Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH:11]=2)=[CH:6][CH:5]=1)=[O:3].[ClH:29]>O1CCOCC1.ClCCl>[ClH:29].[NH:19]1[CH2:20][CH2:21][CH:16]([C:12]2[CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:2]([NH2:1])=[O:3])=[CH:5][CH:6]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(-c3ccc(C(N)=O)cc3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1ccc(-c2cccc(C3CCNCC3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1,1-dimethylethyl 4-[4′-(aminocarbonyl)-3-biphenylyl]-1-piperidine carboxylate (0.95 g, 0.0025 mol; I-VII-3) and 4N HCl in dioxane (5 mL) in dichloromethane (5 mL) was stirred at ambient temperature for 3 hr. The resulting solid was collected by filtration, washed with dichloromethane, diethyl ether and air-dried to give the title compound as a white solid, used without further purification. LC/MS (method A) 1.17 min; m/z 281 (M+H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1([O:17]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:25][N:26]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1)[S:27]([CH2:30][C:31](O)=[O:32])(=[O:29])=[O:28].C(N(C(C)C)C(C)C)C.Cl.NO>CN(C)C=O>[OH:17][NH:8][C:31](=[O:32])[CH2:30][S:27]([N:26]([CH3:25])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:42]=[CH:43][C:44]([C:47]#[N:48])=[CH:45][CH:46]=2)=[CH:37][CH:36]=1)(=[O:28])=[O:29]
Reactant: CN(Cc1ccc(-c2ccc(C#N)cc2)cc1)S(=O)(=O)CC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccc(-c2ccc(C#N)cc2)cc1)S(=O)(=O)CC(=O)NO
Reaction time: 16 h
Yield: 8.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU 263 mg, 0.72 mmol) was added to a solution of 2-({methyl[(4'-cyanobiphenyl-4-yl)methyl]amino}sulfonyl)acetic acid (185 mg, 0.48 mmol) and N-ethyl-N,N-diisopropylamine (0.08 ml, 0.48 mmol) in anhydrous dimethylformamide (3 ml) at ambient temperature under an atmosphere of nitrogen. After stirring for 20 minutes a solution of hydroxylamine hydrochloride (131 mg, 1.92 mmol) and N-ethyl-NN-diisopropylamine (0.33 ml, 1.92 mmol) in anhydrous dimethylformamide (1 ml) was added and the solution was stirred for a further 16 hours. The mixture was partitioned between aqueous phosphate buffer (at pH 7) and ethyl acetate. The organic layer was washed with water, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol/aqueous ammonia 90:10:1 as eluent) to give the title compound as a colourless solid (14 mg).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][CH:16]([N:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH3:33])=[CH:26][CH:25]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][CH:16]([N:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[CH:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH3:33])=[CH:26][CH:25]=3)[NH:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2N(C)C(=O)OC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCCOc1ccc(C2NN(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2N(C)C(=O)OC)cc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To 5.2 grams (g) (10.6 mmole) of N-(4-trifluoromethoxyphenyl)-3-(4-propoxyphenyl)-4-(N-methyl-N-(methoxycarbonyl)amino)-4,5-dihydro-1H-pyrazole-1-carboxamide in 50 ml of tetrahydrofuran (THF) that had been cooled under a nitrogen atmosphere to -75° C. was added 28 ml of 1.0M diisobutylaluminum hydride (DIBAL-H) in THF. The reaction mixture was warmed to 20° C. and stirred for 5 hours. An additional 6 ml of the 1.0M DIBAL-H solution was added. After stirring at 20° C. overnight, the mixture was cooled to 0° C. and carefully quenched with 10 ml of methanol, a solid forms. Into this mixture was poured a mixture of 20 g of water and 10 ml of 12M aqueous hydrochloric acid. After the solid dissolved, the mixture was concentrated in vacuo and partitioned between diethyl ether and water. The organic layer was washed with dilute aqueous sodium hydroxide and brine and then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was chromatographed on silica gel using diethyl ether and hexanes to give the expected compound, an oil. NMR (200 MHz, CDCl3) 1.1 t 3H, 1.8 sextet 2H, 2.6 s 3H, 3.6 s 3H, 4.0 t 2H, 4.1-4.6 m 3H, 5.5 bd 1H, 6.9 d 2H, 7.1 m 5H, 7.5 d 2H, 8.5 s 1H. Peaks exibit satellites due to hindered rotation. Alternatively, compound 19 h was prepared as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH3:12])(=[O:11])=[O:10].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Cl[C:37]1[N:42]=[C:41]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][C@@H:44]2[CH3:49])[N:40]=[C:39]([C:50]2[CH:55]=[CH:54][C:53]([NH:56][C:57]([NH:59][CH2:60][CH3:61])=[O:58])=[CH:52][CH:51]=2)[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CCO>[CH2:60]([NH:59][C:57]([NH:56][C:53]1[CH:54]=[CH:55][C:50]([C:39]2[CH:38]=[C:37]([C:2]3[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=3[S:9]([CH3:12])(=[O:11])=[O:10])[N:42]=[C:41]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][C@@H:44]3[CH3:49])[N:40]=2)=[CH:51][CH:52]=1)=[O:58])[CH3:61]
Reactant: CCNC(=O)Nc1ccc(-c2cc(Cl)nc(N3CCOC[C@@H]3C)n2)cc1
Reactant: CS(=O)(=O)c1ccc(F)cc1Br
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2cc(-c3cc(F)ccc3S(C)(=O)=O)nc(N3CCOC[C@@H]3C)n2)cc1
Yield: 33.9 %

Procedure:
2-bromo-4-fluoro-1-(methylsulfonyl)benzene (117 mg, 0.46 mmol), bis(pinacolato)diboron (123 mg, 0.48 mmol), potassium acetate (135 mg, 1.38 mmol) and bis(diphenylphosphino)-ferrocenedichloropalladium(II)-DCM-complex (19 mg, 0.02 mmol) in dioxane (1.5 mL) were irradiated in a Biotage microwave for 60 min at 120° C. (S)-1-(4-(6-chloro-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)-3-ethylurea (Intermediate 2) (173 mg, 0.46 mmol), sodium carbonate solution (2M aqueous solution, 0.92 mL, 1.84 mmol) and EtOH (0.3 mL) were added and reaction mixture further irradiated in a Biotage microwave for 60 min at 100° C. The reaction mixture was concentrated in vacuo, and the residue suspended in EtOAc (70 mL), washed with water (2×40 mL) followed by brine (40 mL), dried with sodium sulfate and concentrated in vacuo to leave an orange oil. The oil was purified by flash chromatography (0-20% EtOAc in DCM over 60 min) to yield the title compound as an orange solid (80 mg, 34%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CN(C)C=O>ClCCl>[CH:2]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: CC(=O)Nc1cccc(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
A mixture of N-(3-hydroxymethylphenyl)acetamide (165 mg, 1.0 mmol), celite (165 mg), pyridinium chlorochromate (645 mg, 3.0 mmol), N,N-dimethylformamide (1.0 mL) and dichloromethane (25 mL) was stirred at room temperature for 24 h. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (40 mL) and washed with aqueous sodium bicarbonate solution (2×30 mL). The organic layer was concentrated and the product purified by chromatography over silica gel using ethyl acetate/hexanes (1:1) as eluant to give 130 mg (81%) of N-(3-formylphenyl)acetamide as a brown solid. MS [M+H] 164.2, 1H NMR (CDCl3) δ (ppm) 9.96 (s, 1H), 8.22 (b, 1H), 8.03 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.61 (d, J=6.6 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 2.22 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[I:10].Cl.[NH2:12]O.S([O-])([O-])(=O)=O.[Mg+2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:12])=[CH:4][C:3]=1[I:10]
Reactant: O=Cc1ccc(O)c(I)c1
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: N#Cc1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To a solution of 4-hydroxy-3-iodo-benzaldehyde (7.9 g, 31.8 mmol) (prepared by the method of Barnes at al.; J. Chem. Soc., 1950, 2824) in xylene (120 mL) was added hydroxylamine hydrochloride (2.34 g, 33.4 mmol), magnesium sulphate (12.7 g) and p-toluene sulphonic acid monohydrate (1.27 g, 6.4 mmol). The resulting mixture was heated to reflux and stirred at this temperature for 90 min. The reaction mixture was then allowed to cool to room temperature and filtered. The solid was washed with ethyl acetate then the combined filtrates concentrated. The residue was purified by flash chromatography (eluting with 30% ethyl acetate in hexanes) to give 6.57 g of the title compound. 1H NMR (CDCl3) d 6.1 (bs, 1H), 7.05 (d, J=8 Hz, 1H), 7.55 (dd, J=8, 1 Hz, 1H), 7.99 (d, J=1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2[O:21][CH2:22][CH:23]([F:25])[F:24])=[CH:4][CH:3]=1>[Ni].C1COCC1>[NH2:16][C:14]1[C:13]([NH:19][CH3:20])=[CH:12][C:11]([O:21][CH2:22][CH:23]([F:24])[F:25])=[C:10]([CH:15]=1)[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:26]
Reactant: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1N

Procedure:
The sub-title compound was prepared by hydrogenation according to procedure 3d using N-(4-bromophenyl)-2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzamide (1.01 g; 2.34 mmol), Ra—Ni (14 mg), H2 (8 atm) and THF (50 mL). Yield: 905 mg (97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN1CCOCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32].C(=O)=O.CC(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][N:13]([C:31](=[O:32])[C:30]3[CH:29]=[C:28]([O:27][CH3:26])[C:36]([O:37][CH3:38])=[C:35]([O:39][CH3:40])[CH:34]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2(CCO)CCNC2)cc1OC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C2(CCO)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Temperature: 25 °C

Procedure:
2-[3-(3,4-Dimethoxy-phenyl)-pyrrolidin-3-yl]-ethanol (2.27 g, 9.03 mmol) and dichloromethane (100 mL) were combined. 4-Methylmorpholine (2.28 mL, 22.6 mmol, 2.5 eq.) was added. The mixture was cooled in a ice/NaCl bath and a solution of 3,4,5-trimethoxy-benzoyl chloride (2.19 g, 9.48 mmol) in dichloromethane (30 mL) was added dropwise. After the addition was complete, the dry-ice/acetone bath was changed to an ice bath and the mixture was allowed to warm to ambient temperature and maintained overnight. The solution was extracted with 1N HCl (3×100 mL), saturated K2CO3 (3×100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by chromatography on silica gel eluting with ethyl acetate/methanol (20:1) to obtain a residue. The residue was dissolved in dichloromethane (50 mL), extracted with water (2×50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain a residue. Heated at 110° C./0.3 Torr for 16 h to obtain the title compound: Rf =0.14 (silica gel, 20:1 ethyl acetate/methanol), mp=60°-62° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN(C=O)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: C1CNCCN1
Reactant: N#Cc1cc(Cl)ccc1Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1N1CCNCC1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 20.5 %

Procedure:
A mixture of 2,5-dichlorobenzonitrile (Lancaster; 2.994 g), piperazine (Aldrich; 7.616 g), and DMF (10 mL) is stirred for 4.5 h at 100° C. After cooling, the DMF is removed under reduced pressure and the residue is partitioned between dichloromethane and saturated aq. sodium bicarbonate. The organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (8/92) and the appropriate fractions are combined and concentrated to give 0.79 g of 5-chloro-2-(piperazin-1-yl)benzonitrile; MS m/z 221; IR (mineral oil) 1489, 802, 829, 2223, 845 cm-1 ; 1H NMR (CDCl3) δ3.09, 3.18, 6.94, 7.43, 7.52.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[NH:8]([C:9]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccccc1
Temperature: 25 °C

Procedure:
Iodobenzene 0.10 mL was added to toluene 3.0 mL suspension of tert-butyl 2-amino-4-phenylbenzoate 0.10 g, rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 2.3 mg, palladium acetate 0.8 mg and cesium carbonate 0.24 g, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 2.3 mg and palladium acetate 0.8 mg were added to it, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=20:1] to give tert-butyl 2-anilino-4-phenylbenzoate.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14](Cl)(=O)=O)[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].O.[CH3:19]I.C[O-].[Na+]>C(O)(=O)C.Cl>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14][CH3:19])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1Cc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: CI
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc2c(c1)CC(NC(C)=O)C2
Temperature: 75 °C
Reaction time: 1 h

Procedure:
5.6 g. of N-acetyl-5-chlorosulfonyl-2-indanamine (0.02 mole) (as prepared in Example 3) is dissolved in acetic acid (50 ml.), warmed to 75° C., and 19 g. of stannous chloride (0.1 mole) in concentrated hydrochloric acid (20 ml.) is added. An exotherm occurs. When the reduction is complete the mixture is cooled to 25° C. and poured into water. The N-acetyl-5-mercapto-2-indanamine is filtered and suspended in methanol (50 ml.) under a nitrogen atmosphere. 5.7 g. of methyl iodide (0.04 mole) and 1.1 g. of sodium methoxide (0.02 mole) are added and the mixture is stirred for one hour. The mixture is filtered, evaporated and the residue purified by chromatography to give N-acetyl-5-methylthio-2-indanamine which is hydrolyzed following the procedure of Example 3 to give 5-methylthio-2-indanamine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[N:5]=[C:4]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:3]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH2:26][CH2:27]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:27][CH2:26][O:25][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][O:19]3)[CH:8]=2)[N:5]=[C:4]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:3]=1
Reactant: CC(C)(C#N)c1cc(N)n(-c2cccc(O)c2)n1
Reactant: OCCOC1CCCCO1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To an ice cooled solution of Intermediate 20b (363 mg, 1.50 mmol), 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (329 mg, 305 μL, 2.25 mmol) and triphenylphosphine (786 mg, 3.00 mmol) in anhydrous THF (10 mL) was added dropwise diisopropyl azodicarboxylate (606 mg, 590 μL), and the ice bath removed and stirring continued under an Ar atmosphere. After 3 h, a further 1.0 eq of diisopropyl azodicarboxylate was added and the reaction stirred overnight. The reaction mixture was then concentrated in vacuo and subjected to FCC, eluting with 5-50% EtOAc in cyclohexane. The isolated product was repurified using FCC, eluting with 2.5-7.5% Et2O in DCM, to afford the title compound as a yellow oil (317 mg, 57%). LCMS (Method 3): Rt 3.67 min, m/z 393.3 [M+Na].
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:14][C:15]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][C:18](=[O:25])[NH:19]2>>[Cl:24][C:23]1[C:15]([CH3:14])=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:25])[C:17]2=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Reactant: COc1ccc(C=O)cc1C(C)C
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)c(C)c32)cc1C(C)C

Procedure:
3-Isopropyl-4-methoxybenzaldehyde was condensed with 4-methyl-5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(3-isopropyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=3[C:25]([F:28])([F:27])[F:26])[CH2:13][C@H:12]2[CH3:29])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>ClCCl.[Cu]I>[CH3:29][C@H:12]1[N:11]([S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:30]3[CH:34]=[N:33][CH:32]=[N:31]3)[CH:3]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=2[C:25]([F:27])([F:28])[F:26])[CH2:13]1
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(F)c1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(C#N)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(-n2cncn2)c1
Temperature: 166 °C

Procedure:
A mixture of 4-{(3R)-4-[(3-fluorophenyl)sulfonyl]-3-methylpiperazin-1-yl}-3-(trifluoromethyl)benzonitrile (349 mg, 0.82 mmol), 1,2,4-triazole (112.6 mg, 1.64 mmol), K2CO3 (226.7 mg, 1.64 mmol), and CuI (15.6 mg, 0.082 mmol) were charged to a microwave vial. NMP (3 mL) was introduced under nitrogen atmosphere and the reaction mixture was heated at 166° C. for 3 hr in an oil bath. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via prep HPLC under neutral condition to yield 4-((3R)-3-methyl-4-{[3-(1H-1,2,4-triazol-1-yl)phenyl]sulfonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile as a light tan color solid (176.8 mg, 45.3% yield). HRMS: calcd for C21H19F3N6O2S+H+, 477.13150. found (ESI-FTMS, [M+H]1+), 477.13303.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[C:12]1(=[O:17])[O:16][CH:14]([CH3:15])[CH2:13]1.Cl>[OH-].[Na+]>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH:14]([CH3:15])[CH2:13][C:12]([OH:17])=[O:16]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CC1CC(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(CC(=O)O)Oc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 15.1 %

Procedure:
A solution of 40.5 g (0.25 mol) m-trifluoromethylphenol in 100 ml 2.5N sodium hydroxide was heated at reflux and 20.4 ml (0.25 mol) beta-butyrolactone was added dropwise over 50 minutes. The reaction was cooled to 0° C. and 3 ml concentrated hydrochloric acid was added to bring the pH to 7. The reaction was extracted with 3×100 ml diethyl ether. The pH of the aqueous was brought to 2 with 20 ml concentrated hydrochloric acid and then the aqueous was extracted with 2×100 ml diethyl ether. The latter combined ether extracts were washed with 100 ml water and 100 ml brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 9.4 g (15%) of 3-[3-(trifluoromethyl)phenoxy]-butyric acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20]>C1COCC1.[Zn+2].[Br-].[Br-]>[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)=[O:20]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1c(F)cccc1F
Reaction time: 0.17 h

Procedure:
A solution of ZnBr2 in THF (1.5 M, 2 mL, 3.0 mmol) was added to a solution of (4-(tetrahydro-2H-pyran-2-yloxy)phenyl)magnesium bromide in THF (0.2 M, 15 mL, 3 mmol) under an atmosphere of argon atr.t. The reaction mixture was stirred for 10 minutes, cooled with a dry-ice acetone bath. Palladium tetrakistriphenylphosphine (50 mg) and a solution of 2,6-difluorobenzoyl chloride (0.37 mL, 3 mmol) in THF (2 mL) were added. The mixture was stirred over night at r.t. The organic phase was washed with brine (2×20 mL), dried (Na2SO4) and concentrated yielding a solid. Purified by flash chromatography (eluent: heptane →20% ethyl acetate in heptane). Yield: 318 mg, 33% (approx. 85% pure according to 1H-NMR). 1H-NMR (400 MHz, CDCl3): δ 7.83-7.78 (m, 2H), 7.49-7.38 (m, 1H), 7.14-7.07 (m, 2H), 7.03-6.95 (m, 2H), 5.52 (t, J=3.1 Hz, 1H), 3.83-3.80 (m, 1H), 3.63-3.58 (m, 1H), 2.10-1.90 (m, 1H), 1.89-1.85 (m, 2H), 1.72-1.58 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][N:19]([CH3:30])[C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)([OH:17])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].I[CH3:34]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][C:14]([CH2:18][N:19]([CH3:30])[C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=3)([O:17][CH3:34])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CI
Reactant: COC(=O)c1ccc(N(C)CC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)CC2(OC)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
To the compound (6.0 g) obtained in Example 12 in DMF (50 mL) was added 60% sodium hydride (0.65 g) under cooling with ice-water, followed by stirring at the same temperature for one hour. The reaction mixture was cooled to −40° C., and iodomethane (2.09 g) was added dropwise thereto over twenty minutes. After stirring at −40° C. for one hour and further stirring at −20 to −15° C. for four hours, the reaction mixture was left at −12° C. overnight. The reaction mixture was cooled to −20° C., was mixed with an ice water (100 mL) and was warmed to room temperature. After extracting with ethyl acetate, the organic layer was sequentially washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography [Chromatorex NH™] (eluent; hexane:ethyl acetate=3:1 to 1:1) to yield the titled compound (0.643 g) as a white solid.