Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[N:9][CH:10]=1>O1CCCC1.C(O)C>[CH3:1][N:2]([CH3:3])[C:5]1[CH:10]=[N:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)c1ccc([N+](=O)[O-])nc1
Temperature: 140 °C

Procedure:
6 ml of a 2M solution of dimethylamine in tetrahydrofuran are added to a solution of 1 g of 5-bromo-2-nitropyridine in 5 ml of ethanol. The reaction mixture is heated at 140° C. for 2 hours in a microwave device. After cooling, the solid formed is separated off and washed with ethyl ether to give 850 mg of N,N-dimethyl-6-nitropyridine-3-amine in the form of a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:46][S:47]([O:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]#[N:32])=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1)(=[O:49])=[O:48]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCO)CC2)c2ncnn12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCOS(C)(=O)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.2 g), triethylamine (0.38 mL), methanesulfonyl chloride (0.21 mL), N,N-dimethylpyridin-4-amine (0.028 g) and acetonitrile (20 mL) was stirred at room temperature for 3 hr. The reaction mixture was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.2 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[NH2:41][C:39](=[O:40])[CH2:38][N:15]([S:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[CH:8]=1)(=[O:13])=[O:14])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30]
Reactant: NC(=O)CBr
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(CC(N)=O)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
A solution of tert-butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (1.31 g) in DMF (22 ml) was treated with potassium carbonate (0.786 g) followed by 2-bromoacetamide (0.48 g) and the resultant mixture stirred at room temperature for 22 h. Additional 2-bromoacetamide (0.4 g) and potassium carbonate (0.4 g) were added and the mixture was stirred at room temperature for 24 h. The reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The separated organic layer was washed with water, dried (over magnesium sulphate) and evaporated under reduced pressure to give the title compound (1.4 g) as a white foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCN1CCCC1

Procedure:
The 1-(2-hydroxyethyl)-pyrrolidine (Aldrich, 0.14 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCc1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCc1ccccc1
Yield: 71.4 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-phenethyloxy-phenylamine (0.028 g, 0.07 mmol) was treated with 4-chlorophenyl isocyanate (0.014 g, 0.09 mmol, 1.2 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 66 (0.025 g, 0.05 mmol, 66%) as a solid film. LCMS m/z (%)=525 (M+H79Br35Cl, 85), 527 (M+H81Br35Cl, 100), 529 (M+H81Br37Cl, 31). 1H NMR (400 MHz, acetone-d6) δ: 8.34 (s, 1H), 8.26 (s, 1H), 7.65 (dd, J=2.7, 8.9 Hz, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.53 (s, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.16-7.31 (m, 5H), 7.09-7.16 (m, 3H), 4.11-4.30 (m, 2H), 3.51 (s, 3H), 2.86-3.06 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH:21]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:24]([NH2:26])[CH3:25]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:26][CH2:24][CH3:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2C=O)c1
Product: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (4′-Fluoro-2′-formyl-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][OH:13])=[CH:10][O:9][C:8]=2[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1>[C:28]([O:13][CH2:12][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([Si:14]([CH2:17][CH3:18])([CH2:19][CH3:20])[CH2:15][CH3:16])[O:9][CH:10]=1)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC[Si](CC)(CC)c1occ(CO)c1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCc1coc([Si](CC)(CC)CC)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-phenyl-2-triethylsilyl-4-furanmethanol (345 mg, 1.20 mmol) and triethylamine (182 mg, 1.80 mmol) in tetrahydrofuran (15 ml) at 0 degrees under argon was added lauroyl chloride (786 mg, 3.60 mmol). This solution was allowed to warm gradually to room temperature. After stirring an additional 2 hours the white precipitate was filtered off. The filtrate was taken up into ethyl ether, washed with saturated ammonium chloride, saturated sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 2% ethyl ether/hexanes to give the title compound.
Reaction SMILES: I[C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:4][C:3]=1[CH3:20].CO.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[NH:6][C:5]([C@@H:7]4[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]4[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:4][C:3]=3[CH3:20])=[CH:32][CH:31]=2)=[CH:28][CH:29]=1
Reactant: Cc1nc([C@@H]2C[C@H](C)CN2C(=O)OC(C)(C)C)[nH]c1I
Reactant: OB(O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1nc([C@@H]2C[C@H](C)CN2C(=O)OC(C)(C)C)[nH]c1-c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 75 °C
Yield: 43.6 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(5-iodo-4-methyl-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (289 mg, 0.7387 mmol) in 6 mL of 5:1 toluene:methanol is sequentially added [4-(4-bromophenyl)phenyl]boronic acid (346.7 mg, 1.252 mmol), K3PO4 (199.3 mg, 0.9389 mmol) and Pd(PPh3)4 (71.85 mg, 0.06218 mmol). The reaction mixture is heated at 75° C. for 3 hours. The reaction mixture is concentrated, diluted with ethyl acetate, and washed with water and brine. The organic layer is concentrated to dryness. The residue is dissolved in dichloromethane and purified by flash column chromatography on silica gel (0-10% methanol/dichloromethane) to give (2S,4S)-tert-butyl 2-(5-(4′-bromo-[1,1′-biphenyl]-4-yl)-4-methyl-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (160 mg, 0.322 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:14]=2)[NH:9][N:8]=1)=[O:5].[O:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCl>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:6][C:4](=[O:5])[C:3]1[CH:25]=[CH:26][C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[CH:28][C:2]=1[NH:1][CH:39]1[CH2:40][CH2:41][O:36][CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N)c2)CC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of 2-amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide (1.9 g, 3.98 mmol) in dichloromethane (80 mL) were added tetrahydro-pyran-4-one (0.55 mL, 5.98 mmol), trifluoroacetic acid (4 mL) and tetramethylammonium triacetoxyborohydride (1.57 g, 5.98 mmol). The mixture was stirred at room temperature overnight, and then more tetramethylammonium triacetoxyborohydride (1.57 g) was added. After stirring for additional 3 hours at room temperature the mixture was diluted with dichloromethane, washed with 2N sodium hydroxide and brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol/NH3 5N in MeOH 96:4:0.5 as the eluant, affording 1.61 g of the title compound (72% yield).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C(Cl)Cl.[NH2:28][C:29]1[N:33]=[CH:32][NH:31][N:30]=1.N1C=CC=CC=1>>[NH:31]1[CH:32]=[N:33][C:29]([NH:28][S:17]([C:14]2[CH:15]=[CH:16][C:11]([C:9]([NH:8][CH2:7][C:6]3[CH:21]=[CH:22][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=3)=[O:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[N:30]1
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc[nH]n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(S(=O)(=O)Nc2nc[nH]n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
A solution/suspension of 4-(4-trifluoromethyl-benzylcarbamoyl)-benzenesulfonyl chloride (200 mg, 0.5 mmol) in methylene chloride (1.0 mL, 16 mmol) was added portion-wise to a 0° C. solution of 3-amino-1,2,4-triazole (48.9 mg, 0.581 mmol) in pyridine (1.0 mL, 12 mmol). After addition was complete, the ice-bath was removed, and the reaction mixture was warmed to rt. After 16 h, the reaction mixture was diluted with methylene chloride and partitioned with 1 N HCl. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water, diluted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was loaded onto Celite and purified on the Isco (12 g cartridge, chloroform to 12% MeOH in chloroform) to afford the title compound (150 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[C:8]([CH2:15][CH:16]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]3)=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=[C:6]2[CH:5]=[C:4]([C:24]([O:26]CC)=[O:25])[CH:3]=1.C1COCC1.[OH-].[Na+]>O>[Cl:1][C:2]1[N:7]2[C:8]([CH2:15][CH:16]3[CH2:21][CH2:20][C:19]([F:22])([F:23])[CH2:18][CH2:17]3)=[C:9]([C:11]([F:12])([F:13])[F:14])[N:10]=[C:6]2[CH:5]=[C:4]([C:24]([OH:26])=[O:25])[CH:3]=1
Reactant: CCOC(=O)c1cc(Cl)n2c(CC3CCC(F)(F)CC3)c(C(F)(F)F)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)n2c(CC3CCC(F)(F)CC3)c(C(F)(F)F)nc2c1
Temperature: 25 °C
Yield: 113.9 %

Procedure:
Ethyl 5-chloro-3-(4,4-difluorocyclohexylmethyl)-2-trifluoromethylimidazo[1,2-a]pyridine-7-carboxylate (62 mg, 0.146 mmol) obtained in step 2 was suspended in a mixed solvent of THF (2.0 mL) and water (2.0 mL), and the suspension was stirred under heat and reflux for 3 hours after adding sodium hydroxide (29 mg, 0.730 mmol). The reaction mixture was allowed to cool to room temperature, and the solvent was then evaporated under reduced pressure. The residue was extracted with water after adding chloroform. Following neutralization with 1 mol/L hydrochloric acid, the solvent was evaporated under reduced pressure. After adding a mixed solution of chloroform/methanol=4/1 to the residue, the insoluble matter was removed by filtration. The filtrate solvent was evaporated under reduced pressure to give a crude product of 5-chloro-3-(4,4-difluorocyclohexylmethyl)-2-trifluoromethylimidazo[1,2-a]pyridine-7-carboxylic acid (66 mg).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[H-].[Na+].[CH3:14][N:15]1[C:20]([CH3:21])=[CH:19]C(=O)[O:17][C:16]1=O>O1CCCC1>[CH3:14][N:15]1[C:20]([CH3:21])=[CH:19][C:3]([OH:5])=[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:16]1=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(=O)oc(=O)n1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
At room temperature, 1 ml of a solution of 0.71 g of diethyl malonate in tetrahydrofuran was added to a mixture of 0.19 g of sodium hydride and 4 ml of tetrahydrofuran, and the mixture was stirred for 20 minutes. At room temperature, 3 ml of a solution of 0.59 g of 3,4-dimethyl-2H-1,3-oxazine-2,6(3H)-dione in tetrahydrofuran was added to the mixture, followed by stirring for 2 hours under heat refluxing condition. The reaction mixture was concentrated under reduced pressure. To the residue were added 10 ml of water and 12 ml of 2 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to obtain 0.57 g of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate represented by the formula:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7][NH2:8])[CH:2]=[CH2:3].[O:15]1[C@@H:17]([C@@H:18]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7][NH:8][CH2:16][C@@H:17]([OH:15])[C@@H:18]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: C=CCOc1ccc(OC)cc1CN
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: C=CCOc1ccc(OC)cc1CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
Step AS (5). A mixture of 2-allyloxy-5-methoxybenzylamine (375 mg, 1.94 mmol), (2S,3S)-1,2-epoxy-3-(BOC-amino)-4-phenylbutane (818 mg, 3.1 mmol), and lithium perchlorate (514 mg, 4.85 mmol) in acetonitrile (6 mL) was stirred at 60° C. for 2.5 h. The reaction was concentrated and the residue was purified by silica gel chromatography, eluting with a mixture of 5% 2N ammonia in methanol and 95% EtOAc to yield 0.8 g of tert-butyl (2S,3R)-4-(2-(allyloxy)-5-methoxybenzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate. The BOC-protected amine was dissolved in 10 mL 10% TFA/DCM and stirred at rt for 3 h. The reaction was concentrated under vacuum and the residue purified by reverse phase prep-HPLC to yield the titled compound as the ditrifluoroacetic acid salt (440 mg, 39%). LC-MS (M+H)+=357; 1H NMR (400 MHz, CD3OD) δ 7.30 (m, 5H) 7.00 (m, 3H) 6.10 (m, 1H) 5.40 (m, 1H) 5.30 (m, 1H) 4.61 (m, 2H) 4.22 (m, 3H) 3.76 (s, 3H) 3.66 (m, 1H) 3.18 (m, 1H) 2.90 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.S(Cl)([Cl:14])=O>CN(C=O)C>[Cl:14][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[N:7]=1
Reactant: Sc1nc2cc(Cl)ccc2o1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ccc2oc(Cl)nc2c1
Temperature: 65 °C

Procedure:
Subsequently, 5-chloro-2-mercaptobenzoxazole (3.1 g, 16.7 mmol) was dissolved in thionyl chloride (30 mL, 413 mmol). DMF (1.5 mL) was added and the reaction mixture was heated at 65° C. for 45 min. The solvent was removed under reduced pressure and to the residue was added toluene (2×60 mL) followed by evaporation each time to remove the excess SOCl2 (azetrope). The resultant crude product was dissolved in ethyl acetate (100 mL), washed with water (100 mL) and dried over Na2SO4. Evaporation of ethyl acetate gave 2,5-dichlorobenzoxazole, compound 19, as a red oil (3.2 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[N:12]=[CH:13][N:14]([CH3:17])[C:15]=2Br)[CH:6]=1)=[O:4].[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=2B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=2[C:15]2[N:14]([CH3:17])[CH:13]=[N:12][C:11]=2[C:7]2[CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][N:8]=2)[CH2:19][CH2:20]1
Reactant: CC1(C)OB(c2cc(F)c(F)cc2OCC2CC2)OC1(C)C
Reactant: COC(=O)c1ccnc(-c2ncn(C)c2Br)c1
Product: Cn1cnc(-c2cc(C(=O)O)ccn2)c1-c1cc(F)c(F)cc1OCC1CC1
Yield: 5 %

Procedure:
The title compound was prepared in 5% yield from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carboxylic acid methyl ester and 2-(cyclopropylmethoxy)-4,5-difluorophenylboronic acid pinacol ester according to the procedure for the preparation of Example 3, part A followed by hydrolysis. 1H NMR (400 MHz, DMSO-d6): δ 0.29-0.32 (2H, m), 0.53-0.58 (2H, m), 1.22 (1H, m), 3.43 (3H, s), 3.82 (2H, d, J=7.0 Hz), 6.82 (1H, br s), 7.09-7.14 (1H, m), 7.27 (1H, t, J=7.7 Hz), 7.42 (1H, d, J=3.6 Hz), 7.90 (1H, s), 8.20 (1H, d, J=4.3 Hz), 8.30 (1H, s). [M+H] Calc'd for C20H12F2N3O3, 386. Found, 386.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.CO[CH:9]([O:28][CH3:29])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:13][CH:12]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:29][O:28][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:15][CH:16]=1)[C:5]#[N:6]
Reactant: COC(Cc1ccc(OCCN(C)c2ccccn2)cc1)OC
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(C#N)Cc1ccc(OCCN(C)c2ccccn2)cc1
Reaction time: 1.5 h

Procedure:
Trimethylsilyl cyanide (3.4 mL) was added dropwise to a solution of 1,1-dimethoxy-2-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]ethane (2.64 g) in dichloromethane (70 mL) at room temperature. The mixture was stirred during the addition of boron trifluoride etherate (0.3 mL), and stirring continued at room temperature for 1.5 hrs prior to the addition of a further portion of boron trifluoride etherate (1 mL). After a further 2 hours the mixture was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (2×300 mL), water (2×300 mL) and brine (300 mL), dried (MgSO4) and evaporated The residue was chromatographed on silica gel with 1% methanol in dichloromethane as eluent to afford the title compound, a gum, which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]([Si:11]([CH3:33])([CH3:32])[O:12][CH2:13][C@@H:14]([O:16][C:17]1[CH:18]=[C:19]([CH:28]=[C:29]([OH:31])[CH:30]=1)[C:20]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:21])[CH3:15])([CH3:10])[CH3:9].[N:34]1([C:38]([C:40]2[CH:41]=[CH:42][C:43](Cl)=[N:44][CH:45]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1>C(#N)C>[N:34]1([C:38]([C:40]2[CH:41]=[CH:42][C:43]([O:31][C:29]3[CH:28]=[C:19]([CH:18]=[C:17]([O:16][C@@H:14]([CH3:15])[CH2:13][O:12][Si:11]([C:8]([CH3:9])([CH3:10])[CH3:7])([CH3:33])[CH3:32])[CH:30]=3)[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:21])=[N:44][CH:45]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1
Reactant: O=C(c1ccc(Cl)nc1)N1CCC1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2nccs2)c1
Temperature: 160 °C

Procedure:
Potassium carbonate (0.14 g, 0.98 mmol) was added to a mixture of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-1,3-thiazol-2-ylbenzamide (200 mg, 0.49 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (96 mg, 0.49 mmol) in acetonitrile (5.0 mL) and the stirred mixture heated at 160° C. in a ‘Biotage initiator Microwave’ for 4 hours. The mixture was allowed to reach RT and pressure and was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with water (5×50 mL), brine (50 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 60-100% ethyl acetate in isohexane, to give the desired compound. (0.15 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Cl[C:14]1[N:19]=[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])[C:17]([CH3:31])=[C:16]([CH3:32])[N:15]=1>CN(C)C=O>[CH3:31][C:17]1[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])=[N:19][C:14]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][C:16]=1[CH3:32]
Reactant: COCCN
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCNc1nc(C)c(C)c(N2CCc3ccccc3C2C)n1
Yield: 56.3 %

Procedure:
After 2-methoxyethylamine(0.23 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.5 g, 1.74 mmol) in dimethylformamide, 320 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.