Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:1][CH:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:26])=[CH:20][CH:19]=1
Reactant: NC(c1ccccc1)C(O)c1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)NC(c1ccccc1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of (-)-[R-(R*,S*)]-2-amino-1,2-diphenylethanol (1.0 g, 4.7 mmol) in dichloromethane (10 mL) is added dropwise a solution of 4-chlorophenyl isocyanate (0.72 g, 4.7 mmol) in dichloromethane (5 mL). The resulting mixture is stirred 1 hour at room temperature before filtering off the solid product and washing with CH2Cl2 (2X). The product is dried in vacuo at 114° C. to provide 1.4 g (81%) of desired product, mp 198° C. IR (KBr): 3327, 1665, 1549, 1234, 703 cm-1 ; NMR (DMSO-d6): 4.95 (m, 1H), 5.74 (m, 1H), 6.84-7.5 (m, 16H, 8.84 (S, 1H). Analysis calculated for C21H19ClN2O2.0.42H2O: C, 67.37; H, 5.34; N, 7.48. Found: C, 67.36; H, 5.16; N, 7.61.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[C:14]([NH:21][C@@H:22]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C@@H:23]([OH:38])[CH2:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:26]([OH:28])=[O:27])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CN(C=O)C>[C:14]([NH:21][C@@H:22]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C@@H:23]([O:38][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12])[CH2:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:26]([OH:28])=[O:27])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
133 g (1.95 mol) of imidazole and 164 g (1.09 mol) of tert-butyldimethylchlorosilane are added, under an argon atmosphere, to an ice-cold solution of 124 g (238 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoic acid in 800 ml of DMF. After 17 h at RT, the reaction mixture is poured onto 1.9 l of ice-water and extracted 3× with 0.8 l of ethyl acetate on each occasion. The organic phases are washed with water, sat. NaHCO3 solution, water, 10% citric acid solution, water and, finally, saline, dried with Na2SO4 and evaporated. The residue is dissolved in 700 ml of methanol and 175 ml of THF, and 175 g of K2CO3 in 820 ml of water are added to this solution, which is then stirred at RT for 1 h. The resulting emulsion is partially evaporated on an RE, and the residue is diluted with ice-water, and this mixture is acidified to pH 4 with 10% citric acid solution while stirring vigorously. The mixture is extracted 3× with ethyl acetate, and the organic phases are washed with water and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane→hexane/ethyl acetate 95:5→9:1→2:1→1:1) results in the title compound: TLC Rf (E)=0.15; tRet (II)=22.7 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>C(O)(=O)C>[C:12]1(=[O:17])[N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:7]=2)[C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: CCC(=O)c1ccc(N)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCC(=O)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 1-(4'-aminophenyl)-propan-1-one (30 g, 0.2 mol), phthalic anhydride (60 g, 0.4 mol) and of acetic acid (300 ml) is heated at reflux for 2 h. The reaction mixture is cooled to room temperature and the precipitate consisting of 1-(4'-phthalimidophenyl)-propan-1-one (41 g, 0.150 mol, yield 75%) is filtered and dried in vacuo
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.[CH3:11][NH2:12]>C1COCC1.CCN(C(C)C)C(C)C>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:12][CH3:11])[N:7]=1
Reactant: CN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Cl)nc(Cl)n1
Temperature: -70 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
Cyanuric chloride (10 g, 54.3 mmol, 1 equiv.) was dissolved in THF (200 mL) and cooled to −70° C. DIPEA (36.3 mL, 1.42 mmol, 2 equiv.) and methylamine hydrochloride (3.7 g, 1 equiv.) were added to the reaction mixture, which was stirred 2 h at −70° C. and 1 h at rt. The THF was removed under reduced pressure and the remaining material was taken up in DCM and washed with water. The organic layer was dried with MgSO4 and the DCM removed to give a colourless powder (9.5 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])=[CH:4][N:3]=1.[H][H]>[Pd].CO>[CH3:18][C:10]1[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A mixture of 2-methyl-5-(2-methyl-4-nitro-phenoxy)-pyridine (11.5 g, 47.1 mmol) and palladium on carbon (300 mg, 10 wt. %, wet) in MeOH (200 mL) was flashed with hydrogen. A hydrogen balloon was then applied to the reaction mixture. The reaction was stirred for 2 hours and the solution was filtered through a pad of celite, and the pad was washed with MeOH (300 mL). Concentration of the solution gave crude product (8.8 g, 87%) as light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:5][N:6]=1.[C:14](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:28])[CH2:15][C:16](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:17].ClC1C=CC=CC=1>CCCCCC>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:14]([OH:28])=[CH:15][C:16](=[O:17])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: CCCCCCSc1nnc(N)s1
Solvent: CCCCCC
Solvent: Clc1ccccc1
Product: CCCCCCSc1nn2c(=O)cc(O)nc2s1
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of 65.2 g of the thus obtained 2-amino-5-hexylthio-1,3,4-thiadiazole, 141.7 g of bis(2,4,6-trichlorophenyl) malonate and 240 ml of chlorobenzene was heated to 137°~140° C. and stirred for 1 hour. After cooling, hexane was added to the mixture, and the formed precipitate was separated by filtration, the residue was washed with hexane, and thus 74.7 g of 2-hexylthio-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][NH:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:2]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)CCCBr
Solvent: CCO
Product: CCOC(=O)CCCNC1CCCCC1
Temperature: 25 °C
Yield: 107.1 %

Procedure:
7 g of 4-bromobutyric acid ethyl ester and 20 g of cyclohexylamine were added to 50 mL of ethanol, and the mixture was stirred at a room temperature for one week. The stirred mixture was concentrated under reduced pressure and extracted with 200 mL of ethyl acetate. The extracted material was washed with purified water, dried with magnesium sulfate, and then concentrated. The obtained residue was distilled under reduced pressure to give 8.2 g of N-cyclohexyl-gamma-aminobutyric acid ethyl ester. The obtained N-cyclohexyl-gamma-aminobutyric acid ethyl ester was added to sodium hydroxide solution (1.68 g of sodium hydroxide/100 mL of purified water), and THF was added thereto till the mixture became homogeneous. After stirring at room temperature for 3 hours, the mixture was neutralized with DOWEX50W [H+ form] and concentrated under reduced pressure. The obtained residue was recrystallized to give 4.1 g of the desired product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[CH:7]1.[C:15](=O)(O)[O-:16].[Na+]>CN(C=O)C>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1
Reactant: O=C([O-])O
Reactant: c1cnc2[nH]ccc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ncccc12
Temperature: 5 °C

Procedure:
Phosphorus oxychloride (36.5 mL) was added dropwise to cooled solution of DMF (40 mL) while maintaining the temperature below 10° C. The resulting solution was further cooled to 5° C. and a solution of 7-azaindole in DMF (40 mL) was added slowly over 30–40 min, maintaining the temperature below 25° C. The mixture was heated at 95° C. for 48 h then cooled to 35° C. and added cautiously with stirring over an hour to a cooled solution of saturated aqueous sodium bicarbonate solution (800 mL). The mixture was extracted with ethyl acetate (4×500 mL) and the combined extracts washed with water (500 mL) and brine (500 mL), then dried (MgSO4), filtered and concentrated in vacuo to afford a dark brown semi-solid. This crude product was purified using column chromatography eluting with a 50:50 mixture of ethyl acetate:hexane, gradually increasing to 90:10 mixture. 1H-NMR (400 MHz/D6-DMSO): δ=7.25 (m, 1H), 8.38 (m, 2H), 8.42 (s, 1H), 9.92 (s, 1H), 12.62 (br.s, 1H). MS (ES+): 147 [MH+].
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CC(C)=O>[F:14][C:8]1[CH:7]=[CH:6][C:5]([S:2]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)(=[O:4])=[O:3])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Reactant: CN1CCNCC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(S(=O)(=O)c2ccc(F)c(C(=O)O)c2)CC1
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A solution of 5-chlorosulphonyl-2-fluorobenzoic acid (47.72 g, 0.2 mol) in acetone (250 ml) was added to a mixture of N-methylpiperazine (22.04 g, 0.22 mol) and triethylamine (24.29 g, 0.24 mol) and the reaction was stirred at ambient for three hours. The mixture was filtered, the resulting solid was recrystallised from water to afford the title compound (14.63 g, 24.2%) as a white solid. δ (DMSO): 2.30 (3H, s), 2.58 (4H, m), 2.95 (4H, m), 7.52 (1H, m), 7.90 (1H, m), 8.10 m/z (Found: 303 [M+H]+, 100%, C12H16FN2O4S requires 303).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[S:31][CH:32]=[C:33]([C:35]([OH:37])=O)[N:34]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:49]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:50].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[S:31][CH:32]=[C:33]([C:35]([N:54]6[CH2:55][CH2:56][N:51]([CH2:49][CH3:50])[CH2:52][CH2:53]6)=[O:37])[N:34]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:44][CH:43]=1
Reactant: CCN1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3nc(C(=O)O)cs3)cn2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)c2csc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)n2)CC1

Procedure:
To 2-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-thiazole-4-carboxylic acid (77 mg), N-ethylpiperazine (36 μl), WSCI (68 mg), HOBt (48 mg) and triethylamine (48 μl) were left to act in DMF (3 ml), to obtain a crude product of [2-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-thiazol-4-yl]-(4-ethyl-piperazin-1-yl)-methanone, and then the PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-120) as an ivory powder (38 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])[C:5]([C:14]([OH:16])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:26]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])[C:5]([C:14]([F:26])=[O:16])=[CH:4][N:3]=1
Reactant: CC(C)(O)CNc1nc(Cl)ncc1C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1nc(Cl)ncc1C(=O)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution containing 12.64 g (51.45 mmol) of the acid prepared in step 17.1 and 7.89 mL (56.60 mmol) of triethylamine in 250 mL of dichloromethane are added 6.51 mL (77.18 mmol) of cyanuric fluoride. The mixture is stirred at room temperature overnight and the solution is diluted with 590 mL of CH2Cl2 and 190 mL of ice-cold aqueous NaHCO3. The organic phase is washed twice with 250 mL of ice-cold aqueous NaHCO3 and dried over MgSO4. The solvent is then evaporated off under reduced pressure. 12.3 g of the expected product are obtained in the form of a yellow oil that solidifies slowly, and which is used as obtained in the following step. Yield=96%.
Reaction SMILES: [NH2:1][CH: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.[Cl:15][CH2:16][CH2:17]N=C=O>O1CCCC1>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:17][CH2:16][Cl:15])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C=NCCCl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NCCCl)CC1
Yield: 116.1 %

Procedure:
A solution of 4-amino-1-t-butoxycarbonylpiperidine (200 mg, 1.0 mmol) in tetrahydrofuran (5 mL) was treated with 2-chloroethyl isocyanate (0.090 mL, 1.0 mmol) overnight. The solvent was evaporated to provide the title compound as a white solid (305 mg).
Reaction SMILES: [Cl:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH:8]=[O:9].[CH3:10][Mg]Br.CC(O)C>C1COCC1>[Cl:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH:8]([OH:9])[CH3:10]
Reactant: O=CC1=C(Cl)CCCC1
Reactant: C[Mg]Br
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(O)C1=C(Cl)CCCC1
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-cyclohex-1-enecarbaldehyde (13.6 mmol) in THF at 0° C. was added methyl magnesium bromide (3M in THF; 5.4 mL, 16.32 mmol). The reaction was stirred under N2 for 1 hour, and then iPrOH (2 mL) was added. The mixture was concentrated, and the residue was diluted with 1N aqueous HCl and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NH4Cl, dried over MgSO4, filtered, and concentrated, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][OH:13]>S(=O)(=O)(O)O.[Pd]>[CH3:12][O:13][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([NH2:9])=[C:2]([CH3:1])[CH:7]=1
Reactant: CO
Reactant: Cc1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Product: COc1cc(C)c(N)cc1C
Yield: 66 %

Procedure:
2,5-Dimethylnitrobenzene, (46.8 ml, 0.35 mol) was dissolved in sulfuric acid (47.1 ml)/methanol (650 ml) and then 5% palladium on carbon (50% hydrate, 0.35 g) was added. The mixture was allowed to react for 3 hours under hydrogen atmosphere at the pressure of 5 atms at 40° C. After cooling, the catalyst was removed, and methanol was removed under reduced pressure. The residue was poured into a 25% aqueous ammonia solution with cooling on ice, and extracted with toluene. The extract was washed with 5% sodium hydrosulfite, dried over sodium sulfate and purified by column chromatography on a small amount of silica gel (toluene:ethyl acetate=1:1). The solvent was removed under reduced pressure and crystallization from hexane yielded 35.0 g of the title compound.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])(=[O:3])[NH2:2].[C:30]([SH:33])(=[O:32])[CH3:31].[H-].[Na+].O>CN(C)C=O>[C:30]([S:33][C@@H:10]1[CH2:9][N:8]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C@H:7]([CH2:6][O:5][CH2:4][C:1](=[O:3])[NH2:2])[CH2:11]1)(=[O:32])[CH3:31]
Reactant: CC(=O)S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)S[C@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
A solution of (2S,4R)-2-(carbamoylmethyl)oxymethyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.98 g) in dimethylformamide (2 ml) was added to a reaction mixture of thioacetic S-acid (0.25 ml) and sodium hydride (62.8% in oil suspension) (0.11 g) in dimethylformamide (10 ml) in a nitrogen stream and the mixture was heated at 70°-75° C. for 3 hours. The mixture was poured into water (100 ml), extracted with ethyl acetate (50 ml×3), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99 v/v) to give (2S,4S)-4-acetylthio-2-(carbamoylmethyl)oxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.72 g).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=1[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)=[O:24]>CN(C=O)C.O>[Cl:20][C:21]1[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=1[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)=[CH:27][CH:26]=1)=[O:24]
Reactant: O=C(c1ccc(CBr)cc1)c1ccccc1Cl
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccccc3Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 83.2 %

Procedure:
To a solution of theophylline (0.90 g) in DMF (20 ml) were added potassium carbonate (0.83 g) and 4-(2-chlorobenzoyl)benzyl bromide (1.55 g) and the mixture was stirred at room temperature for 13 hours. This reaction mixture was diluted with water and extracted with ethyl acetate and the extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as needles (1.70 g, 83%). 1H-NMR (CDCl3) δ: 3.39(3H,s), 3.60(3H,s), 5.58(2H,s), 7.30-7.48(6H,m), 7.63(1H,s), 7.76-7.85(2H,m).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[F:22][C:23]1[CH:45]=[CH:44][C:26]([C:27]([C:29]2[C:38](O)=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:34]3)=[O:28])=[CH:25][CH:24]=1.S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[C:38]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([S:40]([NH2:43])(=[O:41])=[O:42])=[CH:34]3)=[O:28])=[CH:44][CH:45]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: NS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(O)ccc2c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
Pyridine (4.25 ml, 52.1 mmol) and trifluoromethanesulfonic anhydride (4.4 ml, 26.1 mmol) were added to a solution of 5-(4-fluorobenzoyl)-6-hydroxy-2-naphthalenesulfonamide (3.0 g, 8.7 mmol), [prepared as described in step 1 above], in methylene chloride (50 ml) at 0° C. After 0.5 h, 1N sodium bisulfate was added and the stirring was continued for an additional 30 minutes. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was removed in vacuo to give 3.1 g of 5-(4-fluorobenzoyl)-6-trifluoromethylsulfonyloxy-2-naphthalenesulfonamide as an oil (75% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][C:15](OCC)=[O:16])([O-:13])=[O:12].N1CCCCC1>CC1C=CC=CC=1C>[I:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][C:15](=[O:16])[C:14]([N+:11]([O-:13])=[O:12])=[CH:4]2
Reactant: Nc1ccc(I)cc1C=O
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: Cc1ccccc1C
Solvent: C1CCNCC1
Product: O=c1[nH]c2ccc(I)cc2cc1[N+](=O)[O-]

Procedure:
A stirred mixture of 2-amino-5-iodobenzaldehyde (2.0 g), ethyl nitroacetate (4.2 g), and piperidine (0.7 g) was heated under reflux for 1.5 hours in o-xylene (100 cm3). The cooled solution was then concentrated in vacuo and the solid residue was recrystallised from chloroform-isopropanol to afford 6-iodo-3-nitro-2-(1H)-quinolone, m.p. 279°-282°, (1.14 g).
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1)=O.[Cl:16][C:17]1[N:22]=[N:21][C:20]([NH2:23])=[C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:18]=1>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:20]2[N:21]([CH:2]=[C:3]([CH:5]3[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]3)[N:23]=2)[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)CBr)C1
Reactant: Nc1nnc(Cl)cc1N1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(c2cn3nc(Cl)cc(N4CCOCC4)c3n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 3-(2-bromoacetyl)azetidine-1-carboxylate (207 mg, 0.744 mmol) in DMF (1 mL) was added to a solution of compound 19a (99.8 mg, 0.465 mmol) and Na2HPO4 (165 mg, 2.50 mmol) in DMF (20 mL). The resulting mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue obtained was purified by normal phase column chromatography on silica gel (0-100% EtOAc/heptane) to obtain compound 19b. Mass Spectrum (LCMS, ESI pos.): Calcd. for C19H25ClN4O3: 393.2 (M+H). found: 393.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.[CH3:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1C=CC=CC=1>[CH3:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)[CH2:19][CH2:18]1
Reactant: CC1CCNCC1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Solvent: c1ccccc1
Product: CC1CCN(c2cncc(C(=O)Nc3nnn[nH]3)n2)CC1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 20 ml of benzene, 2.96 ml of 4-methylpiperidine was added, and the mixture was refluxed for 5 hours. The reaction mixture was evaporated, ethanol was added to the residue, and then the ethanol solution was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 1.02 g of the desired compound as yellow columns, m.p. 246.5°-248.5° C. (decomp.).