Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([NH2:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1>>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2([CH2:8][C:9]([NH2:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: NC(=O)CC1(N)CCCCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: NC(=O)CC1(Nc2nc(Cl)ncc2Cl)CCCCC1

Procedure:
2-[1-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide was prepared from 2-(1-Amino-cyclohexyl)-acetamide (2.0 g, 0.013 mol) (Suzuki, T.; Imanishi, N. Itahana, H.; Watauki, S.; Ohta, M.; Mase, T., Synthetic Communications, 1988, 28(4), 701-712) and 2,4,5-Trichloro-pyrimidine (1.5 mL, 0.013 mol) in an analogous manner to Example 1d. Product isolated as a white solid (2.28 g, 59%). MP: 124-128° C. 1HNMR (400 MHz, DMSO-d6, δ, ppm): 8.19 (s, 1H), 7.51 (br s, 1H), 7.34 (br s, 1H), 7.04 (br s, 1H), 2.62 (s, 2H), 2.58-2.52 (m, 2H), 1.55-1.30 (m, 8H). MS: 303.00 (MH)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[C:2]#[CH:3].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[O-2].[Mg+2]>CC(N(C)C)=O>[CH2:18]([O:17][C:15]([CH2:14][N:4]([CH2:1][C:2]#[CH:3])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:16])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: C#CCNc1cccc(C#N)c1
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(=O)N(C)C
Product: C#CCN(CC(=O)OCC)c1cccc(C#N)c1

Procedure:
A mixture of 0.78 g (5 mmol) of 3-propargylamino-benzonitrile, 0.55 ml (5 mmol) of ethyl bromoacetate and 0.2 g (5 mmol) of magnesium oxide are stirred in 20 ml of dimethylacetamide for 6 days at 75° C. Then the mixture is filtered, the filtrate is diluted with ethyl acetate and washed with water. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with dichloromethane.
Reaction SMILES: [Cl:1][CH:2]1[N:7](Cl)[CH:6]=[CH:5][N:4]=[CH:3]1.CN(C=O)C.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClC1C=NC=CN1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3,4-Dichloro-pyrazine (3 g, 20.1 mmol, 1.0 eq.), dry DMF (20 mL) and piperazine-1-carboxylic acid tert-butyl ester (7.3 g, 40 mmol, 2 eq). The reaction mixture was heated to 90° C. and allowed to stir for 4 hours. After allowing the reaction to return to room temperature water (100 mL) was added and the product extracted with DCM (2×200 mL). The organic layer was washed 1 N HCl (2×) and brine (2×) and dried over NaSO4. After removing the solvent the product was isolated as an orange oil (6 g, 80%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11].[Br:12][CH:13](Br)[CH3:14]>O.C(O)C>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[O:11][CH2:14][CH2:13][Br:12]
Reactant: CC(Br)Br
Reactant: Cc1cccc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C)c1OCCBr

Procedure:
To a solution containing sodium hydroxide (80 g) in water (1 liter) and ethanol (0.5 liter) are added 2,6-dimethyl-phenol (245 g) dissolved in ethanol (0.5 liter), and then dibromoethane (750 g). The mixture is refluxed for 48 hours, under vigorous stirring. It is then extracted with methylene chloride. After washing with dilute aqueous sodium hydroxide and then with water, the solvent is evaporated in vacuo. 2(2,6-Dimethyl-phenoxy)-1-bromo-ethane boils at 148°-150° C./25 mm Hg.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[O:5]1[CH2:9][CH2:8][O:7][CH:6]1[C:10]1[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[O:5]1[CH2:9][CH2:8][O:7][CH:6]1[C:10]1[CH:11]=[C:12]([NH:16][C:1](=[O:3])[CH3:2])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(C2OCCO2)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C2OCCO2)c1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A solution of acetyl chloride (3.75 g, 0.048 mol, 3.4 mL) in CH2Cl2 (6.5 mL) was added dropwise over 15 min to an ice-bath chilled solution of 3-[1,3]dioxolan-2-yl-phenylamine (7.18 g, 0.043 mol) and pyridine (3.40 g, 0.043 mol, 3.5 mL) in CH2Cl2 (85 mL). The solution was then brought to room temperature, stirred for 1 hr, and poured onto ice-water (60 mL). The phases were separated, and the organic layer washed with water, saturated NaHCO3, brine and dried with MgSO4. Removal of the solvent in vacuo afforded N-(3-[1,3]dioxolan-2-yl-phenyl)-acetamide (8.01 g, 90%). 1H NMR (CDCl3) δ 2.08 (s, 3H), 4.03 (d of mult., ethylenedioxy), 5.71 (s, 1H), 7.17 (d, J=8 Hz, 1H), 7.26 (t, J=8 Hz, 1H), 7.53 (d, J=8 Hz, 1H), 7.62 (s, 1H), 8.32 (br s, 1H). 13C NMR (CDCl3) δ 168.9, 138.8, 138.3, 129.1, 122.3, 120.8, 118.1, 103.5, 65.4, 24.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]2.B(O[O-])=[O:30].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([OH:30])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]2
Reactant: O=BO[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c2C1=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(O)cc(F)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of 144g (16.0 g, 40.9 mmol) in THF (200 mL) and H2O (200 mL) was added sodium perborate (26.4 g, 171.8 mmol) in one portion at RT under N2. See FIG. 3. The mixture was stirred at room temperature for 8 h. The mixture was filtered and the filtration was extracted with EtOAc (400 mL×5). The combined organic phase was washed with saturated brine (200 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=30/1, 5/1) to afford 9.50 g (82.6%) of tert-butyl 8-fluoro-6-hydroxy-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate 144h. 1H NMR (400 MHz, CDCl3) δ 6.56-6.60 (d, J=13.6 Hz, 1H), 6.49 (s, 1H), 3.83-3.86 (m, 2H), 2.82-2.84 (m, 2H), 1.49 (s, 9H), 1.20 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:11]=[CH:10][C:9]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:30])[CH2:28]Br)[CH:22]=1>CN(C)C=O.[Cl-].[Na+].O>[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:11]=[CH:10][C:9]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH2:28][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:30])[CH:22]=1
Reactant: C1COCCN1
Reactant: Nc1c(C(=O)c2cccc(C(=O)CBr)c2)cnn1-c1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(C(=O)c2cccc(C(=O)CN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Reaction time: 16 h
Yield: 21.9 %

Procedure:
To a solution of morpholine (0.25 ml, 2.79 mmol) in dimethylformamide (5 ml) was added a solution of 5-amino-4-[3-(2-bromoacetyl)benzoyl]-1-(4-fluorophenyl)pyrazole (0.22 g, 0.56 mmol) in dimethylformamide (5 ml). After 16 h, the reaction mixture was poured into brine and the product was extracted into ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: ethyl acetate-10% methanol/ethyl acetate) to give 5-amino-1-(4-fluorophenyl)-4-[3-(morpholin-4-ylmethylcarbonyl)benzoyl]pyrazole (0.05 g) as a solid.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:33][OH:34])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:30])[F:31])[CH:23]=1)[CH2:33][O:34][C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1
Reactant: OCc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)c(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (3-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenoxy)phenyl)methanol.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[C:5]1=[O:11].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>CN(C)C=O>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[C:6](=[O:10])[C:5]1=[O:11]
Reactant: CN1CCNC(=O)C1=O
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C=O)cc2)C(=O)C1=O
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
0.34 g of 60% sodium hydride was added to a solution of 1.00 g of 1-methyl-2,3-piperazinedione in 10 mL of N,N-dimethylformamide, and this mixture was stirred for 10 minutes at 50° C. Then, 0.88 mL of 4-fluorobenzaldehyde was added thereto and the mixture was stirred for 30 minutes at 120° C. The mixture was cooled to room temperature, and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=15:1] to yield 0.80 g of 4-(4-methyl-2,3-dioxo-1-piperazinyl)benzaldehyde as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:21])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.O>[CH2:29]([N:26]([CH2:27][CH3:28])[CH2:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[CH2:19][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:3][CH:4]=2)[CH:9]=[N:10]1)[CH3:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(N)cc2)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(NS(C)(=O)=O)cc2)c1-c1ccccc1

Procedure:
A solution of 8 lg (0.02 mol) of 4-(4-aminophenyl)-N-[3-(diethylamino)propyl]-5-phenyl-1H-pyrazole-1-acetamide of example 46 in 50 mL of pyridine was cooled to 5° C. and 4.6 g (0.04 mol) of methanesulfonyl chloride was added dropwise below 10° C. The reaction was stripped below 60° C. in vacuo, dissolved in about 75 mL of water, treated with excess saturated aqueous sodium bicarbonate, extracted into methylene chloride and stripped. The product was recrystallized from acetonitrile, 7.2 g, mp 179°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Cl-].[Br:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[F:27])[CH:18]=[N+:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.BrC1C=C(C=CC=1F)C=O.N1CCCC1>>[Br:14][C:15]1[CH:16]=[C:17]([CH:18]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=[CH:11][CH:10]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Fc1ccc(-n2cccc2)cc1
Reactant: Fc1ccc(C=[N+]2CCCC2)cc1Br
Agent: O=Cc1ccc(F)c(Br)c1
Agent: [Cl-]
Solvent: C1CCNC1
Product: Fc1ccc(-n2cccc2C(c2ccc(F)c(Br)c2)N2CCCC2)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-(4-fluoro-phenyl)-1H-pyrrole and 1-(3-bromo-4-fluoro-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 4 from 3-bromo-4-fluorobenzaldehyde and pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
According to Scheme 3 Step 1, Method A: 2-Chloro-1-fluoro-4-nitrobenzene (1.12 mmol, 0.20 g) was added to a suspension of 3-chlorophenol (1.02 mmol, 0.10 mL), Cs2CO3 (1.25 mmol, 407 mg) in DMF/ACN (40:60, 3.6 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was used without further purification to obtain 2-chloro-1-(3-chlorophenoxy)-4-nitrobenzene (1.02 mmol, 288 mg, 100%) as an orange solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.CC(C1C=C(S[C@@H]2CCCC[C@H]2S[CH2:31][C:32](N(C)CCC2C=CC=CN=2)=[O:33])C=C(C(C)(C)C)C=1)(C)C>>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:32](=[O:33])[CH3:31])=[CH:4][CH:5]=1
Reactant: NCc1ccncc1
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Product: CC(=O)NCc1ccncc1

Procedure:
Substituting 4-(aminomethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-(4-pyridinylmethyl)-acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[C:12]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[C:9]2[O:10][CH2:12][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)c2c(c1)OCO2
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of 3-chloro-4,5-dihydroxybenzaldehyde (8.0 g, 46 mmol) and BrClCH2 (23.9 g, 185 mmol) in dry DMF (100 mL) was added Cs2CO3 (25 g, 190 mmol). The mixture was stirred at 60° C. overnight and was then poured into water. The resulting mixture was extracted with EtOAc (50 mL×3). The combined extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 7-chlorobenzo[d][1,3]dioxole-5-carbaldehyde (6.0 g, 70%). 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.42 (d, J=0.4 Hz, 1H), 7.26 (d, J=3.6 Hz, 1H), 6.15 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Cl[CH2:10][CH2:11][CH2:12][C:13]#[N:14]>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])[CH2:3]1
Reactant: N#CCCCCl
Reactant: CC1CNCC(C)C1
Solvent: c1ccccc1
Product: CC1CC(C)CN(CCCC#N)C1

Procedure:
Into a solution under reflux of 50 g (0.424 mole) of 3,5 dimethylpiperidine at 96% in 60 ml benzene are run in25 minutes 22 g (0.212 mole) of 4-chlorobutyronitrile and the reflux is continued for 2h.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]1[CH:32]=[CH:33][C:34]2[N:35]([C:37]([C:40](O)=[O:41])=[CH:38][N:39]=2)[CH:36]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]1[CH:32]=[CH:33][C:34]2[N:35]([C:37]([C:40]([NH:16][S:13]([C:10]3[CH:9]=[CH:8][C:7]([N:4]4[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]4)=[CH:12][CH:11]=3)(=[O:15])=[O:14])=[O:41])=[CH:38][N:39]=2)[CH:36]=1
Reactant: O=C(O)c1cnc2ccc(N3CCCCC3c3cc(F)ccc3F)cn12
Reactant: NS(=O)(=O)c1ccc(N2CCC(O)C2)cc1
Product: O=C(NS(=O)(=O)c1ccc(N2CC[C@H](O)C2)cc1)c1cnc2ccc(N3CCCCC3c3cc(F)ccc3F)cn12

Procedure:
The title compound was prepared by the method similar to that of Example 31 employing 4-(3-hydroxypyrrolidin-1-yl)benzene sulfonamide (Int-51) and 6-(2-(2,5-difluorophenyl)piperidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Int 23) to afford an enantiomeric mixture which was purified by column chromatography using CHIRALPAK AD-H column and n-HEXANE:ETHANOL, 80:20 isocratic solution as eluent to afford 6-(2-(2,5-difluorophenyl)piperidin-1-yl)-N-((4-((S)-3-hydroxypyrrolidin-1-yl)phenyl)sulfonyl)imidazo[1,2-a]pyridine-3-carboxamide (0.012 g) (Isomer-II) MS (ESI): m/z 582.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 12.00 (1H, S), 8.83 (1H, s), 8.4 (1H, s), 7.76-7.74 (2H, m), 7.58-7.56 (1H, m), 7.46-7.43 (1H, m), 7.07-6.99 (2H, m), 6.91-6.90 (1H, m), 6.65-6.62 (1H, m), 5.04-5.03 (1H, d), 4.42 (2H, bs), 3.50-3.38 (4H, m), 3.28-3.20 (1H, m), 2.90-2.85 (1H, m), 2.06-2.03 (1H, m), 1.91-1.88 (3H, m), 1.76-1.67 (1H, m), 1.64-1.53 (1H, m) ppm.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:6][N:5]=1.CN(C)C(=O)C.[SH:23][C:24]1[NH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>CC(C)=O>[ClH:2].[CH3:10][C:9]1[C:4]([CH2:3][S:23][C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
12.71 g (0.0459 mole) of 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine hydrochloride were suspended in 322 ml of acetone in the presence of 2.52 ml N,N-dimethylacetamide. Then 7.24 g (0.0597 mole) of 2-mercaptobenzimidazole were added. The mixture was heated to reflux and stirred for 5 hours. After cooling to room temperature, the resulting suspension was filtered to obtain the wet product.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[O:22]([CH2:29][CH2:30][CH2:31]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:31][CH2:30][CH2:29][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: BrCCCOc1ccccc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCCOc2ccccc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g--see Preparation B), 3-phenoxypropylbromide (0.24 g), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. On cooling to room temperature water (40 ml) was added and the resulting mixture extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 7%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.23 g.
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].CN(C)C=O>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=3[O:36][CH3:37])[CH2:3][CH2:2]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCN(c2n[nH]c3ccccc23)CC1
Yield: 85.7 %

Procedure:
A mixture of 3-(1-piperazinyl)-l H-indazole (4.0 g, 20 mmol), K2CO3 (3.0 g, 22 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI, and dimethylformamide (60 ml) was stirred at 90 C for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed (brine), dried (MgSO4), and the solvent was concentrated to afford a white solid, which was triturated with diethyl ether and collected to yield 7.0 g of product. Two recrystallizations from absolute ethyl alcohol yielded 5.3 g (64%) of analytically pure 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-ethanone, m.p.=155°-157° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[N:38]=[CH:39][S:40][CH:41]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1cscn1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cscn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-(chloromethyl)-1,3-thiazole hydrochloride (0.58 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 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 purified by silica gel column chromatography to give the title compound as a colorless solid (1.01 g, 66%).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=2)[CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[ClH:1].[CH2:10]1[C:11]2[C:16](=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2)[CH2:17][NH:9]1
Reactant: [H][H]
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CNC2
Yield: 84 %

Procedure:
10% Pd/C (4.3 g) was added to a solution of methyl 2-benzylisoindoline-5-carboxylate hydrochloride (43 g; 1 equiv.) in 800 ml of methanol. The mixture was hydrogenated for 90 minutes at 60 mm hydrogen. When the conversion was complete, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the crude product was recrystallised from chloroform. In this manner the desired product (25.39 g; 84%) was obtained in the form of a white solid having a purity of 98.63%.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][CH:11]=1.[C:14](Cl)([CH3:16])=[O:15]>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][C:11]=1[C:14](=[O:15])[CH3:16]
Reactant: CC(=O)Cl
Reactant: COc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(Cl)c1
Temperature: -10 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a mixture of AlCl3 (42.08 g; 315.60 mmol) in CH2Cl2 (300 mL) was added dropwise 3-chloroanisole (22.50 g; 157.80 mmol), at −30° C. To the resulting mixture was added dropwise a solution of AcCl (10.50 mL; 147.63 mmol) in CH2Cl2 (100 mL) at such a rate to keep the temperature below −15° C. The resulting mixture was stirred for 4 hours at −10° C. Subsequently, the mixture was poured onto ice and extracted with CH2Cl2. The combined organic layers, were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:9) to afford 1-(2-chloro-4-methoxy-phenyl)-ethanone (17.68 g).