Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14](O)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(#N)C.[C:20]1(=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[CH:22]=C1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([C:14]3[C:20](=[O:31])[C:29]4[C:24]([C:23](=[O:30])[CH:22]=3)=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: O=C(O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C1C=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 2.5 °C

Procedure:
To a stirred solution of silver nitrate (17.5 g, 0.104 moles) dissolved in 100 ml water, 50 g (0.209 moles) trans-4-(4-chlorophenyl)cyclohexane carboxylic acid was added. To this solution acetonitrile (250 ml) was added and under stirring and heated to reflux. 33.1 g (0.209 moles) 1,4-naphthoquinone was then added. 120 g (0.525 mole) ammonium persulfate dissolved in 400 ml water was added drop-wise to the stirred solution and continued reflux for 2 hours. The reaction solution was then cooled to 0-5° C. and extracted with methylene chloride. The organic layer was first washed with water, followed by 10% sodium carbonate aqueous solution, and further with water until the pH is neutral. The organic layer was distilled to eliminate methylene chloride and was then stirred in acetonitrile and filtered. The solid obtained was crystallized from acetonitrile to obtain 15 g of trans-2-[4-(4-chlorophenyl)cyclohexyl]-1,4-naphthoquinone (20% yield). M.P. 146-149 (uncorrected), 1H NMR (400 MHz), δH (d6-CDCl3) 8.07-8.14 (2H, m, Naphth), 7.65-7.74 (2H, m, Naphth), 7.27-7.30 (2H, d, arom.), 7.07-7.19 (2H, d, arom.), 6.80 (1H, s, naphtho.), 2.98-3.01 (1H, tt, CH), 2.54-2.58 (1H, tt, CH—), 1.25-2.03 (8H, multi, CH2).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O[C:16]1[CH:17]=[C:18]([C:22](=[O:24])[CH3:23])[CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[C:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.9 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.00 g, 19.9 mmol), 1-(3-hydroxyphenyl)ethanone (2.71 g, 19.9 mmol), and triphenylphosphine (5.73 g, 21.9 mmol) in tetrahydrofuran (100 mL) was added slowly diisopropyl azodicarboxylate (4.25 mL, 21.9 mmol) at 0° C. under Nitrogen. The resulting mixture was stirred at room temperature for 17 hours. The mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water (200 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (4:1) to give 4.70 g (74%) of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]=[C:8]=[S:9])=[O:5])[CH3:2].[CH2:10]([N:14]1[C:19]([NH:20][NH2:21])=[CH:18][C:17](=[O:22])[N:16]([CH2:23][CH2:24][CH3:25])[C:15]1=[O:26])[CH2:11][CH2:12][CH3:13]>O1CCOCC1>[CH2:10]([N:14]1[C:19]([NH:20][NH:21][C:8]([NH:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[S:9])=[CH:18][C:17](=[O:22])[N:16]([CH2:23][CH2:24][CH3:25])[C:15]1=[O:26])[CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)CN=C=S
Reactant: CCCCn1c(NN)cc(=O)n(CCC)c1=O
Solvent: C1COCCO1
Product: CCCCn1c(NNC(=S)NCC(=O)OCC)cc(=O)n(CCC)c1=O

Procedure:
Ethoxycarbonylmethylisothiocyanate (15 g) was added dropwise to a stirred solution of 1-butyl-6-hydrazino-3-propylpyrimidine-2,4(1H,3H)-dione (11 g) in dioxane (100 ml).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH2:14]1[O:24][C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[O:17][CH:15]1[CH3:16].CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CCOCC.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:14]1[O:24][C:18]2([CH2:23][CH2:22][N:21]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH2:20][CH2:19]2)[O:17][CH:15]1[CH3:16]
Reactant: FC(F)(F)COc1ccccc1Br
Reactant: CC1COC2(CCNCC2)O1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC1COC2(CCN(c3ccccc3OCC(F)(F)F)CC2)O1
Temperature: 80 °C

Procedure:
A solution of 50 (1.786 g, 7.00 mmol) and 4-piperidone propylene ketal (2.645 g, 16.82 mmol) in toluene (30 mL) was treated with sodium tert-butoxide (1.88 g, 19.56 mmol), (S)-BINAP (44 mg, 0.07 mmol), and tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol) at room temperature. The mixture was heated in an oil bath (80° C., 3 h). The mixture was diluted with ether and brine. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6 mm, 20% EtOAc-80% hexane) afforded the title compound (51).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][NH2:9])[CH2:4][CH3:5])[CH3:2].[CH2:10]1[CH2:15][C@@H:14]2[CH2:16][CH2:17][CH2:18][C:19](=O)[C@H:13]2[CH2:12][CH2:11]1>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][CH2:8][NH:9][CH:15]1[CH:14]2[CH:13]([CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:12][CH2:11][CH2:10]1)[CH3:2]
Reactant: O=C1CCC[C@H]2CCCC[C@H]12
Reactant: CCN(CC)CCCN
Product: CCN(CC)CCCNC1CCCC2CCCCC21

Procedure:
Following the general procedure of Example 46, but starting with diethylaminopropylamine and trans-1-decalone, the title compound is produced. IR (liquid film) 3307, 2968, 2920, 2853, 2799, 1455, 1447, 1383, 1369, 1201, 1164, 1159, 1128, 1105, 1085, 1070. (PLA 2, diabetes-)
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[CH2:6]=[C:7]1[O:10][C:9](=O)[CH2:8]1>CO>[CH3:1][N:2]1[C:7]([CH3:6])=[CH:8][C:9](=[O:10])[NH:5][C:3]1=[O:4]
Reactant: CNC(N)=O
Reactant: C=C1CC(=O)O1
Solvent: CO
Product: Cc1cc(=O)[nH]c(=O)n1C
Temperature: 25 °C
Yield: 18 %

Procedure:
A solution of 1-methylurea (30 g, 0.356 mol) in 4-methyleneoxetan-2-one (26.4 g, 0.356 mol) was heated at 100° C. for 18 h, cooled to RT then diluted with MeOH (50 mL). The reaction was filtered and the filtered solid was washed with MeOH (20 mL) and dried to give 1,6-dimethylpyrimidine-2,4(1H,3H)-dione (9 g, 18% yield) as a white solid. 1H NMR (CDCl3) δ: 8.33 (s, 1H), 5.58 (s, 1H), 3.38 (s, 3H), 2.26 (s, 3H). LCMS: MH+ 141 and TR=0.368 min. Used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2>CO.O1CCOCC1.[Pd]>[NH2:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:2]1[CH3:1])=[O:27]
Reactant: Cc1c(CCCC(=O)O)c2ccccc2n1C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(CCCC(=O)O)c2ccccc2n1C(=O)c1cccc(N)c1
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 88.9 %

Procedure:
To a solution of 4-[2-methyl-1-(3-nitrobenzoyl)indol-3-yl]butyric acid (600 mg) in a mixture of methanol (30 ml) and 1,4-dioxane (30 ml) was added 10% palladium on activated carbon (300 mg), and the mixture was stirred under hydrogen atmosphere (3 atm) at 20° C. for 45 minutes. The catalyst was filtered off and the filtrate was evaporated. The residue was chromatographed on a silica gel column (25 ml) eluting with a mixture of chloroform and methanol (10:1) to give 4-[1-(3-aminobenzoyl)-2-methylindol-3-yl]butyric acid (490 mg) as a yellow foam.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH2:5]([O:7][CH:8](OCC)[CH2:9][CH2:10]Cl)[CH3:6].[I-].[K+]>C(O)C>[NH2:1][C:2]1[S:3][CH2:10][CH2:9][CH:8]([O:7][CH2:5][CH3:6])[N:4]=1
Reactant: NC(N)=S
Reactant: CCOC(CCCl)OCC
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC1CCSC(N)=N1

Procedure:
A mixture of 10 g. of thiourea, 50 ml. of β-chloropropionaldehyde diethyl acetal, 75 ml. of absolute ethanol, and 2 g. of potassium iodide was refluxed for 2 days. The solvent was evaporated, and the residue was partitioned between water and ether. The aqueous phase was extracted twice more with ether, basified with sodium carbonate and extracted 4 times with chloroform. The chloroform was concentrated to dryness, and the residue was thoroughly extracted with ether. The ether extracts were evaporated to a small volume which deposited 6.88 g. of crystalline 2-amino-4,5-dihydro-4-ethoxy-6H-1,3-thiazine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:17][O:18][C:19](=[O:44])[CH2:20][CH2:21][C:22]1[C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]/[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)=[CH:26][CH:25]=[C:24](I)[N:23]=1>>[CH3:17][O:18][C:19](=[O:44])[CH2:20][CH2:21][C:22]1[C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]/[C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)=[CH:26][CH:25]=[C:24]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][S:10]([C:13]([F:16])([F:14])[F:15])(=[O:12])=[O:11])[CH:4]=2)[N:23]=1
Reactant: C#Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Product: COC(=O)CCc1nc(C#Cc2cccc(NS(=O)(=O)C(F)(F)F)c2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 32.7 %

Procedure:
Under the conditions of example 5 A, 370 mg of crude N-(3-ethinylphenyl)-1,1,1-trifluoromethanesulfonamide is reacted with 735 mg of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-20% ethyl acetate. 299 mg of 3-{3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-[2-(3-trifluoromethanesulfonamidophenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCNC2
Product: CC(=O)N1CCc2ccccc2C1

Procedure:
A mixture of 100 g. (0.75 mole) 1,2,3,4-tetrahydroisoquinoline and 150 ml. acetic anhydride was stirred at ambient temperature for 24 hours and then concentrated to dryness at reduced pressure. The residual liquid was dissolved in methylene chloride and solid potassium carbonate was added to neutralize the solution. The excess potassium carbonate was removed by filtration and the filtrate was concentrated to dryness at reduced pressure to afford 2-acetyl-1,2,3,4-tetrahydroisoquinoline as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].[N:13]([CH2:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)=[N+:14]=[N-:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:13]([CH2:16][CH2:17][CH2:18][C:19](=[N:10][NH:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N+:14]=[N-:15]
Reactant: Cc1ccc(Cl)cc1C(=O)NN
Reactant: [N-]=[N+]=NCCCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1C(=O)NN=C(CCCN=[N+]=[N-])c1ccccc1
Reaction time: 16 h
Yield: 59.4 %

Procedure:
To a solution of 5-chloro-2-methylbenzohydrazide (2.70 g, 14.62 mmol) prepared as in Example 1, Step B, in toluene (100 mL) was added 4-azido-1-phenylbutan-1-one (3.04 g, 16.1 mmol) prepared as in Example 70, Step A, followed by p-toluenesulfonic acid monohydrate (0.28 g, 1.46 mmol). The reaction was heated to reflux and stirred under a Dean-Stark trap for 16 hours. The cooled mixture was diluted with EtOAc (300 mL) and washed with NaHCO3 (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics were washed with brine (100 mL), dried over Na2SO4 and concentrated. The residue was triturated with ether and filtered to afford the product (3.09 g, 59%) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=2[F:25])[NH:4][CH:3]=1.C([Li])CCC.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])=[CH:14][C:13]=2[F:25])[N:4]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH:3]=1
Reactant: O=C(Nc1ccc(Cc2ccnc3[nH]cc(Br)c23)c(F)c1)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cc4ccc(NC(=O)C(F)(F)F)cc4F)ccnc32)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1.70 g (4.08 mmol) of N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl]-3-fluorophenyl}-2,2,2-trifluoroacetamide are dissolved in 50 ml of THF and cooled to −78° C. A solution of n-butyllithium (2.81 ml, 1.6M in hexane, 4.49 mmol) is added dropwise. After 15 min, a solution of 860 mg (4.49 mmol) of p-toluenesulfonyl chloride in 5 ml of THF is added dropwise. The mixture is allowed to warm to RT and stirred for 1 h. Water and saturated sodium bicarbonate solution are then added, and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase dichloromethane:ethanol=50:1).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([NH2:26])[CH:8]=[C:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[CH3:25])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])C.[CH2:27]([O:29][CH:30]([O:37]CC)[CH2:31][C:32](OCC)=O)[CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.O>[CH2:27]([O:29][C:30]([C:31]1[C:4](=[O:5])[C:6]2[N:7]([CH:8]=[C:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[CH3:25])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:26][CH:32]=1)=[O:37])[CH3:28]
Reactant: CCOC(=O)CC(OCC)OCC
Reactant: CCOC(=O)c1c(-c2ccccc2)c(Cc2cccc(F)c2C)cn1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)c1c[nH]n2cc(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1=O
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 75.2 %

Procedure:
To a solution of the compound of step 5 (6.290 g, 17.85 mmol) in 180 ml of anhydrous DMF under nitrogen were added ethyl 3,3-diethoxy-propanoate (10.42 ml, 53.55 mmol) and p-toluenesulfonic acid hydrate (0.509 g, 2.68 mmol), and the solution was heated at 90° C. for 1.5 h. After cooling to 60° C., DBU (13.32 ml, 89.24 mmol) was added dropwise and the mixture was stirred for 45 min at 60° C. The solution was then cooled to room temperature, water (600 ml) was added and the solution was extracted four times with EA (200 ml). The combined organic phases were washed with 0.5 N hydrochloric acid (300 ml) and brine (300 ml), dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was triturated several times with cyclohexane and dried in vacuo at 50° C. 5.43 g of the title compound were obtained as a brown solid melting at 176-177° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[O:11]1[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=[C:10]1[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3cnccc3o2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cccc(-c2nc3cnccc3o2)c1
Yield: 84.5 %

Procedure:
A suspension of 2-(3-nitrophenyl)oxazolo[4,5-c]pyridine (1.50 g, 6.2 mmol), iron powder (1.867 g, 31.8 mmol) and NH4Cl (2.86 g, 53.5 mmol) in CH3OH/H2O (4: 1, 311.2 mL) was refluxed for 6 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel (eluted with petroleum ether: EtOAc : Et3N=160:40:1) to afford 3-(oxazolo[4,5-c]pyridin -2-yl)benzenamine as a white solid (1.107 g, yield: 85%). 1H NMR (400 MHz, DMSO-d6) δ: 5.54 (2H, s), 6.82 (1H, d, J=8.0 Hz), 7.24 (1H, t, J=8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 7.44 (1H, s), 7.86 (1H, d, J=5.6 Hz), 8.56 (1H, d, J=5.6 Hz), 9.07 (1H, s); MS (ESI) calcd. for C12H9N3O (m/z): 211, found: 212 [M+1]+.
Reaction SMILES: CO.[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35]CC2C=CC=CC=2)=[C:31]([O:43]CC2C=CC=CC=2)[CH:30]=1)[C:12]([O:14][C@H:15]([CH3:27])[C@H:16]([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])[CH3:17])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[H][H].C(OCC)(=O)C>O1CCCC1.CCCCCC.[Pd]>[OH:43][C:31]1[CH:30]=[C:29]([CH2:28][C@H:11]([NH:10][C:8]([O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[O:9])[C:12]([O:14][C@H:15]([CH3:27])[C@H:16]([O:18][C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])[CH3:17])=[O:13])[CH:34]=[CH:33][C:32]=1[OH:35]
Reactant: [H][H]
Reactant: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
200 mg of 10% Pd—C pre-mixed with 10 mL of methanol was added to a solution of (1R,2R)-1-methyl-2-phenylcarbonyloxypropyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (2.6 g, 3.9 mmol) in 40 mL of tetrahydrofuran under a nitrogen atmosphere. The nitrogen was exchanged with hydrogen and the mixture stirred under hydrogen at room temperature for 2 h. After filtration and washing with methanol, the filtrate was concentrated and chromatography (silica gel, 30% ethyl acetate in hexane) of the residue afforded 1.8 g (95% yield) of (1R,2R)-1-methyl-2-phenylcarbonyloxypropyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate. MS (ESI) m/z 474.31 (M+H)+ and 472.18 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2cc(Oc3c(F)cccc3F)ccc2c1O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOC(=O)c1nc(C#N)c2cc(Oc3c(F)cccc3F)ccc2c1O
Temperature: 150 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A mixture of 1-bromo-7-(2,6-difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (156 mg) and CuCN (66 mg) in NMP was stirred at 150° C. for 1 h; then cooled, diluted with DCM, filtered, then washed with water, dil. NaCl solution, dried over sodium sulphate, filtered, concentrated, the residue was column purified to give the desired product (100 mg). LC MS ESI: 371 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]([OH:11])CO)=[C:6]([C:12]2[N:16]=[CH:15][N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:13]=2)[S:5][C:4]=1[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:24]=1)#[N:2].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[C:1]([C:3]1[C:7]([CH:8]=[O:11])=[C:6]([C:12]2[N:16]=[CH:15][N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:13]=2)[S:5][C:4]=1[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:24]=1)#[N:2]
Reactant: COC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(C(O)CO)c2C#N)ccn1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(C=O)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
Methyl (4-{3-cyano-4-(1,2-dihydroxyethyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate (0.362 g, 0.769 mmol) was dissolved in acetone (40 mL) and water (10 mL). Sodium metaperiodate (0.494 g, 2.31 mmol) was added and the mixture was stirred at room temperature for 6 hours. Sodium metaperiodate (0.329 g, 1.54 mmol) was added and the mixture was stirred for 16 more hours. The mixture was concentrated in rotavapor. The residue was triturated with water, filtered and washed thoroughly with water, then dried in lyophilizer to give a dry solid product (0.320 g, yield 94.8%). LC/MS: (FA) ES+ 439. 1H NMR (400 MHz, d6-dmso) δ 10.67 (s, 1H), 10.57 (s, 1H), 9.05 (s, 1H), 8.49 (m, 1H), 8.28 (s, 1H), 7.50 (m, 1H), 5.69-5.73 (m, 1H), 3.94-3.98 (m, 1H), 3.73 (s, 3H), 3.66-3.71 (m, 1H), 1.93-2.12 (m, 3H), 1.58-1.71 (m, 3H).
Reaction SMILES: C(C1C=CC(=O)NC=1C=CN(C)C)(=O)C1C=CC=CC=1.[C:21]([C:23]1[CH:42]=[CH:41][C:26]([C:27]([C:29]2[CH:30]=[CH:31][C:32](=[O:40])[NH:33][C:34]=2[CH:35]=[CH:36][N:37](C)C)=O)=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:42]=[CH:41][C:26]([C:27]2[N:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32](=[O:40])[NH:33]3)=[CH:25][CH:24]=1)#[N:22]
Reactant: CN(C)C=Cc1[nH]c(=O)ccc1C(=O)c1ccc(C#N)cc1
Agent: CN(C)C=Cc1[nH]c(=O)ccc1C(=O)c1ccccc1
Product: N#Cc1ccc(-c2nccc3[nH]c(=O)ccc23)cc1

Procedure:
Following the procedure described in Example C-1 using in place of 5-benzoyl-6-[2-(dimethylamino)ethenyl]-2(1H)-pyridinone a molar equivalent quantity of 5-(4-cyanobenzoyl)-6-[2-(dimethylamino)ethenyl]-2(1H)-pyridinone, it is contemplated that there can be obtained 5-(4-cyanophenyl)-1,6-naphthyridin-2(1H)-one.
Reaction SMILES: [O:1]([C:9]1[C:10]([CH3:45])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]3[S:43][C:42]4[N:44]5[C:35](=[CH:36][N:37]=[C:38]5[CH:39]=[CH:40][CH:41]=4)[CH:34]=3)=[O:32])[CH2:26][CH2:25]1)([CH3:21])[CH2:13][CH2:12]2)[Si](C(C)(C)C)(C)C.[ClH:46].CO>C(O)C>[ClH:46].[ClH:46].[OH:1][C:9]1[C:10]([CH3:45])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]3[S:43][C:42]4[N:44]5[C:35](=[CH:36][N:37]=[C:38]5[CH:39]=[CH:40][CH:41]=4)[CH:34]=3)=[O:32])[CH2:26][CH2:25]1)([CH3:21])[CH2:13][CH2:12]2
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)CCC(C)(CCN1CCC(NC(=O)C3=Cc4cnc5cccc(n45)S3)CC1)O2
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCN1CCC(NC(=O)C3=Cc4cnc5cccc(n45)S3)CC1)O2
Temperature: 25 °C
Reaction time: 90 h

Procedure:
To a solution of 1.17 g (1.78 mM) of N-[1-[2-(6-tert-butyldimethylsiloxy-2,5,7,8-tetramethylchroman-2-yl)ethyl]piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (5 ml) was added 5.0 ml (20 mM) of 4N—HCl/methanol and the mixture was stirred at room temperature for 90 hours. After the solvent was distilled off under reduced pressure, ethanol and diethyl ether were added and the resulting crystals were collected by filtration and rinsed with ethanol and diethyl ether to provide the title compound as orange-colored crystals.