Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:29][CH3:30])=[C:18]([O:21]CC5C=CC=CC=5)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C([O-])=O.[NH4+].O>[Pd].CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:29][CH3:30])=[C:18]([OH:21])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][N:8]=2)[CH:3]=[CH:2]1
Reactant: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A solution of 4-(7-azaindol-5-yloxy)-6-benzyloxy-7-methoxyquinazoline (0.36 g, 0.873 mmol), ammonium formate (0.55 g, 8.73 mmol) and 10% palladium on carbon (0.05 g) in DMF (7 ml) containing water (0.3 ml) was stirred at ambient temperature for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was triturated under diethyl ether and the solid was filtered, washed with ether and dried under vacuum. The solid was triturated under water, filtered, washed with water and dried under vacuum over P2O5 to give 4-(7-azaindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.26 g, 85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].C([O:11][C:12](=O)[CH2:13][C:14]([CH3:16])=O)C>>[CH3:16][C:14]1[CH2:13][C:12](=[O:11])[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)CC(C)=O
Product: CC1=NN(c2ccccn2)C(=O)C1

Procedure:
From the reaction of 2-pyridylhydrazine and ethylacetoacetate, 2,4-dihydro-5-methyl-2-(2-pyridyl)-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 4-(2-ethylanilinomethylene)-2,4-dihydro-5-methyl-2-(2-pyridyl)-3H-pyrazol-3-one, Mp 182.9° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:10]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19](Br)=[N:20][CH:21]=2)[CH:14]=[CH:13][N:12]=[CH:11]1>>[Cl:1][C:2]1[S:6][C:5]([C:19]2[CH:18]=[CH:17][C:16]([CH2:15][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)=[CH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: Clc1ccc(-c2ccc(Cn3ccnc3)cn2)s1

Procedure:
Synthesized using 5-chloro-2-thiophenylboronic acid (205 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 83 mg, 0.30 mmol, 47%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.17 (s, 2H), 6.91-6.92 (m, 2H), 7.13 (s, 1H), 7.33 (d, J=4.0 Hz, 1H), 7.46 (dd, J=8.2, 2.1 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.80 (s, 1H), 8.42 (d, J=1.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.3, 118.16, 119.1, 124.2, 127.3, 129.5, 129.8, 133.1, 135.9, 137.2, 142.5, 148.5, 152.1; MS (ESI): m/z=275.98 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.[CH2:6]([O:8][C:9](=[O:22])[CH2:10][C:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH3:13])[CH3:12])[CH3:7].[Li+].CC([N-]C(C)C)C.C(Br)C=C>C(OCC)C>[CH2:6]([O:8][C:9](=[O:22])[CH:10]([C:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH3:13])[CH3:12])[CH2:5][CH:1]=[CH2:2])[CH3:7]
Reactant: CCOC(=O)CC(C)(C)c1ccc(Cl)cc1Cl
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: CCOCC
Product: C=CCC(C(=O)OCC)C(C)(C)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 52 %

Procedure:
Cool a THF solution of 1.0 equivalent of 3-(2,4-Dichloro-phenyl)-3-methyl-butyric acid ethyl ester, obtained above, to −78° C., treat with LDA (2.0 eq), followed by allyl bromide (1.1 eq), warm to room temperature and stir 17 h. Quench reaction with NH4Cl, dilute with diethyl ether, wash organics with 0.1 N HCl, brine, dry over sodium sulfate, filter and evaporate. Chromatography, (silica, hexanes/EtOAc, 98:2) provides 2-[1-(2,4-dichloro-phenyl)-1-methyl-ethyl]-pent-4-enoic acid ethyl ester in 52% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[CH:31][C:32]=1[F:33]>>[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35](=[O:36])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)cc3)cc2C1=O

Procedure:
The compound of example 31 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 3,4-difluorophenyl isocyanate. The compound of example 31 was used directly without isolation for the preparation of compound of example 32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:41])=[O:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:50][CH2:49]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Agent: Cl
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CCCS(C)(=O)=O)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. LC-MS: 701.2 [(M+H)+]
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[Cl-].[OH:34][NH3+:35].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:34][N:35]=[C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:15]([F:16])([F:17])[F:18])=[O:12])=[CH:5][C:4]=1[C:29]([F:30])([F:32])[F:31])[NH2:2]
Reactant: N#Cc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F

Procedure:
1.17 g (2.51 mmol) of (2E)-3-[4-cyano-3-(trifluoromethyl)phenyl]-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}acrylamide from Example Ia-46 were initially charged in a mixture of 11.7 ml of ethanol and 2.9 ml of water and admixed with 209.6 mg (3.01 mmol) of hydroxylammonium chloride and 399.5 mg (3.77 mmol) of sodium carbonate. The reaction mixture was heated under reflux for 18 hours and then admixed with water. After extracting repeatedly with ethyl acetate, the combined organic phases were dried over magnesium sulphate, the solvent was distilled off under reduced pressure and the residue was chromatographed using silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 0% ethyl acetate to 100% ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[Br:14]Br>CCOCC>[Br:14][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: BrBr
Reactant: COc1ccc2c(c1)CCCC2=O
Solvent: CCOCC
Product: COc1ccc2c(c1)CCC(Br)C2=O

Procedure:
6-Methoxytetralone (2.0 g, 11.4 mmol) and bromine (0.6 ml, 11.7 mmol) were refluxed in ether (50 ml) for 30 minutes. The reaction mixture was cooled, concentrated, the residue partitioned between ethyl acetate and dilute NaHSO3. The organic layer was washed with saturated NaHCO3 and water, dried over CaSO4, and concentrated to an oil (2.83 g, 100%); 1H-NMR 8.03 (d, J=9.0Hz, 1H), 6.84 (dd, J1 =9.0 Hz, J2 =2.7 Hz, 1H), 6.69 (d, J=2.3 Hz, 1H), 4.66 (t, J=4.1Hz, 1H), 3.84 (s,3H), 3.20-3.30 (m, 1H), 2.82-2.90 (m, 1H), 2.34-2.50 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24]([CH:7]2[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]2)=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(Cl)CCc1cccc(F)c1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CCc2cccc(F)c2)C1
Yield: 48 %

Procedure:
tert-Butyl 3-(3-(3-fluorophenyl)propanoyl)-4-oxopiperidine-1-carboxylate (285 mg, 48%) was synthesised from tert-butyl 4-oxopiperidine-1-carboxylate and 3-(3-fluorophenyl)propanoyl chloride according to the general procedure for the preparation of diketones. MS (ES+) m/z 250 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4cccc(F)c4)C3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3cccc(F)c3)C2)n1
Temperature: 150 °C
Yield: 70.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(3-fluorophenyl)-3-piperidinecarboxamide (90 mg, 0.207 mmol), 3 mL of EtOH, Hunig's base (0.109 mL, 0.621 mmol), and hydrazine anhydrous (0.026 mL, 0.829 mmol) were added, and the yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned into black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (65 mg) as a light yellow solid. LC-MS (ES) m/z=447 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.35-1.44 (m, 1H), 1.69 (m, 1H), 1.91-2.11 (m, 2H), 2.12-2.27 (m, 1H), 2.61-2.78 (m, 1H), 3.39-3.80 (m, 1H), 4.24-4.41 (m, 1H), 4.68-5.17 (m, 1H), 6.85 (m, 2H), 7.22-7.47 (m, 3H), 7.51-7.60 (m, 1H), 7.79 (m, 1H), 7.89-8.01 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[CH2:25]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1)[CH3:26]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[C@H:27]([CH2:25][CH3:26])[CH2:31][O:30][C:29]4=[O:32])=[C:3]([F:24])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Reactant: CC[C@@H]1COC(=O)N1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1F
Yield: 57.7 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 66 and (R)-4-ethyloxazolidin-2-one (138 mg) described in Preparation Example 26, the title compound (246 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)C(C)C)C.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(OCC)C>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CCCBr
Reactant: Nc1ccccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Yield: 63.7 %

Procedure:
30.0 g of 2-aminobiphenyl, 23.4 g of ethyl diisopropylamine and 35.4 g of ethyl 4-bromobutyrate are heated together to 150° for 3 hours while stirring. After cooling, the reaction product is stirred with diethyl ether, the precipitated salt is filtered off, and the residue (remaining after evaporating off the ether) is recrystallized from isopropyl alcohol to obtain 32.0 g (63.7% of theory) of ethyl 4-(biphenyl-2-yl)aminobutyrate, MP 60° to 62°.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](S(C)=O)[N:8]([CH3:15])[C:7]2=[O:16].IC1C=CC=C2C=1N=C(S(C)(=O)=[O:29])N(C)C2=O.O[Li].O>C1COCC1.O>[OH:29][C:9]1[N:8]([CH3:15])[C:7](=[O:16])[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cn1c(S(C)=O)nc2c(I)cccc2c1=O
Reactant: Cn1c(S(C)(=O)=O)nc2c(I)cccc2c1=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(O)nc2c(I)cccc2c1=O
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
A suspension of 8-iodo-3-methyl-2-(methylthio)quinazolin-4(3H)-one (700a; 15 g, 45.2 mmol) in 400 mL of DCM was set stirring at 0° C. before adding 3-chlorobenzoperoxoic acid (15.59 g of 77% max. Aldrich, 70 mmol) portion wise over 10 min. The ice bath was removed; and the reaction mixture was stirred at RT for 30 min. It was diluted with 200 mL of DCM, washed sequentially with ice cold 2×50 mL of saturated Na2CO3 followed by sat. Na2SO3 solution and 15 mL of brine. The organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to give yellow crystalline solid (700b) containing a mixture of 8-iodo-3-methyl-2-(methylsulfinyl)quinazolin-4(3H)-one and 8-iodo-3-methyl-2-(methylsulfonyl)quinazolin-4(3H)-on. The crude material of yellow crystalline solid (700b) in 40 mL of THF and 40 mL of water at RT was treated with LiOH—H2O (6.60 g, 275 mmol). The reaction mixture was stirred in an oil bath at 75° C. for 2.5 h. It was concentrated to half of its volume under reduced pressure. The precipitated solid was filtered, rinsed with 2×5 mL of water followed by 2×5 mL of ether. The off-white crystalline solid was dried in a vacuum oven at 45° C. for 48 h to give 2-hydroxy-8-iodo-3-methylquinazolin-4(3H)-one (700c; 12.79 g, 42.3 mmol, 94% yield). The crude material was used in the next step. m/z (ES, +ve) 302.9 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][NH:15][CH2:14][CH2:13][NH:12]2)[CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH3:3].C(N(CC)CC)C.[N+:25]([C:28]1[S:32][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:29]=1)([O-:27])=[O:26]>C(Cl)Cl>[CH3:3][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][N:15]([S:33]([C:31]3[S:32][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=3)(=[O:35])=[O:34])[CH2:14][CH2:13][NH:12]2)[CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH3:1]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Reactant: CC(C)C1C(=O)NCCN1C[C@H]1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a stirred solution of 3-(1-methylethyl)-4-((2R)-2-piperazinylmethyl)-2-piperazinone (186 mg, 0.774 mmol) and triethylamine (324 μL, 2.32 mmol) in CH2Cl2 (5.00 mL) was added a solution of 5-nitrothiophene-2-sulfonyl chloride (190 mg, 0.836 mmol, Enamine, Kiev, Ukraine) in CH2Cl2 (1 mL) drop-wise at room temperature. The solution was stirred for 30 min and then the mixture was concentrated. The residue was dissolved in CH2Cl2, the organics were washed with water followed by brine. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia/MeOH to give 3-(1-methylethyl)-4-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-2-piperazinone (263 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:21])[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9]2)=[O:4].[CH3:22]I>CN(C)C=O>[CH3:1][N:2]([CH3:22])[C:3]([C:5]1[N:6]([CH3:21])[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9]2)=[O:4]
Reactant: CI
Reactant: CNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Temperature: 0 °C

Procedure:
A suspension of 9.0 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid methylamide in 120 ml. of dimethylformamide is treated under argon at 0° C. with 5.0 g. of potassium tert. butylate and then stirred in an ice-bath for 30 minutes. At 0°-5° C. there are added 8 ml. of methyl iodide in one batch, the mixture is subsequently stirred for 2 hours at room temperature and poured onto 2 liters of ice-water. After the addition of 100 g. of sodium chloride, the separated oil is extracted with methylene chloride. The organic phase is washed with a solution of sodium chloride, dried over sodium sulfate and concentrated to dryness under reduced pressure. The oily residue is dissolved in 200 ml. of hot hexane. The solution obtained is cooled in an ice-bath, colorless crystals separating, and there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid dimethylamide having a melting point of 86°-88° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:13][C:14]([F:17])([F:16])[F:15])(=O)=O.[Br:20][C:21]1[C:22]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[N:23][NH:24][C:25]=1[CH:26]=[O:27].O>CN(C)C=O>[Br:20][C:21]1[C:22]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[N:23][N:24]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:25]=1[CH:26]=[O:27]
Reactant: O=Cc1[nH]nc(-c2cccs2)c1Br
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(Br)c(-c2cccs2)nn1CC(F)(F)F
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 32.3 %

Procedure:
Cesium carbonate (1.56 g, 4.78 mmol) and 2,2,2-triflouroethyl trifluoromethanesulfonate (0.92 mL, 6.38 mmol) were added to a solution of 4-bromo-3-(thiophen-2-yl)-1H-pyrazole-5-carbaldehyde (34c) (0.82 g, 3.19 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at 100° C. for 50 minutes. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×40 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 100/0 to 94/6), to provide 4-bromo-3-(thiophen-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carbaldehyde (34d) (350 mg, 1.03 mmol, 32%).
Reaction SMILES: Cl[NH:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C:15]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][CH2:25][C:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:31]
Reactant: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NCl)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 42F (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:36][O:37][CH3:38])[C:4]([CH3:35])=[C:5]([C:26]([O:28][CH2:29][O:30][C:31](=[O:34])[CH2:32][CH3:33])=[O:27])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([O:10]COC(=O)CC)=[O:9]>C(OC(C)C)(C)C.O>[CH3:1][C:2]1[N:3]([CH2:36][O:37][CH3:38])[C:4]([CH3:35])=[C:5]([C:26]([O:28][CH2:29][O:30][C:31](=[O:34])[CH2:32][CH3:33])=[O:27])[C@@H:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCC(=O)OCOC(=O)C1=C(C)N(COC)C(C)=C(C(=O)OCOC(=O)CC)C1c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCC(=O)OCOC(=O)C1=C(C)N(COC)C(C)=C(C(=O)O)[C@@H]1c1cccc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 69.2 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 267 mg of bis(propionyloxymethyl) 1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate obtained in Example 12, and 50 mg of Lipase B was added thereto, followed by stirring at 0° to 5° C. for 8 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane=l/2) to obtain 155 mg (yield: 71%) of (S)-1,4-dihydro-2,6-dimethyl-l-methoxymethyl-(3-nitrophenyl)-5-propionyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[Br:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](O)=[O:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[Br:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([NH:10][C:8]1[S:9][C:5]([CH2:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[Cl:1])=[CH:6][N:7]=1)=[O:18]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Reaction time: 16 h
Yield: 75 %

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (450 mg, 2.0 mmol) and bromo-phenyl-acetic acid (430 mg, 2.0 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (280 μL, 2.0 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (836 mg, 2.2 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by silica gel chromatography using a gradient of 10-30% ethyl acetate in hexanes to yield a pale yellow solid (633 mg, 1.50 mmol, 75.0%). ESI-MS m/z calc. 420.0. found 421.2 (M+1)+ Retention time 3.63 minutes.