Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+].[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36]1>CN1CCCC1=O.C(#N)C>[N:35]1([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: c1ccc2c(c1)CCN2
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCc3ccccc32)nc1-c1ccc(C)cc1
Yield: 30.9 %

Procedure:
A solution of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.104 g; 0.312 mmol), N,N-diisopropylethylamine (0.122 mL; 0.781 mmol), sodium iodide (0.047 mg; 0.312 mmol) and indoline (0.074 mL; 0.625 mmol) in a mixture of 1-methylpyrrolidin-2-one (0.5 mL) and acetonitrile (0.5 mL) was irradiated in a microwave oven at 160° C. for 30 min. The solution was partitioned between ethyl acetate and water and the organic layer was washed with a saturated solution of sodium thiosulphate, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica using a gradient of ethyl acetate (2-20%) in heptane furnished 0.040 g (31%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[NH:13][C:14]([NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[N:20][N:21]2C(OC)=O)=[O:15].[OH-].[Na+]>O1CCCC1.CO.O>[NH:21]1[C:22]2[C:18](=[C:17]([NH:16][C:14]([NH:13][CH:8]3[C:7]4[C:12](=[C:3]([C:2]([F:1])([F:31])[F:30])[CH:4]=[CH:5][CH:6]=4)[O:11][CH2:10][CH2:9]3)=[O:15])[CH:25]=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCOc4c3cccc4C(F)(F)F)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccc2[nH]ncc12)NC1CCOc2c1cccc2C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
A solution of Example 37F (0.68 g, 1.56 mmol) in a mixture of 5 ml tetrahydrofuran and 5 ml methanol was treated with sodium hydroxide (5M in methanol, 3 ml, 15 mmol), and the reaction stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water, and the precipitate that formed was collected by filtration. After drying, the solid was purified using reverse-phase HPLC (acetonitrile-water with 0.1% trifluoroacetic acid as eluent) to provide 0.29 g of title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 13.01 (s, 1H), 8.59 (s, 1H), 8.03 (s, 1H), 7.67 (d, J=7.46 Hz, 1H), 7.62 (d, J=7.80 Hz, 1H), 7.55 (d, J=7.80 Hz, 1H), 7.22 (t, J=7.80 Hz, 1H), 7.04-7.11 (m, 2H), 6.96 (d, J=7.80 Hz, 1H), 4.96-5.03 (m, 1H), 4.41-4.49 (m, 1 H), 4.30 (m, 1H), 2.18 (m, 1H), 2.06-2.13 (m, 1H). MS (ESI) m/e 377 (M+H)+. Calcd. For C18H15N4O2F3.0.15trifluoroacetic acid: C, 55.87; H, 3.88; N, 14.24. Found C, 55.95; H, 3.82; N, 14.28.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7])=O.Cl.[NH2:19]O>C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7])#[N:19]
Reactant: COc1c(C=O)cc(C(=O)O)cc1C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: O=CO
Product: COc1c(C#N)cc(C(=O)O)cc1C(F)(F)F
Yield: 27.2 %

Procedure:
3-formyl-4-methoxy-5-trifluoromethylbenzoic acid (58.04 g) was dissolved in formic acid (290 mL), and hydroxylamine hydrochloride (17.07 g) was added to the solution, and the mixture was refluxed for 19 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (15.62 g) as a brown solid.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>CN(C)C(=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:10][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[CH:11][CH:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Nc1ccc(-n2cccn2)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-n2cccn2)cc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Yield: 95.2 %

Procedure:
To a solution of 4-(1H-pyrazol-1-yl)aniline (1.00 g, 6.28 mmol) and pyridine (1.52 ml, 18.8 mmol) in N,N-dimethylacetamide (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.30 ml, 9.42 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was poured into ice-water, and 2.00 g (95.2%) of the desired product was collected by filtration as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]([CH2:14][CH3:15])[CH2:12][OH:13].[CH3:16]OCOC>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]2[C:4]=1[CH:11]([CH2:14][CH3:15])[CH2:12][O:13][CH2:16]2
Reactant: CCC(CO)c1cc(OC)ccc1OC
Reactant: COCOC
Solvent: CCOCC
Product: CCC1COCc2c(OC)ccc(OC)c21
Reaction time: 8 h

Procedure:
Under argon atmosphere, the product from step 2 herein, 2.74 g (13.03 mmol) was dissolved in 55 ml of dry ether. Dimethoxy methane 1.65 ml (19.55 mmol) and boron trifluoro etherate 4.9 ml (39.09 mmol) were then added to this solution. The obtained reaction mixture was left stirring overnight. The reaction mixture was quenched using aqueous NaHCO3 and extractions were done using ether. The combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed. The residue was purified by flash chromatography using hexanes-ethyl acetate (80:20) and (70:30) as eluent. The isolated titled product was a white solid (1.56 g; 54%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18]([OH:20])=O)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl.[S:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:21])[C:18]([NH:29][CH:26]2[CH2:27][CH2:28][S:23][CH2:24][CH2:25]2)=[O:20])[CH2:15][CH2:16]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NC1CCSCC1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCSCC2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 28.5 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (Example 44, 0.60 g, 2.07 mmol), tetrahydro-2H-thiopyran-4-amine hydrochloride (0.23 g, 2.48 mmol), triethylamine (433 μL, 3.11 mmol), EDCI (0.39 g, 2.48 mmol) and HOBt (0.38 g, 2.48 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 days. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 to 50:50) to give the title compound (0.23 g, 82%) as a white amorphous.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40]>>[CH2:39]([N:41]([CH2:42][CH3:43])[CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1)[CH3:40]
Reactant: CCNCC
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Product: CCN(CC)CCC[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and diethylamine were converted to the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH:7]([O:9][C:10](=[O:30])[C@H:11]([CH3:29])[N:12](C12C(C)(C)C1CCC(C)C2=O)OC(C)(C)C)[CH3:8])=[O:5])[CH3:2].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH2:1]([O:3][C:4]([O:6][CH:7]([O:9][C:10](=[O:30])[C@H:11]([CH3:29])[NH2:12])[CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)OC(C)OC(=O)[C@H](C)N(OC(C)(C)C)C12C(=O)C(C)CCC1C2(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)OC(C)OC(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound from step 1 (12.9 g) is solubilised in 25 ml of CH2Cl2 and 25 ml of trifluoroacetic acid is added at 0° C. The mixture is stirred at ambient temperature for 3 hours. When the reaction is complete, the reaction mixture is evaporated to dryness. The residue is taken up 3 times with cyclohexane and the mixture is re-evaporated to remove the excess TFA. Slightly brown oil, 13.4 g (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24](OC)=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=3)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21.[BH4-].[Li+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 30 h
Yield: 94.6 %

Procedure:
To a stirred solution of methyl 10-chloro-1-(3,5-dichloropyridin-2-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole-7-carboxylate (426 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was added lithium borohydride (54.5 mg, 2.50 mmol) at 0° C. After being stirred for 30 h at room temperature, the reaction mixture was diluted with ethyl acetate, quenched with aqueous ammonium chloride, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo to get the title compound as colorless solid (376 mg, 0.946 mmol, 95%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([CH3:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1.Cl.ClC1C=CC(NN)=CC=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:8](=[O:10])[C:7]3=[CH:6][NH:5][C:4]([CH3:13])=[C:3]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:2]3=[N:29]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cnc(C)c(-c2ccccc2)c1Cl
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: NNc1ccc(Cl)cc1
Product: Cc1[nH]cc2c(=O)n(-c3ccc(F)cc3)nc-2c1-c1ccccc1
Yield: 19 %

Procedure:
Following a similar procedure to that described in Example 4, except using ethyl 4-chloro-2-methyl-3-phenyl-5-pyridinecarboxylate and 4-fluorophenylhydrazine hydrochloride instead of ethyl 4-chloro-3-propyl-5-pyridinecarboxylate and 4-chlorophenylhydrazine hydrochloride, the title compound was prepared, after further purification by flash chromatography (silica gel, 5% MeOH/CH2Cl2), in 19% yield as a yellow solid; mp 303-317° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ2.25 (3H, s), 7.20 (2H, t, J 9.0 Hz), 7.42 (1H, m), 7.50-7.51 (4H, m), 8.09 (2H, dd, J 9.2, J′5.2 Hz), 8.55 (1H, d), 12.43 (1H, br s); MS (ES+) m/z 320 [MH]+. Anal. found: C, 69.91; H, 4.15; N, 13.25. C19H14FN3Oe.0.3H2O requires: C, 70.27; H, 4.53; N, 12.94%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Br[C:47]1[CH:48]=[CH:49][CH:50]=[C:51]2[C:56]=1[N:55]=[CH:54][CH:53]=[CH:52]2.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.[Cl-].[NH4+].C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH:8]([C:4]2[CH:3]=[C:2]([C:47]3[CH:48]=[CH:49][CH:50]=[C:51]4[C:56]=3[N:55]=[CH:54][CH:53]=[CH:52]4)[CH:7]=[CH:6][CH:5]=2)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:17][CH:18]=1
Reactant: Brc1cccc2cccnc12
Reactant: Clc1ccc(C(Cc2ccncc2)c2cccc(Br)c2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc(C(Cc2ccncc2)c2cccc(-c3cccc4cccnc34)c2)cc1
Temperature: 21 °C
Reaction time: 18 h

Procedure:
A solution of 4-[2-(3-bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-pyridine from Step 1 above (400 mg, 1.07 mmol), diboron pinacol ester (300 mg, 1.18 mmol), KOAc (315 mg, 3.2 mmol) and PdCl2(dppf) (26 mg, 0.032 mmol) in DMF (20 mL) was heated at 80° C. under N2 for 5 h. The resulting reaction mixture was cooled to 21° C., 8-bromoquinoline (290 mg, 1.4 mmol), Na2CO3 (2M, 1.61 mL, 3.2 mmol) and PdCl2(dppf) (26 mg, 0.032 mmol) was then added. The reaction mixture was stirred 18 h at 80° C., then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 50:50 to 25:75) provided the 8-{3-[1-(4-chloro-phenyl)-2-pyridin-4-yl-ethyl]-phenyl}-quinoline compound (319 mg).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C1C=C(C=CC=1)CNC(C1C=CN=C(C2C=C(N3CCCCC3)C=CC=2NC(=O)C2C=CC=C(C(N(CCC(NCCOC)=O)C)=O)C=2)C=1)=O.[O:99]1[CH2:104][CH2:103][N:102]([CH2:105][CH2:106][NH2:107])[CH2:101][CH2:100]1>>[O:99]1[CH2:104][CH2:103][N:102]([CH2:105][CH2:106][NH:107][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C:17]3[CH:18]=[CH:19][C:20]([N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:21][C:16]=3[C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]4[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:43])([F:1])[F:44])[CH:4]=4)[CH:15]=[CH:14][N:13]=3)=[O:30])[CH:32]=2)[CH2:101][CH2:100]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: COCCNC(=O)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: O=C(NCCN1CCOCC1)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid 4.1e using the procedure described for the preparation of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N3-(3-(2-methoxyethylamino)-3-oxopropyl)-N3-methylisophthalamide 4.2. 2-Morpholinoethanamine was used as the amine component in this coupling. 1H-NMR (300 MHz, DMSO-d6, ppm) δ 12.60 (s, 1H), 9.68 (s, 1H), 9.57 (t, 1H), 9.00 (d, J=5.1 Hz, 1H), 8.95 (t, 1H), 8.50 (s, 1H), 8.36 (s, 2H), 8.09 (t, 2H), 7.85 (d, J=5.1 Hz, 1H), 7.64 (m, 6H), 7.28 (s, 1H), 4.63 (d, J=6.0 Hz, 2H), 4.02 (m, 4H), 3.69 (m, 6H), 3.43 (m, 8H), 1.65 (m, 6H). MS (ES, m/z): 715 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]1[C:29](=[O:30])[CH2:28][CH:27]([CH2:31]OS(C)(=O)=O)[CH2:26]1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:31][CH:27]2[CH2:28][C:29](=[O:30])[N:25]([C:19]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=3[F:17])[CH2:26]2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)OCC1CC(=O)N(c2ccc(F)cc2F)C1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC2CC(=O)N(c3ccc(F)cc3F)C2)c1
Temperature: 57.5 °C
Yield: 88.3 %

Procedure:
A mixture of 1H-Pyrazole-4-carboxylic acid ethyl ester (0.100 g, 0.713 mmol), potassium carbonate (0.019 g, 1.42 mmol), Methanesulfonic acid 1-(2,4-difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl ester (0.32 g, 1.07 mmol) were taken in DMF (2 ml). The reaction mixture was heated at 55-60° C. for 20 hour. The mixture was cooled to room temperature and then to this reaction mixture water (20 ml) was added and extracted with ethyl acetate (3×25 ml), organic layers were combined and washed with brine (25 ml), dried over Na2SO4 and evaporated to dryness to obtain 1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.22 g, 91%) as a brownish sticky mass.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)=[O:11].[BH4-].[Na+]>CO>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][CH:12]([CH:10]([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[OH:11])[CH2:17][CH2:16]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(CCN2CCC(C(=O)c3nc4ccccc4s3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CCN2CCC(C(O)c3nc4ccccc4s3)CC2)cc1
Temperature: 0 °C

Procedure:
Dissolve [2-benzothiazolyl][1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methanone (3.0 g, 7.88 mmol) in methanol (150 mL) and cool to 0° C. Add sodium borohydride (597 mg, 15.77 mmol) and stir for 1.5 hours, adding additional sodium borohydride after 30 minutes. Evaporate the solvent in vacuo and partition the residue between water and methylene chloride. Separate the organic phase, wash with saturated sodium chloride, dry (MgSO4) and evaporate the solvent in vacuo. Purify by recrystallization (ethyl acetate) to give the title compound as white fluffy crystals; mp 127°-129° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)#[N:2].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1>C1C=CC=CC=1>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[O:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)#[N:2]
Reactant: OCc1cccnc1
Reactant: N#CCc1ccc(N=C=O)cc1
Solvent: c1ccccc1
Product: N#CCc1ccc(NC(=O)OCc2cccnc2)cc1
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of p-cyanomethylphenyl isocyanate (3.75 g., 0.0237 mole) in 100 ml. of benzene was added 3-pyridyl carbinol (2.59 g., 0.0237 mole). An exothermic reaction occurred and a precipitate formed. The reaction mixture was heated to reflux then allowed to stand at ambient temperatures for 3 hrs. The solid was filtered off and dried to give 5.8 g. melting at 157°-161.5° C. The product is a 92% yield of 3-pyridylmethyl N-(4-cyanomethylphenyl)carbamate. Recrystallization from methanol gave a solid melting at 162°-163.5° C.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.B(F)(F)F>ClCCl.C(O)(=O)C.C(Cl)(Cl)Cl>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3([S:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: Sc1ccccc1
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@]12C[C@H](O)[C@@]3(F)[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CCC2(Sc1ccccc1)Sc1ccccc1
Yield: 78.8 %

Procedure:
A solution of 9.0 g of 9-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione in 50 ml of dichloromethane and 50 ml of glacial acetic acid is stirred with 18.68 g of thiophenol and 7.5 ml of boron trifluoride ethereate at room temperature under nitrogen. After 50 minutes the solution is diluted with 350 ml of chloroform. The chloroform solution is washed successively with water, saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 11.6 g of an oil. This is dissolved in 1:3 hexane-chloroform and chromatographed on a 200 g-silica gel column. Elution with 1:3 hexane-chloroform and chloroform gives 3.5 of a tlc-homogeneous material. Crystallization from chloroform-methanol gives 2.0 g of the title compound, melting point 249°-250° C (dec.), with consistent spectral data.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10]([C:11](=[O:13])[CH3:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[C:10]([C:11](=[O:13])[CH3:12])=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[N:7]3[N:8]=2)=[CH:15][CH:16]=1
Reactant: C1CCNC1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Product: CC(=O)c1c(-c2ccc(F)cc2)nn2c(N3CCCC3)cccc12
Yield: 92.8 %

Procedure:
In a similar manner as described in Example 1, from 1-[7-chloro-2-(4-fluorophenyl)-pyrazolo[1,5-α]pyridin-3-yl]ethanone (0.30 g, 1.0 mmol) and pyrrolidine (0.43 mL, 5.2 mmol), 1-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (0.30 g, 91%) was obtained as a yellow solid. 1H NMR (CDCl3): δ 7.78 (d, 1H), 7.56 (m, 2H), 7.36 (t, 1H), 7.13 (t, 2H), 6.16 (d, 1H), 3.72 (m, 4H), 2.11 (s, 3H), 1.99 (m, 4H); MS m/z 324 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:9]2Cl)=[O:5])[CH3:2].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:9]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2ncc(S(C)(=O)=O)c(Cl)c2c1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc2ncc(S(C)(=O)=O)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.9 %

Procedure:
To the solution of 4-chloro-3-methanesulfonyl-quinoline-6-carboxylic acid ethyl ester (example 61f, 200 mg, 0.64 mmol) in DME (8 mL), phenylboronic acid (116 mg, 0.96 mmol), a catalytical amount of tetrakis(triphenylphosphine)-palladium(0) (147 mg, 0.13 mmol), and sodium carbonate solution (2 M, 1.12 ml, 2.23 mmol) were added. The resulted solution was heated under the microwave irradiation at 150 degrees for 15 min. After cooling to room temperature, the reaction mixture was filtered through a bed of celite with DME. The filtrate was quenched with water, and then extracted with ethyl acetate. The organic layers were collected, washed with brain, dried over sodium sulfate, and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 30%-50% ethyl acetate in hexane in 15 min, then 50% ethyl acetate in hexane in 9 min) afforded 3-methanesulfonyl-4-phenyl-quinoline-6-carboxylic acid ethyl ester (159 mg, 70%). LC-MS m/e 356 (MH+).