Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.N([O-])=O.[Na+].C(=O)([O-])O.[Na+].[C-:23]#[N:24].[K+]>Cl.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:23]([C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3)#[N:24]
Reactant: [C-]#N
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)C(=O)C1(CC1)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
5-Aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.75 g.) was dissolved in conc. HCl (2.5 ml.) and ice-water (20 ml.), and to the solution was added dropwise 2 ml of aqueous solution of sodium nitrite (0.7 g.) under ice-cooling. After stirring for one hour and adding toluene (5 ml.), the solution was neutralized with sodium hydrogen carbonate at -20° C. To 18 ml of another aqueous solution of cuprous cyanide prepared from cuprous chloride (2.4 g.) and potassium cyanide (4.4 g.) was added ethyl acetate (20 ml.), and, to the mixture was added, under ice-cooling and stirring, the above neutralized solution of diazonium salt. The mixture was stirred for half an hour at room temperature and further stirred for half an hour at 70° C. The insolubles were removed by filtration, and the filtrate was extracted with ethyl acetate. The extract was washed with aqueous solution of sodium carbonate, diluted hydrochloric acid and water in the order mentioned, and dried. The solvent was evaporated off under reduced pressure, and the obtained residue was recrystallized from methanol to give colorless needles of 5-cyanospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.4 g.) m.p. 148°-149° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[S:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:18].[K+].[K+]>S(=O)(=O)(O)O>[F:16][C:2]([F:15])([F:1])[S:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:18])=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 65 °C
Yield: 114.5 %

Procedure:
A suspension of 4-(trifluoromethanesulfonyloxy)benzaldehyde (5.2 g, 20.5 mmol, described in JACS, 1987, 109, 5478) and potassium dichromate (2.5 g) in sulfuric acid (30%, 47 mL) was heated at 65° C. for 1 h. The mixture was allowed to cool to ambient temperature and then poured on ice. The formed precipitate was filtered off and washed with several portions of water. The crude product was recrystallized from water/ethanol (1:1) affording 2.63 g (47% yield) of the title compound: mp 178-180° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, 2 H), 7.64 (d, 2 H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]=3[CH:29]=2)=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:40]([O:42][CH2:43][CH:44]([CH3:46])[CH3:45])=[O:41].C(O)(C(F)(F)F)=O>ClCCl>[O:21]1[C:15]2[CH:14]=[CH:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:2]4[N:3]([C:40]([O:42][CH2:43][CH:44]([CH3:46])[CH3:45])=[O:41])[CH:4]=[CH:5][N:1]=4)=[CH:7][CH:8]=3)=[CH:29][C:16]=2[CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)cc3)cc2C1
Reactant: CC(C)COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
1,1-dimethylethyl 7-[4-(1H-imidazol-2-yl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (490 mg, 1.25 mmol) was taken into dichloromethane (20 mL) followed by sequential addition of DIPEA (0.4 mL, 2.3 mmol) and isobutyl chloroformate (0.18 mL, 1.4 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated then partitioned with ethyl acetate and 10% aqueous citric acid. The organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. The residue thus obtained was taken into TFA (5 mL) and allowed to stand for 30 minutes at room temperature. The mixture was concentrated and the residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated to give 2-methylpropyl 2-[4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)phenyl]-1H-imidazole-1-carboxylate (361 mg, 65% yield). MS (EI) for C23H25N3O3: 392 (MH+).
Reaction SMILES: C([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2=O)C1C=CC=CC=1.CC1C=CC(N=[CH:29][C:30]2[C:31]([NH2:39])=[CH:32][C:33]3[O:37][CH2:36][O:35][C:34]=3[CH:38]=2)=CC=1>>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][C:14]2[C:13]3=[N:39][C:31]4[CH:32]=[C:33]5[O:37][CH2:36][O:35][C:34]5=[CH:38][C:30]=4[CH:29]=[C:12]3[CH2:11][C:10]=2[C:9]=1[OH:8]
Reactant: COc1ccc2c(c1OCc1ccccc1)CCC2=O
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Product: COc1ccc2c(c1O)Cc1cc3cc4c(cc3nc1-2)OCO4
Yield: 50.1 %

Procedure:
Using the procedure of Example 1, 4-benzoxy-5-methoxyindan-1-one (mg, 2 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (510 mg, 2 mmol) to yields 8-methoxy-9-hydroxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (308 mg, 38.7% of theory) which is used as a starting material for part (B).
Reaction SMILES: [CH2:1]([Sn:5]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4].[F:22][C:23]([F:39])([F:38])[C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:27][N:28]=[N+:29]=[N-:30]>C1(C)C=CC=CC=1>[F:22][C:23]([F:38])([F:39])[C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:27][N:28]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][CH3:21])[N:30]=[N:29]1
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Yield: 88 %

Procedure:
Heat a mixture of tri-n-butyl-phenylethynyl-stannane (11.0 g, 30.0 mmol) and 3,5-bis-trifluoromethyl-benzyl azide (9.68 g, 36.0 mmol) in toluene (40 mL) at reflux until reaction is complete. Concentrate to remove the solvent in vacuo and purify the residue by flash chromatography on silica gel (elution with 17% ether in hexanes) to give the title compound (17.5 g, 26.4 mmol, 88%). MS (ES) 660.1, 662.1 (M+1); LC Rf=0.1 (17% ether in hexanes).
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[N+]([O-])([O-])=O.[Na+].[Br-:24].[Na+]>C(O)(=O)C.O.Br.C(Cl)(Cl)Cl>[Br:24][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)CC(=O)CCC2
Reactant: [Br-]
Agent: Br
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2ccc(Br)cc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of 3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (9.42 g) in a mixture of acetic acid (1.85 ml), conc. sulfuric acid (9.24 ml) and water (24.56 ml) was added portionwise a solution of sodium nitrate (4.08 g) in water (6.00 ml) with ice salt bath cooling and the whole was stirred for 1 hour. The solution was added to a solution of cuprous bromide (10.02 g) and sodium bromide (9.40 g) in a mixture of 47% hydrobromic acid (27.72 ml) and water (61.52 ml) at 75° C. and the whole was stirred for 0.5 hour. After cooling, ice water (100 ml) and chloroform (200 ml) were added to the mixture. The insoluble material was filtered off. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and treated with active carbon (0.65 g). The solution was evaporated in vacuo and the residue was purified by column chromatography on silica gel with toluene as an eluent to give 3-bromo-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (6.34 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:29]=[CH:28][C:15]([O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([N+:24]([O-])=O)=[CH:19][C:18]=3[Cl:27])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCOCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[CH:29]=[CH:28][C:15]([O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([NH2:24])=[CH:19][C:18]=3[Cl:27])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(S(=O)(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cc(Cl)c(Oc2ccc(S(=O)(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1
Yield: 91.7 %

Procedure:
To a 100 mL flask equipped with condenser, stirrer, under nitrogen atmosphere was added 26.9 g. (0.11 mol) of stannous chloride, 23.9 mL of concentrated hydrochloric acid, and 17.9 mL of p-dioxane. The resulting mixture was warmed to 40° to obtain a homogeneous solution. To the above solution was added 16.6 g (0.036 mol) of 4-(4-[4-chlorophenylsulfonyl]phenoxy)-3,5-dichloronitrobenzene. The mixture was heated to reflux for 0.5 hour, cooled, and poured into chilled aqueous sodium hydroxide (pH 14). This mixture was extracted twice with methylene chloride. The combined organic layer was washed successively with aqueous sodium hydroxide, water, and brine. It was then dried over sodium sulfate and was concentrated to give 14.2 g (0.033 mol) of a white solid; mp 186°-187° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=O.O.[NH2:15][NH2:16]>C(O)C>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[C:6]2[CH2:10][CH2:9][CH2:8][C:7]=2[NH:16][N:15]=1
Reactant: NN
Reactant: COC(OC)C(=O)C1CCCC1=O
Solvent: CCO
Solvent: O
Product: COC(OC)c1n[nH]c2c1CCC2

Procedure:
5.7 g (30.6 mmol) of 2-(2,2-dimethoxyacetyl)cyclopentanone is dissolved in 50 mL of ethanol and after the addition of 6 g (96 mmol) of hydrazine hydrate (80%) refluxed for 2.5 hours. The ethanol is distilled off, the residue is combined with water and extracted with ethyl acetate. The organic extracts are dried and concentrated by evaporation. The crude product is chromatographed on silica gel, eluting with petroleum ether/ethyl acetate 1:2. Yield: 3.1 g (56%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([F:12])[C:9](F)=[CH:8][C:7]=1[Cl:14])[C:2]#[CH:3].[CH2:16]([OH:19])[C:17]#[CH:18].[H-].[Na+].Cl>CN(C=O)C>[CH2:1]([O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:19][CH2:16][C:17]#[CH:18])=[CH:8][C:7]=1[Cl:14])[C:2]#[CH:3]
Reactant: C#CCO
Reactant: C#CCOC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOC(=O)c1cc(F)c(OCC#C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.4 %

Procedure:
To a mixed solution of 150 ml of DMF, 12.7 g of 2-chloro-4,5-difluorobenzoic acid 2-propynyl ester and 3.4 g of propargyl alcohol, 2.4 g of 60% sodium hydride (oily) was added under ice cooling. After stirring at room temperature overnight, the reaction mixture was added with hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed in turn with water and saturated brine, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 19 g of 2-chloro-5-fluoro-4-(2-propynyloxy)benzoic acid 2-propynyl ester was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1.C(OCC)(=O)C>[C:39]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:41])[CH3:40]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3ccc(C)c(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.452 mmol) produced in Example A7(vii) in tetrahydrofuran (2.0 mL) were added pyridine (180 μL, 2.25 mmol) and acetyl chloride (51 μL, 0.723 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (20 mL), washed with 5% aqueous sodium hydrogencarbonate solution (10 mL) and saturated brine (10 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from 2-butanone/hexane to give the title compound (138 mg, 63%) as colorless crystals.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[O:10]>>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:9]=[O:10])[OH:2]
Reactant: Oc1cccc(O)c1
Reactant: C=O
Product: O=Cc1c(O)cccc1O

Procedure:
In the case of using RF-gel as carbon precursor, aqueous solutions containing 20 to 60 weight percent of inorganic template particles stabilized with surfactants specified in the step (a) are prepared, and the resulting aqueous solution is mixed with 30 to 70 weight percent aqueous solution of the mixture of resorcinol and formaldehyde (1:2 to 1:3 molar ratio) to produce mixtures with weight ratio of 1:1 to 1:20 (resorcinol-formaldehyde:inorganic template), followed by polymerizing at 20° C. to 95° C. to produce inorganic template/carbon precursor composites as specified in the step (a). In the case of commercial silica sol as template, resorcinol and formaldehyde can be polymerized without using catalyst, because weak basic property of the silica sol solution readily induces polymerization. In order to accelerate the specified polymerization reaction, catalyst such as sodium carbonate can be also added.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](C=O)=[CH:3][CH:2]=1.[CH3:9][O:10][CH:11](OC)[O:12][CH3:13].S(=O)(=O)(O)O.C[O-].[Na+]>CO>[CH3:9][O:10][CH:11]([O:12][CH3:13])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccncc1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-pyridinecarboxaldehyde (100.00 g, 0.93 mol) and trimethylorthoformate (159.20 g, 1.50 mol) in methanol (180 mL) at 0° C., under N2, was added concentrated sulfuric acid (41 mL, 0.45 mol). The resulting white suspension was heated to reflux and stirred for 24 hours. The reaction solution became clear after 2 h. After cooling to room temperature, the reaction mixture was poured slowly into a solution of 25 wt. % sodium methoxide (360 mL) in methanol (300 mL). The mixture was then concentrated in vacuo to a light brown thick oil. To this crude oil was added t-butylmethyl ether (500 mL), followed by the slow addition of water (40 mL) (to convert the inorganics to filterable solids). After filtration through a pad of Celite, the filtrate was concentrated to yield a light brown oil. The crude oil was vacuum distilled to yield the desired product as a colorless oil
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:24](O)=[O:25])[CH:4]=[N:3]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:25])=[O:23])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Reactant: C1COCCN1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
A mixture of 1-methyl-5-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 422 μmol), morpholine (368 μl, 4.22 mmol), propylphosphonic anhydride (50% in ethyl acetate, 622 μl, 1.06 mmol) and N,N-diisopropylethylamine (215 μl, 1.27 mmol) in tetrahydrofuran (6 ml) was stirred for 18 hours at 70° C. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate, washed with water. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid (2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (109 mg, 60.8%) as a light yellow solid. mp: 194-197° C., MS: m/z=425.3 (M+H+).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[NH:9][C:10](=[O:14])[NH:11][C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>O>[CH3:13][C:12]1[NH:11][C:10](=[O:14])[NH:9][C:8]=1[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([N:21]2[CH:22]=[C:18]([CH3:17])[N:19]=[CH:20]2)=[CH:3][CH:4]=1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Reactant: Cc1c[nH]cn1
Solvent: O
Product: Cc1cn(-c2ccc(C(=O)c3[nH]c(=O)[nH]c3C)cc2)cn1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
4-(4-Fluorobenzoyl)-1,3-dihydro-5-methyl-2H-imidazol-2-one (6.6 g 30 mmol) is combined with 4-methyl-1H-imidazole (33 g, ca. 400 mmol) in a sealed flask and the mixture heated with stirring at ca. 140° C. overnight. The mixture is cooled, water (120 mL) added and the mixture stirred in an ice bath. The suspension is filtered and the filter cake washed with water and acetone. The solid is heated under reflux in a mixture of 2-propanol (300 mL) and water (200 mL) until dissolution is complete. The solution is filtered, reheated to dissolve some precipitated solid and allowed to cool slowly to room temperature. After 2.5 days the mixture is cooled in ice for 2 hr, the solid collected by filtration, washed with acetone, and dried in vacuo at 105° C. for 23 hr to produce the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:63]([CH:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)([CH3:65])[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH2:70][CH:66]1[CH:63]([CH3:65])[CH3:64])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(C)C1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC3C(C)C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-isopropyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH:11]([CH2:28][CH2:29][CH3:30])[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH:11]([CH2:28][CH2:29][CH3:30])[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5]
Reactant: CCCC(Br)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCC(Oc1ccccc1C=O)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.6 %

Procedure:
A mixture of 2-hydroxybenzaldehyde (2.44 g), diphenylmethyl 2-bromopentanoate (7.26 g), and potassium carbonate (3.45 g) in dimethylsulfoxide (20 ml) was stirred at room temperature for 5 hours. The mixture was diluted with water, neutralized with 1N hydrochloric acid, and was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated to give diphenylmethyl 2-(2-formylphenoxy)-pentanoate (8.04 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17]C)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[I:19].B(Br)(Br)Br>C(Cl)Cl>[I:19][C:3]1[CH:4]=[C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COc1ccc2nc(-c3ccc(N)c(I)c3)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccc(-c2nc3ccc(O)cc3s2)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.1 %

Procedure:
To a solution of 2-(4′-Amino-3′-iodophenyl)-6-methoxy benzothiazole (5) (8.0 mg, 0.02 mmol) in CH2Cl2 (2.0 mL) was injected 1 M BBr3 solution in CH2Cl2 (0.20 ml, 0.20 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 18 hrs. After the reaction was quenched with water, the mixture was neutralized with NaHCO3. The aqueous layer was extracted with ethyl acetate (3×3 mL). The organic layers were combined and dried over MgSO4. The solvent was then evaporated under reduced pressure and the residue was purified by preparative TLC (Hexanes:ethyl acetate=7:3) to give 2-(3′-iodo-4′-aminophenyl)-6-hydroxybenzothiazole (4.5 mg, 58%) as a brown solid. 1HNMR (300 MHz, acetone-d6) δ (ppm): 8.69 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 7.77 (dd, J1=2.0 Hz, J2=8.4 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.02 (dd, J1=2.5 Hz, J2=8.8 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 5.47 (br., 2H). HRMS m/z 367.9483 (M+calcd for C13H9N2OSI 367.9480).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)(=[O:3])[CH3:2].[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([C@@H:28]([OH:30])[CH3:29])[CH2:24][CH2:23]1>C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([OH:30])[CH3:29])=[CH:24][CH:23]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: C[C@H](O)C1CCC(CN)CC1
Reactant: CC(=O)c1cccc(Oc2ncccc2C(=O)O)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc([C@H](C)O)cc2)c1

Procedure:
Prepared from 2-(3-Acetyl-phenoxy)-nicotinic acid and (S)-(−)-1-(4-Aminomethyl-cyclohexyl)-ethanol. mp 102-4° C. αD (CHCl3) −13.8°.