, 30.5 mmol) in THF (20 mL) was cooled to −78° C. and LiHMDS (30.5 mL, 30.5 mmol) was added, followed by prior made solution of 2-fluoro-4-methylbenzoyl chloride in THF (10 mL). The reaction was allowed to warm to room temperature slowly and stirred for 4 h. Quenched with AcOH (2 mL), extracted with EtOAc, washed with brine, dried over MgSO4, and purified by column chromatography to give the title compound as clear liquid (7.10 g). LCMS m/z=301.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.07 Hz, 3H), 2.32 (s, 3H), 4.22 (q, J=7.07 Hz, 2H), 5.77 (s, 1H), 7.03-7.17 (m, 3H), 7.24-7.40 (m, 4H), 7.82 (t, J=8.21 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6](O)[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:22]([O:27]C)([O:25][CH3:26])[O:23][CH3:24]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])/[CH:6]=[C:7](\[C:9]([CH3:12])([CH3:11])[CH3:10])/[CH2:8][P:22]([O:25][CH3:26])([O:23][CH3:24])=[O:27])[CH3:2]
Reactant: C=C(C(O)C(NC=O)C(=O)OCC)C(C)(C)C
Reactant: COP(OC)OC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C(/CP(=O)(OC)OC)C(C)(C)C)NC=O

Procedure:
The starting material is manufactured as follows: Reaction of 3,3-dimethyl-2-methylene-butanal with isocyanoacetic acid ethyl ester in amanner analogous to that described in Example 1 yields 5-(3,3-dimethylbuten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed analogously to Example 17 to 2-formylamino-3-hydroxy-4-tert.-butyl-4-pentenoic acid ethyl ester. Subsequent reaction with thionyl bromide followed by treatment with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-tert.-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH:12]1[CH2:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:19]([F:29])[CH:18]=3)(O)[CH2:13]1)=[O:11])[CH2:2]2.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH:5]12[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:10]([CH:12]1[CH2:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[C:19]([F:29])[CH:18]=3)=[CH:13]1)=[O:11])[CH2:4]2
Reactant: O=C(C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1)N1CC2CCC(CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(C1C=C(c2ccc(CN3CCCC3)c(F)c2)C1)N1CC2CCC(CC2)C1

Procedure:
A solution of example 26, 3-aza-bicyclo[3.2.2]nonan-3-yl(3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-hydroxycyclobutyl)methanone (0.59 g, 1.48 mmol) in trifluoroaceticacid (2.5 mL) and 1,2-dichloroethane (16 mL) was refluxed for 20 h and concentrated to give crude 3-aza-bicyclo[3.2.2]nonan-3-yl(3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclobut-2-enyl)methanone trifluoroacetate salt as a dark purplish-brown oil, with residual TFA. This material was dissolved in EtOH (40 mL) and added to a hydrogenation bottle containing 10% palladium on carbon (93 mg) slurried in EtOH (˜3 mL). The mixture was shaken at room temperature under 48 psi of hydrogen for 2 h, filtered through diatomaceous earth with an EtOH rinse and concentrated to yield an orange oil. This was dissolved in EtOAc and washed with aqueous K2CO3 and brine, dried over MgSO4 and concentrated to afford 0.38 g of light orange oil. Flash chromatography on a 2″×3.5″ silica gel column flushing with 2% MeOH/EtOAc (500 mL) and then eluting with 500 ml each 5% and 10% MeOH/EtOAc afforded 0.256 g (45%) of the title compound as a light orange oil: Rf=0.21 (20% MeOH/EtOAc).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:13]([CH3:15])[CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:18]1>>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:19]2[CH2:20][CH2:21][CH:17]([NH:16][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([Cl:1])[C:3]([N:13]([CH3:15])[CH3:14])=[CH:4][C:5]=3[O:11][CH3:12])[CH2:18]2)=[CH:28][CH:27]=1
Reactant: COc1cc(N(C)C)c(Cl)cc1C(=O)O
Reactant: NC1CCN(Cc2ccc(F)cc2)C1
Product: COc1cc(N(C)C)c(Cl)cc1C(=O)NC1CCN(Cc2ccc(F)cc2)C1

Procedure:
Following the procedure set forth in general method A supra using 1.15 g. of 5-chloro-4-dimethylamino-2-methoxybenzoic acid and 1.07 g. of 3-amino-1-(4-fluorobenzyl)-pyrrolidine, 0.9 g. of N-[1-(4-fluorobenzyl)-3-pyrrolidinyl]-5-chloro-4-dimethylamino-2-methoxybenzamide was obtained.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13](/[CH:15]=[CH:16]/[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH2:20][OH:21])=[N:12][C:11]=2[CH:25]=1.N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C(OCC)(=O)C>[Si:31]([O:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17](/[CH:16]=[CH:15]/[C:13]2[S:14][C:10]3[CH:9]=[CH:8][C:7]([F:6])=[CH:25][C:11]=3[N:12]=2)[CH:18]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(/C=C/c2nc3cc(F)ccc3s2)c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(/C=C/c2nc3cc(F)ccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 ml of dimethylformamide containing 2.0 g of 3-(5-fluorobenzothiazol-2-yl-trans-ethenyl)benzyl alcohol and 1.19 g of imidazole was added 1.37 g of t-butyldimethylsilyl chloride and the reaction mixture stirred overnight under nitrogen at room temperature. After 48 hours of reaction time, the mixture was poured into 500 ml of ethyl acetate and washed with water (3×150 ml), a 1N hydrochloric acid solution (2×150 ml), water (1×200 ml) and a brine solution (1×200 ml) The organic layer was separated, dried over sodium sulfate and concentrated to a white solid. The residue was recrystallized from ethyl acetate--hexane, 1.57 g, m.p. 91°-93° C.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:1]([C:3]1[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCc1cc2c(OC)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(OC)cccc2n1Cc1ccccc1
Reaction time: 1.5 h
Yield: 48.7 %

Procedure:
2-Ethyl-4-methoxy-1H-indole (4.2 g, 24 mmol) was dissolved in 30 mL of DMF and 960 mg (24 mmol) of 60% NaH/mineral oil was added. After 1.5 hours, 2.9 mL(24 mmol) of benzyl bromide was added. After 4 hours, the mixture was diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate was washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 3.1 g (49% yield) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[N:8][C:7]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[Br:19]N1C(=O)CCC1=O>CS(C)=O.O>[Br:19][C:9]1[C:10]([NH2:12])=[N:11][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[C:7]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cnc(-c2ccncc2)c(-c2ccco2)n1
Solvent: CS(C)=O
Solvent: O
Product: Nc1nc(-c2ccco2)c(-c2ccncc2)nc1Br
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 76.1 %

Procedure:
To a 0° C. stirred solution of 6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5, 195 mg, 0.82 mmol) in dimethylsulfoxide (1.5 mL) and water (40 μL), was added portionwise N-bromosuccinimide (146 mg, 0.82 mmol). The mixture was stirred at room temperature for 40 min, then poured into water, extracted with dichloromethane (×3), the organic layers washed with brine, dried (MgSO4) and evaporated to furnish the title compound (198 mg, 75%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:23]=[C:22]([CH2:24][CH3:25])[S:21][C:10]=2[N:11]([CH3:20])[C:12](=[O:19])[C:13]=1[C:14]([O:16]CC)=[O:15].[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:23]=[C:22]([CH2:24][CH3:25])[S:21][C:10]=2[N:11]([CH3:20])[C:12](=[O:19])[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(CC)sc2n(C)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cc2c(-c3ccccc3Cl)c(C(=O)O)c(=O)n(C)c2s1
Temperature: 80 °C
Yield: 89.4 %

Procedure:
A mixture of ethyl 4-(2-chlorophenyl)-6,7-dihydro-2-ethyl-7-methyl-6-oxothieno[2,3-b]pyridine-5-carboxylate (1.10 g), KOH (0.49 g) and 80% ethanol (10 ml) was heated at 80° C. for 20 minutes and water was added. Then, the mixture was made acidic with 2N HCl and extracted with ethyl acetate. The extract was washed with water and dried over MgSO4, and then the solvent was distilled off. To the residue was added hexane to obtain 4-(2-chlorophenyl)-6,7-dihydro-2-ethyl-7-methyl-6-oxothieno[2,3-b]pyridine-5-carboxylic acid as crystals (0.91 g, 89.3%). The crystals were recrystallized from ethanol to obtain colorless prisms, mp: 155°-156° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46](O)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]>C(Cl)Cl>[CH3:1][N:2]([C:46](=[O:47])[C:45]1[CH:49]=[C:41]([CH2:40][C:34]2[C:35](=[O:39])[C:36]([O:37][CH3:38])=[C:31]([O:30][CH3:29])[C:32](=[O:55])[C:33]=2[CH3:54])[CH:42]=[CH:43][C:44]=1[O:50][C:51](=[O:53])[CH3:52])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:7][CH:8]=1
Reactant: CNc1ccc(C(F)(F)F)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N(C)c3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
N-Methyl-4-trifluoromethylaniline (0.200 g, 1.143 mmol), triethylamine (0.116 g, 1.143 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.193 g, 1.143 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.285 g, 0.762 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.140 g, 0.263 mmol, 35%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.C([N:16]1[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)(=O)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([CH:19]2[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:30])=[CH:24][CH:25]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(F)cc1)(c1ccccn1)C1CCNCC1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 36.3 g (0.23 mole) of 2-bromopyridine in 500 ml of anhydrous tetrahydrofuran (THF) at -65° C. was added 88 ml (0.22 mole) of a commercial solution of 2.5M n-butyllithium in hexane at such a rate that the temperature did not exceed -60° C. The dark solution was stirred at -65° C. for 1 hr and then treated dropwise with a solution of 24.9 g (0.1 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 250 ml of THF at such a rate that the temperature did not exceed -60° C. The mixture was stirred for 1 hr at -65° C. and overnight at ambient temperature. The dark mixture was poured into 2 liters of a saturated ammonium chloride solution. The layers were separated, and the aqueous layer was extracted once with a 500-ml portion of methylene chloride. The combined organic layers were washed successively with 500 ml of water, 500 ml of a 4% sodium hydroxide solution, 250 ml of water, and 250 ml brine.
Reaction SMILES: [Ti](Cl)(Cl)(Cl)[Cl:2].[CH:6]([O:9][Ti:10](OC(C)C)([O:15][CH:16]([CH3:18])[CH3:17])[O:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7]>ClCCl>[Cl:2][Ti:10]([O:15][CH:16]([CH3:18])[CH3:17])([O:11][CH:12]([CH3:14])[CH3:13])[O:9][CH:6]([CH3:8])[CH3:7]
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: ClCCl
Product: CC(C)O[Ti](Cl)(OC(C)C)OC(C)C

Procedure:
0.38 g (2.0 mmol) of titanium tetrachloride and 2 mL of anhydrous dichloromethane were weighed in a test tube equipped with a lid, and 1.7 g (6.0 mmol) of tetra-iso-propoxy titanium was added dropwise thereto while stirring. After stirring at room temperature for 60 minutes, the reaction solution was transferred to a 10-mL volumetric flask, and anhydrous dichloromethane was added thereto for diluting to 10 mL, whereby a uniform, colorless and transparent dichloromethane solution (0.80 mol/L) of chloro-tri-iso-propoxy titanium was obtained.
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:34]1[CH2:38][C@@H:37]([CH3:39])[C:36](=[O:40])[O:35]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[CH2:19][C:18]1([CH3:33])[CH3:32])([CH3:11])([CH3:10])[CH3:9].O.[CH:43]1([NH2:49])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[CH2:19][C:18]1([CH3:33])[CH3:32])[C@@H:34]([OH:35])[CH2:38][C@H:37]([C:36](=[O:40])[NH:49][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[CH3:39])([CH3:11])([CH3:9])[CH3:10]
Reactant: NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3c(F)cccc3F)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Agent: Oc1ccccn1
Solvent: O
Product: C[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2c(F)cccc2F)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NC1CCCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
7.9 mg of 2-hydroxypyridine (0.08 mmol) was added to a solution of 200 mg of {(S)-2-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (93b) (0.41 mmol) in cyclohexylamine (1.0 ml), and the mixture was stirred at 80° C. for three hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 218 mg of the title compound (yield: 88%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16](=O)[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=3[CH3:26])=[C:7]([C:11](OCC)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.O.[NH2:29][NH2:30]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=4[CH3:26])=[N:30][NH:29][C:11](=[O:12])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1[nH]c2cc(Br)ccc2c1C(=O)c1cccc([N+](=O)[O-])c1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1c(-c2n[nH]c(=O)c3[nH]c4cc(Br)ccc4c23)cccc1[N+](=O)[O-]
Yield: 81.8 %

Procedure:
A solution of ethyl 6-bromo-3-(2-methyl-3-nitrobenzoyl)-1H-indole-2-carboxylate (6.02 g, 13.96 mmol) and hydrazine hydrate (2.446 g, 48.9 mmol) in ethanol (200 mL) was heated at reflux for 16 hr. The mixture was concentrated under vacuum to a volume of approximate 30 mL. The insoluble product (4.56 g, 11.42 mmol, 82% yield) was collected by suction filtration and dried under vacuum at 50° C.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:12][CH2:13][CH:14]=[CH2:15])([CH2:7][CH2:8][C:9]([OH:11])=O)=[O:6])[CH:2]=[CH2:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:28]([O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][NH:35]1)([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[CH2:13]([O:12][P:5]([O:4][CH2:1][CH:2]=[CH2:3])([CH2:7][CH2:8][C:9]([N:35]1[CH2:36][CH2:37][CH2:38][C@H:34]1[C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:39])=[O:11])=[O:6])[CH:14]=[CH2:15]
Reactant: C=CCOP(=O)(CCC(=O)O)OCC=C
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: C=CCOP(=O)(CCC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)OCC=C
Reaction time: 1 h

Procedure:
3-[bis(2-propenyloxy)phosphinyl]propionic acid (3.4 g., 0.014 mol.) is dissolved in 75 ml. of acetonitrile and stirred in an ice bath under a drying tube. 1,1'-Carbonyldiimidazole (2.26 g., 0.014 mole) in 25 ml. of acetonitrile is added and the mixture is stirred for 1 hour. L-Proline t-butyl ester (2.38 g., 0.014 mole) is added, the ice bath is removed, and the mixture is stirred overnight. The solution is evaporated in vacuo, the residue dissolved in ethyl acetate and washed with 5% potassium bisulfate, saturated sodium bicarbonate solution and brine, then dried (Na2SO4) and evaporated to a viscous liquid, 1-[3-[bis(2-propenyloxy)phosphinyl)]-1-oxopropyl]-L-proline, tert-butyl ester, yield 4.2 g., 77%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(COc3ccccc3)CC2)cc1
Reaction time: 25 h
Yield: 41.4 %

Procedure:
0.3 g (0.00146 mol) 1-benzyl-4-hydroxymethyl-piperidine, 0.137 g (0.00146 mol) of phenol and 0.45 g (0.0017 mol) of triphenylphosphine were dissolved in 10 ml of toluene, cooled to 10° and treated slowly with 0.264 ml (0.0017 mol) of diethyl azodicarboxylate. The mixture was stirred at 90° for 25 hrs. The solvent was removed, the residue was taken up in ethyl acetate, washed three times with 40 ml of water each time and three times with 40 ml of 2N aqueous NaOH each time and the organic phase was dried over magnesium sulfate. The solvent was removed. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:2) as the eluent. 0.17 g (41.4%) 1-benzyl-4-phenoxymethylpiperidine was obtained as white crystals; m.p. 56°-57°.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]=[CH:14][C:15](=[O:17])[CH3:16].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[OH:23][C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][C:15](=[O:17])[CH:14]=[CH:13][O:12][CH3:11]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC=CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=CC(=O)C=C(O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
LiHMDS (1M in THF, 100 mL, 2 eq) is added dropwise to a cold (−78° C.) solution of 4-methoxy-3-buten-2-one (10 mL, 100 mmol, 2 eq) in THF (400 mL). After a 30 min stirring at −78° C., a solution of pivaloyl chloride (6.12 mL, 50 mmol) in THF (100 mL) is added. The resulting mixture is allowed to warm to it over 2 h and quenched by addition of a saturated solution of NH4Cl. THF is removed under vacuum. The concentrated mixture is extracted with Et2O. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:0→85:15) to afford 6.83 g of the title compound as a yellow oil: ESI-MS: 185.1 [M+H]+; TLC: Rf=0.87 (Hex/EtOAc, 1:1).
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][N:5]2[N:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:4]2[CH2:3]1.[H][H]>CO.[Ni]>[CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][N:5]2[N:9]=[C:10]([NH2:12])[CH:11]=[C:4]2[CH2:3]1
Reactant: [H][H]
Reactant: CC1Cn2nc([N+](=O)[O-])cc2CN1C
Agent: [Ni]
Solvent: CO
Product: CC1Cn2nc(N)cc2CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of 250d (550 mg, 2.8 mmol) in methanol (20 mL) was added Raney Ni (about 600 mg). The reaction was charged with hydrogen gas (via balloon) and stirred for 2 h at room temperature. It was then filtered through a plug of CELITE® and the filtrate was concentrated under reduced pressure to afford 250e as a yellow solid (400 mg, 86%), which was used directly in the next step without further purification. MS-ESI: [M+H]+ 167.3
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]2[CH2:18][O:19][C@@H:5]1[O:6]2)=[N+]=[N-].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH2:11]([O:10][C@@H:8]1[C@H:7]2[CH2:18][O:19][C@H:5]([O:6]2)[C@H:4]([N:1]2[C:23](=[O:24])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:25])[CH2:9]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: [N-]=[N+]=N[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reaction time: 360 h
Yield: 14.3 %

Procedure:
1,6-Anhydro-2-azido-4-O-benzyl-2,3-dideoxy-β-D-ribo-hexoyranose (see Example 13) (1.0 g), phthalic anhydride (0.74 g), triphenylphosphine (1.21 g) and tetrabutylammonium cyanide (0.1 g) were heated under reflux in a nitrogen atmosphere in benzene (50 ml) for 40 h. Methanol (10 ml) was then added and the solution was allowed to stand at room temperature for 15 days. The solution was then evaporated and the residue was chromatographed on silica gel to yield the title compound as a crystaline solid (0.2 g, 14%) from amongst a variety of products (t.l.c.evidence). Recrystallised from ethanol it had m.p. 135°-136° C., [α]D -28.4°; 13C-nmr data: 100.4 (C-1), 51.1 (C-2), 25.0 (C-3), 76.5 and 75.7 (C-4 and C-5), 67.4 (C-6), 70.4 (PhCH2O), 167.7 (C=0), 156.0 and 131.8 (q-aromatic), 134.0, 128.3, 127.6, 127.5 and 123.3 (aromatic).