Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH:10]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][NH:8][C:7](=S)[C:6]1=[O:15].[C:24]([NH:32][NH2:33])(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>C(O)CCC>[Cl:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH:10]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][N:8]2[C:24]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[N:32][N:33]=[C:7]2[C:6]1=[O:15]
Reactant: NNC(=O)c1cccnc1
Reactant: O=C1C(=S)NCC(C2CC2)N1Cc1cccc(C(F)(F)F)c1Cl
Solvent: CCCCO
Product: O=C1c2nnc(-c3cccnc3)n2CC(C2CC2)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A solution of (±)-1-(2-chloro-3-(trifluoromethyl)benzyl)-6-cyclopropyl-3-thioxopiperazin-2-one (100 mg, 0.28 mmol) and nicotinohydrazide (38 mg, 0.28 mmol) in 1-butanol (3 mL) was heated at 130° C. for 16 h. After cooling to rt, the precipitate was filtered and washed with hexanes to afford the desired product as a white solid (68 mg, 55%). MS (ESI): mass calcd. for C21H17ClF3N5O, 447.1; m/z found, 448.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=1.7 Hz, 1H), 8.79 (dd, J=4.8, 1.6 Hz, 1H), 8.21-8.16 (m, 1H), 7.74-7.61 (m, 2H), 7.52 (dd, J=7.9, 4.9 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 5.47 (d, J=15.8 Hz, 1H), 4.76 (d, J=15.8 Hz, 1H), 4.52 (dd, J=12.7, 4.3 Hz, 1H), 4.41 (dd, J=12.7, 3.1 Hz, 1H), 3.18-3.11 (m, 1H), 1.08-0.90 (m, 1H), 0.84-0.69 (m, 1H), 0.59-0.47 (m, 2H), 0.20-0.14 (m, 1H).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:14])=[C:10]([O:12]C)[CH:11]=1>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([OH:12])[C:9]([Cl:14])=[CH:8][CH:7]=1
Reactant: COc1cc(Br)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 50 mL of a 1M solution of boron tribromide in CH2Cl2 at 0° C. was added 5.71 g (25.8 mmol) of 5-Bromo-2-chloroanisole. After 2 hours, the reaction was allowed to warm to room temperature. After 5 hours, the solution was cooled to 0° C., and quenched with methanol. The resulting solution was partitioned between water and ethyl acetate, and the phases were separated. The aqueous phase was back-extracted once with ethyl acetate. The combined ethyl acetate phases were diluted with one volume of ether, and were extracted twice with 1M NaOH. The combined basic aqueous phases were acidified with 12M HCl, and were extracted once with ethyl acetate. The final ethyl acetate phase was washed once with brine, dried over MgSO4, filtered, and concentrated to give the phenol as a tan solid. 1H NMR (DMSO-d6, 400 MHz) 10.66 (s, 1H), 7.27 (d, 1H), 7.08 (s, 1H), 6.95 (d, 1H) ppm.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:16]([O:23][C:24]([NH:26][C@@H:27]([CH2:40]O)[C:28]([O:30][CH2:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)CCl.C1(C)C=CC=CC=1.C(OCC)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:8]1([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([O:12][CH2:40][C@H:27]([NH:26][C:24]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25])[C:28]([O:30][CH2:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29])=[O:11]
Reactant: O=C(N[C@@H](CO)C(=O)OCC(=O)c1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(=O)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
15.06 g of N-Boc-(L)-proline (69.96 mmol) and 25.00 g (69.96 mmol) of the serine ester from example 1A are dissolved in methylene chloride (250 ml) under argon. The solution is cooled to −20° C. and treated with 13.41 g of EDC (69.96 mmol) and 0.85 g of DMAP (7.00 mmol). The reaction solution is stirred at −20° C. for 1 h and then at room temperature for 48 h, evaporated and the residue is taken up in ethyl acetate. The solution is washed with aq. citric acid, aq. saturated sodium hydrogen-carbonate solution and aq. saturated sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. 32.47 g (84% of th.) of product are isolated after silica gel chromatography using toluene/ethyl acetate (5/1).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13][CH:14]=2)[O:3]1.CI.[C:26](=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:26][N:15]([C:12]1[N:11]=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:23])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:14][N:13]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Cs+]
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
Tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-ylcarbamate (250 mg) was treated with 3 equivalents methyl iodide and cesium carbonate at room temperature for one hour. The crude reaction mixture was extracted with ethyl acetate and water. The initial organic layer is discarded. The aqueous layer was acidified to pH 5 and the product was extracted out of the aqueous with ethyl acetate. This organic layer was dried with magnesium sulfate, filtered and concentrated to give 150 mg crude tert-butyl methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-ylcarbamate.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C:12]([CH3:48])([CH2:17][CH2:18][C:19](=[O:47])[N:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[O:34][C:35](=[O:46])[C:36]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:40]=4[S:39][C:37]=3[N:38]=2)[CH:28]=1)[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:13]([O:15][CH3:16])=[O:14].[N:49]1([CH2:55][CH2:56][C:57]2[CH:63]=[CH:62][C:60]([NH2:61])=[CH:59][CH:58]=2)[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.[Cl-].[NH4+]>C1COCC1>[CH3:48][C:12]([CH3:11])([CH2:17][CH2:18][C:19]([N:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33](=[O:34])[NH:38][C:37]2[S:39][C:40]3[CH2:45][CH2:44][CH2:43][CH2:42][C:41]=3[C:36]=2[C:35](=[O:46])[NH:61][C:60]2[CH:62]=[CH:63][C:57]([CH2:56][CH2:55][N:49]3[CH2:50][CH2:51][O:52][CH2:53][CH2:54]3)=[CH:58][CH:59]=2)[CH:28]=1)[CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:47])[C:13]([O:15][CH3:16])=[O:14]
Reactant: Nc1ccc(CCN2CCOCC2)cc1
Reactant: CCC(CC)N(Cc1cccc(-c2nc3sc4c(c3c(=O)o2)CCCC4)c1)C(=O)CCC(C)(C)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCN4CCOCC4)cc2)CCCC3)c1)C(=O)CCC(C)(C)C(=O)OC
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
Lithium hexamethyldisilazide (1.0 M in THF) 1.1 mL was added dropwise to a mixture of 200 mg of methyl 2,2-dimethyl-5-oxo-5-{[3-(4-oxo-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-2-yl)benzyl](pentan-3-yl)amino}pentanoate, 90 mg of 4-[2-(morpholin-4-yl)ethyl]aniline, and 5.0 mL of THF under ice cooling, followed by stirring for 30 minutes at the same temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), thereby obtaining 164 mg of methyl 2,2-dimethyl-5-[(3-{[3-({4-[2-(morpholin-4-yl)ethyl]phenyl}carbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]carbamoyl}benzyl)(pentan-3-yl)amino]-5-oxopentanoate.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8]2)=[CH:4][C:3]=1[F:18].[CH2:19]([C:26]1[CH:37]=[CH:36][C:29]2[CH:30]=[C:31](B(O)O)[O:32][C:28]=2[CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([C:26]1[CH:37]=[CH:36][C:29]2[CH:30]=[C:31]([C:2]3[CH:17]=[CH:16][C:5]([CH2:6][N:7]4[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8]4)=[CH:4][C:3]=3[F:18])[O:32][C:28]=2[CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1cc2ccc(Cc3ccccc3)cc2o1
Reactant: CCOC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Product: CCOC(=O)C1CN(Cc2ccc(-c3cc4ccc(Cc5ccccc5)cc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B2 and general procedure F using ethyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (0.150 g, 0.474 mmol) and 6-benzylbenzofuran-2-ylboronic acid (0.155 g, 0.617 mmol) to give ethyl 1-((4-(6-benzylbenzofuran-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylate. MS (ESI) m/z: Calculated: 443.2; Observed: 444.1 (M++1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].C(=O)(O)O.[K+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:17]=[C:18]([C:28]5[CH:29]=[N:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=5)[CH:19]=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C(O)O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)n2)cn1
Temperature: 80 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide (36 mg, 0.10 mmol) and 6-methoxypyridin-3-ylboronic acid (19 mg, 0.12 mmol) were dissolved in 1 mL of N,N-dimethylformamide (DMF) containing 0.2 mL of a 2M aqueous solution of potassium carbonate potassium carbonate and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (Pd(dppf)Cl2, 7.1 mg, 0.010 mmol). The resulting solution was stirred and heated to 80° C. for 16 hours. The resulting material was cooled to room temperature, filtered, and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product. ESI-MS m/z calc. 389.1. found 390.1 (M+1)+. Retention time 3.57 minutes
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.[CH3:20][S:21]([NH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[CH3:12][C:9]1([CH3:13])[O:8][C:6]2[N:7]=[C:2]([C:29]3[CH:30]=[C:25]([NH:24][S:21]([CH3:20])(=[O:22])=[O:23])[CH:26]=[CH:27][CH:28]=3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[O:11][CH2:10]1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)COc2c(nc(-c3cccc(NS(C)(=O)=O)c3)nc2N2CCOCC2)O1
Temperature: 120 °C
Yield: 14.5 %

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), 3-(methanesulfonylamino)phenylboronic acid (57 mg, 0.27 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then evacuated and back filled with nitrogen before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 114 as a white solid (11 mg, 15%). LCMS: RT=4.22 min, [M+H]+=421. 1H NMR (400 MHz, CDCl3): δ 8.19-8.12 (1H, m), 8.05-8.02 (1H, m), 7.44-7.37 (2H, m), 6.34 (1H, broad s), 3.92 (2H, s), 3.88-3.79 (8H, m), 3.00 (3H, s), 1.47 (6H, s)
Reaction SMILES: N[C@@H](C([N:6]([CH2:36][CH:37]([CH3:39])[CH3:38])[NH:7][C:8](=[O:35])[C@@H:9]([CH:14]([C:25](=[O:34])[NH:26][O:27]C1CCCCO1)[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:10][CH:11]([CH3:13])[CH3:12])=O)C.O.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1>CO>[C:41]1([CH3:51])[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:48])=[O:49])=[CH:45][CH:46]=1.[CH:19]1([CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([C@@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:8]([NH:7][NH:6][CH2:36][CH:37]([CH3:38])[CH3:39])=[O:35])[C:25](=[O:34])[NH:26][OH:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)N)C(CCCCC1CCCCC1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)CNNC(=O)[C@H](CC(C)C)C(CCCCC1CCCCC1)C(=O)NO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 0.210 g of 2′-(D-alanyl)-2(R)-[5-cyclohexyl-1(RS)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]pentyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of methanol was treated with 0.080 g of p-toluenesulphonic acid monohydrate. The mixture was stirred at room temperature for 6 hours and evaporated. The residue was triturated with diethyl ether to give 0.151 g of 2′-D-alanyl)-2(R)-[5-cyclohexyl-1(RS)-(hydroxycarbamoyl)pentyl]-2′-isobutyl-4-methylvalerohydrazide p-toluenesulphonate in the form of a white solid.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C.Cl.[CH3:21][C:22]1([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CCOC(C)=O.O>[CH2:1]([N:25]1[CH2:26][CH2:27][C:22]([CH3:21])([C:28]([NH2:30])=[O:29])[CH2:23][CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CC1(C(N)=O)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C(N)=O)CCN(Cc2ccccc2)CC1
Reaction time: 16 h
Yield: 97.8 %

Procedure:
Benzyl chloride (1.90 g) and sodium carbonate (1.59 g) were added to a DMF (70 ml) suspension of 4-methylpiperidine-4-carboxamide hydrochloride (2.24 g), and stirring was performed at room temperature for 16 hours. After adding water to the reaction liquid, extraction was performed with EtOAc. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (MeOH/chloroform) to obtain 1-benzyl-4-methylpiperidine-4-carboxamide (2.85 g).
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([C@H:17]1[O:19][CH2:18]1)[Cl:16]>>[Cl:16][CH2:15][C@@H:17]([OH:19])[CH2:18][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: ClC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1nccn1C[C@H](O)CCl

Procedure:
Alternatively, reaction of 2-nitroimidazole, anhydrous potassium carbonate, and (S)-(+)-epichlorohydrin as described in Example 1(a) gives the product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21]2[CH:31]=[CH:30][C:24]([C:25](OCC)=[O:26])=[CH:23][N:22]=2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO.O>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21]2[N:22]=[CH:23][C:24]([CH2:25][OH:26])=[CH:30][CH:31]=2)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(N[C@@H]2CCCN(Cc3ccccc3)C2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(N[C@@H]2CCCN(Cc3ccccc3)C2)nc1
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a suspension of lithium aluminum hydride (70 mg, 1.8 mmol) in tetrahydrofuran (2 mL) was added a solution of ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}nicotinate (250 mg, 0.74 mmol) in tetrahydrofuran (5 mL) dropwise at 0° C. under nitrogen and the mixture was stirred at same temperature for 3 hrs. To the reaction mixture was added methanol and water dropwise at 0° C. and the mixture was stirred for 1 h. The precipitate was removed by vacuum filtration and the filtrate was evaporated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give (6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)methanol (219 mg, 100%) as an oil.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[O:31]1CC[CH2:33][CH:32]1CN>>[O:31]1[CH2:32][CH2:33][CH2:12][CH:11]1[CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCC1CCCO1
Product: O=C(NCC1CCCO1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 1-(tetrahydrofuran-2-yl)methaneamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 343 (M+H) 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 10.54 (1H, s) 8.01 (1H, d, J=7.03 Hz) 7.67 (1H, d, J=5.27 Hz) 7.42 (1H, d, J=5.27 Hz) 7.39 (1H, dd, J=3.42, 1.85 Hz) 6.97 (1H, d, J=6.83 Hz) 6.66 (1H, dd, J=3.42, 1.66 Hz) 3.95 (1H, qd, J=6.80, 4.59 Hz) 3.72 (1H, dt, J=8.15, 6.56 Hz) 3.57-3.66 (1H, m) 3.29-3.48 (2H, m) 1.87-1.97 (3H, m) 1.77-1.86 (2H, m) 1.48-1.60 (1H, m)
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([F:34])=[C:26]([CH2:35][C:36]2[S:37][C:38](Br)=[CH:39][CH:40]=2)[CH:25]=1)(=O)C.[C:42]([C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1)#[N:43]>>[C@@H:6]1([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([F:34])=[C:26]([CH2:35][C:36]3[S:37][C:38]([C:48]4[CH:47]=[CH:46][CH:45]=[C:44]([C:42]#[N:43])[CH:49]=4)=[CH:39][CH:40]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(Br)s3)c(F)c3ccccc23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c4ccccc4c3F)s2)c1

Procedure:
The 1-(β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-fluoronaphthalene obtained in Example 137 was treated in a manner similar to Example 106-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-fluoronaphthalene. APCI-Mass m/Z 624/626 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-fluoronaphthalene was treated in a manner similar to Example 158-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(2-thienylmethyl)-4-fluoronaphthalene. APCI-Mass m/Z 590 (M+NH4). (3) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(2-thienylmethyl)-4-fluoronaphthalene was treated in a manner similar to Example 159-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-fluoronaphthalene. APCI-Mass m/Z 668/670 (M+NH4). (4) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-fluoronaphthalene and 3-cyanophenylboronic acid were treated in a manner similar to Example 168 to give 1-(β-D-glucopyranosyl)-3-(5-(3-cyanophenyl)-2-thienylmethyl)-4-fluoronaphthalene. APCI-Mass m/Z 523 (M+NH4).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2([C:20](OCC)=[O:21])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(#N)C.C(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[OH:21][CH2:20][C:7]1([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C1(c2ccncc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
A flask was charged with 1-tert-butyl 4-ethyl 4-(pyridin-4-yl)piperidine-1,4-dicarboxylate (250 mg, 0.748 mmol) in tetrahydrofuran (3 mL) and cooled to −50° C. (acetonitrile/dry ice). Lithium aluminum hydride (0.785 ml, 1.570 mmol) was added dropwise, and the reaction was allowed to stir for 30 min. The flask was then warmed to room temperature and slowly diluted with ethyl acetate (5 mL). Water (61 μL) was added and the reaction allowed to stir for 5 min. Sodium Hydroxide (1 N in water, 120 μL) was then added and the reaction allowed to stir for 5 min. An additional portion of water (61 μL) and a small amount of sodium sulfate was added and the resulting mixture allowed to stir for 5 min. The suspension was filtered through celite, and the resulting pad washed with hot ethyl acetate. The filtrate was concentrated in vacuo to yield 90 mg (41%) of desired product. Mass Spec.: 294.05 (MH)+. LC tr=1.79 min (HPLC Method 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.O.[CH:18]1[CH:23]=CC=C[CH:19]=1>C(O)(C)C>[CH:18]([O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([Br:1])[CH:10]=[C:9]([Br:11])[CH:8]=1)([CH3:23])[CH3:19]
Reactant: c1ccccc1
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(Br)cc(Br)c1

Procedure:
A solution of 3,5-dibromobenzoic acid (Aldrich, 2.4 g, 8.6 mmol) in benzene (150 mL) and isopropanol (50 mL) was treated with concentrated sulfuric acid (2 mL) and heated to reflux overnight using a Dean-Stark water trap. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with water and saturated, aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a clear oil that was used as such for the next step (2.7 g, ˜100%).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:6])(=[O:3])[CH3:2].C([O-])(=O)C.CC(O)CCCCCCC>C1C=CC=CC=1>[C:1]([O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH2:6])(=[O:3])[CH3:2]
Reactant: CCCCCCCC(C)OC(C)=O
Agent: CC(=O)[O-]
Agent: CCCCCCCC(C)O
Solvent: c1ccccc1
Product: C=C(CCCCCCC)OC(C)=O

Procedure:
This reaction was performed as in Example 1 with bis(cyclooctadienyl)rhodium tetrafluoroborate (10 mg; 0.025 mmol; 0.01 equiv), R,R-1,2-bis(2,5-dimethylphospholano)benzene (6, R"=CH3 ; 9 mg; 0.03 mmol; 0.012 equiv) and non-1-en-2-yl acetate (461 mg; 2.5 mmol) in 10 mL of degassed THF until hydrogen uptake ceased (2 h) to afford 0.46 g of crude product. 1H NMR analysis indicated 2-nonyl acetate as the sole product, and chiral GC analysis and comparison to racemate indicated 64.0% ee for 2-nonyl acetate. Hydrolysis of the acetate to 2-nonanol and comparison of the optical rotation, [α]D24 -13.9° (c 1.15, benzene), with the literature value for the (S) enantiomer, [α]D18 +11.4° (c 1.30, benzene) (Mori, K.; Ogita, H. Leibigs Ann. Chem. 1994, 1065.), indicated the (R) configuration for 2-nonyl acetate.