Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[C:15]2[CH:21]=[C:22]([O:25][CH2:26][C@@H:27]([NH:32]C(=O)OC(C)(C)C)[CH2:28][CH:29]([CH3:31])[CH3:30])[CH:23]=[CH:24][C:14]3=2)=CC=1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl.O.C(#N)C>[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].[NH2:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[N:16]([CH3:20])[C:15]1[CH:21]=[C:22]([O:25][CH2:26][C@@H:27]([NH2:32])[CH2:28][CH:29]([CH3:30])[CH3:31])[CH:23]=[CH:24][C:14]2=1
Reactant: COc1ccc(CNc2nccc3c2c(=O)n(C)c2cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc32)cc1
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)COc1ccc2c3ccnc(N)c3c(=O)n(C)c2c1
Temperature: 45 °C
Yield: 31.7 %

Procedure:
To a stirred solution of (S)-tert-butyl (1-((4-((4-methoxybenzyl)amino)-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.145 mmol) in DCM (10 mL) at rt was added TFA (4 mL, 51.9 mmol) dropwise and the reaction was heated at 45° C. for 12 h. After the completion of reaction, the volatile organics were evaporated under reduced pressure and the residue obtained was purified by prep. HPLC (0.1% TFA in water/acetonitrile as mobile phase) to yield (S)-4-amino-8-((2-amino-4-methylpentyl)oxy)-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (16 mg, 0.046 mmol, 32% yield) as a mono TFA salt as an off white solid. LC/MS (ESI) m/e 341.2 [(M+H)+, calcd for C19H25N4O2 341.2]; LC/MS retention time (method B): tR=1.08 min; HPLC retention time (method A): tR=8.02 min; HPLC retention time (method B): tR=8.40 min; 1H NMR (400 MHz, MeOD) δ 8.44 (d, J=8.80 Hz, 1H), 8.00 (d, J=7.20 Hz, 1H), 7.71 (d, J=7.20 Hz, 1H), 7.24 (d, J=2.40 Hz, 1H), 7.21-7.22 (m, 1H), 4.51 (dd, J=3.20, 10.80 Hz, 1H), 4.34 (dd, J=6.40, 10.40 Hz, 1H), 3.84 (s, 3H), 3.78-3.82 (m, 1H), 1.65-1.89 (m, 3H), 1.08 (d, J=4.40 Hz, 3H), 1.06 (d, J=4.40 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([F:13])[CH:3]=1.[C:14]([O:18][C:19]([N:21]1[C@@H:26]([CH:27]=[O:28])[CH2:25][O:24][C@@H:23]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:14]([O:18][C:19]([N:21]1[C@@H:26]([C@@H:27]([OH:28])[C@@H:9]([N+:10]([O-:12])=[O:11])[CH2:8][C:6]2[CH:5]=[C:4]([F:13])[CH:3]=[C:2]([Cl:1])[CH:7]=2)[CH2:25][O:24][C@@H:23]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](C=O)CO1
Reactant: O=[N+]([O-])CCc1cc(F)cc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(Cl)c2)[N+](=O)[O-])CO1
Yield: 58.9 %

Procedure:
Add 1-chloro-3-fluoro-5-(2-nitroethyl)-benzene (0.343 g, 1.68 mmol) in dry tetrahydrofuran (2 mL) to a solution of (2R,5R)-2-(2,2-dimethylpropoxy)-5-formylmorpholine-4-carboxylic acid tert-butyl ester (0.462 g, 1.53 mmol) in tetrahydrofuran (7 mL). Add tetrabutylammonium fluoride (0.77 mL, 0.765 mmol, 1.0 M in tetrahydrofuran) and stir at room temperature for 1 hour. Dilute with ethyl acetate and wash with saturated aqueous sodium chloride, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 2:98 ethyl acetate:dichloromethane) to give the desired compound as a white foam (0.455 g, 59%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([NH2:32])=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[OH:36]/[N:35]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([NH2:32])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CCC(C(N)=O)CC3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCC(C(N)=O)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-1-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)piperidine-4-carboxamide and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow foam, MS (ESI+): m/z=457.5 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20](=[O:21])[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]2=[O:22])=[C:4]([F:11])[S:5][C:6]=1[CH2:7][C:8]([OH:10])=[O:9].[CH2:23](O)[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:12]2[C:13](=[O:22])[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]2=[O:21])=[C:4]([F:11])[S:5][C:6]=1[CH2:7][C:8]([O:10][CH2:23][CH3:24])=[O:9]
Reactant: O=C(O)Cc1sc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1Cl
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1sc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1Cl

Procedure:
To a solution of 2-(4-chloro-2-fluoro-5-carboxymethylthiophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (1.2 g) and ethanol (1.0 g) in toluene (20 ml), there was added a small amount of p-toluenesulfonic acid, and the mixture was refluxed for 3 hours. Water was added to the reaction mixture. The toluene layer was separated, dried and concentrated. The residue was purified by silica gel chromatography to give 0.1 g of 2-(4-chloro-2-fluoro-5-ethoxycarbonylmethylthiophenyl-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione. nD18 1.5670.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)=[C:11]([O:25][C:26]3[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=3)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]2[C:12]([C:13]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:15])=[C:11]([CH:10]=[CH:9][CH:8]=2)[O:25][C:26]2[N:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[N:31]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(OC)nc(Oc2cccc(-c3ccccc3)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1
Reactant: CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Oc2cccc(-c3ccccc3)c2C(=O)NS(C)(=O)=O)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step I, using equimolar amounts of 4-nitrophenyl 6-phenyl-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoate, methanesulfonamide, and potassium carbonate in acetonitrile to yield 2-[3-phenyl-2-(methylsulfonylaminocarbonyl)phenoxy]-4,6-dimethoxypyrimidine.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][C:10]=1[F:11])(=[O:4])=[O:3]>ClCCl.CO.[Pd]>[NH2:12][C:7]1[CH:8]=[CH:9][C:10]([F:11])=[C:5]([S:2]([NH2:1])(=[O:3])=[O:4])[CH:6]=1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(F)c(S(N)(=O)=O)c1
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
To a solution of 3-aminosulfonyl-4-fluoronitrobenzene (360 mg, 1.62 mmol) in dichloromethane (6 mL) and methanol (3 mL) was added 10% Pd/C (36 mg) and shaken under a hydrogen atmosphere at 50 psi for 15 minutes. The mixture was filtered through Celite and the cake was washed with methanol (5 mL). The combined organic solvent was concentrated under reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 240 mg of 5-amino-2-fluorobenzensulfonamide as a light yellow solid. 1H NMR (DMSO-d6): δ 7.38 (s, 2H), 7.03-6.94 (m, 2H), 6.70-6.66 (m, 1H), 5.33 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]5[N:29]([CH2:33][C:34]6[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=6)[N:30]=[C:31](I)[C:24]=45)=[C:18]([F:42])[CH:17]=3)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:43]1([C:49]([C:51]2[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=2)=[O:50])[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH2:7][C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]5[N:29]([CH2:33][C:34]6[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=6)[N:30]=[C:31]([C:54]6[CH:53]=[CH:52][C:51]([C:49]([N:43]7[CH2:48][CH2:47][O:46][CH2:45][CH2:44]7)=[O:50])=[CH:56][CH:55]=6)[C:24]=45)=[C:18]([F:42])[CH:17]=3)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(-c5cnc(CC6CCCCC6)n(C)c5=O)cc4F)ccnc32)cc1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: COc1ccc(Cn2nc(-c3ccc(C(=O)N4CCOCC4)cc3)c3c(Oc4ccc(-c5cnc(CC6CCCCC6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 98.2 %

Procedure:
A suspension of 2-(cyclohexylmethyl)-5-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one (0.025 g, 0.037 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (0.010 g, 0.044 mmol), Pd(PPh3)4 (0.002 g, 0.002 mmol) and lithium chloride (0.006 g, 0.147 mmol) in dioxane (1 mL) and 2 M aqueous Na2CO3 (1 mL) was stirred at 100° C. for 35 minutes and then at room temperature overnight. The reaction mixture was partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield 0.027 g crude product as a yellow gum. The crude material was used without further purification in the following step. LRMS (APCI pos) m/e 743 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][NH:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:34][C:35]2([CH3:39])[CH2:38][O:37][CH2:36]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:34][C:35]1([CH2:39][N:10]2[C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=3[C:8]([C:11]3[CH:12]=[CH:13][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:15][CH:16]=3)=[N:9]2)[CH2:38][O:37][CH2:36]1
Reactant: NS(=O)(=O)c1ccc(-c2n[nH]c3cc[nH]c(=O)c23)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(Cn2nc(-c3ccc(S(N)(=O)=O)cc3)c3c(=O)[nH]ccc32)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (34.5 mg) in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 7.13 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (45.7 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (14.2 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][NH:5][C:4]([Br:10])([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)c(F)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClCCCl
Product: CC1(Br)C=C(Cl)C(F)=CN1
Temperature: 75 °C
Yield: 69 %

Procedure:
4-Chloro-5-fluoro-2-picoline (2.9 g, 20 mmol), the product of Example 66, was dissolved in 50 mL of 1,2-dichloroethane in a dry flask. The resultant solution was heated, with stirring, to 75° C. and 4.09 (23 mmol) of N-bromosuccinimide was added, followed by 100 mG (0.7 mmol) of 2,2-azobisisobutyronirile (AIBN), a free radical initiator. After the reaction mixture was stirred at 75° C. for 24 hours, it was diluted with 450 mL of methylene chloride and washed with 3 X 400 mL of water. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried in vacuo to give 3.5 g (69% yield) of the title compound as an amber oil; 1H NMR (CDCl3) d 4.50 (s, 2H), 7.54 (d, 1H), 8.44 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Br)[CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>O>[CH2:1]([O:8][CH:9]1[CH2:12][N:17]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: BrCC(CBr)OCc1ccccc1
Solvent: O
Product: CC(C)N1CC(OCc2ccccc2)C1
Temperature: 80 °C

Procedure:
11 parts of 2-benzyloxy-1,3-dibromo-propane, 30 parts of iso-propylamine and 30 parts of water were added to a stainless autoclave, and the mixture was heated at 80° C. for 2 hours with agitation. The reaction mixture was cooled and treted in the same manner as in Example 29, followed by distillation under reduced pressure. As a result 18 parts of 3-benzyloxy-1-(iso-propyl)azetidine boiling at 104° - 107° C. under 2 mm Hg were obtained
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][C:18]([F:22])([F:21])[CH2:19][CH3:20])[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[BrH:23]>>[BrH:23].[NH2:11][C@@H:12]([CH2:17][C:18]([F:21])([F:22])[CH2:19][CH3:20])[C:13]([O:15][CH3:16])=[O:14]
Reactant: CCC(F)(F)C[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Agent: Br
Product: CCC(F)(F)C[C@H](N)C(=O)OC

Procedure:
Following the procedure of Synthesis Example 2, a mixture of (S)-methyl 2-(benzyloxycarbonylamino)-4,4-difluorohexanoate and hydrogen bromide were reacted together to give (S)-methyl 2-amino-4,4-difluorohexanoate hydrobromide.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.Cl[CH:30]([C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:36])[C:31]([O:33][CH3:34])=[O:32].O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([O:28][CH:30]([C:31]([O:33][CH3:34])=[O:32])[C:35]([C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)=[O:36])=[O:27])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1
Reactant: COC(=O)C(Cl)C(=O)c1ccc(F)cc1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(OC(=O)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
IPEA (3 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (1 g) and methyl 2-chloro-3-(4-fluorophenyl)-3-oxopropionate (CAS #160727-96-8, 1.1 g) in DMF (10 mL), and the reaction solution was stirred at room temperature for two hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 792 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[Si:5]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(N)cc1
Yield: 91.6 %

Procedure:
To a suspension of Pd/C (2.5 g) in methanol (30 mL), in a 100 mL 3-neck RBF, was added tert-butyldimethyl(2-(4-nitrophenoxy)ethoxy)silane (5.0 g) under a nitrogen atmosphere at room temperature. Hydrogen gas was bubbled through the reaction for 3 hr at room temperature. The reaction was monitored on TLC using ethyl acetate:hexane (3:7) as mobile phase. After completion, the reaction mixture was filtered using Celite and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure at 40° C. to give 4.12 g of 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)aniline as a brown liquid. M+1=309.2.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][CH2:9]1)[CH3:2]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-acetylpiperidine-1-carboxylate from the previous step was dissolved in 50 ml methanol. NaBH4 (2.01 g, 53 mmol) was added in batches at 0° C. The resulting reaction mixture was stirred at 0° C. for 30 minutes. The volatiles were removed under vacuum. The residue was partitioned between 150 ml 10% KOH solution and 200 ml ether. The organic layers were washed with 100 ml brine, dried over sodium sulfate and concentrated to give 22.5 g colorless oil, which was azotropically dried by addition of 50 ml toluene and reconcentration under vacuum. This material was used for next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C-:9]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10]1.[CH-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[Fe+2:22].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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].CO.O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C-:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[N:3]=1.[CH-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[Fe+2:22]
Reactant: Brc1cccc(Br)n1
Reactant: OB(O)[c-]1cccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: Brc1cccc(-[c-]2cccc2)n1
Temperature: 60 °C

Procedure:
See Scheme 3. Toluene (15 mL) was added to 2,6-dibromopyridine (0.341 g, 1.44 mmol, purchased from Sigma-Aldrich) and ferrocenylboronic acid (0.321 g, 1.40 mmol, purchased from Sigma-Aldrich) to form an orange suspension. A suspension of (dppf)PdCl2.CH2Cl2 (0.047 g, 0.058 mmol, purchased from Strem) (dppf=1,1′-bis(diphenylphosphino)ferrocene) in toluene (5 mL) was then added followed by a 1 M solution of Na2CO3 (10 mL, 10 mmol) in 4:1 water:methanol. The biphasic mixture was heated to 60° C. for 23 hours. At this time 1H NMR spectroscopic analysis indicated approximately 45% conversion to the desired product. The organic layer was separated, washed with a little water and then brine. The organics were then dried over MgSO4 and filtered. Removal of the volatiles afforded an orange residue. The remaining 2,6-dibromopyridine was removed by sublimation at 45° C./ca. 100 mTorr over 2 hours. The crude was purified on an Al2O3 column using 4% ethyl acetate in hexane as the elutant. The product was still contaminated with some 2,6-diferrocenylpyridine. Pure 2-bromo-6-ferrocenylpyridine was isolated by crystallization from hexamethyldisiloxane. Yield: 0.058 g (12%). 1H NMR (C6D6): δ 6.87 (1H, d), 6.79 (1H, d), 6.64 (1H, t), 4.83 (2H, m), 4.11 (2H, m), 3.83 (5H, s).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH:3]=[CH:2]1.[Na].P([O-])(O)(O)=[O:19].[Na+]>C(O)(C)(C)C.CC(=CC)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:19])=[O:11])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(C=O)cc1OC1C=CCC1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)O)cc1OC1C=CCC1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A solution of 3-cyclopent-2-enyloxy-4-methoxybenzaldehyde (7.70 g) in t-butanol (160 mL) and 2-methyl-2-butene (40 mL) is treated dropwise with an aqueous solution (150 mL) containing sodium chicrite (80% technical grade; 4.39 g) and sodium dihydrogen phosphate (38.49 g), and left to stand overnight. The resulting mixture is extracted with dichloromethane (2×250 mL), and the combined organic layers are dried over sodium sulfate, the solvent is removed under reduced pressure, and the resulting residue is recrystallized from ethyl acetate, to give 3-cyclopent-2-enyloxy-4-methoxybenzoic acid (5.89 g), in the form of a colorless solid. m.p. 160°-163° C. [Elemental analysis: C,66.4; H,6.0%; calculated: C,66.7; H,6.0%].
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N.[CH:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[C:31](O)[CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(Cl)(Cl)Cl>[N+:35]([C:34]1[CH:29]=[CH:30][C:31]([O:19][C:18](=[O:20])[C@H:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:32][CH:33]=1)([O-:37])=[O:36]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Yield: 83.3 %

Procedure:
N,N-dibenzyl-L-phenylalanine hydrochloride (7.64 g, 20.0 mmol) was added to 50 ml of chloroform, and 20.0 ml of 10% aqueous ammonia were added dropwise to the suspension for neutralization. The organic layer was separated, washed with 20 ml of water, then dried over magnesium sulfate, and filtered. The filtrate was concentrated, the resulting residue was dissolved in 50 ml of chloroform, and 2.89 g (20.4 mmol) of p-nitrophenol and 4.13 g (20.0 mmol) of N,N′-dicyclohexylcarbodiimide were added to the solution in this order while being cooled with ice. The mixture was reacted overnight. To the reaction solution were added 30 ml of ethyl acetate, and the N,N′-dicyclohexylurea which precipitated was removed by filtration. The filtrate was washed with a 10% potassium carbonate aqueous solution. The organic layer was separated, and concentrated. The resulting residue was redissolved in 30 ml of ethyl acetate, and the insoluble materials which precipitated were removed by filtration. The filtrate was concentrated, and the resulting crude product was purified through silica-gel column chromatography to obtain 7.77 g (16.65 mmol) of the above-mentioned compound (Ib).