Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][NH:12][C@@H:11]([CH3:15])[C:10]1=[O:16])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:27](=[O:28])[NH:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)[C@@H:11]([CH3:15])[C:10]1=[O:16])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1NCCN(CCC(=O)OC(C)(C)C)C1=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1C(=O)N(CCC(=O)OC(C)(C)C)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 0.75 g (3.10 mmol) of 3-((S)-3-methyl-2-oxo-piperazin-1-yl)-propionic acid tert-butyl ester with 0.1HCl in 16 ml of dichloromethane was treated at 0° C. with 0.70 g (3.70 mmol) of 3,4-dichlorophenyl isocyanate and 0.52 ml (3.70 mmol) of triethylamine. After 30 min the reaction was warmed to room temperature and extracted with aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield after purification by flash silica gel column (EtOAc/n-heptane 1:2 to 3:1) 0.91 g (68%) of the titled compound as white foam. MS: 374.1 (MH+, 2Cl).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].C([Si](C)(C)[O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[OH:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:22][CH:21]=1
Reactant: O=Cc1cc(I)ccc1F
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(I)ccc1Oc1ccc(OCCO)cc1
Yield: 98.9 %

Procedure:
In a manner similar to the method described in Example 50a, 2-fluoro-5-iodobenzaldehyde (2.5 g, 10 mmol) (Aldrich) was reacted with 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenol (2.7 g, 10 mmol) and K2CO3 in N,N-dimethylacetamide at 170° C. for 0.5 h to give 2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo-benzaldehyde as a yellow solid (Yield 3.8 g, 98%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25](Cl)=[O:26])=[CH:22][C:21]=2[CH:28]=1.CO>C1(C)C=CC=CC=1>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:25]([C:23]1[O:24][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:28][C:21]=2[CH:22]=1)=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1cc2cc(Br)ccc2o1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(c1cc2cc(Br)ccc2o1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A solution of 50 ml of toluene and 7.9 g of dibenzylamine are added dropwise with stirring at 50-60° C. in the course of 10 min. to 5.2 g of 5-bromobenzofuran-2-carbonyl chloride in 100 ml of toluene. A colourless solid is obtained. After dropwise addition is complete, the mixture is additionally stirred at 100-110° C. for a further 3 hours. After cooling to 10° C., the solid product (dibenzylammonium chloride) is filtered off with suction. The filtrate is then treated with a mixture of 150 ml of water and 10 g of sodium carbonate and thoroughly shaken. The organic phase is separated off, washed again with 100 ml of water, dried using sodium sulfate and filtered. The, filtrate is concentrated on a Rotavapor in vacuo to a residue (residue: 9.5 g). After recrystallization from 100 ml of methanol, 6.5 g of product (yield 77%) remain after isolation.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH2:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([CH2:27][CH3:28])=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CCc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CCc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, white solid (94 mg, 82%), MS (ISP) m/z=459.5 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-ethyl-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[C:12]([C:15]#[N:16])[C:13]#[N:14])SC)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CCO>[NH2:14][C:13]1[NH:19][N:18]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]=1[C:15]#[N:16]
Reactant: CSC(Nc1ccc(Cl)cc1)=C(C#N)C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1c(Nc2ccc(Cl)cc2)n[nH]c1N
Temperature: 0 °C

Procedure:
Dissolved 2-(((4-chlorophenyl)amino)(methylthio)methylene)malononitrile in EtOH (100 mL) and added hydrazine hydrate (1 eq), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-((4-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].Cl[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=2)[N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=4)[N:25]=3)=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c(Cl)c(NCc2ccc(O)cc2)n1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C)c(Cl)c(NCc2ccc(Oc3ccc4ncc([N+](=O)[O-])n4n3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
8.0 g (30 mmol) of 4-[(5-chloro-2,6-dimethylpyrimidin-4-ylamino)methyl]phenol, 6.0 g (30 mmol) of 6-chloro-3-nitroimidazo[1,2-b]pyridazine and 20.7 g (150 mmol) of potassium carbonate in 150 ml of anhydrous dimethylformamide are heated at 80° C. with vigorous stirring for 1 h. After cooling to room temperature, the mixture is poured into water (1 l) and extracted with ethyl acetate (3×500 ml). The combined organic extracts are washed with water (500 ml), dried over sodium sulfate and concentrated. The beige solid (12.5 g) remaining is purified by chromatography on silica gel (mobile phase: toluene/acetone=2:1). The fractions with Rf=0.4 are collected and concentrated. The residue is suspended in 100 ml of methanol and the suspension is stirred for 30 min. Following filtration, this operation is repeated. After drying in a vacuum drying cabinet at 40° C., 7.8 g (61%) of the title compound are isolated as an almost white powder. m.p.: 203° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:12]([OH:14])=O)[O:4][N:3]=1.S(Cl)([Cl:17])=O.C(Cl)(Cl)=O>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:12]([Cl:17])=[O:14])[O:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1c(C)noc1C(=O)O
Agent: O=C(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)noc1C(=O)Cl

Procedure:
13.3 g of the carboxylic acid from Example b and 20 ml of thionyl chloride are refluxed in the presence of a little dimethylformamide until the evolution of gas is complete. The crude carbonyl chloride which remains in quantitative yield after evaporation is directly reacted further.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:36]([O:38][C:39](Cl)=[O:40])[CH3:37]>C1COCC1>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:39]([O:38][CH2:36][CH3:37])=[O:40])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(CN)cc3)c2)CC1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
To 1.0 g (2.19 mmol) of {4-[3-(4-aminomethyl-phenoxy)-5-hydroxy-benzoyl-amino]-cyclohexyl}-carbamic acid tert-butyl ester, dissolved in 5 ml of THF, 0.13 g (5.47 mmol) of sodium hydride was added at 0° C. and the mixture was stirred for 15 min at same temperature. 0.26 g (2.40 mmol) of ethylchloroformate, dissolved in 2 ml of THF, was added dropwise to the stirred solution during 10 min and then the reaction mixture was stirred at RT for 6 h. After reaction completion, solvent was removed under reduced pressure and the obtained residue was dissolved in 200 ml of ethyl acetate. Organic layer was washed with (3×100 ml) of brine followed by water (2×100 ml). Organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 0.56 g of required product which was used for the next step witout further purification. Percentage purity (LCMS): 59.7%, (M+1)=527.2+1.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]([C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([CH:15]=1)[OH:14])[CH3:8].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:13]([C:13]1([CH:15]=[C:9]([CH:7]([CH:6]([CH3:5])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:8])[CH2:10][C:11]([C:11](=[O:16])[CH3:10])([OH:16])[CH:12]1[C:24]1[CH:23]=[N:22][CH:27]=[CH:26][C:25]=1[C:6]([CH3:7])=[CH2:5])[OH:14])(=[O:14])[CH3:12]
Reactant: c1ccncc1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Solvent: O=S(Cl)Cl
Product: C=C(C)c1ccncc1C1C(O)(C(C)=O)C=C(C(C)C(C)CCCCC)CC1(O)C(C)=O
Temperature: 0 °C

Procedure:
Thionyl chloride (5 ml.) was added dropwise to a stirred solution of 1.27 g. of 1,3-diacetyl-2-{4-[1-hydroxy-1-methyl)ethyl]-3-pyridyl}-5-(3-methyl-2-octyl)resorcinol in 40 ml. of pyridine, cooled in an ice-salt bath at -10°. The mixture was stirred and the temperature was allowed to rise to 0° within 11/2 hours. The mixture was poured into ice water and was extracted with ether. The ether extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was chromatographed on a Florisil column (60-100 mesh) using graded methanol/benzene solvent mixtures to give the pure product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.FC(F)(F)C(O)=O.[H-].[Na+]>>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C1=COCCC1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: c1cnn(C2CCCCO2)c1

Procedure:
To pyrazole (14.3 g, 0.21 mol) was added 3,4-dihydro-2H-pyran (29 ml, 0.315 mol) and, after complete dissolving, trifluoroacetic acid (0.1 ml, 0.0013 mol) was added to the obtained solution. The reaction mixture was refluxed for 5 h, sodium hydride (0.2 g, 0.008 mol) was added, and the mixture was distilled to give 1-(tetrahydro-pyran-2-yl)-1H-pyrazole; b.p. ˜60-65° C./0.5-1 torr.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Br[C:69]1[CH:74]=[CH:73][C:72]([F:75])=[CH:71][CH:70]=1>O1CCOCC1>[CH2:1]([N:8]1[C@H:13]2[CH2:14][CH2:15][C@@H:9]1[CH2:10][N:11]([C:69]1[CH:74]=[CH:73][C:72]([F:75])=[CH:71][CH:70]=1)[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)cc1
Reactant: c1ccc(CN2C3CCC2CNC3)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: Fc1ccc(N2C[C@H]3CC[C@@H](C2)N3Cc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 65.5 %

Procedure:
To a stirred solution of 8-benzyl-3,8-diazabicyclo[3.2.1]octane (2.5 g, 12.36 mmol) in 1,4-dioxane (15 ml) in sealed tube at 25° C. was added 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.770 g, 1.23 mmol), sodium tert-butoxide (2.37 g, 24.72 mmol), 1-bromo-4-fluorobenzene (1.63 ml, 14.83 mmol) and tris(dibenzyllideneacetone)dipalladium (0) [Pd2(dba)3] (0.566 g, 0.618 mmol). The resulting reaction mixture was purged with nitrogen for 10 min and stirred at 100° C. for 15 h. The reaction mixture was then cooled to 25° C., filtered through a celite bed, and the celite bed was washed with ethyl acetate (2×20 ml). The combined filtrate was concentrated under reduced pressure to get crude compound. The resulting crude compound was purified by using flash column chromatography over silica gel (100-200 mesh) using 10% ethylacetate in hexane to obtain title compound (2.4 g 66%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([N:14](C)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C@@H:7]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:6][C@@H:7]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@@H]1CCCCOC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CN)C[C@@H]1CCCCOC1
Yield: 96 %

Procedure:
Above tert-butyl (S)-1-azido-3-((S)-oxepan-3-yl)propan-2-yl(methyl)carbamate was hydrogenated under H2 (40 psi), catalyzed by 10% Pd/C, in MeOH for 1 h. The catalyst was filtered off and concentrated to give tert-butyl (S)-1-amino-3-((S)-oxepan-3-yl)propan-2-ylcarbamate (76.8 mg, 96% over 2 steps). MS ESI +ve m/z 287 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7]C2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[CH3:31][C:32]1[N:37]=[C:36](C=O)[CH:35]=[CH:34][N:33]=1>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:34]2[CH:35]=[CH:36][N:37]=[C:32]([CH3:31])[N:33]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1
Reactant: Cc1nccc(C=O)n1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Product: Cc1nccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)n1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 2-methylpyrimidine-4-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.59 (d, J=5.0 Hz, 1H), 8.03 (s, 1H), 7.20 (d, J=5.0 Hz, 1H), 4.84-4.76 (m, 1H), 4.13-4.08 (m, 2H), 3.97-3.93 (m, 1H), 3.70-3.67 (m, 1H), 3.61-3.53 (m, 2H), 3.40 (t, J=8.3 Hz, 1H), 3.14 (d, J=9.5 Hz, 1H), 2.88 (m, 1H), 2.72 (s, 3H), 2.69-2.63 (m, 1H), 2.47-2.27 (m, 3H), 2.10-2.08 (m, 1H), 1.91-1.83 (m, 2H), 1.21 (d, J=7.1 Hz, 3H). MS: (M+H m/z 410.2).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])O[C:10](C)(C)[O:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:18][C:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C(C)=CC=CC=1>[CH3:13][C:12]1[O:11][CH2:10][N:18]([C:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:8](=[O:16])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=NC(C)(C)C(C)(C)C
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(C)(C)C)CO1
Yield: 46.7 %

Procedure:
A mixture of 5-phenyl-2,2,6-trimethyl-2h,4h-1,3-dioxin-4-one (0.65 g), N-methylene-1,1,2,2-tetramethylpropylamine (0.54 g) and xylene (2 ml) was heated at reflux for 30 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.40 g).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[CH:8][C:7]2[N:10]=[C:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[NH:12][C:6]=2[CH:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:31][CH3:32]>CN(C=O)C.O>[CH2:31]([N:10]1[C:7]2[CH:8]=[N:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=2[N:12]=[C:11]1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH3:32]
Reactant: CC(C)c1cc2[nH]c(Cn3ccnc3-c3nccs3)nc2cn1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cc(C(C)C)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-isopropyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-1H-imidazo[4,5-c]pyridine (160 mg, 0.493 mmol) in DMF (1.0 mL) at room temperature under N2 is added Cs2CO3 (168 mg, 0.518 mmol) followed by iodoethane (0.047 mL, 0.592 mmol). The mixture is stirred at room temperature for 1 h and then diluted with water and extracted twice with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated. The residue is purified by preparative TLC, developing with 15:1 CHCl3-MeOH (+0.5% Et3N). The less polar (top) band affords 3-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 300 MHz) δ 8.70 (d, J=1.2 Hz, 1H), 7.83 (d, J=3.0 Hz, 1H), 7.53 (d, J=0.9 Hz, 1H), 7.39 (d, J=3.0 Hz, 1H), 7.18 (d, J=0.9 Hz, 1H), 7.14 (d, J=0.9 Hz, 1H), 6.32 (s, 2H), 4.32 (q, J=7.2 Hz, 2H), 3.18 (sept, J=6.9 Hz, 1H), 1.34 (d, J=6.9 Hz, 6H), 1.17 (t, J=7.2 Hz, 3H) ppm. The more polar (bottom) band affords 74 mg (43%) of 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 300 MHz) δ 9.01 (s, 1H), 7.83 (d, J=3.2 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.15 (8, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 6.32 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 3.17 (sept, J=6.8 Hz, 1H), 1.34 (d, J=6.8 Hz, 6H), 1.10 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:17][C:16]([SH:18])=[N:15][N:14]=2)=[CH:9][CH:8]=1.[OH-].[K+].[F:21][C:22]([F:29])([F:28])[C:23]([F:27])=[C:24](F)[F:25]>C(Cl)(Cl)Cl>[F:25][C:24]([S:18][C:16]1[S:17][C:13]([C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=2)=[N:14][N:15]=1)=[C:23]([F:27])[C:22]([F:29])([F:28])[F:21]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: Sc1nnc(-c2ccc(Cl)cc2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: FC(Sc1nnc(-c2ccc(Cl)cc2)s1)=C(F)C(F)(F)F
Temperature: 60 °C

Procedure:
60 ml of dimethylformamide and 6.85 g of 5-(4-chlorophenyl)-2-mercapto-1,3,4-thiadiazole and 0.7 g of potassium hydroxide are stirred in an autoclave. 20 g of hexafluoropropylene are pressed in, and the reaction mixture is heated for 19 hours at 60° C. (10-12·105Pa). After cooling and release of pressure, the solution is poured into ice-water, the product is taken up in chloroform, the chloroform solution is washed with 1n sodium hydroxide solution, and the solvent is removed in vacuo, affording as reside the title compound in the form of an crystals with a melting point of 69°-70° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C:8](=O)[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[N:13]=1)([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=1[N+:31]([O-])=O>>[C:1]([O:5][C:6]([C:7]1[C:23]2[C:24](=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=2)[NH:31][C:8]=1[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[N:13]=1)([CH3:11])[CH3:10])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C(C)(C)C(=O)CC(=O)OC(C)(C)C)n1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: COc1cccc(C(C)(C)c2[nH]c3cc(C#N)ccc3c2C(=O)OC(C)(C)C)n1

Procedure:
According to the method that is used for the preparation of Compound PR5-1, the title compound was synthesized from 4-(6-methoxy-pyridin-2-yl)-4-methyl-3-oxo-pentanoic acid tert-butyl ester and 4-chloro-3-nitrobenzonitrile
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:26])[CH:25]=1)[C:20]([OH:22])=O>CCCCCCC.CCOC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:26])[CH:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: O=C(O)c1cc(F)cc(Cl)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(Cl)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-chloro-5-fluorobenzoic acid (CAS RN 25026-64-6) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Yellow solid (17%). MS (ESI): m/z=355.10 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](SC)=[N:13][CH2:14][Si](C)(C)C)=[CH:8][C:7]=1[Br:21])(=[O:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([C:31]([F:34])([F:33])[F:32])=[CH2:30])[CH:26]=[C:25]([Cl:35])[CH:24]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.COC(C)(C)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:30][C:29]([C:27]3[CH:26]=[C:25]([Cl:35])[CH:24]=[C:23]([Cl:22])[CH:28]=3)([C:31]([F:32])([F:34])[F:33])[CH2:14][N:13]=2)=[CH:8][C:7]=1[Br:21])(=[O:3])[CH3:2]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(COC(C)=O)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(=O)OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Yield: 93.2 %

Procedure:
Under argon atmosphere, a mixed solution of 2-bromo-4-[(methylsulfanyl){[(trimethysilyl)methyl]imino}methyl]benzyl acetate (0.90 g) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.56 g) in THF was cooled to −5° C. to be stirred, and a solution of tetrabutylammonium fluoride (0.56 ml, of 1.0 M in THF) was added thereto gradually. The reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was diluted with t-butyl methyl ether and washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]benzyl acetate (1.1 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>>[CH3:13][C:14]([CH3:18])([CH2:17][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:15][OH:16]
Reactant: C1CCNC1
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(CO)CN1CCCC1
Temperature: 25 °C
Yield: 26.2 %

Procedure:
Pyrrolidine (1.82 g, 25 mmol), K2CO3 (3.0 g, 1.04 eq.), 3-bromo-2,2-dimethyl-propan-1-ol (8.45 g, 50 mmol, 2 eq.) were heated together at 90° C. overnight. The reaction was allowed to cool to room temperature and quenched with 2M HCl solution (50 ml) and extracted with TBME (3×50 ml). The aqueous phase was basified to pH 14 with 2M NaOH solution and extracted with DCM (3×50 ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give the title compound (1.03 g, 26%) as a pale yellow oil.