Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:16][C:17]([OH:19])=O)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:20][N:21]([CH3:24])[CH:22]=O>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16](=[CH:20][N:21]([CH3:24])[CH3:22])[CH:17]=[O:19])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: CN(C)C=O
Reactant: COc1ccc(CC(=O)O)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(C=O)=CN(C)C)cc1OC
Temperature: 70 °C

Procedure:
The intermediate 2-(3,4-dimethoxyphenyl)-3-dimethylamino-2-propenal was prepared as follows: To a chilled 1260 ml. portion of dimethylformamide was added dropwise 230 ml. of phosphorus oxychloride followed by addition of 196 g. of α-(3,4-dimethoxyphenyl)acetic acid. The reaction mixture was heated at about 70° C. on a steam both for 3 hours, allowed to cool and then concentrated in vacuo to remove the solvent and excess volatile reactants. The resulting product was used directly in the above procedure.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18](I)[C:17]([O:21][CH3:22])=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.CO[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([B:30]3[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]3)[C:17]([O:21][CH3:22])=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: COc1nn([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1nn([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4-iodo-3-methoxy-1H-pyrazole (0.0500 g, 0.114 mmol) in anhydrous degassed THF (2.0 mL) was cooled to −10° C. and dropwise charged with 1.30 M of isopropylmagnesium chloride in THF (0.352 mL, 0.458 mmol) over a 5 min period under an atmosphere of Argon. The reaction was maintained at −10° C. for 40 min then charged with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.0939 mL, 0.573 mmol) and stirred for an additional 1 h at 0° C. The reaction mixture was quenched with sat NH4Cl (2.0 mL) and partitioned between EtOAc and H2O. The aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a crude yellow oil. The crude was purified by chromatography on silica gel [ISCO Combiflash, 4 g gold cartridge, eluting with 100% heptane→30% EtOAc in heptane] resulting in the title compound as a white waxy solid. 1H NMR (400 MHz, CD3OD): δ=−0.02-0.02 (m, 6H), 0.79-0.84 (m, 9H), 1.19 (s, 12H), 1.32-1.44 (m, 2H), 1.66-1.78 (m, 2H), 1.85-1.92 (m, 2H), 1.94-2.02 (m, 2H), 3.60-3.69 (m, 1H), 3.76-3.79 (m, 3H), 3.86 (tt, J=3.8, 12 Hz, 1H), 7.50 (s, 1H). MS (ES+): m/z 436.27, 437.26, 438.29 [MH+]. HPLC: tR=4.05 min (vvnonpolar—5 min, ZQ3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].S([O-])(O)(=O)=O.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[OH-].[Na+]>ClCCl>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Reactant: BrCCCCCCBr
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCCOCCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 20.1 %

Procedure:
A stirred mixture of 4-(4-nitrophenyl)butan-1-ol (2.0 g, 10 mmol), tetra-n-butylammomium hydrogen sulfate (0.17 g, 0.5 mmol), and 1,6-dibromohexane (3.2 mL, 20 mmol) in dichloromethane (10 mL) was treated with aqueous sodium hydroxide solution (10 M, 1 mL). The reaction mixture was stirred for 6 days at room temperature. The organic and aqueous phases were separated. The aqueous phase was extracted thrice with dichloromethane. The combined organics were washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via automated flash silica gel chromatography, using a 40 g SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound as a pale straw-colored oil (0.72 g, 20%). ES/MS calcd. for C16H25BrNO3+ 358.1, found m/z=358.2 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][CH:13]=[N:12][C:11]=1[CH:15]=[CH2:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:15]([C:11]1[N:12]=[CH:13][S:14][C:10]=1[CH2:9][OH:8])=[CH2:16]
Reactant: C=Cc1ncsc1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=Cc1ncsc1CO
Yield: 87.4 %

Procedure:
A solution of 5-{[(tert-butyldimethylsilyl)oxy]methyl}-4-ethenyl-1,3-thiazole (763 mg, 3.0 mmol) and a tetrabutylammonium fluoride solution (1M in THF; 4 mL, 4.0 mmol) in anhydrous THF (30 mL) was stirred at room temperature for 1.5 hours. The solvent was evaporated, and the residue was treated with EtOAc (50 mL). The solution was extracted with water (3×50 mL) and brine (1×50 mL), dried over MgSO4, filtered, and evaporated. The residue was dried in vacuo, affording (4-ethenyl-1,3-thiazol-5-yl)methanol (370 mg, 87%). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.Cl.[F:32][C:33]1([F:37])[CH2:36][NH:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[N:35]1[CH2:36][C:33]([F:37])([F:32])[CH2:34]1
Reactant: FC1(F)CNC1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1nc(N2CC(F)(F)C2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 130 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A vial was charged with 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.100 g, 0.214 mmol), 3,3-difluoroazetidine hydrochloride (0.055 ml, 0.428 mmol), and potassium carbonate (0.053 g, 0.384 mmol). DMSO (1.070 ml) was added and the reaction was stirred at 130° C. overnight. The reaction was filtered through a syringe filter. The resulting solution was purified via reverse phase HPLC (Xbridge 19×100 mm, 10 um, 40 ml/min, 25-85% 0.1% TFA in Acetonitrile) to afford 1-(5-chloro-6-(3,3-difluoroazetidin-1-yl)-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.038 g, 0.073 mmol, 33.9% yield) as a brown oily solid. 1H NMR (500 MHz, DMSO-d6) δ=11.65 (br. s., 1H), 8.73 (d, J=1.7 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.20 (d, J=9.7 Hz, 1H), 7.92-7.80 (m, 2H), 6.97 (d, J=9.0 Hz, 1H), 6.78 (d, J=9.6 Hz, 1H), 6.44 (d, J=1.7 Hz, 1H), 4.68 (t, J=12.6 Hz, 4H), 3.75 (s, 3H). m/z (ESI) 524.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10](I)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]([CH3:23])[CH:21]=[N:20][C:19]=1[I:24])CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[I:24][C:19]1[N:20]=[CH:21][N:22]([CH3:23])[C:18]=1[C:10]1[S:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([S:2][CH3:1])[C:4]=2[CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(I)ncn1C
Reactant: CSc1ncnc2sc(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1ncnc2sc(-c3c(I)ncn3C)cc12
Temperature: 100 °C
Yield: 67.3 %

Procedure:
4-Methylthio-6-iodo-thieno[2,3-d]pyrimidine (Intermediate 91) (949 mg), 5-tributylstannyl-4-iodo-1-methyl-1H-imidazole (Intermediate 92) (2.76 g) and tetrakis(triphenylphosphine)palladium(0) (178 mg) were stirred in anhydrous DMF (50 mL), degassed with nitrogen for 10 min, then heated to 100° C. for 18 hours under an inert atmosphere. The reaction mixture was concentrated in vacuo and the crude product triturated with DCM (20 mL) to afford the title compound as a yellow solid (805 mg, 67%);
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:27](Cl)(=[O:29])[CH3:28]>N1C=CC=CC=1.C(Cl)Cl>[C:27]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:20]=1)(=[O:29])[CH3:28]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccccc2)o1
Reaction time: 48 h
Yield: 97.8 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (example 1) (200 mg, 0.54 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added acetyl chloride (58 μL, 0.81 mmol). Upon complete addition the reaction mixture was stirred for 48 h, then quenched with 10% aqueous HCl (15 mL). The mixture was partitioned between H2O (25 mL) and CH2Cl2 (35 mL). The aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic extracts were washed with NaHCO3 (40 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (30-60% EtOAc in hexanes) to provide the title compound as a colourless solid (217 mg, 98%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.01 (dm, J=8.0 Hz, 2H), 7.60-7.49 (m, 3H), 7.41 (d, J=8.6 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 5.58 (pentet, J=6.1 Hz, 1H), 5.16 (d, J=8.0 Hz, 1H), 5.02 (dd, J=5.9, 8.0 Hz, 1H), 2.32 (s, 3H), 2.13 (s, 3H), 1.38 (d, J=6.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][O:5][N:6]=1.C[Si]([N:13]=[N+:14]=[N-:15])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:13]1[C:7]([C:3]2[C:2]([NH2:1])=[N:6][O:5][N:4]=2)=[N:8][N:15]=[N:14]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1nonc1N
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Nc1nonc1-c1nnn[nH]1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of 4-amino-furazan-3-carbonitrile (0.10 g, 0.90 mmol) and trimethylsilyl azide (0.21 g, 1.82 mmol) in toluene (10 mL) was added dibutyl tin oxide (0.227 g, 0.91 mmol) and the mixture was heated for 20 hours at 130° C. until complete consumption of nitrile was observed by LC-MS. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in methanol and partitioned between ethyl acetate and 10% sodium bicarbonate solution and the organic portion was washed with a further portion of 10% sodium bicarbonate solution. The combined aqueous extracts were acidified to pH 2 with 10% HCl solution and re-extracted into ethyl acetate (2×30 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to yield 4-(1H-tetrazol-5-yl)-furazan-3-ylamine as a white solid (0.122 g, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:5]=[CH:6][CH:7]=1>[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][S:8][C:4]=2[CH:3]=1
Reactant: O=C(CSc1cccc(Br)c1)c1ccccc1
Agent: [Pd]
Product: Brc1ccc2c(-c3ccccc3)csc2c1

Procedure:
Heat 2-(3-bromo-phenylthio)-1-phenyl-ethanone (4 g, 13 mmol) in polyphosphoric acid (4g) at 80° C. for 4 h. Add EtOAc and water to the mixture and wash with saturated aqueous NaHCO3 and brine. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Slurry the residue in hexane and purify by chromatography on silica gel eluting with hexane to give the desired intermediate that is used without further purification (2.7 g, 72%). MS (GCMS) m/z: 289 M+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[NH2:39][C@@H:40]([CH3:43])[CH2:41][OH:42].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[C:20]([N:19]1[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:39][C@@H:40]([CH3:43])[CH2:41][OH:42])=[CH:8][CH:7]=2)=[N:16][N:17]=[N:18]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(4′-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole made as described in Preparation 1 (9.7 g, 17.4 mmol), (2S)-2-aminopropan-1-ol (3.9 g, 52.3 mmol), and potassium carbonate (2.4 g, 17.4 mmol), in THF (170 mL) was stirred at room temperature overnight. Water (100 mL) was added, and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography gave intermediate (5a).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]1([N:27]=[C:28]=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[S:29])[C:3]1=[O:20]
Reactant: S=C=Nc1ccccc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=S)Nc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and phenylisothiocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 209°-211° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([C:12](=[O:32])[CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[N:29][C:30]#[N:31])[CH2:16][CH2:15]3)=[CH:6][C:5]=2[O:4]1>C(O)C>[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]([OH:32])[CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[N:29][C:30]#[N:31])[CH2:16][CH2:15]3)=[CH:6][C:5]=2[O:4]1
Reactant: N#CN=c1[nH]c2ccccc2n1C1CCN(CC(=O)c2ccc3c(c2)OCO3)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CN=c1[nH]c2ccccc2n1C1CCN(CC(O)c2ccc3c(c2)OCO3)CC1
Yield: 88 %

Procedure:
In this example, 600 mg of sodium borohydride is added to a suspension of 715 mg of the product obtained in Example 9 in 30 ml of ethanol at room temperature. After completion of the addition, the reaction mixture is concentrated. The residue is mixed with water, and the crystals deposited are separated by filtration and dried. The crude crystals are recrystallized from methanol to obtain 632 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>>[F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:20]/[S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Product: CC(C)(C)[S@](=O)/N=C/c1ccc(C(F)(F)F)cc1F
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield (1.17 g, a pale yellow solid) from 2-fluoro-4-(trifluoromethyl)benzaldehyde (800 mg, 4.16 mmol) and (S)-2-methylpropane-2-sulfinamide (606 mg, 5.00 mmol) by the similar manner in Step-1 of Amine-88.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[H-].[Na+].C(OP([CH2:26][C:27]([O:29]CC)=[O:28])(OCC)=O)C.CN(C)C=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:6][CH:7]=1
Reactant: Cn1ncc(C=O)c1-c1ccc(F)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A mixture of 5-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (350 mg), sodium hydride (60% in oil, 120 mg), ethyl diethylphosphonoacetate (673 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the precipitated solids were collected by filtration. After drying with airflow, the solids were dissolved in a mixed solvent of tetrahydrofuran (10 ml) and ethanol (10 ml). A 1N aqueous sodium hydroxide solution (5 ml) was added and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into a 10% aqueous citric acid solution and the precipitated solids were collected by filtration, washed with water and dried with airflow to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (354 mg, 84%) as crystals. Recrystallization thereof from methanol-isopropyl ether gave colorless prism crystals. melting point: 212-213° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]1[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>>[CH3:19][O:20][CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]1[N:32]=[CH:31][C:30]([NH:33][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:29][CH:28]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COC[C@H]1CCCN1c1ccc(N)cn1
Product: COC[C@H]1CCCN1c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-ylamine. LCMS calcd for C22H21F3N4O3 (m/e) 446, obsd 447 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=3[F:28])[CH2:15][CH2:14]2)[O:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:15][CH2:14][CH:13]([C:11]3[O:10][C:9](=[O:29])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:12]=3)[CH2:18][CH2:17]2)=[C:20]([F:28])[CH:21]=1
Reactant: O=c1oc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)nn1Cc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1ccc(N2CCC(c3nn(Cc4ccccc4)c(=O)o3)CC2)c(F)c1
Yield: 85.5 %

Procedure:
5-[1-(2-Fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.23 g, 4 mmol) on reacting with C6H5CH2Br (0.82 g, 1 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-benzyl-5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6f, 1.52 g, 96%). Nitro compound (6f, 1.59 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7 h, 1.26 g, 86%). To a stirred solution of 5-nitro2-furanoic acid in DMF add. HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethyl aminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7 h, 0.36 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-benzyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperi dino]-3-fluorophenyl-5-nitro-2-furamide (8 h, 430 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc(N2CCN(C(=O)Nc3nc4cc(OC)ccc4nc3OC)CC2)cc1
Yield: 81 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 81%). 1H NMR (200 MHz, CDCl3): δ 3.16 (s, 4H), 3.78-3.88 (m, 9H), 4.12-4.17 (m, 4H), 6.84-6.97 (m, 4H), 7.16-7.32 (m, 3H), 7.62-7.66 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28](I)=[C:27]([CH:30]5[CH2:32][CH2:31]5)[N:26]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:23]4=[N:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[CH:62][CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48](B2OC(C)(C)C(C)(C)O2)[C:47]([CH3:60])=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:48]5[C:47]([CH3:60])=[N:46][N:45]([CH2:44][C:43]6[CH:61]=[CH:62][CH:63]=[C:41]([F:40])[CH:42]=6)[C:49]=5[CH3:50])=[C:27]([CH:30]5[CH2:32][CH2:31]5)[N:26]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:23]4=[N:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(I)c(C3CC3)n4C(=O)OC(C)(C)C)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c(C2CC2)n(C(=O)OC(C)(C)C)c2ncc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Yield: 178.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2-cyclopropyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 35) (50 mg, 0.07763 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (30 mg, 0.08540 mmol) in sodium carbonate (25 mg, 0.2329 mmol), Pd(PPh3)4 (5 mg, 0.00388 mmol) and DME/water (5/1 ml) to afford 100 mg of the crude product which was taken as such for next reaction. MS: m/z=721.0 (M+1).