Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.[CH:24]1([C:27]([NH:29][NH2:30])=[O:28])[CH2:26][CH2:25]1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[CH:24]1([C:27]([NH:29][NH:30][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=2)(=[O:16])=[O:15])[CH:3]=[C:2]3[I:1])=[O:13])=[O:28])[CH2:26][CH2:25]1
Reactant: NNC(=O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NNC(=O)C4CC4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
To a stirring suspension of 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (1.944 g, 4.41 mmol) and cyclopropanecarbohydrazide (0.441 g, 4.41 mmol) (Enamine) in THF (40 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.919 mL, 11.01 mmol) (Sigma-Aldrich) followed by HATU (1.843 g, 4.85 mmol) (Oakwood Products) in one portion and the solution was stirred at RT for 45 min. Several ice chunks were added to the mixture followed by H2O (75 mL). The mixture was extracted with EtOAc (2×100 mL). The organic layer was washed with 50 mL of sat. NaHCO3, then brine, dried over MgSO4, filtered, and concentrated to a volume of about 50 mL of EtOAc. A precipitate formed and was isolated by filtration. The filter cake was washed with EtOAc (2×10 mL) to give N′-(cyclopropanecarbonyl)-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (1.13 g, 2.159 mmol, 49.0%) as an off-white solid. MS (ESI, pos. ion) m/z: 523.8 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (s, 1H), 10.14 (s, 1H), 8.14-8.21 (m, 1H), 8.01-8.09 (m, 1H), 7.89-8.01 (m, 4H), 7.41 (d, J=8.2 Hz, 2H), 2.32 (s, 3H), 1.63-1.74 (m, 1H), 0.63-0.87 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11])(=[O:21])[CH3:20]
Reactant: COc1cc(CO)ccc1O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CO)ccc1OC(C)=O
Reaction time: 1 h

Procedure:
A partial solution of 4-hydroxy-3-methoxybenzyl alcohol (1.23 g, 8 mmol), triethylamine (810 mg, 1.12 mL, 8 mmol) and 32 mL of dry CH2Cl2 was chilled in an ice bath. To the cold mixture was added dropwise acetyl chloride (628 mg, 570 μL, 8 mmol). The mixture was stirred at ice bath temperature 1 for one hour. Stirring at room temperature was allowed to take place overnight. The reaction mixture was diluted with CH2Cl2 and extracted with 1N HCl, water and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Column chromatography on silica gel using CH2Cl2/MeOH (98:2, v/v) gave 548 mg (35%) of CO as a clear oil: Rf=0.22 (hexanes/ethyl acetate, 6:4 v/v); 1HNMR (CDCl3) δ 7.00 (d, 4J=1.5 Hz, 1H), 6.99 (d, 3J=8.5 Hz, 1H), 6.89 (dd, 3J=8.0 Hz, 4J=1.5 Hz, 1H), 5.27 (s, 2H), 4.66 (s, 2H), 3.83 (s, 3H) and 2.30 (s, 3H). Exact mass (FAB+) calculated for C10H12O4[M+] 196.0736. found 196.0739.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][C:36]2=[N:39][O:40][C:41]([CH3:42])=[C:35]2[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][C:36]5=[N:39][O:40][C:41]([CH3:42])=[C:35]5[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: Cc1onc2c1CN(CCCCl)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCc2noc(C)c2C1
Temperature: 80 °C
Reaction time: 7 h
Yield: 42.8 %

Procedure:
A mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (1.20 g), K2CO3 (2.60 g) and 5-(3-chloropropyl)-3-methyl-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine (0.97 g) in 10 mL of DMF was stirred at 80° C. for 7 h, and treated with 250 mL of ice-water. Then the mixture was extracted with CH2Cl2 (50 mL×2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (0.80 g, 45.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 498.1 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 2.08 (m, J=4.0 Hz 2H), 2.51 (s, 3H), 2.70 (m, J=4.0 Hz, 6H), 2.37 (m, J=4.0 Hz, 2H), 3.94 (s, 3H), 4.20 (m, J=8.0 Hz, 2H), 7.21 (s, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.44 (s, 2H), 8.11 (t, J=4.0 Hz, 1H), 8.50 (s, 1H) ppm.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[CH2:17]([NH2:20])[CH2:18][NH2:19].C(Cl)Cl>CN1CCCC1=O.CO>[NH2:19][CH2:18][CH2:17][NH:20][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: Cn1cc(C(=O)O)c(=O)c2ccc(Cl)cc21
Solvent: CO
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cn1cc(C(=O)O)c(=O)c2ccc(NCCN)cc21
Temperature: 130 °C
Yield: 30.3 %

Procedure:
To a solution of 7-chloro-1-methyl-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (1.5 g, prepared according to H. Agui and T. Nakagome, J. Heterocycl. Chem., (1979), 16(7), 1353–60) in 1-methyl-2-pyrrolidinone (15 mL), was added ethylenediamine (1.9 g). The mixture was heated at 130° C. for 24 hours. The reaction mixture was cooled and poured into DCM (20 mL). The precipitate obtained was dispersed in MeOH, filtered giving the title compound (500 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:30])[C:10]#[C:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:16][C:15]=1[F:29])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[C].[Pd].O1CCCC1.C(O)C>[Si:1]([O:8][C@H:9]([CH3:30])[CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:16][C:15]=1[F:29])=[O:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: C[C@H](C#CC(=O)c1ccc(NC(=O)c2cnccn2)cc1F)O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](CCC(=O)c1ccc(NC(=O)c2cnccn2)cc1F)O[Si](C)(C)C(C)(C)C

Procedure:
100 mg of 10% palladium-carbon catalyst was added to a solution of 513 mg of N-(4-((4R)-4-((tert-butyl(dimethyl)silyl)oxy)-2-pentynoyl)-3-fluorophenyl)pyrazine-2-carboxamide in 5 ml of tetrahydrofuran and 20 ml of ethanol, and the reaction liquid was stirred in a hydrogen atmosphere for 1.5 hours. The catalyst was removed through filtration, the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 1/1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[S:10])=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: Nc1ccc(NC(=S)NCc2ccncc2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(NC(=S)NCc2ccncc2)cc1
Reaction time: 0.5 h

Procedure:
To a chilled (circa 0° C.) solution of 5.16 gms. (0.02 mole) of 1-(p-aminophenyl)-3-(4-pyridylmethyl)-2-thiourea (Example 19, supra.) and 75 ml. of pyridine there is added dropwise 1.48 gms. (0.02 mole) of acetyl chloride with stirring, while maintaining the temperature at circa 0° C. Upon completion of the addition, the reaction mixture is stirred for an additional 30 minutes and then allowed to stand at room temperature for about 16 hours. Solvent is then removed in vacuo and the residue suspended in water. Water is then removed to give a residue of 1-(p-acetomidophenyl)-3-(4-pyridylmethyl)-2-thiourea.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2[F:36])[CH2:2]1.[CH3:38][C:39]([CH3:41])=O>>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[C:11]([O:13][CH3:14])=[CH:12][C:7]([C:6]([NH:5][CH:3]5[CH2:2][N:1]([CH:39]([CH3:41])[CH3:38])[CH2:4]5)=[O:37])=[C:8]([F:36])[CH:9]=4)=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)=O
Product: COc1cc(C(=O)NC2CN(C(C)C)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized by following the Reductive Amination Procedure using N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide and acetone. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.06 Hz, 6H) 1.44-1.80 (m, 6H) 1.95 (br. s., 2H) 2.27 (m, 6.09 Hz, 1H) 2.89 (t, J=7.33 Hz, 2H) 3.50 (t, J=7.33 Hz, 2H) 3.92 (s, 3H) 4.08 (t, J=13.89 Hz, 2H) 4.29-4.42 (m, 1H) 4.72-4.89 (m, 1H) 7.19 (d, J=6.82 Hz, 1H) 8.05 (s, 1H) 8.25 (d, J=13.39 Hz, 1H) 8.29-8.32 (m, 1H) 8.40 (d, J=7.07 Hz, 1H). [M+H] calculated for C27H34F3N7O3, 562. found 562.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].Br[CH2:26][C:27]#[C:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][CH:30]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:26][C:27]#[C:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:31][CH:30]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: BrCC#Cc1ccc(OCCCCOc2ccccc2)cc1
Product: COC(=O)c1ccc(OCC#Cc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 1-(3-bromoprop-1-yn-1-yl)-4-(4-phenoxy-butoxy)benzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)[CH2:9]O)=[N:6][CH:7]=1.[H-].[Na+].CI.CN([CH:28]=[O:29])C>O.C(OCC)(=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:15][CH2:16]2)([O:29][CH3:28])[CH3:9])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: COC(=O)[C@H]1CC[C@H](C(CO)c2ccc(Br)cn2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](C(C)(OC)c2ccc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Racemic methyl trans-4-[1-(5-bromopyridin-2-yl)hydroxyethyl]cyclohexanecarboxylate (500 mg, 1.461 mmol) was dissolved in DMF (7.3 mL) and cooled to 0° C. Sodium hydride (60 wt %, 117 mg, 2.92 mmol) was added in one portion. The mixture was stirred and allowed to warm to room temperature. After 20 minutes, methyl iodide (0.183 mL, 2.92 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. The mixture was diluted with water, ethyl acetate, and brine. The layers were separated, and the organic portion dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel column chromatography (20% EtOAc:hexanes) gave racemic methyl trans-4-[1-(5-bromopyridin-2-yl)-1-methoxyethyl]cyclohexanecarboxylate as a colorless oil. MS ESI calcd. for C16H23BrNO3 [M+H]+ 356 and 358. found 356 and 358. 1H NMR (500 MHz, DMSO-d6) 8.64 (d, J=2.2 Hz, 1H), 8.01 (dd, J=2.3, 8.5 Hz, 1H), 7.37 (d, J=9.1 Hz, 1H), 3.54 (s, 3H), 2.98 (s, 3H), 2.20-1.50 (m, 5H), 1.55 (s, 3H), 1.40-0.75 (m, 5H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([OH:27])[C@@H:18]([NH:20]C(=O)C(F)(F)F)[CH3:19])=[CH:13][C:12]=1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO>[NH2:20][C@@H:18]([CH3:19])[C@@H:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[C:12]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:13]=1)[OH:27]
Reactant: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](N)[C@H](O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Yield: 810.7 %

Procedure:
A 5 mol/L aqueous solution of sodium hydroxide (6.3 mL) was added to a solution of N-[(1S,2R)-2-(4-benzyloxy-3-methanesulfonylaminophenyl)-2-hydroxy-1-methylethyl]-2,2,2-trifluoroacetamide (5.5 g) in methanol (100 mL) at room temperature, and the mixture was heated under reflux for 5.5 hrs. After being cooled to room temperature, 2 mol/L hydrochloric acid (15.7 mL) was added to the mixture. The solvent was evaporated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluent: ethanol) to afford the title compound (35 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.N1C=CC=CC=1>O>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][S:31]([C:28]4[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=4)(=[O:33])=[O:32])=[CH:3][CH:4]=3)[CH:10]=2)=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)n(C)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 102 %

Procedure:
A mixture of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (750 mg, 2.32 mmol), p-toluenesulfonyl chloride (486 mg, 2.55 mmol) and pyridine (6 mL) was stirred at 80° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure and dried to give the title compound (1.13 g, 99%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[C:45]([CH3:50])=[N:46][O:47][C:48]=1[CH3:49]>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[C:45]([CH3:50])=[N:46][O:47][C:48]=3[CH3:49])=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: Cc1noc(C)c1Br
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3c(C)noc3C)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 4-bromo-3,5-dimethylisoxazole.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:16][CH2:17][CH2:18][CH:19]=C)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1.BrC1C(NCCCC=C)=CC=CN=1.CC([O:38]C(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[O:38]=[C:19]1[CH2:18][CH2:17][CH2:16][N:8]([C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]1=2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=CCCCN(C(=O)OC(C)(C)C)c1cccnc1Br
Agent: C=CCCCNc1cccnc1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(=O)c2ncccc21
Temperature: 25 °C

Procedure:
tert-butyl (2-bromopyridin-3-yl)(pent-4-en-1-yl)carbamate. To a solution of 2-bromo-N-(pent-4-en-1-yl)pyridin-3-amine (1 eq.) and DCM (0.2 M) is added (Boc)2O (1.5 eq.). The solution is stirred at room temperature until judged complete by TLC. The solution is concentrated in vacuo and purified by column chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1)=[O:6].[OH:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.CN(C)CC(O)=O>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([O:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:11]=[CH:10][N:9]=1)=[O:6]
Reactant: O=C(Nc1cc(Cl)ccn1)c1cccc(Cl)c1
Reactant: Oc1cccnc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cc(Oc2cccnc2)ccn1)c1cccc(Cl)c1
Temperature: 90 °C
Yield: 38.8 %

Procedure:
Compound 1 (50 mg, 0.19 mmol, 1.0 eq), 3-hydroxypyridine (26.7 mg, 0.281 mmol, 1.50 eq), CuI (3.7 mg, 0.019 mmol, 0.10 eq), Cs2CO3 (122 mg, 0.374 mmol, 2.00 eq) and N,N-dimethylglycine hydrochloride (7.8 mg, 0.056 mmol, 0.30 eq) were dissolved in 1,4-dioxane (1 mL) in a flame-dried sealed tube and heated overnight at 90° C. The reaction was cooled to rt, plugged through celite and concentrated. Purification by flash chromatography on silica gel afforded 24 mg (40%) of the title compound as a pale yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.55-8.53 (m, 2H), 8.31 (d, J=5.7 Hz, 1H), 8.01 (m, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.73 (ddd, J=8.4, 2.6, 1.2 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.55 (dd, J=8.4, 4.7 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H) 6.82, (dd, J=5.7, 2.4 Hz, 1H); ES-MS [M+1]+: 326.1.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:7]=1[CH3:21])=[O:4].[CH3:22][C:23]1([CH3:33])[N:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:26]2[C:25](=[O:32])[NH:24]1.C(N(CC)CC)C>CN(C)C=O>[CH3:21][C:7]1[CH:8]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:30]1[CH2:29][CH2:28][N:27]2[C:23]([CH3:33])([CH3:22])[NH:24][C:25](=[O:32])[CH:26]2[CH2:31]1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CCl
Reactant: CC1(C)NC(=O)C2CNCCN21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CN1CCN2C(C1)C(=O)NC2(C)C
Temperature: 70 °C
Reaction time: 20 h
Yield: 66.8 %

Procedure:
A mixture of 13.36 parts of 2-chloro-N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]acetamide, 6.76 parts of hexahydro-3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one, 7.8 parts of N,N-diethylethanamine and 180 parts of N,N-dimethylformamide was stirred for 20 hours at 70° C. The reaction mixture was evaporated. The residue was taken up in water and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 11.66 parts (66.8%) of N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]hexahydro-3,3-dimethyl-1-oxoimidazo-[1,5-a]pyrazine-7(8H)-acetamide; mp. 223.8° C. (int. 1).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:8]([C:6]5[C:5]([CH3:11])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:45]=[CH:44][CH:43]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: CCn1cc(C(=O)O)c(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CCn1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C)n1
Yield: 79.9 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (198 mg, 1.28 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (230 mg, 80%) was obtained as a white solid.
Reaction SMILES: [Na:1].N1(C2(OC[C@H](OCP(O)(O)=O)C2)O)C=C(C)C(=O)NC1=O.[O:23]=[CH:24][C@H:25]([C@@H:27]([CH2:29][OH:30])[OH:28])[OH:26].[N:31]1([C:39]2([O:56][CH2:55][C@H:42]([O:43][CH2:44][P:45]([O:51]C(C)C)([O:47]C(C)C)=[O:46])[CH2:41]2)[OH:40])[CH:38]=[CH:37][C:35]([NH2:36])=[N:34][C:32]1=[O:33].I[Si](C)(C)C>>[Na:1].[O:23]=[CH:24][C@H:25]([C@@H:27]([CH2:29][OH:30])[OH:28])[OH:26].[N:31]1([C:39]2([O:56][CH2:55][C@H:42]([O:43][CH2:44][P:45]([OH:47])([OH:51])=[O:46])[CH2:41]2)[OH:40])[CH:38]=[CH:37][C:35]([NH2:36])=[N:34][C:32]1=[O:33]
Reactant: CC(C)OP(=O)(CO[C@H]1COC(O)(n2ccc(N)nc2=O)C1)OC(C)C
Agent: C[Si](C)(C)I
Agent: Cc1cn(C2(O)C[C@@H](OCP(=O)(O)O)CO2)c(=O)[nH]c1=O
Agent: O=C[C@@H](O)[C@H](O)CO
Product: Nc1ccn(C2(O)C[C@@H](OCP(=O)(O)O)CO2)c(=O)n1
Yield: 73 %

Procedure:
This compound was prepared as described for 3f, using 22 (200 mg, 0.53 mmol) as a starting material and iodotrimethysilane (0.6 mL, 4.2 mmol). Compound 3h (130 mg, 0.38 mmol) was obtained as a colorless solid, in 73% yield, which was characterized as follows:
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][C:20]#[C:21][CH2:22]Cl.O>CN(C=O)C>[Cl:18][CH2:19][C:20]#[C:21][CH2:22][N:2]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCC#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC#CCCl
Temperature: 80 °C
Reaction time: 5 h
Yield: 28.8 %

Procedure:
To a solution of 1H-isoindole-1,3(2H)-dione (441 mg) in DMF (5 mL) were added potassium carbonate (829 mg) and 1,4-dichlorobut-2-yne (2.21 g) at room temperature. The reaction mixture was stirred at 80° C. for 5 hr. The reaction mixture was added to water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (202 mg).