Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[N:4]=1.[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=O)[CH3:15].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]1[N:2]([CH3:1])[C:3]2=[N:4][C:5]([C:10]([F:11])([F:12])[F:13])=[CH:6][CH:7]=[C:8]2[N:9]=1)[CH3:15]
Reactant: CCSc1ccccc1C(=O)O
Reactant: CNc1nc(C(F)(F)F)ccc1N
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCSc1ccccc1-c1nc2ccc(C(F)(F)F)nc2n1C
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A mixture of N2-methyl-6-trifluoromethylpyridin-2,3-diamine (0.96 g), 2-ethylsulfanylbenzoic acid (1.01 g), WSC (1.06 g), and pyridine (5 ml) was stirred under reflux for 3 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. To the resulting residue, a mixture of tripotassium phosphate (2.65 g) and 1-propanol (10 ml) was added, and stirred under reflux for 4 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.98 g of 2-(2-ethylsulfanylphenyl)-3-methyl-5-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 151).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]2[O:14][CH2:13][C:12]3[C:11]([C:15](=[O:19])[CH2:16][C:17]#[N:18])=[N:10][N:9]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:8]=3[C:6]=2[CH:7]=1.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:17]([CH:16]([C:15]([C:11]1[C:12]2[CH2:13][O:14][C:5]3[C:4]([CH2:26][N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[CH:3][C:2]([F:1])=[CH:7][C:6]=3[C:8]=2[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]=1)=[O:19])[C:40]([NH:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:41])#[N:18]
Reactant: N#CCC(=O)c1nn(-c2ccccc2)c2c1COc1c(CN3CCOCC3)cc(F)cc1-2
Reactant: O=C=Nc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1COc1c(CN3CCOCC3)cc(F)cc1-2
Temperature: 0 °C
Yield: 53.2 %

Procedure:
3-(8-fluoro-1,4-dihydro-6-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanenitrile (2.8 g) is reacted with phenylisocyanate (0.8 g) in dimethylformamide (20 ml) in the presence of triethylamine (0.7 g) at 25°-30° C. for 30 min. The reaction mixture is diluted with ice water and acidified with citric acid to pH 3. The precipitate is filtered and dissolved in chloroform. The organic solution is washed with 2% citric acid solution and then with water until neutral. Evaporation to dryness in vacuo gives a residue which is crystallized from chloroform/ethanol to yield 1.9 g of 2-cyano-3-(8-fluoro-1,4-dihydro-6-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 249°-253° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:16])[CH:13]([OH:15])[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([CH3:16])[CH:13]([CH3:14])[OH:15])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=Cc1ccc(C(C)(C)C)cc1)C(C)O
Reactant: [H][H]
Agent: [Pd]
Product: CC(O)C(C)Cc1ccc(C(C)(C)C)cc1

Procedure:
65 g of 3-(p-tert.butyl-phenyl)-1,2-dimethyl-allyl alcohol are dissolved in 650 ml of alcohol and treated with 6 g of 5% palladium/carbon while gassing with nitrogen. The mixture is hydrogenated until the hydrogen uptake has been completed. Subsequently, the catalyst is removed by filtration and the alcohol filtrate is evaporated. By distillation there is obtained pure 3-(p-tert.butyl-phenyl)-1,2-dimethyl-propanol of boiling point 110° C./0.03 Torr.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](=[O:25])[NH:14][C@H:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:11][C@H:10]([NH:26][C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][C@@H:32]([C:44](=[O:56])[NH:45][C@H:46]4[C:55]5[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=5)[CH2:49][CH2:48][CH2:47]4)[N:33](C(OC(C)(C)C)=O)[CH2:34]3)=[CH:29][CH:28]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:46]1([NH:45][C:44]([C@@H:32]2[CH2:31][C:30]3[C:35](=[CH:36][C:27]([NH:26][C@H:10]4[CH2:11][C@@H:12]([C:13](=[O:25])[NH:14][C@H:15]5[C:24]6[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=6)[CH2:18][CH2:17][CH2:16]5)[NH:8][CH2:9]4)=[CH:28][CH:29]=3)[CH2:34][NH:33]2)=[O:56])[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49][CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N[C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)OC(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCCc2ccccc21)[C@@H]1Cc2ccc(N[C@@H]3CN[C@H](C(=O)N[C@@H]4CCCc5ccccc54)C3)cc2CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of (S)-tert-butyl 7-(((3S,5S)-1-(tert-butoxycarbonyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)amino)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (150 mg, 0.20 mmol) in CH2Cl2 (2.2 mL) was added TFA (303 μL, 3.93 mmol). The resulting solution was stirred at room temperature for 1 h. Additional TFA (303 μL, 3.93 mmol) was added. The reaction mixture was stirred for 2 h, then quenched carefully with sat. aq. NaHCO3 solution and poured into a separatory funnel containing EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (111 mg, 100%) as a tan solid. MS (ESI+) m/z 564.4 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=C2[N:29]=NN(O)C2=CC=1.O.C(Cl)CCl.[NH4+].[OH-]>CN(C=O)C.CCOC(C)=O.O>[NH2:29][C:20](=[O:22])[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(N)=O
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A solution of N-Boc-D-tryptophan (1.00 g, 3.29 mmol), HOBt monohydrate (0.600 g, 3.92 mmol) and EDC (0.820 g, 4.27 mmol) in DMF (12 mL) was stirred at room temperature for 2 h, conc. NH4OH (1.10 mL, ca. 15.4 mmol) was added. The mixture was stirred for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-tert-butyl 1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-ylcarbamate (0.963 g)
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[N:22].C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[C:10]([I:11])=[C:9]2[C:5]([CH2:6][N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])[C:8]2=[O:12])=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1CBr
Reactant: O=C1NCc2ccc(F)c(I)c21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1CN1Cc2ccc(F)c(I)c2C1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
A mixture of 6-fluoro-7-iodo-2,3-dihydro-isoindol-1-one (0.070 g, 0.25 mmol), 1-bromomethyl-2-cyano-benzene (0.059 g, 0.3 mmol), Cs2CO3 (0.098 g, 0.3 mmol), and 18-crown-6 (0.007 g, 0.025 for mmol) in acetone (5 mL) was stirred at 70° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 6-fluoro-7-iodo-2-(2-cyano-benzyl)-2,3-dihydro-isoindol-1-one (0.040 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.33 (s, 2H), 5.04 (s, 2H), 7.04-7.71 (m, 6H), GC-MS: m/z 392 (M)+.
Reaction SMILES: [Mg].II.[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].N>C(OCC)C>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:19]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCCC1
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: II
Agent: N
Agent: [Cl-]
Solvent: CCOCC
Product: OC1(c2cccc(OCc3ccccc3)c2)CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1.85 g of magnesium was suspended in 15 mL of diethyl ether, to which a catalytic amount of iodine was added and then a solution of 20.00 g of 1-(benzyloxy)-3-bromobenzene in 40 mL of diethyl ether was added dropwise and this mixture was stirred for 8 hours while heating it under reflux. The reaction mixture was cooled to 5° C., to which a solution of 6.72 mL of cyclopentanone in 20 mL of diethyl ether was added dropwise, and this mixture was stirred for one hour at room temperature. Then an aqueous solution of ammonia chloride was added to the ice-cooled reaction mixture, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to yield 7.65 g of 1-[3-(benzyloxy)phenyl] cyclopentanol as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](/[CH:26]=[CH:27]/[C:28](=O)[CH2:29][CH3:30])=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O>C(O)(=O)C.C(O)C.[Fe]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[C:28]([CH2:29][CH3:30])[CH:27]=[CH:26]4)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCC(=O)/C=C/c1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1ccc2c3c(ccc2n1)OCC(COS(=O)(=O)c1ccc(C)cc1)O3

Procedure:
To a solution of {(2R)-7-nitro-8-[(E)-3-oxo-1-pentenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (1.57 g, 3.50 mmol) in 100 mL of acetic acid/ethanol (1:1) was added 1.00 g (17.9 mmol) of iron powder and the mixture was heated at reflux under nitrogen for 8 hours. After the reaction was complete, 150 mL of water was added and the mixture filtered through a pad of celite. The filtrate was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel using a gradient elution commencing with 20% ethyl acetate/hexane and ending with 70% ethyl acetate/hexane to give 0.94 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet 8.2 δ (1 H); doublet 7.8 δ (2 H); doublet 7.55 δ (1 H); 7.2-7.3 δ (4 H); multiplet 4.6 δ (1 H); multiplet 4.2-4.4 δ (3 H); multiplet 4.1 δ (1 H); quartet 3.0 δ (2 H); singlet 2.4 δ (3 H); triplet 1.4 δ (3 H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH2:23]([N:31]=[C:32]=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:32]([NH:31][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:33])=[CH:4][CH:3]=1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: O=C=NCCc1ccccc1
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)NCCc1ccccc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using phenethyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:12])[CH:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7]2.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][C:2]1[NH:3][C:4](=[O:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:6]2[C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: O=[N+]([O-])O
Reactant: Cc1[nH]c(=O)cc2c1CCCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c([N+](=O)[O-])c2c1CCCC2
Temperature: 0 °C

Procedure:
To a solution of 1.63 g of 2,3,5,6,7,8-hexahydro-1-methyl-3-oxoisoquinoline in 10 ml of acetic acid, 1 ml of concentrated sulfuric acid and 5 ml of concentrated nitric acid (d=1.42) were dropwise added under cooling on ice. After the reaction was completed, the reaction mixture was poured into ice water and deposited crystals were filtered out. There was obtained 1.0 g of 2,3,5,6,7,8-hexahydro-1-methyl-4-nitro-3-oxoisoquinoline. mp: 255° C. (decomposition).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH:19]=[C:18]([C:20]([O-:22])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:2]1
Reactant: O=C([O-])c1cc(-c2c[nH]c3ccccc23)nc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(-c2c[nH]c3ccccc23)nc2ccccc12
Reaction time: 0.5 h

Procedure:
To a 3 mL plastic tube fitted with a frit containing 50 mg of resin-bound 2-(3-indolyl)quinoline-4-carboxylate (0.035 mmol) was added 1 mL of a 50% mixture of TFA and DCM. The reaction mixture was agitated on an orbital shaker for 30 min. The mixture was filtered and the resin washed with DCM (3×3 mL). The organic solutions were combined and of evaporated by a stream of nitrogen. The residual solid was lyophilized to give 2-(3-indolyl)quinoline-4-carboxylic acid or amide (80-100% yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[NH2:1][C@@H:2]([CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:3]([O:5][CH2:24][CH3:25])=[O:4]
Reactant: CCO
Reactant: N[C@@H](CCN1C(=O)c2ccccc2C1=O)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H](N)CCN1C(=O)c2ccccc2C1=O

Procedure:
A solution of 2-(S)-Amino-4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butanoic acid (2 g) and concentrated sulphuric acid (0.5 mL) in absolute ethanol (30 mL) was heated under reflux for 15 h. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by chromatography using 20% ethyl acetate-dichloromethane then 75% ethyl acetate-dichloromethane as eluent to afford the title compound as a white solid (473 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:32][OH:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:32][O:33][C:41](=[O:43])[CH3:42])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)NC(CO)c2ccccc2N2CCCCC2)cc1OCC
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(CC(=O)NC(COC(C)=O)c2ccccc2N2CCCCC2)cc1OCC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of ethyl 2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (0.227 g, 0.5 mmol) and absolute triethylamine (0.126 ml, 0.9 mmol) in absolute chloroform (3 ml), a solution of acetyl chloride (0.063 ml, 0.9 mmol) in absolute chloroform (1 ml) is added dropwise. After 4 days' stirring at ambient temperature the mixture is diluted with chloroform, washed with dilute aqueous sodium bicarbonate solution, the chloroform solution is dried and filtered and evaporated down in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone=4/1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.C[C:12]([CH3:14])=[O:13]>>[N:3]1([CH:4]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH3:5])[CH2:14][CH2:12][O:13][CH2:7][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)=O
Product: CC(c1ccc(N)cn1)N1CCOCC1

Procedure:
A4-11 was made using a variation of the above approach from methylketone 35. The methylketone was synthesised from 2-chloro-5-nitropyridine (21).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH2:12]([N:14]1[C:18](=[O:19])[CH2:17][O:16][C:15]1=[O:20])[CH3:13].C1COCC1.[H-].[Na+]>O>[CH2:12]([N:14]1[C:18](=[O:19])[C:17](=[CH:7][C:6]2[CH:1]=[CH:2][C:3]3[O:11][CH2:10][O:9][C:4]=3[CH:5]=2)[O:16][C:15]1=[O:20])[CH3:13]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CCN1C(=O)COC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1C(=O)OC(=Cc2ccc3c(c2)OCO3)C1=O
Yield: 16.8 %

Procedure:
1.16 g (7.73 mmol) of piperonal and 1.00 g (7.75 mmol) of N-ethyl-2,4-oxazolidinedione are introduced into a 50 ml of eggplant-shaped flask, and a spiral condenser and a drying tube are mounted thereon. The reaction vessel is internally charged with an atmosphere of nitrogen and about 10 ml of THF dried with molecular sieve is added, followed by dissolution by stirring with a magnetic stirrer. After dissolution, 0.36 g (9.0 mmol) of NaH (60 wt. %, oily) is added little by little under stirring with magnetic stirrer. After stirring at room temperature for 2 hours, the reaction mixture is poured into water. The oily substance formed is extracted with ethyl acetate, and after drying over magnesium sulfate, the solvent is removed under reduced pressure, followed by recrystallization from methanol to give 0.34 g (1.3 mmol) of N-ethyl-5-(3,4-methylenedioxy-benzylidene)-2,4-oxazolidinedione at a yield of 17 % (m.p.=135°-137 ° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[N:6][CH:7]=1.C([Li])CCC.[CH3:27][S:28]SC>C1COCC1>[CH3:15][C:14]1[O:13][N:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]=1[CH2:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([S:28][CH3:27])=[CH:7][N:6]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(Br)cn1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 5-bromo-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine (300 mg, 0.87 mmol) in THF (3 mL) was added n-butyllithium (1.6 M, 543.1 μL, 0.87 mmol) and the resulting mixture stirred at −78° C. for 30 min. Then methyl disulfide (78.7 μL, 0.87 mmol) was added and the resulting mixture stirred overnight. The mixture was then evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate 8:2 to 1:3) afforded the title compound (136 mg, 50%) as a light yellow oil. MS: m/e=313.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[C:13]([Cl:19])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.Cl[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28]>C1COCC1.C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[C:13]([Cl:19])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(CO)c(Cl)c2)n1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2N)cc1Cl)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
To a solution of 3-(tert-butyl)-1-(3-chloro-4-(hydroxymethyl)phenyl)-1H-pyrazol-5-amine (1.15 g, 70% purity, 2.9 mmol) in dry THF (10 mL) under N2 was added imidazole (320 mg, 4.7 mmol) and chlorotriisopropylsilane (970 μL, 870 mg 4.5 mmol) and the reaction mixture maintained at RT for 18 hr. The resulting mixture was diluted with DCM (5.0 mL) and was treated with an additional aliquot of chlorotriisopropylsilane (970 μL, 870 mg, 4.5 mmol) and after a further 5 hr with imidazole (320 mg, 4.7 mmol). After 20 hr the reaction mixture was treated for a third time with chlorotriisopropylsilane (200 μL, 180 mg, 0.90 mmol) and imidazole (100 mg, 1.6 mmol) and after 3 days was evaporated in vacuo. The residue was taken up into EtOAc (20 mL) and was washed with water (20 mL) and brine (10 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-100%, gradient elution) and then by SCX capture and release to afford a blue oily liquid which comprised of a mixture of starting material and the desired product. This mixture was taken up into THF (1.0 mL) and was treated with imidazole (50 mg, 0.74 mmol) chlorotriisopropylsilane (140 μL, 130 mg, 0.65 mmol) and maintained at RT for 24 hr and then evaporated in vacuo. The residue was taken up EtOAc (10 mL) and was washed with water (10 mL) and brine (10 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 0-100%, gradient elution) to afford the title compound, Intermediate A22 as a white solid (300 mg, 24%); Rt 3.42 min (Method 2); m/z 436 (M+H)+, (ES+).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH:22]([C:26](O)=[O:27])[C:23](O)=[O:24]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][C:22]1[C:23](=[O:24])[O:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:26]=1[OH:27]
Reactant: O=C(O)C(Sc1ccccc1Cl)C(=O)O
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: O=c1oc(-c2ccccc2)cc(O)c1Sc1ccccc1Cl

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(2-chlorophenyl)thio]propanedioic acid (1.53 g, 5.07 mmol). m.p. 275°-280° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.78 (s, 1H), 6. 89 (dd, 1H), 7. 08 (tt, 1H), 7. 19 (tt, 1H), 7.42 (dd, 1H), 7.56 (m, 3H), 8.06 (m, 2H).