Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-])=O.C(O)C.O.O.[Sn](Cl)Cl>C(=O)(O)[O-].[Na+]>[CH2:11]1[C:12]2[NH:13][C:14]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=3)[C:7]=2[CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2[nH]c3c(c2c1)CCCC3
Temperature: 70 °C
Yield: 95.3 %

Procedure:
6-Nitro-2,3,4,9-tetrahydro-1H-carbazole (0.100 g, 0.462 mmol) was dissolved in a 40 mL scintillation vial containing a magnetic stir bar and 2 mL of ethanol. Tin(II) chloride dihydrate (1.04 g, 4.62 mmol) was added to the reaction mixture and the resulting suspension was heated at 70° C. for 16 h. The crude reaction mixture was then diluted with 15 mL of a saturated aqueous solution of sodium bicarbonate and extracted three times with an equivalent volume of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate, and evaporated to dryness to yield 2,3,4,9-tetrahydro-1H-carbazol-6-amine (82 mg, 95%) which was used without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[N+](=[CH2:15])=[N-]>CCOCC>[Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:15])=[O:7]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccccc1CCBr
Solvent: CCOCC
Product: COC(=O)c1ccccc1CCBr

Procedure:
2-(2-Bromoethyl)-benzoic acid (11.4 g, 50 mmol) is added to a solution of diazomethan in ether at 0° C. The reaction mixture is concentrated in vacuo, and the residue purified by chromatography to give the desired compound as a colourless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[N:14]=[C:15]([CH3:17])[CH:16]=[C:12]3[N:11]=[C:10]([NH:18][C:19](=[O:30])[C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[CH:9]=2)[CH2:4][CH2:3]1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>N1C=CC=CC=1>[CH:31]1([C:34]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]3[N:13]4[N:14]=[C:15]([CH3:17])[CH:16]=[C:12]4[N:11]=[C:10]([NH:18][C:19](=[O:30])[C:20]4[CH:21]=[CH:22][C:23]([C:26]([OH:29])([CH3:27])[CH3:28])=[CH:24][CH:25]=4)[CH:9]=3)[CH2:4][CH2:3]2)=[O:35])[CH2:33][CH2:32]1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(N)CC3)n2n1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(NC(=O)C4CC4)CC3)n2n1
Temperature: 25 °C
Yield: 7.5 %

Procedure:
N-(7-(4-aminopiperidin-1-yl)-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (6B, 250 mg, 0.612 mmol) was dissolved in anhydrous pyridine (1.2 mL). Cyclopropanecarbonyl chloride (61 μL, 0.673 mmol) was added at 0° C., and the mixture was stirred in an ice bath and warmed to room temperature. The reaction was complete as determined by LCMS analysis. The reaction was then quenched with saturated NaHCO3; pyridine was removed in vacuo and the residue was extracted with EtOAc. Purification by preparatory HPLC (30-50% MeCN/H2O gradient+0.01% TFA) provided the titled compound as a white solid (22 mg, 8%). Melting point (214.0-214.1° C.). 1H NMR (DMSO-d6) δ: 10.83 (s, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.99 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.6 Hz, 2H), 7.36 (s, 1H), 6.15 (s, 1H), 4.35 (br. s., 2H), 3.93 (br. s., 2H), 3.15-3.26 (m, 2H), 2.38 (t, 3H), 1.92 (d, J=9.9 Hz, 2H), 1.48-1.71 (m, 3H), 1.45 (s, 6H), 0.55-0.73 (m, 4H). ESI-MS: m/z 477.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[CH3:13][C:14]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].ON1C2C=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:14]=1[CH3:13])=[O:9])([O-:3])=[O:2]
Reactant: Cc1cccc(N)c1C
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1C
Reaction time: 16 h

Procedure:
To a solution of 3-nitrobenzoic acid (3.0 g ) and 2,3-dimethylaniline (2.17 g) in 20 mL of DMF was added 1-hydroxybenzotriazole (2.75 g), EDC (3.44 g) and triethylamine (7.39 mL). The resulting solution was stirred for 16 h. The DMF was evaporated in vacuo and the residue was partitioned with ethyl acetate and water. The ethyl acetate layer was extracted w/50 mL each of 2% potassium hydrogen sulfate, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a solid. NMR (300 MHz, CDCl3) δ 8.72 (1H, s), 8.40 (1 H, d, J=6 Hz), 8.26 (1H, d, J=9 Hz), 7.93 (IH, s), 7.69 (1H, t, J=9 Hz), 7.45 (1 H,d, J=9 Hz), 7.14 (1H, t, J=8 Hz), 7.08 (1H, d, J=9 Hz), 2.32 (3H, s), 2.21 (3H, s).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][C@H:15]([CH3:24])[CH2:16][O:17]C3CCCCO3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>C(O)C>[CH:10]1[C:11]2[N:12]([CH2:14][C@H:15]([CH3:24])[CH2:16][OH:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](COC1CCCCO1)Cn1c2ccccc2c2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@H](CO)Cn1c2ccccc2c2ccccc21
Temperature: 50 °C
Reaction time: 24 h
Yield: 6.5 %

Procedure:
Compound 9 (0.47 g, 0.0145 mol) was mixed with pyridinium-4-toluene-sulfonate (PPTs) (0.037 g, 0.15 mmol) in ethanol (20 mL). The resulting mixture was stirred at 50° C. for 24 h. The solvent was evaporated in vacuo. Purification of the crude product on a silica gel column (Eluent: ethyl acetate/n-heptane (1:1)) gave the title compound 0.226 g (65%) as a solid. M.p. 80-81° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[SH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)CCCS
Product: CCOC(=O)CCCSc1ccc(Br)cc1C=O
Yield: 78 %

Procedure:
Ethyl 4-(4-bromo-2-formylphenylthio)butyrate was synthesized from 5-bromo-2-fluorobenzaldehyde and ethyl 4-mercaptobutyrate in the same manner as Example 2. After column chromatography, crystallization from hexane/isopropyl ether yielded ethyl 4-(4-bromo-2-formylphenylthio)butyrate (Yield 78%) as yellow crystals.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](O)[CH:8]=[C:7]([CH2:12][CH2:13][O:14][CH3:15])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:18].O>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([C:5]1[N:10]=[C:9]([Cl:18])[CH:8]=[C:7]([CH2:12][CH2:13][O:14][CH3:15])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCc1cc(O)nc(C(C)(C)C)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COCCc1cc(Cl)nc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 2-tert-butyl-6-(2-methoxy-ethyl)-pyrimidin-4-ol (20 g, 95 mmol) in toluene (200 mL) and DMF (2 mL) was added dropwise POCl3 (36.5 g, 238 mmol) in an ice bath. The mixture was stirred for 3 hrs at room temperature. The reaction mixture was poured into water, extracted with DCM (400 mL×3). The organic layer was dried over Na2SO4 and concentrated to give the title compound (20 g, 92% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([C:14]2(O)[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:12][CH:11]=[C:10]([N:22]2[CH2:26][C@@H:25]([O:27][CH3:28])[C@H:24]([OH:29])[CH2:23]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([C:8]1[C:13]([C:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH:15]=2)=[CH:12][CH:11]=[C:10]([N:22]2[CH2:26][C@@H:25]([O:27][CH3:28])[C@H:24]([OH:29])[CH2:23]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2ccc(C3(O)CCN(C)CC3)c(Cc3ccccc3)n2)C[C@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CO[C@@H]1CN(c2ccc(C3=CCN(C)CC3)c(Cc3ccccc3)n2)C[C@H]1O
Temperature: 70 °C
Reaction time: 9 h
Yield: 17 %

Procedure:
A mixture of 63.0 mg of 4-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]-1-methyl-4-piperidinol (Example 3) and 1.5 ml of 1 M acetic acid solution of hydrogen chloride was stirred at 70° C. for 9 hours. The reaction mixture was neutralized with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed. To the residue were added 50 mg of potassium carbonate and 1 ml of methanol, followed by stirring at room temperature for 1 hour. NH-silica gel was added to the reaction mixture and the solvent was removed. It was purified by NH-silica gel column chromatography with 5% methanol/ethyl acetate, to give 10.2 mg of the title compound.
Reaction SMILES: [H-].[Na+].[S:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[O:13].C(OCC)(=O)C>CN(C=O)C.CCCCCC.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12](=[O:13])[CH2:11][N:5]2[C:6](=[O:8])[CH2:7][S:3][C:4]2=[O:9])=[CH:15][CH:16]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CN1C(=O)CSC1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
To a suspension of 3.15 g of sodium hydride (60% in mineral oil, 78.8 mmol) in 70 mL of DMF at 0° C. was added 9.76 g (75 mmol) of 2,4-thiazolidinedione portion-wise. The reaction mixture was stirred for 20 minutes, then 17.5 g of 2-bromo-4′-chloroacetophenone (75 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 5 hours. Ethyl acetate and water were added, the organic phase was separated, and washed with water and brine. The combined aqueous extracts were washed with additional ethyl acetate which was then washed with water and brine and combined with the rest of the organic layer. The ethyl acetate phases were dried over magnesium sulfate, filtered and stripped to give 23 g of crude product. Recrystallization from 1:1 toluene:hexane gave 16.25 g of 3-(2-(4-chlorophenyl)-2-oxo-ethyl)-thiazolidine-2,4-dione, (85% yield) mp 122–124° C.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][C:21]([O:23]CC)=O.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][C:31]=1[C:32]#[N:33]>C1COCC1>[NH2:33][C:32]1[C:31]2[CH:30]=[CH:29][S:28][C:27]=2[NH:26][C:21](=[O:23])[C:20]=1[C:12]1[NH:11][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=1
Reactant: N#Cc1ccsc1N
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(-c2nc3ccccc3[nH]2)c(=O)[nH]c2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiHMDS (4.3 eq) was added to ethyl 1H-benzimidazol-2-ylacetate (1.1 eq) and 2-aminothiophene-3-carbonitrile (1.0 eq) in THF at 0° C. After 1 hour, the resulting mixture was warmed to room temperature and then stirred overnight. The mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a brown solid. LC/MS m/z 283.1 (MH+), Rt 1.88 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].CC1(C)CC1C(N[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=O>CN(C)C=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:30]2[CH2:31][CH2:32][CH2:27][CH2:28][CH2:29]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC1(C)CC1C(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-nitrobenzyl bromide (24:X=Br) (110 mg, 0.5 mmol), potassium carbonate (352 mg, 2.55 mmol) and sodium iodide (76.5 mg, 0.5 mmol) were added to a dimethylformamide (5mil) solution of the piperidine (23) obtained in the process 1, and then stirred under the argon atmosphere at the room temperature for 2 hours. This was further stirred at 70° C. for 1 hour and was extracted with hexan-ethyl acetate (3:1) mixed solvent, and then washed with water and saturated saline solution, dried and vacuum concentrated, thus obtained a 4-nitrobenzylpiperadine compound (25:R=2,2-dimethylcyclopropane) in the form of a yellow crystal (95 mg, 57%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]1[CH2:9][CH2:10]2)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:6][CH:7]1[CH2:12][CH:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]1[CH2:9][CH2:10]2)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(COS(C)(=O)=O)C2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1C(CN=[N+]=[N-])C2
Temperature: 100 °C
Yield: 92.8 %

Procedure:
To the title compound of step A (3.4 g, 11.1 mmol) in DMF (15 mL) was added sodium azide (2.1 g, 33.4 mmol). The mixture was heated at 100° C. overnight, cooled to rt, poured into H2O and extracted with DCM. The combined organics were washed with brine and dried (Na2SO4). Purification via silica gel chromatography (10% EtOAc in petroleum ethers) gave the title compound (2.6 g).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][N:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:23]=[CH:22]4)[C:15]2=[O:35])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CC(O)=O.[Pd]>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:23]=[CH:22]4)[C:15]2=[O:35])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1N(c2ccc(Oc3ccccc3)cc2)CCN1c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-(4-phenoxyphenyl)-3-[1-(2-pyrrolidin-1-ylethyl)-1H-indazol-5-yl]-1,3-dihydro-2H-imidazol-2-one (Example 118) (0.100 g, 0.215 mmol) was dissolved in 20 mL of AcOH and 100 mg of Pd/C (10% mol/mol) was added. The mixture was subjected to an atmosphere of hydrogen gas at a pressure of 60 psi in a Parr shaker apparatus, and shaken at room temperature for 6 hours. The mixture was filtered through celite, and the solvents removed under reduced pressure. The residue was purified by RP-HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.52–1.77 (m, 4 H) 2.34–2.50 (m, 4 H) 2.87 (t, J=6.61 Hz, 2 H) 3.88–4.13 (m, 4 H) 4.50 (t, J=6.61 Hz, 2 H) 6.93–7.02 (m, J=7.80 Hz, 2 H) 7.03–7.15 (m, 3 H) 7.33–7.45 (m, J=8.65, 7.29 Hz, 2 H) 7.61–7.72 (m, 3 H) 7.72–7.78 (m, J=2.03 Hz, 1 H) 7.79–7.89 (m, 1 H) 8.02 (s, 1 H); MS (ESI) m/z 468 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(COC)OC.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccccc2)cc1Cl
Temperature: 25 °C

Procedure:
0.30 g of methyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate, 0.19 g of bromobenzene, 57mg of 1,1-bis(diphenylphosphino)ferrocene dichloropalladium and 0.55 g of potassium carbonate were dissolved in 15 ml dimethoxyethane, and the mixture was heated under reflux for 1 hour. After cooling the reaction solution to room temperature, ethyl acetate and water were added thereto. The mixture was filtered through Celite, and the mother liquor was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (5:1), methyl 2-chloro-4-phenylbenzoate was obtained. Then, the resulting methyl 2-chloro-4-phenylbenzoate was dissolved in 4 ml methanol, and 2 ml of 1N sodium hydroxide was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was ice-cooled and neutralized with 1N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated, to give 0.12 g of 2-chloro-4-phenylbenzoic acid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]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>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[C:6]2=[N:7][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N:25]4[CH2:24][CH2:23][O:22][CH2:27][CH2:26]4)[CH:33]=3)=[CH:3][N:4]=[C:5]2[NH:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4cccc(N5CCOCC5)c4)nc32)c1Cl
Temperature: 90 °C
Yield: 61 %

Procedure:
A mixture of 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine (0.14 mmol, 51 mg), 3-morpholinophenylboronic acid pinacol ester (0.16 mmol, 46 mg), and Pd(PPh3)4 (0.015 mmol, 17 mg) was placed in a Schlenk tube. This tube was degassed via 3 cycles of vacuum—refill with N2. THF (3 mL, from sureseal bottle) and aqueous K2CO3 (2.0 M, 1 mL, degassed by bubbling with N2 for 10 min) was then added to the solid mixture in the Schlenk tube. The reaction was stopped after heating at 90° C. for 16 hrs. Extraction and concentration of combined organic layers gave a residue, which was purified on a silica gel column by using 6:1 ratio of CH2Cl2/MeOH (pre-saturated with ammonia gas) as eluents, furnishing 1-(2-chloro-3,6-difluorobenzyl)-7-[3-(morpholin-4-yl)phenyl]-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine in 61% yield (38 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[F:10][C:11]([F:22])([F:23])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]#[N:9])=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1ccc(OC(F)(F)F)cc1
Yield: 70 %

Procedure:
Prepared in 70% yield from 2-chloro-3-cyanopyridine and 4-trifluoromethoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 265.0 (M+H)+; 1H NMR (CDCl3) δ 7.37-7.44 (m, 3H), 7.98-8.03 (m, 2H), 8.10 (dd, J=8.0, 1.9 Hz, 1H), 8.89 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([CH2:5][Cl:6])[CH:3]=[O:4].[CH:8]([NH2:10])=[O:9]>>[OH:4][CH:3]([NH:10][CH:8]=[O:9])[C:2]([Cl:7])([Cl:1])[CH2:5][Cl:6]
Reactant: O=CC(Cl)(Cl)CCl
Reactant: NC=O
Product: O=CNC(O)C(Cl)(Cl)CCl
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A mixture consisting of 16.2 gm of 2,2,3-trichloropropionaldehyde and 4.5 gm of formamide was stirred on a boiling water bath for 30 minutes. Recrystallization of the reaction product from benzene yielded 17 gm of the desired compound, m.p. 105°-109° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Br:17][C:16]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=12
Reactant: Fc1ccc(-c2cc3ncccn3n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: Fc1ccc(-c2nn3cccnc3c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine (5.8 g, 0.027 mol) in chloroform (60 mL) is added, at 0° C., N-bromosuccinimide (4.8 g, 0.027 mol). The mixture is stirred at room temperature for 1 h 30. The reaction mixture is then poured into water and extracted with dichloromethane (3×100 mL). The organic layer is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is filtered through a short pad of silica. 6 g (75%) of 3-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine are obtained as a brown solid which is used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([CH:5]([N:7]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]([NH:17][C:18](=[O:20])[CH3:19])[C:8]1=[O:21])[CH3:6])=[O:4]>C(O)C.[Pd]>[C:18]([NH:17][C@H:9]([C:8]([NH:7][C@H:5]([C:3]([OH:4])=[O:2])[CH3:6])=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:20])[CH3:19]
Reactant: COC(=O)C(C)N1C(=O)C(NC(C)=O)C1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](C)C(=O)O
Reaction time: 7 h
Yield: 101.7 %

Procedure:
According to the same procedure as in Example 1, 1-(1-methoxycarbonylethyl)-3-acetylamino-4-phenylazetidin-2-one (400 mg.) was subjected to hydrogenolysis at 50° C. in ethanol (30 ml.) under a hydrogen pressure of one atmosphere in the presence of a 10% Pd-C (580 mg.). The reaction was completed in 7 hours. The same after-treatment as in Example 1 was followed to give methyl ester of N-acetylphenylalanylalanine (390 mg., yield: 96.8%) melting at 147.0°-155.0° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl-].[CH3:28][O:29][NH2+:30][CH3:31].C(N(C(C)C)CC)(C)C>CCOCC.O1CCCC1>[CH3:28][O:29][N:30]([CH3:31])[C:12]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1)=[O:14]
Reactant: C[NH2+]OC
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a 100 ml round bottom flask was added 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (3.75 g, 18.6 mmol) and 20 ml tetrahydrofuran, followed by CDI (3.63 g, 22.4 mmol). Vigorous gas evolution was observed. After gas evolution stopped, the reaction mixture was stirred at room temperature for additional 30 minutes. Methoxy(methyl)ammonium chloride (2.55 g, 26.1 mmol) was added, followed by diisopropylethyl amine (6.5 ml, 37.3 mmol). The resulting reaction mixture was stirred at room temperature overnight. It was diluted with 120 ml ether and washed with 60 ml saturated NH4Cl. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column, eluted with 1:2 to 3:2 ethyl acetate/hexane to give 3.6 g desired product was colorless oil.