Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3=[N:17][N:18]([CH:21]4[CH2:26][CH2:25][CH2:24][O:23][CH2:22]4)[C:19](=[O:20])[C:9]3=[N:8]2)=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[N:30]1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.O.[Cu]I>[O:23]1[CH2:24][CH2:25][CH2:26][CH:21]([N:18]2[C:19](=[O:20])[C:9]3=[N:8][N:7]([CH2:6][C:5]4[CH:27]=[CH:28][C:2]([N:29]5[CH:33]=[CH:32][N:31]=[N:30]5)=[CH:3][CH:4]=4)[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:10]3=[N:17]2)[CH2:22]1
Reactant: O=c1c2nn(Cc3ccc(I)cc3)c3ccccc3c-2nn1C1CCCOC1
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: O=c1c2nn(Cc3ccc(-n4ccnn4)cc3)c3ccccc3c-2nn1C1CCCOC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(±)-5-(4-Iodobenzyl)-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 45), 25 mg, 0.051 mmol] was dissolved in degassed dimethylsulfoxide (1 mL) and water (0.2 mL), which was treated with copper(I)iodide (3.9 mg, 0.021 mmol, 0.4 equiv), 1,2,3-triazole (4.3 mg, 0.062 mmol, 1.2 equiv), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (1.5 mg, 0.0010 mmol, 0.2 equiv) and potassium phosphate (27 mg, 0.15 mmol, 3 equiv). The vessel was sparged under nitrogen, sealed and placed into an oil bath preheated at 100° C. for 5 hours. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (15 mL, aqueous saturated) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound as a red solid: 1H-NMR (400 MHz, CDCl3) δ 8.30-8.28 (1H, m), 7.96 (1H, d, J=0.9 Hz), 7.84 (1H, d, J=0.9 Hz), 7.76 (2H, m), 7.74 (2H, d, J=8.6 Hz), 7.58-7.55 (1H, m), 7.46 (2H, d, J=8.4 Hz), 5.87 (2H, s), 4.75-4.67 (1H, m), 4.04 (1H, dd, J=10.7, 1.4 Hz), 3.99 (1H, d, J=11.1 Hz), 3.82 (1H, ap t, J=10.7 Hz), 3.51 (1H, td, J=11.0, 3.3 Hz), 2.29-2.18 (2H, m), 2.12 (1H, br d, J=12.4 Hz), 1.94-1.83 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 428.1849 [(M+H)+; calculated for C23H22N7O2: 428.1829].
Reaction SMILES: [Na].C[Si](C)(C)[C:4]#[C:5][CH:6]([N:13]=CC1C=CC=CC=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C[O-].[Na+].[Cl-].[NH4+]>CO.CCOCC>[NH2:13][CH:6]([C:5]#[CH:4])[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCC(C#C[Si](C)(C)C)N=Cc1ccccc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: C#CC(N)CCC(=O)OC
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
0.1 g of sodium was dissolved in 10 ml of methanol, under nitrogen. 1.5 g of 3A was stirred in 12 ml of dry methanol at 0° C. under nitrogen and 0.23 ml of the sodium methoxide solution was added drop-by-drop at 0° C. The resulting mixture was stirred at 0° C. for 3.5 hours, then stored in a freezer over a week-end. Then 30 mg of ammonium chloride was added, the mixture was stirred for 15 minutes at 0° C., stripped to a mush, slurried with ether and filtered. The ether was evaporated from the filtrate, the residue was dissolved in 25 ml of tetrahydrofuran and the solution was added drop-by-drop over one minute to a vigorously stirred ice-cold 0.2N hydrochloric acid solution. The resulting mixture was stirred at 0° C. for 3.5 hours, the solvent was evaporated and the residue was extracted with ether. The water was evaporated from the aqueous phase, toluene was added to the residue and residual water removed by azeotropic distillation. The residue was dissolved in methanol, toluene was added and the mixture was distilled azeotropically. The residue was dissolved in methylene chloride, the solution was dried (Na2SO4), filtered and the solvent was evaporated. The residue was subjected to low pressure distillation, to give 3, as a gum.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:25][C:26](O)=[O:27].[C:29]([C:33]1[CH:38]=[C:37]([CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[N:36]=[C:35]([NH2:46])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:29]([C:33]1[CH:38]=[C:37]([CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[N:36]=[C:35]([NH:46][C:26](=[O:27])[CH2:25][C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]4[CH:15]=[CH:16][C:17]([C:19]5[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=5)=[CH:18][C:13]4=[N:12][CH:11]=3)=[CH:9][C:4]=2[F:3])[CH:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(O)Cc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1F
Reactant: CC(C)(C)c1cc(N)nc(CN2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CN2CCOCC2)nc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccncc5)ccn34)cc2F)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64 %

Procedure:
Dissolve [2-fluoro-4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetic acid dihydrochloride (6.24 g, 14.84 mmol) and 4-tert-butyl-6-morpholin-4-ylmethyl-pyridin-2-ylamine (3.70 g, 14.84 mmol) in anhydrous DMF (40 mL). Add diisopropyl-ethylamine (8.5 mL, 48.97 mmol) and HATU (6.21 g, 16.32 mmol). Stir the reaction mixture at room temperature for 40 minutes. Dilute with ethyl acetate (800 mL). Wash with aqueous saturated sodium chloride (3×100 mL), sodium bicarbonate (sat. 3×100 mL), water (3×100 mL). Dry the organic layer over magnesium sulfate, filter off the drying reagent, and concentrate to oil. Chromatograph the crude product on silica (0-4% 2 M ammonia methanol/dichloro-methane). Recrystallize from dichloromethane/ether/hexane to provide the title compound 5.50 g (9.5 mmol, 64%) white solid as product. MS (ES), m/z 579 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].N([O-])=O.[Na+].[N-:23]=[N+:24]=[N-].[Na+]>C(O)(=O)C.O>[N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])=[N+:23]=[N-:24]
Reactant: Nc1ccccc1N1C(=O)c2ccccc2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1ccccc1N1C(=O)c2ccccc2C1=O
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
To a suspension of the 2-(2-aminophenyl)isoindole-1,3-dione (360 mg, 1.5 mmol) in acetic acid (20 mL) and water (4 mL) was added dropwise a solution of sodium nitrite (98 mg, 1.42 mmol) in water (2 mL). The mixture was allowed to stir for 10 minutes and then sodium azide (98 mg, 1.51 mmol) was added. The reaction mixture was stirred for 15 minutes before it was poured into water and was extracted with dichloromethane (3×50 mL). The extracts were washed with water and brine and dried over magnesium sulfate. Filtration and concentration in vacuo gave 373 mg (94%) of 2-(2-azidophenyl)isoindole-1,3-dione as a solid: 1H NMR (300 MHz, DMSO-d6) δ 7.94 (m, 4H), 7.58 (m, 1H), 7.48 (m, 2H), 7.32 (m, 1H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][CH:11]=1>CC#N>[Br:8][C:11]1[CH:12]=[CH:13][C:14]([NH2:16])=[N:15][C:10]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(F)n1
Solvent: CC#N
Product: Nc1ccc(Br)c(F)n1
Temperature: 15 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
NBS (50.0 g, 280.99 mmol) was added slowly to 6-fluoropyridin-2-amine (30 g, 267.61 mmol) in MeCN (300 mL) cooled to 10-20° C. over a period of 30 minutes. The resulting solution was stirred at ambient temperature for 60 minutes then the solvent removed under reduced pressure. The residue was diluted with water, the precipitate collected by filtration, washed with water (200 mL) and dried under vacuum to afford the desired material (50.0 g, 98%) as a white solid, which was used without further purification. NMR Spectrum: 1H NMR (300 MHz, DMSO-d6) δ 6.29 (1H, d), 6.57 (2H, bs), 7.65 (1H, t). Mass Spectrum: m/z (ES+)[M+H]+=191.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N([O-])=O.[Na+].[CH3:21][CH:22](C(C)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].CC([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>O.Cl.CCO>[CH2:26]([O:25][C:23]([C:22]1[NH:16][C:13]2[C:14]([CH:21]=1)=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[CH:11][CH:12]=2)=[O:24])[CH3:27]
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71 %

Procedure:
A stirred solution of 4-(2-(morpholin-4-yl)ethoxy)phenylamine (11) (4.00 g, 18.0 mmol) in water (38 mL) and concentrated HCl (12 mL) was treated dropwise at 0° C. with a solution of NaNO2 (1.36 g, 19.8 mmol) in water (3.8 mL) and the resulting mixture was stirred for 30 min at 0° C. (solution A). Ethyl 2-methylacetoacetate (2.75 mL, 18.9 mmol) was added dropwise to a suspension of NaOAc (15.3 g) in EtOH (29 mL) at 0° C. After stirring for 30 min at this temperature, ice (18 g) was added (solution B). Then, solution A was added to solution B by a transfer cannula at 0° C., the mixture was allowed to warm to room temperature and was stirred for a further 2.5 h. After that, the reaction mixture was basified by slow addition of a saturated aqueous solution of Na2CO3 at 0° C. and extracted with CH2Cl2 (3×200 mL). The combined organic layers were washed with water (300 mL), dried (MgSO4), and the solvent was removed in vacuo. The residue was then dissolved in absolute EtOH (15 mL), treated with a freshly prepared saturated solution of HCl in absolute EtOH (15 mL) and heated at reflux for 40 min. After cooling to room temperature the solvent was removed under reduced pressure and the residue was partitioned between water (50 mL) and CH2Cl2 (100 mL). The aqueous layer was basified using a saturated aqueous solution of Na2CO3 and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4), and concentrated in vacuo. Purification by crystallization from iPr2O and column chromatography (CH2Cl2/MeOH, 20:1) of the residue after evaporation of the mother liquor provided 12 (4.07 g, 71% overall yield) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 1.41 (t, J=7.1 Hz, 3 H, OCH2CH3), 2.61 (mc, 4 H, 3″-H2, 5″-H2), 2.84 (t, J=5.7 Hz, 2 H, 2′-H2), 3.76 (mc, 4 H, 2″-H2, 6″-H2), 4.15 (t, J=5.7 Hz, 2 H, 1′-H2), 4.40 (q, J=7.1 Hz, 2 H, OCH2CH3), 6.99 (dd, J=9.0, 2.4 Hz, 1 H, 6-H), 7.08 (d, J=2.4 Hz, 1 H, 4-H), 7.13 (d, J=1.3 Hz, 1 H, 3-H), 7.30 (d, J=9.0 Hz, 1 H, 7-H), 9.13 (sbr, 1 H, NH) ppm; 13C NMR (50.3 MHz, CDCl3): δ=14.4 (OCH2CH3), 54.1 (C-3″, C-5″), 57.7 (C-2′), 60.9 (OCH2CH3) 66.2 (C-1′), 66.9 (C-2″, C-6″), 103.7 (C-4), 108.1 (C-3), 112.7 (C-7), 117.3 (C-6), 127.7, 127.9 (C-2, C-3a), 132.3 (C-7a), 153.7 (C-5), 162.0 (C═O) ppm; MS (70 eV, EI): m/z (%)=318 (14) [M]+, 100 (100) [CH2N(CH2)4O]+; C17H22N2O4 (318.37): calcd. C, 64.13; H, 6.97; found C, 63.85; H, 7.12.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[OH:12][CH:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15].CS([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:12][CH:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])[N:3]=1
Reactant: COC(=O)C(O)C(C)(C)C
Reactant: COc1cc(OC)nc(Cl)n1
Agent: CS(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(C)C
Reaction time: 2 h

Procedure:
4.38 g (25 mmol) of 2-chloro-4,6-dimethoxypyrimidine, 3.90 g (25 mmol) of methyl (+/-)-2-hydroxy-3,3-dimethylbutanoate and 0.66 g (6.3 mmol) of sodium methanesulfinate were heated in the presence of 5.17 g (37.5 mmol) of potassium carbonate in 25 ml of N,N-dimethylformamide to 120° C. with stirring. After 2 hours, the solvent was removed in a rotary evaporator at 70° C./20 mbar. The residue was taken up in 30 ml of water and 30 ml of dichloromethane. After the organic phase had been separated off, the aqueous phase was again extracted with 20 ml of dichloromethane. The combined organic phases was washed with water, dried over magnesium sulfate and evaporated. The title product was obtained in a yield of 5.93 g (82.7 percent of theory) in the form of pale yellowish crystals (GC content 99.2 percent). The melting point of the title compound was 104.4° to 107.0° C. Other data concerning the title compound was:
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:12]([NH2:15])[CH:13]=2)[N:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:7]1)(=[O:3])[CH3:2].[C:31]([O:36][CH3:37])(=[O:35])[C:32]([CH3:34])=O.C(O)(=O)C.O>C1C=CC=CC=1.CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][CH2:5][C@H:6]1[C:14]2=[C:13]3[C:12](=[C:11]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:10]=[C:9]2[N:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:7]1)[NH:15][C:32]([C:31]([O:36][CH3:37])=[O:35])=[CH:34]3)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)=O
Reactant: CC(=O)OC[C@@H]1CN(C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)c(N)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1cc2c3c(cc(OCc4ccccc4)c2[nH]1)N(C(=O)OC(C)(C)C)C[C@H]3COC(C)=O
Yield: 10.1 %

Procedure:
1.24 g (3.0 mmole) of (3S)-3-acetoxymethyl-5-amino-6-benzyloxy-1-t-butoxycarbonylindoline, 0.46 g (4.5 mmole) of methyl pyruvate, and 0.2 ml of acetic acid were heated to reflux in 30 ml of benzene for 5 hours using a Dean-Stark apparatus (Chem.Pharm.Bull. 24,1273 (1976)). The reaction mixture was washed with 5% sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and filtrated. The obtained filtrate was concentrated to give a residue, to which 1.35 g (6.0 mmole) of palladium acetate was then added, and the resulting mixture was heated in 100 ml of dimethylacetamide at 90° C. for 1 hour. The obtained reaction mixture was poured into water, the resulting mixture was thrice extracted with toluene-hexane (5:1), the combined organic layer was dried over anhydrous sodium sulfate, and filtrated. The obtained filtrate was concentrated to give a residue, which was then purified by silica gel column chromatography with changing an eluate from hexane:ethyl acetate (3:1) to hexane:ethyl acetate (2.5:1) to give 0.15 g of methyl (1S)-1-acetoxymethyl-5-benzyloxy-3-t-butoxycarbonyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-7-carboxylate. Yield, 10%. This sample gave the same spectroscopic data as those obtained in Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:23])[C:10]2[N:11]=[CH:12][C:13]3[N:18]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[S:16][C:14]=3[N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:24][C:25]1[C:33]([C:34]([C:37]#[N:38])([CH3:36])[CH3:35])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:20]([NH:19][C:17]1[S:16][C:14]2[N:15]=[C:10]([N:9]([CH3:23])[C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:33]([C:34]([C:37]#[N:38])([CH3:36])[CH3:35])[C:25]=4[Cl:24])[CH:3]=3)[N:11]=[CH:12][C:13]=2[N:18]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1nc2cnc(N(C)c3ccc(F)c(N)c3)nc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(N(C)c3ccc(F)c(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)nc2s1
Temperature: 90 °C
Reaction time: 5 h
Yield: 51.9 %

Procedure:
A solution of N-{5-[(3-amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (100 mg, 301 μmol) produced in Example D17(iv), 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (202 mg, 902 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (342 mg, 902 μmol) in pyridine (4 mL) was stirred at 90° C. for 5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/90→0/100) and silica gel column chromatography (hexane/ethyl acetate=40/60→10/90), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (84 mg, 52%) as colorless crystals.
Reaction SMILES: [CH3:1]I.[CH2:3]([C:7]1[C:8](=[O:14])[NH:9][C:10](=[S:13])[NH:11][CH:12]=1)[CH2:4][CH2:5][CH3:6].[OH-].[Na+]>O.C(O)C>[CH2:3]([C:7]1[C:8](=[O:14])[NH:9][C:10]([S:13][CH3:1])=[N:11][CH:12]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCc1c[nH]c(=S)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1cnc(SC)[nH]c1=O
Yield: 25.2 %

Procedure:
Methyl iodide (2.74 g) was added to a stirred solution of 5-butyl-2,3-dihydro-2-thioxo-4(1H)-pyrimidinone (3.5 g) and sodium hydroxide (0.78 g) in water (10 ml) and ethanol (20 ml) at room temperature and heated at 70° for 45 minutes. The solid which separated on standing was filtered and washed with ethanol and water to give the title compound (0.95 g) m.p. 138°-140.5°.
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][CH2:15][C:14]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:13]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(#N)C.[I-].[Na+]>[CH3:22][CH:3]([CH2:2][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][CH2:15][C:14]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:13]=2)=[CH:8][CH:7]=1
Reactant: C1CCNCC1
Reactant: CC(CCl)COc1ccc(C2=NC3(CCCCC3)CO2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(COc1ccc(C2=NC3(CCCCC3)CO2)cc1)CN1CCCCC1
Yield: 40 %

Procedure:
A solution of 2-[4-(3-chloro-2-methylpropoxy)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-ene ax64 (0.35 g, 1.1 mmol, 1 eq) in acetonitrile (20 ml) is treated with potassium carbonate (0.3 g, 2.2 mmol, 2 eq), sodium iodide (0.01 g, 0.073 mmol, 0.07 eq) and piperidine (0.52 ml, 5.2 mmol, 4.7 eq), and the mixture is stirred at reflux for 5 days. After this time, the mixture is concentrated, taken up in ethyl acetate and washed with water. The organic layer is dried over magnesium sulfate and concentrated to dryness to give 0.36 g of a yellow oil. This crude product is purified by flash chromatography over silica gel (eluent: dichloromethane/methanol/ammonia 96:3.6:0.4) to give 0.13 g of 2-[4-(2-methyl-3-piperidin-1-ylpropoxy)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-ene 38 as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32](COCC[Si](C)(C)C)[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:7][N:6]([C:8]2[CH:19]=[CH:18][C:11]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[C:10]([F:20])[CH:9]=2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][NH:32][C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:7][N:6]([C:8]2[CH:19]=[CH:18][C:11]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[C:10]([F:20])[CH:9]=2)[CH2:5]1)#[N:2]
Reactant: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-fluoro-N-isopropylbenzamide (0.7 g, 1.19 mmol) was dissolved in methylene chloride (5.0 mL) and to this was added trifluoroacetic acid (5.0 mL) and the solution was stirred at room temperature for 1 hour. LC/MS data indicated that the main reaction component was the desired product (LCMS (M+H)+: m/z=489.2). The volatiles were removed in-vacuo and the residue was azeotropically washed with acetonitrile (3×10 mL). The resulting residue was dissolved in methanol (4 mL) followed by the addition of ethylenediamine (400 μL) and ammonium hydroxide (1.2 mL). After stirring at room temperature for 2 hours, LC/MS data indicated that the main reaction component was the desired product. The crude reaction mixture was purified by RP-HPLC (pH=2) to afford the desired product as TFA salt. LCMS (M+H)+: m/z=459.2. 1H NMR (500 MHz, CD3OD): δ 9.09 (s, 1H), 8.90 (s, 1H), 8.56 (s, 1H), 7.85 (d, J=3.7 Hz, 1H), 7.66 (t, J=8.5 Hz, 1H), 7.33 (d, J=3.8 Hz, 1H), 6.47 (dd, J=8.6, 2.2 Hz, 1H), 6.39 (dd, J=13.5, 2.2 Hz, 1H), 4.61 (d, J=8.8 Hz, 2H), 4.44 (d, J=8.8 Hz, 2H), 4.22-4.13 (m, 1H), 3.68 (s, 2H), 1.23 (d, J=6.6 Hz, 6H).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[Br:31][CH2:32][C:33](Br)=[O:34]>C(Cl)Cl>[Br:31][CH2:32][C:33]([NH:11][CH2:10][CH2:9][S:8][C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:34]
Reactant: O=C(Br)CBr
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution S-triphenylmethyl-2-aminoethanethiol (48 g, 0.15 mol) and Et3N (20.9 ml, 0.15 mol) in DCM (180 ml) was slowly added to a stirred solution of bromoacetyl bromide (13.9 ml, 0.15 mol) in DCM (100 ml) at a temperature of -20° C. The reaction was allowed to warm to room temperature over a one hour period. The reaction was washed with 500 ml portions of H2O, 0.2N HCl, saturated NaHCO3, and saturated NaCl. The organic solution was dried (MgSO4) and concentrated to an oil. This oil was crystallized from DCM-hexane to give product (54.9 g, 83%) as a colorless solid, MP 137°-139.5° C. (J. A. Wolff, Ph.D. Thesis, Massachusetts Institute of Technology, February 1992, MP 130°-135° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][NH:13][CH3:14].C(O)C.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:12][N:13]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:14]
Reactant: BrCCCCc1ccccc1
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCO
Product: CN(C)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8.67 h

Procedure:
To 426 mg of the colorless liquid (4-bromobutyl)benzene were added 1.05 ml of 50% dimethylamine aqueous solution and 1 ml of ethanol, and the mixture was stirred at a room temperature for 520 minutes. To the reaction mixture were added 30 ml of ethyl acetate and 10 ml of 5% sodium bicarbonate aqueous solution. The separated organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain a residue. To the residue was added 20 ml of benzene, then was washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain 287 mg of the title compound as colorless liquid.