Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:3]=[N:4][C:5]([C:9]([OH:11])=O)=[C:6]([OH:8])[N:7]=1.[NH3:12]>CN(C)C=O>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([NH2:12])=[O:11])=[N:4][NH:3]1
Reactant: O=C(O)c1nnc(O)nc1O
Reactant: N
Solvent: CN(C)C=O
Product: NC(=O)c1n[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In 10 mL of dimethylformamide is suspended 0.5 g of 3,5-dihydroxy-1,2,4-triazine-6-carboxylic acid obtained according to the method described in literature (JP-A-54-79292). Then, 2.06 g of N,N′-carbonyldiimidazole is added thereto, and the resulting solution in stirred at ambient temperature for 6 hours. The reaction mixture is cooled with ice, saturated with gaseous ammonia, and then stirred for 15 minutes at the same temperature as above. The deposited crystals are collected by filtration to obtain 0.37 g of 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]2[N:19]=[C:20](S(C)(=O)=O)[N:21]=[C:4]2[N:3]=1.[O-:26][CH2:27][CH3:28].[Na+]>C(O)C>[CH2:27]([O:26][C:20]1[N:21]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:5]2[N:19]=1)[CH3:28]
Reactant: Cc1cc(Nc2ccc(C(F)(F)F)cc2)n2nc(S(C)(=O)=O)nc2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2nc(C)cc(Nc3ccc(C(F)(F)F)cc3)n2n1
Temperature: 120 °C

Procedure:
Intermediate 16 (0.14 g, 0.377 mmol) was added to sodium ethoxide (ALDRICH, 0.077 g, 1.131 mmol) in ethanol (3 mL). The mixture was heated under microwave irradiation at 120° C. for 30 minutes. Solvent was removed under vacuum to yield a yellowish residue which was purified by flash chromatography (Si, eluting with a 90:10% DCM: MeOH mixture) to yield the title compound as a beige solid.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:29])[C@@H:12]([NH2:28])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH3:9][C:2]([NH:10][C:11](=[O:29])[C@@H:12]([NH:28][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To 80 ml of a methylene chloride solution containing 2.14 g of (2S)-N-(α,α-dimethylbenzyl)-2-amino-6-(benzyloxycarbonylamino)hexanamide (prepared as described in Preparation 9) and 0.51 g of pyridine were added dropwise, whilst ice-cooling, 30 ml of a methylene chloride solution containing 0.76 g benzoyl chloride, over a period of 10 minutes, with stirring. The mixed solution was stirred for a further 1.5 hours at room temperature, and then the solvent was distilled off. The residue was dissolved in ethyl acetate containing a small amount of water. A 10% w/v aqueous solution of citric acid was added, and then the solution was extracted with ethyl acetate. The extract was washed with a 5% w/v aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. The fraction eluted with a 1:1 by volume mixture of ethyl acetate and hexane gave 2.06 g of the title compound as an amorphous substance melting at 53°-58° C. (with decomposition)
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2>CO>[CH3:1][O:2][C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c2ncccc12
Temperature: 80 °C
Yield: 92.8 %

Procedure:
NaOMe (570 mg, 10.5 mmol) was added to a solution of 5-chloro-8-nitroquinoline 27 (550 mg, 2.64 mmol) in MeOH (15 ml) and the mixture was heated at 80° C. for 2 h. The solvent was removed in vacuo and the residue was diluted with water and the aqueous phase was extracted with DCM. The organic phase was washed with brine and concentrated in vacuo to give the title compound (500 mg, 93%) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28](S(C)(=O)=O)[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([N:28]2[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:33])([F:1])[CH2:3][CH2:4]2)=[O:9])=[CH:37][CH:36]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To the solution of 0.15 (0.37 mmol) (4,4-difluoro-piperidin-1-yl)-{1-methanesulfonyl-5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 20) in 5 ml dichloromethane. 0.13 g (0.74 mmol) copper(II) acetate, 0.17 g (1.1 mmol) 4-chlorophenylboronic acid and 0.12 ml (0.12 mg, 1.5 mmol) pyridine were added and the suspension was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was flash-chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give the compound as a light yellow solid (88%).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)#[N:12].[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[C:11]([C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:2]3[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=3[CH3:8])[CH2:21][CH2:20]2)=[CH:17][CH:18]=1)#[N:12]
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Br
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1[nH]c(=O)[nH]c(=O)c1N1CCN(c2ccc(C#N)cc2)CC1
Temperature: 140 °C
Yield: 29.9 %

Procedure:
A mixture of 20.5 g (0.10 mole) of 5-bromo-6-methyl-2,4(1H,3H)-pyrimidinedione, 18.1 g (0.10 mole) of 4-(4-cyanophenyl)piperazine, 6.4 g (0.11 mole) of anhydrous potassium fluoride, 15.2 g (0.1 mole) of powdered potassium carbonate in 100 ml of hexamethyl phosphoramide was heated at 140° C. for 24 hours. The mixture was cooled and poured into 500 ml of ice water. The solid was collected and washed with 100 ml of water. Recrystallization from N,N-dimethylformamide and drying in vacuo at 78° C. for 16 hours gave 9.3 g of the product as a dull solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:6]2[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:16][CH:17]=1
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(N)cc1
Yield: 90.3 %

Procedure:
To a solution of 2-n-butyl-4-chloro-5-methoxymethyl-1-(4-nitrobenzyl)imidazole (11.22 g) in methanol (100 mL) under N2 was carefully added 1.0 g of 10% palladium on charcoal. Hydrogen gas was then bubbled through the solution for 4 hours. The solution was filtered through Celite ® and the solvent removed in vacuo to yield 9.23 g of an amber oil. NMR (200 MHz, CDCl3) δ 7.99 (s, 1H); 6.78 (d of d, 4H, J=5,5Hz); 5.05 (s, 2H); 4.24 (s, 2H); 3.27 (s, 3H); 2.59 (t, 2H, J=7Hz); 1.62 (t of t, 2H, J=7,7Hz); 1.32 (t of q, 2H, J=7,7Hz); 0.84 (t, 3H,J=7Hz). Mass Calcd. for C16H23ClN3O; 307.1451. Found: 307.1460.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=1)[C:4](O)=[O:5].[BH4-].[Na+]>C(O)C.O>[NH2:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([I:14])=[CH:12][CH:13]=1)[CH2:4][OH:5]
Reactant: NC(Cc1ccc(I)cc1)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(CO)Cc1ccc(I)cc1

Procedure:
A mixture of 28.5 g (75.0 mmol) 2-amino-3-(4-iodophenyl)propanoate hydrochloride in 300 mL ethanol and 300 mL water is added to a mixture of 14.2 g (375 mmol) NaBH4 and 600 mL water (gas evolution!) and the resulting mixture is stirred at reflux for 2 h. The ethanol is evaporated in vacuo and the remaining aq. Phase is extracted with DCM (4×). The combined organic layers are dried with Na2SO4 and the solvent is removed in vacuo. The compound is used without further purification.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:32][CH2:33][CH2:34][O:35][CH3:36])[C:29](O)=[O:30])=[CH:23][CH:22]=1)[CH3:17]>ClCCl>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:32][CH2:33][CH2:34][O:35][CH3:36])[C:29]([Cl:4])=[O:30])=[CH:23][CH:22]=1)[CH3:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O
Solvent: ClCCl
Product: COCCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Oxalyl chloride (92 mg) was added to (±)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)propanoic acid (100 mg) in dichloromethane (2 mL). The mixture was stirred at room temperature for 16 hours and evaporated to dryness to give the title compound as a gum which was used without further purification.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[I:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1>[Cu]I.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.C1COCC1>[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:10][CH:9]=1
Reactant: Ic1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(I)cc1
Temperature: 40 °C
Yield: 130.9 %

Procedure:
To a mixture of (trimethylsilyl)-acetylene (2.0 mL, 14 mmol) and 1,4-diiodobenzene (9.4 g, 28 mmol) in freshly distilled TEA (40 mL) and THF (20 mL) in a 100 mL Schlenk flask were added CuI (0.19 g, 1.0 mmol) and PdCl2(PPh3)2 (0.30 g, 0.43 mmol) with stirring. The flask was then evacuated and purged with argon (3 times) on a Schlenk line. The mixture was heated at 40° C. (oil bath), sealed and stirred for 4 h. The solvents were removed under reduced pressure. The residue was dissolved in ethyl ether (150 mL), washed with H2O (3×100 mL), dried (MgSO4) and filtered. The solvent removed under reduced pressure. The resulting residue was purified by column chromatography (silica, petroleum ether/ethyl ether, 10:1) to afford 5.5 g (85%) of an off-white solid. mp 57-59° C. (lit.25 56-58° C.); 1H NMR δ 0.33 (s, 9H), 7.18, 7.64 (AA′BB′, J=8.7 Hz, 2×2H); 13C NMR δ 0.24, 94.2, 96.1, 102.6, 123.4, 133.5, 137.8; FAB-MS obsd 299.9821, calcd exact mass 299.9882 (C11H13ISi).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH:18]([CH3:20])[CH3:19])=[C:11]([O:21][CH3:22])[CH:10]=2)[CH:4]=1.[CH2:23]1[O:32][C:26]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[O:25][CH2:24]1>>[CH2:23]1[O:32][C:26]2([CH2:31][CH2:30][N:29]([CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[C:5]([C:9]4[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH:18]([CH3:20])[CH3:19])=[C:11]([O:21][CH3:22])[CH:10]=4)[CH:4]=3)[CH2:28][CH2:27]2)[O:25][CH2:24]1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC(C)C
Reactant: C1CC2(CCN1)OCCO2
Product: COc1cc(-c2cc(CN3CCC4(CC3)OCCO4)ccn2)cc(OC)c1OC(C)C

Procedure:
4-Chloromethyl-2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridine (643 mg) and 4-piperidone ethylene ketal (287 mg) were coupled in the same manner as described in Example 2 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.CO[C:12](OC)(OC)[CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCO>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[NH:8][C:12]([CH2:13][CH2:14][CH3:15])=[N:1]2
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1ncnc(Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCc1nc2ncnc(Cl)c2[nH]1

Procedure:
To a solution of 4,5-diamino-6-chloropyrimidine (0.289 g, 2 mmol) in 2-methoxyethanol (10 ml) were added trimethylorthobutyrate (0.5 ml, 3 mmol) and p-toluenesulfonic acid (0.03 g), and the mixture was refluxed for 18 hours and then concentrated in vacuo. The residue was partitioned between water and and ethylacetate. The organic phase was then washed with brine and dried (MgSO4). The crude product obtained after evaporation of the solvent was purified by flash column chromatography on silica-gel using ethylacetate/hexane (1:1). The fractions containing pure product were pooled and concentrated in vacuo, and then allowed to stand at room temperature overnight. The crystalline product was filtered and dried. Yield 0.17 g (43%); NMR (CDCl3): δ 1.05 (t, J=9 Hz, 3H), 2.0 (q, 2H), 3.1 (q, 2H), 8.74 (s, 1H); FAB mass-spectra: m/e 197 and 199 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([S:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[CH:13]=[N:14][NH:15][C:3]=23)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Reactant: Sc1ccccc1
Product: CCOC(=O)c1cnc2cn[nH]c2c1Sc1ccccc1

Procedure:
The above compound was prepared from ethyl 7-chloro-1H-pyrazolo[4,3-b]pyridine-6-carboxylate and thiophenol in an analogous manner to the preparation of Example 1 giving a white solid, m.p. 130°-131° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[C:11]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[N:21]1([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)[CH:25]=[N:24][CH:23]=[N:22]1.N1CCC[C@H]1C(O)=O>CO>[CH3:18][C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:20]=[C:28]1[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)([CH3:19])[CH2:16][CH3:17]
Reactant: O=Cc1ccccc1-n1cncn1
Reactant: CCC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CO
Product: CCC(C)(C)n1c(-c2ccccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C

Procedure:
A reaction mixture of 4-(2-amino-pyrimidin-5-yl)-N1-(1,1-dimethyl-propyl)-benzene-1,2-diamine (130 mg, 0.48 mmol), 2-1,2,4-triazol-1-yl-benzaldehyde (110 mg, 0.64 mmol) and L-proline (5 mg) in MeOH (25 mL) is refluxed for 16 hours. The reaction mixture is allowed to cool to room temperature and is concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography with 8% MeOH in CH2Cl2 as the eluent to afford 5-[1-(1,1-dimethyl-propyl)-2-(2-1,2,4-triazol-1-yl-phenyl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine. LCMS (ESMS): m/z 425.20 (M++1)
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(cnn2-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(cnn2-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c1
Reaction time: 15 h
Yield: 45.6 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-methoxy-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (22 mg, 44.5 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.3 mL). After 15 h, the mixture was concentrated in vacuo and 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% of a methanol containing 10% ammonium hydroxide solution in dichloromethane) gave 2-(5-methoxy-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (7.4 mg, 46%). MS (M+H)+=365; 1H NMR (DMSO-d6) d: 9.04 (s, 1H), 8.70 (dd, J=9.3, 4.6 Hz, 1H), 8.52 (d, J=0.8 Hz, 1H), 8.41 (s, 1H), 7.76 (dd, J=8.9, 2.3 Hz, 1H), 7.63 (s, 1H), 7.49 (d, J=2.6 Hz, 1H), 3.86 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:26][CH2:27][CH3:28])[C:23]([NH2:25])=O)=[CH:17][CH:16]=1)[CH3:11].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1.O>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:26][CH2:27][CH3:28])[C:23]([NH2:25])=[S:38])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(N)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(N)=S

Procedure:
3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropanamide (428 mg, 1.1 mmol) was suspended in toluene and Lawesson's reagent (1.1 eq) added. After 3 h at refluxed the suspension was cooled and poured into water. After extraction with chloroform (×3) the extracts were washed with aqueous ammonia, dried and concentrated. Chromatography (methanol/dichloromethane) gave the product as a white solid m.p.=46-48° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=[C:20]1[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.ClCCl>C(N(CC)CC)C>[NH2:32][C:23]1[C:22]2[N:21]=[C:20]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:12])[C:31]=2[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:24]=1
Reactant: O=C(Cl)c1ccc2ccccc2n1
Reactant: COc1ccc(Cc2nc3c(N)nc4ccccc4c3n2CCCCN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2nc3c(N)nc4ccccc4c3n2CCCCNC(=O)c2ccc3ccccc3n2)cc1
Yield: 27.5 %

Procedure:
Quinoline-2-carbonyl chloride (0.28 g in 10 ml dichloromethane, 1.46 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.49 g, 1.3 mmol), dichloromethane (140 ml) and triethylamine (0.5 ml). The reaction was maintained for 17 hours and then concentrated in vacuo. The yellow residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic fraction was dried (MgSO4), filtered, and concentrated. The crude residue was purified by flash column chromatography (silica gel, gradient elution using dichloromethane to 95:5 dichloromethane\methanol) to provide 0.19 g of N2-{4-[4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-2-quinolinecarboxamide as an off white solid, m.p. 95.1-97.4° C. 1H NMR (300 MHz, DMSO-d6) δ 8.97 (t, J=6.0 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.16-8.07 (m, 3H), 7.96 (d, J=7.7 Hz, 1H), 7.87 (m, 1H), 7.72 (m, 1H), 7.58 (dd, J=8.3, 1.1 Hz, 1H), 7.31 (m, 1H), 7.23 (d, J=8.7 Hz, 2H), 7.08 (m, 1H), 6.82 (d, J=8.7 Hz, 2H), 6.58 (broad s, 2H), 4.50 (m, 2H), 4.33 (s, 2H), 3.63 (s, 3H), 3.34 (m, 2H), 1.65 (m, 4H); MS (EI) m/e 530.2431 (530.2430 calcd for C32H30N6O2).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:44]1[CH2:49][CH2:48][CH:47]([NH:50][C:51]2[CH:60]=[CH:59][N:58]=[C:57]3[C:52]=2[C:53]2[CH:65]=[CH:64][CH:63]=[CH:62][C:54]=2[C:55](=[O:61])[NH:56]3)[CH2:46][CH2:45]1>CN(C=O)C>[C:1]1([CH2:7][C:8]([N:44]2[CH2:45][CH2:46][CH:47]([NH:50][C:51]3[CH:60]=[CH:59][N:58]=[C:57]4[C:52]=3[C:53]3[CH:65]=[CH:64][CH:63]=[CH:62][C:54]=3[C:55](=[O:61])[NH:56]4)[CH2:48][CH2:49]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c2nccc(NC3CCNCC3)c2c2ccccc12
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccccc1)N1CCC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
Phenylacetic acid (10 mg, 0.07 mmol), DIEA (28 mg, 0.22 mmol), and HATU (28 mg, 0.07 mmol) were dissolved in DMF (1 mL), and stirred for 30 min at room temperature. 358 (17 mg, 0.06 mmol) was added, and the reaction mixture was stirred for another 1 h at room temperature. The crude material was purified directly via HPLC to provide 360 (10 mg, 30% yield) as a solid. LC-MS (M+H=413, obsd.=413).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>>[Cl:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(O)nc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(Cl)nc1

Procedure:
Alternatively, 2-chloro-5-nitropyridine can be prepared using the procedure described in the Journal Chemical Society 9 (1941), starting with 2-aminopyrimidine. Nitration of 2-aminopyridine gives 2-amino-5-nitropyridine, which can be converted into 2-hydroxy-5-nitropyridine by a diazonium reaction. Subsequent heating of 2-hydroxy-5-nitropyridine in a phosphorous pentachloride/phosphorous oxychloride mixture yields 2-chloro-5-nitropyridine. The synthesis is summarized below: ##STR13##
Reaction SMILES: C[O-].[Na+].F[C:5]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:6]=1[CH:7]=[O:8].[C:17](O)(=[O:19])C>>[CH3:17][O:19][C:5]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C(F)(F)F)cc1C=O

Procedure:
To a stirred and ice-cooled solution of NaOMe (904 mg, 4.68 mmol) was added 2-fluoro-5-(trifluoromethyl)benzaldehyde (500 mg, 2.60 mmol) portionwise. The dropping funnel employed was washed with THF. The resultant suspension was stirred at room temperature for 5 hr. The reaction mixture was neutralizing for acetic acid (0.3 ml, 5.0 mmol), the solvent was removed. To the solid residue was added water and the mixture was extracted with CH2Cl2. The combined CH2Cl2 extracts were washed with sat. NaHCO3 aq., dried with MgSO4, and concentrated to give crude Compound 4 as a white solid. This was purified with preparative TLC to give pure Compound 4 as a white crystalline (363 mg, 68.4%).