Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[CH2:21]([Mg]Br)[CH3:22].CCCCCC.C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:21][CH3:22])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Cl)cc1Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a solution of 4-chloro-N-methoxy-N-methyl-2-phenylamino-benzamide (5.0 g, 17.2 mmol) in THF (60 mL) was added ethylmagnesium bromide (1M solution in THF, 70 mL, 70 mmol) dropwise at 0° C. under nitrogen. The mixture was slowly warmed to room temperature and stirred for 2 hr. Completion of the reaction was monitored by silica TLC (mobile phase; hexane:ethyl acetate=4:1; Rf=0.5). Reaction was quenched with an aqueous solution of 1N HCl (50 mL) at 0° C. and was extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified using silica gel (100-200 mesh) column chromatography, using gradient polarity mobile phase (ethyl acetate:hexane=1:91:4), to give 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (4.15 g, 92.9% yield) as a yellow oil. 1H NMR (DMSO-d6) δ ppm 10.53 (s, 1H) 8.00 (d, J=8.7 Hz, 1H) 7.34-7.51 (m, 2H) 7.28 (d, J=7.7 Hz, 2H) 7.13-7.23 (m, 1H) 7.07 (d, J=1.8 Hz, 1H) 6.82 (dd, J=8.6, 1.9 Hz, 1H) 3.07 (q, J=7.2 Hz, 2H) 1.09 (t, J=7.3 Hz, 3H).
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])C.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[NH:30][NH2:31]>C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([N:8]1[CH2:9][CH2:10][C:11]2[NH:31][N:30]([C:21]3[CH:22]=[N:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]=3)[C:4](=[O:5])[C:6]=2[CH2:7]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NNc1cnc2ccccc2n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2[nH]n(-c3cnc4ccccc4n3)c(=O)c2C1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (500 mg, 1.84 mmol; Tetrahedron 1994, 50, 515) in toluene (10 mL) was added quinoxalin-2-yl-hydrazine (295 mg, 1.85 mmol; Heterocycles 1985, 23, 2603). This mixture was stirred at reflux overnight, cooled to room temperature, concentrated, and purified by flash column chromatography (25→75% ethyl acetate/hexanes) to give 600 mg (89%) of the title compound of Example 75, Step A as a light orange solid. 1H NMR (CDCl3, 250 MHz, 5:1 mixture, of taunters) δ 11.94 (brs, 0.83H), 10.16 (s, 0.17H), 9.57 (s, 0.83H), 8.13 (dd, 1H), 7.91-7.69 (c, 3H), 4.45 (s, 1.66H), 4.33 (s, 0.34H), 3.79-3.72 (c, 2H), 2.82-2.72 (c, 2H), 1.52 (s, 9H); MS (APCI) 368 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:21]4[S:25][C:24]([CH3:26])=[N:23][C:22]=4[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=O)=O)=CC=1.[Na+].[I-:34]>CC(C)=O.C(Cl)Cl>[I:34][CH2:12][C:13]12[CH2:20][CH2:19][C:16]([C:21]3[S:25][C:24]([CH3:26])=[N:23][C:22]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:17][CH2:18]1)[O:15][CH2:14]2
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4sc(C)nc4-c4ccccc4)(CC2)OC3)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1nc(-c2ccccc2)c(C23CCC(CI)(CC2)CO3)s1
Temperature: 85 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A mixture of (1-(2-Methyl-4-phenylthiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate (125 mg, 0.266 mmol) and NaI (120 mg, 0.799 mmol) in acetone (5 mL) was stirred in a seal tube at 85° C. for 18 h. The reaction was cooled to rt, diluted with DCM (5 mL), and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on SiO2 (0-30% EtOAc:hexanes) to afford the title compound (100 mg, 88% yield) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.45-7.34 (m, 5H), 3.79 (s, 2H), 2.96 (s, 2H), 2.66 (s, 3H), 2.12-2.00 (m, 2H), 1.90-1.78 (m, 2H), 1.71-1.51 (m, 4H).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(O)C.C(OCC)C>[ClH:1].[C:29]([CH2:28][CH2:27][N:12]1[CH2:13][CH2:14][C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C@H:10]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[CH2:11]1)#[N:30]
Reactant: Fc1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Reactant: N#CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: CC(C)=O
Product: N#CCCN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc3c(c2)OCO3)C1

Procedure:
1 g of (-)-trans-4-(4-fluorophenyl)-3-(3,4-methylene dioxyphenoxymethyl)-piperidine hydrochloride in 50 ml 99.9% ethanol was mixed with 3-bromopropionitrile (7 ml) and 2 g potassium carbonate. The mixture was refluxed for 70 h. After cooling 25 ml acetone and 25 ml diethylether were added, the precipitate filtered off, and the filtrate evaporated in vacuo. The residue was extracted with 1N NaOH/ether, the ether layer dried (MgSO4) and evaporated to dryness. The residue was dissolved in acetone and excess conc. HCl was added. Subsequent evaporation gave a hard glass, which was purified on a silica gel column using 99.5% ethanol as eluent. The title compound was isolated, and its structure confirmed by the IR and NMR data. M.p. 156° C.
Reaction SMILES: [H-].[Na+].[C:3](OC)(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[C:16]1([CH2:22][CH2:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.O>[OH:6][C:5]1[CH2:7][C:24]([CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:33][C:3](=[O:8])[CH:4]=1
Reactant: O=C(CCc1ccccc1)CCc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1C=C(O)CC(CCc2ccccc2)(CCc2ccccc2)O1
Reaction time: 0.17 h

Procedure:
Freshly distilled THF (25 mL) was cooled in an ice bath under a nitrogen atmosphere, then charged with 660 mg (16.5 mmol) sodium hydride (60% dispersion). This suspension was treated with 1.89 g (16.3 mmol) methyl acetoacetate dropwise, and the reaction was stirred for 10 minutes. n-Butyllithium (10.3 mL of 1.6 M in hexanes; 16.5 mmol) was dripped in and the reaction was stirred 30 minutes. At this time 3.10 g (13 mmol) of 1,5-diphenyl-3-pentanone (Ram and Spicer, Tetrahedrom Lett., 1988, 29 (31), 3741) in 20 mL THF was added dropwise over 15 minutes. After 4 hours 100 mL H2O was added and the reaction stirred overnight. The reaction was extracted with diethyl ether, and the organics set aside. The aqueous layer was chilled, treated with 50% HOAc until a precipitate formed, and then extracted with EtOAc. These organics were washed with saturated brine, dried (Na2SO4), and concentrated. 1H NMR (DMSO-d6) δ 2.0 (d of d, 4 H), 2.65 (m, 6 H), 5.0 (s, 1 H), 7.15-7.35 (m, 10 H), 11.4 (bs, 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CO>[C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCCCCO
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)NCCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-amino-1-hexanol (0.650 g, 6.31 mmol) in methanol (15 mL) is cooled to 0° C. and treated with triethylamine (1.62 mL, 11.6 mmol) followed by acetic anhydride (0.891 mL, 9.45 mmol). The reaction mixture is stirred at room temperature overnight. Additional triethylamine (1.6 mL, 11.6 mmol) and acetic anhydride (0.9 mL, 9.5 mmol) is added at room temperature and the solution is stirred 16 h further. Concentration in vacuo and flash chromatography affords 6-acetamido-1-hexanol. To a solution of 6-acetamido-1-hexanol (22.2 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4-methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 6-acetamido-1-hexyltriflate (25) which is used without further purification.
Reaction SMILES: BrN1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=C(C)C=C[C:31]=1[F:37]>C(Cl)(Cl)(Cl)Cl>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[C:4]([CH:3]=[O:8])[CH:5]=[CH:6][C:31]=1[F:37]
Reactant: COC(=O)c1cc(C)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(C=O)ccc1F
Temperature: 25 °C
Yield: 19.9 %

Procedure:
Add N-bromosuccinimide (2.46 g, 13.86 mmol) and benzoyl peroxide (0.152 g, 0.630 mmol) to a solution of 2-fluoro-5-methyl-benzoic acid methyl ester (1.06 g, 6.30 mmol) in carbon tetrachloride (50 mL). Heat the mixture at reflux for 4 h. Cool the mixture to room temperature and wash with saturated aqueous sodium bicarbonate solution (10 mL) and brine (10 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Dissolve the resulting residue in dimethylsulfoxide (30 mL) and heat at reflux for 16 h. Cool the mixture to room temperature and dilute with water (100 mL) and ethyl acetate (100 mL). Extract the aqueous layer with ethyl acetate (3×100 mL). Wash the combined organic layers with water (3×100 mL), followed by brine (100 mL). Dry the organic layer over anhydrous sodium sulfate, filter and concentrate. Purify the residue by chromatography over silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as a tan solid (0.228 g, 20%). 1H NMR (CDCl3, 300 MHz) δ 3.89 (s, 3H), 7.31-7.44 (m, 1H), 8.05-8.12 (m, 1H), 8.44-8.53 (m, 1H), 10.00 (s, 1H); TLC Rf=0.65 (3:1 Hexanes/Ethyl Acetate).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[O:25][CH2:26][CH:27]2[CH2:29][O:28]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[O:25][CH2:26][CH:27]([OH:28])[CH2:29][N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(CCCCc2ccccc2OCC2CO2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC#N
Product: OC(COc1ccccc1CCCCc1ccccc1)CN1CCN(c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 34.6 %

Procedure:
3.89 g of N-phenylpiperazine were added to a solution of 1.69 g of 2-[2-(4-phenylbutyl)phenoxymethyl]oxirane [prepared as described in Example 1(a)] in 30 ml of acetonitrile, and the resulting mixture was stirred at 50° C. for 3 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 920 mg (yield 34%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([C:6]([F:9])([F:8])[F:7])[CH2:5][O:4]1.[S:12]([O-:15])([OH:14])=[O:13].[Na+:16]>O>[F:1][C:2]([F:11])([F:10])[C:3]([OH:4])([C:6]([F:9])([F:8])[F:7])[CH2:5][S:12]([O-:15])(=[O:14])=[O:13].[Na+:16]
Reactant: O=S([O-])O
Reactant: FC(F)(F)C1(C(F)(F)F)CO1
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CC(O)(C(F)(F)F)C(F)(F)F
Temperature: 40 °C
Reaction time: 10 h

Procedure:
Using the 2,2-bis(trifluoromethyl)oxirane prepared in Synthesis Example 1-2, synthesis was carried out in accordance with the procedure described in US 20100209827. A mixture of 30 g of 2,2-bis(trifluoromethyl)oxirane, 26 g of sodium hydrogensulfite, and 120 g of water was stirred at 40° C. for 10 hours, obtaining an aqueous solution of sodium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate. Subsequently, 34 g of an aqueous solution of 2,000 g/mol of triphenylsulfonium chloride and 400 g of methylene chloride were added to the aqueous solution, which was stirred for 4 hours at room temperature. At the end of stirring, the organic layer was taken out, washed with water, and concentrated under reduced pressure. The concentrate was combined with methyl isobutyl ketone and concentrated again under reduced pressure to distill off the residual water. To the residue, diisopropyl ether was added for recrystallization, obtaining 74 g of triphenylsulfonium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate (yield 85%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])#[N:2].[H-].[Na+].[CH3:18]I>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:18])[C:10](=[O:15])[C:11]([F:13])([F:12])[F:14])#[N:2]
Reactant: N#Cc1ccccc1NC(=O)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)C(F)(F)F)c1ccccc1C#N
Reaction time: 4 h
Yield: 93.9 %

Procedure:
N-(2-Cyanophenyl)-2,2,2-trifluoroacetamide (3 g, 0.014 mol) was added to sodium hydride (60% in oil, 0.62 g, 0.026 mol) in THF (40 ml) under nitrogen and stirred for 4 h. Methyl iodide (8.7 ml, 0.14 mol) was added and stirring continued overnight. The mixture was poured onto brine and extracted with ethyl acetate, dried over sodium sulphate and evaporated to give the product (3 g), MS (+EI) 228 (M+). 1H NMR (CDCl3) 7.8 (1H, d), 7.7 (1H, dd), 7.4 (1H, dd), 7.4 (1H, d), 3.43 (3H, s).
Reaction SMILES: [CH3:1]CN(CC)CC.[CH2:8]1[CH:12]2[CH2:13][NH:14][CH2:15][CH:11]2[CH2:10][N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:23]([N:14]1[CH2:15][CH2:11][C:12]2([CH2:8][N:9]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:10][CH2:1]2)[CH2:13]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(C(=O)c3ccccc3)C2)C1
Temperature: 115 °C

Procedure:
Et3N (0.5 mL) was added into a solution of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.2 g) and benzoyl chloride (0.1 mL) in THF (10 mL). The mixture was heated to 115° C. for 24 hours. The reaction was quenched with water (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phase was dried over MgSO4 and concentrated to give a residue which was purified by silica gel chromatography to give tert-butyl 7-benzoyl-2,7-diazaspiro[4.4]nonane-2-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][C@H:14]([C:16]([F:19])([F:18])[F:17])[CH2:13][C@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11]1)([O-])=O.CC(O)=O>[Fe].O>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][C@H:14]([C:16]([F:17])([F:19])[F:18])[CH2:13][C@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2[N+](=O)[O-])C1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 124.9 %

Procedure:
A mixture of tert-butyl [(3S,5R)-1-(3-nitropyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (1 g, 2 mmol), iron powder (0.57 g, 10 mmol), AcOH (16 mL) and water (2 mL) was stirred at room temperature for 1 h. The mixture was allowed to cool to room temperature, concentrated under reduced pressure and the resulting residue was diluted with EtOAc. The resulting mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 1 M NaOH aqueous solution and extracted with EtOAc (100 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.9 g (100% yield) of the sub-title compound as a brown solid. LCMS calc. for C16H24F3N4O2(M+H)+: m/z=: 361.2. found: 361.1.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:8]2[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].CO[Na].[C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br)#[N:27]>CS(C)=O>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[C:26]#[N:27])=[CH:18][CH:17]=2)[C:8]2[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1CBr
Reactant: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(O)cc1
Agent: CO[Na]
Solvent: CS(C)=O
Product: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(OCc2ccccc2C#N)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 2.97 g of 2-butyl-3-p-hydroxybenzyl--4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine (obtainable from IIIa and p-hydroxybenzyl bromide), 0.5 g of CH3ONa and 40 ml of DMSO is stirred for 0.5 hour. A solution of 2.2 g of o-cyanobenzyl bromide in 15 ml of DMSO is added dropwise and the mixture is stirred at 20° for 16 hours and evaporated to give 2-butyl-3-(4-o-cyanobenzyloxybenzyl)-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine after conventional working-up.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([CH2:18]O)[CH:16]=[CH:17][C:11]=2[C:10]=1[CH3:20])=[O:8]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([CH2:18][Cl:3])[CH:16]=[CH:17][C:11]=2[C:10]=1[CH3:20])=[O:8]
Reactant: COC(=O)c1sc2cc(CO)ccc2c1C
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc2cc(CCl)ccc2c1C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.75 ml.) was added cautiously to a solution of 6-hydroxymethyl-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (0.70 g.) and pyridine (3 drops) in chloroform (7.5 ml.) and the resulting solution was allowed to stand for 1 hour. It was then washed successively with water, sodium bicarbonate solution and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallized from petrol (b.p. 60°-80°) to give 6-chloromethyl-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (0.63 g.), m.p. 128°-129° C.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2].[CH:35]1([NH2:38])[CH2:37][CH2:36]1.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20]([NH:38][CH:35]3[CH2:37][CH2:36]3)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2]
Reactant: NC1CC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)NC3CC3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, abs. THF (3 ml) was stirred with molecular sieve (4 Å, 30 mg) for 30 min. (7R)-6-Cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (63%, 50 mg, 62 μmol), cyclopropylamine (13 μl, 0.19 mmol, 3 eq.) and triethylamine (9 μl, 63 μmol, 1 eq.) were added, and the mixture was stirred at RT for 12 h. The reaction solution was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (27 mg, 82% of theory).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH2:6]1)(=[O:4])=[O:3].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH2:6]1)(=[O:3])=[O:4]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCCN(S(C)(=O)=O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@@H]4CCCN(S(C)(=O)=O)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66.3 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methanesulfonyl-piperidin-3-yl)-amide (103 mg, 0.167 mmol) was dissolved in dichloromethane (0.8 ml) and trifluoroacetic acid (0.5 ml, 6.6 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in dichloromethane (0.8 ml) and ethylenediamine (0.67 ml, 9.92 mmol) was added. The resultant light yellow suspension was stirred at room temperature for 45 min then quenched with water and diluted with ethyl acetate. The suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 54 mg (63%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methanesulfonyl-piperidin-3-yl)-amide as a light yellow powder. MS: (M+H)+=488; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.06 (s, 1H), 8.47 (s, 1H), 8.41 (d, J=8.7 Hz, 1H), 8.13 (d, J=7.6 Hz, 1H), 8.00 (s, 1H), 7.36 (d, J=8.7 Hz, 1H), 4.17 (s, 3H), 4.06-4.15 (m, 1H), 3.66-3.75 (m, 1H), 3.34-3.41 (m, 1H), 2.89-2.99 (m, 1H), 2.86 (s, 3H), 2.80 (d, J=10.6 Hz, 1H), 2.11 (br. s., 1H), 1.87 (br. s., 1H), 1.51-1.74 (m, 2H)