Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([C@H:8]([CH3:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([I:15])[N:5]=[CH:4][N:3]=1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)C(C)C)(C)C>CO>[I:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:26]2[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]2)[C:7]=1[C@@H:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)C[C@@H](C)c1c(I)ncnc1I
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@@H](C)c1c(I)ncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
Into a solution of (R)-methyl 3-(4,6-diiodopyrimidin-5-yl)butanoate (212 g, 491 mmol) and Boc-piperazine (101 g, 540 mmol) in methanol (424 mL) was added N,N-diisopropylethylamine (94.3 mL, 540 mmol). The mixture was heated at 60° C. for 24 h. Methanol was distilled off under reduced pressure below 40° C. To the mixture was added 318 mL of tetrahydrofuran. The above solvent swap process was repeated twice. To the mixture were added 424 mL of tetrahydrofuran, 212 mL of saturated aqueous ammonium chloride, and 21.2 mL of water. The organic layer was washed with 212 mL (1.00 vol.) of saturated aqueous ammonium chloride. This tetrahydrofuran solution was used for next step without further purification (91% weight assay yield). 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 3.80-3.67 (m, 1H), 3.65 (s, 3H), 3.60-3.56 (m, 4H), 3.21-3.18 (m, 4H), 3.14 (dd, J=16.2, 9.0 Hz, 1H), 2.81 (dd, J=16.2, 5.7 Hz, 1H), 1.48 (s, 9H), 1.47 (d, J=7.2 Hz, 3H). HRMS calcd. For C18H28IN4O4 [M+H]+: 491.1150. found 491.1154.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[NH:19][C:20](=[O:22])[CH3:21])C(=O)C2=CC=CC=C12.O.NN>C(O)CC>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[NH:19][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCCO
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCCN
Temperature: 0 °C

Procedure:
0.03 mol (11.5 g) of 2-acetylamino-4-nitrophenyl γ-phthalimidopropyl ether and 3 cm3 of 98% pure hydrazine hydrate in 120 cm3 of normal propyl alcohol are heated for 15 minutes on a boiling waterbath. After hot filtration, the filtrate is cooled to 0° C. The expected product precipitates. It is taken up in a dilute solution of sodium hydroxide, and the sodium hydroxide phase is extracted with chloroform. By concentrating the solvent in vacuo, the expected product, which melts at 110°-120° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].[CH3:10][CH:11]([CH3:29])[CH2:12][CH2:13][NH:14][C:15]([C:17]1[N:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16]>>[CH3:10][CH:11]([CH3:29])[CH2:12][CH2:13][NH:14][C:15]([C:17]1[N:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:5](=[O:6])[CH2:4][CH2:3][C:2]([F:9])([F:8])[F:1])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)CCC(F)(F)F
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)CCC(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 14, making variations only as required to use 4,4,4-trifluorobutyric acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white flaky solid (49% yield). 1H NMR (300 MHz, CDCl3) δ 8.07, 7.85, 7.00, 3.91, 3.82, 3.72, 3.67, 3.50, 2.50-2.67, 1.70, 1.50, 0.95. MS (ES+) m/z 402 (M+1).
Reaction SMILES: [Li]CCCC.CN(C)CCO.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][CH2:20]2)=[CH:15][N:14]=1.[F:22][C:23]1[N:34]=[CH:33][CH:32]=[CH:31][C:24]=1[C:25](N(OC)C)=[O:26]>CCCCCC.O1CCCC1>[Cl:12][C:13]1[N:14]=[C:15]([C:25]([C:24]2[C:23]([F:22])=[N:34][CH:33]=[CH:32][CH:31]=2)=[O:26])[C:16]([CH:19]2[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: Clc1ccc(C2CC2)cn1
Reactant: CON(C)C(=O)c1cccnc1F
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1cccnc1F)c1nc(Cl)ccc1C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
A 2.5M solution of nBuLi (10.94 ml, 27.34 mmol) was added to a solution of 2-(dimethylamino)ethanol (1.37 ml, 13.67 mmol) in hexane (15 ml) cooled to −78° C. The reaction mixture was stirred at −78° C. for 30 minutes then, a solution of 2-chloro-5-cyclopropylpyridine (700 mg, 4.56 mmol) in hexane (10 mL) was added dropwise. The reaction mixture was stirred for 90 minutes. A solution of 2-fluoro-N-methoxy-N-methylnicotinamide (3.36 g, 18.23 mmol) in tetrahydrofuran (15 mL) was added dropwise and the reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was partitioned between a saturated solution of ammonium chloride and ethyl acetate. The organic extract was washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a colourless oil (1.14 g, 61% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:5][CH:4]=1.C(OCC)(=O)/C=C\C(OCC)=O>[C].[Pd].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=C2CCCCC2=O)cc1
Agent: [Pd]
Agent: CCOC(=O)/C=C\C(=O)OCC
Solvent: Cc1ccccc1
Product: COc1ccc(Cc2ccccc2O)cc1
Temperature: 180 °C
Reaction time: 6 h
Yield: 62.1 %

Procedure:
In a 100-ml, four-necked flask equipped with a mechanical stirrer, a reflux condenser and a thermometer were placed 21.6 g (0.1 mole) of the 2-(4-methoxybenzylidene)cyclohexanone produced in Example 8 and 51.7 g (0.3 mole) of diethyl maleate in this order. The flask inside was purged with nitrogen. Thereto was added 2.2 g (10 wt. %, 1.0 mmole as palladium) of 5% palladium carbon (a product of Wako Pure Chemical Industries, Ltd.). The mixture was stirred at 180° C. for 6 hours and cooled to room temperature. 200 ml of toluene was added to the system. Filtration was conducted to remove the palladium carbon. The filtrate was extracted with 150 ml of a 7% aqueous sodium hydroxide solution, and this operation was repeated twice. The aqueous layer was washed with 50 ml of toluene. To the resulting aqueous layer was added 35% hydrochloric acid until the aqueous layer became acidic, after which the aqueous layer was extracted with 150 ml of ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous sodium chloride solution in this order. The ethyl acetate layer was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove ethyl acetate, to obtain 13.3 g of light yellow crystals. Yield: 62% The purity of the intended product in the crystals was 97% as measured by high performance liquid chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:12])([CH3:11])[CH2:7][C:8](O)=[O:9])=[O:5])[CH3:2].S(Cl)([Cl:15])=O>>[CH2:1]([O:3][C:4]([C:6]([CH3:12])([CH3:11])[CH2:7][C:8]([Cl:15])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)(C)CC(=O)O
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C(C)(C)CC(=O)Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3-ethoxycarbonyl-3,3-dimethylpropionic acid (1 g) and 3 ml of thionyl chloride was stirred at room temperature for 20 hours. The excess thionyl chloride was removed in vacuo to afford 1,1 g of 3-ethoxycarbonyl-3,3-dimethylpropionyl chloride.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:3].C(Cl)(=O)C(Cl)=O.[CH2:19]([N:21]1[C:29]2[CH:28]=[C:27]([NH2:30])[N:26]=[CH:25][C:24]=2[C:23]([CH3:31])=[CH:22]1)[CH3:20]>C1(C)C=CC=CC=1.ClCCl>[CH2:19]([N:21]1[C:29]2[CH:28]=[C:27]([NH:30][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([C:2]([CH3:3])=[CH2:1])=[CH:12][CH:11]=3)[N:26]=[CH:25][C:24]=2[C:23]([CH3:31])=[CH:22]1)[CH3:20]
Reactant: C=C(C)c1ccc(C(=O)O)cc1
Reactant: CCn1cc(C)c2cnc(N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C(C)c1ccc(C(=O)Nc2cc3c(cn2)c(C)cn3CC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
In a 50 ml round bottom flask, 4-(prop-1-en-2-yl)benzoic acid (1.0 g, 6.3 mmol) was dissolved in 15 ml toluene and 2.0 M oxalyl dichloride (6.3 ml, 13 mmol) in dichloromethane was added slowly. Stirring continued for 3 hours, and then volatiles were evaporated from the reaction mixture. To the residue was added 5 ml toluene and the mixture was concentrated in vacuo to azeotropically remove residual water. The residue was then dissolved in DMA (10 ml) and 1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridin-6-amine (1Q, 550 mg, 3.14 mmol) was added. Stirring continued at 50° C. overnight. The mixture was then poured into ice water. The precipitate was collected and dried to obtain the product N-(1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(prop-1-en-2-yl)benzamide (6B, 820 mg, 82%). This was used in the next step without further purification.
Reaction SMILES: CS[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:10][CH:11]=2)[CH2:6]1)=[NH:4].[ClH:29].[OH:30][NH2:31].C([O-])(=O)C.[Na+].O>C(O)C>[ClH:29].[ClH:29].[N:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:21][CH2:22][CH:17]([CH2:16][O:15][C:9]3[CH:8]=[C:7]4[C:12]([CH2:13][CH2:14][N:5]([C:3](=[N:31][OH:30])[NH2:4])[CH2:6]4)=[CH:11][CH:10]=3)[CH2:18][CH2:19]2)=[CH:24][CH:25]=1
Reactant: NO
Reactant: CSC(=N)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 40 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioimidic acid methyl ester (135 mg) in ethanol (3 ml) were added hydroxyamine hydrochloride (47 mg) and sodium acetate (56 mg), and the mixture was stirred at 40° C. for 2 hours. After completion of the reaction, water was added and the mixture was washed with chloroform. Thereto was added 4N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained solid was treated with hydrogen chloride—ethanol solution and dried under reduced pressure to give the title compound (82 mg).
Reaction SMILES: [OH:1][C@@H:2]([CH3:13])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12].[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>C(Cl)Cl>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH2:3][C@@H:2]([OH:1])[CH3:13])[CH:8]=3)=[O:11])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)cn1C[C@H](C)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1C[C@H](C)O
Yield: 13.7 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from (S)-1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid (0.608 mmol, 112 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.507 mmol, 141 mg) using DMF (2 ml) as the solvent. After the reaction had stopped, DCM was added and the reaction mixture was evaporated. The residue was purified by flash chromatography. The purified product was dissolved in a mixture of MeOH/DCM and washed twice with 1M NaHCO3. The organic phase was dried, filtered and evaporated. The product was further purified by trituration from diethyl ether, filtered and dried with vacuum. 31 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.01-1.08 (m, 6H), 2.33 (s, 3H), 3.68-3.91 (m, 3H), 4.22-4.48 (m, 3H), 4.91 (d, 1H), 7.02 (d, 1H), 7.47 (s, 1H), 7.86 (d, 1H), 7.94 (d, 1H), 8.01 (s, 1H), 8.06 (d, 1H).
Reaction SMILES: [CH2:1]([C@@:3]1([C:13]([O:15][CH3:16])=[O:14])[CH2:7][C:6]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:5]=2[O:4]1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][O:15][C:13]([C@:3]1([CH2:1][CH3:2])[CH2:7][C:6]2[CH:8]=[C:9]([O:12][CH2:7][CH2:3][CH:1]=[CH2:2])[CH:10]=[CH:11][C:5]=2[O:4]1)=[O:14]
Reactant: CC[C@@]1(C(=O)OC)Cc2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCOc1ccc2c(c1)C[C@@](CC)(C(=O)OC)O2
Temperature: 50 °C
Reaction time: 16 h
Yield: 101.3 %

Procedure:
A mixture of methyl (2S)-2-ethyl-5-hydroxy-2,3-dihydro-benzofuran-2-carboxylate (0.22 g, 1.0 mmol), prepared in Example 10, Step 2,4-bromo-1-butene (1.35 g, 10 mmol) and Cs2CO3 (1.63 g, 5.0 mmol) in DMF (20 mL) was stirred at 50° C. for 16 hrs. The reaction was diluted with ethyl acetate and washed with water. After removal of the solvent, the reisdue was purified by preparative TLC to give 0.14 g (2S)-5-But-3-enyloxy-2-ethyl-2,3-dihydro-benzofuran-2Carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH:11]=2)[N:9]=1)[NH2:3].O.NN>C(O)C>[NH2:17][CH2:16][C:12]1[CH:11]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[CH:15]=[CH:14][N:13]=1
Reactant: NC(N)=Nc1nc(-c2ccnc(CN3C(=O)c4ccccc4C3=O)c2)cs1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cc(-c2csc(N=C(N)N)n2)ccn1
Yield: 97.1 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-(2-phthalimidomethylpyridin-4-yl)thiazole (1.57 g) and hydrazine hydrate (0.63 g) in ethanol (25 ml) was refluxed for two hours. The resulting precipitate was filtered off and washed with methanol (20 ml). The two organic layer was combined and evaporated in vacuo to give 4-(2-aminomethylpyridin-4-yl)-2-(diaminomethyleneamino)thiazole (1.00 g).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:14]1[CH:27]=[CH:26][C:17]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu](I)I.O1CCOCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:17]2[CH:26]=[CH:27][C:14]([N:11]3[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9][C:10]3=[O:12])=[CH:15][CH:16]=2)=[CH:20][CH:21]=1
Reactant: O=C1CCC(c2ccccc2)N1
Reactant: Clc1ccc(Oc2ccc(I)cc2)cc1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CCC(c2ccccc2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 110 °C

Procedure:
Step A (Method 1, Using Standard Buchwald Coupling Conditions): To a 10 mL reaction tube fitted with a screw cap is charged with 5-phenylpyrrolidin-2-one (26.8 mg, 0.166 mmol), 1-(4-iodophenoxy)-4-chlorobenzene (66 mg, 0.199 mmol, 1.2 eq), copper iodide (6.3 mg, 0.033 mmol, 0.2 eq), K3PO4 (70.6 mg, 0.333 mmol, 2.0 eq), trans-cyclohexane-1,2-diamine (3.8 mg, 0.033 mmol, 0.2 eq) and 1,4-dioxane (2 mL). The system is degassed with argon then sealed and heated to 110° C. for 20 h. The reaction is cooled to room temperature, dissolved in ethyl acetate and washed with water and brine. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. Purification on silica gel (0-33% ethyl acetate in hexane) gives 1-[4-(4-chlorophenoxy)phenyl]-5-phenylpyrrolidin-2-one as a slightly brown oil (30.0 mg, 50%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([F:12])=[N:10][CH:11]=1.C([N-]C(C)C)(C)C.[Li+].[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.[OH-].[Na+]>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([B:21]([OH:26])[OH:22])[C:9]([F:12])=[N:10][CH:11]=1
Reactant: Fc1ccc(C2OCCO2)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: OB(O)c1cc(C2OCCO2)cnc1F
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 61.6 %

Procedure:
5-(1,3-Dioxolan-2-yl)-2-fluoropyridine (18.803 g, 111 mmol) was dissolved in THF (300 mL) in a 1 L round-bottom flask, and the flask was cooled in a dry ice/acetone bath under nitrogen. Then, lithium diisopropylamide (2.0 M in heptane/tetrahydrofuran/ethylbenzene; Acros) (89 mL, 178 mmol) was added via syringe over 20 min. After 75 min, triisopropyl borate (40.8 mL, 178 mmol) was added via syringe over 5 minutes, and then the reaction was allowed to slowly warm up to room temperature while being stirred under nitrogen. After 4.5 h, the reaction mixture was treated with 1 N NaOH (300 mL). The layers were separated, and the organic phase was discarded. The aqueous phase was treated with concentrated HCl and 5 N aqueous HCl to lower the pH to about 5. Then, the aqueous phase was extracted with 10:1 DCM/MeOH. The aqueous phase was treated with 5 N HCl during the extractions to maintain the pH at 5-6. Brine was also added to the aqueous phase to aid extraction. The extracts were combined, concentrated, and dried under high vacuum to give 14.56 g of product. m/z (ESI, +ve ion) 214 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]2=O)=[CH:4][CH:3]=1.C(N(CC)C(N1CCNC(=O)C1C1C=CC=CC=1)C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:9]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:8]2)=[CH:27][CH:28]=1
Reactant: CCN(CC)CCN1CCN(Cc2ccc(Cl)cc2)C(=O)C1c1ccccc1
Agent: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Product: CCN(CC)CCN1CCN(Cc2ccc(Cl)cc2)CC1c1ccccc1

Procedure:
1-(4'-Chloro benzyl)-2-keto-3-phenyl-4-diethylamino ethyl piperazine prepared according to Example 10, is reduced by following the procedure described hereinabove in Example 8 (a) whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-(4'-Chloro benzyl)-2-keto-3-phenyl-4-diethylamino ethyl piperazine is used. The resulting 3-phenyl piperazine compound is obtained in the form of a light yellow oil boiling at 180° C./0.01 mm. Hg.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:2]([CH3:1])[CH2:3][CH2:4][O:5][S:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)(=[O:15])=[O:14])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNCCO
Product: CN(CCOS(=O)(=O)c1ccc(F)cc1)S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-methylamino ethanol and 4-fluorophenyl sulfonyl chloride using the method described in Description 1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:13][CH2:14][OH:15])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.O.[CH2:17]([O:24]/[N:25]=[C:26]1\[CH2:27][CH2:28][C:29]2[C:34]\1=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:17]([O:24]/[N:25]=[C:26]1\[CH2:27][CH2:28][C:29]2[C:34]\1=[CH:33][CH:32]=[C:31]([C:2]1[CH:3]=[N:4][N:5]([CH2:13][CH2:14][OH:15])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH:30]=2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OCCn1ncc(Br)c1-c1ccncc1
Reactant: OB(O)c1ccc2c(c1)CC/C2=N\OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCCn1ncc(-c2ccc3c(c2)CC/C3=N\OCc2ccccc2)c1-c1ccncc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
To 2-(4-bromo-5-(pyridin-4-yl)-1H-pyrazol-1-yl)ethanol (0.050 g; Example 2, Step 2) dissolved in 5 mL acetonitrile was added 2 mL water, (E)-1-(benzyloxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (0.058 g; Example 2, Step 4), and 0.155 g potassium carbonate. The mixture was purged with nitrogen and about 20 mg tetrakis(triphenyphosphine)palladium(0) catalyst was added. The mixture was heated at 75° C. After 1 hour, the reaction mixture was filtered through celite, the filter cake washed with ethyl acetate, and the filtrate evaporated under vacuum. The residue was partitioned between ethyl acetate and water. The ethyl acetate was washed with saturated aqueous sodium carbonate, brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to yield 0.05 g crude product as a colorless glass. The crude material was purified by chromatography, eluting with a mixture of 8:1 dichloromethane-methanol to afford 18.6 mg (23% yield) product as a colorless glass. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 425.2 by positive ESI.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([Cl:18])[C:16]=1[F:17])[C:11]([OH:13])=[O:12].[CH2:19](I)[CH3:20]>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([Cl:18])[C:16]=1[F:17])[C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: CCI
Reactant: O=C(O)c1cc(Cl)c(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Cl)c(F)c(Cl)c1
Temperature: 80 °C

Procedure:
Potassium carbonate (36 g, 0.26 mol) was added to a stirred mixture of 3,5-dichloro-4-fluorobenzoic acid (27.6 g, 0.13 mol), ethyl iodide (41.2 g- 0.26 moles) and dry dimethylformamide (300 ml) under nitrogen. The reaction was heated to 80° C. for 6 hours. The dimethylformamide was removed in vacuo and the residue treated with water (200 ml) acidified with dilute hydrochloric acid and extracted with ethylacetate (2×250 ml). The organic layer was washed with water, dried over magnesium sulphate and evaporated in vacuo, to give an orange oil which was purified by chromatography on silica, using a 4:1 mixture of petrol and diethylether as eluent. The pink oil obtained crystallised on standing, and washing with ice-cold 40-60 petrol gave white crystals of ethyl 3,5-dichloro-4-fluorobenzoate (29 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=O)(C)(C)C.ClC1C=C(OC[C@@H]2CCCN2C(OC(C)(C)C)=O)C=NC=1.C(O[C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[CH2:48]O)=O)(C)(C)C>>[CH3:48][C:44]1[C:45]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:46][CH:47]=[CH:41][N:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Cl)c1
Product: Cc1ncccc1OC[C@H]1CCCN1

Procedure:
Replacing (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol of Example 15 with (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (Aldrich Chemical Co.), and following the procedure of steps 15a and 15b, the title compound was prepared. The MS and 1H NMR spectra were similar to compound 15a.