Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[S:39][C:38]([C:40]([O:42]CC)=[O:41])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[S:39][C:38]([C:40]([OH:42])=[O:41])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(CC)n4)cc3OC)c(C)o2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(C(=O)O)s4)oc3C)c(OC)c2)cs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a mixture of ethyl 5-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylate (0.63 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (5 mL) and water, and the precipitated crystals were collected by filtration to give 5-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylic acid as colorless crystals (0.51 g, yield 85%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 150-151° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[OH-].[Na+].S.[Na].Cl[CH2:14][C:15]([OH:17])=[O:16]>O>[C:15]([CH2:14][S:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[NH2:2])([OH:17])=[O:16]
Reactant: NC(CS)C(=O)O
Reactant: O=C(O)CCl
Agent: Cl
Agent: S
Agent: [Na+]
Solvent: O
Product: NC(CSCC(=O)O)C(=O)O
Reaction time: 3 h

Procedure:
As starting material there served (RS)-cysteine hydrochloride which was produced by the process of German OS No. 2645748. 140 grams (1 mole) of this material together with 160 grams (4 moles) of sodium hydroxide were dissolved in 1000 ml of water. To this solution there was first added 3 grams of sodium hydrogen sulfide and then in the course of 45 minutes 95 grams (1 mole) of monochloroacetic acid. The temperature of the mixture in the meanwhile was held at 20° C. and after that held for 3 hours at 20° to 30° C. The reaction mixture was subsequently adjusted to a pH of 3.0 by addition of concentrated, aqueous hydrochloric acid. Hereby the S-(carboxymethyl)-(RS)-cysteine separated out. It was filtered off at 10° C. and washed with water until it was free from chloride ions. Then it was dried under reduced pressure at 105° C. The yield was 173 grams, corresponding to 97% based on the cysteine hydrochloride employed. The melting point (decomposition point) of the S-(carboxymethyl)-(RS)-cysteine was 188° to 192° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1([CH2:17][CH2:18][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CCO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:19][CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCc1ccccc1
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1NCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (4.4 g, 31.2 mmol) in EtOH (32 mL) was added at 0° C., 2-phenylethanamine (4.11 mL, 32.8 mmol). Mixture went from light yellow to bright orange instantly and it was stirring overnight at RT. Another equivalent of 2-phenylethanamine was added (4.11 mL, 32.8 mmol) and the mixture was heated to 50° C. overnight. Water was added (20 ml) and the resulting orange solid was isolated by filtration to afford 6.99 g of 2-nitro-N-phenethylbenzenamine (Yield: 92%) as an orange crystalline solid.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(O)=O>CC1C=CC(C(C)C)=CC=1.CC1C=CC(S([N-][C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.[Cl-].[Ru+2].O>[OH:8][C@H:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]#[N:11]
Reactant: N#CCC(=O)c1ccccc1
Agent: [Ru+2]
Agent: Cc1ccc(S(=O)(=O)[N-][C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Agent: [Cl-]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: N#CC[C@H](O)c1ccccc1
Reaction time: 24 h
Yield: 86.2 %

Procedure:
A 50 ml Schlenk flask was charged with 7.26 g (50.0 mmol) of benzoylacetonitrile, 18.1 ml (130 mmol) of triethylamine, 5.8 ml (155 mmol) of formic acid, and 31.8 mg (0.05 mmol, S/C=1000) of RuCl[(S,S)-Tsdpen](p-cymene) under an atmosphere of argon, and stirring was carried out at 30° C. for 24 hours. The solution was poured into water and extracted with ether, the organic layer was washed with saturated brine and then dried with anhydrous sodium sulfate, and the solvent was distilled off under vacuum. The crude product so obtained was distilled under vacuum (0.4 mmHg, 145° C.) to give 6.34 g (yield 86%, 1H-NMR) of (S)-3-hydroxy-3-phenylpropanenitrile. When this was analyzed using a CHIRALCEL OJ column (manufactured by Daicel Chemical Industries, Ltd., eluant; n-hexane:2-propanol=20:1) it was found that the optical purity was 98% ee.
Reaction SMILES: [CH2:1]([C:4]([C@:6](C(=O)C1C=CC=CC=1)([C@@:8](C(=O)C1C=CC=CC=1)([C@@H:10]([N:13]=[N+:14]=[N-:15])[CH2:11][OH:12])[OH:9])[OH:7])=[O:5])[CH:2]=[CH2:3].C1COCC1.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([C:4]([C@H:6]([C@@H:8]([C@@H:10]([N:13]=[N+:14]=[N-:15])[CH2:11][OH:12])[OH:9])[OH:7])=[O:5])[CH:2]=[CH2:3]
Reactant: C=CCC(=O)[C@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)c1ccccc1)[C@H](CO)N=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCC(=O)[C@@H](O)[C@H](O)[C@H](CO)N=[N+]=[N-]
Reaction time: 5 h

Procedure:
1-allyl-2,3-dibenzoyl-4-azido-4-deoxy-L-xylose 35 (12.0 g, 28.3 mmol) was dissolved in 5:1 methanol:THF (70 mL); to this solution was added sodium methoxide (650 μL of 25% solution, 2.83 mmol). The solution was stirred for 5 h, then to it was added acetic acid (175 μL, 3.11 mmol) and the reaction stirred for 1 min. The solvent was removed in vacuo to give 36 as a thick oil. The material was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C=O.O.[Cu]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Clc1ccnc2ccccc12
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(-c2ccnc3ccccc23)c1C
Temperature: 20 °C
Reaction time: 0.2 h
Yield: 103.6 %

Procedure:
2.75 g (17.9 mmol) of 3-ethoxycarbonyl-2-methyl-1H-pyrrole are added at 20° C. under an argon atmosphere to 0.756 g (18.9 mmol) of sodium hydride, at 60% by weight in liquid petroleum jelly, suspended in 12 mL of dimethylformamide. After stirring at 20° C. for 0.2 hour, 0.114 g (1.79 mmol) of copper powder and 2.35 mL (17.9 mmol) of 4-chloroquinoline are added. After stirring at 140° C. for 48 hours, the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 100 mL of water and then extracted with 3 times 70 mL of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give 5.2 g of a brown oil which is purified by flash chromatography [eluent: dichloromethane/ethyl acetate (97/3 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 3 g of 3-ethoxycarbonyl-2-methyl-1-(quinol-4-yl)-1H-pyrrole are obtained in the form of an orange-coloured oil. Mass spectrum (EI): m/e 280 (M+.), m/e 251, m/e 235.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH2:16][O:17][CH3:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[CH3:18][O:17][CH2:16][C:11]1([NH2:10])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COCC1(NC(=O)OCc2ccccc2)CCCC1
Agent: [Pd]
Solvent: CO
Product: COCC1(N)CCCC1
Temperature: 70 °C

Procedure:
To a solution of (1-methoxymethyl-cyclopentyl)-carbamic acid benzyl ester (150 mg, 0.57 mmol) in MeOH (5 mL) was added HCO2NH4 (216 mg, 3.42 mmol), followed by Pd/C (10%, 6 mg, 0.057 mmol). The resulting mixture was heated, to 70° C., for 2 hours. The reaction mixture was filtered and concentrated to provide the titled compound. MS (DCI) m/e 130 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][CH:12]([C:16]2([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:13][O:14][CH3:15])[CH2:5][CH2:4]1.[CH:27](O)=O.C=O>C(OCC)(=O)C>[CH3:27][N:11]([CH:12]([C:16]1([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:17][CH2:18][CH2:19]1)[CH2:13][O:14][CH3:15])[CH2:10][CH2:9][N:6]1[CH2:5][CH2:4][O:3][CH2:8][CH2:7]1
Reactant: O=CO
Reactant: COCC(NCCN1CCOCC1)C1(c2ccc(Cl)cc2)CCC1
Agent: C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: COCC(N(C)CCN1CCOCC1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product of Example 208 in the form of its free base (2.0 g), 98% formic acid (8 ml) and 37-40% aqueous formaldehyde solution (25 ml) was stirred at room temperature for 2 hours. The mixture was then heated at 95°-100° C. for 18 hours, cooled, basified and extracted with ether. The extract was washed with water and dried. Dry hydrogen chloride gas was passed into the ethereal solution. Evaporation of the solvent gave a residue which was heated with ethyl acetate (20 ml) to give a white solid which was partitioned between ether and water. The aqueous phase was basified and then extracted with ether. The extract was dried and evaporated to give a residue which was distilled using a Buchi Kugelrohr apparatus (200° C./0.5 mm) to give N-methyl-N-(2-morpholinoethyl)-1-[1-(4-chlorophenyl)cyclobutyl]-2-methoxyethylamine.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][C:39]([CH3:46])([CH2:43][CH:44]=[CH2:45])[C:40](O)=[O:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:40](=[O:41])[C:39]([CH3:46])([CH3:38])[CH2:43][CH:44]=[CH2:45])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=CCC(C)(C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C=CCC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 19.4 %

Procedure:
A procedure similar to that described in Example 3, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 466 mg (3.6 mmol) of 2,2-dimethyl-4-pentenoic acid, to provide 231 mg of the title compound.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(OCC)C>O.O1CCCC1>[CH3:14][C:13]([O:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)=[O:15]
Reactant: OCCc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)Oc1ccc(CCO)cc1
Yield: 66.6 %

Procedure:
5.6 g (0.1 mole) potassium hydroxide in 10 ml water was added to a cooled solution of 13.8 g (0.1 mole) p-hydroxyphenethyl alcohol in 50 ml tetrahydrofuran. 10.2 g (0.1 mole) acetic anhydride was slowly added under stirring. After 2 hours diethyl ether and water were added. The phases were separated and the organic phase was dried, filtered and evaporated in vacuo. The product contained 15% starting material and was therefore redissolved in diethyl ether and washed twice with dilute sodium carbonate. Drying, filtration and evaporation of solvents in vacuo gave 12 g (yield 67%) of 2-(4-methylcarbonyloxyphenyl)-1-ethanol which was used without further purification.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[Cl:11][C:12]1[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([CH:19]=1)[CH:17]=O.CCO.C([BH3-])#N.[Na+]>CC(O)=O>[Cl:11][C:12]1[CH:19]=[C:16]([CH2:17][N:8]2[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]2)[CH:15]=[N:14][C:13]=1[Cl:20]
Reactant: O=Cc1cnc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)N1CCN(Cc2cnc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
1-methanesulfonylpiperazine (1.1 g, 6.8 mmol) followed by a catalytic amount of AcOH (0.020 mL, 0.34 mmol) were added to a stirred solution of 5,6-dichloronicotinaldehyde (1.20 g, 6.8 mmol) in EtOH (100 mL, 1713 mmol), the mixture was stirred at room temperature for 1 h (white precipitate formed), and the resulting suspension was treated portionwise with sodium cyanoborohydride (0.43 g, 6.8 mmol) (slightly exothermic) and stirred for another 2 h. The mixture was concentrated and quenched with 1 N HCl(aq), water (10 mL each) and EtOAc (50 mL). The separated aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was purified with flash column chromatography (ISCO Combiflash system, pure DCM to 3% 2 M NH3/MeOH in DCM) to give 1-((5,6-dichloropyridin-3-yl)methyl)-4-(methylsulfonyl)piperazine (1.16 g, 52%) as a white solid. LCMS (API-ES) m/z 325 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H) 7.78 (s, 1H) 3.54 (s, 2H) 3.26 (br. s., 4H) 2.80 (s, 3H) 2.57 (br. s., 4H).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.BrCCBr.[F:15][C:16]([F:24])([F:23])[C:17]([C:19]([F:22])([F:21])[F:20])=[O:18].Cl>O1CCCC1.CCOCC.O>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:17]([OH:18])([C:19]([F:22])([F:21])[F:20])[C:16]([F:24])([F:23])[F:15])[CH:4]=1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: COc1cccc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: CCOCC
Product: COc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reaction time: 18 h

Procedure:
To a suspension of 13.5 g (0.55 g atoms) of sublimed magnesium chips in 25 ml of anhydrous tetrahydrofuran in a reaction flask fitted with a water-cooled condenser are added 10 g (0.05 mole) of 3-bromo-1-methoxybenzene and 0.5 ml of 1,2-dibromoethane. The resulting reaction mixture is stirred and heated gently until a reaction is initiated. To the stirred reaction mixture is added dropwise a solution of 90 g (0.48 mole) of 3-bromo-1-methoxybenzene in 250 ml of anhydrous tetrahydrofuran at such a rate that gentle reflux is maintained. The reaction mixture is stirred for an additional two hours. The resulting solution is then cooled to 0° and the reaction flask is fitted with a jacketed dropping funnel topped by a dry ice condenser. The water condenser is replaced by an additional dry ice condenser. To the jacketed dropping funnel are added 85 g (50 ml) (0.55 mole) of condensed hexafluoroacetone. The condensed hexafluoroacetone is added dropwise to the stirred solution which is cooled to 0° to -10° with an ice-acetone bath. When the addition of the hexafluoroacetone is complete, the resulting solution is allowed to warm to 20°-25° and stirring is continued for an additional 18 hours. The solution is cooled to 0° and treated with 6N hydrochloric acid to obtain an acidic solution to which is added 1-liter of ether. The resulting ether layer is washed with water, washed with a 5% sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to yield a residual solid which is recrystallized from chlorobutane to give 78 g of 1-methoxy-3-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzene.
Reaction SMILES: CO.[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(O)(=O)C>[O:3]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Yield: 66 %

Procedure:
To a 100 ml methanol solution of 3.51 g of the compound (3) synthesized in Reference Example 3 were added 200 mg of palladium carbon and 1 ml of acetic acid for hydrogenation at atmospheric pressure and room temperature. After the end of the reaction, the insolubles were filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methylene chloride, then adjusted by a 10% aqueous solution of sodium hydroxide to pH=9 to 10, then was shaken. The organic layer was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=20:1!) to obtain the above-reference compound (4) in all amount of 2.32 g (yield of 66%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12](=[O:18])[NH:13]3)=[CH:4][CH:3]=1.[CH3:19][N:20](C)C=O>>[C:19]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12](=[O:18])[NH:13]3)=[CH:4][CH:3]=1)#[N:20]
Reactant: O=c1ccc2c(-c3ccc(Br)cc3)nccc2[nH]1
Reactant: CN(C)C=O
Product: N#Cc1ccc(-c2nccc3[nH]c(=O)ccc23)cc1
Reaction time: 96 h

Procedure:
A mixture containing 15 g of 5-(4-bromophenyl)-1,6-naphthyridin-2(1H)-one, 300 ml of dimethylformamide and 8.6 g of cuprous cyanide was refluxed with stirring for 96 hours, cooled and stripped to dryness using a rotary evaporator. To the residue was added 300 ml of concentrated aqueous ammonium hydroxide solution and 20 ml of glacial acidic acid. The resulting mixture was chilled in ice, next treated with 71 ml of (5.25% aqueous sodium hypochlorite solution, then stirred in an ice bath for 3 hours and allowed to stand at room temperature for 4 hours. The brown solid was collected, washed with water, dried, dissolved in 300 ml of boiling dimethylformamide, the hot solution treated with decolorizing charcoal and filtered, and the filtrate concentrated to dryness. The residue was recrystallized from dimethylformamide to produce 8.6 g of 5-(4-cyanophenyl)-1,6-naphthyridin-2(1H)-one, m.p. >300° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[Cl:6][C:7]1[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:8]=1[C:15]1([F:19])[CH2:18][CH2:17][CH2:16]1.Cl([O-])=[O:21].[Na+].Cl[O-].[Na+].[OH-].[Na+].Cl>C(#N)C.O.CC1(C)N([O])C(C)(C)CCC1>[Cl:6][C:7]1[N:12]=[C:11]([C:13]([OH:21])=[O:14])[CH:10]=[CH:9][C:8]=1[C:15]1([F:19])[CH2:18][CH2:17][CH2:16]1
Reactant: [O-][Cl+][O-]
Reactant: OCc1ccc(C2(F)CCC2)c(Cl)n1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc(C2(F)CCC2)c(Cl)n1
Temperature: 35 °C
Reaction time: 20 h
Yield: 123.9 %

Procedure:
Aqueous phosphate buffer (pH=6.7, 0.7 mL) and TEMPO (2.54 mg, 16.2 μmol) were added to a solution of (6-chloro-5-(1-fluorocyclobutyl)pyridin-2-yl)methanol (Example 130 d, 50 mg, 232 μmol) in acetonitrile (1 mL) under an argon atmosphere. The reaction mixture was warmed to 35° C. A solution of sodium chlorite (52.4 mg, 464 μmol) in 150 μL water and a solution of sodium hypochlorite (2.66 mg, 2.19 μL, 4.64 μmol) in 100 μL water were added simultaneously over a period of 30 min. Stirring was continued at 35° C. for 20 h. Water (40 mL) and 2 N NaOH solution (8 mL) were added. The mixture was poured into an ice cold Na2SO3 solution (1.62 Na2SO3 g in 30 mL water) and stirred for 30 min. at ambient temperature. Under ice cooling the mixture was acidified with 25 mL 2 N HCl solution and extracted with a mixture of 100 mL EtOAc and 20 mL THF. The organic layer was dried over Na2SO4, filtered and the solvent concentrated in vacuo to give the title compound (66 mg, 90%) as yellow oil, MS(ESI): m/e=230.4 [MH+].
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10].[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:51]2[C:52]3[C:32]([CH2:33][C@@H:34]4[C:46]([C:47]=3[CH:48]=[CH:49][CH:50]=2)=[CH:45][C@@H:37]([C:38](=[O:44])[N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:36][N:35]4[CH3:53])=[CH:31]1.C(N(CC)CC)C>C1COCC1>[O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:26][CH2:27][CH2:28][CH2:29][N:30]3[C:51]4[C:52]5[C:32]([CH2:33][C@@H:34]6[C:46]([C:47]=5[CH:48]=[CH:49][CH:50]=4)=[CH:45][C@@H:37]([C:38](=[O:44])[N:39]([CH2:40][CH3:41])[CH2:42][CH3:43])[CH2:36][N:35]6[CH3:53])=[CH:31]3)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10]
Reactant: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3c(cn4CCCN)C[C@H]2N(C)C1
Reactant: O=C(Cl)c1ccc(-c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3c(cn4CCCNC(=O)c3ccc(-c4ccc(C(=O)ON5C(=O)CCC5=O)cc4)cc3)C[C@H]2N(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A solution of 850 mg (2.375 mmol) of 12 in 65 mL of dry THF under argon was cooled to 0° C. in an icebath, then treated with a solution of 900 mg (2.365 mmol) of 10 in 50 mL of dry THF and 0.6 mL (4.3 mmol) of triethylamine added dropwise over a 20 minute period. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to room temperature, with stirring, for 1 hour. The mixture was concentrated at reduced pressure and the residue was dissolved in 100 mL of methylene chloride. The solution was washed with 100 mL of H2O, 100 mL of saturated sodium bicarbonate solution, 100 mL of saturated brine solution, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a brown residue. This was chromatographed on a short column of 100 g of silica gel using first methylene chloride as eluent, then 9:1 methylene chloride-ether as eluent to elute front running impurities, then 14:1 methylene chloride-isopropyl alcohol as eluent to elute the product to yield 650 mg (39%) of 13 as a cream colored solid [α]D=+34.3° (c=0.45%; CHCl3).