Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[OH-].[K+].[CH:6]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[S:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH2:30][N:29](C(=O)C(F)(F)F)[CH2:28][CH2:27]4)(=[O:23])=[O:22])=[C:16]([F:49])[CH:15]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1>O1CCCC1.O>[CH:6]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[S:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH2:30][NH:29][CH2:28][CH2:27]4)(=[O:22])=[O:23])=[C:16]([F:49])[CH:15]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COc1ccc(CN(c2ccc(CCCC3CCCC3)cc2F)S(=O)(=O)c2ccc3c(c2)CCN(C(=O)C(F)(F)F)C3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1ccc(CN(c2ccc(CCCC3CCCC3)cc2F)S(=O)(=O)c2ccc3c(c2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
An aqueous solution (10 mL) of ethanol (20 mL) and potassium hydroxide (730 mg, 12.86 mmol) was added to a solution of N-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-N-(4-methoxybenzyl)-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (4.07 g, 6.43 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 15 hr. The mixture was diluted with water and extracted with chloroform. The organic layer was concentrated under reduced pressure, a mixed solvent of hexane and ethyl acetate (6:1) was added to the residue, and a precipitated solid was collected by filtration to afford the title compound as a colorless powder (3.11 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:18]2[O:34][CH2:35][O:36][C:17]2=[CH:16][CH:15]=1.O[CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:38][CH2:39][N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:18]2[O:34][CH2:35][O:36][C:17]2=[CH:16][CH:15]=1
Reactant: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1O
Reactant: OCCN1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.9 %

Procedure:
Diethyl azodicarboxylate (0.182 ml) was added dropwise to a stirred mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-6-methoxyquinazoline (0.2 g), N-(2-hydroxyethyl)pyrrolidine (0.086 g), triphenylphosphine (0.303 g) and methylene chloride (3 ml) and the reaction mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was evaporated and the residue was purified by column chromatography on silica using a 45:4:1 mixture of methylene chloride, methanol and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.033 g) as a white solid; NMR Spectrum: (DMSOd6 and CF3CO2D) 1.9 (m, 2H), 2.1 (m, 2H), 3.2 (m, 2H), 3.7 (m, 2H), 3.8 (m, 2H), 4.05 (s, 3H), 4.6 (m, 2H), 6.2 (s, 2H), 7.1 (d, 1H), 7.2 (d, 1H), 7.5 (s, 1H), 8.2 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M−H− 441 and 443.
Reaction SMILES: [CH:1]12[CH2:12][CH:7]([CH:8](CO)[CH2:9]1)[CH:6]1[CH:2]2[CH2:3][CH:4](CO)[CH2:5]1>C(O)CO>[CH3:8][CH2:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:12]
Reactant: OCC1CC2C3CC(CO)C(C3)C2C1
Solvent: OCCO
Product: CCCCCCCCCC

Procedure:
The same procedure as in Example 1 was repeated except that 6.2 parts of ethylene glycol was replaced with 19.6 parts of tricyclo[5,2,1,02,6 ]decane-4,8-dimethanol, thereby obtaining 55.9 parts of 4,8-bis[N-(3-isopropenyl-α,α-dimethylbezyl)carbamoyloxymethyl]tricyclo]5,2,1,02,6 ]decane in the form of a colorless transparent liquid.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([CH2:23][O:24][CH2:25][C:26]([OH:28])=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[C:29]([O:33][C:34]([CH:36]1[CH2:39][N:38]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47](=[N:49]O)[NH2:48])=[CH:43][CH:42]=2)[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2([CH2:23][O:24][CH2:25][C:26]3[O:28][N:49]=[C:47]([C:44]4[CH:43]=[CH:42][C:41]([CH2:40][N:38]5[CH2:37][CH:36]([C:34]([O:33][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:35])[CH2:39]5)=[CH:46][CH:45]=4)[N:48]=3)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)cc2)C1
Reactant: O=C(O)COCC1(c2ccc(F)cc2)CCCCC1
Agent: CC(C)N=C=NC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(COCC4(c5ccc(F)cc5)CCCCC4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63.6 %

Procedure:
N,N′-Diisopropylcarbodiimide (17 mg, 135 μmol) was added to a stirred solution of crude 2-((1-(4-fluorophenyl)cyclohexyl)methoxy)acetic acid (30 mg, 113 μmol) and tert-butyl-1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (34 mg, 113 μmol) in dichloromethane (1.5 mL). The reaction mixture was stirred at room temperature for 40 min and concentrated. The residue was diluted with acetonitrile (1.5 mL) and treated with a 1 M solution of tetra-n-butylammonium fluoride (113 μL, 113 μmol). The mixture was stirred at room temperature for 16 h and concentrated. The crude residue was chromatographed on silica gel (Teledyne-Isco RediSep 12 g column), and eluted with 10%, 20% and 30% EtOAc in hexanes to obtain tert-butyl 1-(4-(5-(((1-(4-fluorophenyl)cyclohexyl)methoxy)methyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (38.5 mg, 64% yield) as a viscous colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17]O)[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[C:4]([I:9])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: CN1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(COc2ccc(Cl)cc2I)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred solution of 4-chloro-2-iodophenol (1.72 g, 6.75 mmol) in anhydrous THF (10.0 mL) were sequentially added (1-methylpiperidin-4-yl)methanol (1.31 g, 10.14 mmol) and triphenyl phosphine (2.66 g, 10.14 mmoL). The reaction mixture was cooled to 0° C., and to it diisopropyl-azodicarboxylate (1.96 mL, 10.14 mmol) was added in drop wise manner. After the addition was over, stirring continued for another 0.5 h at 0° C. and then for 12 h at room temperature. Solvents were removed in vacuum and the residue was purified by silica gel column chromatography, providing Compound 173 (1.85 g, 75%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][C:17]=1[C:29]([NH:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:30].C(OCC)(=O)C>CN(C)C=O.O>[C:8]1([CH2:7][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][C:17]=2[C:29]([NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:30])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCc1ccc(O)c(C(=O)Nc2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reaction time: 1 h

Procedure:
Cesium carbonate (171 mg, 0.53 mmol) and benzyl bromide (0.05 ml, 0.42 mmol) were added to a solution of ethyl 3-{4-hydroxy-3-[(3-pyridinylamino)carbonyl]phenyl}propanoate (may be prepared as described in Description 98; 110 mg, 0.35 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for one hour and then ethyl acetate (10 ml) and water (10 ml) were added. The organic layer was separated, washed further with water (3×10 ml), dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a yellow solid. 126 mg.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:33]([CH:35]([CH3:37])[CH3:36])#[C-:34]>CO.O>[Cl:12][C:13]1[CH:14]=[C:15]([C:16]2[N:9]=[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]3[C:34]=2[NH:33][CH:35]([CH3:37])[CH3:36])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: [C-]#[N+]C(C)C
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)Nc1c(-c2cccc(Cl)c2)nc2ccc(C(F)(F)F)cn12
Reaction time: 0.08 h
Yield: 81.5 %

Procedure:
5-(trifluoromethyl)pyridin-2-amine (100 mg, 617 μmol, Eq: 1.00), 3-chlorobenzaldehyde (86.7 mg, 70.2 μl, 617 μmol, Eq: 1.00) and p-toluenesulfonic acid monohydrate (35.2 mg, 185 μmol, Eq: 0.3) were dissolved in MeOH (1.00 mL) and the intensive yellow solution was stirred for 5 min. To this yellow solution was added dropwise 2-isocyanopropane (42.6 mg, 58.2 μL, 617 μmol, Eq: 1.00) and the corresponding yellow solution was stirred for 90 min. To the yellow solution was added dropwise water and oil was formed. The water/MeOH was separated from the oil and the yellow oily residue was purified by flash column chromatography (40 g SiO2, hexane/AcOEt 100:0 to 0:100) to yield a yellow solid (178 mg, 78.3%). MS: 354.0 [M+H]+; 1H-NMR (D6-DMSO): δ 8.92 (s, 1H), 8.29 (s, 1H), 8.19 (d, 1H), 7.72 (d, 1H), 7.51 (t, 1H), 7.47-7.36 (m, 2H), 5.13 (d, 1H), 3.26 (m, 1H), 1.08 (d, 6H).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)=[CH:11][CH:10]=1.C(I)(C)C>CN(C)C=O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]([CH:2]([CH3:3])[CH3:1])[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[N:19]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C(F)(F)F)cn2C(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
At an internal temperature of 0°-50°, 10 g of potassium tert.-butoxide are added to a solution of 20 g of 2-(4-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazole in 200 ml of dimethylformamide. After 20 minutes 10.7 ml of isopropyl iodide are added and the reaction mixture is subsequently stirred at room temperature. After 24 hours in each case, a further 10 g of potassium tert.-butoxide are added and then 10.7 ml of isopropyl iodide. In total, these measures are repeated three times. The total reaction period is 120 hours. Finally, the solvent is removed in a rotary evaporator, the residue is taken up in water and extracted several times with ethyl acetate. After evaporating off the organic phase, the residue is chromatographed on silica gel with ethyl acetate/hexane and 2-(4-methoxyphenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole is isolated from the main fractions in the form of a yellowish oil.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].CO>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][N:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccccn2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(2-pyridyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 90% overall yield. FDMS m/e=352 (M+ of free base). α[D]589=−31.14 (c=0.86, methanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([N:10]=[S@:11]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31]([NH:35][C:36]([C:38]2[N:42]([CH3:43])[N:41]=[C:40]([CH3:44])[CH:39]=2)=[O:37])[CH:32]=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(C)=O.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>[CH3:43][N:42]1[C:38]([C:36]([NH:35][C:31]2[CH:30]=[C:29]([C:27]#[C:28][C:2]3[CH:3]=[C:4]([C:8]([N:10]=[S@:11]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=3)[CH:34]=[CH:33][CH:32]=2)=[O:37])=[CH:39][C:40]([CH3:44])=[N:41]1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Reactant: COC(=O)CCCC[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCC[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To the flame-dried 100 mL round bottom flask containing (S)-Methyl 5-{N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl}pentanoate (609 mg, 1.39 mmol), N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (0.50 g), triethylamine (0.77 mL), bis(triphenylphosphine)palladium(II) dichloride (97.3 mg), and triphenylphosphine (9.1 mg) under nitrogen/hydrogen (1:1) atmosphere at room temperature was added copper(I) iodide (52.8 mg). The resulting reaction mixture was heated and stirred at 60° C. for 1 hour. It was then diluted with EtOAc, washed sequentially with saturated aqueous NaHCO3 (2×), brine (1×), and finally dried with anhydrous sodium sulfate. The solution was decanted and concentrated with silica gel. Chromatography (EtOAc-Hex from 1:2 to 3:2) yielded the title compound as white foam in amount of (712 mg, 86%).
Reaction SMILES: BrC1C(OC)=C(C=CC=1CSC1C=CC=CC=1C)C(OCC)=O.[Br:24][C:25]1[C:26]([O:44][CH3:45])=[C:27]([C:33]([CH2:36][S:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:34][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29].[Cl:46]C1C=C(S)C=CC=1>>[Br:24][C:25]1[C:26]([O:44][CH3:45])=[C:27]([C:33]([CH2:36][S:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:46])[CH:39]=2)=[CH:34][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: Sc1cccc(Cl)c1
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Agent: CCOC(=O)c1ccc(CSc2ccccc2C)c(Br)c1OC
Product: CCOC(=O)c1c(CSc2cccc(Cl)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 77, starting from ethyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 87) and 3-chlorothiophenol.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:19](O)=[O:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)Cl.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:38][NH:39][O:40][CH3:41]>CCOC(C)=O>[CH:13]1([C@H:11]2[CH2:12][N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C@H:9]([C:19](=[O:20])[N:39]([O:40][CH3:41])[CH3:38])[CH2:10]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H]1C[C@@H](C2CCCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
(2S,4S)-Boc-4-cyclohexyl-pyrrolidine-2-carboxylic acid (Chem Impex Int'l, Wood Dale, Ill., 997 mg, 3.35 mmol) was treated with DCM (25 mL) followed by 1,1′-carbonyldiimidazole (598 mg, 3.69 mmol). The solution was allowed to stir at room temperature for 1.5 h then the reaction mixture was then treated with N,O-dimethyl hydroxylamine hydrochloride (360 mg, 3.69 mmol) and allowed to stir over the weekend at room temperature. The reaction mixture was diluted with EtOAc (50 mL), washed with a saturated solution of NaHCO3 (30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated affording crude (2S,4S)-tert-butyl 4-cyclohexyl-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1.14 g, 3.35 mmol, 99% yield) as a clear, colorless viscous oil. MS (ESI) 363.2 [M+Na]+. The crude material was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=12.[BH4-].[Na+].O.ClCCl.CO>CO>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=12
Reactant: O=Cc1ccc2nccn2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: OCc1ccc2nccn2c1
Yield: 57 %

Procedure:
0.90 g of the 6-imidazo[1,2-a]pyridinecarbaldehyde prepared in the Preparative Example 5 was dissolved in 20 ml of methanol. The obtained solution was stirred under cooling with ice, followed by the addition of 90 mg of sodium borohydride. The obtained mixture was stirred for 50 minutes, followed by the addition of water. The obtained mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1 to 10:1) to give 0.52 g of the title compound as a faintly orange-yellow solid (yield: 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@H:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C@H:7]([C:19]([OH:21])=[O:20])[C:6]=2[CH:22]=1.Cl.[CH3:24]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@H:9]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:8][C@H:7]([C:19]([O:21][CH3:24])=[O:20])[C:6]=2[CH:22]=1
Reactant: CO
Reactant: O=C(O)[C@H]1C[C@H](CCc2ccccc2)Oc2ccc(F)cc21
Agent: Cl
Product: COC(=O)[C@H]1C[C@H](CCc2ccccc2)Oc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Cis and trans 2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-carboxylic acid (2.9 gm) was dissolved in methanol, cooled to 0° C., and the mixture saturated with gaseous HCl. After 24 hours, the mixture was concentrated in vacuo, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (2:1 hexane/diethyl ether, SiO2) to yield the title compound (1.9 gm, Rf=0.3,2:1 hexane/diethyl ether, SiO2).
Reaction SMILES: [BrH:1].[CH:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6])([CH3:4])[CH3:3].BrBr>C(Cl)(Cl)Cl>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]([C:2]([Br:1])([CH3:4])[CH3:3])=[O:6])=[CH:12][CH:11]=1
Reactant: Br
Reactant: CC(C)C(=O)c1ccc(Cl)cc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(Br)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 59.2 g (0.47 mol) of dimethyl sulphate and 32 g (0.517 mol) of dimethyl sulphide in 270 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 87 g of 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone in 80 ml of acetonitrile is then added dropwise at 20° to 25° C., in the course of approx. 2 hours. 28.7 g (0.53 mol) of sodium methylate are introduced at the same temperature, and the mixture is stirred for a further 12 hours and then concentrated. The residue is stirred overnight with a mixture of 200 ml of ethyl acetate and 150 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 49 g (76% of theory) of crude 2-(4 chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane are obtained, and this compound is directly reacted further. ##STR158## 52 g (0.3982 mol) of p-chlorophenol and 55 g (0.3982 mol) of potassium carbonate in 400 ml of toluene are heated under reflux for 2 hours in a water separator. The mixture is cooled to 40° C., and a solution of 2-bromo-prop-2-yl 4-chlorophenyl ketone in 170 ml of toluene is added dropwise. This reaction mixture is stirred for a further 5 hours at 100° C. and then cooled, water is added and the organic phase is separated off. This is washed with dilute sodium hydroxide solution and water, dried over sodium sulphate and concentrated. 87 g (85% of theory) of crude 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone are obtained, and this compound is directly reacted further. ##STR159## 1 ml of hydrogen bromide/glacial acetic acid is added to 65.5 g (0.36 mol) of 4-chlorophenyl isopropyl ketone in 200 ml of chloroform, and 57.5 g (0.36 mol) of bromine are then added dropwise at 30° C. The mixture is stirred for a further 30 minutes at room temperature, and thereafter concentrated in vacuo. 86.6 g (92% of theory) of crude 2-bromo-prop-2-yl 4-chlorophenyl ketone are obtained, and this compound is directly reacted further.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:12])[CH:10]=[CH2:11])[CH:6]=[CH:7][CH:8]=1.CO[CH:15](OC)[N:16](C)[CH3:17]>>[CH3:15][N:16]([CH3:17])[CH:11]=[CH:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:12]
Reactant: C=CC(=O)c1cccc(OC)c1
Reactant: COC(OC)N(C)C
Product: COc1cccc(C(=O)C=CN(C)C)c1

Procedure:
A mixture of 25 g. of m-methoxyacrylophenone and 25 ml. of dimethylformamide dimethyl acetal is refluxed for 12 hours. Removal of any volatile material in vacuo gives a thick oil. Bulb to bulb distillation gives the desired product.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:26])[CH:11]=2)[N:6]=1)=O.[CH3:27][CH2:28][O:29][C:30]([CH:32](P(OCC)(OCC)=O)[CH3:33])=[O:31].Cl.C(O)C>O1CCCC1>[CH2:28]([O:29][C:30](/[C:32](/[CH3:33])=[CH:3]/[C:5]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:26])[CH:11]=2)[N:6]=1)=[O:31])[CH3:27]
Reactant: O=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
0.52 g (0.013 mol) of sodium hydride was added to a solution of 4.00 g (0.0117 mol) of 2-formyl-4-(3,4-methylene dioxybenzyl)amino-6-chloroquinazoline in 250 ml of tetrahydrofuran. 2.8 ml (0.013 mol) of triethyl 2-phosphonopropionate was dropped into the mixture prepared above under stirring and cooling with ice. The mixture thus prepared was stirred under cooling with ice for a while, heated to room temperature and stirred for additional one hour, followed by the addition of 1.5 ml of 8M hydrochloric acid/ethanol. The obtained mixture was passed through a small amount of silica gel and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from chloroform/n-hexane to give 2.00 g of the title compound.