Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][O:26][CH3:27].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:24][CH2:25][O:26][CH3:27])[CH2:19][CH2:18]3)=[O:14])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCBr
Reactant: O=C(OCC1CCNCC1)N1CCN(c2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCC(COC(=O)N2CCN(c3ccccc3)CC2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
(Piperidin-4-yl)methyl 4-phenylpiperazine-1-carboxylate from the previous step (2.15 g, 7.10 mmol), 2-bromoethylmethylether (0.67 mL, 7.10 mmol) and DIPEA (1.36 mL, 7.81 mmol) were dissolved in DMF (30 mL) and stirred overnight at 70° C. and then concentrated in vacuo. The residue was dissolved in DCM (300 mL) and then washed sequentially with sat aq NaHCO3 solution (2×100 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 98:1:1 mixture of DCM:MeOH:DIPEA) followed by reverse phase chromatography (gradient eluting with MeOH in water, 0-100%) to give the title compound [1-(2-methoxyethyl)piperidin-4-yl]methyl 4-phenylpiperazine-1-carboxylate (0.798 g, 31.1% yield) as a viscous yellow oil.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][CH2:4][NH:3][CH2:2][CH2:1][C:7]=2[CH:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCNCC2
Product: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reaction time: 1 h

Procedure:
1,2,4,5-Tetrahydro-3H-3-benzazepine (1 g) (see P. Ruggli et al., Helv. Chem. Acta, 18, 1388 [1935]) was added slowly, dropwise to stirred fuming nitric acid (25 ml, density 1.5 gm/ml) cooled to -10°. Stirring was continued at -10° for 1 hour, and the reaction mixture was then poured onto ice, the precipitate collected by filtration and dried to give the title compound as the nitrate salt, yield 1.4 g. A sample was recrystallised from water, m.p. 203°-204°.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:19][OH:20])[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)#[N:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH:19]=[O:20])[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)#[N:2]
Reactant: COC(=O)c1ccc(CC(CO)CCCCC#N)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(C=O)CCCCC#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
A solution of 3.8 g (13.80 mmol) of methyl 4-(6-cyano-2-hydroxymethylhexyl)benzoate from Example 117A in 250 ml of dichloromethane is mixed with 3.57 g (16.56 mmol) of pyridinium chlorochromate (PCC) and stirred at room temperature for 12 hours. After conversion is complete, 10 g of silica gel are added and the solvent is cautiously concentrated to dryness in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1). 3.49 g (92% yield) are obtained as a colorless solid.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.Cl[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[C:24]([Cl:32])=[CH:23][C:22]=1[Cl:33].[O:34]1CC[CH2:36][CH2:35]1>>[Cl:33][C:22]1[CH:23]=[C:24]([Cl:32])[C:25]2[C:30](=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:21]=1[CH2:20][CH2:36][CH:35]=[O:34]
Reactant: ClCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=CCCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of n-butyl lithium in hexane (3.2 ml, 4.3 mmoles) was added dropwise (3 minutes) to a solution of diisopropylamine (0.45 g, 4.5 mmoles) in dry tetrahydrofuran (10 ml) with cooling (ice bath). After stirring under nitrogen for 15 minutes, ethylidene cyclohexylimine (0.55 g, 4.3 mmole) was added dropwise (5 minutes) at 0° C. The mixture was stirred for 15 minutes and then the ice bath was replaced by a dry-ice-acetone bath. A solution of 1-chloromethyl-2,4,7-trichloronaphthalene (1.0 g, 3.8 mmoles) in tetrahydrofuran (15 ml) was added (5 minutes) at -75° C. The reaction mixture was stirred at -70° C. for 30 minutes and at room temperature overnight (20 hours) and then concentrated to dryness in vacuo. The residual oil was taken up in ether (100 ml) and 5% aqueous oxalic acid (100 ml) and the mixture stirred at room temperature for 31/2 hours. The layers were separated and the aqueous phase extracted (2X) with ether. The ether extracts were combined, washed with cold water and brine, and dried over MgSO4. The solution was filtered and concentrated in vacuo to give a red-brown oil (1.1 g). This material was chromatographed using a 50 mm flash column containing 150 g of silica gel (230-400 mesh) eluting with 30% methylene chloride in hexane (v/v) to give 0.21 g of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1([C@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[C:11]1[O:14][C:13](=[O:15])[CH2:12]1>O1CCCC1.CN(C1C=CN=CC=1)C>[O:14]=[C:11]([CH3:10])[CH2:12][C:13]([O:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])=[O:15]
Reactant: C=C1CC(=O)O1
Reactant: C[C@@H](O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
To a solution of (R)-1-phenylethanol (6.0 ml, 50 mmol) in dry tetrahydrofuran (75 ml) at room temperature was added 4-(N,N-dimethylamino)pyridine (610 mg, 5.0 mmol) followed by dropwise addition of 4-methyleneoxetan-2-one (3.83 ml, 50 mmol). The reaction was stirred for 12 hours at room temperature, then the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate, poured into a separatory funnel, and washed with 1M aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, then brine. The organic phase was separated and the solvent removed under resuced pressure to provide (R)-1-phenylethyl 3-oxobutanoate as a light reddish oil (10.3 g, 100%). 1H NMR (CDCl3, 400 MHz) δ 7.4-7.2 (m, 5H); 5.94 (q, 1H, J=6.6 Hz); 3.45 (s, 2H); 2.22 (s, 3H); 1.56 (d, 3H, J=6.6 Hz).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].NC[CH2:13][C:14]([OH:16])=[O:15]>>[C:14]([CH2:13][CH2:9][N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:10])([OH:16])=[O:15]
Reactant: NCCC(=O)O
Reactant: Cc1c(O)c(=O)ccn1C
Product: Cc1c(O)c(=O)ccn1CCC(=O)O

Procedure:
A reaction analogous to that used for the synthesis of 3-hydroxy-1,2-dimethyl-4-pyridinone was employed starting with β-alanine (2.5 g). No precipitate was observed after concentration and, at this point, the pH was set to 4 with hydrochloric acid. Following extraction with dichloromethane, the solvent was removed by rotary evaporation. Hydrogenolysis was performed as before, although the final product was not recrystallized. An off-white powder was obtained (2.3 g). Proton NMR (D20): 7.89 (d, 1H), 6.88 (d, 1H), 4.39 (t, 2H), 2.76 (t, 2H), 2.38 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:28][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: COc1cccc(CN)c1
Solvent: CC(C)O
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1
Temperature: 22.5 °C

Procedure:
tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3, 245 mg, 0.82 mmol) is suspended in isopropyl alcohol (6 mL) and 3-methoxybenzylamine (160 microL, 1.22 mmol) is added with stirring at 20-25 degrees C. This mixture is heated to gentle reflux (bath temp 85 degrees C.) under nitrogen for 2 hours, whereupon the resulting mixture is concentrated under reduced pressure to give the title compound. The title compound is purified by flash chromatography (2-5% methanol/methylene chloride; gradient elution) to give purified title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25]C(=O)OCC=C)[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.CC(O)=O.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([CH:22]=[CH:23][CH:24]=2)[NH2:25])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (57 g, 120 mmol) (prepared by a process analogous to that described for Intermediate 26) in DCM (500 mL), HOAc (17.3 g, 288 mmol), Pd(PPh3)2Cl2 (1.68 g, 2.4 mmol) were added. Then tri-n-butyltin hydride (38.4 g, 132 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by adding saturated NaHCO3 (300 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (1 L×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (500 mL) to afford the title compound (43 g, 91.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (d, J=5.5 Hz, 1H), 6.95-7.07 (m, 1H), 6.83-6.92 (m, 1H), 6.74-6.80 (m, 1H), 6.70 (d, J=5.5 Hz, 1H), 3.57-3.63 (m, 4H), 3.75-3.88 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=O)[O:9][C:5]=2[CH:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:22][C@@H:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:16])[F:15])[CH:14]=[CH:13][C:6]=3[CH:7]=2)=[O:12])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)cc2o1
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Product: O=C(c1cc2ccc(C(F)(F)F)cc2o1)N1CCC[C@H]1CN1CCCCC1

Procedure:
71 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 6-(trifluoromethyl)benzofuran-2-carboxylic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=2[N:13]=[C:12]1[CH3:20])[C:5]([OH:7])=O.C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:42]=[CH:41][C:34]2[NH:35][C:36]([C@@H:38]([NH2:40])[CH3:39])=[N:37][C:33]=2[CH:32]=1.ClCl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=2[N:13]=[C:12]1[CH3:20])[C:5]([NH:40][C@H:38]([C:36]1[NH:35][C:34]2[CH:41]=[CH:42][C:31]([Cl:30])=[CH:32][C:33]=2[N:37]=1)[CH3:39])=[O:7]
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1nc2c(n1-c1ccc(C(=O)O)cc1Cl)CCCC2
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2c(n1-c1ccc(C(=O)N[C@@H](C)c3nc4cc(Cl)ccc4[nH]3)cc1Cl)CCCC2
Yield: 35 %

Procedure:
Prepared analogously to Example 1d from 3-chloro-4-(2-methyl-4,5,6,7-tetrahydrobenzimidazol-1-yl)benzoic acid, PFTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylformamide. Yield: 35%; C24H23Cl2N5O (468.386); mass spectrum: (M+H)+=466/468/470 (chlorine isotope).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(O)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2ccc(Cl)cc2)C1

Procedure:
62.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 4-chloro-benzoic acid to give (R)-3-[(4-chloro-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester. Yellow oil. MS 339.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[NH:15][CH2:14][CH2:13][N:12]([C:16]4[CH:25]=[C:24]5[C:19]([C:20](=[O:31])[C:21]([C:28]([OH:30])=[O:29])=[CH:22][N:23]5[CH2:26][CH3:27])=[CH:18][C:17]=4[F:32])[CH2:11]3)=[CH:7][C:6]=2[CH:33]=1.[CH:34](O)=O>C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[N:15]([CH3:34])[CH2:14][CH2:13][N:12]([C:16]4[CH:25]=[C:24]5[C:19]([C:20](=[O:31])[C:21]([C:28]([OH:30])=[O:29])=[CH:22][N:23]5[CH2:26][CH3:27])=[CH:18][C:17]=4[F:32])[CH2:11]3)=[CH:7][C:6]=2[CH:33]=1
Reactant: O=CO
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc5cc(Cl)ccc5o4)C3)cc21
Agent: C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(c4cc5cc(Cl)ccc5o4)C3)cc21

Procedure:
A 150 mg portion of 7-[3-(5-chloro-2-benzofuranyl)-1-piperazinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was suspended in 0.6 ml of 37% formaldehyde and 0.75 ml of 90% formic acid was added. The mixture was heated on a steam bath for 2 hours, then evaporated to dryness. A 5 ml portion of water was added, the pH adjusted to 7.0 with lN sodium hydroxide and the solid collected, washed with water and dried, giving 113 mg of the desired product, mp 248°-249° C.
Reaction SMILES: [F-].C([N+:6](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][N:26]2COCC[Si](C)(C)C)=[CH:22][C:21]=1[C:43]1[CH:48]=[CH:47]C([N+]([O-])=O)=[CH:45][CH:44]=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][NH:26]2)=[CH:22][C:21]=1[C:43]1[CH:44]=[CH:45][N:6]=[CH:47][CH:48]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc([N+](=O)[O-])cc3)cc12
Agent: O=C([O-])O
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccncc3)cc12

Procedure:
36.8 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 3 g of N-[6-chloro-5-(4-nitrophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 135 cm3 of tetrahydrofuran. The medium is then refluxed for 18 hours and is then allowed to return to room temperature to add 100 cm3 of ethyl acetate and 75 cm3 of saturated aqueous sodium hydrogen carbonate solution. The organic phase is separated out after settling of the phases has taken place, washed with 100 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 100 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa; 50° C.); the residue is taken up in 35 cm3 of diisopropyl ether, filtered off on a sinter funnel and then washed with 2×20 cm3 of diisopropyl ether. After drying (90 Pa; 50° C.), 88 mg of N-[6-chloro-5-(4-nitrophenyl)-1H-indazol-3-yl]butanamide are obtained in the form of yellow crystals melting at 260° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:44][CH2:45][CH3:46])([CH2:41][CH2:42][CH3:43])[C:7](=[O:40])[C:8]([C:13]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([NH:23][S:24]([NH:27]C(=O)OCC5C=CC=CC=5)(=[O:26])=[O:25])=[CH:22][C:16]=4[S:15](=[O:39])(=[O:38])[N:14]=3)=[C:9]2[OH:12])=[CH:4][CH:3]=1>[Pd].CO.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:44][CH2:45][CH3:46])([CH2:41][CH2:42][CH3:43])[C:7](=[O:40])[C:8]([C:13]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([NH:23][S:24]([NH2:27])(=[O:25])=[O:26])=[CH:22][C:16]=4[S:15](=[O:39])(=[O:38])[N:14]=3)=[C:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)=C(O)c2cc(F)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(N)(=O)=O)ccc3N2)=C(O)c2cc(F)ccc21
Yield: 57.7 %

Procedure:
A solution of the product of Example 17D (28 mg, 0.042 mmol) in 2:1 methanol-ethyl acetate (15 mL) was treated with 10% Pd/C (20 mg) and hydrogenated at one atmosphere for 18 h. The mixture was filtered through celite® and the filtrate concentrated in vacuo to afford the title compound (13 mg).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][OH:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.O1CCOC[CH2:18]1.Cl>C(OCC)(=O)C>[NH:10]1[CH2:9][CH2:8][C:7]2([C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:18][O:14][CH2:13]2)[CH2:12][CH2:11]1
Reactant: OCC1(c2ccccc2)CCNCC1
Reactant: C1COCCO1
Agent: C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)COCC21CCNCC1
Yield: 50 %

Procedure:
A mixture of (4-phenyl-piperidin-4-yl)-methanol (0.1 g, 0.5 mmol), paraformaldehyde (0.11 g, 3.7 mmol), 1,4-dioxane (5 ml) and concentrated hydrochloric acid solution (1.3 ml) was heated at reflux for 80 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with 0.5 M aqueous sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography of the crude product with dichloromethane/methanol as eluent gave the title compound (0.053 g, 50%) as yellow solid. MS m/e: 204 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH2:15][F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH2:15][F:16])[NH:13][C:12](=[S:27])[CH2:11][O:10][CH2:9]2)[CH:7]=1
Reactant: O=C1COCC(CF)(c2cc(Br)ccc2F)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: FCC1(c2cc(Br)ccc2F)COCC(=S)N1

Procedure:
A mixture of 7.34 g (22.65 mmol) 5-(5-bromo-2-fluoro-phenyl)-5-fluoromethyl-morpholin-3-one and 5.19 g (12.46 mmol) Lawesson's reagent in 73 ml of THF was refluxed for 1 h. The mixture was concentrated and crystallized from DCM/hexane and recrystallized from EtOH to yield the desired product as colorless crystals.
Reaction SMILES: [Li]CCCC.CCCCCC.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[C:21]3[CH:27]=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1COCC1.CN(C1C=CN=CC=1)C>[C:29]([Si:32]([CH3:34])([CH3:33])[N:25]1[C:22]2=[N:23][CH:24]=[C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=3)[CH:20]=[C:21]2[CH:27]=[CH:26]1)([CH3:31])([CH3:30])[CH3:28]
Reactant: Fc1cccc(-c2cnc3[nH]ccc3c2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(-c3cccc(F)c3)cnc21
Yield: 80.6 %

Procedure:
2.5 M solution of n-BuLi in hexane (13.7 mL, 34.3 mmol) was added dropwise to a stirred and cooled (−78° C.) solution of azaindole 7 (6.04 g, 28.5 mmol) in THF (30 mL). After the mixture was stirred for 10 min at −78° C., DMAP (66 mg, 0.54 mmol) was added, followed by a solution of TBSCl (5.14 g, 34.1 mmol) in THF (2.5 mL). The mixture was stirred at −78° C. for 1 h. Cooling bath was removed, the mixture was stirred at r.t. for 3 days, and separated between AcOEt:saturated aqueous NaHCO3 solution. The aqueous layer was extracted with AcOEt (3×). Combined organic solutions were dried (MgSO4), concentrated, and separated by means of SGC with hexane:benzene as eluent in gradient (up to 15% benzene) to afford 8 (7.50 g, 81%) as white solid. 1H NMR (400 MHz, CDCl3) δ 0.67 (s, 6H), 0.96 (s, 9H), 6.59 (d, J=3.5 Hz, 1H), 6.99-7.07 (m, 1H), 7.29 (d, J=3.5 Hz, 1H), 7.33 (ddd, J=10.9, 3.0, 1.7 Hz, 1H), 7.38-7.44 (m, 2H), 8.04 (d, J=2.3 Hz, 1H), 8.51 (d, J=2.3 Hz, 1H).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:16]([N:19](C(C)C)C#N)(C)C>C1C=CC=CC=1.CCCCCC>[C:16]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)#[N:19]
Reactant: c1cnc2c(c1)CCCC2
Reactant: CC(C)N(C#N)C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: N#CC1CCCc2cccnc21
Yield: 71 %

Procedure:
A solution of 5,6,7,8-tetrahydroquinoline (6.5 ml, 50 mM) in benzene (35 ml) maintained below 10° was treated with 1.6M butyl lithium in hexane (31.25 ml, 50 mM). The resulting anion solution was heated to reflux then treated with a solution of diisopropylcyanamide (6.3 g, 50 mM) in benzene (15 ml). After 15 min. the mixture was cooled and quenched with water (20 ml). The organic phase was separated, dried and evaporated. Distillation of the residue gave the title compound (5.6 g, 71%) Bp. 135°-140°/2 mm, identical with authentic material. Hydrochloride mp 185° C.--see Example 37 UK Pat. No. 1,432,378.
Reaction SMILES: O[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2nccnc2O)cc1
Product: COc1ccc(-c2nccnc2Cl)cc1
Reaction time: 4 h

Procedure:
The 2-hydroxy-3-p-methoxyphenylpyrazine is refluxed (120°-130° C.) with excess phosphorus oxychloride under stirring for 3-5 hours. The solution is evaporated to dryness at 50° C. in vacuo, cooled, ice is added, then treated with 10% sodium hydroxide solution, extracted with a suitable solvent such as diethyl ether, the ethereal solution washed with water and evaporated. The crude product is crystallized from a suitable solvent such as ethanol to give 2-chloro-3-p-methoxyphenylpyrazine.