Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])N1C=CN=C1.[OH2:10]>ClCCl>[CH3:1][Si:2]([O:10][Si:2]([CH3:9])([CH3:8])[CH3:1])([CH3:9])[CH3:8]
Reactant: O
Reactant: C[Si](C)(C)n1ccnc1
Solvent: ClCCl
Product: C[Si](C)(C)O[Si](C)(C)C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
A solution of the alcohol 18 (200 mg) and N-(trimethylsilyl)imidazole (0.714 ml) in dichloromethane (13 ml) is stirred at room temperature for 16 hours. After water (4.9 ml) has been added, the mixture is left stirring for 20 minutes. The mixture is then extracted with ethyl acetate. The organic phases are washed with brine and dried. After concentration under vacuum, the residue is purified by chromatography on silica gel (230-400 mesh) (12% diethyl ether in hexane), to give 200 mg of derivative 15b (80% yield).
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B:31](OC(C)C)([O:36]C(C)C)[O:32]C(C)C>C(O)(=O)C>[C:12]([N:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[B:31]([OH:36])[OH:32])=[N:8][N:9]=[N:10]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: CC(=O)O
Product: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
A solution of 5-phenyl-1-trityl-1H-tetrazole (70.0 g, 180.20 mmol, 1.00 equiv) in THF(dried) (560 mL) was placed in a flask that had been purged and maintained with an inert atmosphere of nitrogen. The mixture was cooled to −25° C. Butyllithium was added to quench the trace of water in the reaction mixture until the color of the mixture remained red for at least 5 minutes. Butyllithium (80.0 mL, 2.5 mol/L) was then added dropwise to the mixture over a period of about 40 minutes at a temperature below −25° C. The temperature of the mixture was raised to −5° C., and the mixture was stirred at −5° C. for 3 hours. The mixture was then cooled to −25° C. and triisopropyl borate (50.8 g, 270.11 mmol, 1.50 equiv) was added dropwise. The mixture was warmed to temperature in the range of 25-35° C. and stirred for 2 hours. The mixture was cooled again in the range of 0-5° C., and 3% aqueous acetic acid (470 mL) was slowly added over 30-40 minutes. The mixture was stirred for 30-40 minutes and then filtered. The crude product was washed with water (2×300 mL) and dried over reduced pressure. The crude product was then purified by re-crystallization from EtOAc (1 g/15 ml) to yield 54 g (69%) of the title compound as a white solid. ES m/z: [M+H]+ calcd for C26H21BN4O2 433.1. found 433.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].C[O:13][C:14]([C:16]1[C:20]([NH2:21])=[CH:19][NH:18][N:17]=1)=[O:15].C(OC(C1C(N)=CNN=1)=O)C.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:21][C:20]1[C:16]([C:14]([OH:15])=[O:13])=[N:17][NH:18][CH:19]=1)=[O:5]
Reactant: COC(=O)c1n[nH]cc1N
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: CCOC(=O)c1n[nH]cc1N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(O)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2,6-dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (prepared in a manner analogous to 165B) (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxan (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50° C. for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid as a pale violet solid.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])C>ClC1C=CC=CC=1>[Br:13][C:8]1[C:7]2[S:6][CH:5]=[CH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(CSc1ccccc1Br)OCC
Solvent: Clc1ccccc1
Product: Brc1cccc2ccsc12
Yield: 93.2 %

Procedure:
Chlorobenzene (100 mL) and polyphosphoric acid (30.4 g, PPA) were combined and heated to reflux. The 2-(2-bromophenylthio)acetaldehyde diethyl acetal (13.7 g, 44.88 mmol, Scheme I, step A above) dissolved in chlorobenzene (20 mL) was added dropwise to the refluxing mixture over 20 minutes. The reaction was refluxed for 4 hours and then cooled. The solvent was decanted from the residue and toluene (2×50 mL) was added to the residue, stirred and decanted. The toluene extracts were concentrated under vacuum and the residue taken up in ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to provide 7-bromobenzo(b)thiophene (8.91 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]CC)=[O:13])[NH:6]2.[OH-].[K+].[CH2:19](O)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH3:19])=[C:5]([C:12]([OH:14])=[O:13])[NH:6]2
Reactant: CCOC(=O)c1cc2c(Cl)ccc(C)c2[nH]1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Cl)c2c(C)c(C(=O)O)[nH]c12
Yield: 68 %

Procedure:
In 20 ml of ethanol and 5 ml of water were dissolved 1.50 g (6.0 mmol) of ethyl 4-chloro-7-methylindole-2-carboxylate and 0.5 g (9.0 mmol) of potassium hydroxide. The reaction mixture was refluxed for 4 hours. The solution was concentrated and then 1N HCl aqueous solution was added. The precipitates were separated by filtration, dissolved in 50 ml of diethyl ether and extracted with 30 ml of aqueous sodium hydrogencarbonate solution three times. The extract was washed with 30 ml of diethyl ether. The water layers were made acid with 1N HCl aqueous solution and extracted with 30 ml of diethyl ether three times. The extract was dried over anhydrous magnesium sulfate and concentrated to provide 0.91 g of beige crystals. Yield: 68%
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Br[CH2:34][CH2:35][CH2:36][OH:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:34][CH2:35][CH2:36][OH:37])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCO)C[C@H]1Cc1c[nH]c2ccccc12
Reaction time: 9 h
Yield: 77.3 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (5 g) and 3-bromopropanol (1.68 g) in N,N-dimethylformamide (40 ml) was heated at 60° C. in the presence of potassium carbonate (4.55 g). After 9 hours, the reaction mixture was poured into water (400 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel using dichloromethanemethanol (30:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(1H-indol-3-ylmethyl)piperazine (4.36 g) as a powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[N:3]=1.[CH:34]1[C:39]([OH:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41].[Al+3].[Cl-].[Cl-].[Cl-].N1C=CC=NN=1>ClC1C=CC=CC=1>[OH:40][C:39]1[CH:34]=[C:35]([CH3:41])[CH:36]=[CH:37][C:38]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[N:3]=1
Reactant: Cc1cccc(O)c1
Reactant: Clc1nc(-c2ccc(Oc3ccccc3)cc2)nc(-c2ccc(Oc3ccccc3)cc2)n1
Agent: [Al+3]
Agent: [Cl-]
Agent: c1cnnnc1
Solvent: Clc1ccccc1
Product: Cc1ccc(-c2nc(-c3ccc(Oc4ccccc4)cc3)nc(-c3ccc(Oc4ccccc4)cc3)n2)c(O)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 0.9 gm of 2-chloro-4,6-bis(4-phenoxyphenyl)-1,3,5-triazine, 0.24 gm of m-cresol and 0.4 gm AlCl3 in 5 ml chlorobenzene was heated to 70° C. under nitrogen and efficient stirring. After about 4 hr at 70° C., the reaction mixture was analyzed by HPLC, which showed the formation of a new product, and almost disappearance of the starting triazine. The reaction mixture was cooled to room temperature and quenched with water. It was then extracted with methylene chloride, and the organic layer separated, washed with water, dried, and concentrated to give a crude product. The crude product was crystallized from acetone to give almost pure 2-(2-hydroxy-4-methylphenyl)-4,6-bis(4-phenoxyphenyl)-1,3,5-triazine identified by HPLC, NMR and mass spectroscopy.
Reaction SMILES: [C:1]([N:9]([CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[C:1]([N:9]([CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:26]2[S:22][C:23](=[O:28])[NH:24][C:25]2=[O:27])=[CH:16][CH:15]=1)[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: CN(CCOc1ccc(C=O)cc1)C(=O)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)C(=O)c1ccccc1

Procedure:
A mixture of 4-[2-(N-benzoyl-N-methylamino)ethoxy]benzaldehyde (3.94 g), 2,4-thiazolidinedione (1.79 g), benzoic acid (0.2 g) and piperidine (0.2 ml) were heated at reflux in toluene (250 ml) in a Dean and Stark apparatus. After 5 hours at reflux the mixture was allowed to cool and crystallise overnight. The title compound, mp 178-180° C., was filtered off, washed with cold toluene and dried under vacuum.
Reaction SMILES: Cl.CO[C:4](=[NH:9])[CH2:5][CH:6]1[CH2:8][CH2:7]1.[CH3:10][C:11]1([CH3:19])[O:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[O:12]1.C(N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[NH2:9][C:4](=[C:14]1[C:15](=[O:17])[O:16][C:11]([CH3:19])([CH3:10])[O:12][C:13]1=[O:18])[CH2:5][CH:6]1[CH2:7][CH2:8]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(=N)CC1CC1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)C(=C(N)CC2CC2)C(=O)O1
Yield: 8.6 %

Procedure:
1 g (7 mmol) 2-Cyclopropyl-acetimidic acid methyl ester hydrochloride, 963 mg (7 mmol) 2,2-dimethyl-[1,3]dioxane-4,6-dione and 1.07 ml (8 mmol) triethylamine were heated under reflux in 7 ml chloroform for 14 h. The mixture was diluted with dichloromethane, washed neutral with brine/ice water 1/1 and the organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 128 mg (0.6 mmol, 9%) of the title compound as yellow crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[I:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.C(N(CC)CC)C.[CH2:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26]>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([N:27]([CH2:25][CH3:26])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:12])=[C:8]([I:7])[CH:16]=1
Reactant: CCNc1ccccc1
Reactant: O=C(O)c1ccc(Cl)cc1I
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(C(=O)c1ccc(Cl)cc1I)c1ccccc1
Temperature: 23 °C

Procedure:
Oxalyl chloride (2.3 ml, 3.4 g, 26.6 mmol) was added dropwise to a solution of 2-iodo-4-Chlorobenzoic acid (5 g, 17.7 mmol) in dichloromethane (35 ml). N,N-Dimethylformamide (0.01 ml) was added to the reaction mixture via syringe and the reaction mixture was stirred at 23° C. for an hour. The reaction mixture was concentrated in vacuo. The residue was taken up in dichloromethane (50 ml) followed by the addition of DMAP (10 mg) and triethylamine (3.73 ml, 2.7 g, 26.6 mmol). The mixture was cooled to 0° C. and N-ethylaniline (2.6 ml, 2.6 g, 21.2 mmol) was added. The reaction mixture was warmed to 23° C. After an hour at this temperature, the reaction mixture was diluted with 1:1 ethyl acetate/hexanes (150 ml) and washed with 1N HCl (2 50-ml portions) and saturated aqueous sodium chloride (50 ml). The organics were dried over anhydrous sodium sulfate and concentrated. Purification of the residue by flash column chromatography (25% ethyl acetate in hexanes) afforded 4-chloro-N-ethyl-2-iodo-N-phenyl-benzamide I-14a (6.0 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:16][N:17]1[CH2:22][C:21]([CH3:24])([CH3:23])[O:20][CH2:19][CH:18]1[C:25](O)=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:25]([CH:18]3[CH2:19][O:20][C:21]([CH3:23])([CH3:24])[CH2:22][N:17]3[CH3:16])=[O:26])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN1CC(C)(C)OCC1C(=O)O
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Product: CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 61 %

Procedure:
The desired compound was prepared according to Method B from 6-chloro-9H-β-carboline-8-ylamine and 4,6,6-trimethyl-morpholine-3-carboxylic acid in 61% yield.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[C:8]2[S:9][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[C:8]2[S:9][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc(-c3ccccc3)cc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)sc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A mixture of 2-[chloro(cyclohexyl)methyl]-3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene (0.9 g) obtained by the above-mentioned reaction, methyl 4-aminobenzoate (0.9 g), sodium carbonate (0.6 g) and sodium iodide (1.8 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 100° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give methyl 4-{[cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methyl]amino}benzoate as an amorphous compound. The obtained methyl 4-{[cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methyl]amino}benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (2 mL) was added, and the mixture was stirred at 70° C. overnight. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.2 g, 20%) as an amorphous compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:43])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:28]C2CCCCO2)[CH:21]([CH3:27])[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C@H:16]([O:35]C2CCCCO2)[CH2:15][C@H:14]1[Cl:42])(=[O:4])=[O:3]>C(O)(=O)C.O.O1CCCC1>[CH3:1][S:2]([NH:5][C:6](=[O:43])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([OH:28])[CH:21]([CH3:27])[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C@H:16]([OH:35])[CH2:15][C@H:14]1[Cl:42])(=[O:3])=[O:4]
Reactant: CC(C)=CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](CCCCCCC(=O)NS(C)(=O)=O)[C@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)=CCC(C)[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)NS(C)(=O)=O)[C@H](Cl)C[C@H]1O
Yield: 45 %

Procedure:
103 mg of (13E)-(8R,9R,11R,12R,15S,16RS)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-13,18-prostadienoic acid methylsulfonylamide was stirred for 24.5 hours under argon at room temperature with 1.9 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). Then the mixture was concentrated under vacuum and the residue purified by column chromatography on silica gel with hexane/0-100% ethyl acetate as the eluent, thus obtaining 34.3 mg of the title compound.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16](O)[C:17]3[CH:18]=[C:19]([Br:24])[CH:20]=[N:21][C:22]=3[CH:23]=2)=[CH:10][CH:9]=1>>[Cl:3][C:16]1[N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([Br:24])[CH:20]=[N:21]2
Reactant: COc1ccc(-c2cc3ncc(Br)cc3c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3ncc(Br)cc3c(Cl)n2)cc1
Temperature: 100 °C
Yield: 94 %

Procedure:
POCl3 (3 mL) was added to 7-(4-methoxyphenyl)-3-bromo-[1,6]naphthyridin-5-ol (Example 22) (115 mg, 0.4 mmol). The mixture was heated at 100° C. for 3 hours. The excess POCl3 was concentrated under reduced pressure. The residue was diluted with CH2Cl2, washed with sat. NaHCO3, dried over Na2SO4, and concentrated giving 5-chloro-7-(4-methoxyphenyl)-3-bromo-[1,6]naphthyridine (115 mg, 94%) as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].Cl[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12]>[OH-].[Na+]>[CH2:14]([O:13][C:11]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:12])[CH:15]=[CH2:16]
Reactant: C=CCOC(=O)Cl
Reactant: CSCC[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)N[C@H](CCSC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 15.00 g D-methionine in 25.2 ml 4N sodium hydroxide cooled to about 0° C. is added, with stirring, 15.60 ml allyl chloroformate and 41.49 ml 4N sodium hydroxide. After the addition is completed, the reaction is stirred for an additional ten minutes at 0° C. and then allowed to warm to room temperature for an additional 20 minutes. The reaction mixture is then washed twice with ethyl ether. The aqueous layers are separated, acidified to pH2 with concentrated hydrochloric acid and then refrigerated for one hour. The cooled solution is then extracted three times with 100 ml portions of ethyl ether. The ether extracts are combined, dried over anhydrous sodium sulfate and the solvents removed under vacuum to afford the title product having
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][N:17]=2)[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=1.[Br-].[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([Zn+])=[N:30][CH:31]=1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([C:2]2[C:3]3[N:4]([C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][N:17]=3)[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=2)=[N:30][CH:31]=1
Reactant: Cc1ccc([Zn+])nc1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c2nnc(-c3ccccc3)n2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cn3c(-c4ccccc4)nnc23)nc1
Temperature: 75 °C
Yield: 26.6 %

Procedure:
To a degassed solution of tert-butyl 8-chloro-3-phenyl[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (0.22 g, 0.67 mmol) and bis(tri-tert-butylphosphine)palladium(0) (17.1 mg, 33 μmol) in dioxane (2 mL) was added 5-methyl-2-pyridylzinc bromide (0.5 M in THF; 4.0 mL, 2.0 mmol). The mixture was heated 75° C. After 181, the mixture was cooled to ambient temperature and concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (69 mg): LC-MS [M+1]=387.1.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:21]#[N:22])[CH:14]=[C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][C:16]=12.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:17]1[C:16]2=[C:11]([N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[N:12]=[C:13]([C:21]#[N:22])[CH:14]=[C:15]2[CH:19]=[C:18]1[CH3:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc2cc(C#N)nc(N3CCc4ccccc4C3)c2[nH]1
Reactant: BrCc1ccccc1
Product: Cc1cc2cc(C#N)nc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Yield: 87 %

Procedure:
In accordance with the same procedures as in Example 657, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 2 of Example 917 and benzyl bromide, the titled compound was obtained as a white solid. (Yield: 87%)
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[N:15]1([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28]([CH:33]=O)=[CH:27]3)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.N1CCCCC1>C(O)C>[N:15]1([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28]([CH:33]=[C:10]2[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:8]=4)[NH:3][C:2]2=[O:1])=[CH:27]3)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCOCC4)ccc3[nH]1)C(=O)N2
Temperature: 90 °C
Yield: 73.7 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide (27 mg, 0.12 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (30 mg, 0.11 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 90° C. for 2 hours. The reaction was cooled at 0° C. for overnight. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 38 mg (62%) of the title compound as an orange solid.
Reaction SMILES: N1([C:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)CCCC1.[S:16](Cl)(=[O:19])(=[O:18])[NH2:17].C(N(CC)CC)C.[O:28]1CCCC1>>[O:28]=[C:15]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[S:16]([NH2:17])(=[O:19])=[O:18]
Reactant: C1CCOC1
Reactant: C1=C(N2CCCC2)CCc2ccccc21
Reactant: NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)C1Cc2ccccc2CC1=O
Reaction time: 24 h
Yield: 74.6 %

Procedure:
A solution of 19.9 g (0.1 mol) of 2-pyrrolidino-3,4-dihydronaphthalene in 200 ml of tetrahydrofuran was treated, over a period of 1 hour, at -30° C., with a solution of 17.3 g (0.15 mol) of sulfamoyl chloride in 50 ml of tetrahydrofuran and then, at the same temperature, with a solution of 15.2 g (0.15 mol) of triethylamine in 50 ml of tetrahydrofuran, the mixture was brought to 20° C. within 3 hours and filtered, the filtrate was freed of solvent in vacuo and the residue was stirred with 200 ml of 2N HCl and 40 ml of CH2Cl2 for 24 hours. The solid obtained was recrystallized from isopropanol to give 16.9 g (74.6%) of a product of melting point 145°-146° C.