Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:6](=[O:8])[CH:7]=1.[C:15]1(B(O)O)[C:28]2[S:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].N#N>O1CCOCC1.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>[C:25]1([C:2]2[O:3][C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:5][C:6](=[O:8])[CH:7]=2)[C:26]2[S:27][C:28]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:20][C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1cccc2c1Sc1ccccc1S2
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=c1cc(-c2cccc3c2Sc2ccccc2S3)oc(N2CCOCC2)c1
Temperature: 90 °C
Yield: 4.4 %

Procedure:
2-Chloro-6-morpholin-4-yl-pyran-4-one (3) (863 mg, 4 mmol), thianthrene-1-boronic acid (1.145 g, 4.4 mmol), and ground potassium carbonate (1.105 g, 8 mmol) were suspended in dioxane (10 ml) and degassed (sonication for 5 minutes then saturated with N2). Pd(PPh3)4 (231 mg, 0.2 mmol) was then added and the reaction mixture was then heated at 90° C. for 24 hours under a vigorous stirring and a N2 atmosphere. The solvent was removed in vacuo and the residue was then suspended in water 50 ml) and extracted with ethyl acetate (3×100 ml). The organics were combined, washed with saturated brine and dried over sodium sulphate. The solvent was removed in vacuo and the residue was purified by column chromatography (silica; ethyl acetate:ethanol; 9:1) to give the title compound as a white solid (70 mg, 4%). 1H-NMR (300 MHz, DMSO-d6): δH=3.44 (4H, t, J 5 Hz); 3.76 (4H, t, J 5 Hz); 5.57 (1H, d, J 2 Hz); 6.30 (1H, d, J 2 Hz); 7.43 (2H, m); 7.53 (1H, t, 8 Hz); 7.66 (3H, m); 8.49 (1H, dd, J land 8 Hz). m/z (LC-MS, ESP): 396 (M++1).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:45][O:44][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][N:19]1[C:20]2[C:25](=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[CH:22][CH:21]=2)[C:17]([C:14]2[N:15]=[C:16]3[C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:9][N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:11]3=[N:12][CH:13]=2)=[N:18]1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 100 °C
Yield: 82.6 %

Procedure:
A microwave vial was charged with 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (100 mg, 0.19 mmol), methyl 4-bromobutanoate (69 mg, 0.38 mmol), cesium carbonate (184 mg, 0.57 mmol) and DMF (0.85 ml). The vial was flushed with argon, sealed and heated in a microwave reactor at 100° C. for 2 h. The reaction was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 99 mg (83%) of 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-butyric acid methyl ester as a light yellow solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:7][CH:6]=[C:5]([CH:8]=[O:9])[CH:4]=1.B(F)(F)F.CCOCC.[CH3:21][C:22]([CH3:35])=[CH:23][CH2:24][CH2:25][C:26]([CH:33]=[CH2:34])=[CH:27][O:28][Si](C)(C)C>C(Cl)Cl>[OH:9][CH:8]([C:5]1[CH:4]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:7][CH:6]=1)[CH2:34][CH:33]=[C:26]([CH2:25][CH2:24][CH:23]=[C:22]([CH3:21])[CH3:35])[CH:27]=[O:28]
Reactant: C=CC(=CO[Si](C)(C)C)CCC=C(C)C
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)=CCCC(C=O)=CCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 5-trimethylsilyl-3-furanaldehyde (0.444 g, 2.6 mmol) in 5 ml methylene chloride at -60° under argon was added dropwise boron trifluoride etherate (0.33 ml, 2.7 mmol). After one to two minutes a solution of 2-(4-methyl-3-pentenyl)-1-trimethylsilyloxy-1,3-butadiene (0.604 g, 2.7 mmol) in 3 ml methylene chloride was added dropwise. The solution was stirred for 20 hours at -60°, quenched with saturated sodium bicarbonate solution, warmed to room temperature, and taken up in ethyl ether. The organic portion was washed twice with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give an orange oil which was complex by TLC. The mixture was purified by flash chromatography (silica, 30% ethyl acetate/hexane). Eluted last was the desired hydroxyaldehyde as an orange oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11](OC2C=CC=C(C)C=2)=[O:12])=[CH:2]1.[BH4-].[Na+].Cl.C1(C)C(O)=CC=CC=1>C(O)(C)C.O>[CH:6]1[CH:7]=[CH:8][C:9]2[NH:1][CH:2]=[C:3]([CH2:10][CH2:11][OH:12])[C:4]=2[CH:5]=1
Reactant: Cc1cccc(OC(=O)C(=O)c2c[nH]c3ccccc23)c1
Agent: Cc1ccccc1O
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CC(C)O
Product: OCCc1c[nH]c2ccccc12
Reaction time: 5 h

Procedure:
A stirred suspension of m-cresyl 3-indolylglyoxylate (55.8 g.) and sodium borohydride (22.7 g.) in isopropanol (300 ml.) was slowly heated to reflux and held for 5 hours. The cooled mixture was diluted with water (2 l.), acidified with hydrochloric acid and extracted with dichloromethane. The extract was washed with sodium carbonate solution, dried and evaporated to give a mobile oil smelling strongly of cresol. This was distilled at 0.5 - 1 mm and the fraction collected at 160°-200° vapour temperature was crystallised from toluene (60 ml.), giving tryptophol as white crystals m.p. 57°-59°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:24][O:25][CH:26](Br)[CH3:27]>CN(C)C=O>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([O:17][CH2:27][CH2:26][O:25][CH3:24])=[CH:7][C:8]=1[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1cc(C(C)(C)C)c(O)cc1C(C)(C)C
Reactant: COC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C(C)(C)C)c(OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
2,5-di-tert-butyl-4-methoxyphenol (9 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 ml). Cesium carbonate (13 mmol) and 1-bromoethyl methyl ether (9 mmol) were added to the solution. The reaction mixture was then stirred at room temperature overnight. After removal of the solvent, the residue was partitioned between dichloromethane (DCM) and aqueous NaHCO3 (0.1 M). The organic portion was separated and dried over Na2SO4 and then the solvent was removed under vacuum. The crude product was chromatographed (silica, hexanes/DCM from 5:1 to 1:1) to afford pure 1-methoxy-4-(2-methoxyethoxy)-2,5-di-tert-butyl-benzene in an 85% yield. 1H NMR (300 MHz, CDCl3): δ/ppm 6.84 (s, 1H), 6.83 (s, 1H), 4.11 (t, J=4.5 Hz, 2H), 3.78 (m, 5H), 3.45 (s, 3H), 1.38 (s, 9H), and 1.35 (s, 9H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)C.O.[NH2:18][NH2:19]>C(O)C>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH2:6][CH2:5][C:4]([NH:18][NH2:19])=[O:3])=[CH:8]1
Reactant: CCOC(=O)CCc1c[nH]c2ccccc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CCc1c[nH]c2ccccc12
Yield: 98 %

Procedure:
A solution of 3-(1H-Indol-3-yl)-propionic acid ethyl ester (4.30 g, 1 eq) and hydrazine hydrate (˜9.6 ml, 10 eq) in ethanol (70 ml) is heated at 60° C. overnight. The reaction mixture is concentrated under reduced pressure and diluted with methylene chloride. The new organic solution is washed with water, dried over MgSO4, filtered and evaporated to dryness, to afford the title compound as white solid (3.9 g, 98% yield), which is used as such for the next step.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[C:3](I)([F:5])[F:4].C1([Mg]Br)C=CC=CC=1.[Cl:20][CH2:21][C:22]([CH2:24][Cl:25])=[O:23].C(O)(=O)C>C(OCC)C.O>[Cl:20][CH2:21][C:22]([C:3]([F:5])([F:4])[C:2]([F:11])([F:1])[C:7]([F:10])([F:9])[F:8])([OH:23])[CH2:24][Cl:25]
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Reactant: O=C(CCl)CCl
Agent: Br[Mg]c1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: OC(CCl)(CCl)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Heptafluoropropyliodide (5 g, 6.9 mmole) was stirred at -78° C. in dry diethylether (20 ml). A solution of phenylmagnesium bromide in ethyl ether (10 ml of a 1.88 M solution) was added over a half-hour period. When this addition was complete, the reaction mixture was stirred at -20° C. for one hour. To this solution was added, at -78° C., 1,3-dichloroacetone (3.25 g, 25.6 mmole) in dry diethylether (20 ml) dropwise, keeping the temperature below -65° C. The mixture was then stirred four hours between -20° and -50° C. Glacial acetic acid (3 ml) in diethylether (5 ml) was added slowly followed by water (15 ml). The mixture was allowed to warm to 5° C. and then the phases were separated. The aqueous phase was washed with ether (2×25 ml). The ethereal extracts were combined, dried (MgSO4) and evaporated to give crude 1,3-dichloro-2-(heptafluoropropyl)propan-2-ol, which was used directly in the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1.[H-].[Na+].I[CH3:22].[NH4+].[OH-]>CC#N.C(Cl)(Cl)Cl.CC(=O)OCC>[CH3:22][N:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nccs2)C1
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(c1nccs1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A solution of 8.73 g (32.4 mmol) of tert.-butyl 3-(thiazol-2-ylamino)pyrrolidine-1-carboxylate (synthesis described in Example 11) in MeCN (120 ml) was combined with 1.56 g (38.9 mmol, 60% strength in mineral oil) of sodium hydride and stirred for 30 min at RT. 4.04 ml (64.8 mmol) of iodomethane were then added and stirring was continued for a further 3 h at RT. After addition of a conc. aq. NH4OH soln. (30 ml), the phases were separated and the aqueous phase was extracted with EA. The collected organic phases were dried over MgSO4, filtered and evaporated under a vacuum. 3.16 g (11.2 mmol, 34%) of tert.-butyl 3-(methyl(thiazol-2-yl)amino)pyrrolidine-1-carboxylate were obtained by CC (chloroform/EA 20:1) with the residue.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.ClCCl.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>[CH3:12][O:11][C:5]1[C:6]2[CH:7]=[N:8][S:9][C:10]=2[C:2]([CH3:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)c2sncc12
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(C)c2sncc12
Temperature: 110 °C
Yield: 26.1 %

Procedure:
A solution of 7-bromo-4-methoxy-benzo[d]isothiazole (460 mg, 1.88 mmol), K2CO3 (780 mg, 5.64 mmol), and Pd(PPh3)4 (217 mg, 0.188 mmol) in 1,4-dioxane (5 mL) was added trimethylboroxine (290 μL, 2.07 mmol) and the solution was heated to 110° C. for 18 h. The reaction was cooled to rt and diluted with water and dichloromethane. The organic phase was separated and the aqueous phase was extracted with 2×30 mL dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 1:10] to yield 4-methoxy-7-methyl-benzo[d]isothiazole (88 mg, 26%). A method similar to that described for the preparation of benzo[d]isothiazol-4-ol (above) using 4-methoxy-7-methyl-benzo[d]isothiazole (88 mg, 0.491 mmol) and pyridine hydrochloride (567 mg, 5 mol) gave the title compound (30 mg, 37%): δH (300 MHz, CDCl3): 8.99 (1H, s), 7.15 (1H, d, J=7.5 Hz), 6.70 (1H, d, J=7.5 Hz), 2.45 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([Br:21])=[C:17]([CH3:20])[CH:18]=2)[CH:13]=[C:12]1[CH:22](C(C)(C)C(C)C)O[SiH](C)C)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[F-].[NH4+]>CO>[C:1]([O:5][C:6]([N:7]1[CH2:8][C@@H:9]([CH3:10])[N:11]2[C:19]3[CH:18]=[C:17]([CH3:20])[C:16]([Br:21])=[CH:15][C:14]=3[CH:13]=[C:12]2[CH2:22]1)=[O:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(cc1Br)cc(C(O[SiH](C)C)C(C)(C)C(C)C)n2[C@H](C)CNC(=O)OC(C)(C)C
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc2c(cc1Br)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A mixture of 0.75 g (R)-(2-{5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-indol-1-yl}-propyl)-carbamic acid tert-butyl ester and 0.52 g ammonium fluoride in 7.5 ml methanol was stirred 18 h at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with 10% citric acid, 10% sodium bicarbonate and brine, dried over magnesium sulfate and evaporated to dryness. The residue was taken up in 6 ml dichloromethane and 0.59 g manganese dioxide was added. The mixture was stirred 2 h at room temperature. The solids were removed by filtration over dicalite and the filtrate was evaporated to dryness. The residue was taken up in 5 ml dichloromethane and 0.072 ml acetic acid and 1.00 g molecular sieve (powder, 4 Å) were added. To the resulting suspension was added 0.536 g triacetoxyborohydride, and the mixture was stirred 1 h at room temperature. Another 0.536 g triacetoxyborohydride was added and the mixture was stirred 1 h. The solids were removed by filtration over dicalite and the filtrate was purified by chromatography on silica gel with hexane:ethyl acetate=2:1 to yield 0.295 g of the title compound as a yellow solid melting at 113–114° C. after crystallisation from hexane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH3:22])[C:17]([C:19](O)=[O:20])=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH3:22])[C:17]([C:19]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[O:20])=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2ncnn3cc(C(=O)O)c(C)c23)cc1O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2ncnn3cc(C(=O)N4CCN(C)CC4)c(C)c23)cc1O
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a solution of Example 20 (7 mg, 0.023 mmol) in DMF (0.4 mL) at 25° C. was added N-methyl piperazine (3.5 μL, 0.03 mmol), 1-hydroxybenzotriazole (3 mg, 0.023 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7 mg, 0.05 mmol). After 24 hrs., the mixture was concentrated, diluted with water (2 mL), and extracted with ethyl acetate (5×2 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (2×5 mL). The crude material was purified by chromatography on silica gel eluting with a gradient of 5-10% methanol in chloroform to provide 6.23 mg (70%) of the title compound as white solid. MS: [M+H]+=381.3; 1H NMR (CDCl3): δ 7.76 (s, 1H), 7.48 (s, 1H), 7.08 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 3.82-3.44 (m, 2H), 2.54 (s, 3H), 2.53-2.28 (d, 6H), 2.27 (s, 3H), 2.10 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:12]=[C:11]([CH:13]([CH3:16])[CH2:14][OH:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:19]S(O)(=O)=O>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:12]=[C:11]([CH:13]([CH3:16])[C:14]([OH:19])=[O:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CC(CO)c1cc(C(=O)c2ccc(Cl)cc2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CC(C(=O)O)c1cc(C(=O)c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 11.0 g of 2-[3-(4-chlorobenzoyl)-isoxazol-5-yl]propan-1-ol in 1000 ml of CH2Cl2, a few crystals of tetra-n-butylammonium hydrogen sulfate and 150 ml of 9M H2SO4 was added 12.3 g of pulverized K2Cr2O7. The resulting mixture was stirred at room temperature for 1.5 hour. After allowing the mixture to settle, it was decanted from the unreacted dichromate. The aqueous phase was separated and the organics were washed with water and brine, and dried over MgSO4. Concentration of the product gave 8.0 g of a solid. Recrystallization from toluene with norite for decolorizing gave 2.0 g of a solid, m.p. 119°-123°. A second recrystallization from toluene gave 1.6 g (13%) of a solid, m.p. 122.5°-124.5°.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([N:34]5C(=O)C6=CC(C)=CC=C6C5=O)[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:46])[C:14]2=[O:15])[N:3]=1.O.NN>C(O)C>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:28]2[CH2:29][C@H:30]([NH2:34])[CH2:31][CH2:32][CH2:33]2)=[N:18][C:17]2[N:16]([CH3:46])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccc(C)cc4C3=O)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Agent: NN
Solvent: O
Solvent: CCO
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 79 °C

Procedure:
In a clean round bottom flask, 9 ml of ethanol, 90 mg of 1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-4-methylphthalimidopiperidin-1-yl)-xanthine & 0.9 ml of hydrazine hydrate were charged. The temperature of the reaction mass was raised to 78-80° C. & the reaction mass was maintained for 3 hours. The reaction mass was cooled to 50° C. & ethanol was distilled off. 9 ml methylene dichloride was added to the obtained residue & stirred at RT to get the solid. Undesired solid was filtered. The filtrate was concentrated & 9 ml methyl tert butyl ether was added to the residue to get the solid Linagliptin. Reaction mass was stirred at RT & filtered. Wet cake was washed with 2 ml IPA. Dry wt 45 mg
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26](Cl)=O.O=P(Cl)(Cl)Cl>>[CH3:14][O:15][C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1cccc(CCC(=O)Cl)c1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)c1OC

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol), TEA (0.153 ml; 1.1 mmol), 2,3-dimethoxyphenylpropionylchloride (228 mg, 1.1 mmol) and POCl3 (0.5 ml; 5.5 mmol) as described in method 1; yield: 0.016 mg (4.6%); MS m/z; 351.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.06-3.10 (m, 2H); 3.17-3.21 (m, 2H); 3.73 (s, 3H); 3.79 (s, 3H); 6.82-6.84 (m, 1H); 6.90-6.92 (m, 1H); 6.95-6.99 (m, 1H); 7.75-7.77 (m, 1H); 7.80-7.82 (m, 1H); 8.14 (br s, 1H); 8.41 (s, 1H); HPLC (METHOD [A]): rt 11.49 min (94.5%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[C:15]([F:25])=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.II.O[PH2]=O.[OH-].[Na+]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:14]3[C:15]([F:25])=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(O)(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: II
Agent: O=[PH2]O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reaction time: 0.08 h

Procedure:
(rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(5,7-difluoro-quinolin-6-yl)-ethanol (Stage 182.2, 570 mg, 1.58 mmol), iodine (1.203 g, 4.74 mmol) and H3PO2 (1.293 mL of a 50% aqueous solution, 23.7 mmol) were charged together with acetic acid (16 mL) in a microwave vial. The mixture was subjected to MW-irradiation at 150° C. for 5 min. It was then taken up with water and basified with NaOH (2.5 M). It was extracted with EtOAc twice and the organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The title compound was obtained as a yellow solid (tR 1.1 min (conditions 2), MH+=346).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][CH:5]([O:7]COCCOC)[C:4]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:14][CH3:15])[O:3]1.CO.Cl>C(OCC)C>[CH3:25][C:2]1([CH3:1])[CH2:6][CH:5]([OH:7])[C:4]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:14][CH3:15])[O:3]1
Reactant: CCC1(COCc2ccccc2)OC(C)(C)CC1OCOCCOC
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCC1(COCc2ccccc2)OC(C)(C)CC1O
Yield: 91.4 %

Procedure:
The compound of Example 25 (3.85 g) was added to methanol (50 ml) containing 0.6 ml of 36% hydrochloric acid and the resulting mixture was refluxed for 21/2 hours. The mixture was then cooled and the methanol was evaporated to give an oily residue. This residue was dissolved in diethyl ether, washed with brine, dried over magnesium sulphate and evaporated to give 2.64 g (91.7%) of the pure desired product. This product was shown to be pure, and to consist of a mixture of isomers, by thin layer chromatography.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:52][O:53][C:54]1[CH:66]=[CH:65][C:57]([CH2:58][C:59]2[S:63][C:62]([NH2:64])=[N:61][CH:60]=2)=[CH:56][CH:55]=1>CN(C=O)C.O>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[NH:64][C:62]1[S:63][C:59]([CH2:58][C:57]2[CH:65]=[CH:66][C:54]([O:53][CH3:52])=[CH:55][CH:56]=2)=[CH:60][N:61]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(Cc2cnc(N)s2)cc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cc2cnc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Z-Pro-OH (0.96 g, 3.84 mmol), HATU (1.46 g, 3.84 mmol), and DIEA (0.094 mL, 5.4 mmol) in DMF (30 mL) was stirred at room temperature for 1 hour. 1 mL of this solution was added to 10 mg of 5-(4-Methoxy-benzyl)-thiazol-2-ylamine and reaction mixture stirred at room temperature overnight. The resulting mixture was diluted with DMF (5 mL) and water (0.5 mL) and purified using reverse phase HPLC to furnish the corresponding product. MS: 452.1 (M+H+)