Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8][C:7]=1[C:15]1[NH:16][C:17](=[O:28])[C:18]2[C:19](=[C:21]([CH2:25][CH2:26][CH3:27])[N:22]([CH3:24])[N:23]=2)[N:20]=1)[CH:2]([CH3:4])[CH3:3].Cl[CH2:30][C:31](=O)[CH3:32]>C(O)C>[CH2:1]([O:5][C:6]1[C:7]([C:15]2[NH:16][C:17](=[O:28])[C:18]3[C:19](=[C:21]([CH2:25][CH2:26][CH3:27])[N:22]([CH3:24])[N:23]=3)[N:20]=2)=[CH:8][C:9]([C:12]2[S:14][CH:30]=[C:31]([CH3:32])[N:13]=2)=[CH:10][N:11]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCc1c2nc(-c3cc(C(N)=S)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Reactant: CC(=O)CCl
Solvent: CCO
Product: CCCc1c2nc(-c3cc(-c4nc(C)cs4)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Yield: 78 %

Procedure:
6-Isobutoxy-5-(2-methyl-7-oxo-3-propyl-6,7-dihydro-2H-pyrazolo[4,3-d]-pyrimidin-5-yl)-3-pyridinecarbothioamide (Example 37) (77 mg, 0.19 mmol) and chloroacetone (36 mg, 0.38 mmol) were heated to reflux for 14 h in ethanol (5 mL). The reaction mixture was cooled and concentrated. Purification by flash column chromatography (gradient elution from 100% dichloromethane to 3% methanol:dichloromethane) gave 65 mg of product.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14](I)[CH:13]=[CH:12][C:3]=1[N:4]([CH3:11])[C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[SH:17][C:18]1[CH:19]=[C:20]([C:24]2([O:30][CH3:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>>[Cl:1][C:2]1[CH:15]=[C:14]([S:17][C:18]2[CH:19]=[C:20]([C:24]3([O:30][CH3:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:12][C:3]=1[N:4]([CH3:11])[C:5](=[O:10])[C:6]([F:9])([F:8])[F:7]
Reactant: CN(C(=O)C(F)(F)F)c1ccc(I)cc1Cl
Reactant: COC1(c2cccc(S)c2)CCOCC1
Product: COC1(c2cccc(Sc3ccc(N(C)C(=O)C(F)(F)F)c(Cl)c3)c2)CCOCC1
Yield: 8 %

Procedure:
Using a similar procedure to that described in Example 12, 2'-chloro-4'-iodo-2,2,2-trifluoro-N-methylacetanilide was reacted with 4-(3-mercaptophenyl)-4-methoxytetrahydropyran to give 4-[3-(3-chloro-4-(N-methyltrifluoroacetamido)phenylthio)phenyl]-4-methoxytetrahydropyran in 8% yield as a gum.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([I:27])C(=O)C1>CC#N.CCOC(C)=O>[I:27][C:9]1[NH:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2nc(-c3ccccc3)[nH]c2I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
The product of Step 1 (700 mg, 2.85 mmol) was dissolved in 10 mL of MeCN, to which was added NIS (770 mg, 3.42 mmol) and catalytic amount of TPA. After stirring at rt overnight, the reaction was diluted with EtOAc, washed with aq NaHCO3, aq Na2S2O3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give 770 mg of 4-(5-iodo-2-phenyl-1H-imidazol-4-yl)benzonitrile. LCMS: [M+1]=372.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[O:17][C:16](=[O:25])[CH:15]=2)=[CH:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([C:11]3[CH:12]=[CH:13][O:9][CH:10]=3)=[CH:15][C:16](=[O:25])[O:17]2)=[CH:22][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(-c3ccoc3)cc(=O)oc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1cc(-c2ccoc2)c2ccc(CBr)cc2o1
Reaction time: 0.17 h
Yield: 49.2 %

Procedure:
N-Bromosuccinimide (0.90 g, 5.06 mmol) was added to a stirred solution of the compound from Step 2 (1.04 g, 4.60 mmol) in CCl4 (150 ml) followed by a catalytic amount of azobis (isobutyronitrile). After the mixture was refluxed for 3 h., the precipitated solid was removed by filtration and the solvent was evaporated in vacuo. The residue was stirred for 10 min. in 15 ml Et2O, filtered and dried to give 0.69 g of the title compound, m.p. 155°-156° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:21].BrBr>CO.C([O-])(O)=O.[Na+]>[Br:21][CH:18]([C:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13]1)=[O:20])[CH3:19]
Reactant: Br
Reactant: CCC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(Br)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 3 (3.3 g, 11.6 mmol) in CH3OH (50 ml) under Ar with 48% HBr (100 μL) was added dropwise at room temperature bromine (1.9 g, 11.8 mmol). After stirring overnight, the solution was poured in saturated NaHCO3 and the aqueous solution extracted with EtOAc (3×). The combined organic extracts were backwashed with brine, dried, filtered and concentrated to dryness to yield 4.3 g of 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH2:22])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1.[CH3:31][C:32]1[O:36][C:35]([C:37](O)=[O:38])=[N:34][N:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH:22][C:37]([C:35]5[O:36][C:32]([CH3:31])=[N:33][N:34]=5)=[O:38])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1
Reactant: Cc1nnc(C(=O)O)o1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(N)CC2)n1
Product: Cc1nnc(C(=O)NC2(C(=O)NC3CSc4cc(-c5cc(Cl)cc(F)c5-c5nnn(C)n5)ccc43)CC2)o1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-2,3-dihydro-benzo[b]thiophen-3-yl}-amide (example 61) has been coupled with 5-methyl-[1,3,4]oxadiazole-2-carboxylic acid to yield the title compound as light yellow amorphous solid. MS: 555.1 (MH+, 1Cl).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]1.N12CCCN=C1CCCCC2>O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: OCC1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(CO)CC2)nn1

Procedure:
To a stirred solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide (0.200 g, 0.90 mmol) in 1,4-dioxane (10 mL) was added 4-piperidine methanol (0.155 g, 1.40 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 mL, 2.700 mmol) and tetrabutyl ammonium bromide (0.032 g, 0.10 mmol). The resulting mixture was stirred at reflux for 18 hours. 1,4-Dioxane was removed in vacuo and the obtained crude product was used without further purification.
Reaction SMILES: O[C:2]([CH2:4][C:5]1([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14])=[O:3].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=1>CN(C)C=O>[CH3:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:2]([CH2:4][C:5]2([NH:15][C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[O:17])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]2=[O:14])=[O:3])=[CH:53][CH:54]=1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1ccc(NC(=O)NC2(CC(=O)O)C(=O)Nc3ccccc32)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)Nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.8 %

Procedure:
To a solution of 0.150 g of (RS)-3-(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one and 0.103 g of dicyclohexylcarbodiimide in 10 ml of N,N-dimethylformamide were added successively 0.074 g of 1-hydroxybenzotriazole and 0.052 g of p-toluidine. The resulting mixture was stirred at room temperature for 18 hours, followed by concentration. The residue was diluted with ethyl acetate and washed successively with dilute hydrochloric acid and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain 0.083 g (44%) of the title compound as a white powder.
Reaction SMILES: NC(N)=O.[CH:5]1([NH:8][S:9]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=2[OH:20])(=[O:11])=[O:10])[CH2:7][CH2:6]1.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:30]([NH:29][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=2[Cl:21])=[O:31])=[C:13]([OH:20])[C:12]=1[S:9]([NH:8][CH:5]1[CH2:7][CH2:6]1)(=[O:11])=[O:10]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 46.5 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-cyclopropyl -3-amino-6-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.84 mmol) and 2,3-dichlorophenylisocyanate (190 mg, 1/01 mmol) were coupled to form the desired urea (176 mg, 46%). LC-MS (m/z) 452.0 (M+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][CH:16]([NH:18][C:19](=[O:34])[CH2:20][NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[OH:42][C:36]([C:38]([F:41])([F:40])[F:39])=[O:37].[NH2:7][CH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:20][NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)=[O:34])[CH2:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
A solution of {4-{3-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-azetidin-1-yl}-cyclohexyl)-carbamic acid tert-butyl ester (less polar isomer, as prepared in the previous step 5.6 g, 11.2 mmol) in DCM 10 mL and TFA (10 mL) was stirred for 4 hours at room temperature. The solvent was removed and the residue was dried in vacuo to afford the title compound as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:22]=[C:23]([F:26])[C:24]=1F.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C.CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:22]=[C:23]([F:26])[C:24]=1[O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)n1ncc2ccc(O)cc21
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Yield: 52.6 %

Procedure:
Ethyl 2-(6-hydroxyindazol-1-yl)propionate (30 mgs) was dissolved in 0.72 cm3 of a mixture of dry methyl isobutyl ketone (6cm3) and 1 drop of dry DMF. 3-chloro-4,5-difluorobenzotrifluoride (42 mg) and dry potassium carbonate (27mg) were added. The mixture was stirred and heated under reflux for 7 hours, additional dry potassium carbonate being added after 3 hours. After cooling, the solvents were removed under vacuum and diethyl ether added to the residue, the mixture filtered and the inorganic portion washed thoroughly with diethyl ether. The combined ethereal filtrate was concentrated under vacuum and the residue purified by chromatography (SiO2 ; hexane:t-butylmethylether,4:1) to give compound 1, ethyl 2-[6-(2-chloro- 4-trifluoromethyl-6-fluorophenoxy) indazol-1-yl]propionate (29 mg). M+ =430.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][O:8][C:4]=2[CH:3]=1.O=[C:15]([CH3:28])[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]3[CH2:9][CH2:10][NH:11][C:15]([CH2:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])([CH3:28])[C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: NCCc1coc2cc(I)ccc12
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CN2C(=O)c3ccccc3C2=O)NCCc2c1oc1cc(I)ccc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-(6-iodo-benzofuran-3-yl)-ethylamine (2.00 g, 6.97 mmol) and 2-(2-oxo-propyl)-isoindole-1,3-dione (4.25 g, 20.9 mmol) was added trifluoroacetic acid (8.00 mL, 104 mmol) and then heated at 80° C. After 16 h, additional ketone (3 eq) was added and heating continued. After a total of 3 days, the reaction mixture was basified (DCM-aq. NaHCO3) and the resulting precipitate was filtered, rinsed with DCM and dried to give an off-white solid. mp 302-304° C. dec.; MS m/z 473 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.Br[CH2:21][C:22]1[CH:30]=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1.[NH4+].[Cl-]>C1CCCCC1.C1COCC1>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([CH2:21][CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9]3=[O:14])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: BrCc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=C1C(Cc2ccc3c(c2)OCO3)CCCN1Cc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1-Benzyl-piperidin-2-one (4.8 g, 25.4 mmol) in abs. THF (200 ml) is cooled to −70° C.; sec.-BuLi (23.4 ml of a 1.3 M solution in cyclohexane; 30.4 mmol) is added dropwise under an Ar atmosphere and the mixture is stirred at −70° C. for 30 min. A solution of 5-bromomethyl-benzo[1,3]dioxole (see Harrowven et al., Tetrahedron (2001), 57(29), 4447) (8.0 g, 37.2 mmol) in abs. THF (80 ml) is added dropwise, stirring is continued at −70° C. for 3 h, then at rt for 15 h. sat. aq. NH4Cl solution is added, the organic layer is separated, dried over Na2SO4 and evaporated. The oily residue is purified by MPLC (140 g silica gel, eluent cyclohexane, then cyclohexane:AcOEt 7:3) to give 3-benzo[1,3]dioxol-5-ylmethyl-1-benzyl-piperidin-2-one as a yellow oil. Preparative resolution using a Chiralpak AD 5×50 cm/20 μm column (Daicel Chiral Technologies, Inc., Exton USA; a chiral stationary phase); eluent hexane: isopropanol 90:10; flow 80 ml/min; UV detection (210 nM) gives (−)-3-benzo[1,3]dioxol-5-ylmethyl-1-benzyl-piperidin-2-one ([α]Drt=−61.1° (c=0.5, EtOH)).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]4[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=4[O:20][C:21]=3[C:22]#[N:23])=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:40]=[N+:41]=[N-:42])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]4[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=4[O:20][C:21]=3[C:22]3[NH:42][N:41]=[N:40][N:23]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2c(C#N)oc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2c(-c3nnn[nH]3)oc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A solution of methyl 2-butyl-1-[[4-(2-cyanobenzo[b]furan-3-yl)phenyl]methyl]benzimidazole-7-carboxylate (1.3 g) and trimethyltin azide (2.9 g) in toluene (125 ml) was heated under reflux for 2 days. After concentration to dryness, the residue was dissolved in a mixture of methanol (150 ml) and 1N hydrochloric acid (25 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and the residue was dissolved in methylene chloride. The resulting solution was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give pale yellow powders (1.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[N:17]1([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[N:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH2:30][CH2:29]1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: C1CN(CCN2CCOCC2)CCN1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/N1CCN(CCN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.1 %

Procedure:
A mixture of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (200 mg, 0.709 mmol), 2-morpholinylethylpiperazine (141.3 mg, 0.709 mmol) in 1 mL of N,N-dimethylformamide is stirred at room temperature for 15 min. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide (DMF) and ether to give 64 mg (20%) of yellow solid mp 156-156.5° C.; HRMS (ESI) m/z 449 (M+H)+1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][NH:7]2.[O:16]1COCO[CH2:17]1.Cl>O1CCOCC1>[OH:16][CH2:17][C:5]1[C:4](=[O:15])[C:3]2[C:8](=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:2]=2[CH3:1])[NH:7][CH:6]=1
Reactant: C1OCOCO1
Reactant: Cc1ccc([N+](=O)[O-])c2[nH]ccc(=O)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])c2[nH]cc(CO)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a stirred mixture of 1,4-dihydro-5-methyl-8-nitro-4-oxoquinoline (1.5 g) and 1,3,5-trioxane (3.31 g) in dioxane (15 ml) was added conc. hydrochloric acid (30 ml), and the mixture was stirred at 100° C. overnight. The mixture was evaporated in vacuo, and the residue was treated with acetonitrile to give 1,4-dihydro-3-hydroxymethyl-5-methyl-8-nitro-4-oxoquinoline (1.3 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][O:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:31][CH2:30][CH2:29][CH2:28][O:27][CH3:26])=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: COCCCN
Product: COCCCNc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-(3-Methoxy-propylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 3-methoxypropylamine. Mass spectrum (ES) MH+=409.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Br:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:17]>CO>[NH2:17][C:2]1[C:3]2[C:10]([Br:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCCOCn1cc(Br)c2c(Cl)ncnc21
Reactant: N
Solvent: CO
Product: Nc1ncnc2c1c(Br)cn2COCCO
Temperature: 125 °C

Procedure:
5-Bromo-4-chloro-7-(2-hydroxyethoxymethyl)pyrrolo-[2,3-d]pyrimidine (8b, 0.7 g) was dissolved in dry methanol (10 mL) and methanol saturated with ammonia (40 mL) was then added to this solution. The reaction mixture was heated at 125° C. in a sealed reaction vessel for 10 hours. The solvent was removed at 40° C. under reduced pressure and the resulting solid was then subjected to column chromatography. Elution of the silica gel column (20×3 cm) with 5% MeOH in CHCl3 yielded a solid after evaporation of the appropriate UV absorbing fractions.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([S:20][CH3:21])[CH:13]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:40])C=1.[Na]>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([S:20]([CH3:21])=[O:40])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(SC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Solvent: ClCCl
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(S(C)=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a solution of 200 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methylsulfanyl-benzonitrile (prepared according to the method described in example 23) in 4 ml of dichloromethane at 0° C. was added 74 mg of meta-chloroperbenzoic acid. The resulting mixture was stirred at 0° C. for 2 hours then kept in the freezer overnight. A saturated aqueous solution of sodium hydrogenocarbonate was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 203 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methylsulfinyl-benzonitrile, which was transformed into 3-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methylsulfinyl-phenyl}-4H-[1,2,4]oxadiazol-5-one according to the method described in example 1.
Reaction SMILES: Cl[C:2]1[N:11]([CH2:12][C:13]([O:15]CC)=O)[CH:10]([CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:19])[N:3]=1.[NH3:20]>C(O)C>[CH3:18][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:19])[N:3]=[C:2]2[NH:20][C:13](=[O:15])[CH2:12][N:11]12
Reactant: N
Reactant: CCOC(=O)CN1C(Cl)=Nc2cccc(C)c2C1C
Solvent: CCO
Product: Cc1cccc2c1C(C)N1CC(=O)NC1=N2
Reaction time: 16 h
Yield: 69.1 %

Procedure:
To a solution of 4.3 g (15.4 mmole) of 2-chloro-3-(carbethoxymethyl)-4,5-dimethyl-3,4-dihydroquinazoline in 50 ml of absolute ethanol was added a solution of 2.0 g (120 mmole) of ammonia in 25 ml of absolute ethanol, the system was stoppered and immersed in an oil bath (100°). After 16 hrs. of heating, the solution was cooled, the solvent removed in vacuo and the residue crystallized from 1N hydrochloride acid affording 2.29 g (59% yield) of yellow crystals mp 235°-40°.
Reaction SMILES: [C:1](O)(=O)[C:2]1C(=CC=C[CH:8]=1)O.[C:11]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)(N1C=CN=C1)=O>O1CCCC1>[NH2:20][CH:21]1[CH:2]2[CH2:8][CH2:11][N:18]([CH2:19][CH2:1]2)[CH2:22]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccccc1O
Solvent: C1CCOC1
Product: NC1CN2CCC1CC2
Reaction time: 1 h
Yield: 120 %

Procedure:
A solution of salicylic acid (3.46 g, 25 mmole) in anhydrous tetrahydrofuran (20 ml) under nitrogen is treated with 1,1'-carbonyldiimidazole (4.22 g, 26 mmole), stirred for one hour, then degassed with a stream of nitrogen. A solution of 3-aminoquinuclidine (from 30 mmole of dihydrochloride) in tetrahydrofuran (10 ml) is prepared, and the solution is added dropwise to the first solution. After 18 hours at room temperature, the reaction mixture is concentrated in vacuo and partitioned between methylene chloride (200 ml) and water (100 ml). The resultant organic layer is separated and the aqueous solution is extracted with methylene chloride (100 ml). The combined organic solutions are dried (Na2SO4), concentrated in vacuo, and passed through a short column of alumina (eluted first with 5% methanol/tetrahydrofuran, then with 25% methanol/tetrahydrofuran) to provide 3.20 g (52%) of product as a colorless foam.