Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[C:18](O)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=1.[OH-].[Na+]>O>[Br:11][C:5]1[CH:6]=[C:7]([C:8]2[O:10][C:18]3[C:13]([N:12]=2)=[N:14][C:15]([CH3:20])=[CH:16][CH:17]=3)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Cc1ccc(O)c(N)n1
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2oc(-c3cc(Br)cnc3N)nc2n1
Temperature: 200 °C
Reaction time: 5 h
Yield: 35.6 %

Procedure:
A mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g), 2-amino-6-methyl-pyridin-3-ol (1.4 g) and polyphosphoric acid (10 g) was stirred at 200° C. for 5 hours. The resulting mixture was cooled to room temperature, diluted with water (4 ml) and basified to pH 12 with aqueous NaOH 10N, then 2N. The reaction mixture was extracted with dichloromethane/acetonitrile, the organic phase was washed with water, a saturated aqueous solution of brine, dried over magnesium sulfate and concentrated to afford the crude product 5-bromo-3-(5-methyloxazolo[4,5-b]pyridin-2-yl)pyridin-2-amine (0.500 g) as a solid. NMR Spectrum: (DMSOd6) 2.60 (s, 3H), 7.35 (d, 1H), 7.85 (bs, 2H), 8.10 (d, 1H), 8.35 (d, 1H), 8.37 (d, 1H); Mass spectrum: M+H+ 304-306.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.I[CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:24][CH2:25][CH2:26][CH3:27])[C:8]=2[N:9]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a suspension of NaH (60% in mineral oil, 34 mg) in 6 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (202 mg, 0.66 mmol). The mixture was heated to 50° C., resulting in a clear solution. 1-Iodobutane (105 μL, 0.92 mmol) was added, and the solution was stirred at 50° C. for 30 minutes, then cooled to room temperature and poured onto 40 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The residue was dried and purified by flash chromatography, eluting with a gradient of 1:1 hexane:ethyl acetate to all ethyl acetate to provide 152 mg (64%) of 2-amino-8-butyl-6-(2,6-dichlorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one; mp 202°-205° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:12](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:13].C(N(CC)CC)C.[S:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>C(Cl)Cl>[S:34]1[CH2:38][CH2:37][N:36]([C:12]([NH:11][C:5]2([C:3]([OH:2])=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:13])[CH2:35]1
Reactant: C1CSCN1
Reactant: COC(=O)C1(N)CCCCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)O)CCCCC1)N1CCSC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A solution of 78 mg (0.6 mmol) of N,N-dimethylaminopyridine and 1 g (6.36 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester in methylene chloride was added to a solution of 1.39 mg (6.36 mmol) of di-t-butyl dicarbonate in 10 ml of methylene chloride, and the mixture was stirred at room temperature for 30 minutes. Thereafter, a solution of 1.29 g (12.7 mmol) of triethylamine and 680 mg (7.6 mmol) of thiazolidine in methylene chloride was added thereto, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated, the residue was dissolved in ethyl acetate, and the mixture was washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, tetrahydrofuran and 1N aqueous sodium hydroxide solution were added to the residue, and the mixture was heated under reflux for 3 hours. After ether was added to the reaction solution to wash it, the aqueous layer was neutralized by concentrated hydrochloric acid, and it was extracted with ethyl acetate. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.1 g (66%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC([OH:15])C.N1C=CC=CC=1.C(O)(=O)C.[C:26](OC)([CH3:29])([CH3:28])[CH3:27]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:10][CH2:27][CH:26]([CH3:29])[CH3:28])(=[O:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)O
Reactant: COC(C)(C)C
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC(C)COS(=O)(=O)c1ccc(Br)cc1
Temperature: 10 °C
Yield: 87 %

Procedure:
4-bromobenzenesulfonyl chloride 850 g, 0.19 mol) was suspended in 2-propanol (45 ml, 3 eq) and the slurry was cooled to less then 10° C. Pyridine (32 ml, 2 eq) was added in portions while maintaining the reaction temperature below 10° C. After reaction completion (ca. 3 hours), 11 ml of glacial acetic acid followed by 250 ml of methyl tert-butyl ether (MTBE) were added. The layers were separated and the rich organic layer was successively washed with 125 ml of 1N aqueous hydrochloric acid and 150 ml of saturated sodium bicarbonate solutions. The rich MTBE solution was solvent exchanged into hexane (i.e., the addition of hexane with concurrent distillation of MTBE) to induce crystallisation. The crystal slurry was filtered, washed and dried in vacuo at no more than 25° C., to give 48 g (87% yield) of isobutyl 4-bromobenzenesulfonate.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CC(=O)CC.O>[CH2:12]([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[CH2:13][C:14]#[CH:15]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCC(C)=O
Product: C#CCCn1ccnc1
Yield: 89.9 %

Procedure:
A mixure of but-3-ynyl 4-methylbenzenesulfonate (1.04 g), imidazole (573 mg) and K2CO3 (3.88 g) in 2-butanone (10 mL) was heated to reflux overnight. Work-up (DCM, H2O), drying (Na2SO4) and concentration gave 1-(but-3-ynyl)-1H-imidazole (501 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:20][NH:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl.C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]2)=[C:6]([CH:10]=1)[C:7]([N:21]([CH3:22])[CH3:20])=[O:9]
Reactant: CNC
Reactant: O=C(O)c1cc(Br)cnc1N1CCN(CCO)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Br)cnc1N1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
630 mg (1.90 mmol) of 5-bromo-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-nicotinic acid was suspended in 50 ml of dichloromethane, 6 ml of 2 M dimethylamine in THF and 850 mg (1.63 mmol) of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate were added and the resulting mixture was stirred for 18 h at ambient temperature. The resulting mixture was diluted with dichloromethane and washed with water. The aqueous phase was extracted with dichloromethane and the organic phases were combined, dried over sodium sulfate and evaporated to afford crude 5-bromo-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N,N-dimethyl-nicotinamide as a pale brown oil containing tris(pyrrolidinyl)phosphoramidate as a contaminant. MS: m/z 357 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[O:4].C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.[H][H]>C1(C)C=CC=CC=1>[C:3]([O:2][CH3:1])(=[O:4])[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6]
Reactant: [H][H]
Reactant: COC(=O)C(=O)c1ccccc1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](O)c1ccccc1
Yield: 88.5 %

Procedure:
The cross-linked Ir cluster composition obtained in Example 10 (14.4 mg, 0.01 mmole), methyl benzoyl formate (164.2 mg, 1.0 mmole), (−) cinchonidine (3.8 mg, 0.013 mmole) and toluene (5 ml) were mixed in an autoclave and agitated for five hours at room temperature in a hydrogen atmosphere at 50 atmospheres pressure. The cross linked Ir cluster composition was removed by filtration after the reaction. The filtrate was concentrated, and the residue was purified using PTLC to obtain (R)-methyl mandelate (147.1 mg, 88.5% yield). The asymmetric yield was 47.1% ee.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:26])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.O.[OH-].[Li+].Cl>CO>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:27])=[O:2])=[O:26])=[CH:13][CH:14]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccccc1C(=O)O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
To 2-(4-benzyloxy-benzoylamino)-benzoic acid methyl ester (50 mg) in methanol (3 mL) was added lithium hydroxide monohydrate (6.3 mg) and the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was then reacidified using 1N HCl and the product was then purified by column chromatography (SiO2, ethyl acetate-ethanol: 0-20%) to give 2-(4-benzyloxy-benzoylamino)-benzoic acid as a white solid (39 mg). MS (m/e): 346.3 (M−H−, 100%).
Reaction SMILES: [N:1]([C:3]1C=CC=CC=1)=O.[C]=[O:10].[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Rh]>[C:11]1([N:1]=[C:3]=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [C]=O
Reactant: O=Nc1ccccc1
Reactant: c1ccccc1
Agent: [Rh]
Product: O=C=Nc1ccccc1
Temperature: 190 °C

Procedure:
The procedure of Example 14 is repeated using 12.3 parts of nitrosobenzene, 80 parts of benzene, 5 parts of rhodium on carbon and 0.5 part of ferrous chloride. After carbon monoxide is introduced to a pressure of 2,700 p.s.i., the pressure vessel is heated at 190°C. for 5 hours. Phenyl isocyanate is obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:14][CH:13]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: O=Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2ccccc2C=O)cc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
2-Bromobenzaldehyde (3.7 g, 20 mmol) and 4-(methylthio) benzeneboronic acid (3.36 g, 20 mmol) were dissolved in toluene (80 mL) and sodium carbonate (2M, 10 mL, 20 mmol) was added. To this reaction mixture was added ethanol (5 mL) followed by tetrakis (triphenylphosphine)palladium (240 mg, 0.2 mmol) and the reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (50 mL), stirred well, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (2×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give the crude product. Purification by flash column chromatography using 5% ethyl acetate in hexane gave the title compound as a colorless thick oil (4.4 g, 96% yield). 1H NMR (CDCl3) δ9.98 (s, 1H), 8.01 (dd, J=7.8 Hz and 1.2 Hz, 1H), 7.6 (dt, J=7.5 and 1.4 Hz, 2H), 7.62-7.40 (m, 2H), 7.3-7.25 (m, 3H), 2.53 (s, 3H); LRMS (APIMS) m/z 329 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.O=[CH:23][CH2:24][NH:25]C(=O)OC(C)(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C.C(#N)C>[NH2:25][CH2:24][CH2:23][NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC#N
Product: NCCNc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Temperature: 170 °C

Procedure:
A solution of EXAMPLE 12 (0.06 g, 0.2 mmol) and tert-butyl (2-oxoethyl)carbamate (0.035 g, 0.2 mmol) in ethanol (1 mL) and acetonitrile (1 mL) was treated with sodium cyanoborohydride (0.014 g, 0.2 mmol) and acetic acid (0.2 mL). The mixture was heated in a microwave at 170° C. for 40 minutes and concentrated. The residue was purified by flash chromatography on silica gel with 10% methanol/dichloromethane/0.1% ammonium hydroxide to provide the title compound. 1H NMR (DMSO-d6) δ 12.30 (s, 1H), 10.06 (s, 1H), 8.11-8.19 (m, 2H), 7.89-7.96 (m, 1H), 7.58-7.67 (m, 2H), 7.52 (t, J=7.6 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 6.27 (s, 1H), 3.30-3.36 (m, 4H), 2.08 (s, 3H).
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[CH:9][C:10]1[S:14][CH:13]=[CH:12][CH:11]=1)=O)C.[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21](=[NH:23])[NH2:22])[CH3:17]>C(O)C>[CH2:16]([O:18][C:19]([C:20]1[CH:8]([CH2:9][C:10]2[S:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:19]([O:18][CH2:16][CH3:17])=[O:24])=[C:5]([CH3:4])[NH:23][C:21]=1[NH2:22])=[O:24])[CH3:17]
Reactant: CCOC(=O)CC(=O)C=Cc1cccs1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1Cc1cccs1
Yield: 73 %

Procedure:
Upon heating a solution of 12.2 g of (2-thenylidene)-acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 4 hours, 2-amino-6-methyl-4-(2-thenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 170°C (ethanol) is obtained.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:19]([C:5]2[S:4][C:3]([CH2:1][CH3:2])=[CH:7][CH:6]=2)[OH:20])[CH:21]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: CCc1cccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2cc(Br)ccc2OC)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A solution of 2-ethylthiophene (3.00 g) in tetrahydrofuran (36 ml) was cooled to 0° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.56 M hexane solution, 17.1 ml). The mixture was stirred at the same temperature for 30 minutes, and cooled to −78° C., and thereto was added dropwise a suspension of 5-bromo-2-methoxybenzaldehyde (5.74 g) in tetrahydrofuran (60 ml). The mixture was stirred at the same temperature for 2 hours, warmed to 0° C., and thereto was added a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-85:15) to give 5-bromo-2-methoxyphenyl-5-ethyl-2-thienylmethanol (5.99 g) as a pale yellow syrup. APCI-Mass m/Z 309/311 (M+H—H2O). (2) The above 5-bromo-2-methoxyphenyl-5-ethyl-2-thienylmethanol was treated in a manner similar to Reference Example 1-(2) to give 5-bromo-(5-ethyl-2-thienylmethyl)-2-methoxybenzene as oil. APCI-Mass m/Z 311/313 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:26]=2)[C:16]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:15]1.C(N(CC)CC)C>CO.CCOC(C)=O.[Pd]>[CH3:12][C:7]1[C:6]([CH3:13])=[C:5]([N:14]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[CH:26]=3)[C:16]3([CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH2:15]2)[C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[N:8]=1
Reactant: Cc1nc2ccc(Cl)cc2c(N2CC3(CCOCC3)c3ccc(N4CCOCC4)cc32)c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2c(N2CC3(CCOCC3)c3ccc(N4CCOCC4)cc32)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(6-chloro-2,3-dimethylquinolin-4-yl)-6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.027 g, 0.058 mmol), triethylamine (0.008 mL, 0.058 mmol), and 10% Pd/C (0.02 g, 0.0188 mmol) in MeOH-EtOAc (2:1, 3 mL) was stirred under hydrogen at rt. After 3 h, the mixture was filtered through a Celite™ pad and the pad was washed with MeOH and EtOAc to give a tan solid. The tan solid was purified by column chromatography on a silica gel column using 0 to 100% gradient of EtOAc in hexane as eluent to give 1-(2,3-dimethyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 7.97 (1H, d, J=8.3 Hz), 7.71 (1H, d, J=8.1 Hz), 7.62-7.68 (1H, m), 7.42-7.49 (1H, m), 7.08 (1H, d, J=8.3 Hz), 6.23 (1H, dd, J=8.2, 2.1 Hz), 5.41 (1H, d, J=2.2 Hz), 3.77-3.96 (4H, m), 3.52-3.59 (4H, m), 3.41-3.51 (2H, m), 2.81 (4H, dd, J=5.4, 2.9 Hz), 2.68 (3H, s), 2.22 (3H, s), 1.91-2.03 (2H, m), 1.78-1.85 (1H, m), 1.65-1.72 (1H, m); Mass Spectrum (ESI) m/e=430.2 (M+1).
Reaction SMILES: CO[C@H]1CC[C@H](C[N:10]2C(=O)CNC3N=CC(C4C(C)=CC(C(N)=O)=NC=4)=[N:20][C:11]2=3)CC1.[CH3:31][O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH2:39][N:40]2[C:45](=[O:46])[CH2:44][NH:43][C:42]3[N:47]=[CH:48][C:49]([C:51]4[C:52]([CH3:59])=[CH:53][C:54]([C:57]#[N:58])=[N:55][CH:56]=4)=[N:50][C:41]2=3)[CH2:35][CH2:34]1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:31][O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH2:39][N:40]2[C:41]3=[N:50][C:49]([C:51]4[CH:56]=[N:55][C:54]([C:57]5[N:20]=[CH:11][NH:10][N:58]=5)=[CH:53][C:52]=4[CH3:59])=[CH:48][N:47]=[C:42]3[NH:43][CH2:44][C:45]2=[O:46])[CH2:35][CH2:34]1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C#N)cc4C)nc32)CC1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(N)=O)cc4C)nc32)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(-c5nc[nH]n5)cc4C)nc32)CC1
Temperature: 65 °C

Procedure:
5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide. 5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinonitrile (0.607 g, 1.55 mmol), trifluroacetic acid (2.0 mL, 26.0 mmol) and sulfuric acid (0.5 mL, 9.38 mmol) were combined and heated at 65° C. for 1 h. Reaction pH was adjusted to 10 with sodium carbonate and the resulting solution was extracted with ethyl acetate (3×15 mL). Organic layers were collected, dried over magnesium sulfate, concentrated and purified using reverse-phase preparatory HPLC (10-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Clean fractions were combined and condensed under reduced pressure and dried under high vacuum to afford the title compound as a yellow solid (0.425 g, 1.04 mmol, 67% yield). MS (ESI) m/z 411.5 [M+1]+.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/C(C1C(C)(C)CC=CC=1C)=O.CC1OC=CC(=O)C=1O.[CH3:24][CH2:25][C:26]1O[CH:31]=[CH:30][C:28](=O)[C:27]=1O>>[CH3:24][C:25]1[CH2:26][CH2:27][CH:28]([C:2]([CH3:3])=[CH2:1])[CH2:30][CH:31]=1
Reactant: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Reactant: CCc1occc(=O)c1O
Agent: Cc1occc(=O)c1O
Product: C=C(C)C1CC=C(C)CC1

Procedure:
Beta-damascenone (having the structure: ##STR13## Maltol; Ethyl maltol;
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:37]([O:39][CH3:40])=[O:38])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Oc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) was dissolved in dry CH2Cl2 (5 ml). DIPEA (500 μl ) and methyl chloroformate (199 μl ) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H2O. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.C(O[CH2:24][CH:25]=[CH2:26])(=O)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([C:11]1[C:2]([OH:1])=[N:3][C:4]2[C:9]([C:10]=1[OH:12])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:25]=[CH2:24]
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: C=CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCc1c(O)nc2ccccc2c1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a degassed solution of 2,4-dihydroxyquinoline (10.0 g) in DMF (100 ml) was added triethylamine (9.51 ml), Pd(Ph3P)4 (2.151 g), followed by allyl acetate (7.43 ml). The mixture was allowed to stir at 60° C. under nitrogen for 18 hours. The reaction mixture was cooled to room temperature and quenched into water (600 mL). The pH was adjusted to 12 using a saturated sodium carbonate solution. Dichloromethane was added and the layers were cut. The aqueous layer was extracted with dichloromethane once more. Then, the aqueous layer was cooled with ice and the pH was slowly adjusted to 2.5 with 12N HCl to give a pink solid. The solids were filtered and washed with water to give 11.5 g (92% yield). LRMS (ES+) M/Z (M+H)+ 202.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[CH2:25][CH:24]([CH3:26])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[N:21]([CH3:31])[C:20]1=[O:32]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[CH2:25][CH:24]([CH3:26])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[N:21]([CH3:31])[C:20]2=[O:32])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1CC(N)C(=O)N(C)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CC1CC(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)C(=O)N(C)c2ccccc21

Procedure:
Following General Procedure C above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (prepared from 4-methyltetralone (Aldrich) using General Procedure 6-A), the title compound was prepared as a solid having a melting point of 115–119° C. Purification was by flash chromatography using 5% methanol/dichloromethane as the eluant.