Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=[C:11](Cl)[C:10]=2[Cl:20])=[C:4]([Cl:21])[CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C.O>[N:22]([C:11]1[C:10]([Cl:20])=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:21])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(N=[N+]=[N-])c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.3 %

Procedure:
Methyl 4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinate (1.690 g, 4.14 mmol) was suspended in 30 ml DMF and the suspension was heated until everything went into solution. It was cooled down to room temperature and to that solution was added solid sodium azide (0.533 g, 8.2 mmol). The yellow solution was stirred for 17 h at room temperature and was diluted with water. The precipitate was filtered, washed with water and hexanes and dried in oil-pump vacuo at 50° C. for 2 h to obtain the title compound as a light-brown solid (1.5422 g, 90%). 1H-NMR (300 MHz, DMSO-D6): δ=9.85 (s, 1H), 8.90 (s, 1H), 7.80-7.79 (d, 1H), 7.46-7.40 (dd, 1H), 6.95-6.90 (d, 1H), 3.80 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH2:17])[N:3]=1.[CH:18]([NH2:22])([CH2:20][CH3:21])[CH3:19]>>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH:22][CH:18]([CH2:20][CH3:21])[CH3:19])=[N:3][C:4]=3[NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(C)N
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCC1
Product: CCC(C)Nc1nc(N)c2ncn(C3CCCCC3)c2n1

Procedure:
Reaction of 2-chloro-9-cyclohexyl-9H-adenine with sec.-butylamine according to the procedure of Example 1 affords the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: CC(C)c1ccc(C=NNc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Yield: 92.1 %

Procedure:
In 20 ml of methanol was dissolved 3.06 g of 4-nitrophenylhydrazine. With 2.96 g of 4-isopropylbenzaldehyde added, the solution was refluxed at 100° C. for one hour. With the progress of reaction, crystals gradually precipitated. The crystals were collected by suction filtration, washed with methanol, and dried at 80° C. for 2 hours, obtaining 5.21 g (yield 92%) of pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[NH:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.N([O-])=[O:27].[Na+]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([OH:27])=[CH:6][C:5]=1[NH:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(N)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(O)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Yield: 82.6 %

Procedure:
This compound was produced using similar methods as those used in Step 3, example 27, starting with 4-amino-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (1.80 g, 5.08 mmol), trifluoroacetic acid (30 mL) and sodium nitrite (0.42 g, 6.15 mmol in 10 mL of water). The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 20/80) to give 4-hydroxy-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (1.49 g, 83%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6); δ 11.98 (s, 1H), 10.62 (s, 1H), 8.21 (d, 1H), 8.06 (d, 2H), 7.90 (d, 1H), 7.61 (d, 2H), 6.61 (dd, 1H), 3.84 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N+:11]([O-])=O)[C:5]([CH3:14])=[N:4]1)[CH3:2].Cl>C(O)C.O.[Fe]>[NH2:11][C:6]1[C:5]([CH3:14])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[C:8]([NH2:10])=[O:9]
Reactant: CCn1nc(C)c([N+](=O)[O-])c1C(N)=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCn1nc(C)c(N)c1C(N)=O

Procedure:
A mixture of 20 g (0.1 mol) of the above amide in 150 ml of ethanol and 30 ml of water containing 3 ml of conc. HCl is stirred under reflux with 25 g of iron powder for three hours and filtered warm using filter-cell. The filtrate is evaporated in vacuo to yield a pink solid, mp 143°-145° C. (from ethyl acetate-pet. ether) of 4-amino-1-ethyl-3-methylpyrazole-5-carboxamide. The reaction of this aminopyrazole with 18 ml acetic anhydride in 250 ml of methylene dichloride gives 18.5 g of N-(1-ethyl-5-carboxamido 3-methylpyrazol-4-yl)acetamide, mp 248°-250° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:21][C:20]([CH2:22][CH3:23])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:21][C:20]([CH2:22][CH3:23])=[N:19][C:14]=3[CH:15]=[N+:16]([O-:29])[C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2s1
Solvent: ClC(Cl)Cl
Product: CCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2s1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
To a stirred solution of 7-benzyloxy-2-ethylthiazolo[4,5-c]quinoline (15.0 g, 46.8 mmol) in chloroform (150 mL), 3-chloroperoxybezoic acid (m-CPBA. 50% w/w, 16.15 g, 46.8 mmol) was slowly added in small portions. The reaction was maintained at room temperature overnight. The reaction mixture was transferred to a separatory funnel and washed with 10% aqueous sodium carbonate (2×50 mL). The chloroform layer was concentrated to provide 15.4 g of 7-benzyloxy-2-ethylthiazolo[4,5-c]quinoline 5-oxide as a light tan solid. MS (ACPI) m/z=337 (M+H)+. This material was carried on without further purification to the next step.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH:7]2[NH:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1.C=O.[CH:14](O)=O.[OH-].[Na+]>O>[CH3:14][N:11]1[CH:7]([C:3]2[CH:2]=[CH:1][CH:6]=[N:5][CH:4]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=CO
Reactant: c1cncc(C2CCCN2)c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCCC1c1cccnc1
Temperature: 85 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
To a solution of nornicotine (50 g 0.338 mol) in 100 ml water a mixture of 37% formaldehyde (49.7 g, 1.656 mol) and 85% formic acid (37.26 g 0.81 moles) was added and stirred at 85° C. for 20 hrs. The reaction was cooled and pH adjusted to >13 using NaOH, extracted with dichloromethane (100 ml×3) dried over Na2SO4 and solvent removed completely to get crude oil (52.5 g, 94.33% purity by GC). It was further purified by high vacuum distillation at 0.1 mm Hg to obtain colorless (R,S)-nicotine (44.54 g, 81.3% yield, 99.1% purity by GC). 1H NMR (CDCl3): δ 1.72-2.0 (3H, m), 2.1 (3H, s), 2.25 (1H, m), 2.3 (1H, m), 3.08 (1H, m), 3.23 (1h, t), 7.25 (1H, m), 7.69 (1H, dt), and 8.5 (2H, m). 13C-NMR (CDCl3): 149.71, 148.76, 139, 134.97, 123.7, 68.9, 57.1, 40.5, 35.5, and 22.83. IR: 3233, 1642, and 1402 Cm−1.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH:16]([C:18]1[CH:19]=[CH:20][C:21](O)=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:17]>C(Cl)Cl>[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:17]
Reactant: COC(=O)c1cc(C=O)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
Triflic anhydride (7.74 mL) was added to methyl 5-formyl-2-hydroxybenzoate (7.5 g) in 150 mL CH2Cl2 at 0° C., and the reaction was stirred and allowed to warm to room temperature over 3 hours. The reaction was diluted with CH2Cl2 (150 mL), washed with 3× brine, dried over Na2SO4, and concentrated. The product was used without further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O=[C:7]([NH:12][CH:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[C:8]([O:10][CH3:11])=[O:9]>C(Cl)CCl>[F:21][C:16]([F:22])([C:17]([F:20])([F:19])[F:18])[CH2:15][CH2:14][C:13]1[N:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=12
Reactant: COC(=O)C(=O)NC(CCC(F)(F)C(F)(F)F)c1ccccn1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1nc(CCC(F)(F)C(F)(F)F)c2ccccn12
Temperature: 120 °C

Procedure:
Phosphoryl chloride (1.428 mL, 15.36 mmol) was added to a stirred solution of the intermediate from Step D (0.6534 g, 1.920 mmol) in dry ClCH2CH2Cl (14.44 mL). The resulting solution was heated at 120° C. overnight. Another 8 eq. POCl3 was added and the reaction was heated at 120° C. for 2 days. The reaction was cooled to room temperature and concentrated in vacuo. The reaction was diluted with water and EtOAc and basified by the careful addition of saturated aq. NaHCO3 until not further effervescence was observed. The layers were separated and the aqueous layer was further extracted with EtOAc (2×). The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by silica gel chromatography using a hexanes/EtOAc gradient to afford the desired product, as a colorless solid. 1H NMR (500 MHz, CHCl3-d) δ 9.31 (d, J=7.2 Hz, 1H); 7.59 (d, J=9.1 Hz, 1H); 7.08 (dd, J=9.0, 6.6 Hz, 1H); 6.96-6.90 (m, 1H); 4.03 (s, 3H); 3.25-3.19 (m, 2H); 2.66-2.52 (m, 2H). m/z=323.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:25]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:23])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15]>C(O)=O>[Cl:1][C:2]1[C:3]([C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:25]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:23])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1
Solvent: O=CO
Product: O=C(O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1

Procedure:
A solution of the compound obtained in Example 113 (600 mg) in formic acid (7 ml) was stirred at room temperature for 6 hours and then concentrated under reduced pressure. The residue was diluted with methylene chloride and washed with water and dried (MgSO4) and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain (4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenoxy)acetic acid from the fraction eluted with chloroform-ethyl acetate (7:1) and then chloroform-methanol (10:1) (476 mg, 88%). It was recrystallized from methanol-hexane. Colorless prisms. Melting point 205–206° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1([CH3:22])[O:14][CH:13]([CH2:15][O:16][C:17]2[N:18]=[CH:19][S:20][CH:21]=2)[CH2:12][O:11]1>CC#N>[Br:8][C:21]1[S:20][CH:19]=[N:18][C:17]=1[O:16][CH2:15][CH:13]1[CH2:12][O:11][C:10]([CH3:22])([CH3:9])[O:14]1
Reactant: CC1(C)OCC(COc2cscn2)O1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC1(C)OCC(COc2ncsc2Br)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., NBS (11.94 g, 67.1 mmol) was added over 90 min to a soln. of 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)thiazole (13.75 g, 63.9 mmol) in MeCN (320 mL). The mixture was further stirred at 0° C. for 30 min, then, it was quenched by the addition of aq. 5% NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with aq. 5% NaHCO3 and brine, dried over MgSO4, and conc. in vacuo.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl.[C:6]([Cl:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]>O.C(Cl)(Cl)Cl>[ClH:11].[C:6]([NH:3][CH2:2][CH2:1][NH2:4])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCN
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NCCN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of ethylenediamine (15 mmol, 10.1 cm3) in water (150 cm3) at 0° C. was adjusted to pH 8.5 with 3N HCl. To this, was added a solution of methacryloyl chloride (16.5 mmol, 16.1 cm3) in chloroform (100 cm3), dropwise, over 2 h. After the addition was complete, the reaction mixture was stirred at 0° C. for a further 2 h. The organic and aqueous layers were then separated, and the aqueous layer extracted with chloroform (3×50 cm3). The aqueous layer was then collected and conc. in vacuo (freeze-dryer) to give a white solid. The residue was subjected to repeated fractional recrystallization from room temperature methanol, and the filtrate concentrated to give N-methacryloyl-ethylenediamine monohydrochloride as a clear, yellow oil (14.32 g, 58%). N-methacryloyl-ethylenediamine monohydrochloride (16 mmol, 20.0 g) was stirred in 2M NaOH (60 cm3) for 10 min. This solution was subsequently diluted to a volume of 160 cm3 with water, and stirred at 0° C. To this mixture was added a solution of acryloyl chloride (17.6 mmol, 14.3 cm3) in chloroform (300 cm3), dropwise, over 3 h. After the addition was complete, the reaction mixture was then stirred at 0° C. for a further 2 h. The organic and aqueous layers were separated, and the aqueous portion extracted with chloroform (3×100 cm3). The organic extracts were combined and concentrated to give the crude product as a white solid. Recrystallization from acetonitrile then gave N-acryloyl, N′-methacryloyl-ethylenediamine as colorless needles (10.70 g, 37%), m.p. 140-142/C. δH (400 MHz; CDCl3) 6.84 (1H, br s), NH; 6.74 (1H, br m), NH; 6.27 (1H, dd, J 16.9, 1.5 Hz), HC═CHaHb; 6.13 (1H, dd, J 17.0, 10.2), HC═CHaHb; 5.74 (1H, s), (H3C)C═CHcHd; 5.65 (1H, dd, J 10.3, 1.6 Hz), HC═CHaHb; 5.34 (1H, br m), (H3C)C═CHcHd; 3.49 (4H, m), 2×CH2; 1.95 (3H, s), CH3. δC (75.4 MHZ; CDCl3) 169.4, NHOC(H3C)C═CH2; 167.0, NHOCHC═CH2; 139.2, (H3C)C═CH2; 130.7, HC═CH2; 126.2, HC═CH2; 120.1, (H3C)C═CH2; 40.4, CH2CH2; 39.5, CH2CH2; 18.4, CH3. Found: M+. 182.1059.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:7][C:6]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CO.[Zn]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])=[CH:7][C:6]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1N
Temperature: 25 °C

Procedure:
81 g (1.24 mol) of zinc powder were added to a solution of 25.19 g (77.9 mmol) of 2-t-butyl-5-(t-butyldimethylsilyloxymethyl)-1-nitrobenzene (prepared as described in Preparation 11) in 270 ml of methanol, and then 10.8 ml of acetic acid were added to the resulting mixture, with ice-cooling. After the exothermic reaction had subsided, the reaction mixture was heated under reflux for 3 hours and then allowed to cool to room temperature, after which it was filtered using a Celite (trade mark) filter aid, and the zinc used was washed with methanol. The filtrate was combined with the washings and the combined mixture was concentrated by evaporation under reduced pressure. The concentrate was dissolved in ethyl acetate, and the resulting solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give 22.9 g (a quantitative yield) of the title compound as an oily substance. The compound could be used without purification.
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]=3[C:12]([C:27]#[C:28][Si](C)(C)C)=[CH:11]2)[O:7][C@@H:6]1[CH2:33][O:34][S:35]([NH2:38])(=[O:37])=[O:36])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[S:35](=[O:36])(=[O:37])([O:34][CH2:33][C@@H:6]1[C@@H:5]([OH:4])[CH2:9][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]=3[C:12]([C:27]#[CH:28])=[CH:11]2)[O:7]1)[NH2:38]
Reactant: CC(=O)O[C@H]1C[C@H](n2cc(C#C[Si](C)(C)C)c3c(CCc4ccccc4)ncnc32)O[C@@H]1COS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cn([C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)O2)c2ncnc(CCc3ccccc3)c12
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of (2R,3S,5R)-2-{[(aminosulfonyl)oxy]methyl}-5-{4-(2-phenylethyl)-5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}tetrahydrofuran-3-yl acetate (0.254 g, 0.457 mmol) in MeOH (5 mL) at r.t. was added K2CO3 (0.168 g, 1.22 mmol) and the mixture was stirred for 2 h. The reaction mixture was diluted with CH2Cl2, washed with saturated aq NaHCO3 dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0 to 10% MeOH/DCM) to give the title compound (0.126 g, 62%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl-:11].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:11][C:1]1[CH:6]=[CH:5][C:4]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: [Cl-]
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 101.4 %

Procedure:
An 80° C. stirred solution of p-toluoyl chloride (10.0 g, 64.7 mmol) in chlorobenzene (15 ml) was treated in portions with aluminum chloride (8.63 g, 64.7 mmol) over 20 minutes. The mixture was stirred 15 hours at 80° C., cooled, and quenched by addition of ice-water and concentrated hydrochloric acid (10 ml). The mixture was extracted twice with diethyl ether and once with a small volume of dichloromethane. The combined extracts were washed with water, 10% (w/v) aqueous sodium hydroxide, and water, dried over anhydrous magnesium sulfate, and evaporated to dryness under vacuum. The residue was dissolved in boiling n-hexane, treated with activated charcoal, and filtered hot. The filtrate was cooled and the product was collected by filtration and dried to provide 7.57 g (51%) of 4-(4-chlorobenzoyl) toluene, m.p. 122°-123° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1ccnc2c1C(=O)CC(c1cccc(Cl)c1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cccc(Cl)c1Cl)C2
Yield: 213.3 %

Procedure:
A mixture of 7-(2,3-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (306 mg), aminoguanidine hydrochloride (122 mg) and concentrated hydrochloric acid (0.2 ml) in ethanol (4 ml) was refluxed for 1 hour. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 7-(2,3-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 62) (425 mg) as colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:10]=1[CH2:11][NH:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:5])C.[OH-].[K+].C1COCC1>>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:10]([CH2:11][NH:12][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2F)c1CNC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2F)c1CNC1CCCC1
Yield: 113.6 %

Procedure:
A solution of 2-(4-chloro-phenyl)-5-cyclopentylaminomethyl-1-(2-fluoro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester I-5f (1.2 g, 2.68 mmol) in 1:2 1M KOH/THF was stirred at 55° C. for 17 hours. The reaction mixture was concentrated under vacuum and acidified to pH˜1 with concentrated hydrochloric acid. The residue was slurried in EtOH and filtered to remove KCI. The filtrate was concentrated under vaccum to give I-5k as an off-white solid (1.26 g, 97%): +APCI MS (M+1) 414.0.
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:6][CH2:5]1)=[O:3].[Si]([CH:31]=[N+:32]=[N-:33])(C)(C)C>C1(C)C=CC=CC=1>[N+:32](=[CH:31][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:6][CH2:5]1)=[O:3])=[N-:33]
Reactant: O=C(Cl)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: [N-]=[N+]=CC(=O)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a stirred solution of (9H-fluoren-9-yl)methyl 4-(chlorocarbonyl)piperidine-1-carboxylate (5 g, 13.6 mmol) in toluene at 0° C. was added TMS-diazomethane (30 mL). This reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure to afford of (9H-fluoren-9-yl)methyl 4-(diazoacetyl)piperidine-1-carboxylate (5 g, 98%) as dark brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH2:48][CH2:49][C:50]([N:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][OH:60])[CH2:54][CH2:53]2)=[O:51])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH2:48][CH2:49][C:50]([N:52]6[CH2:53][CH2:54][N:55]([CH2:58][CH2:59][OH:60])[CH2:56][CH2:57]6)=[O:51])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=C(CCc1cccc(Br)c1)N1CCN(CCO)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CCC(=O)N4CCN(CCO)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 3-(3-bromo-phenyl)-1-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propan-1-one (180 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 3-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propan-1-one was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-192) as a pale yellow powder (95 mg, 48%).