Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.N1C2C(=CC=CC=2)C=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 63.7 %

Procedure:
To a mixture of 306 mg (purity: 98.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 833 mg (5.53 mmol) of 2-cyclopropyl-6-methylphenol were added quinoline (2.76 g) and 327 mg (5.55 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 321 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 64%) and 3.4 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.7%) were obtained.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH2:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C1C=CC=CC=1>[Pd].CCO.CCOC(C)=O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:9]=1[OH:8])[CH3:16]
Reactant: C=C(c1ccccn1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(c1ccccn1)c1cccc(-c2ccccc2)c1O
Reaction time: 2.75 h

Procedure:
A solution of 5 (0.50 g, 1.377 mmol, 1.0 equiv) and 20% Pd—C (55% H2O) (0.05 g) in 1:1 EtOH/EtOAc (30 mL) was hydrogenated at 30 psi H2 for 4.25 hr. LCMS showed some 5 remained along with A and a small amount of over-reduction products. The mixture was hydrogenated at 20 psi H2 for 2.75 hr (LCMS showed ˜2% 5 remained). The mixture was filtered through Celite, and the Celite layer was washed with 1:1 EtOH/EtOAc (30 mL). The filtrate was concentrated under reduced pressure to give a brown oil. The crude product was absorbed onto silica gel using DCM and dry-loaded on a column of silica gel (10 g) packed in hexanes. The column was eluted with hexanes (100 mL), 5% EtOAc/hexanes (100 mL) and 10% EtOAc/heptanes (200 mL). Product fractions were concentrated under reduced pressure to give 0.40 g (105%—residual solvent present) of A as a colorless, viscous oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:16])[C:7]=2[CH:17]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:30])C.Cl>O>[O:16]=[C:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:15][C:6]2[CH:5]=[CH:4][C:3]([CH:2]=[O:30])=[CH:17][C:7]1=2
Reactant: O=c1c2cc(CBr)ccc2oc2ncccc12
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: O=Cc1ccc2oc3ncccc3c(=O)c2c1

Procedure:
A mixture of 50 g of 7-bromomethyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine, 48.4 g of hexamethylenetetramine, 167 ml of water and 167 ml of acetic acid is stirred under reflux for 3 hours. To the reaction mixture is added 100 ml of concentrated hydrochloric acid, and the whole mixture is refluxed for 20 minutes. The reaction mixture is diluted with 200 ml of water, and cooled. The crystalline precipitate is filtered off, washed with water, dried, and then recrystallized from dimethylformamide to give 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carbaldehyde melting at 233-235°C.
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8].[CH:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>O1CCCC1.C(OCC)C>[CH3:6][Si:7]([CH3:9])([CH3:8])[C:10]#[C:11][CH:12]([OH:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCCCCC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)C#C[Si](C)(C)C
Temperature: -70 °C

Procedure:
173 mol of n-butyllithium solution (1.6 mol in hexane) is instilled in a solution of 25 g of trimethylsilylacetylene in 500 ml of tetrahydrofuran with stirring and argon atmosphere at -40° C., is stirred for 30 minutes at -40° C., cooled to -70° C. and 48.1 ml of nonanal is instilled at this temperature. After an hour at -70° C., the mixture is allowed to come to -30° C., 300 ml of 2 n hydrochloric acid is added and shaken with diethyl ether. The organic phases are dried (Na2SO4), concentrated by evaporation and the residue is distilled in a bulb tube at 120°-130° C./0.2 mbar. Thus 48.5 of (3RS)-1-(trimethylsilyl)-1-undecin-3-ol is obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:11]([OH:23])[C:12](=[O:22])[NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15]>O1CCCC1>[OH:23][CH:11]([C@@H:10]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([NH:2][CH3:1])=[O:4])[C:12](=[O:22])[NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15]
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCN)NC(=O)OC(C)(C)C)c1ccccc1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)N[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methylisocyanate (0.472 mL, 8.00 mmol) was added to a slurry of tert-butyl (1S)-5-amino-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate (3.03 g, 8.00 mmol) at 0° C. in anhydrous tetrahydrofuran (60 mL) under nitrogen. The mixture was stirred at 0° C. for 1 h, during which time all solids dissolved. The cold bath was then removed, and the solution was stirred overnight. Volatiles were removed under vacuum, and the resulting foam was further purified by column chromatography on silica gel. Elution with a gradient from 50% to 75% acetone in hexane afforded tert-butyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-{[(methylamino)carbonyl]amino}pentylcarbamate as a white solid after drying under vacuum (3.00 g, 86%). 1H NMR (300 MHz, DMSO-d6) δ 8.06-8.01 (m, 1H); 7.38-7.18 (m, 5H); 6.40 (d, J=10 Hz) and 6.08 (d, J=9 Hz) total 1H, 5.86-5.75 (m, 1H); 5.71-5.51 (m, 2H); 5.01-4.91 (m, 1H); 3.94 (br s) and 3.87 (br s) total 1H, 3.79-3.64 (m, 1H); 3.01-2.81 (m, 2H); 2.54 (d, J=5 Hz, 3H); 1.52-1.16 (m, 18H). ES-LCMS m/z 437 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.CCN(CC)CC.Cl.[O:35]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36]1>CN(C=O)C>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]=[CH:8][C:6]3=[N:7][C:2]=2[NH:40][C@H:37]2[CH2:38][CH2:39][O:35][CH2:36]2)[CH2:13][CH2:14]1
Reactant: Fc1ccc(CN2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Reactant: N[C@H]1CCOC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1ccc(CN2CCN(c3nc4ccncc4nc3N[C@H]3CCOC3)CC2)c(F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 23.5 %

Procedure:
To a solution of 3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine (3.0 g, 7.98 mmol) and Et3N (10 mL, 71.7 mmol) in DMF (30 mL) was added (S)-tetrahydrofuran-3-amine hydrochloride (2.96 g, 23.95 mmol) at room temperature. The mixture was stirred at 60° C. for 16 h then separated between water and EtOAc. The organic layer was washed with brine and water, then dried and concentrated to yield the crude residue, which was purified by column to give the title compound (800 mg) as a yellow oil. ESI-MS m/z [M+H]+ 427.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:8]=2)=[CH:3][CH:2]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][O:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:9]2[N:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:12]=[CH:11][N:10]=2)=[CH:15][CH:16]=1
Reactant: Oc1ccc(Nc2nccc(-c3ccncc3)n2)cc1
Reactant: CN(C)CCCCl
Product: CN(C)CCCOc1ccc(Nc2nccc(-c3ccncc3)n2)cc1

Procedure:
A 2.78 g portion of 4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenol and 2.35 g of 3-dimethylaminopropyl chloride were reacted as described in Example 255, giving 850 mg of the desired product, mp 123°-124.5° C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH2:43][CH:44]([CH3:47])[CH2:45][OH:46])[C:39](=[O:48])[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH2:43][CH:44]([CH3:47])[CH2:45][OH:46])[C:39](=[O:48])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CC(CO)Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CC(CO)Cn1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-d ioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-(3-hydroxy-2-methyl-propyl)-1H-pyridin-2-one following a procedure analogous to that described in Example 75. Mass spectrum (ESI+): m/z=519 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH:5]1[CH2:8][NH:7][CH2:6]1.C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1>C(O)(C)C>[Cl:23][C:24]1[N:29]=[C:28]([N:7]2[CH2:8][CH:5]([O:4][C:3]3[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=3[Cl:1])[CH2:6]2)[CH:27]=[CH:26][N:25]=1
Reactant: Clc1ccc(OC2CNC2)c(Cl)c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(OC2CN(c3ccnc(Cl)n3)C2)c(Cl)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
To a solution of 3-(2,4-dichlorophenoxy)azetidine (1.0 g, 4.6 mmol) in isopropanol (14 mL) was added N,N-diisopropylethylamine (DIPEA) (1.0 mL, 6.9 mmol) and 2,4-dichloropyrimidine (0.686 g, 4.6 mmol and the reaction mixture was heated at 80° C. for 7 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×20 mL) and water (2×20 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-4-(3-(2,4-dichlorophenoxy)azetidin-1-yl)pyrimidine (0.600 g, 40%) as a solid. Observed mass (M+1): 330.0
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4C=[CH:20][CH:19]=[C:18](C)[C:17]=4OCOC)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.Cl.[O:30]1[CH2:35][CH2:34]OCC1.C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:20])=[C:35]([OH:30])[CH:34]=4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: COCOc1c(C)cccc1CN1CCN(c2nc3ccc(Cl)cc3s2)CC1
Reactant: C1COCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)cc1O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 6-chloro-2-[4-(2-methoxymethoxy-3-methylbenzyl)piperazine-1-yl]benzothiazole (1.70 g; 4.067 mmol) and 4N hydrochloric acid/dioxane solution (8.5 ml) was stirred at 60° C. for 2 hours. After cooling, the reaction solution was condensed under reduced pressure. To the residue was added saturated aqueous sodium hydrogencarbonate to be alkaline and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The precipitate was washed with diisopropyl ether to give 5-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}-2-methylphenol as colorless crystal (1.33 g; 87%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH:1]=[CH:14][C:15]([OH:17])=[O:16])=[CH:4][CH:5]=1)=[O:8]
Reactant: O=C(O)CC(=O)O
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C=CC(=O)O)cc1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
A solution of methyl p-formylbenzoate (12.33 g), malonic acid (16 g) and piperidine (1 ml) in pyridine (100 ml) is refluxed for two hours. The reaction mixture is poured into ice-water, and the precipitated white powder is collected by filtration, and washed with water, and dried to give 4-methoxycarbonyl cinnamic acid (14.7 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)=[O:5].[C:33]([Mg]Br)#[CH:34]>C1COCC1.CCOCC>[CH3:31][C:7]1[C:6]([C:4](=[O:5])[C:33]#[CH:34])=[CH:30][N:9]2[C:8]=1[C:13]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=1)=[C:12]([C:28]#[N:29])[CH:11]=[N:10]2
Reactant: C#C[Mg]Br
Reactant: CON(C)C(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Temperature: 25 °C
Yield: 54.6 %

Procedure:
To a solution of amide from Example 417 (60 mg, 0.14 mmol) in THF (2 ml) at 0° C. was added ethynylmagnesium bromide (0.5 M in THF, 1.4 ml, 0.7 mmol). The reaction mixture was warmed to rt for 2 h, then heated at 50° C. for 2 h, and at rt overnight. Diluted with ether, washed with saturated NaHCO3, dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (30 mg, 32%) (5% MeOH—CHCl3). It has a retention time of 6.82 min (standard LCl method, 8 min run). LCMS Found: (M+H)+=393.2
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10](C(OCC)=O)[N:9]=2)=[CH:6][N:5]=[C:4]2[NH:18][CH:19]=[CH:20][C:3]=12.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[CH:10][N:9]=2)=[CH:6][N:5]=[C:4]2[NH:18][CH:19]=[CH:20][C:3]=12
Reactant: CCOC(=O)c1noc(-c2cnc3[nH]ccc3c2Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Clc1c(-c2ncno2)cnc2[nH]ccc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a solution of ethyl 5-(4-chloro-1H-pyrrolo[2,3-b]pyridine-5-yl)-1,2,4-oxadiazole-3-carboxylate (350 mg) in ethanol (3.5 ml) was added 1M aqueous sodium hydroxide (1.79 ml), and the reaction solution was stirred at 50° C. for 3 hours. The reaction solution was cooled to 4° C., and 1M hydrochloric acid was added to acidify the solution. The mixture was extracted with a mixture of chloroform and methanol (4:1) and washed with water. The organic layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain 4-chloro-5-(1,2,4-oxadiazole-5-yl)-1H-pyrrolo[2,3-b]pyridine (215 mg) as a white solid.
Reaction SMILES: [F:1][CH2:2][C:3]([N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])([CH2:6][CH2:7][CH2:8][CH2:9]OS(C)(=O)=O)[C:4]#[N:5].[I-:26].[Na+]>CC(C)=O.CCOCC>[F:1][CH2:2][C:3]([N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])([CH2:6][CH2:7][CH2:8][CH2:9][I:26])[C:4]#[N:5]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: N#CC(CF)(CCCCI)N1C(=O)c2ccccc2C1=O

Procedure:
2-Fluoromethyl-2-phthalimido-6-methanesulfonyloxyhexanenitrile (10.84 g, 29.5 mmol) and sodium iodide (8.8 g, 2 equivalents) are refluxed in acetone overnight. The reaction mixture is filtered and solvent is removed by evaporation. The residue obtained is dissolved in ether and washed with water, sodium bisulfite, and water grain. Upon concentration, 2-fluoromethyl-2-phthalimido-6-iodohexanenitrile crystallizes (9.0 g).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8](O)=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].CS([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=O)=O.O>CN(C=O)C>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH:2]=[O:1]
Reactant: CS(=O)(=O)CCc1ccccn1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1CCc1ccccn1
Temperature: 75 °C

Procedure:
Vanillin (2.5 mmol) is added to mixture of K2CO3 (12.5 mmol) and 2-(2-Methanesulfonyl-ethyl)-pyridine (1) (2.5 mmol) in DMF (0.2 M), and the resulting reaction mixture is heated to 75° C. for 16 h. After cooling to approximately room temperature, water is added and the aqueous mixture is extracted 5 times with methylene chloride. The methylene chloride layers are combined and concentrated to afford a residue, which is recrystallized in diethyl ether.
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])N1CCCC.Cl.[OH2:26]>>[OH:26][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[O:1]1
Reactant: CCCCN1C(=O)c2cccnc2C1(O)c1cccc([N+](=O)[O-])c1
Reactant: O
Agent: Cl
Product: O=C1OC(O)(c2cccc([N+](=O)[O-])c2)c2ncccc21

Procedure:
The 7-hydroxy-7-(3-nitrophenyl)-6-(n-butyl)-6,7-dihydropyrrolo[3,4-b]pyridin-5-one was mixed with 500 mL of water and 250 mL of concentrated hydrochloric acid was added. The mixture was heated under reflux for 20 hours. After cooling the mixture was diluted with 500 mL of water and the solid was removed by filtration. After washing the solid with water (500 mL) and methanol (200 mL) the material was dried to give 39.85 of 7-hydroxy-7-(3-nitrophenyl)-7H-furo[3,4-b]pyridin-5-one.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[Cl:30])[CH2:14][CH2:13]2)=[N:6][CH:5]=1.[OH-].[Na+]>CO>[Cl:30][C:21]1[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:20]=1[C:19]([NH:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=2)[CH2:13][CH2:14]1)=[O:31]
Reactant: COC(=O)c1ccc(NC[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(NC[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)nc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Trans-6-{[4-(2-Chloro-5-trifluoromethyl-benzoylamino)-cyclohexylmethyl]-amino}-nicotinic acid methyl ester (Example 19.15) (30 mg, 0.06 mmol) is placed in a vial with MeOH (2 mL). 1M NaOH (1 mL) is added and the reaction mixture is stirred at RT for 3 days. The reaction mixture is acidified and the resulting precipitate in the aqueous layer which was filtered and dried to afford the title compound. [MH+ 456.31], NMR: δH (400 MHz, DMSO); 12.29 (1H, s), 8.53 (1H, d), 8.48 (1H, d), 7.78 (4H, m) 7.35 (1H, m), 6.50 (1H, d), 3.71 (1H, m), 3.19 (2H, m), 1.96 (2H, m), 1.83 (2H, m), 1.52 (1H, m), 1.23 (2H, m), 1.08 (2H, m).
Reaction SMILES: [C:1]([O:4][C:5]1[C:24]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])=[C:23]([O:30][CH2:31][O:32][CH3:33])[CH:22]=[C:21]([O:34][CH2:35][O:36][CH3:37])[C:6]=1[C:7](=[O:20])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:4][C:5]1[C:24]([CH2:25][CH:26]=[C:27]([CH3:28])[CH3:29])=[C:23]([O:30][CH2:31][O:32][CH3:33])[CH:22]=[C:21]([O:34][CH2:35][O:36][CH3:37])[C:6]=1[C:7](=[O:20])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COCOc1ccc(C=CC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2OC(C)=O)cc1
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(CCC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 46.1 %

Procedure:
An ethanol solution (100 ml) of the 9.89 g of the 2'-acetoxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone obtained as the intermediate in Specific Example 18 was added into a suspension of 5.0 g of 5% palladium/carbon in 70 ml of ethanol, in which a hydrogen gas had been sufficiently absorbed in advance, and hydrogen was absorbed by stirring the mixture at 0° C. under atmospheric pressure in a hydrogen gas atmosphere for 1.5 hours with 430.55 ml of a hydrogen gas. After the reaction, the reaction mixture was filtered and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chromatography [280 g of [230-400 mesh silica gel; n-hexane/ethyl acetate (5/1); 0.3 kg/cm2 ]. Fractions of 100 ml were collected and the 30th to 52nd fractions to obtain 4.58 g (yield=46.1%) of 1-[2-acetoxy-4,6-bis(methoxymethoxy)-3-(3-methyl-2-butenyl)phenyl]-3-(4-methoxymethoxyphenyl)-1-propanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:11]([F:16])[F:15]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1ccc(Cl)cc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
To a solution of 2-bromo-4-chlorophenol (4.98 g, 24.0 mmol) in 25 mL DMF was added sodium chlorodifluoroacetate (8.42 g, 55.2 mmol), cesium carbonate (10.97 g, 33.67 mmol) and 2.5 mL water. The reaction was stirred at 100° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (0 to 20% ethyl acetate in heptanes) to yield 2.98 g (48%) of 2-bromo-4-chloro-1-(difluoromethoxy)benzene as a clear, colorless oil. LCMS (ESI) no m/z signal; 1H NMR (400 MHz, DMSO-d6) δ: 7.90 (d, 1H), 7.54 (dd, 1H), 7.38 (d, 1H), 7.28 (t, 1H).