Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=3)[CH2:5]1.Br[C:47]1[NH:51][C:50]([C@@H:52]2[CH2:56][C@H:55]([CH3:57])[CH2:54][N:53]2[C:58](=[O:68])[C@@H:59]([NH:63][C:64](=[O:67])[O:65][CH3:66])[CH:60]([CH3:62])[CH3:61])=[N:49][CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:66][O:65][C:64]([NH:63][C@H:59]([C:58]([N:53]1[CH2:54][C@@H:55]([CH3:57])[CH2:56][C@H:52]1[C:50]1[NH:51][C:47]([C:32]2[CH:33]=[C:34]3[CH2:35][O:36][C:23]4[CH:22]=[C:21]5[C:26]([CH:27]=[CH:28][C:18]6[NH:17][C:16]([C@@H:6]7[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][N:7]7[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[N:20][C:19]=65)=[CH:25][C:24]=4[C:29]3=[CH:30][CH:31]=2)=[CH:48][N:49]=1)=[O:68])[CH:60]([CH3:62])[CH3:61])=[O:67]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(Br)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2nc3c(ccc4cc5c(cc43)OCc3cc(-c4cnc([C@@H]6C[C@H](C)CN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]4)ccc3-5)[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Yield: 31.9 %

Procedure:
To a solution of (2S,4S)-tert-butyl 4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (438 mg, 0.72 mmol), methyl (S)-1-((2S,4S)-2-(5-bromo-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (276 mg, 0.72 mmol), tetrakis(triphenylphosphine) palladium(0) (41 mg, 0.04 mmol) and dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II) (52 mg, 0.07 mmol) in a mixture of 1,2-dimethoxyethane (8.6 mL) and dimethylformamide (1.5 mL) was added a solution of potassium carbonate (2M in water, 1.07 mL, 2.15 mmol). The resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield tert-butyl (2S,4S)-2-[9-(2-{(2S4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (182 mg, 32%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]3[CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:29][CH2:30][CH3:31])=[C:6]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:5]=1[OH:38])=[O:3].S(OC)(O[CH3:43])(=O)=O.[OH-].[K+]>C1COCC1>[NH2:1][C:2]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]3[CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:29][CH2:30][CH3:31])=[C:6]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:5]=1[O:38][CH3:43])=[O:3]
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)ccc2c1OC(CCC(=O)OC)CC2
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)ccc2c1OC(CCC(=O)OC)CC2

Procedure:
The compound of Example 73 is treated with dimethyl sulfate and KOH in THF under the conditions described in Example 61. Chromatographic purification of the crude product on silica gel using ethyl acetate/hexane (4:6) as eluant affords the product.
Reaction SMILES: [C:1]([N:8]([CH3:14])[CH2:9][CH:10]([OH:13])CO)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>O>[C:1]([N:8]([CH3:14])[CH2:9][CH:10]=[O:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN(CC(O)CO)C(=O)OC(C)(C)C
Solvent: O
Product: CN(CC=O)C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 78.9 %

Procedure:
To a solution of N-Boc-N-methyl-1-amino-2,3-propandiol (20g, 0.097 mol) in water (100 ml) was added KIO4 (24.68g, 0.108 mol). The reaction mixture was stirred for 2.5 hr under an atmosphere of nitrogen and then filtered. The filtrate was extracted with chloroform (5×50 ml). The resulting chloroform extracts are dried over MgSO4, filtered, and evaporated to dryness. The title compound 13.26g (79%) was isolated as a clear oil (bp 76-80° C. at 0.5 mm Hg).
Reaction SMILES: [CH3:1][N:2]1[C:6](Cl)=[N:5][N:4]=[N:3]1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([CH2:16][CH2:17][CH2:18][SH:19])=[O:15].[OH-].[Na+]>CO>[CH3:1][N:2]1[C:6]([S:19][CH2:18][CH2:17][CH2:16][C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=2)=[O:15])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1Cl
Reactant: O=C(CCCS)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nnnc1SCCCC(=O)c1ccccn1
Yield: 7.6 %

Procedure:
1-Methyl-5-chloro-1,2,3,4-tetrazole (1.4 g) and 3-mercaptopropyl 2-pyridyl ketone (1.8 g) is dissolved in methanol (100 ml). Sodium hydroxide (0.6 g) is added to the solution and the mixture is refluxed for 3 hours. Methanol is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with dil. aqueous sodium hydroxide, water and saturated aqueous sodium chloride and dried over sodium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Wakogel C-200, eluant: chloroform) and the product is recrystallized from hexane-ether to obtain 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole (0.2 g) as colorless needles, m.p. 73°-75° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.BrCCCC[C:22]1[CH:32]=[CH:31][CH:30]=[C:24]2[C:25]([NH:27][C:28](=[O:29])[C:23]=12)=[O:26]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:16][CH2:2][CH2:3][CH2:4][N:27]4[C:28](=[O:29])[C:23]5=[CH:22][CH:32]=[CH:31][CH:30]=[C:24]5[C:25]4=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 47.1 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.5 g, 25 inmol), 4-bromobutylphthalimide (8.0 gi 28.3 mmol, 1.13 eq), K2 CO3 (4.55 g, 32 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of the reaction, the mixture was filtered. The insolubles were washed with dichloromethane (200 ml). The organic solution was concentrated gradually to allow cystallization. The crude crystals (5.9 g) were collected. The mother liquor was concentrated to a solid (5.5 g). Purification was by flash chromatography over a silica gel column. The product (3.8 g) thus purified was recrystallized from ethanol (70 ml) to give 2.48 g of N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimide as white crystals, m.p.=144°-146° C.
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[N:9]1([C:5]2[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: O=C1NOCC(=S)N1
Product: O=C1N=C(N2CCOCC2)CON1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
To a solution of 0.5 g (0.0037 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione dissolved in 10 ml of dry freshly distilled dioxane is added 0.34 g (0.0039 mole) of morpholine. After stirring at room temperature for 17 hours, the solution is filtered, washed with chloroform and dried to give a yield of 0.5 g (74 percent) of 5-(4-morpholinyl)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[OH-].[Na+]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1CCC(NCc2ccc(Cl)cc2)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1CCC(NCc2ccc(Cl)cc2)CC1
Temperature: 50 °C

Procedure:
23.9 g (0.1 Mol) of 4-[N-(4-chlorobenzyl)-amino]-cyclohexanol are suspended in 125 ml of ice water and 32 ml of concentrated sulphuric acid are added. Then 29.4 g (0.1 Mol) of potassium dichromate are added in 2 batches and the mixture is heated for 5 hours at 50° C. It is then cooled, made alkaline with sodium hydroxide solution and extracted with chloroform. After concentration, a yellowish oily liquid is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.Br[CH:25]([C:27]1[CH:28]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:31][CH:32]=1)[CH3:26].C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:23][CH:25]([C:27]2[CH:28]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:31][CH:32]=2)[CH3:26])[C:5]([C:21]#[N:22])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: COC(=O)c1cccc(C(C)Br)c1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SC(C)c3cccc(C(=O)OC)c3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg (0.919 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulfanylpyridine-3,5-dicarbonitrile (Example 15A), 245 mg (1.01 mmol) of methyl 3-(1-bromoethyl)benzenecarboxylate (Example 61A) and 231 mg (2.76 mmol) of sodium bicarbonate were dissolved in 3 ml of DMF and the mixture was stirred at RT overnight. Water was added to the reaction mixture until a clear solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[NH2:62][CH2:63][C:64]([CH3:67])([OH:66])[CH3:65]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:62][CH2:63][C:64]([OH:66])([CH3:67])[CH3:65])=[O:19])[CH:8]=1)=[O:5]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)CNC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
5-(2,4-dichloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 107, 78 g, 166 mmol) was sonicated in DMF (300 mL) with N,N-diisopropylethylamine (58 mL, 332 mmol) to give a clear solution, which was cooled to 10° C. TPTU (74 g, 249 mmol) was added portionwise and the mixture stirred at 10° C. for 20 minutes. A solution of 1-amino-2-methylpropan-2-ol (22.1 g, 249 mmol) in DMF (50 mL) was added dropwise at 10° C. and the mixture then allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was partitioned between EtOAc (600 mL) and water (600 mL). The aqueous layer was separated and extracted with additional EtOAc (3×200 mL). The combined organic layers were washed with saturated aqueous ammonium chloride solution (300 mL), water (5×200 mL), dried (magnesium sulphate) and concentrated in vacuo to give an orange oil. The oil was treated with acetonitrile (300 mL) and the resulting solid collected by filtration, washed with acetonitrile and dried under vacuum to afford the title compound as a colourless solid (60 g, 66%).
Reaction SMILES: [F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:28])=[C:11]([F:29])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[CH3:30][CH:31](O)[CH3:32]>S(=O)(=O)(O)O>[F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:28])=[C:11]([F:29])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][CH:31]([CH3:32])[CH3:30])=[O:7]
Reactant: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
2-[2,4-Difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetic acid (I(b)) (70 mg, 0.17 mmol, 1.0 eq) was dissolved in iPrOH (5 mL). Concentrated sulphuric acid (2 drops) was added and the solution was stirred at room temperature overnight. The reaction was quenched by addition of aqueous NaHCO3 and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give the crude product. The compound was triturated in a mixture of petroleum ether and DCM and dried under vacuum to give the title compound (II(d)) as a gummy solid (52 mg, 68%).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([OH:26])[C@H:5]([S:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[NH2:25])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C(O)C.[OH-].[Na+]>O>[NH2:25][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[S:14][C@H:5]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[C@H:4]([OH:26])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)[C@@H](O)[C@H](Sc1ccc2ccccc2c1N)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc([C@@H](Sc2ccc3ccccc3c2N)[C@H](O)C(=O)O)cc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A mixture of 6.6 g (0.017 mol) of (±)-(R*,R*)-β-[(1-amino-2-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid methyl ester, 45 ml ethanol and 100 ml 1N sodium hydroxide was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and extracted with ether. The aqueous solution was chilled, then neutralized with acetic acid and extracted with ethyl acetate (3×60 ml). The combined extracts were washed with water (50 ml) and dried (MgSO4). Removal of the solvent gave 5.5 g of crude (±)-(R*,R*)-β-[(1-amino-2-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid which was dissolved in methylene chloride and chromatographed on a column using 55 g of silica gel. The column was eluted with 50 ml portions of methylene chloride. Fractions 12-17 were collected, and the solvent was removed under reduced pressure to afford 1.3 g (20%) of (±)-(R*,R*)-β-[(1-amino-2-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid. The analyzed sample was recrystallized from ether, mp 160°-161°.
Reaction SMILES: [C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([NH:32]C(OC(C)(C)C)=O)[CH:28]=4)=[CH:23][CH:22]=3)[C:10](=[O:40])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CO>[C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([NH2:32])[CH:28]=4)=[CH:23][CH:22]=3)[C:10](=[O:40])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2cc(NC(=O)OC(C)(C)C)no2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2cc(N)no2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 6.4 %

Procedure:
To a mixture of 3-t-butyl-5-[4-(3-t-butoxy carbonylamino-5-isoxazolyl)-phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.036 g, 0.7 mmol) and methanol (2 mL), conc. hydrochloric acid (0.07 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The precipitate was collected by filtration and recrystallized (methanol/dichloromethane) to give 3-t-butyl-5-[4-(3-amino-5-isoxazolyl)phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.02 g, 68%) as pale yellow crystals.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH3:10].[CH:12]1(C#C)[CH2:14][CH2:13]1>O1CCOCC1.CN(C)C(N(C)C)=N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:12]1([C:9]2[NH:8][C:3]3[C:4]([CH:10]=2)=[CH:5][CH:6]=[CH:7][CH:2]=3)[CH2:14][CH2:13]1
Reactant: CC(=O)Nc1ccccc1I
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: C1COCCO1
Product: c1ccc2[nH]c(C3CC3)cc2c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-iodophenyl)acetamide (100 mg, 0.38 mmol) in dioxane (750 mL) and 1,1,3,3-tetramethylguanidine (750 mL) was added cyclopropylacetylene (41 mL, 0.49 mmol), bis(triphenylphosphine)palladium(II) chloride (35 mg, 0.05 mmol), and copper(I) iodide (10 mg, 0.05 mmol). The reaction was stirred overnight at 80° C. The solution was cooled and partitioned between water and methylene chloride. The organic layer was dried (MgSO4) and concentrated to give the uncyclized Sonagashira coupling product. Dioxane (750 mL) and 1,1,3,3-tetramethylguanidine (750 mL) were added and the reaction was stirred overnight at 90° C. The solution was again partitioned between water and methylene chloride. The organic layer was dried (MgSO4) and concentrated to give the desired indole, which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:22])=[CH:6][C:7]([CH3:21])([CH3:20])[NH:8]2.C(N(CC)CC)C.[F:30][C:31]([F:37])([F:36])[S:32](Cl)(=[O:34])=[O:33]>ClCCl.C(Cl)(Cl)Cl>[OH:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][S:32]([C:31]([F:37])([F:36])[F:30])(=[O:34])=[O:33])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:22])=[CH:6][C:7]([CH3:21])([CH3:20])[NH:8]2
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC1=CC(C)(C)Nc2ccc(-c3ccccc3O)c(CO)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1=CC(C)(C)Nc2ccc(-c3ccccc3OS(=O)(=O)C(F)(F)F)c(CO)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
5-Hydroxymethyl-6-(2-hydroxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 293 mg, 0.992 mmol) was dissolved in anhydrous dichloromethane (5 mL) and then triethylamine (167 μL, 1.20 mmol) and trifluoromethanesulfonyl chloride (106 μL, 0.996 mmol) were added thereto at 0° C. After the reaction mixture was stirred at 0° C. for 1 hour, it was diluted with chloroform (20 mL). The whole was washed with saturated aqueous NaHCO3 solution (20 mL) and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (177 mg) as an orange solid. (Yield 42%)
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]2[CH:13]=[C:14]([Cl:19])[C:15]([Cl:18])=[C:16]([Cl:17])[C:4]=2[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[N:33][NH:34][CH:35]=1)=[O:30])[CH3:27].CN(C=O)C>CCOC(C)=O>[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[N:33][N:34]([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]3[CH:13]=[C:14]([Cl:19])[C:15]([Cl:18])=[C:16]([Cl:17])[C:4]=3[N:3]=2)[CH:35]=1)=[O:30])[CH3:27]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: COCCOCn1c(Cl)nc2c(Cl)c(Cl)c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3c(Cl)c(Cl)c(Cl)cc3n2COCCOC)c1
Temperature: 80 °C

Procedure:
A mixture of 2,4,5,6-tetrachloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole (0.275 g, 0.80 mmol), Cs2CO3 (0.524 g, 1.61 mmol), 1H-pyrazole-4-carboxylic acid ethyl ester (0.124 g, 0.89 mmol), and DMF (4 mL) was heated to 80° C. for 2 h. The mixture was cooled to 23° C. EtOAc was added and the mixture was washed with brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified (FCC) to yield the titled compound as a mixture of regioisomers (0.166 g, 46%). MS (ESI/CI): mass calcd. for C17H17Cl3N4O4, 446.0; m/z found, 447.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.01-8.97 (m, 2H), 8.40 (t, J=2.3 Hz, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 6.09 (s, 2H), 6.01 (s, 2H), 4.30 (qd, J=7.1 Hz, 2.9, 8H), 3.58-3.51 (m, 2H), 3.44 (d, J=4.9 Hz, 2H), 3.11 (s, 3H), 3.08 (s, 3H), 1.32 (tt, J=7.1 Hz, 1.7 Hz, 6H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][C:4]=2[N:3]=[C:2]1[SH:13])[CH2:10][CH2:9][CH2:8]3.[OH-].[Na+].Cl.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24]Cl)=[N:22][CH:23]=1>O>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][S:13][C:2]2[NH:3][C:4]3[CH:12]=[C:11]4[C:7](=[CH:6][C:5]=3[N:1]=2)[CH2:8][CH2:9][CH2:10]4)=[N:22][CH:23]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: Sc1nc2cc3c(cc2[nH]1)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CSc2nc3cc4c(cc3[nH]2)CCC4)nc1
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To 13.5 g of 1,5,6,7-tetrahydroindeno(5,6-d)imidazole-2-thiol, suspended in 200 ml of alcohol, were added dropwise while stirring 5.9 g of sodium hydroxide in 100 ml of water and, after 30 minutes, 13.0 g of 5-methyl-2-chloromethyl-pyridine hydrochloride were added. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in methylene chloride. This was washed neutral and, after drying over sodium sulfate, evaporated in vacuo. The residue, recrystallized from acetonitrile, gave 11.9 g (56.9% of theory) of 1,5,6,7-tetrahydro-2-[[(5-methyl-2-pyridyl)methyl]thio]indeno(5,6-d)imidazole of melting point 157°-158° C.
Reaction SMILES: OC(C)(C)[C:3]#[C:4][C:5]1[CH:6]=[N:7][C:8]([C:15]2[NH:16][C:17](=[O:24])[C:18]([CH:21]([CH3:23])[CH3:22])([CH3:20])[N:19]=2)=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11].[OH-].[Na+].Cl>O>[C:4]([C:5]1[CH:6]=[N:7][C:8]([C:15]2[NH:16][C:17](=[O:24])[C:18]([CH:21]([CH3:22])[CH3:23])([CH3:20])[N:19]=2)=[C:9]([CH:14]=1)[C:10]([OH:12])=[O:11])#[CH:3]
Reactant: COC(=O)c1cc(C#CC(C)(C)O)cnc1C1=NC(C)(C(C)C)C(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.5 g of 5-(3-hydroxy-3-methyl-1-butynyl)-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid, methyl ester, and 0.185 g of sodium hydroxide in 12 mL water is heated at reflux for 21/2 hours, then stirred at room temperature overnight. The reaction is then cooled to 10°, acidified to pH 3 with concentrated hydrochloric acid and extracted with methylene chloride. The organic phase is dried and concentrated in vacuo to afford the crude, desired product. An analytical sample, purified via its methyl ester, had mp 190°-195°.