Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH2:20]([NH:23][C:24](=[O:27])[O:25][CH3:26])[C:21]#[CH:22]>CN(C=O)C.CCN(CC)CC.[Cu]I.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>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[N:5]=[C:6]([C:22]#[C:21][CH2:20][NH:23][C:24](=[O:27])[O:25][CH3:26])[CH:7]=[CH:8][C:9]=2[C:10](=[O:16])[C:11]=1[C:12](=[O:13])[NH:14][CH3:15]
Reactant: C#CCNC(=O)OC
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CCNC(=O)OC)nc21

Procedure:
A suspension of 0.8 g (2.85 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide in 22 ml of a DMF/Et3N (v/v; 2.2/1) mixture is placed in a 10 ml microwave tube. Argon is sparged into this suspension for 10 minutes and then 0.98 g of methyl (prop-2-yn-1-yl)carbamate (8.66 mmol), 0.076 g of CuI (0.40 mmol) and 0.139 g of bis(triphenylphosphine)palladium(II) dichloride (0.20 mmol) are successively added.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:13]([F:31])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:13]([F:31])[CH:12]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CCOC(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Temperature: 105 °C
Yield: 53 %

Procedure:
Ethyl 4chlorobutyrate (0.154 ml, 1.1 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, 1 mmol), (prepared as described for the starting material in Example 2), and anhydrous potassium carbonate (690 mg, 5 mmol) in DMF (10 ml). The mixture was stirred and heated at 105° C. for 4 hours then allowed to cool. The mixture was diluted with methylene chloride and the insolubles were removed by filtration. The solvent was removed from the filtrate by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (1008/1). The purified product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(3-ethoxycarbonylpropoxy)-6-methoxyquinazoline (230 mg, 53%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[NH:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:3]1.[Cl:16][C:17]([Cl:22])([Cl:21])[C:18](Cl)=[O:19].CN(C)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[N:6]([C:18](=[O:19])[C:17]([Cl:22])([Cl:21])[Cl:16])[CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:3]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC1(C)NCC(COc2ccccc2)O1
Agent: CN(C)C
Solvent: c1ccccc1
Product: CC1(C)OC(COc2ccccc2)CN1C(=O)C(Cl)(Cl)Cl

Procedure:
To 24.8 milliliters of 25 percent w/v, 2,2-dimethyl-5-phenoxymethyl oxazolidine in 50 milliliters of benzene was added 5.5 grams of trichloroacetyl chloride. To this solution was added dropwise with cooling 3.1 grams of trimethylamine. After work-up with water, drying and removal of the benzene in vacuo, there was obtained 8.1 grams of the title compound, nD30 1.5272. Analytical data supports the structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.Br[Mg][CH3:14].C(OCC)C.[Cl-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[N:4][C:3]=1[C:9]([OH:11])([CH3:14])[CH3:10]
Reactant: CC(=O)c1ncc(O)cc1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1ncc(O)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-(3-Chloro-5-hydroxypyridin-2-yl)ethanone (0.075 g, 0.0068 mol) was dissolved in THF (2 mL). The mixture was degassed three times then cooled to 0° C. with an ice bath. Then bromo(methyl)magnesium in diethylether (0.3 mL, 0.0009 mol) was added dropwise to the reaction mixture under nitrogen keeping the temperature at 0° C. with an ice bath. When the addition was complete, it was left to warm up to room temperature for 16 hours. Then bromo(methyl)magnesium in diethylether (0.3 mL, 0.0009 mol) was added dropwise to the reaction mixture and was stirred at room temperature for further 3 hours. A saturated aqueous solution of sodium chloride was slowly added to the reaction mixture (10 mL) and then it was extracted with EtOAc (2×10 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to obtain the title compound as a translucent solid (0.049 g, 4% yield):
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([NH:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Reactant: CCCCN
Product: CCCCNc1ncnc2ccc(-c3ccc(F)cc3)cc12
Yield: 68 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and n-butylamine in 68% yield, using the procedure described for example 37. The product was characterized by its mass spectrum as follows: MS (m/z): 296 ([M+H]+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[N:5]2[CH:20]=[CH:21][N:22]=[C:4]2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[S:32][CH:31]=[N:30][CH:29]=1)CCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[N:5]4[CH:20]=[CH:21][N:22]=[C:4]4[CH:3]=[C:2]([C:28]4[S:32][CH:31]=[N:30][CH:29]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:19][CH2:18]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: N#CCC(C1CC1)n1cc(-c2nc(Cl)cc3nccn23)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#CCC(C1CC1)n1cc(-c2nc(-c3cncs3)cc3nccn23)cn1
Temperature: 100 °C
Yield: 78.1 %

Procedure:
To a flask charged with 3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-cyclopropylpropanenitrile (Preparation M; 0.020 g, 0.064 mmol), 5-(tributylstannyl)thiazole (0.029 g, 0.077 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.0061 g, 0.013 mmol), and tris(dibenzylideneacetone)dipalladium (0.0059 g, 0.0064 mmol), evacuated and backfilled with argon, was added 1.5 mL of dioxane. Argon was bubbled through the reaction for 5 minutes and the flask was sealed and heated to 100° C. for 3 hours. The reaction mixture was loaded onto a silica gel column pre-wetted and eluted with ethyl acetate containing 0.5% ammonium hydroxide to afford the title compound (0.018 g, 0.050 mmol, 78% yield). MS (apci) m/z=362.1 (M+H).
Reaction SMILES: I[CH2:2][Si:3]([CH3:11])([CH3:10])[O:4][Si:5]([CH2:8]I)([CH3:7])[CH3:6].[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C1(C)C=CC=CC=1>O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[CH2:8][Si:5]([CH3:6])([CH3:7])[O:4][Si:3]([CH3:11])([CH3:10])[CH2:2]1
Reactant: NCc1ccccn1
Reactant: C[Si](C)(CI)O[Si](C)(C)CI
Solvent: O
Solvent: Cc1ccccc1
Product: C[Si]1(C)CN(Cc2ccccn2)C[Si](C)(C)O1
Reaction time: 24 h

Procedure:
To 41.4 g. (0.1 mole) of 1,3-bis-iodomethyl-1,1,3,3-tetramethyl-disiloxane there is added dropwise with stirring 32.4 g. (0.3 mole) of 2-aminomethyl-pyridine while maintaining the temperature at 20° C. Stirring is continued at room temperature for 24 hours. The now heterogeneous mixture is combined with approximately 0.5 l. of toluene followed by approximately 0.5 l. of water. The equilibrated aqueous phase is then extracted with two 100 ml. portions of toluene. The combined organic phase is then washed twice with approximately 100 ml. of water to give 4-(2-pyridylmethyl)-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6-disilacyclohexane as the crude free base.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:43]=[CH:42][C:41]([C:44](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:45])=[CH:40][CH:39]=3)[N:28]=2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([N:10]4[CH2:11][CH2:12][N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:8][CH2:9]4)=[O:45])=[CH:40][CH:39]=3)[N:28]=2)=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from intermediate product A2 and 1-phenylpiperazine as described for compound 8. Crystallised from diethyl ether as the free base. M.p. 185–186° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[C:3]1=[O:9].[CH3:10][Mg]Br>CCOCC>[CH3:10][C:3]1([OH:9])[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1]
Reactant: C[Mg]Br
Reactant: CC1CCCC(C)C1=O
Solvent: CCOCC
Product: CC1CCCC(C)C1(C)O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of 2,6-dimethylcyclohexanone (35 g, 0.277 mole) in ether (200 ml) was cooled to -78° C. and treated with a 2-fold excess of a solution of methyl magnesium bromide in ether (2.8M, 198 ml). After stirring at -78° C. for 3 hours the reaction mixture was warmed to 0° C. and quenched carefully with water and brine. The organic layer was separated, dried (MgSO4) and the ether evaporated under reduced pressure to give 1,2,6-trimethylcyclohexanol (32.2 g).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]N2C3C=CC=CC=3N=N2)=[CH:10][CH:9]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=NC2C=CC=CC=2)=[CH:27][CH:26]=1>CN(C=O)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=2)=[CH:27][CH:26]=1
Reactant: Fc1ccc(Cn2nnc3ccccc32)cc1
Reactant: Fc1ccc(C=Nc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(C#Cc2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
To potassium t-butoxide (1.5 g, 13.4 mmol) in DMF (15 mL) at 75° C. was added as quickly as possible and all at once [(4-fluorophenyl)methyl]-1H-benzotriazole (1.14 g, 5 mmol) and (4-fluorophenyl)methylenebenzenamine (1.00 g, 5 mmol) dissolved in DMF (10 mL). Within a minute the solution is poured into ice-cold water (75 mL) crystallizing the title compound which was filtered and then chromatographed (PE). The acetylene 0.54 g (50%) recrystallizes as needles: mp 95°-96° C. (MeOH); (lit.1 94°-95° C.).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:26]([CH3:27])=[N:25][N:24]([CH3:28])[C:12]2=[N:13][C:14]=1[N:15]([CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].Cl[C:45]([O:47][CH3:48])=[O:46].O>C1COCC1>[CH3:48][O:47][C:45](=[O:46])[N:7]([CH2:6][C:5]1[CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:4]=1)[CH2:8][C:9]1[CH:10]=[C:11]2[C:26]([CH3:27])=[N:25][N:24]([CH3:28])[C:12]2=[N:13][C:14]=1[N:15]([CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][CH3:17]
Reactant: COC(=O)Cl
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c(C)nn2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
A mixture of {5-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl }-cyclopentylmethyl-ethyl-amine (0.25 g, 0.47 mmol) and potassium carbonate (0.19 g, 1.4 mmol) in THF (10 mL) was stirred for 20 min at RT. Thereafter, methyl chloroformate (0.55 mL, 0.7 mmol) was added and stirring was continued overnight. To this mixture was added water (100 mL) and the product was extracted with ethyl acetate (×30 mL). Theorganic extracts were combined and concentrated and the residue was purified by column chromatography over 230-400 mesh silica gel. Elution with 20% ethyl acetate in hexanes gave the pure product as a colorless, gummy mass (yield: 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])[S:11][C:12]=2[CH2:13][CH2:14][CH2:15][C:16](OCC)=[O:17])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])[S:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCc1sc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCCO)s1
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Ethyl 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-thiazolebutanoate (2.00 g) was dissolved in 20 ml of tetrahydrofuran, to which was added gradually lithium aluminum hydride (195 mg) under ice-cooling. The resulting mixture was stirred for 1 hour. Water (0.5 ml) was carefully added to the reaction mixture, the resulting mixture was filtered, and the residue on the filter paper was washed with ethyl acetate. The filtrate was concentrated to give crystals of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-thiazolebutanol (1.28 g, 72%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)([O-:3])=[O:2].[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>CO>[CH3:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][C:27]3[N:30]=[C:15]([C:5]4[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH:9]5[CH2:14][CH2:13][CH2:12][CH2:11][O:10]5)[N:6]=4)[NH:31][C:26]=3[CH:25]=2)[CH2:22][CH2:23]1
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Solvent: CO
Product: CN1CCN(c2ccc3nc(-c4nn(C5CCCCO5)cc4[N+](=O)[O-])[nH]c3c2)CC1
Temperature: 22 °C
Reaction time: 3 h
Yield: 27.3 %

Procedure:
742 mg of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde are added to a solution of 680 mg of 4-(4-methylpiperazino)-1,2-benzenediamine in 30 mL of methanol. The reaction medium is stirred at 22° C. for 3 hours. The reaction medium is heated at 60° C. using an oil bath for 1H30, and then stirred at 22° C. for 64 hours. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge. The elution is carried out in dichloromethane containing 10% methanol. 370 mg of 6-(4-methylpiperazin-1-yl)-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzimidazole are isolated. Analytical LC/MS: tr=1.88 min; [M+H]+=412.32; ELSD=97%; DAD=93%. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.50 to 2.23 (m, 6H); 2.25 (s, 3H); 2.50 (m masked, 4H); 3.14 (m, 4H); 3.70 (m, 1H); 4.00 (m, 1H); 5.59 (broad d, J=9.5 Hz, 1H); from 6.90 to 7.15 (m, 2H); from 7.39 to 7.54 (m, 1H); 9.17 (s, 1H); from 12.5 to 12.7 (m, 1H).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g) and triethylamine (1.0 ml), and 3,5-dichlorobenzoyl chloride (1.5 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].I[CH2:18][CH2:19][CH2:20][CH3:21]>CN(C=O)C>[CH2:18]([N:6]1[C:7]2[C:3](=[C:2]([I:1])[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=2)[CH:4]=[CH:5]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCI
Reactant: COC(=O)c1cc(I)c2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCn1ccc2c(I)cc(C(=O)OC)cc21
Temperature: 80 °C

Procedure:
To a mixture of methyl 4-iodo-1H-indole-6-carboxylate (1.0 g) in DMF (10 mL) was added potassium hydroxide (0.392 g) and 1-iodobutane (0.8 mL). The mixture was heated to 80° C. for 18 h. The mixture was cooled to room temperature and partitioned between water and ethyl acetate. The layers were separated and the organic layer washed twice with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 20% ethyl acetate in hexanes as eluent to give 0.73 g of the title compound: 1H NMR (CDCl3) δ 0.940, 1.32, 1.81, 3.95, 4.15, 6.45, 7.31, 8.09, 8.18.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]3[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=34)=[N:16]2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]3[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=34)=[N:16]2)[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1C1CCCC(O)C1
Yield: 97.7 %

Procedure:
A solution of 3-[2-{3-(tert-butyldimethylsilyloxy)cyclohexyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (570 mg) and 70% aqueous tetrabutylammonium fluoride (4.3 g) in tetrahydrofuran (10 ml) was stirred for overnight at room temperature. A reaction mixture was diluted with ethyl acetate (100 ml), which was washed in turn with water (50 ml×4) and saturated sodium chloride in water (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (40 ml) eluting in turn with 30%, 50% ethyl acetate in dichloromethane and ethyl acetate. Fractions containing desired product were concentrated under reduced pressure to give residue, which was recrystallized from ethanol to give 3-[2-(3-hydroxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (430 mg).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[CH2:13]1)C1C=CC=CC=1>C1C=CC=CC=1>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: Clc1cccc(Cl)c1OC1CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(Oc2c(Cl)cccc2Cl)C1
Reaction time: 72 h

Procedure:
To a solution of 170 ml of 2M phosgene (0.34 mole) stirred at 15° C. was added 109.2 g (0.34 mole) of 1-benzyl-3-(2,6-dichlorophenoxy)pyrrolidine in 300 ml of benzene. The color turned from yellow to deep amber. For convenience, the solution was allowed to stir for 72 hr, then concentrated to give a deep amber colored viscous oil. The oil was triturated with 1.6 liters of 30/60 petroleum ether. The petroleum ether wash was cooled to give 101.5 g of nearly pure title compound containing a trace of benzyl chloride. The yield was nearly quantitative.
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>CO>[CH3:4][C:2]1[N:9]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C:6]([CH3:7])=[CH:5][CH:1]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NCCN1CCCC1=O
Solvent: CO
Product: Cc1ccc(C)n1CCN1CCCC1=O

Procedure:
5.7 g (0.05 mmol) of acetonylacetone and 6.4 g (0.05 mmol) of 1-(2-aminoethyl)-2-pyrrolidinone are heated under reflux in 70 ml of methanol for 2 h. The reaction mixture is then concentrated and, after the concentration, the crude reaction product is then precipitated by addition of petroleum ether. The crude product is recrystallized from diethyl ether. Yield: 3.2 g (31% of theory), Melting point: 66°-68° C. Elemental analysis: C12H18N2O (206.29) calculated: C 69.9 H 8.8 N 13.6 0 7.8 found: C 69.4 H 8.7 N 13.7 0 8.11
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([CH:38]=1)[CH2:7][N:8]([C:24]([C:26]1[S:30][C:29]2[C:31]([F:36])=[CH:32][CH:33]=[C:34]([F:35])[C:28]=2[C:27]=1[Cl:37])=[O:25])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]1.[CH2:41]([S:43]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)(=[O:45])=[O:44])[CH3:42]>>[Cl:37][C:27]1[C:28]2[C:34]([F:35])=[CH:33][CH:32]=[C:31]([F:36])[C:29]=2[S:30][C:26]=1[C:24]([N:8]([CH2:7][C:6]1[CH:38]=[C:2]([C:49]2[CH:48]=[CH:47][C:46]([S:43]([CH2:41][CH3:42])(=[O:45])=[O:44])=[CH:51][CH:50]=2)[CH:3]=[CH:4][C:5]=1[O:39][CH3:40])[CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:13][CH2:14]1)=[O:25]
Reactant: COc1ccc(Br)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Product: CCS(=O)(=O)c1ccc(-c2ccc(OC)c(CN(C(=O)c3sc4c(F)ccc(F)c4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1

Procedure:
Aryl bromide 220 (200 mg, 0.30 mmol) is coupled to 4-(ethanesulfonyl)-benzene boronic acid (65 mg, 0.30 mmol) using Method A to afford the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C@H:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)=[CH:5][CH:4]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C.C(OCC)(=O)C.Cl>[OH:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C@H:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C[C@H]2CCc3ccccc3O2)cc1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: Oc1ccc(C[C@H]2CCc3ccccc3O2)cc1
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
(R)-(-)-3,4-Dihydro-2-(4-methoxybenzyl)-2H-benzopyran (812 mg, 3.2 mmol), and lithium iodide (750 mg, 5.6 mmol) were dissolved in 2,4,6-collidine (2 ml) and heated to reflux for 24 hours. The reaction mixture was cooled, diluted with ethyl acetate (20 ml) and 10% HCl (20 ml), and stirred for 10 minutes. The layers were separated and the aqueous portion was extracted with ethyl acetate (50 ml). The combined organics were washed with water (20 ml), brine (20 ml), and were dried (MgSO4). The solvent was removed in vacuo and the residue purified on silica gel using hexanes/ethyl acetate (3:1) as eluent to afford 730 mg of a colorless oil which crystallized upon standing, m.p. 60°-62° C.; [α]D -110.2° (c 1.0, MeOH); 1H NMR (300 MHz, CDCl3) δ1.7 (m, 1H), 2.0 (m, 1H), 2.7-2.8 (m, 3H), 3.1 (dd, 1H), 4.2 (m, 1H), 6.8 (m, 3H), 7.0-7.2 (m, 4H).