Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@H:14]2[C@@H:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C@@H:17]3[C@@H:16]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:15]2)=[N:4][C:5]([S:9][CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[Cl:8].C(O[N:35]=O)CC(C)C>C(#N)C>[Cl:8][C:7]1[C:2]2[N:1]=[N:35][N:13]([C@H:14]3[C@@H:18]4[O:19][C:20]([CH3:22])([CH3:23])[O:21][C@@H:17]4[C@@H:16]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:15]3)[C:3]=2[N:4]=[C:5]([S:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: CC(C)CCON=O
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCC(=O)O)[C@H]3OC(C)(C)O[C@H]32)n1
Solvent: CC#N
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCC(=O)O)[C@H]4OC(C)(C)O[C@H]43)c2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a solution of compound 8a (10 g) in acetonitrile (100 mL) was added isoamylnitrite (4.0 g) at 10-30° C. The reaction mixture was stirred at 50-70° C. for 3-5 h. The reaction was monitored by TLC. After completion, the reaction was quenched with 10% aqueous NaHSO3 (10 ml) and concentrated under reduced pressure. The obtained residue was extracted with ethyl acetate (10 vol). The extract was washed with water and then concentrated at reduced pressure to provide the product (9.5 g, 92.68%).
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=[O:3].[NH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1>CCOCC>[O:3]=[C:2]([CH3:4])[CH:1]=[N:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CC(=O)C=O
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(N=CC(C)=O)CC1
Reaction time: 0.33 h
Yield: 58.1 %

Procedure:
To a solution of pyruvaldehyde (40% w/w solution in water, 2.67 mL, 3.15 g, 17.5 mmol) in 50 mL of Et2O at room temperature was added dropwise ethyl 4-amino-piperidinecarboxylate (3.0 mL, 3.01 g, 17.5 mmol). After 20 min, the solution was diluted with 50 mL of Et2O and washed with 3×30 mL of water. The solution was concentrated in vacuo to yield 2.3 g (58%) of the imine product which was used as such in the subsequent step: 1H NMR (CDCl3) δ 7.58 (1H, s), 4.07 (2H, q, J=7.1 Hz), 4.04 (2H, m), 3.39 (1H, m), 3.02 (2H, m), 2.31 (3H, s), 1.65 (4H, m), 1.19 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([O:7][CH2:8][C:9]1[O:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:14]C1OC(CBr)=CC=1>CCOCC>[CH2:8]([O:7][CH2:1][C:2]1[O:6][C:5]([CH3:14])=[CH:4][CH:3]=1)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1coc(COCc2ccco2)c1
Reactant: Cc1ccc(CBr)o1
Solvent: CCOCC
Product: Cc1ccc(COCc2ccco2)o1

Procedure:
d. 5-Methyl-furfuryl furfuryl ether was prepared by the procedure described by J. E. Zanetti in J.Am.Chem.Soc. 49, 1066 (1927) for the difurfuryl ether, starting with 5-methylfurfuryl bromide (Compt.Rend. 222, 1441 (1946)) instead of furfuryl bromide of Zanetti. The product was isolated by ether extraction of the crude mixture after having diluted with water. For purification the ether extract was distilled twice--b.p. 68°-70° C. at 0.01 mm./Hg vacuum. The product was a viscous colourless liquid, darkening rapidly on contact with air.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([CH2:26][O:27][C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:20]C1C=CON=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H][H]>O1CCCC1.C(O)C.[Pd]>[CH2:1]([O:17][CH2:18][C@H:19]([CH2:26][O:27][C:28]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1ccon1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
4.400 g of 1-O-hexadecyl-2-O-(3-isoxazolyl)-3-O-triphenylmethyl-sn-glycerol described in Preparation 4 was dissolved in a mixture of 10 ml of tetrahydrofuran and 90 ml of ethanol and the solution was placed in a Paar apparatus and then shaken in the presence of 4.40 g of 10% w/w palladium-on-carbon in an atmosphere of hydrogen at 4 times atmospheric pressure for 49 hours. After removing the catalyst by filtration, 0.635 g of potassium carbonate was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After filtering off the insoluble material, the solvent was distilled off and the residue was subjected to column chromatography through 100 g of silica gel. 3.327 g of 1-O-hexadecyl-3-O-triphenylmethyl-sn-glycerol was obtained from the fractions eluted with mixtures of hexane and diethyl ether ranging from 19:1 to 9:1 by volume, as white crystals melting at 49°-50° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:39])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]3[CH:38]=[CH:37][C:28]4[C@H:29]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:30][O:31][C:27]=4[CH:26]=3)[CH:18]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13].CO.[OH-].[Na+].Cl>O.O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:39])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]3[CH:38]=[CH:37][C:28]4[C@H:29]([CH2:32][C:33]([OH:35])=[O:34])[CH2:30][O:31][C:27]=4[CH:26]=3)[CH:18]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)c(Cl)c4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCCS(C)(=O)=O)c(Cl)c(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of methyl [(3S)-6-({3′-chloro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.676 g, 1.18 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1.2 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from diethyl ether-ethyl acetate to give the title compound (0.418 g, yield 63%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[N:8]=1)[CH3:2].C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+]>CN(C=O)C.C1COCC1>[NH2:14][C:13]1[C:12]2[C:7](=[N:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:11]=2)[O:6][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:29]
Reactant: CCOC(=O)COc1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a magnetically stirred solution of 2.69 g (6.30 mmol) of the product of Step A dissolved in 60 mL of DMF was slowly added 12.6 mL of a 1 M solution of lithium bis(trimethylsilylamide) in THF at 0° C. The reaction mixture was stirred at room temperature for 20 min then partitioned between EtOAc and 10% aq. NaHSO4. The organic extracts were separated, washed with 10% aq. NaHSO4, brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–20% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 427.0 (M+1), 428.9 (M+3); Rt=4.03 min.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:14][CH:10]([F:15])[O:8][C:7]1[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccnc1Br
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1cccnc1Br
Temperature: 100 °C
Yield: 35.2 %

Procedure:
To a solution of 2-bromo-3-pyridinol (1.26 g, 7.23 mmol) in DMF (35 mL) and water (5 mL) was added sodium chlorodifluoroacetate (2.93 g, 18.1 mmol) followed by cesium carbonate (4.71 g, 14.5 mmol). The reaction was heated to 100° C. for 36 hours before partitioning between EtOAc and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc:Heptane 1:3 to afford the title compound as a colourless oil (570 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11]>ClCCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([OH:8])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Cl)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCCl
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(F)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
4-chloro-3-fluorophenol (2.38 g, 16.2 mmol) was dissolved in DCE (32 mL) and tetrabutylammonium bromide (0.524 g, 1.62 mmol) was added. HNO3 70% (2.1 mL, 32 mmol) was diluted with H2O (18.9 mL) to make a 7% HNO3 solution. This solution was added to the reaction mixture which was then stirred at rt for 4 h at which time the reaction was judged complete by TLC. The reaction was poured into H2O and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step A (2.29 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (br. s., 1H), 8.18 (d, J=8.1 Hz, 1H), 7.10 (d, J=10.6 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][C:5]([CH2:6]N(C)C)=[CH:4][C:3]=1[CH3:16].[CH2:17]([O:35][C:36](=[O:59])[CH2:37][C:38]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[CH3:60][O-:61].[Na+].Cl>C1(C)C=CC=CC=1.C(Cl)Cl.O>[CH2:17]([O:35][C:36](=[O:59])[C:37]([CH2:16][C:3]1[CH:2]=[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:60]([OH:61])=[C:5]([CH3:6])[CH:4]=1)([CH2:6][C:5]1[CH:10]=[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]([OH:1])=[C:3]([CH3:16])[CH:4]=1)[C:38]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Cc1cc(CN(C)C)cc(C(C)(C)C)c1O
Reactant: C[O-]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)CC(=O)OCCCCCCCCCCCCCCCCCC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)C(Cc1cc(C)c(O)c(C(C)(C)C)c1)(Cc1cc(C)c(O)c(C(C)(C)C)c1)C(=O)OCCCCCCCCCCCCCCCCCC

Procedure:
27.6 G (0.125 mole) of (4-hydroxy-3-methyl-5-tert. butylbenzyl) dimethylamine, 30.5 g (0.05 mole) of malonic acid distearyl ester, and 0.5 g of sodium methylate were refluxed in 100 cc of absolute toluene for 21/2 hours while a current of nitrogen was passed through the reaction mixture. After cooling, the reaction mixture was diluted with methylene chloride, shaken out with 2N hydrochloric acid and water, and evaporated to dryness. The residue was slurried in methanol, filtered, and washed.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[N:10][N:11]([CH3:13])[N:12]=3)=[CH:4][CH:3]=2)[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: Cn1nnc(-c2ccc(Br)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cn1nnc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1

Procedure:
Prepared in analogy to example 4.4(a) from 5-(4-Bromo-phenyl)-2-methyl-2H-tetrazole and N-BOC-piperazine. MS (m/e): 345.1 (MH+, 41%)
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[CH2:34]([NH:41][CH2:42][CH2:43][OH:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([N:41]([CH2:42][CH2:43][OH:44])[C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:31]1[CH:30]=[CH:29][C:28]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)=[O:7])=[O:18])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: OCCNCc1ccccc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)N(CCO)Cc2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1-biphenyl]-4-carbonyl chloride, and 2-(benzylamino)ethanol, the title compound was obtained in 74% purity by HPLC. MS(ESI+): m/z=472.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:31]([F:34])([F:33])[F:32])=[CH:10]/[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH:19]([NH:23][C:24](=[O:30])[CH2:25][CH:26]([O:28][CH3:29])[CH3:27])[CH2:18][CH2:17]3)=[N:12][OH:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:31]([F:34])([F:32])[F:33])=[CH:10]/[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH:19]([NH:23][C:24](=[O:30])[CH2:25][CH:26]([O:28][CH3:29])[CH3:27])[CH2:18][CH2:17]3)=[N:12][O:13][C:42](=[O:44])[CH3:43])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(C)CC(=O)NC1CCc2cc(C(/C=C(/c3cc(Cl)cc(Cl)c3)C(F)(F)F)=NO)ccc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(C)CC(=O)NC1CCc2cc(C(/C=C(/c3cc(Cl)cc(Cl)c3)C(F)(F)F)=NOC(C)=O)ccc21
Temperature: 25 °C
Yield: 72.1 %

Procedure:
0.5 g of N-[5-{(Z)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-hydroxyimino-2-butenyl}-indane-1-yl]-3-methoxybutyric acid amide and 0.22 g of triethylamine were dissolved in 10 ml of tetrahydrofuran, and 0.1 g of acetyl chloride was added to the resulting solution under ice-cold conditions, followed by stirring at room temperature for one night. The reaction solution was poured into ice-water, extracted with ethyl acetate, washed with saturated brine, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=7/3 (volume ratio)) to obtain 0.39 g of the target compound. Yield was 69%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[CH:27]=1>O1CCCC1.CN(C)C=O.O>[CH:34]1([C:32]([NH:31][C:29]2[N:30]=[C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]4[CH:19]=[C:18]([NH:17][C:8]([C:3]5[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=5)=[O:10])[CH:39]=[CH:38][CH:37]=4)=[CH:27][N:26]3[CH:28]=2)=[O:33])[CH2:35][CH2:36]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Reactant: Cc1cccnc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 3-methylpyridine-2-carboxylic acid (53.5 mg, 0.390 mmol) in tetrahydrofuran (3 mL) were added oxalyl chloride (68.0 μL, 0.780 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in N,N-dimethylacetamide (3 mL). N-[6-(3-Aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (60.0 mg, 0.195 mmol) was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate to give the title compound (58.0 mg, 70%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[CH:11](=[O:15])[CH2:12][CH2:13][CH3:14].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCCC=O
Reactant: N#Cc1cc(I)ccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Br)c(C#N)c1
Temperature: -8 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
A round bottom flask was charged with the 2-bromo-5-iodobenzonitrile (2.00 g, 6.49 mmol) and THF (9 mL). Solution cooled down to −8° C. (ice/brine bath). Turbo Grignard 1.3M in THF (5.50 mL, 7.14 mmol) is then added in one portion and the reaction stirred for 15 minutes at −8° C. Butyraldehyde (0.698 μL, 7.79 mmol) is then charged in another flask and the preformed anion is added over the aldehyde/THF (4 mL) via canula and then, reaction allowed to warmed at room temperature overnight under magnetic stirring. Ammonium chloride (sat. aq.) added to the mixture. Extracted 3× with Ethyl Acetate. Combined organic layers washed with water (1×), with brine (1×), dried over sodium sulfate, filtered and concentrated to afford the crude material. Purification by silica gel flash chromatography (Ethyl Acetate/Heptane) provide the title compound as a yellow oil (1.33 g, 80.6%). 1H NMR (400 MHz, DMSO-d6) δ 0.83 (t, J=7.41 Hz, 3 H) 1.18-1.34 (m, 2 H) 1.46-1.57 (m, 2 H) 4.52-4.58 (m, 1 H) 5.37 (d, J=4.88 Hz, 1 H) 7.56 (dd, J=8.58, 1.95 Hz, 1 H) 7.79 (d, J=8.39 Hz, 1 H) 7.81 (d, J=2.15 Hz, 1 H); MS (M): 255.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:16]1([C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)O)[OH:17].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:17][C:16]3[CH:18]=[CH:20][CH:21]=[CH:22][C:23]=3[O:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccccc1O
Reactant: O=C(c1ccc(Br)cc1)C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Brc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Yield: 87.3 %

Procedure:
A mixture of (4-bromophenyl)-piperidin-4-yl-methanone (536 mg, 2.00 mmol), catechol (880 mg, 8.00 mmol) and p-TsOH.H2O (760 mg, 4.00 mmol) in xylene (20 mL) was heated at reflux with a Dean-Stark apparatus to remove water for 68 hours. Standard work-up and purification gave 4-[2-(4-bromophenyl)-benzo[1,3]dioxol-2-yl]-piperidine (629 mg, 87%) as a yellow foam.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].[OH-].[Na+]>C(Cl)Cl>[CH2:1]([NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=1[O:15][CH3:14])[CH:2]=[CH2:3]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNCc1ccc(OC)cc1OC
Yield: 40 %

Procedure:
0.32 ml of allylbromide (3.66 mmol) and 0.7 ml of diisopropyl ethylamine (3.99 mmol) were added to the reaction solution containing 500 mg of 2,4-dimethoxybenzylamine (3.33 mmol) dissolved in methylene chloride with stirring and the solution was left alone at room temperature. After the reaction mixture was neutralized with 10% NaOH solution, the mixture was extracted with chloroform, washed with saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 276 mg of allyl-(2,4-dimethoxybenzyl)amine (1b) (yield: 40%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26].Cl>O.CN(C=O)C>[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[NH:17][C:18](=[O:26])[CH2:19]3)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Cc2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
AlCl3 (20.0 g, 150 mmol) was placed in a dry 200 mL round bottom flask and DMF (3.30 mL) was added dropwise at 0° C. During the addition of DMF care was taken to ensure that the reaction was allowed to vent to the outside as this addition caused an exotherm to occur. Additionally as the DMF was added a white suspension formed. This suspension was allowed to stir for 30 min at room temperature, after which 4-nitrobenzoyl chloride (2.984 g, 16 mmol) was added. The mixture was warmed to 50° C. and stirred for 15 min at that temperature. The 50° C. mixture then was treated with oxindole (2.051 g, 15 mmol). The resulting reaction mixture was heated to 90° C. and allowed to stir for 5 hours during which the reaction mixture turned from a yellowish suspension to a thick black oil. The reaction was cooled to room temperature. Ice was added directly to the flask followed by water, turning the black oil into a pale yellow/white precipitate. Concentrated HCl(aq) (3 mL) was added to the reaction and the contents were stirred at room temperature for 15 min. The precipitate was collected via vacuum filtration. The crude solid was purified by washing with sat. NaHCO3(aq) providing 5-(4-Nitro-benzoyl)-1,3-dihydro-indol-2-one as a gray solid (4.05 g, 14.4 mmol, 95%).
Reaction SMILES: C([O:8][CH2:9][C:10]([CH2:23][O:24]CC1C=CC=CC=1)([CH2:14][O:15]CC1C=CC=CC=1)[C:11](O)=[O:12])C1C=CC=CC=1.[OH:32][CH2:33][C@H:34]1[O:38][C:37](=[O:39])[N:36]([C:40]2[CH:49]=[C:48]3[C:43]([CH:44]=[C:45]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[C:57]([F:60])([F:59])[F:58])[NH:46][C:47]3=[O:50])=[CH:42][CH:41]=2)[CH2:35]1.[H][H]>[Pd]>[OH:12][CH2:11][C:10]([CH2:23][OH:24])([CH2:14][OH:15])[C:9]([O:32][CH2:33][C@H:34]1[O:38][C:37](=[O:39])[N:36]([C:40]2[CH:49]=[C:48]3[C:43]([CH:44]=[C:45]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[C:57]([F:59])([F:58])[F:60])[NH:46][C:47]3=[O:50])=[CH:42][CH:41]=2)[CH2:35]1)=[O:8]
Reactant: O=C1O[C@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: O=C(O)C(COCc1ccccc1)(COCc1ccccc1)COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: O=C1O[C@H](COC(=O)C(CO)(CO)CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1

Procedure:
Condensation was carried out by a method similar to that of Example 3-1 using 3-benzyloxy-2,2-bis(benzyloxymethyl)propionic acid obtained in Step B instead of Boc-Sar-OH and 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-13 instead of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14, and deprotection was carried out by a method similar to that of Example 1-36 using a 10% Pd—C catalyst in a hydrogen atmosphere to synthesize the title compound.