Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].Cl[C:14]1[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:14]1[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc([N+](=O)[O-])c(NCc2ccc(OC)cc2OC)s1
Yield: 97.5 %

Procedure:
A mixture of 2,4-dimethoxybenzylamine (58.7 mmol, 8.81 ml, 9.81 g), methyl 5-chloro-4-nitrothiophene-2-carboxylate (45.1 mmol, 10 g) and potassium carbonate (180 mmol, 24.94 g) were stirred at rt in Acetonitrile (226 mL) for 1 h. Reaction was quenched with water and the resulting precipitate was collected to give methyl 5-(2,4-dimethoxybenzylamino)-4-nitrothiophene-2-carboxylate 86 (15.5 g, 97%). NMR (400 MHz, CDCl3) 3.82 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 4.45 (d, J=5.9 Hz, 2H), 6.46 (dd, J=8.2 Hz and 2.3 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.99 (s, 1H), 8.89 (br s, 1). (m/z)=353 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([NH2:17])(=[S:16])[CH2:14][CH3:15]>C1C=CC=CC=1>[N:10](=[C:4]([C:3]1[N:17]=[C:13]([CH2:14][CH3:15])[S:16][CH:2]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:11]
Reactant: CCOC(=O)C(=NO)C(=O)CCl
Reactant: CCC(N)=S
Solvent: c1ccccc1
Product: CCOC(=O)C(=NO)c1csc(CC)n1
Reaction time: 4 h
Yield: 35.3 %

Procedure:
A solution of ethyl γ-chloro-α-oximinoacetoacetate (2.00 g, 10.3 mmol) and thiopropionamide (0.92 g, 10.3 mmol) in dry benzene (15 mL) was heated to reflux. After 4 hours, the reaction mixture was poured onto NaHCO3 (sat. aq., 50 mL), The resulting mixture was extracted with ethyl acetate (2×50 mL), and the combined extracts dried over MgSO4 and evaporated under reduced pressure. Flash chromatography (ethyl acetate:hexane 1:4) then afforded impure ethyl α-oximino-2-ethylthiazole-4-acetate (0.83g). The crude oxime was then dissolved in methanol (25 mL) and formic acid (50% aq., 10 mL) was added. The mixture was cooled to 0° C. and zinc dust (1.00 g, 15.3 mmol) was added portionwise over 30 mins. The reaction mixture was allowed to warm to room temperature, and stirred for 6 hours. The solution was then filtered, basified to pH 9 with solid NaHCO3, and extracted with ethyl acetate (3×80 mL). The combined extracts were then dried and evaporated to afford DL-2-ethylthiazol-4-ylglycine ethyl ester (0.56 g, 2.6 mmol). The ester (560 mg, 2.6 mmol) was then dissolved in tetrahydrofuran (50 mL). Triethylamine (0.4 mL, 3.9 mmol) was added, followed by di-t-butyl dicarbonate (0.57 g, 2.6 mmol). After stirring at room temperature overnight the mixture was concentrated, water (20 mL) was added and the solution extracted with ethyl acetate (2×20 mL). The combined extracts were evaporated to afford N-t-butyloxycarbonyl-D/L-2-ethylthiazol-4-ylglycine ethyl ester (824 mg,) as a golden oil. The oil was dissolved in methanol (25 mL) and aqueous sodium hydroxide (2 M, 5 mL) was added. After stirring at room temperature for 2 hours, the solution was concentrated, water (30 mL) was added, and the solution extracted with ethyl acetate (30 mL). The aqueous layer was then acidified to pH 4 with 2 N HCl, and extracted with ethyl acetate (2×20 mL), The latter extracts were combined and evaporated to afford N-t-butyloxycarbonyl-D/L-2-ethylthiazol-4-ylglycine (450 mg) as a white solid.
Reaction SMILES: [ClH:1].[C:2]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:19][CH:18]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH:3]=1>C(O)C.[Pd]>[ClH:1].[CH:2]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:19][CH:18]=3)[CH:8]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=O)Cc1ccc(Nc2cc(C3=CCCC3)nc3c2CCC3)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NC(=O)Cc1ccc(Nc2cc(C3CCCC3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of 2-(4-((2-(cyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide hydrochloride (0.042 g, 0.11 mmol) in ethanol (10 mL) was added 10% palladium on carbon (0.005 g). The mixture stirred at rt for 2 h under an atmosphere of hydrogen. After this time, the mixture was filtered over celite, concentrated, and the residue converted to the hydrochloride salt to afford the title compound (0.040 g, 95%) as a white solid. MW=420.38. 1H NMR (DMSO-d6, 500 MHz) δ 13.60 (s, 1H), 9.59 (s, 1H), 7.52 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 6.92 (s, 1H), 6.69-6.66 (m, 1H), 3.42 (s, 1H), 3.18-3.04 (m, 3H), 2.83 (t, J=7.5 Hz, 2H), 2.18 (quin, J=7.5 Hz, 2H), 2.07-1.96 (m, 2H), 1.77-1.69 (m, 2H), 1.68-1.52 (m, 4H), 1.37-1.22 (m, 2H); APCI MS m/z 384 [M+H]+.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1C=CC=CC=1>[CH2:25]([O:24][C:22]([CH:21]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 80.4 %

Procedure:
To a solution of triphenylphosphine (26.20 g, 100 mmol) in benzene (150 ml) was added ethyl bromoacetate (16.70 g, 100 mmol) at 0-5° C. The mixture was kept at room temperature for 16 h. The resulting phosphonium salt was filtered, washed with benzene (100 ml), and dried. To a solution of the solid in water (200 ml) was added benzene (200 ml), followed by 10% NaOH solution (100 ml). The organic layer was separated, and the aqueous layer was extracted with benzene (200 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), concentrated to 50 ml in vacuo, and poured onto hexane (200 ml). The precipitate was filtered and dried to afford the desired phosphorane (28.00 g, 80%) as a colorless solid. mp 128-130° C. 4-Oxocyclohexylideneacetic acid ethyl ester. To a solution of 1,4-cyclohexanedione (5.00 g, 44.64 mmol) in benzene (100 ml) was added the ylide (15.55 g, 44.68 mole). The mixture was heated under reflux for 12 h. After removal of the solvent by evaporation, the residue was purified by flash chromatography (silica gel, 5% ethyl acetate in hexanes) to afford the ketone ester (5.80 g, 71%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ1.26 (t, J=6.4 Hz, 3H), 2.42-2.50 (m, 4H,), 2.60-2.66 (m, 2H), 3.12-3.20 (m, 2H), 4.16 (q, J=6.4 Hz, 2H), 5.86 (s, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1>C(O)C>[NH:2]([C:5]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)[NH2:3]
Reactant: NN
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1NN
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
9.71 g of hydrazine monohydrate was dissolved in 200 mL of ethanol, and cooled to 0° C. To this was added a solution prepared by dissolving 15.0 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate in 200 mL of ethanol, and stirred for 1 hour. The precipitated solid was taken out through filtration, washed with distilled water, and dried to obtain 9.66 g of the entitled compound as a white solid.
Reaction SMILES: CCO[C:4]([S-])=[S:5].[K+:7].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[N:18]=[C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]3[C:26]=2[CH3:27])=[CH:11][C:10]=1[OH:28]>C(O)C>[CH3:27][C:26]1[N:20]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]2=[N:18][C:17]=1[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]2[N:8]=[C:4]([S-:5])[O:28][C:10]=2[CH:11]=1.[K+:7]
Reactant: CCOC(=S)[S-]
Reactant: Cc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1
Agent: [K+]
Solvent: CCO
Product: Cc1ccn2c(C)c(CCc3ccc4nc([S-])oc4c3)nc2c1
Yield: 64.4 %

Procedure:
A mixture of potassium ethylxanthogenate (6.25 g) and 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (10.0 g) in ethanol (80 ml) was refluxed for 3 hours with stirring. The resulting precipitate was collected by filtration to give potassium 6-[2-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-benzoxazolethiolate (8.28 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Cl:12]N1C(=O)CCC1=O>C(#N)C>[Cl:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: O=Cc1ccc2[nH]nc(Cl)c2c1
Temperature: 67.5 °C
Reaction time: 50 h
Yield: 54.4 %

Procedure:
To a solution of 1H-Indazole-5-carbaldehyde (3.2 g, 21.89 mmol) in acetonitrile (140 mL) was added N-Chlorosuccinimide (3.5 g, 26.27 mmol). After stirring for 50 hours at 65 to 70° C., the precipitate was filtered, washed with cold acetonitrile, abundantly with water and dried to afford the title compound as a white solid (2.15 g, 54%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.Cl>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Agent: Cl
Product: CN1CC=C(c2cn(C(=O)c3ccc(F)cc3)c3ccc(C(F)(F)F)cc23)CC1

Procedure:
(22.8 mg, 79%); from 3 -(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and 4-fluorobenzoyl chloride (17.0 mg, 0.107 mmol), HRMS-FAB+ for C22H18N2OF4, calculated MH+ (--HCl): 403.14344; found: 403.14104.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[CH:16]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][N:18]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:17]2>>[CH:20]12[CH2:23][CH2:24][CH:16]([CH2:22][CH2:21]1)[CH2:17][N:18]([CH2:25][CH2:26][CH2:27][NH:28][C:2]1[N:3]=[N:4][C:5]([CH3:15])=[C:6]3[N:14]4[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]4)=[CH:8][C:7]=13)[CH2:19]2
Reactant: Cc1nnc(Cl)c2cc3n(c12)CCCC3
Reactant: NCCCN1CC2CCC(CC2)C1
Product: Cc1nnc(NCCCN2CC3CCC(CC3)C2)c2cc3n(c12)CCCC3

Procedure:
Following the procedure in Example 9, compound XII was allowed to react with 3-(3-azabicyclo[3.2.2]non-3-yl)propylamine to give the title compound which was converted to the dihydrochloride salt: m.p.278°-279° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:31])[C@@H:15]([NH:23]C(=O)OC(C)(C)C)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]([CH3:32])[N:9]=2)[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH:13][C:11]1[N:10]([CH3:32])[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[CH:12]=1)=[O:31]
Reactant: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
To a 250 ml flask was added 18.8 g of tert-butyl (S)-1-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 1.D, 100 ml of DCM and 50 ml of TFA. The reaction was stirred at room temperature for 4 hours at which time the solvent was removed with a stream of nitrogen. The crude was partitioned between 2000 ml of DCM and 500 ml of saturated aqueous sodium bicarbonate. The organic layer was extracted twice more with 500 ml of water, dried over sodium sulfate and the organic solvent was removed by rotary evaporation. The crude was purified using a silica gel column (eluting with 5% MeOH in DCM) to give 8.6 g of (2S)-2-amino-N-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)-3-phenylpropanamide 17.7.E as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH:16]=[C:15]([CH:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)O)[C:14]([CH3:25])=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[C:3]([N:12]2[CH:16]=[C:15]([CH:17]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=3)[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:14]([CH3:25])=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1nn(-c2ncc(C(F)(F)F)cc2Cl)cc1C(O)C1CCCCC1
Product: Cc1nn(-c2ncc(C(F)(F)F)cc2Cl)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 4.8 %

Procedure:
Using {1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-3-methyl-1H-pyrazol-4-yl}(cyclohexyl)methanol (0.74 g) synthesized in Example 31(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.60 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (54.4 mg, 5%) was obtained as an amorphous pale-yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[O:10].[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:15][Si:14]([C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[O:10])([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: NC(=O)Nc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccccc1NC(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a degassed solution of 1-(2-iodophenyl)urea (2.62 g, 10 mmol, 1 eq), ethynyltrimethyl silane (4.16 mL, 3 eq), and triethylamine (5.58 mL, 4 eq) in anhydrous DMF (15 mL) was added bis(triphenylphosphine)palladium(II) dichloride (702 mg, 0.1 eq) and copper(I) iodide (190.4 mg, 0.1 eq). After the reaction mixture was stirred at room temperature for 30 minutes, it was partitioned between aqueous ammonium chloride and ethyl acetate. The organic layer was isolated, washed further with saturated sodium bicarbonate, brine, and lastly dried with sodium sulfate. The upper solution was decanted, concentrated, and the brown solid residue was treated with a small amount of DCM. The mixture was stirred at room temperature for 30 minute and filtered to obtain 1-{2-[(trimethylsilyl)ethynyl]phenyl}urea as a white solid in 1.645 g. The filtrate was concentrated and the residue was subject to a gradient column chromatography (EtOAc-hex from 1:100 to 1:1) to render 1-{2-[(trimethylsilyl)ethynyl]phenyl}urea with a second crop of 0.432 g in a total yield of 90%.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24](Cl)(=[O:26])=[O:25]>C[Si](C)(C)N[Si](C)(C)C.C1COCC1>[CH2:2]([O:4][C:5]([C:7]1[CH2:8][N:9]([S:24]([C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)(=[O:26])=[O:25])[CH2:10][CH2:11][C:12]=1[OH:13])=[O:6])[CH3:3]
Reactant: CCOC(=O)C1CNCCC1=O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(O)CCN(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 140 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
A suspension of 31.15 g (150 mmol) 3-Ethoxycarbonyl-4-piperidone hydrochloride was suspended in 400 ml hexamethyldisilazane and heated under reflux (140° C.) for 2.5 h. The solution was evaporated complete, the residue dissolved in 400 ml THF and treated with 34 g (150 mmol) of naphthalene-2-sulfonylchloride in 150 ml THF. The reaction was stirred 16 h at room temperature, evaporated, treated with 400 ml aqueous 10% NaCl, stirred for 10 min and extracted with EtOAc (3×400 ml). The organic phase was dried (Na2SO4) and evaporated and crystallized from Et2O at 5° C. to give 53.1 g (90%) of 4-hydroxy-1-(naphthalene-2-sulfonyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, MS: 362 (MH+).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[N:16]=O)[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[CH2:1]([N:5]1[C:6]2[CH:15]=[CH:14][C:13]3[C:8]([C:7]=2[N:16]=[C:24]1[C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C=O)cc1
Reactant: CCCCNc1ccc2ccccc2c1N=O
Product: CCCCn1c(-c2ccc(OC)cc2)nc2c3ccccc3ccc21
Yield: 53 %

Procedure:
The compound of the title is prepared by following essentially the same procedure described in example 2 but starting from 2-butylamino-1-nitrosonaphthalene instead of 2-methylamino-1-nitrosonaphthalene and employing 4-methoxybenzaldehyde instead of 4-ethoxybenzaldehyde. Yield 53%. M.p. 99,5°-100,5° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][S:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:33][C:30]4[CH:31]=[CH:32][C:27]([S:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CSc1ccc(CBr)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Product: CSc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 70 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 4-(bromomethyl)phenyl methyl sulfide, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6](Br)[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Cu][C:26]#[N:27].O.Cl>N1C=CC=CC=1>[C:26]([C:6]1[C:5]([NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)(=[O:15])=[O:14])=[C:4]([CH:9]=[C:8]([CH3:10])[CH:7]=1)[C:3]([OH:2])=[O:24])#[N:27]
Reactant: COC(=O)c1cc(C)cc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: N#C[Cu]
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2c(C#N)cc(C)cc2C(=O)O)cc1
Yield: 72.2 %

Procedure:
To a solution of 4.0 g (10 mmol) of the product of Example 135 in 60 ml of pyridine was added 2.0 g (22 mmol) of copper (I) cyanide and the mixture was refluxed for 48 h. The reaction mixture was then cooled to room tempera and poured over cold water. The resulting mixture was stirred for sixteen hours and carefully acidified with concentted HCl solution. The resulting precipitate was filtered and washed with water, dissolved in chloroform, filtered and concentrated. The residue was triturated with ether, filtered and dried to provide 2.5 g (72%) of the desired product as a white solid. m.p. 162° C.; Electrospray Mass Spec 347 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O)=[O:14].[CH:24]([O:26][CH2:27][CH2:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[CH3:38])=[CH2:25].C(OC(=O)C)(=O)C.[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH:24]([O:26][CH2:27][CH2:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:13]2([C:3]3[CH:4]=[CH:5][C:6]([N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])=[CH:7][C:2]=3[CH3:1])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:19])[O:14]2)=[C:30]1[CH3:38])=[CH2:25]
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: C=COCCn1c(C)cc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C=COCCn1c(C)c(C2(c3ccc(N(CC)CC)cc3C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 70 °C
Yield: 76.1 %

Procedure:
A mixture of 15.6 g of 2-(2-methyl-4-dietylaminophenyl)carbonylbenzoic acid, 12.5 g of 1-(2-vinyloxyethyl)-2-methylindole, and 50.0 ml of acetic anhydride was maintained at approximately 70° C. for approximately four hours. The resulting solution was cooled to ambient temperature and slowly poured into a mixture of toluene and 5 percent aqueous ammonium hydroxide. The toluene layer was separated, washed successively once each with water and saturated sodium chloride solution and evaporated to dryness. The residue that remained was heated in a 1:1 mixture of isopropyl alcohol:hexane. The liquid was decanted from a gummy residue. The residue was dissolved in 100.0 ml of acetone and the resulting solution was added dropwise to 1500.0 ml of 2 percent aqueous ammonium hydroxide. The solid which precipitated was collected by filtration, washed with water and dried to obtain 18.86 g of 3-[1-(2-vinyloxyethyl)-2-methylindol-3-yl]-3-(2-methyl-4-diethylaminophenyl)phthalide (Formula I: R1 =CH2 =CHOC2H4 ; R1 =R2 =CH3 ; R3 =R4 =C2H5 ; X=Y=H), a tan-colored solid which melted over the range 135°-141° C. Significant infrared maxima appeared at 1760 (C=O; s) and 1120 (C--O; s)cm-1. A toluene solution of the product spotted on an acid clay or a phenolic resin coated paper developed a cyan-colored image.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19](O)=[O:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[N:1]1([C:19]([C@@H:15]2[CH2:16][CH2:17][CH2:18][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:14]2)=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
To a solution of pyrrolidine (2.134 g, 30 mmol) in N,N-dimethylformamide (240 mL) was added (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (6.878 g, 30 mmol). Then hydroxybenzotriazole (1.028 g, 6 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (5.751 g, 30 mmol), and triethylamine (7.59 g, 75 mmol) were added sequentially. The mixture was stirred at 30° C. for 16 h. The solvent was removed under reduced pressure and an aqueous solution of sodium bicarbonate (200 mL, 0.1M) was added. The mixture was extracted with ethyl acetate (200 mL×3) and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate, which was used in the next step without further purification.
Reaction SMILES: Cl.C([Cl:5])(=O)C.C([NH:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25])(=O)C1C=CC=CC=1>CO>[ClH:5].[NH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccccc1CONC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1ccccc1CON
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of HCl in methanol (prepared by adding 20 mL of acetyl chloride slowly to 200 mL of methanol) was added the title compound of Step B (31.5 g). The mixture was heated to 60° C. for 1.5 h. The solvent was removed in vacuo. The residue was taken up in 100 mL of diethyl ether and stirred at room temperature for 30 minutes. The ether was decanted off and the solid was taken up in 100 mL of tetrahydrofuran and heated to about 50° C. The mixture was then cooled in an ice water bath and the solid was collected by filtration to provide 11.5 g (47% yield) of the title compound of Step C as a white solid melting at 169-170° C.