Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)/[C:8]([OH:10])=[O:9])[N:6]=1.N12CCN(CC1)CC2.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[S:28].O>CC(N(C)C)=O>[CH2:30]([O:29][P:27]([O:9][C:8](=[O:10])/[C:7](/[C:5]1[N:6]=[C:2]([NH2:1])[S:3][CH:4]=1)=[N:11]\[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)([O:32][CH2:33][CH3:34])=[S:28])[CH3:31]
Reactant: CCOP(=S)(Cl)OCC
Reactant: Nc1nc(/C(=N/OC2CCCCO2)C(=O)O)cs1
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOP(=S)(OCC)OC(=O)/C(=N\OC1CCCCO1)c1csc(N)n1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 30 g (Z)-(RS)-(2-aminothiazol-4-yl)-[(tetrahydropyran-2-yloxyimino)]-acetic acid (80.5 mmol) and 90 mg 1,4-diazabicyclo[2.2.2]octane (DABCO) (0.80 mmol) in 300 ml dimethylacetamide was added under argon over 45 min 17 ml diethyl chlorothiophosphate (104.9 mmol). Stirring was continued at 0° C. for 1 h. The reaction was followed by HPLC. To the slightly turbid reaction mixture was added dropwise over 50 min 450 ml water. The precipitated product was filtered, washed with water and dissolved in dichloromethane. The aqueous layer was back-extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure until the product started to crystallize. To the residual solution was added dropwise over 30 min n-hexane. The resulting suspension was cooled to 2° C., stirred for 1 h and then filtered. The crystalline product was washed with n-hexane and dried to constant weight. (Z)-(RS)-(2-aminothiazol-4-yl)-[(tetrahydropyran-2-yloxyimino)]-acetic acid diethoxythio-phosphoryl ester was obtained as a white solid (28.01 g, yield=82%) and was stored under argon at -20° C. No further purificiation was necessary and the product was used as isolated for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[H][H]>O1CCOCC1.[Ni]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([Cl:11])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cc(Cl)cnc1Cl
Yield: 75.5 %

Procedure:
26.0 g of Raney nickel catalyst are washed with ethanol and then added to a solution of 129.2 g (0.69 mol) of 2,5-dichloro-3-nitropyridine in 1300 ml of dioxane. This mixture is hydrogenated with hydrogen under normal pressure and at a temperature in the range from 20° to 35° C. After reaction of 20% of the required amount of hydrogen, a further 30.0 g of Raney nickel catalyst are added to the reaction mixture. After a hydrogenation period of 22 hours, the catalyst is removed, the solvent is evaporated off and the residue is crystallised from ethyl acetate/hexane, affording 84.9 g (78% of theory) of 3-amino-2,5-dichloropyridine, m.p. 129°-132° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:18]Br>CCOCC>[Br:18][CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[C:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: CCCCCC(=O)c1ccccc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCC(Br)C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
Anhydrous aluminium chloride (0.120 g.) is added to an ice-cooled solution of n-hexanophenone (21.1 g.) in anhydrous ether (20 ml.). The mixture is stirred and ice-cooled to a temperature below 10° C. during the dropwise addition of bromine (6.0 ml.) during 1 hour. The mixture is evaporated and the residual oil dissolved in ether (100 ml.). The solution obtained is washed first with a saturated aqueous solution of sodium thiosulphate (3 × 30 ml.) and then with water. After drying (sodium sulphate) the ethereal solution is evaporated to give α-bromo-n-hexanophenone as an oil (28.0 g.) which is used without further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.CCCCCC>ClCCl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:1](=[O:3])[CH3:2])=[CH:12][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc(NC(C)=O)cc1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Acetic anhydride (10.21 g, 9.4 mL, 100 mmol) was added dropwise over 1 hour to a stirred solution of p-anisidine (12.32 g, 100 mmol) in dichloromethane (40 mL) at 25-30° C. The mixture was stirred for an additional 1 hour at the same temperature. Hexane (120 mL) was added dropwise to the mixture at 25-30° C. The obtained suspension was stirred for 1 hour at the same temperature. The precipitated crystals were separated by filtration and dried under reduced pressure to give 15.31 g (92.7%) of N-(4-methoxyphenyl)acetamide [3a] as off-white crystals.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[NH:22][C:23]([NH:25][CH2:26][C:27]1([NH:32][C:33]2[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:24])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[C:36]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:35]=[CH:34][C:33]([NH:32][C:27]2([CH2:26][NH:25][C:23]([NH:22][C:14]3[C:13]([CH:10]([CH3:12])[CH3:11])=[CH:18][CH:17]=[CH:16][C:15]=3[CH:19]([CH3:21])[CH3:20])=[O:24])[CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:38][CH:37]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(Nc2ccc(I)cc2)CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(Nc2ccc(-c3ccccc3)cc2)CCCC1
Temperature: 100 °C
Reaction time: 240 h
Yield: 57.3 %

Procedure:
45 mg (0.37 mmol) of phenylboronic acid are added to 150 mg (0.29 mmol) of 1-(2,6-diisopropylphenyl)-3-[1-(4-iodophenylamino)-cyclopentylmethyl]-urea (Example 6d) in 20 ml of toluene. 370 μl (0.74 mmol) of a 2M aqueous solution of potassium carbonate are added. The reaction medium is degassed with nitrogen for 20 min, then 10 mg (8.65 μmol) of tetrakis-(triphenylphosphine)palladium are added. The medium is heated at 100° C. for 6 hours, then at ambient temperature for 10 days. It is then poured into water and extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated and the residue is chromatographed on silica gel (heptane/ethyl acetate, 80/20 v/v). 78 mg of 1-[1-(biphenyl-4-ylamino)cyclopentylmethyl]-3-(2,6-diisopropyl-phenyl)-urea are obtained in the form of a white solid. (M.Pt.=198° C., Yield=57%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[N:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:30][CH2:31][CH2:32][NH:33][C:18]([C:12]2[CH:11]=[C:10]3[C:15]([C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:8](=[O:21])[NH:9]3)=[CH:14][CH:13]=2)=[O:20])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCCCN1CCCCC1
Reactant: O=C(O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Product: O=C(NCCCN1CCCCC1)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1

Procedure:
55 mg (45%) of the target compound was obtained in the same manner of Example 1, using 3-(4-chloro-benzyl)-2,4-dioxoquinazoline-7-carboxylic acid (90 mg, 0.272 mol) obtained in Example 1 and 3-piperidine-1-yl-propylamine (85 mL, 0.598 mmol).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].Br[C:6]1[CH:7]=[CH:8][C:9]([O:26][CH2:27][CH3:28])=[C:10]([C:12]2[NH:13][C:14](=[O:25])[C:15]3[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=3[N:17]=2)[CH:11]=1>>[CH2:27]([O:26][C:9]1[CH:8]=[CH:7][C:6](/[CH:3]=[CH:2]/[C:1]#[N:4])=[CH:11][C:10]=1[C:12]1[NH:13][C:14](=[O:25])[C:15]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=2[N:17]=1)[CH3:28]
Reactant: C=CC#N
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(/C=C/C#N)ccc3OCC)nc12

Procedure:
The title compound was prepared from acrylonitrile and 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one following the procedure of Example 19 and was obtained as off-white crystals (33%). Found: C,65.99; H,5.52; N,19.07. C20H21N5O2 requires C,66.10; H,5.82; N,19.27%.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28]Cl)[C:23]=1[CH3:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CO.C(OCC)(=O)C>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:23]=1[CH3:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCOc1ccnc(CCl)c1C
Reactant: Sc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 38.7 %

Procedure:
To a liquid prepared by dissolving with stirring 8.7 g (0.058 mol, 0.95 eq.) of 2-mercaptobenzimidazole and 68.2 g (0.354 mol, 5.8 eq.) of a 28% sodium methoxide solution in 400 mL of methanol, a liquid prepared by dissolving the whole amount of 4-heptyloxy-2-chloromethyl-3-methylpyridine in 210 mL of methanol was added at 28° C. Subsequently, the mixture was heated to reflux for one hour and cooled, and then methanol was solid dried under reduced pressure. A yellow brown oily residue resulting therefrom was dissolved in 250 mL of ethyl acetate, and then the organic layer was washed with 100 mL of water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated to dryness. The resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 17.8 g of an orange-colored oily matter. The orange-colored oily matter was recrystallized from ethyl acetate (7 vol.), to obtain 8.7 g of colorless crystals (HPLC: 99.0 Area %, yield 38.7%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]([F:20])([F:19])[S:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>CC(=O)CC>[F:20][C:10]([F:19])([F:9])[S:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24])=[CH:16][CH:17]=1
Reactant: Oc1ccc(SC(F)(F)F)cc1
Reactant: C#CC(C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CC(C)(C)Oc1ccc(SC(F)(F)F)cc1
Reaction time: 20 h

Procedure:
13.8 g (0.1 mol) of dried potassium carbonate and 1.6 g (0.01 mol) of potassium iodide are suspended in a solution of 19.4 g (0.1 mol) of 4-(trifluoromethylthio)phenol in 250 ml of dry butanone and 15.4 g (0.15 mol) of 3-chloro-3-methyl-1-butyne are added dropwise. The mixture is then heated under reflux with stirring for 20 hours, 15.4 g of 3-chloro-3-methyl-1-butyne and 13.8 g of potassium carbonate are added once again and the mixture is further heated under reflux for 40 hours. Inorganic constituents are filtered off, the solution is concentrated, and the residue is taken up in 200 ml of methylene chloride and extracted using 1 N NaOH solution. The organic phase is washed with water, dried and concentrated, and the residue is filtered through silica gel.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([Cl:17])=[C:8]([Cl:16])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.[ClH:18]>O>[Cl:18][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Cl:16])[C:7]=1[Cl:17]
Reactant: Cl
Reactant: Nc1cc(C(F)(F)F)cc(Cl)c1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 55 %

Procedure:
A solution of sodium nitrite (39 g.) in water (85 ml.) is added over 1 hour to a solution of 5-amino-3,4-dichloro-α,α,α-trifluorotoluene (117.5 g., 0.51 mol) in 1700 ml. concentrated hydrochloric acid at -6° C. and the solution stirred for 1 hour then filtered. The filtrate is added to a solution of cuprous chloride (76.5 g.) in concentrated hydrochloric acid (500 ml.) over 5 minutes at 0° to 8° C. and gradually heated to 80° C. over 80 minutes. The reaction mixture is cooled to 35° C. and extracted with hexane (2×300 ml.). The extract is washed with water, 2% sodium hydroxide solution, dried and distilled to give 3,4,5-trichloro-α,α,α-trifluorotoluene (70 g., 55%) b.p. 82°-86° C./10 mm, 95% pure.
Reaction SMILES: C(O)(=O)C.[C:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16](=[O:50])[CH2:17][C@H:18]([NH:36][S:37]([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=2)(=[O:39])=[O:38])[C:19](=[O:35])[N:20]2[CH2:25][CH2:24][O:23][CH:22]([CH2:26][O:27]CC3C=CC=CC=3)[CH2:21]2)[CH2:9]1)(=[NH:7])[NH2:6].[ClH:51]>C(O)C.[Pd]>[ClH:51].[C:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16](=[O:50])[CH2:17][C@H:18]([NH:36][S:37]([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=2)(=[O:39])=[O:38])[C:19](=[O:35])[N:20]2[CH2:25][CH2:24][O:23][CH:22]([CH2:26][OH:27])[CH2:21]2)[CH2:9]1)(=[NH:6])[NH2:7]
Reactant: N=C(N)N1CCCC(CNC(=O)C[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCOC(COCc3ccccc3)C2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: N=C(N)N1CCCC(CNC(=O)C[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCOC(CO)C2)C1

Procedure:
A solution of the product from Example 54 in ethanol/IN hydrochloric acid is hydrogenated in the presence of 10% Pd/C for 30 hours under normal conditions. There is obtained (βS,2RS)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]-2-hydroxymethyl-β-2-naphthylsulfonamido-γ-oxo-4-morpholinebutyramide hydrochloride, FAB-MS: 561 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)=[CH2:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.CO.[H][H]>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:13]([C:15]3[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)[CH3:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: C=C(c1ccc([N+](=O)[O-])cc1)c1ccnc2cc(OC)ccc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(C(C)c3ccc(N)cc3)ccnc2c1
Reaction time: 3 h

Procedure:
A mixture of 7-methoxy-4-(1-(4-nitrophenyl)vinyl)quinoline (0.146 g, 0.477 mmol) and Palladium on carbon, 10% (0.152 g, 1.43 mmol) in EtOAc (10 mL) and MeOH (1 mL) at RT was exposed to an atmosphere of Hydrogen (balloon). After 3 hrs, the mixture was filtered through celite and concentrated in vacuo to afford 4-(1-(7-methoxyquinolin-4-yl)ethyl)benzenamine as a white foam. MH+=279.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:14])=O.CN(C)C=O>CCCCCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccccc1C(=O)O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)Cl

Procedure:
To a stirred solution of 2-Methoxy-benzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h. After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Methoxy-benzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[N:28]=[C:29]=[O:30]>>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[NH:28][C:29](=[O:30])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2
Reactant: O=C=Nc1ccc2ccccc2c1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(Nc1ccc2ccccc2c1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 2 (2), but with 2-naphthylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (14.4 mg, 55%) having the following characteristics.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H](CO)Nc1ncccc1[N+](=O)[O-]
Solvent: CC#N
Product: C[C@@H](CO)Nc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 15 h
Yield: 104.1 %

Procedure:
A solution of (S)-2-(3-nitropyridin-2-ylamino)propane-1-ol (4.88 g, 24.75 mmol) in acetonitrile (50 mL) was cooled to 0° C. and treated with N-bromosuccinimide (4.40 g, 24.75 mmol) in one portion. The ice bath was left in place and allowed to slowly expire over 15 h. The solution was then concentrated under reduced pressure in order to remove most (>90%) of the acetonitrile. The concentrated solution was dissolved in ethyl acetate and washed with half-saturated aqueous sodium bicarbonate solution (2×75 mL) and 5% aqueous sodium chloride solution (1×75 mL). The ethyl acetate solution was then concentrated under reduced pressure to afford (S)-2-(5-bromo-3-nitropyridin-2-ylamino)propane-1-ol (7.11 g) as a dark yellow solution which was used in the next step without purification. MS (ESI, pos. ion) m/z 276. 278 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:9]([NH:11][C:12]3[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=3)([N:10]=1)[N:8]=[CH:7][N:6]=2.[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[CH:4][C:5]3[C:9]([NH:11][C:12]4[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=4)([N:10]=2)[N:8]=[CH:7][N:6]=3)[CH2:21][CH2:20]1
Reactant: Cc1cc(NC23N=CN=C2C=NC(Cl)=N3)n[nH]1
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(NC23N=CN=C2C=NC(N2CCC(C)CC2)=N3)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 mL) was added 5-methyl-1H-pyrazol-3-yl amine (2.05 g, 21.2 mmol). The resulting mixture was stirred at room temperature for 48 h. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 1.524 g (58% yield) of (2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of (2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (200 mg, 0.80 mmol) was added 4-methylpiperidine (4 mL, 8.01 mmol) and the reaction mixture heated at reflux overnight. The solvent was evaporated and the residue dissolved in a mixture EtOH:water (1:3, 4 mL). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (×2) and rinsed with Et2O (×2) to afford IV-33 as a white solid (225 mg, 90%): mp >300° C.; H NMR (DMSO) δ 0.91 (3H, d), 1.10 (2H, m), 1.65 (3H, m), 2.24 (3H, s), 2.84 (2H, m), 4.60 (2H, m), 6.40 (1H, s) 7.87 (1H, m), 9.37-9.59 (1H, m), 12.03-12.39 (2H, m); IR (solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3 (M+H)+.
Reaction SMILES: [H-].[Na+].CN1CCCC1=O.[CH2:10]([S:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)[CH3:11].Cl[C:19]1[N:31]([CH3:32])[C:22]2=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=[C:21]2[N:20]=1>O>[CH2:10]([S:12][C:13]1[N:17]([C:19]2[N:31]([CH3:32])[C:22]3=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=[C:21]3[N:20]=2)[CH:16]=[CH:15][N:14]=1)[CH3:11]
Reactant: Cn1c(Cl)nc2cc(C(F)(F)F)cnc21
Reactant: CCSc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCSc1nccn1-c1nc2cc(C(F)(F)F)cnc2n1C
Reaction time: 0.17 h
Yield: 100.8 %

Procedure:
41 mg of sodium hydride (60% oil-based) was suspended into 4 ml of 1-methyl-2-pyrrolidone (NMP), and 0.13 g of 2-ethylthioimidazol was added under ice cooling. After stirring the mixture for 10 minutes, 0.2 g of 2-chloro-3-methyl-6-trifluoromethyl-3H-imidazo[4,5,b]pyridine was added, and the mixture was stirred under room temperature for 3 hours. Water was poured, and the deposited precipitate was obtained by filtration and was applied to a silica gel column chromatography to obtain 0.28 g of 2-(2-ethylthio-3H-imidazol-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5,b]pyridine (Compound of Present Invention (1)).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[C:4]([O:17][CH3:18])[CH:3]=1.S(Cl)(Cl)=O.[C:23](=O)(O)[O-]>CO>[CH3:23][O:12][C:11](=[O:13])[C:10](=[O:14])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[O:17][CH3:18])([CH3:16])[CH3:15]
Reactant: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)O
Reactant: O=C([O-])O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C(=O)CC(C)(C)c1ccc(I)cc1OC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid (WO 98/54159) is added in a solution of 1.3 ml of thionyl chloride in 12 ml of methanol at 0° C. and stirred for 10 hours at room temperature. It is added to saturated bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with bicarbonate solution and brine, dried (Na2SO4) and concentrated by evaporation. 3.2 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid methyl ester is obtained as a crude product. This ester is mixed with 4.5 ml of trifluoromethyltrimethylsilane in 70 ml of DMF and 1.63 g of cesium carbonate at 0° C. and stirred for 10 hours at room temperature. 20 mg of tetrabutylammonium fluoride is added, and it is stirred for another 30 minutes at room temperature. The batch is added to water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->15%), 1.47 g of the title compound is obtained as a yellow oil.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)[CH2:5][CH:6]=[CH2:7].[OH-].[K+].Cl>O.CO>[CH2:7]=[CH:6][CH2:5][CH:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)[CH2:3][CH:2]=[CH2:1]
Reactant: C=CCC(CC=C)OCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCC(CC=C)OCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reaction time: 6 h
Yield: 95.6 %

Procedure:
13 g of the compound (5) and 6 g of potassium hydroxide were dissolved in a solution mixture of 70 ml of water and 30 ml of methanol, and reflux was carried out for 6 hours. After addition of the reaction solution to 400 ml of water, the mixture was then adjusted approximately to pH 1 with concentrated hydrochloric acid. The white precipitate generated was collected by filtration, washed with water, and dried at 40° C. under reduced pressure, to obtain 12 g of the compound (6). (Yield: 96%)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 5-bromosalicylaldehyde (12 g), potassium carbonate (16.5 g) and benzyl bromide (7.8 ml) in DMF (50 ml) was stirred for 18 hours, poured into ethyl acetate (100 ml), washed with 0.05M HCl (100 ml), sodium bicarbonate (100 ml) and brine (100 ml), dried (sodium sulphate), filtered and evaporated. The residue was triturated with hexane/diethyl ether to give 2-benzyloxy-5-bromo-benzaldehyde (15.8 g) mp.70°-72° C.