Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:18])[C:6]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:4].[Li+].[I-]>N1C=CC=CC=1>[CH2:22]([O:21][C:19]([C:6]1[C:7](=[O:18])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2])=[O:20])[CH3:23]
Reactant: CCOC(=O)c1c(C(=O)OC)ccn(Cc2ccccc2)c1=O
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C(=O)O)ccn(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of 1-benzyl-2-oxo-1,2-dihydro-pyridine-3,4-dicarboxylic acid 3-ethyl ester 4-methyl ester (4.1 g, 13 mmol) in 10 mL of pyridine was added to a refluxing mixture of LiI (7.0 g, 52 mmol) and 50 mL of pyridine. The resulting mixture was refluxed for 1 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was taken up in water (150 mL) and acidified to pH about 2 with 6M HCl. The resulting suspension was extracted several times with CHCl3, and the organic layers were combined and dried over MgSO4. After solvent was evaporated in vacuo, the crude product was chromatographed (100% EtOAc) to give 1.8 g of the title compound as a yellow solid. 1H NMR (CDCl3, 200 MHz): δ=7.20-7.45 (m, 6H), 6.61 (d, 1H, J=7.0 Hz), 5.16 (s, 2H), 4.41 (q, 2H, J=7.4 Hz), 1.37 (t, 3H, J=6.2 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][C:4]([C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]1.Cl>>[NH2:1][CH:2]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1
Reactant: COc1ccc(C2(c3ccccc3)CCC(N)C2)cc1
Agent: Cl
Product: NC1CCC(c2ccccc2)(c2ccccc2)C1

Procedure:
1-amino-3-(4-methoxyphenyl)-3-phenylcyclopentane/PUT 104 /Hydrochloride m.p. 230°-232° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([OH:23])[CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:32](Br)[CH:33]=[CH2:34]>CN(C=O)C>[CH2:34]([O:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH2:14][CH:13]([C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:24][CH3:25])=[CH:9][CH:8]=1)=[O:12])[CH2:22][CH2:21]2)[CH:33]=[CH2:32]
Reactant: C=CCBr
Reactant: CCN(CC)c1ccc(NC(=O)C2CCc3cccc(O)c3C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc2c1CC(C(=O)Nc1ccc(N(CC)CC)cc1)CC2
Yield: 19.8 %

Procedure:
The phenol from Example 6B (68 mg, 0.2 mmol) was dissolved in DMF (0.4 mL) and K2CO3 (41 mg, 0.2 mmol) and allyl bromide (36 mg, 0.3 mmol) were added at ambient temperature. The reaction mixture was worked up and purified by column chromatography to provide the titled compound (15 mg, 20%). 1H NMR (400 MHz, DMSO-D6) δ 9.59 (s, 1H), 7.39 (d, J=9.2 Hz, 2H), 7.05 (t, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.61 (d, J=9.2 Hz, 2H), 6.05 (ddddd, 5.2, 5.2, 10.8, 16.0 Hz, 1H), 5.39 (dddd, J=1.2, 1.2, 1.2, 15.2 Hz, 1H), 5.24 (dddd, J=1.2, 1.2, 1.2, 10.4 Hz, 1H), 4.55 (m, 2H), 3.28 (q, J=6.8 Hz, 4H), 2.3 (m, 1H), 2.79 (m, 2H), 2.61 (m, 2H), 1.99 (m, 1H), 1.69 (m, 1H), and 1.06 (t, J=6.8 Hz, 6H). MS (ESI) positive ion 379 (M+H)+; negative ion 377 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: Cn1cc(Br)cn1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH:13]=[C:14]([P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[F:15])[CH2:11][O:10]C1(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C)(C1NC(C2C=CC(CCCCCCCC)=CC=2)=CN=1)COP(OC(C)(C)C)(OC(C)(C)C)=O)(C)(C)C>CCO>[CH2:19]([O:18][P:16]([C:14]([F:15])=[CH:13][CH:12]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:11][OH:10])(=[O:17])[O:21][CH2:22][CH3:23])[CH3:20]
Reactant: CCOP(=O)(OCC)C(F)=CC1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CCCCCCCCc1ccc(-c2cnc(C(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)NC(=O)OC(C)(C)C)[nH]2)cc1
Solvent: CCO
Product: CCOP(=O)(OCC)C(F)=CC(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
To compound (38) (47 mg, 0.123 mmol) stirring in EtOH (1 mL) was added Dowex 50×8 (150 mg), which was washed with EtOH and dried. The reaction was allowed to stir under nitrogen and at room temperature for 24 hours. The reaction mixture was filtered and the precipitate washed with excess EtOH, then concentrated in vacuo. The crude material was purified by column chromatography on SiO2 (1:1 EtOAc/Hexanes) to yield 34 mg of the expected product.
Reaction SMILES: O1CC1CO[C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1C=N[NH:9]2>C(O)C.Cl.C1C2C(=CC=CC=2)CCC1NCC(O)CC1C=CC=C2C=1C=NN2>[NH2:9][CH:10]1[CH2:11][CH2:12][C:13]2[C:5](=[CH:13][CH:5]=[CH:6][CH:10]=2)[CH2:6]1
Reactant: c1cc(OCC2CO2)c2cn[nH]c2c1
Agent: Cl
Agent: OC(CNC1CCc2ccccc2C1)Cc1cccc2[nH]ncc12
Solvent: CCO
Product: NC1CCc2ccccc2C1
Yield: 201.6 %

Procedure:
Following the procedure of Example 27, but starting from 4-(2,3-epoxypropoxy)indazole (1.91 g), prepared as described in BE 853,949, and 2-aminotetralin (1.49 g) in absolute ethanol (30 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-indazol-4-ylpropanamine hydrochloride is obtained ((i): R=H, Ar=radical 67, wherein Z= Z'=H, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]3[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[NH2:26]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[N:10]([CH2:11][C:12]4[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=4)[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1
Reactant: CCOC(=O)c1ccc(Cn2ccc3ncnc(Cl)c32)o1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)o1
Temperature: 140 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of ethyl 5-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate (200 mg) in 1-methyl-2-pyrrolidone (1.3 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (247 mg), and the mixture was heated to 140° C. and stirred for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:ethyl acetate/methanol=10/0→8/2). The object fraction was concentrated under reduced pressure and dried to give the title compound (307 mg) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][C:29]([CH3:45])([CH3:44])[CH2:30][O:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33]>>[CH3:28][C:29]([CH3:45])([CH3:44])[CH2:30][O:31][S:32]([C:35]1[CH:36]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33]
Reactant: CC(C)(C)COS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Product: CC(C)(C)COS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-Trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid 2,2-dimethyl-propyl ester was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (1.35 g, 3.02 mmol) and 3-(2,2-dimethyl-propyloxysulfonyl)-benzeneboronic acid (example F.4) (1.31 g, 4.81 mmol) according to the general procedure VI. Obtained as a white solid (1.43 g, 80%). MS (ISP) 594.6 [(M+H)+]; mp 157° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][OH:18].[C:19]([N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[OH:18][CH2:17][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:2]=1[C:29]1[CH2:30][CH2:31][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:27][CH:28]=1
Reactant: OCc1nc2c(N3CCOCC3)ccnn2c1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c(CO)nc3c(N4CCOCC4)ccnn23)CC1

Procedure:
Compound 14a (2.5 g, 8.0 mmol) was subjected to Suzuki coupling conditions with N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester as described in Example 38, Step A to obtain compound 41a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H29N5O4: 416.2 (M+H). found: 416.2.
Reaction SMILES: Cl.N[C:3]1[CH:4]=[C:5]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:26]([F:29])([F:28])[F:27])=[N:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N([O-])=O.[Na+].[BrH:34]>O.[Cu]Br>[Br:34][C:3]1[CH:4]=[C:5]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:26]([F:29])([F:28])[F:27])=[N:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Br
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1N
Agent: [Cu]Br
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-amino-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole hydrochloride (0.80 g) in ca. 24% hydrobromic acid (16 ml) was added a solution of sodium nitrite (0.14 g) in water (1 ml) while the internal temperature of the reaction mixture was maintained below 0° C. The above mixture was added to an ice-cooled solution of copper(I) bromide (0.30 g) in ca. 24% hydrobromic acid (8 ml) and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with chloroform) to give the product, which was recrystallized from diisopropyl ether (3 ml)-ethyl acetate (3 ml) to give 1-(3-bromo-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-pyrazole (0.39 g).
Reaction SMILES: CNCC1OC(CSCCN)=CC=1.[CH3:14][NH:15][C:16]([S:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19].CC(C)=O>O>[CH3:14][NH:15][CH:16]([S:21][CH3:22])[CH2:17][N+:18]([O-:20])=[O:19]
Reactant: CNC(=C[N+](=O)[O-])SC
Agent: CNCc1ccc(CSCCN)o1
Solvent: CC(C)=O
Solvent: O
Product: CNC(C[N+](=O)[O-])SC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethanamine (10 g, 0.05 mole) and N-methyl-1-methylthio-2-nitroetheneamine (7.4 g) in water (25 ml) was stirred at 50° for 2 hr. Acetone (350 ml) was added and the solvent was removed by distillation at atmospheric pressure until 275 ml of distillate had been collected. Ethanolic hydrogen chloride (2M; 27.5 ml) was added to the residue and the solution was stirred overnight at room temperature. The product (11.0 g) m.p. 161°, was collected and recrystallised from ethanol as a colourless microcrystalline solid (10.1 g) m.p. 162°. Analysis Found: C, 42.6; H, 6.3; N, 16.4. C12H20N4O3S.HCl requires: C, 42.8; H, 6.2; N, 16.6%.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@:11]([OH:36])([C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([CH3:35])=[N:28][NH:29][C:30]=2[Si](C)(C)C)=[CH:22][CH:21]=1)[CH3:19])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1>O.C(O)C>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@:11]([OH:36])([C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([CH3:35])=[N:28][NH:29][CH:30]=2)=[CH:22][CH:21]=1)[CH3:19])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Cc1n[nH]c([Si](C)(C)C)c1-c1ccc([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1n[nH]cc1-c1ccc([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)cc1

Procedure:
A solution of potassium hydroxide (0.26 g, 4.6 mmol) in water (2.8 ml) was added to a solution of (2R,3S)-2-(2,4-difluorophenyl)-3-(4-[3-methyl-5-trimethylsilylpyrazol-4-yl]phenyl)-1-(1,2,4-triazol-1-yl)butan-2-ol (0.22 g, 0.45 mmol) in ethanol (12 ml) and the mixture was heated under reflux for 4 hours. The cooled mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate (20 ml) and water (25 ml). The aqueous phase was further extracted with ethyl acetate (2×20 ml) and the combined organic layers were washed with brine (20 ml), dried(Na2SO4) and evaporated under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]2[C:11]([C:15]([F:18])([F:17])[F:16])=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S-2:19].[Na+].[Na+].O>CN(C)C=O>[SH:19][C:2]1[CH:9]=[C:8]([C:10]2[C:11]([C:15]([F:18])([F:17])[F:16])=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1Cl
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1S
Temperature: 25 °C
Yield: 97.6 %

Procedure:
5.0 g (18.4 mmol) of 2-chloro-4-(3-trifluoromethylpyrazolyl) benzonitrile in N,N-dimethylformamide was stirred together with 1.86 g (23.9 mmol) of sodium sulfide at 120° C. for 30 minutes. The reaction mixture was cooled to room temperature, mixed with 100 ml of water, washed with 30 ml of ethyl acetate, and the aqueous layer was adjusted at pH 5-6 with citric acid, and extracted with 50 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 50 ml of water twice and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure to obtain 2-mercapto-4-(3-trifluoromethylpyrazolyl)benzonitrile (yield 97.6%) as a pale yellow powder, which was used in Example 1 (2) as the starting material.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([F:13])=[CH:4][C:3]=1[C:14]1[C:18]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][CH:27]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH3:28])[N:20]=2)=[CH:17][N:16]([CH:34]([CH3:36])[CH3:35])[N:15]=1.NC1C=CC=CC=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([F:13])=[CH:4][C:3]=1[C:14]1[C:18]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH3:28])[N:20]=2)=[CH:17][N:16]([CH:34]([CH3:36])[CH3:35])[N:15]=1
Reactant: COC(=O)NC(C)CNc1nccc(-c2cn(C(C)C)nc2-c2cc(F)cc(NS(C)(=O)=O)c2Cl)n1
Agent: CS(=O)(=O)Cl
Solvent: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2cn(C(C)C)nc2-c2cc(F)cc(NS(C)(=O)=O)c2Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
S)-Methyl 1-(4-(3-(2-chloro-5-fluoro-3-(methanesulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate. A mixture of the aniline product of step 1 (46 mg), pyridine (2 ml), triethylamine (1 mL), DCM (4 ml), and methanesulfonyl chloride (23 ul, 0.3 mmol) was stirred at rt for 16 h. The crude reaction mixture was concentrated, then the residue was taken up in a mixture of toluene (9 ml), ethanol (1 ml), sodium carbonate (2 g), and water (10 ml). The stirred mixture was heated at 85° C. for 16 h. Workup as for Step 1 provided the crude product, which was purified by silica gel chromatography (60:1 to 40:1 DCM/methanol eluant) to provide the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>C(Cl)Cl>[NH:18]1[CH2:19][CH2:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
TFA (5 mL) was added to tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1.9 g, 6.87 mmol, CAS 170011-57-1) in DCM (5 mL). The resulting solution was stirred at ambient temperature for 2 hours then added to an SCX column. The desired product was eluted from the column using 2M ammonia in methanol and the solvent evaporated to dryness to give 4-(piperidin-4-yl)aniline (1.210 g, 100%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](O)([CH3:24])[CH3:23])=[C:18]([CH3:26])[CH:17]=2)=[C:12]([CH:27]([CH3:29])[CH3:28])[N:11]=[N:10]1.[SH:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>ClCCCl.[I-].[Zn+2].[I-]>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][C:31]([S:30][C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]3[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]=[N:11][C:12]=3[CH:27]([CH3:28])[CH3:29])=[CH:17][C:18]=2[CH3:26])([CH3:23])[CH3:24])=[CH:32][CH:33]=1
Reactant: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C(C)(C)O
Reactant: COC(=O)c1ccc(S)cc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: COC(=O)c1ccc(SC(C)(C)c2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
To an ambient temperature solution of 2-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-propan-2-ol (100 mg, 0.230 mmol) in DCE (1 mL) is added zinc iodide (37 mg, 0.115 mmol). The reaction is stirred at room temperature for 10 min. A solution of methyl 4-mercaptobenzoate (38 mg, 0.225 mmol) in DCE (1 mL) is added and the reaction is stirred overnight at room temperature. The reaction is concentrated under reduced pressure and the residue is chromatographed (SiO2 40 g, 0% to 30% EtOAC/Hexane to yield 4-(1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-methyl-ethylsulfanyl)-benzoic acid methyl ester (114 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.81 (d, 2H, J=7.9 Hz), 7.52-7.39 (m, 3H), 7.22 (s, 1H), 7.16 (d, 2H, J=7.8 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.63 (d, 1H, J=8.4 Hz), 4.90 (s, 2H), 3.90 (s, 3H), 3.23 (sept, 1H, J=6.6 Hz), 2.01 (s, 3H), 1.64 (s, 6H), 1.46 (d, 6H, J=6.6 Hz).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].[C:20]1([OH:26])C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.O>[C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:20]=[O:26])[C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCC(C)(C)c1ccc(O)c(C(C)(C)CC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CCC(C)(C)c1cc(C=O)c(O)c(C(C)(C)CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4-di-t-amylphenol (70 g, 0.30 mole) was dissolved in 200 ml absolute ethanol in a 1 L round bottom flask equipped with a water-cooled condenser. Sodium hydroxide (82 g, 2.0 moles) was dissolved in 80 ml water and added while still hot to the solution of phenol. Chloroform (149 g, 1.25 mole) was added in 2 ml portions over a 45-minute period. The resulting yellow-brown mixture was stirred 2 hours while cooling to ambient temperature. The mixture was extracted into 400 ml of hexanes and the organic layer rinsed with 400 ml of 1M HCl. The organic layer was isolated in a separatory funnel and dried over anhydrous magnesium sulfate. The mixture was filtered and rotoevaporated to a thick syrup, and the IR spectrum of the crude product showed the characteristic aldehyde carbonyl stretching frequency. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)c(F)c2)CC1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a stirred solution of 4-amino-3-fluorobenzoic acid (4.97 g, 32.04 mmol), tert-butyl piperazine-1-carboxylate (5.97 g, 32.04 mmol) and triethylamine (10 mL) in dichloromethane (100 mL) was added 1-propanephosphonic acid cyclic anhydride (20 mL, 50% solution in ethyl acetate, dropwise). The reaction mixture was stirred for 1 hour then was diluted with ethyl acetate, washed with potassium carbonate (aqueous), dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (9.5 g). MS (ESI) m/z: 324.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7]#[N:8].Cl.[NH2:14][OH:15].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7](=[N:14][OH:15])[NH2:8]
Reactant: Cc1c(Cl)cccc1OCC#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(Cl)cccc1OCC(N)=NO
Yield: 90.2 %

Procedure:
29.2 g (160.7 mmol) of 3-chloro-2-methyl-phenoxyacetonitrile are added to a solution of 13.5 g (194.2 mmol) of hydroxylamine hydrochloride, 7.7 g (194.2 mmol) of sodium hydroxide in 265 ml of ethanol and 68 ml of water. The mixture is heated at reflux temperature until the reaction is complete (approximately 48 to 60 hours) and the entire batch is subsequently stirred into 250 ml of water. The solid which precipitates in this process is separated off, washed with a small amount of water and dried. 31.1 g (90.2% of theory) of 3-chloro-2-methylphenoxyacetamide oxime are obtained.