Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11](SC)[C:12](=[O:18])[NH:13]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].O1CCCC1>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:18])[NH:13]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC1C(=O)Nc2cccc(C(=O)c3ccccc3)c21
Agent: [Ni]
Solvent: C1CCOC1
Product: O=C1Cc2c(cccc2C(=O)c2ccccc2)N1
Reaction time: 1.5 h

Procedure:
A stirred suspension of 7.0 g. (0.0248 mole) of 4-benzoyl-3-methylthioindolin-2-one in 400 ml. of tetrahydrofuran was treated portionwise under a nitrogen atmosphere with 35.0 g. of Raney nickel over a 2.5 hr. period. The reaction mixture was stirred for 1.5 hr. after addition was complete and the catalyst removed by filtration. The filter cake was washed well with tetrahydrofuran and methylene chloride and the filtrate evaporated under reduced pressure. The residue (5.6 g.) was recrystallized from methanol and gave 4.45 g. (76%) of product m.p. 210°-212° C.
Reaction SMILES: C(OC(C1C2C(=CC([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:18][CH:17]=3)=CC=2)C(C(OCC)=O)=CC=1)=O)C.[CH3:38][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([CH3:49])=[CH:41][C:40]=1Br>>[CH3:38][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([CH3:49])=[CH:41][C:40]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c2cc(-c3ccc(OCCC(C)CCCC(C)C)cc3)ccc12
Reactant: Cc1cc(Br)c(C)c2ccccc12
Product: Cc1cc(-c2ccc(OCCC(C)CCCC(C)C)cc2)c(C)c2ccccc12

Procedure:
1,4-dimethyl-2-(4-(3,7-dimethyloctyloxy)phenyl)naphthalene was prepared in accordance with the case of 6-(4-(3,7-dimethyloctyloxy)phenyl)naphthalene-1,4-dicarboxylic-acid diethyl ester described above, but using 1,4-dimethyl-2-bromonaphthalene, as a raw material, which was obtained by brominating 1,4-dimethylnaphtalene with Br2. 1,4-dimethyl-2-(4-(3,7-dimethyloctyloxy)phenyl)naphthalene was dissolved in carbon tetrachloride, and reacted to NBS to obtain 1,4-bis(bromomethyl)-2-{4-(3,7-dimethyloctyloxy)phenyl}naphthalene was obtained.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]1[N:11]([CH3:12])[N:10]=[N:9][N:8]=1)C.[ClH:16].[OH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:21][CH2:22][NH2:23].Cl.C>O.C(O)C>[ClH:16].[CH3:12][N:11]1[C:7]([NH:6][CH2:5][CH:4]2[C:24]3[C:20](=[CH:19][C:18]([OH:17])=[C:26]([OH:27])[CH:25]=3)[CH2:21][CH2:22][NH:23]2)=[N:8][N:9]=[N:10]1
Reactant: CCOC(CNc1nnnn1C)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1nnnc1NCC1NCCc2cc(O)c(O)cc21
Temperature: 60 °C

Procedure:
(1-methyl-1H-tetrazol-5-yl)aminoacetaldehyde diethyl acetal (21.5 g.) and 3,4-dihydroxyphenethylamine hydrochloride (14.6 g.) were added to a mixture of ethanol (130 ml.) and water (35 ml.), and dissolved with heating and stirring. Conc. hydrochloric acid (10.5 ml.) was added thereto and the mixture was refluxed for 8 hours. The reaction mixture was treated with activated charcoal. The charcoal was filtered and washed with ethanol, after which the filtrate and the washings were combined and concentrated under reduced pressure. The residual crystals were recrystallized from a mixture of water and isopropyl alcohol and the obtained crystals (22.5 g.) were warmed for 16 hours at 60° C under reduced pressure to remove excess hydrogen chloride. The crystals were recrystallized from a mixture of a small amount of water, methanol and ether to give 1-(1-methyl-1H-tetrazol-5-yl)aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride trihemihydrate (15 g.), mp 107° to 110° C. Infrared Absorption Spectrum (Nujol) 1604, 1460 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26]C)=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH3:25])[N:9]=2)[CH:7]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH3:25])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(C)cc1NC(=O)c1cnn2cccnc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (synthesized following the procedures described for Example 14) (193.9 mg, 0.5065 mmol) in 8.0 mL dichloromethane was added boron tribromide (1.50 mL of a 1.0M solution in dichloromethane, 1.5 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was then quenched with 1 mL methanol, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated to give 191.5 mg (100%) of N-(3-(5-chloro-2-hydroxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was carried forward without purification. LCMS (ESI) m+H=369.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[C:9]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8]1)=[O:6].[CH2:26]([C:30]1[CH:35]=[CH:34][C:33]([CH:36](Br)[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)[CH:27]([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH2:43]([C:40]1[CH:41]=[CH:42][C:37]([CH:36]([NH:1][C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=3)[C:9]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8]2)=[O:6])[C:33]2[CH:34]=[CH:35][C:30]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[CH:44]([CH3:46])[CH3:45]
Reactant: CC(C)Cc1ccc(C(Br)c2ccc(CC(C)C)cc2)cc1
Reactant: Nc1cccc(C(=O)n2cc(CCCC(=O)O)c3cc(Cl)ccc32)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)n3cc(CCCC(=O)O)c4cc(Cl)ccc43)c2)c2ccc(CC(C)C)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A mixture of 4-[1-(3-aminobenzoyl)-5-chloroindol-3-yl]butyric acid (700 mg), bis(4-isobutylphenyl)methyl bromide (705 mg) and diisopropylethylamine (620 mg) in dichloromethane (20 ml) was stirred at 20° C. for 1 hour, and then bis(4-isobutylphenyl)methyl bromide (150 mg) and diisopropylethylamine (70 mg) were added. After stirred at 20° C. for 3 hours, the reaction mixture was poured into iced 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (20 g) eluting with a mixture of hexane and ethyl acetate (10:1 to 1:1) to give 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-5-chloroindol-3-yl]butyric acid (803 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH:8]=O)[C:4](=O)[CH2:3]1.O.[NH2:13][NH2:14]>CO>[CH3:1][C:2]1([CH3:11])[CH2:3][C:4]2[NH:14][N:13]=[CH:8][C:5]=2[CH2:6][CH2:7]1
Reactant: CC1(C)CCC(C=O)C(=O)C1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC1(C)CCc2cn[nH]c2C1
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, to a suspension of sodium hydride (28 g, 697 mmol) in tetrahydrofuran (500 ml) was added dropwise a solution of 3,3-dimethylcyclohexanone (80 g, 634 mmol) in tetrahydrofuran (250 ml) under ice-cooling over about 1 hr, and the mixture was stirred for 1 hr. Then, a solution of ethyl formate (99 g, 1.3 mol) in tetrahydrofuran (250 ml) was added dropwise over about 1 hr, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated and extracted with 2 N aqueous sodium hydroxide solution. The aqueous layer was acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4,4-dimethyl-2-oxocyclohexanecarbaldehyde. To a solution of the obtained 4,4-dimethyl-2-oxocyclohexanecarbaldehyde in methanol (376 ml) was added dropwise a solution of hydrazine monohydrate (31 ml, 640 mmol) in methanol (31 ml) with heating under reflux over about 1 hr, and the mixture was stirred for 15 min. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added, and the organic layer was separated. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole. To a solution of the obtained 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole in N,N-dimethylformamide (1.4 L) were added iodine (232 g, 915 mmol) and potassium hydroxide (121 g, 1.8 mol) at room temperature, and the mixture was stirred for about 4 hr. Then, under ice-cooling, an aqueous solution (800 ml) of sodium hydrogensulfite (80 g) was added dropwise. Water (2 L) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Then, hexane (350 ml) was added to the residue, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, washed with hexane, and dried under reduced pressure to give 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (41 g, yield 23%).
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:24])[CH2:19][O:20]C(=O)C)[C:10]=1[C:11]#[N:12])=[O:7])(=O)C.N>CO>[OH:4][CH2:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:24])[CH2:19][OH:20])[C:10]=1[C:11]#[N:12])=[O:7]
Reactant: CC(=O)OCC(=O)Nc1cccc(NC(=O)COC(C)=O)c1C#N
Agent: N
Solvent: CO
Product: N#Cc1c(NC(=O)CO)cccc1NC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 2,6-bis(acetoxyacetylamino)benzonitrile (6.7 g) in methanol (700 ml) is added dropwise 28% aqueous ammonia (10 ml). The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethanol to give the title compound (3.8 g) having the following physical properties.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:22])[CH2:9][CH2:10][C:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:20]=O)[CH2:4][CH2:3]1.[CH2:23]([S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2)(=[O:27])=[O:26])[CH3:24]>>[CH2:23]([S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:20]\[C:12]1[NH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:11]=1[CH2:10][CH2:9][C:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:22])(=[O:26])=[O:27])[CH3:24]
Reactant: CN1CCN(C(=O)CCc2c(C=O)[nH]c3c2CCCC3)CC1
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCC(=O)N1CCN(C)CC1)CCCC3)C(=O)N2
Yield: 53 %

Procedure:
3-[3-(4-Methylpiperazin-1-yl)-3-oxo-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde, prepared as described in Example 4 above, was condensed with 5-ethylsulfonyloxindole (see Example 5) following the same procedure used in Example 1 to provide the desired product (80 mg, 53%).
Reaction SMILES: O[C:2]1([C:15]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16]=2[CH:24](O)[CH3:25])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[OH-].[Na+]>[CH2:24]([C:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[S:19][C:15]=1[C:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]=1)[CH3:25]
Reactant: CC(O)c1c(C2(O)CCN(C(=O)OC(C)(C)C)CC2)sc2ccccc12
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(C2=CCNCC2)sc2ccccc12
Temperature: 20 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
Scheme IA, Step B: 4-Hydroxy-4-(3-(1-hydroxyethyl)benzo[b]thiophen-2-yl)-1-(t-butyloxycarbonyl)piperidine (1.038 g, 2.75 mmol) was slowly added in portions to trifluoroacetic acid (6 mL). To this mixture was added triethylsilane (1.0 mL, 6.05 mmol) dropwise. The solution was stirred at 20° C. for 3 hours then diluted with 2 N sodium hydroxide and extracted 3 times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and evaporated. The residue was chromatographed (dichloromethane/20% methanol, 2% anhydrous ammonia in dichloromethane gradient eluent) to give the intermediate title compound as a yellow solid (0.484 g, 72%). FDMS m/e=244 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:1][C:2]2[N:7]=[CH:6][C:5]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)=[N:23][CH:24]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)nc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ccc(Cl)cn3)nc2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
tert-Butyl (RS)-2-(6-aminopyridin-3-yl)morpholine-4-carboxylate (55 mg), 2,5-dichloropyridine (29 mg, CAS 16110-09-1) and cesium carbonate (96 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (6.84 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (6.11 mg) were then added. The reaction mixture was then capped and stirred at 100° C. overnight. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 80% EtOAc in hexanes) to afford tert-butyl 2-(6-(5-chloropyridin-2-ylamino)pyridin-3-yl)morpholine-4-carboxylate (22 mg, 29%) as a yellow solid. MS (ISP): 393.2 ([{37Cl}M+H]+), 391.2 ([{35Cl}M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][C:10]([CH2:12]O)=[CH:11][C:4]=12>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][C:10]([CH3:12])=[CH:11][C:4]=12
Reactant: COc1ccnc2[nH]c(CO)cc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccnc2[nH]c(C)cc12

Procedure:
A suspension of (4-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol 4 (0.90 g, 5.05 mmol) and Pd(OH)2 (100 mg) in methanol containing 4N aq. HCl solution (10 mL) was hydrogenated under hydrogen pressure (50 psi) for 36 h. The acidic mixture was quenched with 1N NaOH solution. Filtration through celite, concentration and purification on silica gel column using 5% methanol in CH2Cl2 to gave 5 as pale yellow syrup. Yield: 0.68 g, 83%; ESI MS: m/z 163.01 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:12][CH2:11][C:5]2([O:9][C:8](=[O:10])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.OS(O)(=O)=O>C(O)CCC>[CH2:1]([O:9][C:8](=[O:10])[CH2:7][CH2:6][C:5]1[CH2:11][CH2:12][C:2]([CH3:13])([CH3:1])[CH2:3][CH:4]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)CCC2(CCC(=O)O2)CC1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)CCC1=CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 8,8-dimethyl-1-oxa-spiro[4.5]decan-2-one (40.2 g, 0.22 mol) was introduced into a 250 ml three necked round bottom flask together with butanol (23 g) and concentrated H2SO4 (0.5 g). Temperature was risen to 140° C. and during 8 hours fresh butanol (42.9 g) was introduced, while collecting a mixture of butanol/water. The reaction mixture was cooled to room temperature and toluene (66 g) and water (66 g) were added. The organic phase was washed with NaHCO3 and water to yield after concentration 51.42 g of the desired compound. Flash distillation (68°–70° C., 0.2 hPa) led to 35.0 g of butylester (overall yield: 47%; GC purity: 96.0%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:27])=[C:11]([CH:15](OC)[C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([CH3:27])=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(c1cccc(OCc2ccccc2)c1C)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1c(Cc2c[nH]c3ncccc23)cccc1OCc1ccccc1
Yield: 77.3 %

Procedure:
A mixture of 3-[(3-benzyloxy-2-methyl-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine (625, 24 mg, 0.067 mmol), trifluoroacetic acid (1 mL, 13 mmol), and triethylsilane (2 mL, 12.5 mmol) in acetonitrile (10 mL) was refluxed for 4 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After removal of solvent, the residue was washed with a mixture of ethyl ether and hexanes (1:1) to provide the compound as a yellow solid (P-1857, 17 mg, 75%). MS (ESI) [M+H+]+=329.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1.[NH3:21]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:10]=[C:11]([S:15]([NH2:21])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(C(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(=O)c2cccc(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
3-(4-Methoxy-benzoyl)-benzenesulfonyl chloride is dissolved in dichloromethane (10 ml) and treated with 1.7 mL of a 2 M solution of ammonia in methanol. The reaction is stirred at ambient temperature for 2 hours and quenched with 1N HCl. The organic phase is separated and evaporated under reduced pressure to give the crude sulfonamide. Purification by silica gel chromatography (gradient of ethyl acetate in hexanes 5-25%) yielded 100 mg (50% yield) of the title compound. 1H NMR (CDCl3, 300 MHz): 8.3 (t, 1H, J=1.6 Hz), 8.1 (m, 1H), 7.95 (m, 1H), 7.8 (d, 2H, J=6.98 Hz), 7.65 (t, 1H, J=7.8 Hz), 7.0 (d, 2H, J=6.98 Hz), 4.95 (s, 2H), 3.9 (s, 3H). MP: 119-122° C. LCMS Elution time 0.81 MS (m/z): 291 (M+1). CHN Calc C, 57.72; H, 4.50; N, 4.81 Found C, 57.65; H, 4.33; N, 4.69
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.[CH3:18][O:19][C:20]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:21]=1[CH2:22][N:23]=[C:24]=[O:25]>C(Cl)(Cl)Cl>[CH3:18][O:19][C:20]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:21]=1[CH2:22][NH:23][C:24]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:10])[CH:7]([CH3:9])[CH3:8])=[O:25]
Reactant: COc1ccc(CN=C=O)c(OC)c1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)NCc1ccc(OC)cc1OC)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a solution of L-valine methyl ester hydrochloride (2.6 g) and triethylamine (1.6 g) in chloroform (30 mL) was added 2,4-dimethoxybenzyl isocyanate (3.0 g), and the mixture was stirred at room temperature overnight. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford methyl N-[(2,4-dimethoxybenzyl)carbamoyl]-L-valinate (4.2 g).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[S:6](=[O:13])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[OH-].[NH4+:17]>>[NH2:17][C:2]1[CH:15]=[CH:14][C:5]2[S:6](=[O:13])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: O=S1c2ccccc2-c2cc(Br)ccc21
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ccc2c(c1)-c1ccccc1S2=O

Procedure:
A mixture of 150 g. of crude 2-bromodibenzothiophene-5-oxide, 160 g. of cuprous bromide and 1700 ml. of ammonium hydroxide is heated at 200° C. in a pressure reactor for about 12 hours. The mixture is then filtered, and the residue is washed with water, then heated in methanol and filtered hot. The product is recrystallized by cooling and separated by filtration to give 2-aminodibenzothiophene-5-oxide, m.p. 169°-172° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.22 g (4.0 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.36 ml (4.0 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.04 ml (0.4 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 1.44 g (quant, yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH2:20][CH2:21][OH:22])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:8](=[O:12])[N:9]([CH3:11])[N:10]=1.CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:19]=[C:18]([CH2:20][C:21]([OH:26])=[O:22])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:8](=[O:12])[N:9]([CH3:11])[N:10]=1
Reactant: CC(C)=O
Reactant: CC(C)c1cc(Oc2c(Cl)cc(CCO)cc2Cl)nn(C)c1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)c1cc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)nn(C)c1=O
Temperature: 11 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A solution of 6-[2,6-dichloro-4-(2-hydroxy-ethyl)-phenoxy]-4-isopropyl-2-methyl-pyridazin-3-one (36) (330 mg, 0.92 mmol) in acetone (5 mL) was treated with Jones Reagent (0.51 mL of a 2.7M solution) slowly dropwise at 10° C. The resulting red reaction mixture was stirred at 11° C. for 30 min. The reaction mixture was then concentrated under vacuum. The resulting residue was diluted with ethyl acetate (25 mL) and water (20 mL) and was treated with sodium bisulfite (100 mg). The resulting mixture was shaken and turned from red to green. The aqueous layer was separated and was re-extracted with ethyl acetate (25 mL). The organic layers were combined and washed with a saturated aqueous sodium chloride solution. The organic layer was separated, dried with sodium sulfate, filtered, and concentrated under vacuum. The resulting solid was recrystallized from ethyl acetate and dried under vacuum overnight to afford [3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-acetic acid (37) (70 mg, 19%) as a white solid; EI(+)-HRMS) m/z calcd for C16H16Cl2N2O4 (M+H)+ 371.0560, found 371.0561. Molecular Weight=371.2229; Exact Mass=370.0487