Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CO>[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([C:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=1)=[CH:7][NH:8]2
Reactant: Fc1cccc2[nH]ccc12
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3cccc(F)c23)CC1
Reaction time: 28 h
Yield: 68.7 %

Procedure:
To a solution of 1.18 gm (21.0 mMol) potassium hydroxide in 10 mL methanol were added 1.00 gm (7.4 mMol) 4-fluoro-1H-indole and 1.82 mL (14.8 mMol) 1-methyl-4-piperidone. The reaction mixture was stirred for 28 hours at reflux and then was allowed to cool. The crystals which formed were filtered, washed with methanol and dried under vacuum at 60° C. to give 1.17 gm (69%) of the title compound.
Reaction SMILES: [CH2:1](Br)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[N:8]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:38]=[C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([C:31]5[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=5)[N:25]4[N:24]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:8]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:38]=[C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:1][CH:2]6[CH2:3][CH2:4][CH2:5][O:6]6)[CH:32]=5)[N:25]4[N:24]=3)=[CH:18][CH:17]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Oc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc(OCC2CCCO2)cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 80 °C

Procedure:
Tetrahydrofurfuryl bromide (20 mg, 0.18 mmol) was added to a stirred solution of 3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenol (50 mg, 0.12 mmol) and potassium carbonate (25 mg, 0.18 mmol) in dimethylformamide (1.5 ml). The mixture was heated overnight at 80° C. then cooled and transferred to a vial for purification by preparatory HPLC. RT: 2.70 min, MI: 500.22, Method: 2.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:44])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])=[CH:9][CH:8]=1.Cl>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:44])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([OH:39])([C:31]([F:33])([F:34])[F:32])[C:35]([F:37])([F:38])[F:36])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.102 mL, 0.102 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 45-(2); 20 mg, 0.034 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at 60° C. for one hour. The reaction mixture was poured into 1 N hydrochloric acid aqueous solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (15 mg, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9]([CH3:11])=[C:8]([CH3:12])[CH2:7][C:6]=1[C:13]([O:15][CH3:16])=[O:14])=[O:4].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClC1C=CC=CC=1>[CH3:16][O:15][C:13](=[O:14])[C:6]1[C:5](=[CH:10][C:9]([CH3:11])=[C:8]([CH3:12])[CH:7]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1=C(C(=O)OC)CC(C)=C(C)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Clc1ccccc1
Product: COC(=O)c1cc(C)c(C)cc1C(=O)OC

Procedure:
To a solution of 4,5-dimethyl-cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (3.84 g, 17.1 mmol) in chlorobenzene was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (7.77 g, 34.2 mmol) at room temperature and the resulting mixture was heated to reflux 48 h. The resulting mixture was cooled and filtered through FLORISIL®. The pad of FLORISIL® was rinsed with diethyl ether and the filtrate filtered another (3×) through a pad of FLORISIL®. The filtrate was evaporated in vacuo to yield an amber syrup, which was purified via flash column chromatography (EtOAc/Heptane 4:1) to yield 4,5-dimethyl-phthalic acid dimethyl ester as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:17])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C1(=O)O[CH2:21][CH2:20][O:19]1>[I-].C([N+](CC)(CC)CC)C.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:15])[CH3:16])[C:9]=2[O:17][CH2:21][CH2:20][OH:19])=[CH:6][CH:7]=1
Reactant: O=C1OCCO1
Reactant: CC(C)c1cccc(-c2ccc(F)cc2)c1O
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: ClCCl
Product: CC(C)c1cccc(-c2ccc(F)cc2)c1OCCO
Temperature: 155 °C
Yield: 26 %

Procedure:
A mixture of 4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-ol (1.84 g), ethylene carbonate (0.78 g) and tetraethylammonium iodide (0.68 g) was heated in an oil bath at 155° C. for 2 hours, then was cooled and taken up in dichloromethane. The solution was washed in turn with water, 1N sodium hydroxide, 1N hydrochloric acid and brine, then was dried (MgSO4) and evaporated. The residual material was chromatographed over 70 g of silica gel (ethyl acetate-hexane; 3:7) to provide 0.57 g of 2-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yloxy]ethanol. The compound was crystallized from hexane to give the analytical sample, mp 77°-78° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:14]2[S:10][C:11](=[O:16])[NH:12][C:13]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(O)cc2)S1
Yield: 90.4 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (3.67 g, 30 mmol), 2,4-thiazolidinedione (3.51 g, 30 mmol) and benzoic acid (4.40 g, 36 mmol) in toluene (100 mL) was added piperidine (4.5 mL, 45 mmol) and the mixture was equipped with a Dean Stark apparatus and brought to a vigorous reflux. After 45 min the mixture was cooled in an ice bath and the supernatant was decanted. The bright yellow solid was made into a suspension by the addition of glacial acetic acid (100 mL) and filtered through a Buchner funnel to yield a pale yellow solid (6.00 g, 90%). 1H NMR: (400 MHz, DMSO-d6): δ 12.45 (bs, 1H), 10.30 (s, 1H), 7.70 (s, 1H), 7.45 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH:27]=[C:26]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.O1CCOCC1.[Pd]>[CH3:41][O:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:20]3[CH:19]=[CH:18][C:17]([N:14]4[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]4)=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)=[CH:30][CH:31]=1
Reactant: COCCCCOc1ccc(C2=CCN(c3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CO
Product: COCCCCOc1ccc(C2CCN(c3ccc(N4CCNCC4)cc3)CC2)cc1
Temperature: 100 °C
Yield: 81.1 %

Procedure:
To a mixture of 4-[4-[4-[4-(4-methoxybutoxy)phenyl]-3,6-dihydro-2H-pyridin-1-yl]phenyl]piperazine-1-carboxylic acid benzyl ester (2.20 g) and ammonium formate (1.25 g) in 90% methanol (44 ml) and dioxane was added 10% palladium on carbon at room temperature. The reaction mixture was heated at 100° C. for 2 hours. After cooling, the reaction mixture was filtered and evaporated. Sodium hydrogen carbonate solution was added to the residue. And the resulting precipitate was collected by filtration, washed with water and dried under hi-vacuum to give 1-[4-[4-[4-(4-methoxybutoxy)phenyl]piperidin-1-yl]phenyl]piperazine (1.36 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.C(N(CC)CC)C.[C:18]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(O)C>[C:21]([O:20][C:18](=[O:19])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[N:7]=[CH:6][N:5]=[C:4]3[NH:8][N:9]=[CH:10][C:3]=23)[CH2:28][CH2:27]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 80 °C
Yield: 26.5 %

Procedure:
To a solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (J. Amer. Chem. Soc. 1957, 79, 6407-6413) (59 mg, 0.38 mmol) in ethanol (2 ml) was added triethylamine (100 μl, 0.72 mmol) and 4-(N-Boc-amino)piperidine (134 mg, 0.67 mmol). The solution was heated at 80° C. for 3 hours, and then cooled to room temperature. The solution was evaporated to dryness and the residue purified by recrystallisation (isopropanol) to yield the product (32 mg, 26% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:30](=[O:36])[CH2:29][CH2:28][CH2:27][C:26]=2[CH:37]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:23]=[CH:24][C:25]4[N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:30](=[O:36])[CH2:29][CH2:28][CH2:27][C:26]=4[CH:37]=3)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1C(=O)CCCc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3CCOC)ncc1Cl
Temperature: 120 °C
Yield: 29.9 %

Procedure:
A microwave vessel was charged with 3-chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (50.00 mg, 0.1508 mmol), 7-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (39 mg, 0.16 mmol), 10-camphorsulfonic acid (6.0 mg, 0.026 mmol) and isopropyl alcohol (2 mL) and heated to at 120° C. for 70 minutes in a microwave reactor (sealed vessel). The reaction was diluted with water (10 mL) and saturated aqueous solution of NaHCO3 before extracting into DCM. The organic layer was dried by passing through a filter funnel loaded with MgSO4; the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 30% EtOAc/Hexane→80% EtOAc gradient). The appropriate fractions were combined, evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (23.9 mg, 30%) as a white foam that had the following properties: m.p.=136-157° C., bubbled; LC/MS (ESI+): 529 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 8.12 (s, 1H), 8.03 (s, 1H), 7.62 (d, J=8.0, 1H), 7.52 (d, J=8.0, 1H), 7.31 (dd, J=8.0, 7.8, 1H), 7.27 (m, 1H), 7.220 (d, J=8.6, 1H), 7.09 (d, J=8.6, 1H), 6.98 (s, 1H), 6.10, (s, 1H), 3.7-4.2 (m, 2H), 3.55-3.47 (m, 2H), 3.30 (s, 3H), 2.95 (d, J=4.9, 3H), 2.9-2.4 (m, 2H), 2.3-2.2 (m, 2H), 1.8-2.3 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12.[CH3:17][C:18]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2>>[CH3:17][C:18]1[C:26]([NH:27][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[O:10][C:3]=23)=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2
Reactant: Clc1ccnc2cc(-c3ccccc3)oc12
Reactant: Cc1c(N)ccc2[nH]ccc12
Product: Cc1c(Nc2ccnc3cc(-c4ccccc4)oc23)ccc2[nH]ccc12

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-phenylfuro[3,2-b]pyridine (60.00 mg; 0.26 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (40.10 mg; 0.27 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one and was obtained as a brown oil (88 mg, 98%). (HPLC (method F): 96%, RT: 3.91 min); MS (m/z) 340 [M+H]+, RT: 2.7 min.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH2:33][NH2:34])[C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH2:33][NH2:34])[C:28]([C:31]#[C:32][C:2]3[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]4)=[CH:4][CH:3]=3)=[N:29][CH:30]=2)=[CH:21][CH:20]=1
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1CN
Reactant: CC1CCN(CCOc2ccc(I)cc2)CC1
Product: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3CN)cc2)CC1

Procedure:
The product was prepared analogously to Example 7.1e starting from 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidine and [5-(4-chlorophenyl)-2-ethynylpyridin-3-yl]methylamine. Yield: 70 mg (21% of theoretical); C28H30ClN3O (M=460.010); calc.: molpeak (M+H)+:460/462 (Cl); found: molpeak (M+H)+:460/462 (Cl); HPLC-MS: 5.30 minutes (method D).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(B(O)O)c1O
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Product: COc1cccc(-c2cccc(-c3cccc(-c4cccc(C)c4O)n3)n2)c1O
Yield: 59 %

Procedure:
6-(2-Hydroxy-3-methoxyphenyl)-6′-(2-hydroxy-3-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-3-methylphenylboronic acid in 59% yield using method F; δH [2H6]-DMSO 13.28,(1H, s), 8.37,(1H, d), 8.35,(1H, d), 8.29,(2H, t), 8.18,(1H, d), 8.10,(1H, d), 7.97,(1H, d), 7.71,(1H, d), 7.29,(1H, d), 7.10,(1H, d), 6.97-6.87,(2H, m), 3.84,(3H, s), 2.29,(3H, s); MS 385 (MH)+; HPLC retention time (system 1) 4.27 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20](F)=[C:19]([C:24]#[N:25])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:19]([C:24]#[N:25])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[CH3:26]
Reactant: C1COCCN1
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(C#N)c2)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(N3CCOCC3)c(C#N)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [1-(3-cyano-4-fluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (Example 54a) (60.7 mg, 0.157 mmol) in acetonitrile (3 ml) is added potassium carbonate (43.3 mg, 0.314 mmol) followed by morpholine (27.6 μl, 0.314 mmol). The reaction mixture is stirred at room temperature for 2 hours and then filtered and concentrated in vacuo to yield the titled compound as an orange oil which is used crude in the next step. (MH+ 455).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[C@@H:18]([S:19][CH2:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]4[CH2:27][CH2:28][O:29][C:25]=4[CH:24]=3)=[O:22])[C:17](=[O:32])[N:16]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:11][CH:10]=1)(C)(C)C>C(O)=O>[O:29]1[C:25]2[CH:24]=[C:23]([C:21](=[O:22])[CH2:20][S:19][C@H:18]3[C:17](=[O:32])[N:16]([C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)[C@@H:15]3[C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:40])=[O:5])=[CH:10][CH:11]=3)[CH:31]=[CH:30][C:26]=2[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCC4)C(=O)N2c2ccc(F)cc2)cc1
Solvent: O=CO
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCC4)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{4-[(2R,3R)-3-[2-(2,3-Dihydro-benzofuran-6-yl)-2-oxo-ethylsulfanyl]1-(4-fluoro-phenyl)-4-oxo-azetidin-2-yl]-phenoxy}-acetic acid tert-butyl ester (77 mg, 0.137 mmol) was dissolved in formic acid (3 mL) and the solution was stirred for 1 h at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The solution was washed with water and then concentrated under reduced pressure. The residue was freeze-dried from MeCN/water to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[O:9])=[CH:6][N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1.[H-].[Na+].[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36]>C1COCC1>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:4]2[N:3]=[C:2]3[NH:1][C:35](=[O:36])[N:10]([CH2:11][C:12]([F:13])([F:14])[F:15])[C:8](=[O:9])[C:7]3=[CH:6][N:5]=2)=[N:17]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1C(=O)NCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2c(=O)n1CC(F)(F)F
Reaction time: 0.42 h

Procedure:
50 mg (0.11 mmol) of 4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)pyrimidine-5-carboxamide (example 103A) were initially charged in 5 ml of THF and, while cooling with ice, 18.0 mg (0.45 mmol) of sodium hydride (60% in mineral oil) were added over a period of 5 min. The mixture was stirred for 25 min, then 27.3 mg (0.17 mmol) of 1,1′-carbonyldiimidazole were added with ice cooling over 5 min. Conversion was effected at room temperature for 1 h and at reflux temperature for 90 min. After cooling, the mixture was hydrolyzed and then the organic phase was diluted with 10 ml of THF. After drying with sodium sulfate, the volatile components were removed by means of a rotary evaporator. Then the crude material was purified by means of preparative HPLC [column: Reprosil C18, 10 μm, 250*30 mm; flow rate: 40 ml/min; eluent: methanol/0.05% formic acid; gradient: 50% methanol→95% methanol)]. The volatile components of the product fractions were removed on the rotary evaporator. Thus, 26 mg (48% of theory) of the target compound were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[O:17]=[C:18]1[NH:23][CH:22]=[C:21]([CH2:24][C:25]#[N:26])[CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([O:17][C:18]3[N:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: N#CCc1ccc(=O)[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Oc2ccc(CC#N)cn2)nc(-c2cccc(Cl)c2)n1
Yield: 15.8 %

Procedure:
A solution of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.300 g, 1.19 mmol), 2-(6-oxo-1,6-dihydropyridin-3-yl)acetonitrile (0.239 g, 1.78 mmol), and potassium carbonate (0.246 g, 1.78 mmol) in DMF (3 mL) was heated with microwave irradiation to 120° C. for 1 h. After this time, the reaction was cooled and concentrated. The residue was purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.066 g, 22%). MW=350.80. 1H NMR (CD3OD, 300 MHz) δ 8.51-8.41 (m, 2H), 8.32-8.28 (m, 1H), 7.89 (s, 1H), 7.64 (dd, J1=12.1 Hz, J2=2.6 Hz, 1H), 7.56-7.47 (m, 2H), 6.70 (d, J=9.5 Hz, 1H), 3.87-3.82 (m, 2H), 2.98 (q, J=7.6 Hz, 2H), 1.46-1.8 (m, 3H); APCI MS m/z 351 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=2)=[O:18])=[CH:20][CH:21]=1)([O-:12])=[O:11]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C)cc(N)c1
Product: Cc1cc(C)cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c1

Procedure:
Using 3,5-xylidine (1.42 ml, 11.0 mmol) and 4-nitrobenzoic acid (1.76 g, 10.4 mmol), the procedure of Reference Example 16 was repeated to obtain 2.72 g (quantitative) of the title compound in the form of light yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[N:34]1([C:40]2[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl>CCO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:43]4[CH:42]=[CH:41][C:40]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:46][CH:45]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: CCO
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1)c1c(F)cccc1F
Temperature: 80 °C
Yield: 43 %

Procedure:
To a slurry of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (100 mg, 0.216 mmol.) in 1 mL of EtOH, added 4-(4-morpholinyl)aniline (38 mg, 0.216 mmol.) and 5 μL of conc. HCl. The reaction contents were heated to 80° C. After heating for 18 h, the reaction was cooled to rt and partitioned between EtOAc and sat. aq. NaHCO3. The layers were separated, extracted the aqueous layer with EtOAc (2×10 mL), the organic layers were pooled, dried over MgSO4, filtered, reduced in vacuo onto silica. Purified via ISCO chromatography (hexanes:EtOAc) to afford the desired compound as a yellow solid, 56 mg, 43% yield. 1H NMR (400 MHz, CD3OD): δ 8.61 (d, J=7 Hz, 1H); 8.40 (d, J=9 Hz, 1H); 8.14 (d, J=5 Hz, 1H); 7.98 (bs, 1H); 7.86 (d, J=7H, 1H); 7.56-7.48 (m, 3H); 7.48-7.37 (m, 3H); 7.12-7.05 (m, 3H); 6.92 (d, J=9 Hz, 2H) 6.58 (d, J=5 Hz, 1H); 3.85-3.83 (m, 4H); 3.11-3.09 (m 4H). HRMS calculated C34H28F2N7O2 [M+H]+ 604.2273, found 604.2271.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:8]([CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1)=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1nc(-c2cccc(CSCc3ccccc3)n2)sc2ccccc12
Solvent: ClC(Cl)Cl
Product: O=c1nc(-c2cccc(CS(=O)Cc3ccccc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
2-[6-[(Benzylthio)methyl]-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.080 g, 0.22 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.037 g, 0.22 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.053 g, 64%) as pale yellow crystals.