Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:6](=[O:8])[CH3:7])[C:3](=[O:5])[CH3:4].[I-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([SH:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Cl:11][C:12]1[CH:13]=[C:14]([S:19][CH:2]([C:6](=[O:8])[CH3:7])[C:3](=[O:5])[CH3:4])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C(Sc1cc(Cl)cc(Cl)c1)C(C)=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 98.7 %

Procedure:
3-Chloro-2,4-pentanedione (723 μL, 6.07 mmol) and then sodium iodide (910 mg, 6.07 mmol) were added to a stirred suspension of 3,5-dichlorothiophenol (1.09 g, 6.07 mmol) and potassium carbonate (923 mg, 6.68 mmol) in acetone (30 ml), at room temperature, in a flask equipped with a calcium chloride drying tube. The mixture became yellow, then orange and finally red accompanied by a slight exotherm and was stirred for 23 hours at room temperature. The mixture was diluted with water (20 ml) and concentrated under reduced pressure in a fumehood (Caution: possible residual lachrymator) to remove acetone. The residue was diluted with 2M hydrochloric acid (20 ml) and extracted with dichloromethane (1×40 ml, 2×20 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to leave an orange solid (1.66 g). The crude product was purified by flash chromatography on silica gel eluting with pentane:diethyl ether (99:1, by volume) to give the title compound (807 mg) as a yellow solid m.p. 79-81° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:31][C:32]1[C:33]([C:39](O)=[O:40])=[N:34][C:35]([Cl:38])=[CH:36][CH:37]=1>C(Cl)(Cl)Cl>[Cl:31][C:32]1[C:33]([C:39]([NH:1][C:2]2[S:6][N:5]=[C:4]([CH3:7])[N:3]=2)=[O:40])=[N:34][C:35]([Cl:38])=[CH:36][CH:37]=1
Reactant: Cc1nsc(N)n1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nsc(NC(=O)c2nc(Cl)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
12 g of 5-amino-3-methyl-1,2,4-thiadiazole, 21.1 g of N-hydroxybenzotriazole hydrate and 29.8 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to a chloroform (500 ml) solution of 21 g of 3,6-dichloro-2-pyridinecarboxylic acid, and stirred at room temperature for 1 hour and then stirred overnight at 50° C. The reaction liquid was diluted with chloroform, then washed with aqueous 0.2 N hydrochloric acid solution, water and saturated saline water. After this was dried with anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure, and ethyl acetate was added to the resulting residue for crystallization to obtain 22.7 g of the entitled compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][O:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=N)[CH3:2].[ClH:19].N([O-])=O.[Na+].[OH-].[Na+]>O>[ClH:19].[CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][O:7][N:8]=[C:9]([Cl:19])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCN(CC)CCCONC(=N)c1cccnc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCN(CC)CCCON=C(Cl)c1cccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
9.5 g (37.9 mmoles) of N-(3-diethylaminopropoxy)-3-pyridinecarboxamidine are added under stirring to the mixture of 65 ml of distilled water and 21.7 ml of concentrated hydrochloric acid, cooled to 0° C. To the yellow solution, 13.08 g (189.5 mmoles) of sodium nitrite dissolved in 54 ml of distilled water are dropwise added at -5° C. during 50 minutes, then the reaction mixture is stirred at a temperature of -5° C. for 2 hours. Subsequently, the pH of the solution is adjusted to 11 by adding 2N sodium hydroxide solution, and the mixture is extracted 3 times with 70 ml of chloroform each. The organic phase is washed with 30 ml of water, dried over sodium sulfate and evaporated. The residue is purified by column chromatography (adsorbent: Merck Kieselgel 60; eluent: chloroform/methanol 1:1). The base obtained in a yield of 5.17 g (50.6%) is transformed by adding methanolic solution of hydrogen chloride to obtain the title hydrochloride, m.p.: 152-153° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Na+:12].[Na+].[CH2:14]([OH:16])[CH3:15]>>[C:4]([O:16][CH2:14][CH3:15])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O-:6])=[O:7].[Na+:12]
Reactant: O=C1C=CC(=O)O1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)/C=C\C(=O)[O-]

Procedure:
Fifty-seven grams (0.57 moles) maleic anhydride is dissolved in 500 mls ethanol. With the aid of a pH meter the pH is adjusted to 8.5-8.6 with sodium carbonate. The solution is evaporated on the roto evaporator and dried in a vacuum oven. Ninety-four grams (0.57 moles) of product having a purity of 99.4% (NMR analysis) is obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.Cl.[NH2:20][C:21]([CH2:28][CH3:29])([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23]>>[CH3:25][O:24][C:22](=[O:23])[C:21]([NH:20][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH2:28][CH3:29])[CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Reactant: CCC(N)(CC)C(=O)OC
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(=O)OC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and methyl 2-amino-2-ethylbutanoate hydrochloride (CAN 92398-54-4) as starting materials. MS (EI): m/e=389.0 [M+H]+.
Reaction SMILES: [NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:2]([C:10]([O:12]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[CH3:36]>C1COCC1.O>[NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C@H:2]([C:10]([NH:34][C@@H:35]([C:37]([OH:39])=[O:38])[CH3:36])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](N)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9.68 g (20.0 mmol) of Z-Phe-OPfp was dissolved in 20 ml of THF and to this was added 2.3 g (25.6 mmol) of H-D-Ala-OH dissolved in 5 ml water, pH 8.5. The reaction mixture was stirred for one day and one night at room temperature. The solvents were removed by evaporation under vacuum, 70 ml ethyl acetate was added, and the mixture was acidified to pH 2-3 by the addition of 70 ml of 2% sulfuric acid. The peptide was extracted twice with 70 ml ethyl acetate, washed with saturated sodium chloride solution to neutral pH, then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under vacuum, leaving a thick oil. The product was crystallized from ether/hexane. The yield was 7.6 g (97.7%), melting point was 153-154° C. Rf=0.40 in chloroform:ethyl acetate:methanol:acetic acid=6:3:1:0.1. Rf=0.53 in acetic acid:chloroform:methanol=0.5:16:1. Rf=0.58 in acetic acid:chloroform:methanol=0.5:9:1. [α]20D=+3.2(C=1, CH3OH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1

Procedure:
56.5 mg of solid white 3-{4-[3-(3-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 3-trifluoromethylphenyl isocyanate.
Reaction SMILES: C[Sn](Cl)(C)C.[Na].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C[Sn](C)C.[I:24]I>COCCOC.CCOC(C)=O>[I:24][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: II
Agent: C[Sn](C)(C)Cl
Agent: C[Sn](C)C
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Ic1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Yield: 86.5 %

Procedure:
A solution of trimethyltin chloride (5.5 g, 27.60 mmoles) in 5 mL of DME was added to a stirred suspension of small cubes of metallic sodium (1.9 g, 82.64 mg atom) in 15 mL of DME under an argon stream in an ice bath. When the addition was complete, the mixture was stirred and chilled in an ice bath for 2 hrs. (the color changed to green). The mixture was cannulated into another dry and under argon round bottom flask to remove excess sodium and cooled to 0° C. A solution of 4-bromobiphenyl (5.4 g, 22.70 mmoles) in 14 mL of DME was added dropwise to the chilled NaSnMe3 solution. The resulting solution was stirred at room temperature overnight at which time TLC analysis showed complete reaction. Rf of the trimethyltin product=0.44 (silica, hexanes). The reaction mixture was then cooled in an ice bath and treated with iodine (6.6 g, 26.00 mmoles). After stirring at room temperature for 1.5 hrs, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and the solvent removed at reduced pressure. The crude product was then purified by column chromatography with hexanes to afford 5.5 g (86% yield) of white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>CC(C)=O>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([CH3:31])=[C:10]3[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)CBr
Reactant: Cc1c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(C)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1,3-dibenzyl-2-methyl-1H-indol-5-yl)-phenol (0.155 g, 0.384 mmol) was reacted with K2CO3 (0.069 g, 0.499 mmol) and methyl bromoacetate (0.076 g, 0.499 mmol) in acetone (5 ml) to give the product (0.152 g, 0.320 mmol, 83%) as a viscous oil. 1H NMR (DMSO-d6) δ 2.35 (s, 3H), 3.70 (s, 3H), 4.10 (s, 2H), 4.80 (s, 2H), 5.42 (s, 2H), 6.94-7.00 (m, 4H), 7.09-7.13 (m, 1H), 7.20-7.30 (m, 8H), 7.39 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.9 Hz, 2H), 7.58 (d, J=1.7 Hz, 1H); [ESI(+)], m/z 476 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=2)=[CH:3][CH:4]=1)([CH3:17])[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: COc1cccc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)c1
Yield: 60 %

Procedure:
Prepared in a similar manner to example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 3-methoxyphenylboronic acid. Yield: 60%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (t, 2H), 3.85 (s, 3H), 6.9 (dd, 1H), 7.1(s, 1H), 7.2(d, 1H), 7.4 (t, 1H), 7.45 (d, 2H), 7.6 (d, 2H). MS (M+H, 326).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[S:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2ccccc2)c(-c2ccccc2)s1
Solvent: ClCCl
Product: CS(=O)c1nc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (ice/water) solution of 1.1 g. of 2-methylthio-4,5-diphenyl-thiazole pre-dissolved in 15 ml. of methylene chloride is added in portions over 5 minutes, 0.8 g. of m-chloro-peroxybenzoic acid. Examination by TLC after 30 minutes indicates the presence of essentially all of the sulfinyl compound (reaction complete). The precipitated m-chloro-benzoic acid is filtered off and the methylene chloride solution is washed successively with a 10% solution of sodium bisulfite and with saturated sodium bicarbonate solution, dried, evaporated in vacuo to dryness and the residue further dried overnight in vacuo to yield 2-methylsulfinyl- 4,5-diphenyl-thiazole, m.p. 102°-103° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([I:19])=[C:11]([N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23][CH:24]=C)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O:35]C(C)=O>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([I:19])=[C:11]([N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23][CH:24]=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCCN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)c2ccccc2c1I
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCC=O)c1cc(OCc2ccccc2)c2ccccc2c1I
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
A solution of 81 (44 mg, 81 μmol) in THF (3 mL) was treated sequentially with a solution of NaIO4 (35 mg, 162 μmol, 2 equiv) in 0.5 mL H2O and a solution of OSO4 (7.5 mM in THF, 0.53 mL, 4 μmol, 0.05 equiv). The reaction mixture was stirred for 6 h at 25° C. EtOAc (20 mL) was added and the organic layer was dried (Na2SO4), filtered through Celite, and the solvent removed under vacuum. Chromatography (SiO2, 1×15 cm, 15% EtOAc-hexane) afforded 110 (35 mg, 80%) as an oil: 1H NMR (CDCl3, 400 MHz) δ 9.73 (t, J=1.3 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.61-7.49 (m, 4H), 7.42-7.32 (m, 3H), 6.77 and 6.72 (two s, 1H), 5.32-5.25 (m, 2H), 3.86 (ddd, J=14.0, 8.6 Hz, 6.7 Hz, 1H), 3.47 (m, 1H), 2.48 (m, 2H), 1.93-1.75 (m, 2H), 1.29 and 1.23 (two s, 9H); IR (film) νmax 3064, 3032, 2975, 2930, 2722, 1638, 1616, 1590, 1407, 1160 cm31 1; FABHRMS (NBA-CsI) m/z 678.0095 (M+Cs+, C26H28INO4 requires 678.0117).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:31][CH:32]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)CCc4ccc(F)cc4)c3)c2c1
Yield: 9.8 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 3-(4-fluorophenyl)propanoic acid (0.12 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 22 mg (9% yield) of the title compound. 1H NMR (DMSO-d6) δ 13.4 (s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.25 (s, 1H), 8.15 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.45 (t, 1H), 7.4–7.3 (m, 3H), 7.2–7.1 (m, 2H), 2.85 (t, 2H), 2.65 (t, 2H); ES-MS (m/z) 403 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:19]([N:21]([CH:35]([CH3:37])[CH3:36])[C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)=[O:20])[C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:9]=2[O:8][C:7]([CH3:39])([CH3:38])[C:6]1=[O:40])[CH2:2][CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:49])C=1.O>ClCCl>[CH3:39][C:7]1([CH3:38])[C:6](=[O:40])[N:5]([CH2:1][CH2:2][CH:3]2[CH2:4][O:49]2)[C:10]2[CH:11]=[C:12]([C:19]([N:21]([CH:35]([CH3:36])[CH3:37])[C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:23]3)=[O:20])[C:13]([C:15]([F:17])([F:16])[F:18])=[CH:14][C:9]=2[O:8]1
Reactant: C=CCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCC1CO1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of tert-butyl (3R)-3-[{[4-but-3-en-1-yl-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (1.7 g) in dichloromethane (15 ml) was added m-chloroperbenzoic acid (775 mg), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (780 mg).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:6]=1.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:15].[Li]CCCC>>[C:4]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:11][CH2:12]2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C=C(C)c1ccccc1
Agent: [Li]CCCC
Product: CC(CN1CCN(c2ccccc2)CC1)c1ccccc1

Procedure:
According to GP, 2.22 mmol (=0.36 g=0.34 ml) of phenylpiperazine and 2.22 mmol (=0.26 g=0.29 ml) of α-methylstyrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate/n-hexane (3:1) gives the product 1-phenyl-4-(2-phenylpropyl)piperazine as a light-yellow solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]#[N:22].C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[C:21]=1[NH2:22]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: COc1ccc(N=[N+]=[N-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-n2nnc(-c3ccc(Cl)cc3Cl)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-4-methoxy-benzene (0.750 g, 1 eq) and commercial (2,4-dichloro-phenyl)-acetonitrile (1.12 g, 1.2 eq) in ethanol (10 ml) kept under nitrogen, a solution of sodium methoxide (0.408 g, 1.5 eq) in ethanol (10 ml) is added drop-wise (25 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (40 ml), washed with water (2×50 ml), dried over MgSO4 and evaporated to dryness. The yellow semisolid residue (0.842 g) is purified by flash chromatography using 60-120 mesh silica gel and eluting with 15% ethylacetate in hexane, to afford the title compound as a white solid (0.428 g, 24% yield). M.p. 154.6-163.9° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.N1CCOCC1>C(Cl)(Cl)Cl>[CH3:13][CH:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:16][CH2:15]1
Reactant: CC1CCNCC1
Reactant: O=[N+]([O-])c1cc(CO)ccc1F
Solvent: C1COCCN1
Solvent: ClC(Cl)Cl
Product: CC1CCN(c2ccc(CO)cc2[N+](=O)[O-])CC1
Temperature: 50 °C

Procedure:
A stirred suspension of (4-fluoro-3-nitro-phenyl)-methanol (171 mg, 1 mmol), 4-methyl piperidine (95 mg, 0.96 mmol) PS morpholine (400 mg, 1 mmol), and chloroform (3 mL) was heated at 50° C. for 2 hrs. The reaction was evaporated onto celite and purified by flash chromatography to give [4-(4-methyl-piperidin-1-yl)-3-nitro-phenyl]-methanol (i). 1H NMR (CDCl3, 300 MHz): δ 7.8 (s, 1H), 7.4 (d, 1H), 7.1 (d, 1H), 4.6 (s, 2H), 3.2 (d, 2H), 2.8 (dd, 2H), 1.8-1.3 (m, 5H), 1.0 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([NH:15][C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
(±)-cis-N-tert-Butoxycarbonyl-1,2-cyclohexanediamine (3.78 g) was dissolved in acetonitrile (80 ml), and to the solution triethylamine (2.44 ml) and benzyl bromide (2.10 ml) were added, and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, dichloromethane and water was added to the residue to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound (3.08 g) as a pale orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[C:20]([F:25])[N:19]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:10][C:22]2[CH:21]=[C:20]([F:25])[N:19]=[C:18]([F:17])[CH:23]=2)[CH:3]=1)[C:8]#[N:9]
Reactant: Fc1cc(F)nc(F)c1
Reactant: N#Cc1cc(O)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2cc(F)nc(F)c2)c1
Temperature: -50 °C

Procedure:
Compound 1-4 (577 mg; 3.76 mmol) and potassium carbonate (779 mg; 5.64 mmol) were added to a solution of 2,4,6 trifluoropyridine (500 mg; 3.76 mmol) in DMF with stirring at −50° C. The reaction mixture was slowly warmed to room temperature and then diluted water and EtOAc, after which the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water (3×), brine (2×), dried over MgSO4, and concentrated to an oil. The crude residue was purified via column chromatography (0-25% EtOAc in hexanes.) to give the title compound. MS M+1=266.9. 1H NMR (CDCl3): 6.32 (m, 2H), 7.30 (m, 1H), 7.36 (m, 1H), 7.56 (m, 1H).