Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.O=[C:13]1[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][C:21]#[N:22])[CH2:15][CH2:14]1>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH:13]2[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14]2)=[CH:11][CH:10]=1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(NC2CCN([C@H](C)CCN)CC2)cc1

Procedure:
Using general procedure A with methyl 4-aminobenzoate (507 mg, 3.35 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (669 mg, 4.03 mmol) followed by general procedure J afforded 4-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-ylamino]-benzoic acid methyl ester as a white foam (390 mg, 38% over 2 steps).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36](=[O:57])[NH:37][C@H:38]([C:46]1[O:47][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[N:49][N:50]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11].C(=O)([O-])O.[Na+].[O:73]=[C:74]1[CH:78]=[CH:77][C:76](=[O:79])N1C(OC)=O.FC(F)(F)C(O)=O>O1CCOCC1.O>[O:73]=[C:74]1[CH:78]=[CH:77][C:76](=[O:79])[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36](=[O:57])[NH:37][C@H:38]([C:46]1[O:47][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[N:49][N:50]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12]
Reactant: COC(=O)N1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
11 mg (12 μmol) of N-(6-aminohexyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 235) were taken up in 500 μl of 1:1 dioxane/water and admixed with 253 μl of 1M aqueous sodium hydrogencarbonate solution and then with 2.8 mg (18 μmol) of methyl 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate. The reaction mixture was stirred at RT for 30 min and then acidified with trifluoroacetic acid. The reaction mixture was purified by means of preparative HPLC. After lyophilization, 0.8 mg (7% of theory) of the title compound was obtained.
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)[CH3:5])=[N+]=[N-].O.CP(C)C.C(OCC)(=O)C>O1CCCC1>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[C:6]([CH:4]([NH2:1])[CH3:5])=[CH:7][CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1cccc(F)c1
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1ccc2cccnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-8-(3-fluorophenyl)quinoline (0.146 g, 0.500 mmol) in tetrahydrofuran (1 mL) and water (0.360 mL, 20.0 mmol) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.600 mL, 0.600 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl twice. The combined extracts were neutralized with solid sodium bicarbonate, and then extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue showed two peaks by LCMS with the same desired mass and was used directly in next step. LCMS calculated for C17H16FN2(M+H)+: m/z=267.1; found: 267.0.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:25]([NH2:30])[CH:26]=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:31]([CH2:32][CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:1]([CH2:2][CH2:3][CH2:4][CH3:5])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCC(OC)(OC)OC
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Product: CCCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Temperature: 25 °C
Yield: 84 %

Procedure:
Under a nitrogen atmosphere, trimethyl orthovalerate (2.7 mL, 16 mmol) was added dropwise to a solution of 7-benzyloxy-N4-(2-phenoxyethyl)quinoline-3,4-diamine (3.0 g, 7.8 mmol), prepared as described in Parts A and B of Example 46, in xylenes (30 mL), and the reaction was heated at reflux for 24 hours. The reaction mixture was allowed to cool to ambient temperature; a precipitate formed, which was isolated by filtration, washed with hexanes, and dried for two hours in a vacuum oven to provide 2.96 g of 7-benzyloxy-2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[C:12]=1N.[N+]([O-])(OCCC(C)C)=O>>[CH3:1][C:2]1[C:3]2[O:9][C:16]3[CH:15]=[C:14]([Cl:19])[CH:12]=[C:11]([Cl:10])[C:17]=3[C:4]=2[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(Cl)ccc1O
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Agent: CC(C)CCO[N+](=O)[O-]
Product: Cc1cc(Cl)cc2c1oc1cc(Cl)cc(Cl)c12
Temperature: 120 °C

Procedure:
20 gms. of 2-methyl-4-chlorophenol (Aldrich Chemicals) and 5 gms. of 2,4,6-trichloroaniline (Aldrich Chemicals) were mixed and heated with stirring to 120° C. 6 mls. of isoamyl nitrate was added dropwise over a thirty minute period and the mixture was stirred for 18 hours at 120° C. The excess phenol was removed by evaporation and the residue was adsorbed on silica gel and added to the top of a silica gel column packed with petroleum spirit/diethylether (3:7). The column was eluted with 500 ml. of the above solvent, the solvent was evaporated, and the residue was dissolved in dimethyl sulfoxide. 500 mg. of anhydrous potassium carbonate was added and the mixture was stirred for two hours at 190° C. It was then adsorbed on 30-40 grams of silica gel. The solvent was evaporated and the silica gel was added to the top of a 20×5 cm silica gel column which was packed and equilibrated with petroleum spirit. 6-methyl 1,3,8-trichlorodibenzofuran was eluted from the column with 500 mls. of petroleum spirit and the residue was crystallized from anisole/methanol (1:9). 280 mgs. of the product was recovered and was 99% pure as determined by gas chromatographic analysis and a molecular weight of 284 was confirmed with a VG 12000 quadrupole mass chromatograph coupled to a Hewlett Packard 500 gas chromatograph. The 220-MHz. proton magnetic resonance spectrum (in deuterochloroform) was determined with a Varian XL200 spectrometer and gave (in CDCL3): 8.07 (H-9,d,J=1.6 Hz) 7.48, 7.33 (H-1/H-3, d,J=1.6 Hz); 7.29, 7.29ppm (H-7,m).
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH2:19][CH2:18][C:12]2([C:16](=[O:17])[NH:15][CH2:14][CH2:13]2)[CH2:11][CH2:10]1)([CH3:8])[C:3](OCC)=[O:4].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH3:8][C:2]([N:9]1[CH2:19][CH2:18][C:12]2([C:16](=[O:17])[NH:15][CH2:14][CH2:13]2)[CH2:11][CH2:10]1)([CH3:1])[CH:3]=[O:4]
Reactant: CCOC(=O)C(C)(C)N1CCC2(CCNC2=O)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C=O)N1CCC2(CCNC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-methyl-2-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)propanoate (3.77 g, 14.1 mmol) in toluene (100 mL) at −78° C. was added DIBAL-H (45.0 mL, 45.0 mmol) dropwise. After 2 h, the reaction was quenched by addition of methanol (10 mL) dropwise, after warmed to rt, 30 mL of saturated sodium sulfate solution was added and the mixture was vigorously stirred at rt for 1 h. After filtration, the filtrate and the filter cake were partitioned between DCM and saturated sodium bicarbonate, the alkaline phase was extracted with DCM three times, the combined organic phase was dried over sodium sulfate, concentrated to give the title compound. LC/MS (M+1+18)+: 243.3; (M+1+32)+: 257.4.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH2:8][NH:9]C(=O)OCC2C=CC=CC=2)=[N:5][C:4]2[CH2:20][CH2:21][O:22][CH2:23][C:3]1=2>CO.[OH-].[Pd+2].[OH-]>[NH2:9][CH2:8][C:6]1[NH:7][C:2](=[O:1])[C:3]2[CH2:23][O:22][CH2:21][CH2:20][C:4]=2[N:5]=1
Reactant: O=C(NCc1nc2c(c(=O)[nH]1)COCC2)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCc1nc2c(c(=O)[nH]1)COCC2
Reaction time: 4 h
Yield: 7.5 %

Procedure:
To benzyl (4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methylcarbamate (1.63 g, 51.7 mmol) in methanol (70 mL) was added 10% palladium hydroxide (726 mg, 0.52 mmol) and the mixture was stirred under 1 atm of H2 for 4 h. The solution was filtered through celite and concentrated under vacuum to give 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (707 mg, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.34 (s, 2H) 3.83 (t, J=5.56 Hz, 2H) 3.54 (s, 2H) 2.54 (t, J=5.56 Hz, 2H).
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C:8]1[C:9]([CH3:18])=[N:10][CH:11]=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[S:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([O:7][C:8]2[C:9]([CH3:18])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[S:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCCC1
Reactant: COC(=S)c1cnc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=S)c1cnc(C)c(OC2CCCC2)c1
Temperature: 60 °C

Procedure:
Cyclopentyl bromide (0.78 mL) is added to a stirred mixture of methyl 5-hydroxy-6-methylthionicotinoate (810 mg) and anhydrous potassium carbonate (1.8 g) in dry dimethylformamide (15 mL). The mixture is heated at 60±5° C. for 8 hours. After cooling the mixture is concentrated in vacuo and the residue partitioned between water and ethyl acetate. The ethyl acetate phase is isolated, washed with water and dried (MgSO4). The solvent is removed in vacuo to give methyl 5-cyclopentyloxy-6-methylthionicotinoate (920 mg) as a light brown oil. [Elemental analysis: C, 58.41; H, 6.41; N, 5.24%. calculated: C, 58.2; H, 6.44; N, 5.33%.].
Reaction SMILES: CC1(C)[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3C=CC=CC=3)=[O:12])[C:8](=[O:9])N2[C@H]1C([O-])=O.[K+].[NH2:25][C@H:26]([C:29]([OH:31])=[O:30])[CH2:27]S.[NH2:32][C@H:33]([C:37]([OH:39])=[O:38])[CH:34]([CH3:36])[CH3:35]>>[CH3:35][C:34]1([CH3:36])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][CH2:14][CH2:27][C@H:26]([NH2:25])[C:29]([OH:31])=[O:30])=[O:12])[C:8](=[O:9])[N:32]2[C@H:33]1[C:37]([OH:39])=[O:38]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [K+]
Product: CC1(C)S[C@@H]2[C@H](NC(=O)CCC[C@H](N)C(=O)O)C(=O)N2[C@H]1C(=O)O

Procedure:
The first two steps in the biosynthesis of penicillin in P. chrysogenum are the condensation of the three amino acids L-5-amino-5-carboxypentanoic acid (L-α-aminoadipic acid) (A), L-cysteine (C) and L-valine (V) into the tripeptide LLD-ACV, followed by cyclization of this tripeptide to form isopenicillin N. This compound contains the typical β-lactam structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(=O)c3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (115 mg, 0.34 mmol) and benzoyl chloride (52.64 mg, 0.37 mmol) were mixed together in dichloromethane (5 mL) under nitrogen and then diisopropylethylamine (0.12 mL, 0.67 mmol) was added to afford clear solution. The resulting solution was stirred for 4 hours at room temperature and then concentrated. Ethyl acetate (20 mL) was added and the mixture was washed with water (20 mL) and brine solution (20 mL) and then dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave a crude residue which was purified using an ISCO (12 g) column, eluting with 5-35% ethyl acetate in hexanes, to afford [4-(4-benzoylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (133 mg, 88.8%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.46 (s, 1 H), 7.93-8.03 (m, 5 H), 7.88 (s, 1 H), 7.51-7.68 (m, 3 H), 7.48 (dd, J=8.6, 1.8 Hz, 1 H), 7.23 (d, J=8.5 Hz, 2 H), 7.18 (d, J=1.8 Hz, 1 H), 3.97 (s, 2 H), 3.66 (s, 3 H), 2.10 (s, 3 H). HRMS calcd. for C27H23ClNO3 [(M+H)+] 444.1361, obsd. 444.1361.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].BrCC1C[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]1.[ClH:50]>>[ClH:50].[ClH:50].[CH2:1]([O:8][C:9]1[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=[C:11]([S:22][CH2:23][CH:24]2[CH2:25][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1csc(Nc2ncc(SCC3CCNCC3)cc2OCc2ccccc2)n1
Yield: 64.6 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (46.9 mg, 0.17 mmol) were reacted according to the method of Example 43 to afford 3-(benzyloxy)-N-(4-methylthiazol-2-yl)-5-(piperidin-4-ylmethylthio)pyridin-2-amine dihydrochloride (54.4 mg, 64.6% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 9.20 (bs, 1H), 9.00 (bs, 1H), 7.97 (m, 1H), 7.65 (m, 3H), 7.45-7.30 (m, 3H), 6.90 (s, 1H), 5.41 (s, 2H), 3.75-3.45 (m, 3H), 3.20 (m, 2H), 2.95 (m, 2H), 2.76 (m, 2H), 2.34 (s, 3H), 1.88 (m, 2H), 1.64 (m, 1H), 1.42 (m, 2H); Mass spectrum (apci) m/z=427.1 (M+H-2HCl).
Reaction SMILES: [O:1]=[C:2]([CH2:11][O:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[N:23]([O-])=[O:24].[Na+].C(OCC)(=O)C>C(O)(=O)C>[OH:24][N:23]=[C:3]([C:2](=[O:1])[CH2:11][O:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OCC(=O)CC(=O)OC(C)(C)C)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC(=O)C(=NO)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 33.9 %

Procedure:
4.5 g of t-butyl 3-oxo-4-p-toluenesulphonyloxybutyrate were dissolved in 40 ml of acetic acid, and then 1.42 g of sodium nitrite were added, at room temperature, to the solution over a period of 10 minutes. The mixture was then stirred at room temperature for 50 minutes, after which 200 ml of ethyl acetate were added and the mixture was then washed with an aqueous solution of sodium chloride. The ethyl acetate solution was dried over magnesium sulphate and, after filtering off the drying agent, the filtrate was concentrated by evaporation under reduced pressure to give a brown, oily substance. This oily substance was purified by column chromatography through silica gel, eluted with a 4:1 by volume mixture of cyclohexane and ethyl acetate, affording 1.66 g of t-butyl 2-hydroxyimino-3-oxo-4-p-toluenesulphonyloxybutyrate, in the form of colourless crystals, melting at 106°-108° C. (with decomposition, recrystallized from a 1:1 by volume mixture of diethyl ether and petroleum ether).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:13])=[C:5]([C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])[CH:6]=[O:7].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(#N)C>[CH3:12][C:8]1[C:9]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:10]([CH3:11])[C:3]([CH3:2])=[C:4]([CH3:13])[C:5]=1[CH:6]=[O:7]
Reactant: Cc1cc(C)c(CCl)c(C)c1C=O
Reactant: C1COCCN1
Solvent: CC#N
Product: Cc1c(C)c(C=O)c(C)c(N2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 0.98 g of 3-chloromethyl-2,4,6-trimethylbenzaldehyde in 20 ml of acetonitrile was treated with 0.87 ml of morpholine. The mixture was stirred at room temperature for 4 hours and thereafter filtered. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed twice with water, dried over anhydrous magnesium sulphate and evaporated to dryness. Distillation of the residue yielded 1.05 g of 2,4,6-trimethyl-3-morpholin-4-yl-methylbenzaldenhyde, b.p. 150° C./0.3 Torr.
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16]C(=O)C2C=CC=CC=2)[O:13][C@@H:12]([N:25]2[C:29]3[N:30]=[CH:31][NH:32][CH2:33][C:34](=[O:35])[C:28]=3[N:27]=[CH:26]2)[C@H:11]1[F:36])(=O)C1C=CC=CC=1.C[O-].[Na+].CO>CO>[F:36][C@H:11]1[C@H:10]([OH:9])[C@@H:14]([CH2:15][OH:16])[O:13][C@H:12]1[N:25]1[C:29]2[N:30]=[CH:31][NH:32][CH2:33][C:34](=[O:35])[C:28]=2[N:27]=[CH:26]1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c2N=CNCC3=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CNC=Nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F

Procedure:
To a suspension in methanol (4 ml) of compound (19) (100.5 mg) as obtained in step (10) above was added a 0.5M sodium methylate-methanol solution (0.6 ml). The resultant mixture was stirred at room temperature for 1 hour to conduct the intended reaction. Thus, the debenzoylation of compound (19) occurred to produce the titled compound (20).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[N:32][CH:33]=1>>[F:40][C:37]1[CH:36]=[CH:35][C:34]([C:31]2[CH:30]=[CH:29][C:28]([C:6]3[N:10]4[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]4=[N:8][CH:7]=3)=[CH:33][N:32]=2)=[CH:39][CH:38]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Fc1ccc(-c2ccc(Br)cn2)cc1
Product: Fc1ccc(-c2ccc(-c3cnc4nc(C(F)(F)F)ccn34)cn2)cc1

Procedure:
3-Tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine was reacted with 5-bromo-2-(4-fluorophenyl)pyridine by the method of Example 1 to furnish 3-[2-(4-fluorophenyl)pyridin-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (47mg) as a yellow solid: δH (400 MHz, CDCl3) 7.19-7.25 (2H, m), 7.31 (1H, d, J 7), 7.90-7.97 (2H, m), 8.06-8.11 (2H, m), 8.19 (1H, s), 8.82 (1H, d, J 7), 8.91 (1H, dd, J 2 and 1); m/z (ES+) 358, 359 (M++H).
Reaction SMILES: [C:1]([C:3]1[C:11]([Cl:12])=[C:10]([Cl:13])[C:6]([C:7](N)=[O:8])=[C:5]([Cl:14])[C:4]=1[Cl:15])#[N:2].Cl[O-].[Na+].S(=O)(=O)(O)[OH:20]>O>[C:1]([C:3]1[C:11]([Cl:12])=[C:10]([Cl:13])[C:6]([C:7]([OH:20])=[O:8])=[C:5]([Cl:14])[C:4]=1[Cl:15])#[N:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(Cl)c(Cl)c(C(N)=O)c(Cl)c1Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: N#Cc1c(Cl)c(Cl)c(C(=O)O)c(Cl)c1Cl
Temperature: 15 °C
Yield: 92 %

Procedure:
4-Cyano-2,3,5,6-tetrachlorobenzamide (284 g) which had been synthesized separately and water (2556 g) were placed in a four-neck flask, and the mixture was cooled to 15° C. with stirring. Subsequently, an aqueous solution (2360 g) of sodium hypochlorite (effective chlorine 12%) was added to the reaction mixture over six hours while a 50% aqueous solution of sulfuric acid was added so as to maintain the pH of the mixture at 5-6. Liquid chromatographic analysis revealed that the reaction mixture contained 262.2 g of 4-cyano-2,3,5,6-tetrachlorobenzoic acid (yield 92%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][C@H:13]([C:15]1[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[CH3:14].CCN(C(C)C)C(C)C>C1COCC1.C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[C:17](=[O:26])[N:16]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]([C@@H:13]([NH:12][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[CH3:14])=[CH:24]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](Nc1nc(Cl)ncc1[N+](=O)[O-])c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.58 h

Procedure:
A solution of 2,4-dichloro-5-nitropyrimidine (250 mg, 1.29 mmol, 1.15 eq.) in THF (2 mL) was chilled in a −78° C. bath. To this solution was slowly added over 40 mins a mixture of compound 1 (335 mg, 1.12 mmol, 1.0 eq.) and DIEA (450 μL, 2.58 mmol, 2.3 eq.) in THF (4 mL). After addition was complete, the reaction was stirred at −78° C. during 30-40 mins, then allowed to warm slowly to 15° C. over 1 h. The reaction mixture was diluted with DCM (40 mL), washed with water and brine (15 mL each), dried over Na2SO4, and concentrated. This residue was purified by flash chromatography eluting with 300 mL each 10/20/30/40% EtOAc/hexanes to give (S)-8-chloro-3-(1-(2-chloro-5-nitropyrimidin-4-ylamino)ethyl)-2-phenylisoquinolin-1(2H)-one 75. ESI-MS m/z: 456.15 [M+H]+.
Reaction SMILES: [CH:1]([O:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:3])[CH3:2].[CH2:26]([OH:29])[C:27]#[CH:28].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.[Cu](I)I.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>[OH:29][CH2:26][C:27]#[C:28][C:14]1[CH:13]=[C:12]([CH2:11][CH:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:17]=[CH:16][CH:15]=1
Reactant: C#CCO
Reactant: CCOC(=O)C(Cc1cccc(OS(=O)(=O)C(F)(F)F)c1)OC(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc(C#CCO)c1)OC(C)C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
550 mg of Ethyl 2-isopropoxy-3-(3-[(trifluoromethyl)sulfonyl]oxyphenyl)propanoate was dissolved in 5 ml of N,N-dimethylformamide, and 160 mg of propargyl alcohol, 13 mg of copper iodide, 83 mg of tetrakis(triphenylphosphine)palladium and 1 ml of triethylamine were added. After stirring was continued at 50° C. for 4 hours under nitrogen atmosphere, the reaction mixture was diluted with ethyl acetate and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off. Then, the residue was purified by silica gel column chromatography, to give 184 mg of the title compound in the 4:1→2:1 hexane-ethyl acetate fraction.