Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:6]=2[CH:19]=1.C1(C)C=CC=CC=1>C(Cl)Cl.C(C(O)=O)(F)(F)F>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:19]=1
Reactant: Cc1cc(C)c2oc(=O)n(CC(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(C)c2oc(=O)n(CC(=O)O)c2c1

Procedure:
A solution of the tert-butyl (5,7-dimethyl-2-oxo-1,3-benzoxazol-3(2H)-yl)acetate from Step B in CH2Cl2 (0.7 mL) and CF3CO2H (0.3 mL) was stood at ambient temperature for 2 h. Toluene (5 mL) was added and the mixture was concentrated in vacuo to give the title compound as a dark solid. MS: m/z=222 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH2:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[I:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:30])=[C:25]([CH:29]=1)[C:26](O)=[O:27]>>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:18][C:26](=[O:27])[C:25]1[CH:29]=[C:21]([I:20])[CH:22]=[CH:23][C:24]=1[NH2:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc(I)cc1C(=O)O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(I)ccc1N
Yield: 74.6 %

Procedure:
(2S)-(2-Amino-5-iodo-benzoyl-amino)-3-biphenyl-4-yl-propionic acid methyl ester (1.53 g) was prepared from (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 4.1 mmol), 5-iodo-2-amino-benzoic acid (1.23 g, 4.9 mmol) as described in general procedure A.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].C1C[CH2:35][N:34]2[C:29](=NCC[CH2:33]2)[CH2:28]C1.C(NC)C.[O:41]1CCOCC1>>[CH2:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([C@@H:23]([NH:25][C:33](=[O:41])[N:34]([CH2:29][CH3:28])[CH3:35])[CH3:24])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)[CH3:3]
Reactant: CCOc1ccc(C2CCN(c3ccc([C@H](C)N)cc3)CC2)cc1
Reactant: C1COCCO1
Reactant: C1CCC2=NCCCN2CC1
Agent: CCNC
Agent: Cl
Product: CCOc1ccc(C2CCN(c3ccc([C@H](C)NC(=O)N(C)CC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 36 mg (0.10 mmol) (S)-1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethylamine hydrochloride (XII.1) in 1.5 mL 1,4-dioxane are added 37 μL (0.25 mmol) DBU and 33 mg (0.20 mmol) CDT. The mixture is stirred for 5 min at rt. Subsequently 7.1 mg (0.12 mmol) ethyl-methyl-amine in 1.0 mL 1,4-dioxane are added and stirring is continued for 12 h at rt. The solvent is removed under reduced pressure, the residue is taken up in DMF and purified by HPLC (Sunfire, narrow gradients, water (+0.1% TFA)/methanol) to yield the desired product.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Cl)[CH3:2].[C:10]([OH:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O.CN(C=O)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:18][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(CCl)OCC
Reactant: O=C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(COC(=O)c1ccccc1)OCC
Temperature: 25 °C
Yield: 55.7 %

Procedure:
Chloroacetaldehyde diethyl acetal (2.00 g), benzoic acid (2.16 g), potassium iodide (0.27 g), potassium carbonate (1.11 g) and DMF (20 mL) were placed in a three-neck flask, followed by refluxing. Twenty hours later, the reaction mixture was cooled to room temperature, and water (30 mL) and ethyl acetate (80 mL) were added thereto, followed by stirring. After filtration, the organic layer was separated, was subjected to vacuum concentration and thereby yielded the target compound (1.74 g) in a yield of 56%.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:34][CH3:35])[C:5]=1[OH:36])(=[O:3])[CH3:2].[N-:37]=[N+:38]=[N-:39].[Na+].Cl.C(N(CC)CC)C>>[CH2:34]([C:6]1[C:5]([OH:36])=[C:4]([C:1](=[O:3])[CH3:2])[CH:33]=[CH:32][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([C:20]3[N:37]=[N:38][NH:39][N:21]=3)[CH:18]=2)=[CH:12][CH:11]=1)[CH3:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1c(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCc1c(OCc2ccc(C(OC3CCCCO3)c3cccc(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O

Procedure:
Employing the procedure of Example 1 using 3-[[4-(4-acetyl-2-ethyl-3-hydroxy-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (869 mg, 1.79 mmol), sodium azide (1.16 g, 17.9 mmol), and triethylamine hydrochloride (2.46 g, 17.9 mmol), the title product is obtained as a clear oil (900 mg, 66%): MS (esi negative) m/z (rel intensity) 527 (100).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[N:10]=[N:9]2)=[CH:5][CH:4]=1.[C:18]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][NH2:33])=[C:27]([CH3:34])[N:26]=1)([CH3:21])([CH3:20])[CH3:19].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>CN(C=O)C>[C:18]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][NH:33][C:13]([C:11]2[N:10]=[N:9][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:17][CH:16]=3)[CH:12]=2)=[O:15])=[C:27]([CH3:34])[N:26]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)c1cn(Cc2ccc(CO)cc2)nn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(CO)cc2)nn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-hydroxymethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid (0.95 g, 4.07 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.024 g, 4.07 mmol), HATU (2.013 g, 5.30 mmol) and DIPEA (2.85 mL, 16.29 mmol) in 50 mL DMF was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with 1 n HCl solution and saturated sodium bicarbonate solution. The organic solution was dried over MgSO4, filtered and concentrated to yield the crude product which was used in the next step without further purification. LCMS (Method A) RtA=1.279; [M+H]+=467.0.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C(#N)C>[CH3:12][N:13]([CH:15]=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(=CN(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.9 %

Procedure:
Ethyl acetoacetate (35.4 g) was dissolved in acetonitrile (200 ml), and dimethylformamide dimethyl acetal (30.9 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give ethyl 2-dimethylaminomethyleneacetoacetate (50.4 g, Y.:99%) as a red oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.C(N(CC)CC)C.CN([C:38]([O:42][N:43]1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.CNO>CN(C=O)C>[CH3:38][O:42][NH:43][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)[C:10]=2[C:17]=1[CH3:18])=[O:21]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCOC3)c12
Agent: CNO
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCOC3)c2c1C
Reaction time: 0.17 h

Procedure:
4-{4-Fluoro-2-[(R)-(tetrahydro-furan-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (100 mg) was dissolved in DMF (3 ml) and triethylamine (79 μl) was added. To this mixture TBTU (90 mg) was added and the reaction was stirred for 10 mins. After this time methylhydroxylamine hydrochloride (27 mg) was added and the reaction was stirred at 40° C. overnight. The mixture was purified by RP-chromatography (method A).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][CH:14]2[CH:13]([CH2:21][OH:22])[O:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][O:43][C:44]([C:46]1[O:50][N:49]=[C:48](O)[CH:47]=1)=[O:45].CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH3:42][O:43][C:44]([C:46]1[O:50][N:49]=[C:48]([O:22][CH2:21][CH:13]2[CH:14]3[CH:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]3)[CH:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[Cl:1])[O:12]2)[CH:47]=1)=[O:45]
Reactant: CC1(C)OC2C(CO)OC(n3cnc4c(Cl)ncnc43)C2O1
Reactant: COC(=O)c1cc(O)no1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCC2OC(n3cnc4c(Cl)ncnc43)C3OC(C)(C)OC23)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of [6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol (0.570 g, 1.74 mmol) in 16 mL of dry dichloromethane was added polymer-bound triphenylphosphine (PS-TPP; Argonaut Tech., 2.14 mmol/g, 0.91 g, 1.2 eq), followed by methyl-3-hydroxy-5-isoxazolecarboxylate (0.248 g, 1 eq). The mixture was sonicated for 15 minutes then stirred at room temperature for 1 h under argon. The reaction mixture was cooled to 0° C. and under argon flow diethylazodicarboxylate (0.33 g, 1.1 eq), dissolved in 1 ml of dichloromethane, was added dropwise via syringe. The mixture was protected from light and stirred at 0° C. for 30 min. then at room temperature for 20 h. The resin was washed liberally with dichloromethane and methanol. The organic solution obtained from the washes was concentrated to give, after flash chromatography purification, 0.740 g of the product as a white solid (95% yield). 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.23 (s, 1H), 6.42 (s, 1H), 6.23 (d, J=2.1 Hz, 1H), 5.43 (dd, J=2.1 Hz, 1H), 5.14 (dd, J=3.6 Hz, 1H), 4.7 (m, 1H), 4.61 (dd, J=3.9 Hz, 1H), 4.49 (dd, J=5.7 Hz, 1H), 3.93 (s, 3H), 1.65 (s, 3H), 1.42 (s, 3H). MW calculated for C18H18ClN5O7 (MH+) 452. found 452 by LCMS.
Reaction SMILES: CC([N:5]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[C:20]3=[C:21]([Cl:29])[CH:22]=[N:23][C:24]4[CH:25]=[CH:26][C:27](=[O:28])[N:18]([C:19]=43)[CH2:17]2)[CH2:11][CH2:10]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:5][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[C:20]3=[C:21]([Cl:29])[CH:22]=[N:23][C:24]4[CH:25]=[CH:26][C:27](=[O:28])[N:18]([C:19]=43)[CH2:17]2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)N(C(=O)[O-])C1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A suspension of 1,1-dimethylethyl{1-[(3-chloro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (1.475 g, 4.63 mmol) in dichloromethane (15 ml) was treated with trifluoroacetic acid (12 ml) and stirred at room temperature for 1 h. The reaction mixture was evaporated and then treated with aqueous sodium bicarbonate solution and a 4:1 dichloromethane:methanol solution. The aqueous phase was extracted about 15 times with a 4:1 dichloromethane:methanol solution and then the combined organic phases were dried and the solvent was removed. The residue was subjected to column chromatography on silica gel using a dichloromethane, methanol and aqueous ammonia gradient to provide the desired compound (0.94 g, 84%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH2:10][CH2:9]1)=[O:7])(C)(C)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=C1CCC(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCC(CC(=O)O)CC1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A solution of diester (B) (12.5 g, 46.3 mmol) and 10% palladium on activated carbon (5 g) in absolute ethanol (200 mL) was exposed to a hydrogen atmosphere (at balloon pressure) and stirred vigorously for 1 h. After removal of catalyst by filtration and concentration, the resultant colorless oil was dissolved in methylene chloride (150 mL) and TFA (75 mL) and stirred for 15 min. All volatiles were removed by rotary evaporation and the resultant colorless oil placed under high vacuum to give (C) 4-carboxymethyl-cyclohexanecarboxylic acid ethyl ester (9.9 g, 99%) as a white solid. Data for cis/trans mixture: 1H NMR (400 MHz, CD3OD) δ4.13 (2q, 4 H), 2.58 (m, 1H), 2.30-2.20 (m, 1 H), 2.20 (2d, 4 H), 2.05-1.80 (m, 7 H), 1.80-1.55 (m, 5 H), 1.50-1.38 (m, 3 H), 1.32-1.25 (m, 1 H), 1.25 (2t, 6 H), 1.10-1.00 (m, 2 H); mass spectrum m/z 215 [(M+H)+; calcd for C11H19O4: 215].
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[CH:13][C:8]2=[C:7]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17]I)[N:6]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH2:36][CH3:37])=[C:30](B(O)O)[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([C:28]3[CH:27]=[C:26]([F:25])[CH:31]=[CH:30][C:29]=3[O:35][CH2:36][CH3:37])[C:8]2=[C:7]([NH:14][CH2:15][C@H:16]([OH:19])[CH3:17])[N:6]=1
Reactant: OC(CI)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]ncc12
Reactant: CCOc1ccc(F)cc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOc1ccc(F)cc1-c1n[nH]c2nc(Oc3ccc(F)cc3F)nc(NC[C@@H](C)O)c12
Temperature: 180 °C
Yield: 30.6 %

Procedure:
1-[6-(2,4-Difluoro-phenoxy)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino-propan-2-ol (200 mg, 0.447 mmol), 5-fluoro-2-ethoxyphenyl boronic acid (246 mg), K3PO4 (285 mg), and Tetrakis(triphenylphosphine) palladium(0) CH2Cl2 (73 mg) were added to 2 mL dioxane in a microwave vial. The vial was sealed and the reaction mixture was heated to 180° C. for 10 minutes. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was filtered through silica gel using 10% MeOH in methylene chloride, then purified by preparative scale thin layer chromatography using 10% MeOH in methylene chloride, to give 62.9 mg of (R)-1-[6-(2,4-Difluoro-phenoxy)-3-(2-ethoxy-5-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol. Mass Spec. M+H=460.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].CCN(CC)CC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[NH2:23]>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:23][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[N:29]=[CH:30][CH:31]=[CH:32][N:33]=1
Reactant: COc1cc(N)ccc1Oc1ncccn1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2ccccn2)ccc1Oc1ncccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
According to Scheme 3 Step 3: Picolinoyl chloride hydrochloride (1.33 mmol, 256 mg) and Et3N (2.67 mmol, 0.37 mL) were added sequentially to a solution of 3-methoxy-4-(pyrimidin-2-yloxy)aniline (0.89 mmol, 193 mg) in DCM (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The organic phase was washed with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over C18 column using water/ACN (70:30) as eluent to afford N-(3-methoxy-4-(pyrimidin-2-yloxy)phenyl)picolinamide (0.17 mmol, 55 mg, 19%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([O:7][CH3:8])(C)[CH:4]=[O:5].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13].[CH3:17]O>>[CH3:13][N:12]([CH3:14])[CH:11]=[CH:17][C:4](=[O:5])[CH:3]([O:7][CH3:8])[O:2][CH3:1]
Reactant: CO
Reactant: COC(OC)N(C)C
Reactant: COC(C)(C=O)OC
Product: COC(OC)C(=O)C=CN(C)C
Yield: 70 %

Procedure:
300 g (307 ml, 2.54 mol) of methylglyoxal dimethylacetal were stirred, at 110° C. for 4 hours (h), with 303 g (337 ml, 2.54 mol) of N,N-dimethylformamide dimethylacetal. The methanol which was formed during the reaction was removed continuously from the reaction solution by distillation. After having been cooled down, the solution was extracted with heptane and the solvents were evaporated. This resulted in 303 g of crude product 16 (yield 70%), which was reacted without any further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14](Br)[S:15][C:16]=1[Br:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1>C(O)C.O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[S:15][C:16]=1[Br:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(Br)sc(Br)c1NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(C)cc2)sc(Br)c1NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Palladium tetrakis-triphenylphosphine is added to a degassed solution of dibromide 155 and p-tolylboronic acid 175 in ethanol: water:toluene (2:1:1) and sodium carbonate. The resulting mixture is heated under N2 and stirred for 1 h at 80° C. The mixture is then cooled filtered through a 0.45 μm syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provides 176.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C-:32]#[N:33].[K+].O>CN(C)C=O>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2[C:32]#[N:33])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Temperature: 100 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
Compound 67a (217 mg, 0.529 mmol) obtained in Example 67 was dissolved in N,N-dimethylformamide (4 mL), to the solution were added cesium carbonate (245 mg, 0.750 mmol, 1.5 equivalents) and potassium cyanide (39 mg, 0.600 mmol, 1.2 equivalents), and the mixture was stirred at 100° C. for 4 hours. To the reaction mixture was added water, and the deposited crystals were collected by filtration to obtain the title compound (125 mg, 73%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].[O-:11][C:12]#[N:13].[K+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH:4][C:12]([NH2:13])=[O:11]
Reactant: COc1ccc(Cl)c(N)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cl)c(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
A solution of 2-chloro-5-methoxyaniline (5 g, 25.76 mmol) and potassium cyanate (5.22 g, 64.41 mmol) in a mixture of acetic acid (125 mL) and water (12.5 mL) was stirred at room temperature overnight. The solvent was evaporated, and the residue taken into a mixture of CH2Cl2 and an aqueous saturated solution of NaHCO3. The layers were separated, the aqueous one being extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography on silica gel (cyclohexane/EtOAc/MeOH:80/20/2) to give 2.06 g (40%) of intermediate 5.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[CH3:28][C:29]1[S:33][CH:32]=[N:31][CH:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:32]4[S:33][C:29]([CH3:28])=[CH:30][N:31]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: Cc1cncs1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4ncc(C)s4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 5-methylthiazole
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Reactant: C1COCCN1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCOCC5)c34)cc2C)cn1
Yield: 9 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and morpholine to give the title compound in 9% yield; NMR Spectrum: 2.19 (s, 3H), 2.44 (s, 3H), 2.50 (hidden by DMSO, 4H), 2.81 (t, 2H), 3.55 (br s, 4H), 4.45 (t, 2H), 6.95 (d, 1H), 7.18-7.25 (m, 2H), 7.60 (d, 1H), 7.65 (s, 1H), 8.16 (s, 1H), 8.30 (s, 1H), 8.32 (s, 1H); Mass Spectrum: 462 (MH+).