Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][I:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])(=O)=O>C(Cl)Cl>[I:10][CH2:9][CH2:8][C@H:2]([O:1][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)[C@@H](O)CCI
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)[C@H](CCI)O[Si](CC)(CC)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 392 (15.5 g, 60.1 mmol), 2,6-lutidine (21.0 ml, 180 mmol) and DCM (125 mL) cooled to 0° C. and maintained under N2 was added dropwise triethylsilyl trifluoromethanesulfonate (17.5 g, 66.1 mmol). The reaction was stirred at 0° C. for 1 h then warmed to RT and stirred for 18 h. The reaction was quenched by adding satd. aq. NH4Cl and extracted with DCM. The organic extract was washed organic with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography (SNAP 100) eluting with EtOAc/hexane (9:1) to afford 18.9 g (76%) of (S)-ethyl 4-iodo-2-(triethylsilyloxy)butanoate (396) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([O:17][C:18](=[O:31])[CH2:19][O:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:31])[CH2:19][O:20][N:21]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CC(C)(C)OC(=O)CONCc1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 49 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with [N-(3,4-dichlorobenzyl)aminooxy]-acetic acid tert-butyl ester as described in the preparation of compound 1-A gave the title amide as white crystals (49% yield): mp 127-129° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.51 (9H, s, t-Bu), 1.78 (6H, s, CH3), 4.38 (2H, s, CH2), 4.90 (2H, s, CH2), 6.49 (1H, s, CH), 7.28 (1H, dd, J=2.5 Hz and J=8.0 Hz, aromatic), 7.41 (1H, d, J=8.0 Hz, aromatic), 7.53 (1H, d, J=2.5 Hz, aromatic). Anal. calcd for C20H23Cl2NO7: C, 52.19; H, 5.04; N, 3.04. Found: C, 52.25; H, 5.11; N, 2.93.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[F:8][C:9]([F:20])([F:19])[C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16](O)=[O:17])[CH2:12][CH2:11]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[F:8][C:9]([F:19])([F:20])[C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:6][OH:7])=[O:17])[CH2:14][CH2:15]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: OC[C@H]1CCCN1
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: O=C([C@H]1CC[C@H](C(F)(F)F)CC1)N1CCC[C@@H]1CO

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 3 using (R)-pyrrolidin-2-ylmethanol and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: O=[C:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1.C1C=CC=CC=1.[C:27](#[N:29])[CH3:28]>>[C:27]([CH:28]=[C:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1)#[N:29]
Reactant: CC#N
Reactant: O=C1CCN2c3ccccc3Cc3ccccc3C2C1
Solvent: c1ccccc1
Product: N#CC=C1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
1 g of 2-keto-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine is mixed with 1 ml of benzene, 0.5 ml of acetonitril and 0.5 g of molecular sieve (4 A). 50 mg of sodium-ethoxyde are added and the mixture is heated for 3 hours (90°-100°C). After cooling the mixture the molecular sieve is filtered off and the filtrate evaporated. The precipitate is recrystallized from ethanol.
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][N:26]([CH3:54])[C:27](=[O:53])[NH:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[N:39]=[C:38]3[C:50](O)=[O:51])[CH:32]=[N:33][CH:34]=1.C(N(C(C)C)CC)(C)C.NC1C=NC=CC=1>CN(C=O)C>[CH3:25][N:26]([CH3:54])[C:27](=[O:53])[NH:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[N:39]=[C:38]3[C:50]([NH:16][C:11]2[CH:10]=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:51])[CH:32]=[N:33][CH:34]=1
Reactant: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C(=O)O)nn3C2CCCCO2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C(=O)Nc2cccnc2)nn3C2CCCCO2)c1
Temperature: 25 °C

Procedure:
HATU (0.190 g, 0.5 mmol) was added to a solution of 5-(5-(3,3-dimethylureido)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXXIV) (0.39 g, 1.21 mmol) and diisopropylethylamine (0.174 mL, 1.0 mmol) in DMF stirred at room temperature under argon. After stirring 5 min, the solution was added with 3-aminopyridine (CXXV) (0.047 g, 0.5 mmol). The solution was stirred overnight at room temperature under argon. The DMF was removed under reduced pressure, and the residue was treated with water, sonicated briefly and filtered. The solids were washed with cold water and dried at room temperature. The product was purified by column chromatography using a 4 g Thomson normal phase silica gel cartridge (100% DCM 5:95 MeOH:DCM) to afford 5-(5-(3,3-dimethylureido)pyridin-3-yl)-N-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (CXXVI) as an off white solid (323 mg, 0.67 mmol, 55% yield). 1H NMR (DMSO-d6) δ ppm 10.56 (s, 1H), 9.06 (d, J=2.0 Hz, 1H), 8.75 (d, J=1.6 Hz, 1H), 8.64 (s, 1H), 8.53 (d, J=1.6 Hz, 1H), 8.46 (s, 1H), 8.34-8.29 (m, 2H), 8.26 (m, 1H), 8.03 (d, J=7.0 Hz, 1H), 7.88 (dd, J=7.0, 1.2 Hz, 1H), 7.43 (dd, J=6.64, 3.84 Hz, 1H), 6.07 (dd, J=8.0, 1.8 Hz, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.98 (s, 6H), 2.63-2.60 (m, 1H), 2.11-2.06 (m, 2H), 1.83-1.81 (m, 1H) 1.52 (m, 2H); ESIMS found for C21H23N5O4 m/z 410.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1OCc1ccccc1)OCc1ccccc1
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of (2-hydroxyphenyl)acetic acid (125 g) in dimethylformamide (1.9 l) was added potassium carbonate (909 g) and benzyl bromide (281 g) successively. After being stirred for 18 hours, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1N aqueous sodium hydroxide solution and brine, dried and evaporated in vacuo. Dichloromethane was added to the residue and the solution was treated with activated carbon. The mixture was filtered and evaporated to give benzyl (2-benzyloxyphenyl)acetate (132 g).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH3:24][C:25]([CH3:32])([CH:30]=O)[C:26]([O:28]C)=[O:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.IC1C=CC=CC=1>[CH3:24][C:25]([CH3:32])([CH2:30][N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C@@H:13]2[CH2:15][C@H:14]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)[C:26]([OH:28])=[O:27]
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: COC(=O)C(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: Ic1ccccc1
Solvent: ClCCCl
Product: CC(C)(CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1)C(=O)O
Reaction time: 18 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (130 mg, 0.398 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 2,2-dimethyl-3-oxopropanoate in iodobenzene (160 mg, 0.478 mmol) and sodium triacetoxyborohydride (118 mg, 0.558 mmol), and the reaction mixture was stirred for 18 h. Additional methyl 2,2-dimethyl-3-oxopropanoate in iodobenzene (320 mg) and sodium triacetoxyborohydride (236 mg) were added and the mixture was stirred at rt for 2 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dissolved in methanol (2.000 mL) and sodium hydroxide (3M, 0.664 mL, 1.992 mmol) was added. The mixture was stirred at rt for 18 h and concentrated. The residue was treated with methanol and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions. The resulting TFA salt was treated with ACN (1 mL) and 1N HCl aqueous solution and concentrated to give 64 mg of product as off-white solid (HCl salt). MS: (M+H)+=311.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.34 (m, 7H), 1.59-1.83 (m, 3H), 1.98 (br. s., 3H), 2.58-2.74 (m, 1H), 2.85-3.24 (m, 7H), 3.42 (br. s., 2H), 7.08-7.43 (m, 5H).
Reaction SMILES: C1(=O)OC(=O)CC1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:12]#[N:13].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([C:12]#[N:13])[CH:14]=[CH:15][C:16]=1[CH2:17][Br:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: N#Cc1ccc(CBr)c(Cl)c1

Procedure:
The preferred compound α-t-butylamino-3-chloro-4-γ-hydroxypropylpropiophenone hemisuccinate, compound 3, ##STR7## (and suitable analogs and derivatives as would be obvious in view thereof) is prepared by reaction of α-t-butylamino-3-chloro-4-(3-hydroxypropyl)propiophenone hydrochloride three-fourths hydrate, compound 5, ##STR8## with succinic anhydride in pyridine to form the o-hemisuccinate. Intermediate compound 5 is suitably prepared from readily available starting materials. Accordingly, 3-chloro-4-methyl-benzonitrile, N-bromosuccinimide and benzoyl peroxide react at reflux with illumination to give 2-chloro-4-cyanobenzyl bromide. The product compound can be reacted with diethyl malonate in a solution of sodium in ethanol to give diethyl 2-(2-chloro-4-cyanobenzyl)malonate which, upon subsequent treatment with sodium chloride and water in DMSO produces ethyl 3-(2-chloro-4-cyanophenyl)propanoate. Treatment with suitable base, such as potassium hydroxide and alcoholic solvent gives the corresponding propanoic acid, 3-(2-chloro-4-cyanophenyl)propanoic acid which is then reduced to the corresponding alcohol, such as by treatment with B2H6 in tetrahydrofuran (THF). A mixture of the alcohol, 3-(2-chloro-4-cyanophenyl)propanol and ethyl magnesium bromide in dry ethyl ether is reacted at reflux to give 3-chloro-4-(3-hydroxypropyl)propiophenone which yields compound 5 upon bromination to α-bromo-3-chloro-4-(3-hydroxypropyl)propiophenone and subsequent reaction of the bromoketone with an excess of t-butylamine in suitable solvent, such as CH3CN.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:40][C:39]([CH3:41])=[N:38][C:37]=2[C:42](O)=[O:43])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[S:40][C:39]([CH3:41])=[N:38][C:37]=2[C:42]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]2[CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[O:43])=[CH:34][CH:35]=1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.3 %

Procedure:
To a solution of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (100 mg, 387 μmol) in DMF was added DIPEA (202 μL, 1.16 mmol) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (137 mg, 580 μmol) and HATU (176 mg, 465 μmol). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1 M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give 2-(((2S,3R)-1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione as a light yellow oil (130 mg, 71%). MS (ESI) 478 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22]O>>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: OCc1cccs1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCc1cccs1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and 2-thiophenemethanol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:22]=4)[C:20]#[N:21])[O:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.CCOC(C)=O>[C:20]([C:19]1[CH:22]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:2]=[CH:3]4)[N:14]=2)[CH:16]=[CH:17][C:18]=1[O:23][CH:24]([CH3:26])[CH3:25])#[N:21]
Reactant: CCOC(=O)C(C)(C)CBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 17.2 %

Procedure:
To a solution of 5-[3-(1H-indazol-5-yl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (D43) (85 mg, 0.246 mmol) in N,N-Dimethylformamide (DMF) (5 ml) was added ethyl 3-bromo-2,2-dimethylpropanoate (D98) (103 mg, 0.492 mmol) and Cs2CO3 (120 mg, 0.369 mmol). The resulting mixture was stirred at 80° C. for 48 h then cooled to room temperature and diluted with EtOAc. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [30-50% EtOAc/cyclohexene] gave the title compound (20 mg, 16%) as a yellow solid. MS (ES) C26H27N5O4 requires 473, found 474 [M+H]+
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][CH2:22][NH2:23])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][CH2:22][NH:23][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(CCN)cc1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNC(=O)c2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 45 parts of benzoyl chloride in 149 parts of chloroform is added portionwise over a 30 minute period to a solution of 78 parts of 3-benzyloxy-4-methoxyphenethylamine in 72 parts of triethylamine and 596 parts of chloroform. The mixture is stirred at room temperature for an additional 90 minutes. It is then washed twice with water and once with dilute aqueous sodium bicarbonate solution, dried over anhydrous calcium sulfate and stripped to a low volume under reduced pressure. Addition of n-hexane results in crystallization of N-(3-benzyloxy-4-methoxyphenethyl)benzamide. That product melts at about 136°-138°C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Cl[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:30][O:29][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[O:27][CH3:28])[C:17]([CH2:16][N:7]1[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5])=[CH:18][CH:19]=[CH:20]2
Reactant: COc1cc2cccc(CCl)c2cc1OC
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: COc1cc2cccc(Cn3c(C(=O)O)cc4ccccc43)c2cc1OC

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 1-chloromethyl-6,7-dimethoxy-naphthalene (Lit. 11) and the product obtained was hydrolyzed to give the title compound as a pale yellow solid. MS: 360.0 ([M−H]−).
Reaction SMILES: C([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[C:13]=2[O:15][CH3:16])[C:8](=[O:19])[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:6]1)(C)(C)C.[N+:25]([O-])([O-:27])=[O:26].[K+]>OS(O)(=O)=O>[F:18][C:11]1[C:10]([N+:25]([O-:27])=[O:26])=[C:9]2[C:14](=[C:13]([O:15][CH3:16])[C:12]=1[F:17])[NH:5][CH:6]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]2=[O:19]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2c(OC)c(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1c[nH]c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A solution of ethyl 1-tert-butyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (20.0 g, 58.9 mmol) in concentrated H2SO4 (120 mL) was treated portionwise at 0° C. with solid KNO3 (8.90 g, 88.0 mmol). After stirring at 0° C. for 1 h, the reaction mixture was poured into 500 mL of ice-water and the resulting precipitate was removed by filtration. The resulting solid washed with EtOH, dried to yield ethyl 6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (12.77 g, 66%) as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:42])[C:33]1[CH:41]=[CH:40][C:39]2[O:38][CH2:37][O:36][C:35]=2[CH:34]=1>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:32]([C:33]3[CH:41]=[CH:40][C:39]4[O:38][CH2:37][O:36][C:35]=4[CH:34]=3)=[O:42])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc5c(c4)OCO5)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and piperonyloyl chloride (0.5 g, 2.8 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was quenched by the addition of MeOH (1 mL). The suspension was filtered, and the solid was rinsed with CH2Cl2 (10 mL) to afford benzo[1,3]dioxole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (0.8 g, 85%): mp, 231-233° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.7 (99%); 1H NMR (DMSO-d6): δ 2.06-2.10 (m, 1H), 2.53-2.64 (m, 2H), 2.86-2.97 (m, 1H), 4.92 (d, J=5.6 Hz, 2H), 5.14-5.20 (dd, J=5, 12 Hz, 1H), 6.11 (s, 2H), 7.03 (d, J=8.1 Hz, 1H), 7.45-7.85 (m, 5H), 9.00 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.33, 48.85, 101.68, 107.34, 107.90, 121.81, 122.35, 127.08, 127.88, 131.50, 133.01, 134.77, 139.44, 147.36, 149.87, 165.70, 166.96, 167.52, 169.82, 172.74. Anal Calcd for C22H17N3O7+0.2H2O: C, 60.19; H, 4.00; N, 9.57. Found: C, 60.15; H, 3.71; N, 9.46.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]1[O:31][N:30]=[C:29]([CH:32]=O)[CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:32][C:29]3[CH:28]=[C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)[O:31][N:30]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=Cc1cc(-c2cccs2)on1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2cc(-c3cccs3)on2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To 10 mL of a chloroform solution containing 407 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 275 mg of 5-(2-thienyl)-3-isoxazolecarbaldehyde, 80 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 468 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=2:1], to give 232 mg of 7-fluoro-1-(2-(4-((5-(thiophen-2-yl)isoxazol-3-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as pale yellow solid.