Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][P:6]([O:39]C(C)(C)C)([O:8][CH:9]([CH3:38])[CH2:10][O:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=2)[C@@:16]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])([F:27])[C:15]1=[O:37])=[O:13])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[P:6]([O:8][CH:9]([CH3:38])[CH2:10][O:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=2)[C@@:16]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])([F:27])[C:15]1=[O:37])=[O:13])([OH:7])([OH:39])=[O:5]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCC(C)OP(=O)(OC(C)(C)C)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCC(C)OP(=O)(O)O)c2cc(C(F)(F)F)ccc21
Yield: 57.4 %

Procedure:
A solution of (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid 2-(di-tert-butoxy-phosphoryloxy)-propyl ester ((S)-VII, n=2) (540 mg, 0.82 mmol) in dichloromethane (30 mL) was stirred with trifluoroacetic acid (0.6 mL) at room temperature for 3 hours. LC-MS indicated the completion of the reaction. After removal of the solvent the residue was dissolved in methanol and the crude product was purified by prep. HPLC, affording the title compound 255 mg (57%) as white solid after lyophilization. 1H NMR (CDCl3, 500 MHz) δ 8.27 (s, 1H), 7.73 (d, 1H), 7.42 (d, 1H), 7.32 (d, 1H), 7.27 (d, 1H), 6.75 (d, 1H), 4.50 (b, 6H, containing some H2O as solvate), 4.54 (m, 2H), 4.17 (b, 2H), 3.49 (s, 3H), 2.1 (m, 2H); MS (m/e) 539.92 (M+−1); LC-MS, 542 (MH+, 98.5%); 31P NMR (CDCl3, 500 MHz) δ 2.03; 19F NMR (CDCl3, 500 MHz) δ−63.4, 153.8; Anal. Calcd. for C20H17ClF4NO8P: C=44.34%, H=3.16%, N=2.58%; Found: C=44.01%, H=3.11%, N=2.45%.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][N:40]=[C:16]2[N:15]1[CH2:41][CH2:42][CH3:43]>C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([CH2:41][CH2:42][CH3:43])[C:16]4[N:17]([N:38]=[CH:39][N:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[NH:34]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CCC)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CCC)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (2.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-[(5-oxo-4,7-dipropyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.26 g, 45%).
Reaction SMILES: [CH3:1]N(C)C=O.[ClH:6].[C:7]1(/[CH:13]=[CH:14]/[C:15]([NH:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].CI>O>[ClH:6].[C:7]1(/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:1])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:21]2)=[O:16])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: O=C(/C=C/c1ccccc1)NCCC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN(CCC1CCN(Cc2ccccc2)CC1)C(=O)/C=C/c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a dimethylformamide solution (5 ml) of (E)-3-phenyl-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide.hydrochloride (0.6 g) obtained in Example 1 was gradually added sodium hydride (80 mg) at room temperature and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was cooled on an ice-bath and there was added methyl iodide (0.21 g), followed by stirring at room temperature for one hour. To the resultant mixture was added water and the mixture was subjected to extraction with dichloromethane. The dichloromethane solution was washed with water and dried over anhydrous sodium sulfate, then the solvent was distilled off. The oily residue was subjected to a silica gel column chromatography [developing solvent : ethyl acetate - methanol=10 : 1(V/V)]. Then the solvent of the solution containing the object compound was distilled off. To the residue was added an ethanolic solution (0.5 ml) of 3N hydrogen chloride, followed by distilling off the solvent to obtain an amorphous powder (0.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:37][C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: ClCc1ccncc1
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCc4ccncc4)c(OC)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (41 mg), were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C., for 3 hr. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 65 mg (yield 66%) of the title compound.
Reaction SMILES: CC(=O)C.CCOC(C(C1(C#N)CCCC1)C#N)=O.C([O-])(=O)C.[NH4+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:34]([CH3:49])=[C:35]([C:47]#[N:48])[C:36](=[O:46])[N:37]([C:39]3[CH:44]=[CH:43][C:42](Cl)=[CH:41][CH:40]=3)[N:38]=2)=[CH:28][CH:27]=1>CCO>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:34]([CH3:49])=[C:35]([C:47]#[N:48])[C:36](=[O:46])[N:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:38]=2)=[CH:28][CH:27]=1
Reactant: Cc1c(Sc2ccc(Cl)cc2)nn(-c2ccc(Cl)cc2)c(=O)c1C#N
Agent: CC(=O)[O-]
Agent: CCOC(=O)C(C#N)C1(C#N)CCCC1
Agent: [NH4+]
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1c(Sc2ccc(Cl)cc2)nn(-c2ccccc2)c(=O)c1C#N

Procedure:
The reaction of 1.8 g (5.9 mmol) of 1-[(4-chlorophenyl)thio]-1-[phenyl)hydmzono]-2-propanone, 1.5 ml of ethylcyano acetate and 750 mg of ammonium acetate as in Example 22, yielded1.29 g of 6-[(4-chlorophenyl)thio]- 2,3-dihydro-2-(4-chlorophenyl)5-methyl-3-oxo-4-pyridazinecarbonitrile, mp 180°-182° C. (EtOH).
Reaction SMILES: I[CH2:2][CH3:3].[CH2:4]([NH:11][C:12](=[O:34])[N:13]([C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][C:22]=2[OH:33])[CH:18]=[CH:19][CH:20]=1)[CH3:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:2]([O:33][C:22]1[CH:23]=[C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:25]=[CH:26][C:21]=1[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N:13]([CH3:14])[C:12]([NH:11][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:34])[CH:16]=1)[CH3:3]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCC)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 200 μL (2.46 mmol, 3 eq) of 1-iodoethane and 350 mg (0.82 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 6 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 4.4 eq) of potassium carbonate at 80° C. for 5 hours, methyl 3-[2-ethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7](=[O:19])[CH2:6][CH2:5]2.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27].N>C(O)C.CO.C(Cl)Cl>[O:19]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[NH:27])[CH:3]=2)[N:8]1[CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)CCC(=O)N2CCN1CCCC1
Agent: I
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)CCC(=O)N2CCN1CCCC1)c1cccs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (165 mg, 0.636 mmol) in 5 mL of ethanol was treated with methyl thiophene-2-carbimidothioate hydroiodide (363 mg, 1.27 mmol) and stirred for 18 hours at room temperature. The mixture was partitioned between CH2Cl2 (50 mL) and saturated sodium bicarbonate (10 mL). The aqueous layer was extracted with an additional 20 mL CH2Cl2. The combined organic layers were dried over sodium sulfate and concentrated to give a yellow residue which was subjected to flash chromatography on a Biotage system using 5-10% 2M NH3 in MeOH/CH2Cl2 to give a yellow solid. Yield: 157 mg of yellow oil (68%). 1H NMR (CDCl3) δ: 7.44 (d, J=5.4 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.84 (d, J=4.2 Hz, 1H), 4.86 (br s, 2H), 4.12-4.06 (m, 2H), 2.88-2.83 (m, 2H), 2.75-2.70 (m, 2H), 2.65-2.60 (m, 6H), 1.82-1.78 (m, 4H). MS (ESI): 369.2 (M+1). ESI-HRMS calculated for C20H25N4SO (MH+): 369.1743, Observed: 369.1731.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C(C1C=CC=CC=1[F:62])#C>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:62])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccccc1F
Reactant: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: Fc1ccccc1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-2-fluorobenzene.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[H-].[Na+].C(OC([N:24]1[CH2:29][C@@H:28]([CH3:30])[N:27]([C:31](Cl)=[O:32])[C@@H:26]([CH3:34])[CH2:25]1)=O)(C)(C)C>>[CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][O:13][C:31]([N:27]2[C@H:28]([CH3:30])[CH2:29][NH:24][CH2:25][C@@H:26]2[CH3:34])=[O:32])=[CH:8][CH:7]=1
Reactant: CC(C)CCOc1ccc(CO)cn1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCOc1ccc(COC(=O)N2[C@H](C)CNC[C@@H]2C)cn1

Procedure:
cis-2,6-Dimethyl-piperazine-1-carboxylic acid 6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester was prepared from [6-(3-Methyl-butoxy)-pyridin-3-yl]-methanol (0.19 g), sodium hydride (60%, 0.048 g) and 4-tert-butoxycarbonyl-1-chlorocarbonyl-cis-2,6-dimethylpiperazine (0.25 g) according to the method described in Example 54 to give the product as a pale oil (0.052 g, 13%): δH (400 MHz, CDCl3) 8.15 (1H, d, J 2.5 Hz), 7.58 (1H, dd, J 8.5, 2.5 Hz), 6.71 (1H, d, J 8.5 Hz), 5.07 (2H, s), 4.32 (2H, t, J 7 Hz), 4.18 (2H, m), 3.95 (2H, m), 2.95 (2H, m), 1.81 (1H, nonet, J 7 Hz), 1.67 (2H, q, J 7 Hz), 1.47 (9H, s), 1.22 (6H, d, J 7 Hz) and 0.96 (6H, d, J 6.5 Hz); HPLC (XTERRA, 50/80, 235 nm) 91% (7.19 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:35])([C:29]2[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH:24]=O)=[CH:4][CH:3]=1.Cl.[CH2:37]([O:44][NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.CO>[CH2:37]([O:44][N:45]=[CH:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([OH:35])[C:29]4[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=4)[CH:10]=3)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=2)[CH:22]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NOCc1ccccc1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(C=O)c1)cc(=O)n2C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(C=NOCc3ccccc3)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-{6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl}-benzaldehyde (202 mg, 0.418 mMol) was dissolved in a solution of DCM (2.0 mL) and MeOH (2.0 mL) under an atmosphere of dry N2. To this solution was added O-benzylhydroxylamine hydrochloride (66.8 mg, 418 mMol) and the mixture was stirred for 24 hours at ambient temperature. The reaction mixture was concentrated under vacuum and was purified by radial chromatography eluting with MeOH/EtOAc/NH4OH (5:95:0.1) to give the titled compound as an oil.
Reaction SMILES: C([N:4](CC)[CH:5]([CH3:7])[CH3:6])(C)C.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=1.C1(N)CC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O>C(OCC)(=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH:4][CH:5]2[CH2:7][CH2:6]2)=[O:19])=[N:15][CH:16]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (0.69 mL, 0.0040 mol) was added to a mixture of 5-bromopyridine-2-carboxylic acid (400 mg, 0.002 mol), cyclopropylamine (0.16 mL, 0.0024 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.1 g, 0.0024 mol) in N,N-dimethylformamide (9.4 mL, 0.12 mol) at 0° C. and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with water and brine successively, dried over sodium sulfate, filtered and concentrated. The product was purified by CombiFlash eluting with CH2Cl2/EtOAc (max.EtOAc 20%). LC-MS: 241.1/243.1 (M+H+)
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:7]=2[N:8]=[C:9](S(C)(=O)=O)[N:10]=1)[CH:2]([CH3:4])[CH3:3].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[OH:42]>>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[O:42][C:9]1[N:10]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:7]=2[N:8]=1
Reactant: Oc1ccccc1F
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(S(C)(=O)=O)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Product: Cc1cc(-c2nc3c(CC(C)C)nc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
Analogously to example 1 (i), the reaction of 60 mg of tert-butyl [4-(7-isobutyl-5-methanesulfonyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate with 2-fluorophenol gave 64 mg (100%) of the title compound.
Reaction SMILES: N1C=CC=C[C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11]N=1)=[O:8].[Br-].[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:18])=[O:17].CC([O-])(C)C.[K+]>C1COCC1>[C:7]([OH:17])(=[O:8])/[CH:9]=[CH:14]/[CH2:13][CH2:12][CH3:11].[C:16]([OH:18])(=[O:17])/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH3:2]
Reactant: O=C(c1ccccn1)c1ccccn1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC/C=C/C(=O)O
Product: CCC/C=C\C(=O)O
Yield: 88.6 %

Procedure:
Prepared as above from 150.0 mg (0.35 mmol) of the pyridyl ketone, 308.2 mg (0.70 mmol) of (4-carboxybutyl)triphenylphosphonium bromide, and 1.4 mL (1.4 mmol) of 1.0M t-BuOK in 1.5 mL of THF at 0° C. for 1.5 hr. Flash chromatography followed by preparative HPLC with MeOH-AcOH-CH2 Cl2 (3.5:1.5:95) furnished 107.9 mg 60.2%) of (E)-hexenoic acid and 35.4 mg (19.8%) of (Z)-hexenoic acid (E/Z=3:1). The title (E)-isomer was characterized as follows: mp 86°-90° C.; 1H NMR (CDCl3) δ8.55 (br s, 1H), 8.45 (d, J=4.7 Hz, 1H), 8.25 (s, 1H), 8.04 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.2 Hz, 2H), 7.21 (m, 1H), 7.12 (distorted t, J=~5.1 Hz, 1H), 6.19 (t, J=7.5 Hz, 1H), 3.44 (dt, J=7.0, 6.7, Hz, 2H), 2.34 (t J=7.1 Hz, 2H), 2.25 (dt, J=7.4, 7.3 Hz, 2H), 1.68-0.82 (m, 19H); FDMS 516 (M+1). Anal. (C31 H37N3O4) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.[H-].[Na+]>>[Cl:10][C:11]1[N:16]=[C:15]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:14]=[CH:13][N:12]=1
Reactant: COc1ccc(S)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(Sc2ccnc(Cl)n2)cc1

Procedure:
The 2-chloro-4-(4-methoxyphenylsulphanyl)pyrimidine was prepared in a similar manner to the analogous starting material of Example 1, from 4-methoxybenzenethiol (1.90 g, 13.4 mmol), 2,4-dichloropyrimidine (2.0 g, 13.4 mmol) and sodium hydride [60% dispersion in oil] (590 mg, 14.8 mmol) as an off-white solid m.p. 69-70°.
Reaction SMILES: [N:1]1([C:11]([NH2:13])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].N1C2C(=CC=CC=2)CC1=O.[Cl:24][S:25](N=C=O)(=[O:27])=[O:26]>>[Cl:24][S:25]([NH:13][C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])=[O:12])(=[O:27])=[O:26]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NC(=O)N1C(=O)Cc2ccccc21
Agent: O=C1Cc2ccccc2N1
Product: O=C1Cc2ccccc2N1C(=O)NS(=O)(=O)Cl

Procedure:
In the second method for preparing the 2-oxindole-1-carboxamide compounds of the formula II, a 2-oxindole of the formula VI is reacted with chlorosulfonyl isocyanate to give the intermediate N-chlorosulfonyl-2-oxindole-1-carboxamide of formula VII, followed by removal of the chlorosulfonyl group by hydrolysis, viz., ##STR10##
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=2[N:6]=1.[Cl:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([I:24])[C:19]=1[Cl:25]>>[Cl-:15].[NH2:1][C:2]1[N:3]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([I:24])[C:19]=2[Cl:25])[C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=2[N+:6]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([I:24])[C:19]=1[Cl:25]
Reactant: COc1cc2nc(N)[nH]c2cc1OC
Reactant: ClCOc1cccc(I)c1Cl
Product: COc1cc2c(cc1OC)[n+](COc1cccc(I)c1Cl)c(N)n2COc1cccc(I)c1Cl
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5,6-dimethoxybenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 2-chloro-3-iodophenyl chloromethyl ether, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=C(C3C=CC=CC=3)[C:3]=12.[I:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.[CH3:32]NN>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:32])[N:15]=[C:28]([C:27]3[CH:30]=[CH:31][C:24]([I:23])=[CH:25][CH:26]=3)[C:3]=12
Reactant: CNN
Reactant: O=Cc1ccc(I)cc1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: Cn1nc(-c2ccc(I)cc2)c2c(Cl)c(-c3ccccc3)nnc21
Reaction time: 4 h

Procedure:
Compound 43 was synthesised following similar procedures outlined in Example 22 (Compound 9), using 4-iodobenzaldehyde instead of benzaldehyde in Step 1 and methyl hydrazine instead of hydrazine hydrate in Step 3. As a slightly modified procedure, Step 3 was performed at 60° C. for 4 h in a sealed tube. Subsequently, the mixture was cooled and filtered, and the residue was washed with cold ethanol. The filtered residue was purified by column chromatography (silica gel, gradient 5 to 10% ethyl acetate/isohexane) yielding Compound 43 as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(N3CCOCC3)ccc21
Product: CC1c2ccc(N3CCOCC3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH2:9][CH3:10].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C>ClCCl>[C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:21])[CH3:20]
Reactant: CCCCN(CCCCO)c1ccc(C=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(CCCCOC(C)=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 249.4 g (1 mole) of 4-(N-4-hydroxybutyl-N-butylamino)benzaldehyde in dichloromethane are added 153.1 g (1.5 moles) of acetic anhydride, 151.8 g (1.5 moles) of triethylamine, and 8.5 g (7 mole %) of 4-N,N-dimethylaminopyridine. The reaction mixture is stirred at room temperature for 16 hours. The product solution is washed with cold 2N HCl and then with filtered through cotton, and evaporated to dryness.