Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:18]S(C(C)(C)C)=O)([C:12]1[N:16]=[C:15]([CH3:17])[O:14][N:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH2:1]([O:8][CH2:9][C:10]([C:12]1[N:16]=[C:15]([CH3:17])[O:14][N:13]=1)([NH2:18])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C(C)(COCc2ccccc2)NS(=O)C(C)(C)C)no1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(C(C)(N)COCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a solution of N-(1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (example 112c, 1.2 g, 2.73 mmol) in methanol (15 ml) was added a 4.0M solution of hydrochloric acid in Dioxane (2.05 ml, 8.19 mmol). The reaction mixture was stirred at room temperature for 2 hours. Volatiles were removed in vacuo and the residue was dissolved in ethyl acetate. The organic phase was extracted with a 1.0M aqueous solution of sodium bicarbonate and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane\ethyl acetate gradient to yield the title compound (577 mg, 85%) as a light yellow oil. MS (ESI, m/z): 248.6 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8]C1N=C(NC(N)=N)C2C(C=1)=CC=C(S(NCC(O)=O)(=O)=O)C=2.Cl.[NH2:32][C:33]([NH2:35])=[NH:34].[C:36]([O:40][C:41](=[O:59])[CH2:42][NH:43][S:44]([C:47]1[CH:56]=[C:55]2[C:50]([C:51]([Cl:58])=[CH:52][N:53]=[C:54]2Cl)=[CH:49][CH:48]=1)(=[O:46])=[O:45])([CH3:39])([CH3:38])[CH3:37]>CS(C)=O.O>[ClH:8].[C:36]([O:40][C:41](=[O:59])[CH2:42][NH:43][S:44]([C:47]1[CH:56]=[C:55]2[C:50]([C:51]([Cl:58])=[CH:52][N:53]=[C:54]2[NH:34][C:33]([NH2:35])=[NH:32])=[CH:49][CH:48]=1)(=[O:45])=[O:46])([CH3:39])([CH3:37])[CH3:38]
Reactant: N=C(N)N
Reactant: N=C(N)Nc1nc(Cl)cc2ccc(S(=O)(=O)NCC(=O)O)cc12
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 36.8 %

Procedure:
N-[(-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]glycine trifluoroacetate ##STR13## NaH (29 mg, 80% dispersion by wt in mineral oil, 0.97 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (146 mg, 1.52 mmol) in DMSO (2.0 mL) and the mixture was heated at 60° C. under N2 for 30 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]glycine t-butyl ester (150 mg, 0.38 mmol) was added and the mixture heated at 90° C. for 9 h. The cooled mixture was diluted with water (30 mL), extracted with EtOAc (4×20 mL) and the combined organic extracts were washed with water, brine, dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in Et2O and a solution of HCl in Et2O (1 M) was added to give a sticky precipitate. The Et2O was decanted and the residue triturated with EtOAc to give a white solid. Filtration with EtOAc and Et2O washing gave N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]glycine t-butyl ester hydrochloride (68 mg, 0.14 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O=[CH:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][CH2:30]2)[CH2:18][CH2:17]1
Reactant: Cn1c(OC2CCNCC2)nc(-c2ccncn2)cc1=O
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cn1c(OC2CCN(CCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a mixture of 1-methyl-2-(piperidin-4-yloxy)-1H-[4,4′]bipyrimidinyl-6-one (290 mg, 1.0 mmol), tert-butyl 4-(2-oxo-ethyl)piperidine-1-carboxylate (300 mg 1.3 mmol) and acetic acid (one drop) in 1,2-dichloroethane (5.0 ml) was added sodium triacetoxyborohydride (530 mg, 2.5 mmol). The mixture was stirred at room temperature overnight. The mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (eluent; hexane/ethyl acetate=30/70) to afford tert-butyl 4-{2-[4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidin-1-yl]ethyl}piperidine-1-carboxylate as a colorless solid (340 mg, 0.67 mmol, 67%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.[CH3:20][C:21]1[CH2:26][CH2:25][CH2:24][C:23]([CH3:28])([CH3:27])[C:22]=1[CH2:29][CH:30]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:1]1([CH:30]([NH:17][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH2:29][C:22]2[C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][CH2:26][C:21]=2[CH3:20])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC1=C(CC=O)C(C)(C)CCC1
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1=C(CC(NC(=O)c2ccc(Cl)cc2)n2nnc3ccccc32)C(C)(C)CCC1

Procedure:
Benzotriazole, 4-chlorobenzamide, (2,6,6-trimethyl-1-cyclohexenyl)acetaldehyde, and p-toluenesulfonic acid were processed as in Example 53A to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH2:9][CH3:10])[N:3]=1.O.[NH2:12][NH2:13]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:12][NH2:13])[N:5]=[C:4]([CH2:9][CH3:10])[N:3]=1
Reactant: CCc1nc(Cl)cc(Cl)n1
Reactant: NN
Solvent: CO
Solvent: O
Product: CCc1nc(Cl)cc(NN)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a stirred, cold (0° C.) solution of 60 g (0.34 mole) of 4,6-dichloro-2-ethylpyrimidine in 500 ml of methanol was added 35 g (0.7 mole) of hydrazine hydrate while maintaining the temperature below 10° C. Stirring was continued for 2 hours after completion of the addition, the temperature being maintained at 0° C. The mixture was allowed to warm to about 20° C. and was stirred for 16 hours. The white solid was collected by filtration and the filtrate was partially evaporated to provide a second crop. The combined solids were washed with water and air dried to provide 51 g (77%) of 4-chloro-2-ethyl-6-hydrazinylpyrimidine, m.p. 147°-150° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[CH:26])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:27][C:28]1[CH:29]=[C:30]2[C:34](=[N:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[NH:33]1[C:34]2[C:30](=[CH:29][C:28]([O:27][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[CH:26])[CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:36][N:35]=2)[CH:31]=[CH:32]1
Reactant: C#CCN1CCN(CCCOc2cc3ncnc(Cl)c3cc2OC)CC1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C#CCN1CCN(CCCOc2cc3ncnc(Oc4cnc5[nH]ccc5c4)c3cc2OC)CC1
Temperature: 85 °C
Yield: 76.2 %

Procedure:
4-Chloro-6-methoxy-7-[3-(4-prop-2-yn-1-ylpiperazin-1-yl)propoxy]quinazoline (300 mg, 0.8 mmol) was dissolved in dimethylacetamide (10 ml). 5-Hydroxy-7-azaindole (118 mg, 0.88 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (122 mg, 0.88 mmol) were added and the mixture heated to 85° C. for 1.5 hours. The reaction mixture was cooled, filtered and concentrated. The resulting residue was preabsorbed on silica and eluted with methylene chloride/methanol (saturated with ammonia) (90/10) to give 4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-prop-2-yn-1-ylpiperazin-1-yl)propoxy]quinazoline (288 mg, 76%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[CH:6]=[C:7]([C:14]([O-:16])=[O:15])[NH:8]2.[C:17](Cl)(=[O:19])[CH3:18].Cl.[CH3:22]N(C=O)C>>[C:17]([N:8]1[C:9]2[C:5](=[C:4]([CH3:3])[CH:12]=[CH:11][C:10]=2[CH3:13])[CH:6]=[C:7]1[C:14]([O:16][CH3:22])=[O:15])(=[O:19])[CH3:18]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C)c2[nH]c(C(=O)[O-])cc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2c(C)ccc(C)c2n1C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A suspension of 0.11 g (4.13 mmol) of sodium hydride in 10 ml of anhydrous DMF was prepared. A solution of 0.8 g (3.94 mmol) of 4,7-dimethylindole-2-carboxylate in 10 ml of anhydrous DMF was added thereto dropwise at 0° C. over a period of 30 minutes and the reaction mixture was stirred for 1 hour. Then a solution of 0.47 g (4.33 mmol) of acetyl chloride in 0.4 ml of anhydrous DMF was added dropwise, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was added dropwise to 300 ml of ice water, acidified with 1N HCl aqueous solution and extracted with ethyl acetate three times. The ethyl acetate solutions were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide 212 mg of white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH2:9]([C:13]1([CH2:16][CH3:17])[CH2:15][NH:14]1)[CH2:10][CH2:11][CH3:12]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:15][C:13]([CH2:16][CH3:17])([NH2:14])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Sc1ccccc1Br
Reactant: CCCCC1(CC)CN1
Solvent: CO
Product: CCCCC(N)(CC)CSc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.4 %

Procedure:
To a solution of 2-bromothiophenol (13.5 g, Lancaster) in methanol (45 ml) was added dropwise 2-butyl-2-ethylaziridine (10.0 g, Synthetic Example 1(f)). The mixture was stirred at room temperature for 1 hour. Solvent was evaporated to afford the title product as a light yellow oil (25.6 g). 1H NMR consistent with the proposed structure.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][C:36](=[O:39])[NH:37][NH2:38])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[S:23][C:24]([CH3:27])=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:52]([O:55][C:56]1[CH:57]=[C:58]([CH:62]=[CH:63][C:64]=1[O:65][C:66](=[O:68])[CH3:67])[C:59]([Cl:61])=[O:60])(=[O:54])[CH3:53].CCOCC>C(Cl)Cl.CO>[ClH:61].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][C:36](=[O:39])[NH:37][NH:38][C:59](=[O:60])[C:58]2[CH:62]=[CH:63][C:64]([O:65][C:66](=[O:68])[CH3:67])=[C:56]([O:55][C:52](=[O:54])[CH3:53])[CH:57]=2)[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[S:23][C:24]([CH3:27])=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NOCC(=O)NN)c4csc(N)n4)[C@H]3SC2)s1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CC(=O)Oc1ccc(C(=O)NNC(=O)CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)c2csc(N)n2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
In 3 ml of methylene chloride was suspended 0.35 g (0.53 mmole) of 7-[2-(2-amino-1,3-thiazol-4-yl)-2-carbazoylmethoxyiminoacetamido]-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid.dihydrochloride obtained in Reference example 9 and the suspension was dissolved by adding 1.35 g (6.66 mmole) of N,O-bis(trimethylsilyl)acetamide. To the mixture was added 0.136 g (0.53 mmole) of 3,4-diacetoxybenzoic acid chloride and the mixture was stirred at room temperature for one hour. The mixture was poured into 200 ml of ether and added thereto a small amount of methanol while stirring. The resulting precipitates were collected by filtration, washed with water and then dried to obtain 0.42 g of the title compound. (Yield: 94.1%)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[F:17][C:18]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:19]=1[O:20]C1C=CN=C2C=C(C3SC=CN=3)SC=12>>[F:17][C:18]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:19]=1[O:20][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Yield: 45 %

Procedure:
Starting from compound 214 (scheme 46) and following the procedure described above for the synthesis of compound 11 (scheme 2, step 3, example 12), title compound 218 was obtained in 45% yield. MS (m/z) 371.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:4]=2[N:3]=1.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[CH2:21]([O:20][C:18]1[CH:17]=[CH:16][C:5]2[C:6]3[C:7]4[CH:8]=[CH:9][N:10]=[CH:11][C:12]=4[C:13](=[O:15])[C:14]=3[C:2]([Cl:1])=[N:3][C:4]=2[CH:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: O=C1c2cnccc2-c2c1c(Cl)nc1cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1c2cnccc2-c2c1c(Cl)nc1cc(OCc3ccccc3)ccc21
Temperature: 90 °C
Reaction time: 2 h

Procedure:
6-Chloro-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one (Example 34a) (27 mg) was dissolved in DMF (2 ml). To the solution were added benzyl chloride (0.016 ml) and potassium carbonate (29 mg). The mixture was stirred at 90° C. for 2 hours. The reaction mixture was dissolved in dichloromethane and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane and dichloromethane-MeOH=50:1. The desired product (12 mg) was obtained as a light yellow solid. EI−MS: m/z 372 (M+); 1H-NMR (CDCl3): δ5.25 (2H, s), 7.30-7.55 (7H, m), 8.00 (1H, dd, J=5 Hz, 1 Hz), 8.36 (1H, d, J=9Hz), 8.95 (1H, d, 5 Hz), 9.03 (1H, d, J=1 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[C:17]1([C:23]2[CH:27]=[CH:26][S:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:28]([C:24]4[S:25][CH:26]=[CH:27][C:23]=4[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[O:29])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1sccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4sccc4-c4ccccc4)CC3C2)n1
Yield: 26.5 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0 mg, 0.28 mmol), 3-phenyl-thiophene-2-carboxylic acid (61.8 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (107.0 mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (30.0 mg, 27.0%). MS (ESI) mass calcd. for C23H24N4OS, 404.54; m/z found 405.2 [M+H]+. 1H NMR (CDCl3): 7.45-7.41 (m, 2H), 7.39 (d, J=5.1, 1H), 7.34-7.27 (m, 2H), 7.18-7.14 (m, 1H), 7.13 (d, J=5.0, 1H), 6.28 (s, 1H), 3.88-3.66 (m, 2H), 3.61-3.49 (m, 2H), 3.30 (dd, J=11.5, 5.1, 1H), 3.19-3.04 (m, 2H), 2.92-2.78 (m, 1H), 2.75-2.61 (m, 2H), 2.37-2.22 (m, 6H).
Reaction SMILES: O.[NH2:2]N.[F:4][C:5]([F:15])([C:11]([F:14])([F:13])[F:12])[C:6](OCC)=O.C(O)(=O)C.[CH:20]([NH2:22])=[NH:21]>C(O)C>[F:4][C:5]([F:15])([C:6]1[N:22]=[CH:20][NH:21][N:2]=1)[C:11]([F:14])([F:13])[F:12]
Reactant: NN
Reactant: N=CN
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: FC(F)(F)C(F)(F)c1nc[nH]n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
1.25 g of hydrazine hydrate was dissolved to 45 ml of ethanol, and it was cooled to 0° C. 5.38 g of ethyl 2,2,3,3,3-pentafluoropropionate was dropped to it over the period of 15 minutes, followed by stirring at 0° C. for 1 hour. 2.61 g of formamidine acetic acid salt was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. 50 ml of acetic acid was added to the residue, followed by stirring at 100° C. for 5 hours. The reaction mixture was concentrated under reduced pressure. Saturated aqueous solution of sodium hydrogen carbonate was added to the residue so as to be around pH 6. And then it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.98 g of 3-pentafluoroethyl-1H-1,2,4-triazole.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:20][C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:21])[N:13]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:41][CH2:42][CH2:43][CH2:44]O.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1(C)C=CC=CC=1.C(O)(C)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([S:11][C:12]2[N:13]([CH2:44][CH2:43][CH2:42][Br:41])[C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: OCCCBr
Reactant: Nc1ncnc2nc(Sc3cc4c(cc3Br)OCO4)[nH]c12
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCCBr
Yield: 21 %

Procedure:
A solution of 8-(6-Bromo-benzo[1,3]dioxol-5-ylsulfanyl)adenine (513 mg, 1.4 mmol), PPh3 (808 mg, 3.08 mmol), 3-bromo-1-propanol (253 mg, 165 L, 1.82 mmol), DBAD (1612 mg, 7 mmol) in toluene (43.8 mL) and CH2C12 (8.75, mL) was stirred at room temperature for 20 min. The reaction mixture was loaded to a silica gel column (CHC13 then CHC13:EtOAc:hexanes: i-Propanol at 4:4:2:1) to provide the 9N-alkylated compound, 8-(6-bromo-benzo[1,3]dioxol-5-ylsulfanyl)-9-(3-bromo-propyl)adenine) (142.6 mg, 21% yield). A solution of this product (142.6 mg, 0.29 mmol) in 1,4-dioxane (12 mL) and i-propylamine (3 mL) was stirred at 100° C. for 2.5 h. The solvent was removed under vacuum and the crude purified by preparatory thin layer chromatography on silica gel (CHC13:MeOH:NH4OH at 10:1:0.5 then EtOAc:CH2C12:MeOH at 2:2:1) to afford 12 (51 mg, 8% yield). 1H NMR (400 MHz, CDC13) 8.30 (s, 1H), 7.04 (s, 1H), 6.81 (s, 1H), 6.48 (bs, 2H), 5.94 (s, 2H), 4.29 (t, J=7.0 Hz, 2H,), 2.74-2.68 (m, 1H), 2.57 (t, J=6.8 Hz, 2H,), 2.02-1.95 (m, 2H), 1.02 (d, J=6.0 Hz, 6H). 13C NMR (100 MHz, CDC13) 154.8, 152.9, 151.5, 148.8, 148.0, 145.2, 123.8, 120.0, 116.7, 113.2, 112.2, 102.3, 48.6, 43.8, 41.7, 30.2, 22.8; MS m/z 465.0 (M+H)+. HPLC: (a) 99.1% (65% water-35% acetonitrile); (b) 98.0% (20% to 40% acetonitrile).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Na+].Br[C:16]1[CH:24]=[CH:23][C:22]2[N:21]([CH3:25])[C:20]3[CH2:26][CH:27]4[NH:31][CH:30]([C:19]=3[C:18]=2[C:17]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]4>>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:16]2[CH:24]=[CH:23][C:22]3[N:21]([CH3:25])[C:20]4[CH2:26][CH:27]5[NH:31][CH:30]([C:19]=4[C:18]=3[C:17]=2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]5)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: O=S([O-])c1ccc(C(F)(F)F)cc1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(C(F)(F)F)cc4)ccc31)C1CCC(C2)N1
Yield: 24 %

Procedure:
Intermediate 17 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) to give tert-butyl 2-(4-trifluoromethylphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (130 mg, 24%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.19 (s, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.67-7.78 (m, 3H), 7.31-7.33 (m, 1H), 5.30 (br s, 1H), 4.70 (br s, 1H), 3.58 (s, 3H), 3.37-3.41 (m, 1H), 2.51 (d, J=16.3 Hz, 1H), 2.16-2.31 (m, 2H), 1.90-1.96 (m, 1H), 1.56-1.65 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:7][CH2:6][N:5]1[CH2:16][C:17]([C:19]1[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1)=[O:18].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:48](=O)([O:56]C1C=CC([N+]([O-])=O)=CC=1)[O:49][CH:50]([O:52][C:53](=[O:55])[CH3:54])[CH3:51].O>CN(C)C=O>[C:53]([O:52][CH:50]([O:49][C:48]([N:13]1[CH2:12][CH2:11][CH:10]([N:8]2[CH2:7][CH2:6][N:5]([CH2:16][C:17]([C:19]3[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=3)=[O:18])[C:4](=[O:3])[CH2:9]2)[CH2:15][CH2:14]1)=[O:56])[CH3:51])(=[O:55])[CH3:54]
Reactant: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCNCC3)CC2=O)cc1
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCN(C(=O)OC(C)OC(C)=O)CC3)CC2=O)cc1
Temperature: 0 °C
Yield: 99.3 %

Procedure:
To a suspension of 107 mg of ethyl 4-[[2-oxo-4-(piperidin-4-yl)piperazin-1-yl]acetyl]phenoxyacetate dihydrochloride synthesized according to the method described in WO962503 in 2 ml of N,N-dimethylformamide were added 110 mg of proton sponge and 85.7 mg of 1-acetoxyethyl 4-nitrophenyl carbonate with stirring at 0° C., and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into 2 ml of water and extracted three times with 4 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was removed by distillation. The residue thus obtained was purified by chromatography on an LH-20 column (chloroform:methanol=1:1) to give 119 mg of the title compound (100%).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([C@H:9](O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](CNC)[CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[CH2:26]([N:28](CC)[CH2:29]C)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][C:11]=1[CH2:26][NH:28][CH3:29])[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(-c2cccc(CNC)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(-c2ccccc2)cc1CNC)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
19.6 g of the crude product methyl (2S,3R)-2-ethoxy-3-hydroxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate are dissolved in 200 ml of trifluoroacetic acid and 41.7 ml (297 mmol) of triethylamine are added. The reaction medium is stirred at room temperature for 48 hours and then extracted with ethyl acetate. The organic phase is decanted off, washed with a sodium hydroxide solution and then with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a dichloromethane and methanol (95/5) mixture. 1.6 g (10%) of the expected product are obtained.