Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C:18]2C=[CH:24][CH:23]=[CH:22][C:19]=2C#N)=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([CH3:16])[CH:10]=2)=[N:6][CH:7]=1.[OH-].[Na+].[C:28]([O:31]CC)(=[O:30])[CH3:29]>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:17][C:18]2[CH:19]=[CH:22][CH:23]=[CH:24][C:29]=2[C:28]([OH:31])=[O:30])=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([CH3:16])[CH:10]=2)=[N:6][CH:7]=1
Reactant: CCn1nc(C)cc1Nc1cc(Nc2ccccc2C#N)c(Cl)cn1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCn1nc(C)cc1Nc1cc(Nc2ccccc2C(=O)O)c(Cl)cn1
Yield: 66.1 %

Procedure:
To a 50 mL round bottom flask was added 2-({5-chloro-2-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)amino]-4-pyridinyl}amino)benzonitrile (300 mg, 0.850 mmol), and NaOH 1 M solution (10 ml, 10.00 mmol) in 1,4-dioxane (10 mL). The mixture was heated under reflux for 18 hours. Ethyl acetate was added (20 mL) and the layers separated—all product stayed in the water phase. The water phase was neutralized with 6 N HCl, and 40 mL of ethyl acetate were added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated. 2-({5-Chloro-2-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)amino]-4-pyridinyl}amino)benzoic acid (220 mg, 0.562 mmol, 66.1% yield) was isolated as off-white solid and used in the next step without further purification. LCMS (M+H)+=372.1; 1H NMR (400 MHz, MeOD) ppm 1.33 (t, J=7.20 Hz, 4 H) 2.22 (s, 3 H) 4.00 (q, J=7.33 Hz, 2 H) 6.01 (s, 1 H) 6.82 (s, 1 H) 7.06 (td, J=7.52, 1.14 Hz, 1 H) 7.39-7.49 (m, 1 H) 7.49-7.55 (m, 1 H) 7.87-7.94 (m, 1 H) 8.05 (dd, J=7.83, 1.52 Hz, 1 H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][N:13]3[C:17](=[O:18])[CH2:16][S:15][C:14]3=[O:19])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:20](=O)[CH2:21][CH2:22][CH3:23].N1CCCCC1>C(O)C>[CH:20](=[C:16]1[S:15][C:14](=[O:19])[N:13]([CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:17]1=[O:18])[CH2:21][CH2:22][CH3:23]
Reactant: O=C1CSC(=O)N1CCSc1cccc2nccn12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.49 g (3.9 mmol) of 3-[2-(imidazo-[1,2-a]pyridin-5-ylthio)ethyl]thiazolidine-2,4-dione and 0.36 ml (4.0 mmol) of n-butyraldehyde in 30 ml of ethanol, 0.04 ml (0.4 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=2/1→1/4), followed by recrystallization (solvent, chloroform-diethyl ether-n-hexane) to yield 0.872 g (56.1%, white crystal) of the desired product.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:18][C@@H:19]1[C@H:25]([OH:26])[C@@H:24]([CH2:27][OH:28])[O:23][CH:21]([OH:22])[C@@H:20]1[OH:29]>C(O)(=O)C>[F:18][C@H:19]([C@@H:25]([C@@H:24]([CH2:27][OH:28])[O:23][CH:21]=[O:22])[OH:26])[CH:20]=[O:29]
Reactant: OC[C@H]1OC(O)[C@H](O)[C@H](F)[C@@H]1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: O=CO[C@H](CO)[C@@H](O)[C@@H](F)C=O

Procedure:
In step 2, compound (2) obtained in step 1 above is dissolved in acetic acid and oxidized with lead tetra-acetate at room temperature to cause an oxidative cleavage of the α-glycol of 3-deoxy-3-fluoro-D-allopyranose, whereby the 2-carbon atom forms a formyl group. Thus, 2-deoxy-2-fluoro-4-O-formyl-D-ribose is formed as the oxidative product, which is then heated at 70°-90° C. in an aqueous solution under an acidic condition for the elimination of O-formyl group, whereby a ring-closing reaction occurs again to form 2-deoxy-2-fluoro-α,β-D-ribofuranose [compound (3)]. In the next step 3, compound (3) above is reacted with methanol in hydrogen chloride-methanol at room temperature for methylglycosidation, whereby forming a mixture of methyl 2-deoxy-2-fluoro-α-D-ribofuranoside [compound (4)] and methyl 2-deoxy-2-fluoro-β-D-ribofuranoside [compound (5)].
Reaction SMILES: O=[C:2]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4](OCC)=[O:5].[CH3:15][NH:16][NH2:17]>C(O)CC>[CH:9]1([C:2]2[CH2:3][C:4](=[O:5])[N:16]([CH3:15])[N:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)CC(=O)C1CCCCC1
Reactant: CNN
Solvent: CCCO
Product: CN1N=C(C2CCCCC2)CC1=O

Procedure:
To ethyl β-oxocyclohexanepropionate (4.4 g, 0.234 mole) in n-propanol (500 ml) is added dropwise with stirring under nitrogen at 80° C. methylhydrazine (13.8 g, 0.3 mole). After heating at reflux during 5 hours, the reaction is cooled and evaporated to a residual oil. Crystallization from ethylacetate gives a white powder mp 170.5° C. to 172° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][CH2:34][C:35]2[NH:44][C:38]3=[N:39][CH:40]=[C:41](I)[CH:42]=[C:37]3[N:36]=2)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:17]([N:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:41]3[CH:42]=[C:37]4[N:36]=[C:35]([CH2:34][CH2:33][C:29]5[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=[CH:31][N:30]=5)[NH:44][C:38]4=[N:39][CH:40]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCN(C(C)=O)CC5)cc4)cnc3[nH]2)c1
Temperature: 85 °C
Yield: 56.1 %

Procedure:
A mixture of 0.347 g of 1-(4-bromo-benzene-sulfonyl)-4-acetyl-piperazine, 0.28 g of bis-(pinacolato)-diboron, 0.017 g of 1,1′-bis-(diphenylphosphino)ferrocene, 0.022 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.294 g of potassium acetate in 6 ml of degassed dioxane are heated to 85° C. in a sealed tube under N2 for 20 hours. To the resulting mixture 4 ml of degassed dioxane, 0.228 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.069 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.165 g of potassium carbonate and 0.051 g of lithium chloride in 4 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 7 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with ethylacetate. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25-20:1). Concentration of the chromatographically pure fractions and crystallization of the residue from ethylacetate/diethylether (9:1) gives 0.175 g of the title compound as a solid of m.p. 138-140° C. The mass spectrum shows the molecular peak MH+ at 521.4 Da.
Reaction SMILES: C([N:8]1[C:12]([CH2:13][CH2:14][CH3:15])=[C:11](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=[N:9]1)C1C=CC=CC=1.C(O)=O>[C].[Pd].C(O)C>[CH2:13]([C:12]1[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][NH:9][N:8]=1)[CH2:14][CH3:15]
Reactant: CCCc1c(/C=C/C(=O)OCC)cnn1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: CCCc1n[nH]cc1CCC(=O)OCC
Yield: 81.6 %

Procedure:
A mixture of ethyl(E)-3-(1-benzyl-5-propyl-1H-pyrazol-4-yl)propenoate (6.00 g), 5% palladium-carbon (12.0 g), formic acid (50 ml), and ethanol (100 ml) was refluxed for 16 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(3-propyl-1H-pyrazol-4-yl)propionate (3.45 g, yield: 82%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.[CH3:12][N:13](C)[CH2:14][CH2:15][CH2:16]N=C=NCC.[CH2:23]([O:25][C:26]([C@@H:28]1[CH2:30][C@H:29]1[C:31]([OH:33])=O)=[O:27])[CH3:24].C(N(CC)CC)C.CNCCC>CN(C)C=O>[CH2:23]([O:25][C:26]([C@@H:28]1[CH2:30][C@H:29]1[C:31](=[O:33])[N:13]([CH3:12])[CH2:14][CH2:15][CH3:16])=[O:27])[CH3:24]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)[C@@H]1C[C@H]1C(=O)OCC
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
Add 1-hydroxybenzotriazole (HOBT) (1.46 g, 10.8118 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2.07 g, 10.8118 mmol) to a solution of crude trans-cyclopropane-1,2-dicarboxylic acid monoethyl ester (1.71 g, 10.8118 mmol) in N,N-dimethylformamide (11 mL). Stir for 30 minutes. Add triethylamine (2.26 mL, 16.2177 mmol) and methylpropylamine (1.11 mL, 10.8118 mmol) and stir for 16 hours. Quench with 10% aqueous potassium carbonate (10 mL) and extract with ethyl acetate (3×50 mL). Combine the organic extracts, wash with 0.1 N aqueous citric acid (30 mL) and 1 N lithium chloride, dry (magnesium sulfate), concentrate and crystallize with xylenes to give the desired compound (1.02 g, 50%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]([C:12]([O:14]C)=O)[NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.CC(C)([O-])C.[K+].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:11]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:24][CH:23]([C:22]([O:26][CH3:27])=[O:25])[C:12]3=[O:14]
Reactant: COC(=O)c1cc2c(SC)nccc2[nH]1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1Cn2c(cc3c(SC)nccc32)C1=O
Temperature: 80 °C

Procedure:
To a suspension of methyl 4-(methylthio)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (0.30 g, 1.35 mmol) in TBF (3 mL)-toluene (12.0 mL) were added a 1.06 M THE solution of potassium tert-butoxide (1.42 mL/1.41 mmol) and methyl acrylate (300 μL). The resulting mixture was heated at 80° C. for 18 h. The mixture was partitioned between EtOAc and NH4Cl, filtered through celite. The organic phase was separated, dried over Na2SO4 and filtered, to provide the title compound.
Reaction SMILES: [OH2:1].I(O)(=O)(=O)=O.[CH:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C)(C)C>[O:13]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:13])=[O:1]
Reactant: O
Reactant: CCCCCC=O
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC(C)(C)O
Product: O=CCCCCCCCCCCC(=O)O
Temperature: 0 °C
Yield: 73 %

Procedure:
A 2.40 g (0.008 mol) sample of the acid was placed in a 250 mL Erlenmeyer flask and dissolved with 18 mL water and 9 mL tertiary butyl alcohol. The mixture was stirred continuously for homogeneity, followed by addition of 1.95 g (0.0086 mol) periodic acid in one portion. The reaction mixture was then stirred for 5 hours, after which 150 mL ice-cold water was added. The mixture was stirred for another 30 minutes and the resulting solid was vacuum-filtered to give crude 12-oxododecanoic acid. The acid was washed, then recrystallized with light petroleum (bp 35°-60° C.) to give 1.22 g 12-oxododecanoic acid (73% yield, m.p. 53°-54° C.) and hexanal. There was no attempt to isolate the hexanal.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1([C:26](=[O:40])[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])[CH:29]=2)[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH3:37][N:36]([CH3:38])[C:35](=[O:39])[O:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([NH:27][C:26]([C:13]2([CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:40])[CH:29]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(CNC(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(CNC(=O)OCc3ccccc3)CCNCC2)c1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 4-((benzyloxycarbonylamino)methyl)-4-(3-(dimethylcarbamoyloxy)phenylcarbamoyl)-piperidine-1-carboxylate from step C (0.245 g, 0.441 mmol) in MeOH (2 mL) was added 4 M HCl in dioxane (0.331 mL, 1.32 mmol). The reaction was heated at 50° C. for 1 hour, and then concentrated under vacuum, re-dissolved in MeOH and re-concentrated twice to give the title compound as the hydrochloride salt. MS (ES+) [M+H]+=455.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[CH3:22].[F-].[Cs+].[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:22][C:3]1[CH:4]=[C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:2]=1[C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)CCc1cccc(OCc2ccc(Br)c(C)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)CCc1cccc(OCc2ccc(-c3cccc(OC)c3)c(C)c2)c1
Temperature: 85 °C
Yield: 82.8 %

Procedure:
To a 2 dram vial charged with methyl ester 1.3 (0.0700 g, 0.193 mmol), tetrakis(triphenylphosphine)palladium (0) (0.0445 g, 0.0385 mmol), cesium fluoride (0.0356 mL, 0.964 mmol), and 3-methoxyphenylboronic acid (available from Aldrich) (0.0878 g, 0.578 mmol), was added DME (1 mL). The resulting mixture was then heated at 85° C. overnight. The reaction was allowed to cool and then filtered and concentrated. The crude product was purified by combiflash (0 to 20% EtOAc/hexanes) yielding 1.4 (0.0624 g, 82.9% yield). MS ESI (pos.) m/e: 391.1 (M+H)+.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[O:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]([OH:18])=O)[CH:7]=[CH:8][CH:9]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.Cl.[NH2:51][C:52]1[N:53]=[C:54]([CH2:57][C:58]2[S:62][C:61]([C:63](=[O:65])[CH3:64])=[CH:60][CH:59]=2)[S:55][CH:56]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:63]([C:61]1[S:62][C:58]([CH2:57][C:54]2[S:55][CH:56]=[C:52]([NH:51][C:16]([C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)=[O:18])[N:53]=2)=[CH:59][CH:60]=1)(=[O:65])[CH3:64]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Reactant: CC(=O)c1ccc(Cc2nc(N)cs2)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(Cc2nc(NC(=O)c3nc(C)oc3-c3cccc(Cl)c3)cs2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid (57 mg, 0.24 mmol) in CH2Cl2 (2.4 mL) was treated sequentially with DMAP (7 mg, 0.06 mmol), HOBt (39 mg, 0.29 mmol), EDC.HCl (114 mg, 0.60 mmol) and DIPEA (0.16 mL, 0.96 mmol) and the resulting mixture was stirred at rt for 30 min. This solution was then treated with 1-[5-(4-amino-thiazol-2-ylmethyl)-thiophen-2-yl]-ethanone hydrochloride (66 mg, 0.24 mmol) and the reaction mixture was stirred for 2 days at rt. CH2Cl2 (20 mL) was then added and the org. phase was washed with water (15 mL) followed by brine (15 mL). The org. phase was then dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (6:4 hept:EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.19. LC-MS-conditions 02: tR=1.18 min, [M+H]+=458.08.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[S:8][C:7]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1>C(O)(=O)C>[Br:1][CH:10]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:9]([C:7]1[S:8][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:17]
Reactant: BrBr
Reactant: O=C(Cc1ccncc1)c1ccc(Cl)s1
Solvent: CC(=O)O
Product: O=C(c1ccc(Cl)s1)C(Br)c1ccncc1
Reaction time: 1.5 h

Procedure:
At room temperature, 26.9 g (167 mmol) of bromine are added dropwise to a solution of 40.0 g (167 mmol) of 1-(5-chloro-2-thienyl)-2-(pyridin-4-yl)ethanone in 200 ml of acetic acid, and the mixture is stirred for 90 min. The resulting precipitate is filtered off, washed with MTBE and dried. This gives 64.5 g (96%) of the desired product; log P (pH2.7): 2.18 with MS (ESI): 315.9 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23].O>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][N:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[N:7][C:2]1=[O:1]
Reactant: Oc1nccc(C(F)(F)F)n1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(C(F)(F)F)ccn1CCCCCl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4.6 g (28.3 mmol) of 2-hydroxy-4-trifluoromethylpyrimidine were stirred in 60 ml of N,N-dimethylformamide (DMF) and 3.9 g (28.3 mmol) of K2CO3 at room temperature for 1 hour. Then 4.9 g (28.3 mmol) of 1-bromo-4-chlorobutane were added dropwise, and the reaction mixture was stirred at room temperature for 6 hours. Water was then added to the reaction mixture, and the aqueous mixture was extracted with diethyl ether. The aqueous phase was made alkaline by adding NaOH, and the aqueous phase was extracted with methylene chloride. The organic phase was then dried, the desiccant was removed by filtration, and the solvent was evaporated to dryness in vacuo; yield: 1.7 g.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]#[C:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[OH-].[Na+]>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]#[C:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)c1ccc(C#Cc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
966 mg (2.4 mmol) of the ester prepared in part (b) above and 20 ml of methanolic sodium hydroxide (2N) were introduced into a round-bottomed flask and heating was carried out at reflux for one hour. The reaction mixture was evaporated to dryness, the residue was taken up in water, acidification was carried out with concentrated hydrochloric acid and the solids which had precipitated were filtered.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:35])[C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)[CH2:16][C@H:15]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:42](OC1(O[Si](C)(C)C)CC1)[CH3:43]>C(Cl)(Cl)Cl>[F:32][C:31]([F:33])([F:34])[C:23]1[CH:22]=[C:21]([C:20]([N:17]2[CH2:18][CH2:19][CH:14]([N:11]3[CH2:12][CH2:13][N:8]([CH:6]4[CH2:43][CH2:42]4)[CH2:9][CH2:10]3)[CH:15]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:16]2)=[O:35])[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(C3CC3)CC2)C(c2ccccc2)C1

Procedure:
The title compound, MS: m/e=526.2 (M+H+), [α]58920=−6.17, [α]43620=−23.81, [α]36520=−74.09 (c=0.1134, chloroform), was prepared in accordance with the general method of example 114 (step1) and example 110 (step 2) from (3S,4R) or (3R,4S)-4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester and [(1-ethoxycyclopropyl)-oxy]trimethylsilane.
Reaction SMILES: [OH-].[Na+].C=O.[CH3:5]CCCCC.[CH3:11][C:12]1[C:16]([CH3:18])([CH3:17])[CH:15]([CH2:19][CH:20]=[O:21])[CH2:14][CH:13]=1>CO.O>[CH3:18][C:16]1([CH3:17])[C:12]([CH3:11])=[CH:13][CH2:14][CH:15]1[C:19](=[CH2:5])[CH:20]=[O:21]
Reactant: CC1=CCC(CC=O)C1(C)C
Reactant: CCCCCC
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C=O)C1CC=C(C)C1(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 215.6 %

Procedure:
A 3 liter 3 neck round bottomed flask was charged with 50 g of sodium hydroxide (1.25 moles) in 250 g of methanol. 200 g of paraformaldehyde, 500 g of hexane and 2.5 g of BHA were added and the flask was cooled to 0° C. With fast agitation 500 g of campholenic aldehyde at a purity of 88.9% (2.92 moles) were added dropwise over 70 minutes keeping the temperature at 0°-5° C. The batch was stirred for 3 hours at 0° C. Then 50 ml of water was added and the layers are separated. The water layer was back extracted with 250 ml of hexane. The hexane extracts were combined and washed with 2×500 ml of 10% sodium hydroxide and 3×500 ml of water. The batch was dried and afforded 1163 g of crude 2-(2,2,3-trimethylcyclopent-3-en-1-yl)propenal in hexane. A second batch was prepared analogously affording 1169 g of crude product.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][N:25]=1)[C:21]#[N:22]>C(O)CCC>[CH3:14][S:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([CH2:5][C:2]3[N:25]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]4=[N:17][CH:3]=3)[CH:16]=[CH:15][C:9]=2[N:10]=1
Reactant: N#Cc1ccnc(N)c1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Solvent: CCCCO
Product: CSc1nc2ccc(Cc3cnc4cc(C#N)ccn34)cc2s1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
A mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal (0.35 g, 1.3 mmol) and 2-aminoisonicotinonitrile (0.30 g, 2.6 mmol) in 1-butanol (15 mL) was heated at reflux overnight. After cooling to rt, the formed solid was collected and washed with water, then dried to afford 3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile as a white solid (0.27 g, 62%). 1H NMR (300 MHz, CDCl3) δ 8.45 (d, J=7.2 Hz, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.75 (s, 1H), 7.37 (dd, J=1.2, 7.8 Hz, 1H), 7.20 (dd, J=1.8, 7.2 Hz, 1H), 4.49 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 337 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]=[N+:19]=[N-:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1>ClCCl>[N:18]([S:15]([C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])=[CH:14][CH:13]=1)(=[O:16])=[O:17])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(N)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: ClCCl
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(NC(=O)/C=C\C(=O)O)cc1
Reaction time: 2 h

Procedure:
100 g maleic acid anhydride are dissolved in 1 liter dichloromethane and to this solution are added drop-wise 198 g of the 4-aminobenzenesulfonylazide (approximately 1 mol) prepared according to (3), dissolved in 400 ml dichloromethane. The reaction mixture is left standing for 2 hours at room temperature. The solution is then concentrated in a rotary evaporator to about 200 ml. The light brown product obtained is cooled, filtered, washed with a small amount of dichloromethane and finally dried.