Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[O:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>O1CCCC1.O>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:25]=[N:24][N:23]([CH:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)[CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: OC1CCOCC1
Reactant: COc1ncc(Cl)c2c1c(-c1cn[nH]c1)nn2-c1c(F)cccc1F
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ncc(Cl)c2c1c(-c1cnn(C3CCOCC3)c1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-1-(2,6-difluorophenyl)-4-methoxy-3-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine in tetrahydrofuran (3 mL) were added tetrahydro-2H-pyran-4-ol (0.160 ml), triphenylphosphine (527 mg) and di-tert-butyl (E)-diazene-1,2-dicarboxylate (2.505 ml) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (140 mg).
Reaction SMILES: N[C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[I:15]CI.N(OCCC(C)C)=O.C(OCC)(=O)C>C1COCC1.[Cu]I.O>[C:13]([C:3]1[C:2]([I:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:14]
Reactant: ICI
Reactant: COC(=O)c1cc(N)c(C#N)cc1F
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)c(C#N)cc1F
Temperature: 25 °C
Yield: 42.3 %

Procedure:
To a solution of methyl 5-amino-4-cyano-2-fluorobenzoate (437 mg, 2.2 mmol) in THF (13 mL) was added copper(I) iodide (419 mg, 2.2 mmol), diiodomethane (890 uL, 11 mmol), and isoamyl nitrite (890 uL, 6.6 mmol). The solution was heated to reflux for 4 h and was then allowed to cool to room temperature. After dilution with ethyl acetate, water was added and the mixture was filtered through celite. The biphasic filtrate was partitioned. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue was then subject to column chromatography to provide impure methyl 4-cyano-2-fluoro-5-iodobenzoate (452 mg, ˜63% purity, ˜0.93 mmol). The remainder of the material consisted primarily of methyl 4-cyano-2-fluorobenzoate and was carried forward into the subsequent reaction without further purification. 1H NMR (400 MHz, CDCl3): 8.44 (d, 1H), 7.43 (d, 1H), 3.97 (s, 3H); MS (EI) for C9H5FINO2: 305 (M+).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.ClCC(NC1C=CC(Cl)=CC=1Cl)=O>C1COCC1>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: O=C(CCl)Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 127.1 %

Procedure:
Using the procedure described in Example 5, treatment of a solution of L-proline-L-isoleucine benzylamide (58 mg, 0.18 mmol), with triethylamine (130 uL, 0.93 mmol, 5.0 eq), and N-chloroacetyl-2,4-dichloroaniline (53 mg, 0.22 mmol, 1.2 eq) in THF (7 mL), provided a crude product. A portion of the product was purified by preparative TLC to provide 30 mg (32%) of L-isoleucine, N-[1-(2,4-dichlorophenylcarbamoylmethyl)-L-proline] benzylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[CH:11][CH:10]=1.B(O[O-])=[O:23].[Na+].O>B1C2CCCC1CCC2>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:23])=[CH:11][CH:10]=1
Reactant: C=CCCCC(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: O=BO[O-]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: O
Product: O=C(CCCCCO)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(2′,4′-Dichloro-biphenyl-4-yl)-hex-5-en-1-one (1.1 g) was dissolved in 0.5 M 9-BBN (6.9 mL) and stirred at room temperature for 4 hours. Sodium perborate (1 g) was added and the mixture stirred at room temperature for 1 hour. Water (3 mL) was added and the mixture stirred at 50° C. for 2 hours, then overnight at room temperature. The mixture was extracted with ether, dried, and evaporated to give an oil. The oil was purified by column chromatography to give an oil which solidified to a white amorphous solid on standing, and which was recrystallised from ether/petrol to give the title compound as a white powder. 13C NMR (CDCl3): δ23.9, 25.5, 32.5, 38.6, 62.7, 127.4, 128.0, 129.7, 129.9, 131.9, 133.1, 134.5, 136.3, 138.0, 142.8 and 199.9. 1H NMR (CDCl3): δ 1.45 (2H, m), 1.60 (2H, m), 1.80 (2H, m), 3.01 (2H, t, J=6.5 Hz), 3.68 (2H, t, J=6.5 Hz), 7.28 (2H, d, J=8.2 Hz), 7.30 (1H, s), 7.50 (2H, m) and 8.01 (2H, d, J=8.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[O:8][C:7]([CH2:12]Cl)=[N:6]2.[I-:14].[Na+].O.[Cl-].[Na+].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[O:8][C:7]([CH2:12][I:14])=[N:6]2
Reactant: [I-]
Reactant: O=c1oc(CCl)nn2ccc(Cl)c12
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=c1oc(CI)nn2ccc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of 5-chloro-2-(chloromethyl)-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-4-one (2.87 g, 13.1 mmol) in 57 mL of dry acetone under inert atmosphere was added 3.93 g (26.2 mmol) of sodium iodide and this mixture was stirred at room temperature overnight. Next day, the reaction mixture was poured into a 1/1 mixture of water/brine (100 mL) and extracted with diethyl ether (2×75 mL). The organic layers were washed with water and brine, dried (MgSO4) and concentrated in vacuum to afford 3.95 g of the title compound (95% yield).
Reaction SMILES: Cl[C:2]1[C:7]2[NH:8][C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[F:32])=[O:20])=[CH:14][CH:13]=3)=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C(O)=[O:34]>>[OH:34][C:2]1[C:7]2[NH:8][C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[F:32])=[O:20])=[CH:14][CH:13]=3)=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(Cc2nc3ccnc(Cl)c3[nH]2)cc1)Nc1cc(C(F)(F)F)ccc1F
Reactant: O=CO
Product: O=C(Nc1ccc(Cc2nc3ccnc(O)c3[nH]2)cc1)Nc1cc(C(F)(F)F)ccc1F

Procedure:
2.4 A solution of 50 mg of “A2” in 1 ml of formic acid (98-100%) is refluxed for 8 hours and subsequently purified via an RP18 column, giving 3 mg of 1-[4-(4-hydroxy-3H-imidazo[4,5-c]pyridin-2-ylmethyl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea (“A3”), Rf 2.88.
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]([NH2:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C=O)C.CCOC(C)=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]([NH:20][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Reactant: O=C(O)c1ccccc1-c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3-c3cccnc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-Amino-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 3.4 mmol) and 2-pyrid-3-yl benzoic acid (0.70 g, 3.7 mmol) in DMF (10 mL) was added HATU (1.42 g, 3.7 mmol) and diisopropylamine (0.65 mL, 3.7 mmol). After stirring at room temperature for 18 h, the reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (4×50 mL). The organic extracts were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure. Chromatography of the resulting residue (SiO2: EtOAc:Hex) yielded 4-[2-fluoro-4-(2-pyridin-3-yl-benzoylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester which was further dissolved in MeOH (20 mL) and 4N HCl in dioxanes. After stirring for 5 h, the reaction mixture was concentrated down, neutralized with 1N NaOH, and extracted with EtOAc (3×75mL). The organic extracts were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.Cl[CH2:11][C:12]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].[CH3:23][N:24]([CH3:30])[CH2:25][CH2:26][CH2:27][Mg]Cl.O>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH3:30])[CH2:25][CH2:26][CH2:27][C:14]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]2[C:12](=[CH:20][C:19]([C:21]#[N:22])=[CH:18][CH:17]=2)[CH2:11][O:15]1
Reactant: CN(C)CCC[Mg]Cl
Reactant: N#Cc1ccc(C(=O)Cl)c(CCl)c1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution of 4-fluoro phenylmagnesium bromide (0.7M in THF, 16 ml) was added to a cooled solution of 2-chloromethyl-4-cyano-benzoyl chloride (1,75 g) in toluene (20 ml) so that the temperature did not rise above 0° C. After 40 minutes a solution of 3-dimethylaminopropylmagnesium chloride (0,85 M in THF, 10 ml) was added so that the temperature did not rise above 2° C. The mixture was stirred for 30 minutes, and water (30 ml) was added. The pH of the mixture was adjusted to 4.5, and the phases were separated. The pH of the aqueous phase was adjusted to 8 and extracted with toluene (30 ml) and 2-propanol (10 ml). The organic phase was concentrated in vacuo to give a viscous oil (1,5 g, 56%). Spectral and analytical data were in accordance with the literature.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[C:6]([CH2:21][CH2:22][CH3:23])[C:5]=1[OH:24])(=[O:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].CI.Cl>C(C(C)=O)C>[CH3:25][N:18]1[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:19]=[CH:20][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:24])[C:6]=2[CH2:21][CH2:22][CH3:23])=[N:15][N:16]=[N:17]1
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(OCCCCCc2nnn[nH]2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCc2nnnn2C)ccc(C(C)=O)c1O

Procedure:
A solution of 5 g. of 5-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]-tetrazole, 3 g. of potassium carbonate, and 2.4 g. of methyl iodide in 250 ml. of methyl ethyl ketone was allowed to reflux overnight. The reaction mixture was treated with dilute hydrochloric acid and the layers were separated. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by chromatography over silica gel (2% ethanol in methylene chloride). The appropriate fractions were pooled and evaporated to an oil. Crystallization from ethyl acetate/hexane afforded 1.5 g. of the title product, m.p. about 72°-75° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=3)N)[CH2:23][CH2:22]2)[N:12]=1.CS(OCCC1C=CC=C([I:49])C=1)(=O)=O>CN(C)C=O>[I:49][C:31]1[CH:30]=[C:29]([CH2:28][CH2:27][N:24]2[CH2:23][CH2:22][N:21]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:18]=3[CH:19]=[CH:20][C:11]([CH3:10])=[N:12]4)[CH2:26][CH2:25]2)[CH:35]=[CH:34][CH:33]=1
Reactant: CS(=O)(=O)OCCc1cccc(I)c1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Temperature: 90 °C
Yield: 86.7 %

Procedure:
N,N-Diisopropylethylamine (1.7 mL; 1.5 eq) was added to a solution of 2-methyl-5-(1-piperazinyl)quinoline (D3) (1.31 g; 0.9 eq) and 2-(3-iodophenyl)ethyl methanesulfonate (2.1 g) in dimethylformamide (20 mL). The reaction mixture was heated to 90° C. for 5 hours. The dark solution was concentrated under reduced pressure, and purified by ion-exchange chromatography (SCX-2), eluting with methanol-ammonia/methanol (1M), (1:0) to (0:1). The combined basic fractions were concentrated under vacuum and purified by column chromatography (SPE cartridge, SiO2) using dichloromethane-methanol (95:5) to afford the title compound (1.5 g, 60% yield).
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[ClH:49]>CCOCC>[ClH:49].[F:18][C:19]1[N:20]=[C:21]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Fc1cccc(F)n1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: Fc1cccc(-n2c(/C=C/c3ccccc3)nc3ccccc32)n1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2,6-difluoropyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was dissolved into diethyl ether and hydrogen chloride gas was passed through the ether solution. Filtration and drying under vacuum yielded the titled compound as pale yellow solids.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.[N+:20]([C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:19][C:15]1([CH3:18])[O:14][CH:13]([CH2:12][N:25]2[CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:27]=[N:26]2)[CH2:17][O:16]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OCC(Cn2cc([N+](=O)[O-])cn2)O1
Yield: 88.9 %

Procedure:
A solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.57 g, 5.5 mmol), 4-nitro-1H-pyrazole (0.57 g, 5.0 mmol) and cesium carbonate (4.89 g, 15.0 mmol) in acetonitrile (30 mL) was stirred at 70° C. under N2 overnight. The reaction mixture was filtered, and the resulting filtrate was concentrated. The residue was diluted with ethyl acetate (50 mL), washed with water (50 mL×2) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to afford 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-nitro-1H-pyrazole (1.01 g, crude), which was directly used in the next step without further purification. MS (ES+) C9H13N3O4 requires: 227, found: 228 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1.[Na+].[Cl-:29]>C1C=CC=CC=1.CCOCC.CN(C=O)C>[ClH:29].[CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: [Cl-]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1CC[C@H](Oc2ccc(C(F)(F)F)cc2)[C@H](c2ccccc2)C1
Product: Cl
Temperature: 13 °C
Reaction time: 48 h

Procedure:
A suspension of 9.56 g of cis-1-methyl-3-phenyl-4-piperidinol, Example 22a above, in 100 ml of benzene is added to a suspension of 1.32 g of sodium hydride in 50 ml of dry benzene. The mixture is heated to reflux, and 50 ml of dry DMF are added in portions over a two hour period. The solution is cooled to 13° C. and a solution of 12.31 g of p-fluorobenzotrifluoride in 50 ml of benzene is added all at once. A slight rise in temperature occurs. After stirring at room temperature under nitrogen for 48 hours, the reaction mixture is poured into a mixture of ether and aqueous NaCl solution. The aqueous phase is extracted with ether, and the combined ether extracts are dried over anhydrous Na2SO4 and concentrated in vacuo to a mixture of an oil and a solid. This material is dissolved in 250 ml of boiling hexane and gravity-filtered to remove insoluble material. The cool filtrate is re-filtered to remove additional impurities, and then is reduced in volume. Scratching causes crystallization of a solid. An oil from the filtrate is separated out by dissolving the oil in dichloromethane and washing with 2 N HCl solution. The dichloromethane phase is washed with 20% aqueous NaOH solution (to liberate the free base of the product), dried over anhydrous Na2SO4, and concentrated in vacuo to an oil (free base). This material is dissolved in ether, filtered, and is then added to a stirred solution of ether saturated with dry HCl gas. The solvent is removed in vacuo and trituration of the residue with an ether causes solidification to occur to yield cis-1-methyl-3-phenyl-4-(4-trifluoromethylphenoxy)piperidine hydrochloride. Recrystallization from toluene affords solid product, mp s 175°, 177.5°-179.5° C.
Reaction SMILES: [CH:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(=O)CCCCCCCCCCC1>>[O:13]1[CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:1]12
Reactant: OC1CCCCCCCCCCC1
Agent: O=C1CCCCCCCCCCC1
Product: C1CCCCCC2OC2CCCC1

Procedure:
After the reaction was completed, the catalyst was removed from the reaction product mixture by filtering, and the reaction product mixture was subjected to gas chromatographic analysis. As a result, it was found that cyclododecanol was obtained in a yield of 6 molar % based on the fed epoxycyclododecadiene, and cyclododecanone was obtained in a yield of 76 molar %. Thus, the total yield of cyclododecanol and cyclododecanone was 82 molar %. In the reaction, epoxycyclododecane was produced in a yield of 16 molar %.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][N:11]=1.[N+](C1C=CC=C[C:24]=1[O:29][P:30]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)(=O)[O:31]C1C=CC=CC=1[N+]([O-])=O)([O-])=O.N12CCCN=C1CCCCC2.CO>ClCCl>[CH3:24][O:29][P:30]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)(=[O:31])[O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=[N+]([O-])c1ccccc1OP(=O)(Oc1ccccc1[N+](=O)[O-])C1CCCCC1
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COP(=O)(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.7 %

Procedure:
The compound cyclohexylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester is prepared according to procedure F using 200 mg of 3-(1H-indol-2-yl)-H-indazol-5-ol (intermediate B) in solution with 325 mg of cyclohexylphosphonic acid bis(nitrophenyl)ester in 6 ml of dichloromethane (stabilized with amylene), to which 120 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in solution in 1 ml of dichloromethane are added. After stirring at ambient temperature for 4 hours 30 minutes, 325 μl of methanol in solution in 1 ml of dichloromethane are added. The mixture is left at ambient temperature overnight and the solvent is then evaporated off and the crude is purified by flash chromatography on 35-70 μm silica, eluent: cyclohexane/ethyl acetate 90/10 to 50/50. The fractions obtained are concentrated and purified by preparative LC/MS to obtain 64.5 mg of cyclohexylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:20]3[CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: NCCCN1CCOCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCN1CCOCC1
Reaction time: 10 h
Yield: 68.2 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.22 ml (0.01525 mol) of N-(3-aminopropyl)-morpholine were added thereto and the mixture was boiled for 43 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with ethyl acetate/methanol 5:1, dissolved in hot isopropyl ether and crystallized at room temperature. There were obtained 3.58 g (68%) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-morpholin-4-yl-propyl)-2H-benzo[e]indol-2-one as white crystals with m.p. 65°-67° and 0.93 g (18%) of oily material from the mother liquors.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH2:49])=[CH:47][CH:48]=1)=[O:42])[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH:34]2[CH2:40][CH2:39][CH:38]1[CH2:37][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH:49][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:25])[CH3:1])[N:14]([CH:15]5[CH2:20][CH2:19][N:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:47][CH:48]=1)=[O:42])[CH2:35]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCN(C(C)(C)C)CC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCN(C(C)(C)C)CC1
Yield: 49.1 %

Procedure:
Following general N—C coupling procedure 1, 1, 7-(1-tert-Butyl-piperidin-4-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (90 mg, 0.247 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (90 mg, 0.272 mmol, 1.1 eq) which gave 3-{6-[7-(1-tert-Butyl-piperidin-4-yl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (80 mg) in 47% yield. MS m/z 660.3 (M+H)+.