Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][C:19](=[O:26])[CH:20](Br)C(OC)=O>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]([C:20]1[O:10][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:9][C:6]=2[CH:7]=1)=[O:26]
Reactant: COC(=O)C(Br)C(=O)OC
Reactant: Cc1ccc(O)c(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(C)ccc2o1
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A stirring suspension of 5methylsalicylaldehyde (1.0 mg, 7.5 mmol), K2CO3 (1.55 g, 11.0 mmol), and Bu4NBr (322 mg, 1 mmol) in toluene (30 ml) was treated with dimethylbromomalo-nate (1.06 ml, 8.0 mmol). The suspension was heated to reflux with a Dean-Stark trap for 20 h. The brown suspension was cooled to 25° C. and concentrated in vacuo. The residue was taken in DCM and filtered. The filtrate was washed with H2O, 1N NaOH and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (10% ethyl acetate/hexane) to afford the title compound 583 (600 mg, 42% yield). LRMS: 190.2 (Calc.). 191.1 (found).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])=[O:14].ClS([N:28]=[C:29]=[O:30])(=O)=O.O>ClCCl>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[NH:15][C:13]([C:3]1[O:4][C:5]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=2[C:2]=1[NH:1][C:29]([NH2:28])=[O:30])=[O:14]
Reactant: COc1ccc2c(N)c(C(=O)Nc3ccc(Cl)cc3Cl)oc2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(NC(N)=O)c(C(=O)Nc3ccc(Cl)cc3Cl)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
3-Amino-N-(2,4-dichlorophenyl)-6-methoxybenzofuran-2-carboxamide ¼ hydrate (0.9 g) obtained in Example 1 was dissolved in dichloromethane (10 ml) and chlorosulfonyl isocyanate (0.4 g) was added under ice-cooling. The mixture was further stirred at room temperature for 1 hr. Then water was added and the precipitated crystals were recrystallized from water-containing dimethylformamide to give the title compound (0.3 g). melting point: >260° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[N:16][C:7]2[N:8]([CH3:15])[C:9](=[O:14])[N:10]([CH3:13])[C:11](=[O:12])[C:6]=2[CH:5]=1)([O-])=O.C>CO.[Pd]>[NH2:1][C:4]1[CH:17]=[N:16][C:7]2[N:8]([CH3:15])[C:9](=[O:14])[N:10]([CH3:13])[C:11](=[O:12])[C:6]=2[CH:5]=1
Reactant: Cn1c(=O)c2cc([N+](=O)[O-])cnc2n(C)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)c2cc(N)cnc2n(C)c1=O
Yield: 71.6 %

Procedure:
0.08 g of Compound 16 was dissolved in methanol and reduced in the presence of 100 mg of Pd-C. Activated charcoal powder was added, and the solution was heated and filtered. The filtrate was distilled under reduced pressure and the residue was recrystallized from methanol to give 0.05 g of 6-amino-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione (Compound 17).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([NH2:8])=[N:5][CH:4]=1)[CH3:2].[CH:9]1[C:22]2[CH:21]([C:23](Cl)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>>[CH2:1]([C:3]1[O:7][C:6]([NH:8][C:23]([CH:21]2[C:22]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:24])=[N:5][CH:4]=1)[CH3:2]
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: CCc1cnc(N)o1
Product: CCc1cnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1

Procedure:
The title compound, white solid, m.p. 212-213° C. and MS: m/e=320.1 (M+) was prepared in accordance with the general method of example 44a from 5-ethyl-oxazol-2-ylamine [Ber. 95, 2419(1962)] and 9-xanthene-carboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:18]([CH3:20])[CH3:19])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@@:10]1([CH3:17])[C:14]([OH:16])=O)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:47][C@@H:48]1[CH2:53][NH:52][CH2:51][CH2:50][N:49]1[C:54]1[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][N:55]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@@:10]1([CH3:17])[C:14]([N:52]1[CH2:51][CH2:50][N:49]([C:54]2[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][N:55]=2)[C@H:48]([CH3:47])[CH2:53]1)=[O:16])=[O:8])[CH:18]([CH3:20])[CH3:19]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C)C(=O)O)C(C)C
Reactant: C[C@@H]1CNCCN1c1ccc([N+](=O)[O-])cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)[C@H](C)C1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.9 %

Procedure:
(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-2-methyl-pyrrolidine-2-carboxylic acid (770 mg, 2.7 mmol) was dissolved in DMA (17 mL) and HATU (1.0 g, 2.7 mmol) was added. The reaction mixture was stirred for 20 min and then (R)-2-methyl-1-(5-nitro-pyridin-2-yl)-piperazine di-HCl (700 mg, 2 mmol; Preparation 47) was added followed by N,N-diisopropylethylamine (2.0 mL, 11 mmol) and the reaction mixture was stirred at 55° C. overnight, cooled to RT, concentrated by rotary evaporation and extracted with EtOAc/water. The organic layer was washed with water, and then brine, dried over sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography (0-100% ethyl acetate:hexanes) to yield the title intermediate (970 mg) as a yellow oil. (m/z): [M+H]+ calcd for C23H34N6O6 491.25 found 491.7.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C@H:10]1[CH2:27][CH3:28])(C(C)(C)C)(C)C.C(O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:27]([C@H:10]1[C@@H:9]([OH:8])[CH2:13][C:12](=[O:14])[N:11]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=1)[CH3:28]
Reactant: CC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.1 %

Procedure:
To a solution of 4-[(2S,3S)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (7.76 g) in tetrahydrofuran (60 mL)-ethanol (30 mL) was added 6 mol/L hydrochloric acid (60 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=50/1→1/4), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound as a colorless solid (yield: 2.36 g, 42%).
Reaction SMILES: [H-].[Na+].C([N:10]1[C@H:13](CCO)[C@@H:12]([C@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])[C:11]1=[O:27])C1C=CC=CC=1.C(Br)C1C=CC=CC=1>O.C1COCC1.CN(C)C=O>[Si:20]([O:19][C@@H:17]([C@@H:12]1[CH2:13][NH:10][C:11]1=[O:27])[CH3:18])([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(Cc2ccccc2)[C@@H]1CCO
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CNC1=O
Temperature: 25 °C
Yield: 58 %

Procedure:
There were added 1 ml of THF and 0.6 ml of dimethylformamide to 13 mg (0.26 mmol) of sodium hydride (oiliness: 50%), to which 2 ml of a THF solution of 64 mg (0.18 mmol) of 1-benzyl-3(S)-[1(R)-t-butyldimethylsilyloxyethyl]-4(R)-(2-hydroxyethyl)-2-azetidinone on the ice bath and the mixture was stirred for 10 minutes. Thereto 0.03 ml (0.25 mmol) of benzyl bromide was added and the mixture was stirred at room temperature for a night. The reaction mixture was added with water, extracted three times with diethyl ether, and the obtained extract was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated. The obtained residue was purified by 10 g of silica gel-column chromatography (eluent; hexane:diethyl ether=1:1) to give 46 mg of 1-benzyl-4(R)-2-benzyloxyethyl)-3(S)-[1(R)-t-butyldimethylsilyloxyethyl]-2-azetidinone (yield: 58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:23][O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH2:29][S:30][CH3:31])[NH2:27].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:23][O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH2:29][S:30][CH3:31])[NH:27][C:13]([CH:12]1[CH2:11][S:10][CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCSC)NC(=O)C1CSC(c2cccnc2)N1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 600 mg of N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid in 10 ml of tetrahydrofuran, there were added, at 4° C. or below, 390 mg of L-methionine methyl ester hydrochloride, 390 mg of 1-hydroxybenzotriazole, 190 mg of N-methylmorpholine and 440 mg of dicyclohexylcarbodiimide, in that order. The mixture was stirred at 4° C. or below for 1 hour and then at room temperature for 1 hour. The resultant precipitate was filtered off, the filtrate was concentrated under reduced pressure, 50 ml of ethyl acetate was added, the insoluble matter was filtered off, and the filtrate was washed in sequence with 0.5M aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 440 mg of [N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carbonyl]-L-methionine methyl ester as an oil.
Reaction SMILES: O[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[OH:20][N:19]=[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCCCCN1CC(C(=O)OCC)=C(O)C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCN1CC(C(=O)OCC)C(=NO)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of the title compound of Example D (5.0 g, 20.2 mmol) in 50 ml of pyridine was added hydroxylamine hydrochloride (1.58 g, 24.2 mmol) and the solution was stirred for 16 h at room temperature. Concentration in vacuo gave an oil which was chromatographed on silica gel eluting with EtOH/CH2Cl2 (10/90) to give the title compound (5.18 g, 98%) as a colorless solid. MS calcd for C12H20N2O4 256, found 256.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:15]([O-])=O)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2.[H][H]>CO.O1CCCC1.[Pd]>[NH2:15][C:5]1[CH:6]=[C:7]2[C:11](=[C:3]([O:2][CH3:1])[CH:4]=1)[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])cc2cc(C(=O)O)[nH]c12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N)cc2cc(C(=O)O)[nH]c12

Procedure:
A mixture of 472 mg 7-methoxy-5-nitro-1H-indole-2-carboxylic acid and 0.1 g Pd/C 10% in 10 ml methanol and 20 ml tetrahydrofuran was stirred for 2 h at ambient temperature under a pressure of 3 bar of hydrogen. The catalyst was filtered and the filtrate was evaporated to obtain brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:33][CH2:32][CH2:31][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:15])=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[NH:8]1[CH2:33][CH2:32][CH2:31][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:15])=[O:11]
Reactant: CCCCCCCCCCCCCCOC(=O)CNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)CNC(=O)[C@@H]1CCCN1
Reaction time: 2 h
Yield: 97 %

Procedure:
A suspension of the compound (9) (1.47 g, 3.02 mmol) in trifluoroacetic acid (14 ml) was stirred for 2 h under ice-cooling. The reaction mixture was diluted with toluene and the resulting mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and sodium hydrogencarbonate aq. The organic layer was washed with water and concentrated in vacuo to give 1.08 g of tetradecyl L-prolyl-glycinate (10) as powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:29])[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[O:29]=[C:7]([CH2:8][S:9][C:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:37]([NH:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:38]
Reactant: O=C=Nc1ccccc1
Reactant: NCCCCCC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(CCCCCNC(=O)Nc1ccccc1)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 7-amino-1-tritylsulfanyl-heptan-2-one (0.36 g, 0.86 mmol) in dichloromethane (10 mL) was added phenylisocyanate (0.10 ml, 0.92 mmol). The mixture was stirred at room temperature for 2 h. Solvent was then removed in vacuo and the crude product was purified by column chromatography (dichloromethane/MeOH=100/1 to 40/1) to provide 1-(6-Oxo-7-tritylsulfanyl-heptyl)-3-phenyl-urea (0.43 g, 93%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].Cl[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:15]1([CH2:14][O:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([OH:7])=[O:6])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: O=C(O)c1cccc(OCc2cccc3ccccc23)c1
Temperature: 25 °C

Procedure:
A mixture comprising ethyl 3-hydroxybenzoate (5.00 g), 1-(chloromethyl)naphthalene (5.40 ml), potassium carbonate (6.24 g), methyl iodide (a catalytic amount) and acetone (50 ml) was heated at reflux for 24 hours. After the reaction mixture was concentrated under reduced pressure to remove the solvent, the residue was mixed with water (200 ml) and was extracted with ethyl acetate. After the organic layer was concentrated, a 1 N aqueous solution of sodium hydroxide (50 ml) was added to the residue dissolved in methanol (50 ml), and the resulting mixture was heated at reflux for 2 hours. After being cooled to room temperature, the reaction mixture was acidified by the addition of concentrated hydrochloric acid and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, was dried with anhydrous sodium sulfate and was then evaporated under reduced pressure to remove the solvent. The resulting residue was recrystallized from ethyl acetate/hexane to obtain 3-(1-naphthylmethoxy)benzoic acid (7.14 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:53])[C:16]([CH2:18][O:19][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:53])[C:16]([CH2:18][O:19][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[NH:27][C:26]4=[O:50])=[CH:22][CH:21]=3)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(OCc3ccccc3)nc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCc3ccccc3)nc21
Yield: 95.2 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 1.00 g of 5-{4-(5-benzyloxy-3-methylimidazo [5,4-b]pyridin-2 -ylmethoxy) benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 95) was treated with 12 ml of a 3:1 by volume mixture of acetic acid and water. After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 0.63 g of the title compound, melting at 210-211° C.
Reaction SMILES: [N:1]#[C:2][NH2:3].[C:4]1([CH2:10][C:11](Cl)=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>[OH-].[Na+].CC(C)=O>[C:2]([NH:3][C:11](=[O:12])[CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:1]
Reactant: N#CN
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: N#CNC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
Cyanamide (5.04 g, 120 mmol) was dissolved in 40 mL of 40% sodium hydroxide. To this solution at 0° C., phenylacetyl chloride (3.97 mL, 30 mmol) in 30 mL of acetone was added over 1 h. After stirring at room temperature for 2 h, the reaction mixture as acidified with concentrated HCl to pH 2. Acetone was removed in vacuo. The resulting suspension was extracted with methylene chloride (30 mL×4). The combined organic extracts were washed with brine and dried over magnesium sulfate. Solvent was removed in vacuo to give N-cyano-2-phenylacetamide (3.96 g, 82%) as a yellow oil.
Reaction SMILES: O=[C:2]1[CH:9]2[CH2:10][C:5]3([C:12]([OH:14])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.O.[NH3:16]>CO.[Pd]>[NH2:16][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([OH:14])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: N
Reactant: O=C1C2CC3CC1CC(C(=O)O)(C3)C2
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NC1C2CC3CC1CC(C(=O)O)(C3)C2
Reaction time: 12 h
Yield: 81 %

Procedure:
In a 250-mL flask, 4-oxo-adamantane-1-carboxylic acid (10 g, 51.5 mmol) was dissolved in 7N NH3 in MeOH (50 ml), and the resultant solution was added with 10% Pd/C (1 g, 10%), followed by stirring under hydrogen gas for 12 hours. After the reaction was completed, the resultant product was added with H2O and filtered to obtain 4-amino-adamantane-1-carboxylic acid (8.17 g, 81%).
Reaction SMILES: C[O-].[Na+].C(=O)(O)[O-].[Na+].[C:9]([O:18]C)(=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15]>>[C:9]([OH:18])(=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CCCCC(=O)[O-]
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCCC(=O)O

Procedure:
The electrolytic condensation was conducted in the same manner as described in Example 2 except for changing the neutral salt group from sodium methylate to sodium bicarbonate by using monomethyl adipate obtained by the half esterification of adipic acid. Electrolytic cell voltage was 7.8 volts. Current efficiency was 67.0% and material yield was 79.8%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1.C[C:14]([N:16](C)C)=O>CCOC(C)=O.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:14]#[N:16])[CH:6]=1
Reactant: CC(=O)N(C)C
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of (3-bromophenyl)-acetic acid methyl ester 46 (1.20 g, 5.28 mmol) in dry dimethyl-acetamide (5 mL) is added under argon zinc cyanide (0.78 g, 6.64 mmol) and tetrakis(triphenylphosphine) palladium (0.63 g, 0.55 mmol). The mixture is stirred for 24 hours at 80° C. After cooling to room temperature, the mixture is diluted with EtOAc (15 mL) and water (20 mL). The resulting precipitate is removed by vacuum filtration. The organic layer of the filtrate is separated and washed with H2O, then dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0 to 20% EtOAc/hexane) to give (3-cyano-phenyl)acetic acid methyl ester 47 as an oil: 1H-NMR (400 MHz, CDCl3) δ=7.63 (d, J=8.0 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.30 (dd, J=1.2 Hz, J=8.0 Hz, 1H), 3.72 (s, 3H), 3.69 (s, 2H). MS calculated for C10H9O2ClN (M+H+) 210.0, found 210.0.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[OH-:12].[Cs+]>C(OCC)(=O)C.CCCCCCC>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:12]
Reactant: Brc1ccc2ccccc2c1
Reactant: [OH-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Oc1ccc2ccccc2c1
Yield: 88 %

Procedure:
Following general operating mode B, 2-bromonaphthalene (207 mg, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of a white solid with a yield of 88% (eluent: ethyl acetat/heptane 20:80).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:3]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:39]1[CH2:43]OC[CH2:40]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[C:3]=1[CH:24]([CH2:40][CH2:39][CH3:43])[C:25]([O:27][CH3:28])=[O:26]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C(F)(F)F)cc1)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C(F)(F)F)cc1)CCC3
Yield: 70 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.114 g; 0.281 mmol), LHMDS 1N in THF (0.312 mL; 0.312 mmol), 1-iodopropane (0.046 mL; 0.472 mmol) in DMF (4 mL) for 3.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.088 g (70%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:4](B(O)O)=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2].Br[C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>>[Cl:23][C:21]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:4]2[CH:5]=[C:6]([O:9][CH3:10])[N:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH:22]=1
Reactant: COc1cc(B(O)O)c(C#N)cn1
Reactant: N#Cc1ccc(Cl)cc1Br
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(C#N)cn1

Procedure:
600 mg (purity 89%, 3.0 mmol) of 5-cyano-2-methoxypyridin-4-ylboronic acid and 649 mg (3.0 mmol) of 2-bromo-4-chlorobenzonitrile in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. After aqueous work-up, the crude product was triturated with water and then with cyclohexane/ethyl acetate (7:3), and the solid was filtered off and dried under high vacuum. Yield: 399 mg (purity 94%, 46% of theory)
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:10]([CH3:13])=[CH:11][CH3:12])[CH2:3][CH2:4]/[CH:5]=[CH:6]/[C:7]([OH:9])=O.ClC(OCC)=O.C(N(CC)CC)C.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.[Cl-].[Na+]>>[CH:28]1([NH:31][C:7](=[O:9])/[CH:6]=[CH:5]/[CH2:4][CH2:3][C:2]([CH3:1])([CH3:14])[C:10]([CH3:13])=[CH:11][CH3:12])[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: CC=C(C)C(C)(C)CC/C=C/C(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC=C(C)C(C)(C)CC/C=C/C(=O)NC1CC1
Yield: 40 %

Procedure:
4-(2,2,3-Trimethyl-3-penten-1-yl)-2E-butenoic acid 1 eq, ethyl chloroformate 1.5 eq, triethylamine 1.5 eq, cyclopropylamine 1.5 eq, quench with 10% sodium chloride solution, yield=40%.