Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH3:20])[C:13](=S)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CI.[CH3:24][C:25]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:26]=1[NH2:27]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH3:20])[C:13](=[N:27][C:26]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:25]=3[CH3:24])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCn1c(-c2ccc(OC)c(OC)c2)cc(=S)n(C)c1=O
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CI
Solvent: C1CCOC1
Product: CCn1c(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Yield: 37 %

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-thioxo-2(1H)-pyrimidinone (0.59 g) in tetrahydrofuran (50 ml) was added methyl iodide (10 ml) and the mixture was refluxed for 90 minutes. The precipitate was added to 2,4,6-trimethylaniline (2 g) and the mixture was heated at 110°-120° C. for 3 hours. The reaction mixture was washed with a mixture of hexane and diisopropyl ether to remove excess 2,4,6-trimethylaniline. The resulting precipitate was collected by filtration and then dissolved in chloroform. The solution was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure to give crude product, which was purified by silica gel column chromatography to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.29 g); mp 57°-61° C. Thus obtained compound was recrystallized from a mixture of ethanol and water (3:1) to give the desired compound as crystals. mp 116°-118° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([N:11]=O)[C:7]([CH3:14])([CH3:13])[CH2:6]1)(=[O:4])=[O:3].[NH2+]([O-])(=O)C(N)=S.C(O)C.[OH-].[Na+]>O>[NH2:11][N:8]1[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7]1([CH3:14])[CH3:13]
Reactant: CC1(C)CN(S(C)(=O)=O)CCN1N=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CN(S(C)(=O)=O)CCN1N

Procedure:
A mixture of 84.2 g of 4-methanesulphonyl-2,2-dimethyl-1-nitrosopiperazine, 90.5 g of thiourea dioxide, 200 ml of ethanol and 200 ml of water is cautiously treated with 85 g of caustic soda and heated to reflux for 30 hours. After cooling, the mixture is filtered and the product is isolated from the filtrate by extraction with methylene chloride. After drying over sodium sulphate and concentrating the methylene chloride solution, the oil which remains is dissolved in a little ethanol and precipitated as the hydrochloride by addition of ethanolic hydrochloric acid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Si:7]([O:14][C@H:15]1[C@H:19]2[O:20][CH2:21][C:22](=O)[C@H:18]2[O:17][CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[C:10]([Si:7]([CH3:8])([CH3:9])[O:14][C@@H:15]1[CH2:16][O:17][C@@H:18]2[C:22](=[CH2:1])[CH2:21][O:20][C@H:19]12)([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(=O)CO[C@@H]21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CO[C@H]2[C@@H]1OC[C@H]2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 234.7 %

Procedure:
A stirred suspension of methyltriphenylphosphonium bromide (1.84 g, 5.16 mmol) and potassium tert-butoxide (578 mg, 5.16 mmol) in tetrahydrofuran (15 mL) was heated at reflux under an atmosphere of argon for 3 hours then allowed to cool to ambient temperature. A solution of ketone (87) (888 mg, 3.44 mmol) in tetrahydrofuran (7.5 mL) was added then heating at reflux continued for 2.25 hours. The mixture was diluted with water (30 mL) then the product extracted into diethyl ether (2×30 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), filtered and reduced in vacuo to leave residue (2.07 g). Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 15:85 gave alkene (88) as a colourless oil (799 mg, 91%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH:22]([OH:24])[CH3:23])[CH:21]=1)[N:18]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:17]=[C:16]2[C:33]#[N:34].[Cl:35][C:36]([Cl:40])([Cl:39])[C:37]#[N:38]>C1COCC1>[Cl:35][C:36]([Cl:40])([Cl:39])[C:37](=[NH:38])[O:24][CH:22]([C:20]1[CH:21]=[C:13]([Cl:12])[CH:14]=[C:15]2[C:19]=1[N:18]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:17]=[C:16]2[C:33]#[N:34])[CH3:23]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Reaction time: 1 h
Yield: 73.4 %

Procedure:
DBU (0.020 mL, 0.130 mmol) was added to a solution of (±)-5-chloro-7-(1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (456 mg, 1.299 mmol) and Trichloroacetonitrile (0.391 mL, 3.90 mmol) in THF (10 mL) and the reaction was stirred for one hour. The solvent was evaporated and the reaction was purified by chromatography on SiO2 with 10:89:1 ethyl acetate/hexanes/triethylamine to give (±)-1-(5-chloro-3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethyl 2,2,2-trichloroacetimidate (472 mg, 0.953 mmol, 73.3% yield) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J=2.0 Hz, 1H), 6.60 (q, J=6.3 Hz, 1H), 6.27 (d, J=11.3 Hz, 1H), 5.25 (d, J=11.3 Hz, 1H), 3.48 (m, 2H), 1.72 (d, J=6.3 Hz, 3H), 0.80-1.05 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:15][O:16][C:17](=[O:22])[CH:18]([CH2:20][OH:21])[NH2:19].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:15][O:16][C:17](=[O:22])[CH:18]([NH:19][C:11](=[O:13])[C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:10])[CH2:20][OH:21]
Reactant: COC(=O)C(N)CO
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CO)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
A round-bottomed flask was charged with Boc-D-alanine (600 mg, 3.17 mmol) and DL-serine methyl ester hydrochloride (691 mg, 4.44 mmol). DMF (12 ml) was added followed by N,N-diisopropylethylamine (1.5 ml, 8.6 mmol) and HATU (1.33 g, 3.49 mmol). The yellow reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 422 mg (41%) of 2-((R)-2-tert-butoxycarbonylamino-propionylamino)-3-hydroxy-propionic acid methyl ester as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](S)=[N:5][N:6]=1.Cl[CH2:9][C:10]#[N:11]>C(O)C>[NH2:1][C:2]1[S:3][C:4]([CH2:9][C:10]#[N:11])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: N#CCCl
Solvent: CCO
Product: N#CCc1nnc(N)s1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A mixture of 2-amino-5-mercapto-1,3,4-thiadiazole (66.5 g, 0.50 mol.), and ethanol (500 ml) is heated to reflux and chloroacetonitrile (41.1 g, 0.55 mol.) is added dropwise at reflux. Heating is continued for four hours and then about 400 ml of distillate is removed using a Dean-Stark trap. The clear solution is cooled to about 75° C. and water (150 ml) is added, allowing the temperature to drop to about 50° C. After adjusting the pH to about seven by adding slowly a solution of Na2CO3, the mixture is cooled to room temperature and the gray product is collected by filtration and washed with water. The moist filter cake is recrystallized from 300 ml of ethanol to yield the desired product which melts at 163°-164° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18](C(OCC2C=CC=CC=2)=O)[CH2:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CC(O)=O.[Pd]>[NH:18]1[CH2:19][CH2:20][CH2:21][CH:16]([NH:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Yield: 85.5 %

Procedure:
10% Pd/C (0.20 gm, 0.19 mmol) was added to a solution of benzyl 3-((1R,2R)-2-(tert-butoxycarbonylamino)cyclohexylamino)piperidine-1-carboxylate, (1.73 gm, 4.01 mmol) in MeOH (14.6 mL) and AcOH (1.46 mL). A H2 atmosphere was then introduced via balloon. After 1 h the reaction mixture was filtered through Celite. The catalyst was rinsed with MeOH and the filtrate was concentrated. The residue was partitioned between EtOAc and sat. NaHCO3. The aqueous phase was isolated and extracted with EtOAc. All organic phases were combined, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give the product tert-butyl (1R,2R)-2-(piperidin-3-ylamino)cyclohexylcarbamate (1.02 gm, 3.43 mmol, 86% yield) as a white foam. Anal. Calcd. for C16H31N3O2 m/z 297.2, found: 298.2 (M+H)+. Crude product was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9](N)[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4].C(#N)C.N([O-])=[O:28].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([OH:28])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4]
Reactant: O=N[O-]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(O)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methoxypyrimidine-4-carboxylic acid methyl ester (200 mg, 0.61 mmol) was dissolved in 20 mL of 9 molar H2SO4 plus 5 mL acetonitrile and treated in portions with NaNO2 (150 mg, 2.2 mmol). After the addition was complete, the mixture was stirred for 30 minutes at 25° C., cooled in ice-salt and treated carefully with 50% NaOH to bring the pH to ca 0.8. The precipitate was taken up by extracting with two 15 mL portions of EtOAc and the combined extracts were washed with 10 mL sat. NaCl, dried (Na2SO4) and evaporated to give the title product 150 mg (75%). Mp: 177-179° C. MS m/z 342; 1H NMR (DMSO-d6): δ 7.81 (m, 1H), 7.31 (m, 1H), 4.05 (s, 3H), 4.01 (s, 3H).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20].[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34]>>[CH3:18][N:4]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[C:2]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: C#C[Si](C)(C)C
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(C#C[Si](C)(C)C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 12, [5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 19) was reacted with trimethylsilylacetylene to give the title compound as dark brown gum. MS: 519.2 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[Br:21][C:19]1[CH:20]=[C:15]([C:13]2[S:14][C:8]3[C:7]([OH:22])=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[N:11]=[CH:10][C:9]=3[N:12]=2)[CH:16]=[N:17][CH:18]=1
Reactant: CCOC(=O)c1ncc2nc(-c3cncc(Br)c3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3cncc(Br)c3)sc2c1O
Temperature: 25 °C
Yield: 24.4 %

Procedure:
A mixture of 2-(5-bromo-pyridin-3-yl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (49 mg, 0.13 mmol) and glycine (193 mg, 2.57 mmol) in 0.5 M sodium methoxide/methanol (4.9 mL) was refluxed for 36 h before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (15 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (2 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (13 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.34 (br s, 1H), 12.83 (br s, 1H), 9.46 (t, 1H), 9.30 (d, 1H), 8.91 (m, 2H), 8.73 (m, 1H), 4.02 (d, J=5.8 Hz, 2H); MS: (+) m/z 408.93, 410.87 (M+1, 79Br/81Br).
Reaction SMILES: [CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8](F)=[C:9]([F:25])[CH:10]=2)[N:5]2[CH:27]=[CH:28][CH:29]=[C:4]12)[CH3:2].[CH3:30]C1C=C(S(Cl)(=O)=O)C=C(C)C=1OC>>[CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH3:24])[C:19]([O:22][CH3:23])=[C:20]([CH3:30])[CH:21]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:25])[CH:10]=2)[N:5]2[CH:27]=[CH:28][CH:29]=[C:4]12)[CH3:2]
Reactant: COc1c(C)cc(S(=O)(=O)Cl)cc1C
Reactant: CCC1c2cccn2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Product: CCC1c2cccn2-c2ccc(F)cc2N1S(=O)(=O)c1cc(C)c(OC)c(C)c1

Procedure:
The title compound was prepared from the product of Example 4 using 3,5 dimethyl-4-methoxy benzenesulfonyl chloride to yield crystals, mp 140-142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][C@H:13]3[CH2:15][C@H:16]([N:18]4[C:22]5[N:23]=[CH:24][N:25]=[C:26]([CH3:27])[C:21]=5[CH:20]=[CH:19]4)[CH2:17][C@H:12]3[CH2:11][O:10]2)=[CH:5][CH:4]=1.[I:28]N1C(=O)CCC1=O>C(Cl)Cl>[I:28][C:20]1[C:21]2[C:26]([CH3:27])=[N:25][CH:24]=[N:23][C:22]=2[N:18]([C@H:16]2[CH2:15][C@@H:13]3[O:14][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[O:10][CH2:11][C@@H:12]3[CH2:17]2)[CH:19]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(C)ncnc54)C[C@@H]3O2)cc1
Solvent: ClCCl
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4cc(I)c5c(C)ncnc54)C[C@@H]3O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of 7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d]-[1,3]dioxin-6-yl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (363 mg, 0.995 mmol, as prepared in Example 1a-f) in DCM (15.0 mL) was added N-iodosuccinimide (256 mg, 1.14 mmol), and the mixture was stirred at rt overnight. Silica gel chromatography eluting with a gradient of 25 to 100% EtOAc in hexanes afforded the title compound (253 mg, 52%). LC/MS: Rt=2.03 min, ES+ 492 (AA standard).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].N1C=CC=CC=1>ClCCl>[CH3:15][O:14][C:3]1[C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[N:4]=1
Reactant: COc1ccc2nc(OC)c(N)nc2c1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 96.1 %

Procedure:
3-Amino-2,6-dimethoxyquinoxaline (616 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 799 mg of the titled compound (yield, 96%).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:24])[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:20]([O:22]C)=[O:21])[C:17]=2[C:18]=1[OH:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CS(C)=O>[C:1]([C:9]1[C:10](=[O:24])[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:20]([OH:22])=[O:21])[C:17]=2[C:18]=1[OH:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2[nH]c(=O)c(C(=O)c3ccccc3)c(O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccccc1)c1c(O)c2c(C(=O)O)cccc2[nH]c1=O
Yield: 94.1 %

Procedure:
To 0.6 grams of methyl 3-benzoyl-4-hydroxy-2-quinolone-5-carboxylate are added 1.5 grams of sodium hydroxide, 30 ml of water and 30 ml of dimethyl sulfoxide, the mixture is heated at 100° to 120° C. for three hours with stirring, cooled, acidified and diluted hydrochloric acid, and crystals separated out therefrom are collected by filtration to give 0.54 grams of 3-benzoyl-4-hydroxy-2-quinolone-5-carboxylic acid, colorless powder, melting at above 300° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].[CH2:33](I)[CH3:34]>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:33][CH3:34])[N:11]=[CH:10]2)[CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc2cn[nH]c2cc1C
Reactant: CCI
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc2cnn(CC)c2cc1C
Yield: 68.3 %

Procedure:
Using the compound (1.68 g, 3.82 mmol) of Example 244, step B and ethyl iodide (0.50 ml, 6.25 mmol), and according to the method of Example 241, step C, the title compound (1.22 g, yield 68%) was obtained as a colorless amorphous solid.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].O>S(=O)(=O)(O)O>[O:11]1[C:4]2[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=2)[CH2:8][CH2:9][CH:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1CCC(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: c1ccc(C2CCc3ccccc3O2)cc1
Reaction time: 2 h
Yield: 21.7 %

Procedure:
2-Hydroxychalcone (28.5 g) was stirred with ethanol (500 ml) whilst sodium borohydride (9.45 g) was added in small portions. The solution, which turned from red to pale yellow was allowed to stand overnight at room temperature, then the solvent was evaporated off and the residue extracted with dichloromethane, washing with water. Evaporation of the solvent yielded 3-(o-hydroxyphenyl)-1-phenylpropan-1-ol (24.4 g). 1.0 g of this carbinol was dissolved in concentrated sulphuric acid, and the solution was allowed to stand at room temperature for 2 hr. The solution was poured into iced water, and the sticky orange product filtered off, washed with water, dried, and chromatographed on alumina, eluting with toluene. Evaporation of the eluate gave flavan (0.20 g), which was recrystallised from petroleum ether, b.p. 40°-60°, to give flavan m.p. 42°-43°.
Reaction SMILES: [C:1]1([NH:7][C:8]([C@@H:10]([NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[NH:20]2)=[O:18])[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([OH:29])(=[S:28])[CH3:27].CC(N=NC(C#N)(C)C)(C#N)C>O1CCOCC1>[O:25]=[C:21]1[NH:20][C@@H:19]([C:17]([NH:16][C@H:10]([C:8](=[O:9])[NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:28][C:26](=[O:29])[CH3:27])=[O:18])[CH2:24][CH2:23][CH2:22]1
Reactant: CC(O)=S
Reactant: C=CCCC[C@H](NC(=O)[C@H]1CCCC(=O)N1)C(=O)Nc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1COCCO1
Product: CC(=O)SCCCCC[C@H](NC(=O)[C@H]1CCCC(=O)N1)C(=O)Nc1ccccc1
Temperature: 0 °C
Yield: 53 %

Procedure:
To a stirred solution of (R)-6-oxo-piperidine-2-carboxylic acid ((S)-1-phenylcarbamoyl-hex-5-enyl)-amide (220 mg, 0.64 mmol), thioacetic acid (460 μl, 6.4 mmol) at 75° C. in degassed dioxane (7 ml) was added AIBN (105 mg, 0.64 mmol). The reaction mixture was stirred until complete conversion of the starting material as monitored by TLC analysis. The reaction mixture was cooled to 0° C. and quenched with an excess of cyclohexene under stirring, the latter being maintained for 20 minutes. Concentration under reduced pressure and purification through chromatography on silica gel using Hexane/DCM/IPA: 50/40/10 as eluent afforded the desired adduct.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C:4]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][CH2:5][C:4]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCC(O)C2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CCC(=O)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of tert-butyl 2-hydroxy-7-azaspiro[4.5]decane-7-carboxylate (252 mg, 1.0 mmol) in DCM (5 mL) was added Dess-Martin periodinane (0.84 g, 1.99 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as yellow oil (197 mg, 79%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(=[O:8])=[O:7].CO.Cl>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[CH2:12][OH:13])(=[O:8])=[O:7]
Reactant: COCCNS(=O)(=O)c1cccc(C(=O)O)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of 4.0 g of 3-[(2-methoxyethyl)aminosulfonyl]benzoic acid in 200 ml of tetrahydrofuran was added dropwise a solution of 1.07 M borane-tetrahydrofuran complex in 43.5 ml of tetrahydrofuran under ice-cooling, and this was stirred for 30 minutes, and stirred at room temperature overnight. After 40 ml of methanol was added dropwise under ice-cooling, 100 ml of 2 N hydrochloric acid was added dropwise. After warmed to room temperature, the solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.0 g of oily 3-[(2-methoxyethyl)aminosulfonyl]benzyl alcohol.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][OH:20])[CH2:3]1.C(N(CC)CC)C.[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:3]1
Reactant: O=C(N[C@H]1CC[C@@H](O)C[C@H]1CO)OCc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@@H](O)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sample of benzyl (1S,2R,4R)-4hydroxy-2-(hydroxymethyl)cyclohexylcarbamate (8.78 g, 31.42 mMol) was dissolved in anhydrous CH2Cl2 prior to the addition of triethylamine (11 mL, 78.55 mMol) followed by DMAP (0.05 g) and then trityl chloride (10.52 g, 37.7 mMol) in one portion. The reaction mixture was stirred at rt overnight. The reaction was partitioned between CH2Cl2 and water. The organic layer was washed with brine and dried (MgSO4), filtered, concentrated and chromatographed. Benzyl (1S,2R,4R)-4-hydroxy-2-(trityloxymethyl)cyclohexylcarbamate was obtained as a white foamy solid (9.85 g, yield=60%).