Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([C:12](=[O:26])[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[O:16])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]>C(O)C>[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]([OH:26])[CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[OH:16])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=C(CCC(=O)c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C(O)CCC(O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.5 %

Procedure:
Sodium borohydride (0.6173 g, 17.74 mmol) was added to a suspension of Example 55A (2.71 g, 8.26 mmol) in ethanol (150 mL) and stirred at ambient temperature for 3 hours. The reaction was quenched with water (˜50 mL) and concentrated to a paste which was taken up in 1:1 MeOH:THF. This suspension was filtered through a celite plug and concentrated. The residue was taken up in toluene and heated with stirring to form a white paste which was then sonicated and scraped until a filterable solid formed. This was filtered, rinsed with toluene and dried under vacuum to afford 2.84 g (100%) of the title compound as an off white solid. MS (DCI) m/z 350 (M+NH4)+.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[N:11]([C:14]3[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35](B(O)O)=[CH:34][N:33]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[CH:19]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:35]4[C:36]([O:38][CH3:39])=[N:37][C:32]([O:31][CH3:30])=[N:33][CH:34]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cn1)N(c1cc(Cl)cn(C)c1=O)C2=O
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cn2)N(c2cc(Cl)cn(C)c2=O)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(5-chloro-pyridin-2-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate BK) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a yellow solid. ESI-MS: tR=0.99 min, [M+H]+ 555/557/559 (LC-MS 1).
Reaction SMILES: [CH:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:15]1[C:20]([CH2:21][CH3:22])=[N:19][C:18]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[C:17]([CH2:31][CH3:32])[N:16]=1>CS(C)=O.O>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:18]1[C:17]([CH2:31][CH3:32])=[N:16][C:15]([O:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[C:20]([CH2:21][CH3:22])[N:19]=1
Reactant: OC1CCCc2ccccc21
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1OC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1,2,3,4-tetrahydronaphthalen-1-ol (248 mg) in DMSO (3 ml) was added to NaH (100 mg) suspended in DMSO (4 ml). The reaction mixture was stirred at r.t. for 1 hour and heated at 75° C. for 1 hour. 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine in DMSO (3 ml) was added. After 24 h, the rxn mixture was diluted with 30 ml of H2O, extracted with CH2Cl2, washed with NaHCO3, brine, dried (MgSO4), filtered and concentrated. Flash chromatography (1:50 EtOAC:Heptane) gave the title compound: 1H NMR (CDCl3) δ 1.23, 1.95, 2.13, 2.20, 2.58, 2.83, 2.96, 6.46, 7.36; HRMS (ESI+) calcd for C24H24Cl2N2O1 (M+H)+ 427.1344, found 427.1359.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][C:8]([F:24])([F:23])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1)[OH:10].[NH2:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[C:28]([Cl:33])[N:27]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:33][C:28]1[CH:29]=[C:30]([O:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:22]=[N:21][CH:20]=[N:19][CH:18]=2)[C:8]([F:7])([F:23])[F:24])[N:31]=[C:26]([NH2:25])[N:27]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OC(c1ccccc1-c1cncnc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OC(c2ccccc2-c2cncnc2)C(F)(F)F)n1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 90.5 %

Procedure:
Cs2CO3 (325 mg, 1.0 mmol) was added to a solution of 2,2,2-trifluoro-1-(2-pyrimidin-5-yl-phenyl)-ethanol (72 mg, 0.28 mmol) in 10 ml of anhydrous THF. The mixture was stirred for 20 min, 2-amino-4,6-dichloro-pyrimidine (36.7 mg, 0.22 mmol) was added and then the reaction mixture was heated at 110° C. until the reaction was completed. After cooling to room temperature, 5 ml of water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 76 mg of crude 4-chloro-6-[2,2,2-trifluoro-1-(2-pyrimidin-5-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine (yield: 92%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25].CCN(CC)CC>C(Cl)Cl>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCC4N)ccc21
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC1CCCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21
Yield: 125.2 %

Procedure:
A cooled (0° C.) brown solution of (rac)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (intermediate A-2) (61.5 mg, 200 μmol) in CH2Cl2 (3.0 ml) was treated with ethanesulfonyl chloride (65.6 mg, 48.3 μL, 500 μmol) and Et3N (40.5 mg, 55.8 μL, 400 μmol). After ½ h the mixture was concentrated in vacuo and purified by flash chromatography (20 g SiO2, Telos-cartridge, CH2Cl2/MeOH (1 to 5%)) to give 100 mg of the title compound together with Et3N×HCl as impurity. Extraction with H2O/EtOAc (3×), and precipitation CH2Cl2/n-pentane gave the pure title compound (46 mg, 58%) as a yellow powder. MS: 400.2 (M+H+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=1>O>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and N-(4-amino-phenyl)-methanesulfonamide [Tetrahedron, 42, 5739. (1986)] according to the method described in Example 2. Melting Point: 221-225° C. (water)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:39]=[CH:38][C:20]([C:21]([N:23]([CH3:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][O:33]C(=O)C)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][OH:33])=[O:22])=[CH:38][CH:39]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OCCOc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(2-acetoxyethoxy)phenyl]benzamide and potassium carbonate (129 mg) in methanol (15 ml) was stirred at ambient temperature for 2 hours and the mixture was diluted with ethyl acetate (30 ml). The solution was washed with water and brine and the organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(2-hydroxyethoxy)phenyl]benzamide (450 mg) as an oil.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:27]=[CH:26][CH:25]=[C:6]([C:7]([NH:9][CH2:10][C@H:11]2[CH2:15][C@@H:14]([C:16]([N:18]3[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]3)=[O:17])[NH:13][CH2:12]2)=[O:8])[CH:5]=1.FC(F)(F)C(O)=O>CO>[F:24][C:20]1([F:23])[CH2:21][CH2:22][N:18]([C:16]([C@H:14]2[NH:13][CH2:12][C@@H:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]3[CH:5]=[C:4]([CH:27]=[CH:26][CH:25]=3)[C:3]([OH:28])=[O:2])[CH2:15]2)=[O:17])[CH2:19]1
Reactant: COC(=O)c1cccc(C(=O)NC[C@@H]2CN[C@H](C(=O)N3CCC(F)(F)C3)C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(O)c1cccc(C(=O)NC[C@@H]2CN[C@H](C(=O)N3CCC(F)(F)C3)C2)c1

Procedure:
A mixture of Example 72 (58.8 mg) in 0.6 mL of methanol was treated with 1 mL of 1.7 NLiOH solution for 4 hours. Trifluoroacetic acid (300 μL) was added, and the mixture was purified by reverse-phase HPLC to provide the desired acid. MS (ESI) m/z 382 [M+H]+; 1H NMR (500 MHz, methanol-d4) δ ppm 1.57 (ddd, J=19.53, 12.97, 9.61 Hz, 1 H) 2.22 (m, 1 H) 2.32 (m, 1 H) 2.50 (m, 1 H) 2.61 (m, 1 H) 3.02 (dd, J=11.60, 9.15 Hz, 1 H) 3.31 (d, J=6.71 Hz, 2 H) 3.32 (m, 1 H) 3.54 (m, 2 H) 3.66 (m, 2 H) 4.36 (dt, J=41.58, 8.66 Hz, 1 H) 7.38 (t, J=7.78 Hz, 1 H) 7.84 (d, J=8.24 Hz, 1 H) 7.98 (d, J=7.93 Hz, 1 H) 8.28 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[F:25][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)[C:11]=12)[NH2:24]
Reactant: CN1CCNCC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(N3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (100.0 mg, 0.2040 mmol, prepared in Example 7, step B), 1-methylpiperazine (61.29 mg, 0.6119 mmol), copper(I)iodide (11.65 mg, 0.06119 mmol), (S)-pyrrolidine-2-carboxylic acid (7.045 mg, 0.06119 mmol), K2CO3 (140.9 mg, 1.020 mmol) and DMSO (10 mL). The reaction mixture, was stirred at 100° C. for 8 hours. The reaction was cooled to room temperature and partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (36.8 mg, 39.01%). LRMS (APCI pos): >99% purity, 254 nm, m/e 463 (M+1).
Reaction SMILES: [CH:1](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32](=O)[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCOCC>[CH3:22][O:23][C:24]1[CH:25]=[C:26](/[C:32](=[CH:1]\[CH3:2])/[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=O)c1ccc(OC)c(OC)c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C/C=C(/C(=O)OCC)c1ccc(OC)c(OC)c1

Procedure:
To a diethyl ether solution of ethylidenetriphenylphosphorane prepared in the usual way from 800 g. of ethyltriphenylphosphonium bromide, 400 g. of ethyl 3,4-dimethoxyphenylglyoxylate in 600 ml. of ether are added dropwise. After refluxing for 4-5 hours, the solvent is evaporated and substituted with tetrahydrofuran. The mixture is then heated for 36 hours and then evaporated to dryness and the residue is extracted with diethyl ether in a Soxhlet apparatus giving 150 g. of the title compound. Pursuant to this procedure, the following other α-arylcrotonate starting materials are prepared:
Reaction SMILES: Cl[C:2]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CCOC(C)=O>[I:11][C:8]1[CH:9]=[CH:10][C:5]([C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)([CH3:4])[CH3:3])=[CH:6][CH:7]=1
Reactant: CC(C)(Cl)c1ccc(I)cc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: CC(C)(c1ccc(I)cc1)N1CCOCC1

Procedure:
To a solution of 1-(1-Chloro-1-methylethyl)-4-iodobenzene (2 g, 7 mmol) in morpholine (10 mL) is added KI (0.5 g). The mixture is irradiated under microwave irradiation for 20 min at 160° C. (×10). The combined reaction mixtures are dissolved in EtOAc, washed with water, brine and dried over sodium sulphate. The solvent is concentrated under vacuum and purified by column chromatography (50% EtOAc in pet ether) to afford title compound as a light brown liquid. 1H NMR (DMSO-d6, 400 MHz): δ 7.65-7.63 (dd, J=2, 6.8 Hz, 2H), 7.30-7.28 (dd, J=2, 6.8 Hz, 2H), 3.53-3.65 (t, 4H), 2.33-2.31 (t, 4H), 1.22 (s, 6H).
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=O)[CH2:4][C:5]([CH3:7])=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=C(F)[C:14]=1[F:23]>C1COCC1>[C:5]([CH2:4][C:3]1[C:14]([F:23])=[C:13]([F:12])[CH:18]=[CH:17][C:16]=1[N+:19]([O-:21])=[O:20])(=[O:6])[CH3:7]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a suspension of sodium hydride (5.42 g, 226 mmol) (prewashed with pentane) in THF (100 ml) cooled at 10° C. was added ethyl acetoacetate (29.4 g, 226 mmol) while keeping the temperature below 15° C. After completion of addition, the mixture was further stirred for 15 minutes and cooled to 5° C. A solution of 1,2,3-trifluoro-4-nitrobenzene (20 g, 113 mmol) in THF (150 ml) was added while keeping the temperature below 5° C. The mixture was then left to warm up to ambient temperature and stirred for 24 hours. The volatiles were removed under vacuum and the residue was partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was dissolved in concentrated hydrochloric acid (650 ml) and acetic acid (600 ml) and the mixture was refluxed for 15 hours. After cooling, the volatiles were removed under vacuum and the residue was partitioned between aqueous sodium hydrogen carbonate (5%) and ethyl acetate. The organic layer was washed with sodium hydrogen carbonate, water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (75/25) to give 3-acetylmethyl-1,2-difluoro-4-nitrobenzene (17.5 g, 72%).
Reaction SMILES: C[Al](C)C.[C:5]1([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]3[CH:20]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O:23][C:24]([C:26]1[C:27]([NH:32][C:33]2[CH:34]=[N:35][CH:36]=[N:37][CH:38]=2)=[N:28][N:29]([CH3:31])[CH:30]=1)=O)C.[O-]S([O-])(=O)=O.[Mg+2]>O1CCOCC1.ClCCl.CO.O>[C:5]1([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH:19][C:24]([C:26]4[C:27]([NH:32][C:33]5[CH:38]=[N:37][CH:36]=[N:35][CH:34]=5)=[N:28][N:29]([CH3:31])[CH:30]=4)=[O:23])[CH:16]=[CH:15][N:14]3[CH:20]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cn(C)nc1Nc1cncnc1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cc(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)c(Nc2cncnc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
Trimethylaluminum (2M solution in toluene, 0.3 ml) was added to a stirred suspension of 2-phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1, 128 mg) in dioxane (5 ml), and the mixture was stirred for 2 h at RT. 1-Methyl-3-(pyrimidin-5-ylamino)-1H-pyrazole-4-carboxylic acid ethyl ester (50 mg) was then added in one portion, and the mixture was heated to 100° C. for 17 h. Upon cooling, water (0.5 ml) was added, followed by small amounts of methanol and dichloromethane to get an almost clear solution. Some MgSO4 was added, the mixture was stirred for 15 min, and filtered. The filtrate was concentrated, and the title compound (23 mg, 28%) was isolated from the residue by column chromatography (silica gel, dichloromethane/methanol gradient), followed by trituration (methanol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCNC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g of β-alanine in 37 ml of a 2N-aqueous sodium hydroxide solution was added 5.8 ml of benzyloxycarbonyl chloride under ice-cooling, and then the mixture was stirred for 30 minutes. The reaction mixture was washed with diethyl ether, adjusted to a pH of 2-3 by adding a 1N-hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 6.53 g of N-benzyloxycarbonyl-β-alanine as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:17]2[CH2:19][CH2:18]2)=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[CH2:21][C:22]1[C:34]([Cl:35])=[CH:33][C:25]([C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:27])=[C:24]([F:36])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].N#N>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.O.O1CCCC1>[Cl:35][C:34]1[C:22]([CH2:21][C:6]2[CH:5]=[N:4][C:3]([CH:17]3[CH2:18][CH2:19]3)=[C:2]([Cl:1])[CH:7]=2)=[CH:23][C:24]([F:36])=[C:25]([CH:33]=1)[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:27]
Reactant: CC1(C)OB(c2cnc(C3CC3)c(Cl)c2)OC1(C)C
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(CBr)cc1F
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: O
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Cc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 65 °C

Procedure:
To a solution of tetrahydrofuran (10 mL) and water (2 mL) was added 3-chloro-2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 221, 32 mg, 0.11 mmol), 4-(bromomethyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide (Preparation 243, 43 mg, 0.13 mmol) and potassium carbonate (46 mg, 0.35 mmol). The flask was degassed with N2 (×5), and tetrakistriphenylphosphinepalladium (13.2 mg, 0.01 mmol) was added. The flask was degassed with N2 (×5), and heated to 65° C. for 18 hours. The reaction was allowed to cool to room temperature and washed with a saturated aqueous solution of ammonium chloride (100 mL). The reaction was extracted into ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4, filtered and the solvent removed to leave a yellow oil. The material was purified by silica gel column chromatography eluting with 1:1 heptane:ethyl acetate to afford the title compound as a yellow oil that solidified to a pale yellow solid upon standing (23 mg, 48%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[N:8]=1)=[O:6].[H-].[Na+].Br[CH2:29][CH2:30][F:31]>CN(C=O)C.C(OCC)(=O)C>[F:31][CH2:30][CH2:29][S:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[N:8]=1)=[O:6]
Reactant: FCCBr
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NCCS)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NCCSCCF)c1
Reaction time: 1 h

Procedure:
1.0 g (0.0027 mol) of N-(2-mercaptoethyl)-4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide (compound No. I-91) was dissolved in DMF, and the obtained solution was mixed with 0.12 g (ca. 60% in mineral oil; 0.0027×1.1 mol) of NaH and then with 0.68 g (0.0027×2.0 mol) of 1-bromo-2-fluoroethane, followed by stirring the solution for about one hour. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water and then washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.