Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][C:3]=1[Cl:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Cl:24][C:3]1[CH:4]=[C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)[CH:22]=[CH:23][C:2]=1[NH:1][C:39]([C:34]1[C:33](=[O:42])[N:32]([C:29]2[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=2)[C:37]([CH3:38])=[CH:36][CH:35]=1)=[O:40]
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1Cl
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2Cl)c(=O)n1-c1ccc(F)cc1
Yield: 93.6 %

Procedure:
Using N-[6-(4-amino-3-chlorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (160 mg, 0.467 mmol), 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (150 mg, 0.607 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (161 μL, 0.934 mmol) and HATU (230.8 mg, 0.607 mmol) and in the same manner as in Example 60, the title compound (250 mg, 94%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH3:10]
Reactant: Oc1c(F)cccc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(F)cccc1F
Yield: 77.9 %

Procedure:
20 g (153.74 mmol) of 2,6-difluorophenol is dissolved in 200 ml of acetone and mixed under nitrogen with 42.5 g (307.48 mmol) of potassium carbonate. After 19.1 ml of methyl iodide (2 equivalents) is added, it is refluxed for three and one-half hours. After cooling, the reaction mixture is filtered, the filter residue is washed with acetone, and the filtrate is spun in until a dry state is reached. The residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 17.27 g (77.9%) of the desired product is obtained. It should be noted that the product is slightly volatile. The bath temperature should not exceed 30° C., and the vacuum of the rotary evaporator is to be adapted.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:8](F)=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13].[CH2:16]([O:23][C:24]([C:26]1[CH:32]=[CH:31][C:29]([O-:30])=[CH:28][CH:27]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[K+].[K]>CN(C)C=O>[CH2:16]([O:23][C:24]([C:26]1[CH:27]=[CH:28][C:29]([O:30][C:8]2[C:7]([F:10])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=2[C:2]([F:1])([F:15])[F:14])=[CH:31][CH:32]=1)=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1c(F)c(F)c(C(F)(F)F)c(F)c1F
Reactant: O=C(OCc1ccccc1)c1ccc([O-])cc1
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(F)c(F)c2C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
35.4 g of octafluorotoluene (0.15 mol) are dissolved in 400 ml of dimethylformamide, the solution is cooled to 0° C. using a cryostat, and a solution of 40 g of potassium 4-benzyloxycarbonylphenoxide (0.15 mol) in 300 ml of dimethylformamide is then added drop wise over the course of 2 hours. After 24 hours at 0° C., the potassium salt has reacted. The dimethylformamide is then removed in a rotary evaporator, the residue is taken up in a little tetrahydrofuran, and the solution is filtered through a silica-gel column. The clear solution obtained is evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is then stirred in n-hexane, filtered off through a fluted filter and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 95%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(-c2ccncc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A mixture of ethyl 4-(4-pyridyl)benzoate (1.0 g), 1 N NaOH (8.8 ml) and ethanol (8.8 ml) was stirred at room temperature for 1 hour and diluted with water, to which was added 1 N hydrochloric acid (8.8 ml) to give the title compound as crystals (0.76 g, 86.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[NH:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.[C:19](Cl)([Cl:21])=[S:20]>CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[N:4]([CH2:5][CH2:6][CH3:7])[C:19]([Cl:21])=[S:20]
Reactant: S=C(Cl)Cl
Reactant: CCCNc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCN(C(=S)Cl)c1ccccc1Cl
Temperature: 25 °C

Procedure:
A solution of 25.4 g. 2-chloro-N-propylaniline and 15.15 g. dry triethylamine in 200 ml. dry ether was added to a solution of 13 ml. thiophosgene in 200 ml. of the same solvent at -20° C. The reaction mixture was allowed to warm to room temperature and then filtered, the filtered solid being washed with ether. The ethereal extract was added to the ethereal liquor and after drying over sodium sulphate, was evaporated to give a dark oil. On standing further solid precipitated, which was then separated from the oil. The oily filtrate was distilled to give the product N-2-chlorophenyl-N-propyl(thiocarbamoyl) chloride, b.p. 119°-120° C./0.4 mm. Hg.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=1)[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:18][CH2:17]1)=[O:11])=[O:6].[OH:41][C:42]1[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[OH:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=2)[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)=[O:11])=[O:6])=[CH:44][CH:43]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NCCNC(=O)c1cccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCNCC(=O)c2cccc(C(=O)NCCNCc3ccc(O)cc3)c2)CC1

Procedure:
A solution of biphenyl-2-ylcarbamic acid 1-(2-{[3-(2-aminoethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (9.31 g, 17.1 mmol; prepared as described in Preparation 8) and 4-hydroxybenzaldehyde (2.30 g, 18.8 mmol, 1.1 eq) in 125 mL MeOH was stirred at room temperature for 2 hours. NaBH(OAc)3 (7.26 g, 34.2 mmol, 2.0 eq) was added to the reaction at room temperature in two portions separated in one hour interval. The reaction was stirred for an additional hour before being concentrated under vacuum. The residue was taken up in 100 mL DCM and stirred with 100 mL of 1.0 N HCl for 1 hour. The aqueous phase was adjusted to pH 9 using 10.0 N NaOH. The mixture was stirred for an additional 10 minutes. The organic phase was separated, dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified using silica gel chromatography (7% MeOH in CH2Cl2 with 1% NH4OH as eluent). The title compound was obtained as an off-white solid (8.08 g, 73%). MS m/z: [M+H+] calcd for C38H43N5O5, 650.34; found, 650.2.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](O)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20].[OH-].[NH4+]>O>[S:20]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:10]1[CH:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1
Reactant: Nc1ccccc1S
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N1CCC(c2nc3ccccc3s2)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a mixture of 1.43 g of 1-acetylpiperidine-4-carboxylic acid and 1.05 g of 2-aminothiophenol was added 5 mL of polyphosphoric acid. After stirring at 110° C. for 18 hours, the reaction was cooled to 40° C. The syrup was poured onto ice and water was added to keep the solution temperature below 10° C. The resulting dark brown solution was basified with ammonium hydroxide. Aqueous phase was extracted with EtOAC (3×). The combined organic phases were washed with brine and dried over anhydrous MgSO4. Concentration under reduced pressure afforded 1.41 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH:16]([CH3:18])[NH:15][CH:14]([CH3:19])[CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH:14]([CH3:19])[N:15]([C:28]([NH:27][C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)=[O:29])[CH:16]([CH3:18])[CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1CN(c2ccnc3cc(Cl)ccc23)CC(C)N1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CO
Solvent: ClCCl
Product: CC1CN(c2ccnc3cc(Cl)ccc23)CC(C)N1C(=O)Nc1ccc(F)cc1

Procedure:
7-Chloro-4-(3,5-dimethylpiperazin-1-yl)quinoline (100 mg, 0.36 mmol) and 4-fluorophenyl isocyanate (70 mg, 0.51 mmol) are reacted according to method C yielding the title product as colorless solid after column chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[N:15]=1)=[CH2:2].[CH3:17][NH:18][CH3:19]>C(Cl)Cl.CO>[CH3:17][N:18]([CH3:19])[CH2:2][CH2:1][C:3]1[S:4][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[N:15]=1
Reactant: CNC
Reactant: C=Cc1nc2c([nH]c(=O)c3ccccc32)s1
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCc1nc2c([nH]c(=O)c3ccccc32)s1
Temperature: 65 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
To a suspension of 2-vinyl-4H-1,3-thiazolo[5,4-c]isoquinolin-5-one (0.05 g, 0.22 mmol) and CH2Cl2/methanol (6 ml; 1/1) was added dimethylamine (0.33 ml of 2M solution in THF, 0.66 mmol). After stirring at 65° C. for 48 hours, the reaction mixture was concentrated under reduced pressure and purified by flash-chromatography (CH2Cl2/methanol, 90/10). Recrystallization from methanol/diethyl ether yielded 0.038 g (a 63% yield) of the title compound as a white solid. m.p. 236-240° C. (dec.); 1H NMR (400 MHz, DMSO) δ 2.85 (s, 6H, (CH2)2N(CH3)2), 3.52-3.56 (m, 4H, (CH2)2N(CH3)2), 7.56-7.59 (m, 1H, Ar), 7.84-7.87 (m, 1H, Ar), 8.19-8.26 (m, 2H, Ar), 12.37 (bs, NH); 13C NMR (100.6 MHz, DMSO) δ 29.71, 44.26, 56.79, 124.03, 125.74, 128.69, 129.79, 133.45, 134.44, 135.15, 158.51, 162.72.
Reaction SMILES: O[C:2]1[CH:10]=CC=C[C:3]=1C([O-])=O.C[O:12][C:13](=[O:28])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:15]=1[OH:27]>>[CH2:10]([O:27][C:15]1[CH:16]=[CH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:19][C:14]=1[C:13]([OH:12])=[O:28])[CH:2]=[CH2:3]
Reactant: O=C([O-])c1ccccc1O
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)ccc1O
Product: C=CCOc1ccc(-c2ccc(F)cc2)cc1C(=O)O

Procedure:
When the 2-hydroxy-benzoate compounds obtained from Example 9 are used in place of methyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate in the above example, there are obtained the corresponding allyloxy-benzoic acid compounds.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N.O.CC#N>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=[O:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Solvent: CC#N
Solvent: O
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously as described for the title compound under E in Scheme 5 from (3S,4R)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. TLC, Rf (CH2CO2/MeOH 95:5)=0.3. tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.16 min.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:10]=[C:9]([CH:11]=[CH2:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C(=O)(O)[O-].[Na+].Cl.[NH2:21][OH:22]>CC(O)C.C(OCC)(=O)C>[OH:22][N:21]=[C:5]([NH2:6])[C:4]1[CH:7]=[CH:8][C:9]([CH:11]=[CH2:12])=[CH:10][C:3]=1[C:2]([F:14])([F:13])[F:1]
Reactant: NO
Reactant: C=Cc1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C=Cc1ccc(C(N)=NO)c(C(F)(F)F)c1
Temperature: 85 °C
Yield: 87.6 %

Procedure:
To a mixture of 2-(trifluoromethyl)-4-vinylbenzonitrile (450 mg, 2.282 mmol) and sodium bicarbonate (767 mg, 9.13 mmol) in 2-propanol (10 mL) was added hydroxylamine hydrochloride (317 mg, 4.56 mmol). The reaction mixture was heated at 85° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated to give 460 mg of N′-hydroxy-2-(trifluoromethyl)-4-vinylbenzimidamide. MS (m+1)=231. HPLC Peak RT=0.78 minutes (Analytical Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(OC([NH:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:34][CH:35]([O:39][CH:40]([CH3:42])[CH3:41])[C:36]([O-:38])=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])=O)(C)(C)C>>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:34][CH:35]([O:39][CH:40]([CH3:42])[CH3:41])[C:36]([OH:38])=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])=[O:6]
Reactant: O=C(O)c1ccc(OC2CCCC2)cc1Cl
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)OC(C)(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(OC2CCCC2)cc1Cl

Procedure:
Using 2-chloro-4-cyclopentyloxybenzoic acid and 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2-chloro-4-cyclopentyloxybenzoyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([C@@H:25](O)[CH3:26])[CH:22]=[CH:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]([C@H:25]([O:17][C:14]2[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=2)[CH3:26])[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: C[C@H](O)c1cccc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(O[C@H](C)c2cccc(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and (1S)-1-(3-chlorophenyl)ethanol (99 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (142 mg, yield: 90%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1([O:17][C:18](N(C)C)=[N+](C)C)[C:12]2N=CC=CC=2N=N1.CONC.C(N(CC)CC)C.[CH:36]1([CH2:39][C:40]([OH:42])=O)[CH2:38][CH2:37]1>C(Cl)Cl>[CH:36]1([CH2:39][C:40]([N:8]([O:17][CH3:18])[CH3:12])=[O:42])[CH2:38][CH2:37]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)CC1CC1
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CC1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (19.0 g), N-methoxymethanamine (5.0 g), and triethylamine (15.1 g) were added to a solution of 2-cyclopropylacetic acid (5.0 g) in CH2Cl2 (200 mL) at 0° C. The mixture was stirred at room temperature for 3 h. The reaction mixture was then washed with water and the aqueous washing phase was extracted with ethyl acetate (5×50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 20:1→5:1) to give the title compound. Yield: 4.1 g (58% of theory).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[CH:10][N:9]=1.[CH3:15][C:16]1[NH:17][C:18]2[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([C:26]([F:29])([F:28])[F:27])[C:19]=2[N:20]=1>CN(C=O)C>[Cl:14][C:12]1[N:11]=[CH:10][N:9]=[C:8]([O:25][C:23]2[CH:22]=[C:21]([C:26]([F:29])([F:28])[F:27])[C:19]3[N:20]=[C:16]([CH3:15])[NH:17][C:18]=3[CH:24]=2)[CH:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1nc2c(C(F)(F)F)cc(O)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c(C(F)(F)F)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
221 mg (1.60 mmol) potassium carbonate were added at RT to 245 mg (1.60 mmol) 4,6-dichloropyrimidine and 330 mg (1.52 mmol) 2-methyl-7-trifluoromethyl-3H-benzimidazole-5-ol in 5.0 mL DMF and the mixture was stirred overnight at RT. The reaction mixture was poured onto water. The precipitate formed was filtered off, washed with water and dried.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])[C:8]([Cl:22])=[N:7][C:6]=2[NH:5][C:3]1=[O:4].[C:23]1(OB(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])[C:8]([Cl:22])=[N:7][C:6]=2[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]1=[O:4]
Reactant: OB(O)Oc1ccccc1
Reactant: Cn1c(=O)[nH]c2nc(Cl)n(Cc3ccccc3C#N)c2c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2C#N)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 829 mg of 1-methyl-7-(2-cyano-benzyl)-8-chloro-xanthine, 640 mg of phenylboric acid, 509 mg of anhydrous copper acetate and 0.43 ml of pyridine in 20 ml methylene chloride is stirred for four days at ambient temperature in the presence of 100 mg of 4 Å molecular sieves. Then another 320 mg of phenylboric acid are added and the reaction mixture is stirred for another day at ambient temperature. For working up the mixture is filtered through talc and washed with ethyl acetate. The filtrate is evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate (7:3 to 1:1) as eluant.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH2:19][CH2:20]2)=[O:14])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1cc(NC(=O)N2CCNCC2)c(OC)nc1C
Reactant: COc1ccc(CCl)cc1
Product: CCc1cc(NC(=O)N2CCN(Cc3ccc(OC)cc3)CC2)c(OC)nc1C
Yield: 42 %

Procedure:
1-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonylpiperazine and 4-methoxybenzylchloride were reacted by the same way with the example 72 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[N-:39]=[N+:40]=[N-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CCOCC>[N:1]([C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[N+:39]=[N-:40]
Reactant: Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
This reaction was performed in a dark environment. To a cold (0–5° C.) solution of 2-(3-aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine (46 mg, 0.10 mmol) in acetic acid (3 mL) was added sodium nitrite (0.31 mL of a 25 mg/mL aqueous stock solution, 7.7 mg, 0.11 mmol). The mixture turned dark and was stirred for 20 minutes at 0° C. Sodium azide was then added and the mixture was stirred for 20 minutes, allowed to warm to room temperature and stirred for an additional 10 minutes. Ether was added and the mixture was neutralized with sodium bicarbonate. Aqueous workup was followed by drying over sodium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 2:1 hexanes-ethyl acetate) provided 2-(3-azidophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine (25 mg, 52%) as a yellow solid. 1H NMR (CDCl3): δ 8.05 (d, 1 H), 7.75 (d, 1 H), 7.45–7.42 (m, 3 H), 7.36 (t, 1 H), 7.13 (m, 1 H), 6.33 (d, 1 H), 6.10–6.03 (m, 2 H), 5.10 (d, 1 H), 4.36 (m, 1 H), 4.05 (m, 1 H), 2.20–1.54 (m, 16 H); MS m/z 480 (M+1); IR 2109 cm−1.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH:10]([NH2:12])[CH3:11].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH:10]([NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH3:11]
Reactant: CCOC(=O)Cl
Reactant: COC(OC)C(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(C)C(OC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 g (0.73 mol) of ethyl chloroformate are added dropwise with ice-cooling to 86.2 g (0.72 mol) of 2-aminopropionaldehyde dimethyl acetal in 350 ml of toluene and 32 g (0.8 mol) of NaOH in 300 ml of water. The mixture is stirred for a further 2 hours at room temperature, the organic phase is separated off, the aqueous phase is extracted using toluene and the toluene solutions are dried over K2CO3. The extracts are concentrated and the residue is distilled.