Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:10][N@@:9]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=O)=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCCC1.CS(C)=O>[CH2:21]([N:28]1[CH2:6][CH2:7][C@H:8]([NH:9][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)[N@]2CC2CCOS(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)[N@@]2CC2CCOS(C)(=O)=O)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N[C@H]2CCN(Cc3ccccc3)C2)cc1

Procedure:
(S)-2-(2'-Methanesulfonyloxyethyl)-1-(p-toluenesulfonyl)aziridine, 3, (54.5 g) was dissolved in warm tetrahydrofuran (50 mL) and the solution added dropwise over 20 minutes to a solution of benzylamine (40 g) and triethylamine (40 g) in dimethyl sulfoxide (250 mL) at 75° to 85° C. The resulting solution was heated another 2.5 hours at 75° to 85° C. and then concentrated under vacuum to remove tetrahydrofuran and dimethyl sulfoxide. The residue was dissolved in toluene (300 mL) and cautiously treated with 10 g of dry ice followed by 1.0N NaOH (150 mL). The layers were separated and the toluene layer treated cautiously with more dry ice (3 g) followed by 20 mL 1.0N NaOH. This carbon dioxide--NaOH extraction procedure was repeated three more times and the resulting toluene solution concentrated under vacuum to give (S)-1-benzyl-3-(p-toluenesulfonylamino)pyrrolidine, 4, as an amber oil. The oil was dissolved in warm (60° -70° C.) toluene (15 mL) and a solution (30 mL) of isopropyl alcohol saturated with hydrogen chloride gas was added. The solution was stirred and cooled to -5° C. where it was maintained for 3 hours. The solid product was collected and washed with isopropyl alcohol and ether and vacuum dried to give (S)-1-benzyl-3-(p-toluenesulfonylamino)pyrrolidine hydrochloride as an off-white solid (46.5 g, 74% combined yield for Steps 3 and 4). A portion was recrystallized from isopropyl alcohol: mp 179°-181° C.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[Cl-].[Ca+2].[Cl-].[Cl-].[Al+3].[Cl-].[Cl-].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=1>C1C2C(=CC=CC=2)CCC1.C1(C)C=CC=CC=1>[CH3:24][C:19]1[CH:18]=[C:17]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=2)[CH:22]=[CH:21][C:20]=1[CH3:23]
Reactant: Cc1ccc(N)cc1C
Reactant: Cc1cccc(N)c1
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: c1ccc2c(c1)CCCC2
Product: Cc1cccc(Nc2ccc(C)c(C)c2)c1
Temperature: 0 °C
Yield: 42.7 %

Procedure:
In a 500-ml four-necked flask were charged 56 ml of 1,2,3,4-tetrahydronaphthalene (boiling point: 207° C.) as a solvent and 45.0 g (0.42 mol) of m-toluidine, followed by the addition of 25.6 g (0.23 mol) of anhydrous calcium chloride and 30.8 g (0.23 mol) of anhydrous aluminum chloride under stirring. After stirring at an internal temperature of 100 to 120° C. for 30 minutes under a nitrogen atmosphere, the reaction mixture was added with 50.9 g (0.42 mol) of 3,4-xylidine. The resulting mixture was reacted at an internal temperature of 210 to 220° C. for 3 hours. After cooling, the reaction mixture was added with 126 ml of toluene, followed by charging in 160 g of ice water. The resulting mixture was stirred and then, allowed to stand, whereby a water layer was separated out. The organic layer was washed successively with 150 ml of a 5% aqueous solution of hydrochloric acid, 100 ml of a 5% aqueous solution of sodium bicarbonate and 100 ml of water. From the organic solvent, the distillate at 134 to 135° C. and a vacuum degree of 0.4 to 0.5 Torr was collected, whereby 37.9 g (yield: 42.7%) of the title compound was obtained as a slightly yellow oil. As a result of HPLC. analysis (column: YMC-A-312, detection UV: 280 nm, flow rate: 1.0 ml/min, eluent: acetonitrile/water=8/2), the compound was found to have a purity of 99.3%.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:13])=[CH:5][CH:6]=[N:7]2.C(O)(=O)C>[Zn].CO>[Cl:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4]([OH:13])=[CH:5][CH:6]=[N:7]2)=[CH:2][N:11]=1
Reactant: Oc1ccnc2cc(Cl)nc(Cl)c12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccnc2cc(Cl)ncc12
Temperature: 60 °C
Yield: 76.7 %

Procedure:
5,7-dichloro-1,6-naphthyridin-4-ol (1.6 g, 7.44 mmol) was added to a round bottom flask, followed by zinc (2.432 g, 37.2 mmol) and MeOH (44.6 mL). Acetic acid (glacial) (4.26 mL, 74.4 mmol) was added and the reaction was heated to 60° C. for 16 hours. The solids were filtered and washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to provide 1.03 g of 7-chloro-1,6-naphthyridin-4-ol as a white solid which was used without further purification. m/z (ESI) 181.2 (M+H)+.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=O)[C:21]1C=CC=[CH:23][CH:22]=1>>[CH:3]1[C:4]2[C:5](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:7][C:2]=1[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Product: CCOC(=O)CCCCCCC(=O)c1ccc2ccccc2c1
Yield: 54 %

Procedure:
Following a procedure analogous to that described above for 49a, but substituting 2-naphthoyl chloride for benzoyl chloride, the title compound was obtained as a white solid in 54% yield: 1H NMR (300 MHz, CDCl3): δ 8.47 (s, 1H), 7.86-8.05 (m, 4H), 7.51-7.62 (m, 2H), 4.12 (q, J=6.9 Hz, 2H), 3.10 (t, J=7.5 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H), 1.80 (m, 2H), 1.62 (m, 2H), 1.41 (m, 4H), 1.25 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](Cl)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:39])[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([N:36]1[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][N:30]([CH3:39])[CH3:29])[CH2:34][CH2:35]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN(C)CCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cc(C(=O)N2CCN(CCN(C)C)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
2,4-Bis-benzyloxy-5-isopropyl-benzoyl chloride (200 mg, 0.5 mmol) was dissolved in DCM (5 ml), treated with 1-(2-dimethylaminoethyl)piperazine (83.6 mg, 0.53 mmol) and triethylamine (0.2 ml, then stirred for 1 hour at room temperature. The reaction mixture was diluted with DCM, washed with water and, dried (MgSO4) and evaporated to give 0.25 g of the title compound. MS: [M+H]+ 516.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)=S.CN(C)C=O>C(#N)C>[C:2]([NH:3][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)=[N:6][CH3:5])#[N:1]
Reactant: N#CN
Reactant: CNC(=S)NCCSCc1c[nH]cn1
Agent: [Pb]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN=C(NC#N)NCCSCc1c[nH]cn1
Yield: 31.1 %

Procedure:
Lead cyanamide (24.7 g.) was added to a solution of N-methyl-N'-[2-(4-imidazolylmethylthio)ethyl]thiourea (11.5 g.) in acetonitrile (250 ml.) containing dimethylformamide. The stirred suspension was heated under reflux for 48 hours. Filtration followed by concentration under reduced pressure and purification of the product or a column of silica gel with ethyl acetate-isopropyl alcohol (2.1) as eluant gave N-cyano-N'-[2-(4-imidazolylmethylthio)ethyl]-N"-methylguanidine (3.7 g.), m.p. 138°-140° (from acetonitrile). (Found: C, 45.7; H, 5.9; N, 35.5; S, 13.5. C9H14N6S requires: C, 45.4; H, 5.9; N, 35.3; S, 13.5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:10]=3[N:9]=2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.CO.[C:26](Cl)(=O)C(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:26])=[O:18])[C:10]=3[N:9]=2)=[C:4]([C:20]([F:22])([F:23])[F:21])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(Cl)cc3C(F)(F)F)nc12
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3C(F)(F)F)nc12
Yield: 75 %

Procedure:
2-(4-Chloro-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (54; 500 mg, 1.46 mmol) was suspended in CH2Cl2 (15 mL). Methanol (2 mL) was added to solubilize. To the reaction solution was added dropwise oxalyl chloride (130 μL, 1.46 mmol). After having stirred the reaction at room temperature overnight, the reaction was concentrated. The residue was taken up in EtOAc and washed successively with saturated NaHCO3 and then brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (EtOAc/pentane) afforded methyl 2-(4-chloro-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylate as an orange solid (structure not shown) (390 mg, yield: 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=2[F:18])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[N:23]#[C:24][NH2:25].FC(F)(F)S(O)(=O)=O>C1COCC1>[C:24](=[NH:23])([O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:19]([F:22])([F:20])[F:21])[CH:4]=2)=[C:10]([F:18])[CH:11]=1)[NH2:25]
Reactant: N#CN
Reactant: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 33.3 %

Procedure:
To the solution of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3-fluorophenyl)ethanol (4.0 g, 11.95 mmol) and cyanamide (0.603 g, 14.34 mmol) in anhydrous THF (25 mL) was added trifluoromethanesulfonic acid (2.55 mL, 28.7 mmol) at 0° C. The reaction mixture was stirred at 60° C. for 4 h. Purification via a reverse phase Biotage then afforded the title compound as a white solid (1.5 g, 23.82% yield). LCMS: rt=3.68 min, [M+H+]=377
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[K+:34].CC(C)=O.O>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+:34]
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1

Procedure:
Hydrated crystalline form 2 is prepared by sonicating a mixture of raltegravir, KOH, acetone and trace amount of water whereas anhydrous crystalline form 3 is obtained by crystallization of amorphous raltegravir potassium from ethanol.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]12([C:37](O)=[O:38])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37]([C:27]34[CH2:36][CH:31]5[CH2:30][CH:29]([CH2:35][CH:33]([CH2:32]5)[CH2:34]3)[CH2:28]4)=[O:38])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C12CC3CC(CC(C3)C1)C2

Procedure:
The title compound, light yellow solid (94 mg, 77%), MS (ISP) m/z=489.4 [(M+H)+], mp 200° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and adamantane-1-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][NH2:6])=[O:4].[CH3:7][N:8]=[C:9]=[S:10]>CCO>[OH:1][CH2:2][C:3]([NH:5][NH:6][C:9]([SH:10])=[N:8][CH3:7])=[O:4]
Reactant: NNC(=O)CO
Reactant: CN=C=S
Solvent: CCO
Product: CN=C(S)NNC(=O)CO
Temperature: 60 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of 2-hydroxyacetohydrazide (4.5 g, 50 mmol) in EtOH was added dropwise methyl isothiocyanate (3.7 g, 50 mmol) under ice cooling. After addition was complete the reaction mixture was brought to room temperature and then stirred for 24 hr at 60° C. Ice water was then added and stirring was continued for 15 min. The reaction mixture was concentrated in vacuuo to give the title compound. Yield: 100%. LCMS (ESI) m+H=164.0.
Reaction SMILES: [Na].[CH2:2]([C:6]1[N:7]([C:11]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]3[C:12]=2[NH:13][CH:14]=[N:15]3)[CH:8]=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].[C:21]1([CH3:47])[CH:26]=[CH:25][C:24]([C:27]([O:29][C@@H:30]2[C@@H:34]([CH2:35][O:36][C:37]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)=[O:38])[O:33][C@H:32](Cl)[CH2:31]2)=[O:28])=[CH:23][CH:22]=1>CC#N.C(Cl)Cl>[CH2:2]([C:6]1[N:7]([C:11]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:32]2[O:33][C@H:34]([CH2:35][O:36][C:37]([C:39]3[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=3)=[O:38])[C@@H:30]([O:29][C:27]([C:24]3[CH:23]=[CH:22][C:21]([CH3:47])=[CH:26][CH:25]=3)=[O:28])[CH2:31]2)[CH:8]=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: CCCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1

Procedure:
The sodium salt of 6-(2-butylimidazol-1-yl)-2-chloropurine (0.139 g, 0.5 mmol) in dried CH3CN (10 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.334 g, 0.86 mmol) in CH2Cl2 (10 mL) by general method 2. Sampling of the reaction mixture showed traces of α-nucleoside by 1H NMR (500 MHz) (1:24). Volatiles were evaporated in vacuo, and the residue was chromatographed (25 g silica gel, EtOAc/hexanes, 3:7→EtOAc) to give the β-anomer (274 mg, 86%) with traces of the α-anomer. Recrystallization (EtOAc/hexanes) gave 6-(2-butylimidazol-1-yl)-2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]purine: UV (MeOH) max 223, 241, 287 nm (∈ 29 900, 33 400, 13 200), min 230, 265 nm (∈ 28 100, 7500); 1H NMR (500 MHz, CDCl3) δ 8.51 (s, 1H), 8.26 (s, 1H), 7.98 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.09 (s, 1H), 6.60 (t, J=6.9 Hz, 1H), 5.80 (br s, 1H), 4.78-4.81 (m, 1H), 4.66-4.70 (m, 2H), 3.31 (t, J=7.8 Hz, 2H), 2.97-3.00 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 1.80 (quint, J=7.4 Hz, 2H), 1.50 (sext, J=7.4 Hz, 2H), 0.97 (t, J=7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.05, 165.98, 154.13, 153.17, 151.43, 147.92, 144.71, 144.39, 142.18, 129.87, 129.53, 129.35, 129.31, 128.91, 126.38, 126.20, 122.70, 120.33, 85.20, 83.57, 74.94, 63.87, 38.61, 30.70, 30.07, 22.64, 21.79, 21.66, 13.91; HRMS 771/z 629.2270 (MH+[C33H34ClN6O5=629.2279]).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]=[N:4][N:3]=1.C([Li])CCC.[C:18]1([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:29]2([OH:32])[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:27][CH2:28]2)=[N:4][N:3]=1
Reactant: Cc1nncn1-c1ccccc1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc(C2(O)CCN(CCc3ccccc3)CC2)n1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.6 g of 3-methyl-4-phenyl-4H-1,2,4-triazole (10 mmol) in 15 ml of THF at -78° C. is added 7.0 ml of n-butyllithium (1.6N in hexane). The mixture is stirred for 50 minutes before a solution of 2.44 g of N-(2-phenylethyl)-4-piperidinone in 12 ml of THF is charged into the flask. After stirring for 30 minutes at -78° C. and then 1 hour at -20° C. the mixture is poured into cold water and is extracted three times with chloroform. The combined chloroform extracts are washed twice with water, brine, dried over sodium sulfate and concentrated in vacuo to yield an amber oil.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][N:7]=[CH:8][NH:9][C:10]1[CH:36]=[CH:35][C:13]([C:14]([O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27](=[NH:29])[NH2:28])[CH:23]=3)[C:18]=2[CH2:30][C:31]([O:33]C)=[O:32])=[O:15])=[CH:12][CH:11]=1>>[NH2:6][N:7]=[CH:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27](=[NH:28])[NH2:29])[CH:23]=3)[C:18]=2[CH2:30][C:31]([OH:33])=[O:32])=[O:15])=[CH:35][CH:36]=1
Reactant: COC(=O)Cc1c(OC(=O)c2ccc(NC=NN)cc2)ccc2cc(C(=N)N)ccc12
Agent: CS(=O)(=O)O
Product: N=C(N)c1ccc2c(CC(=O)O)c(OC(=O)c3ccc(NC=NN)cc3)ccc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
30 Milliliters of 20% aqueous methanesulfonic acid solution was added to 2.5 g of 6-amidino-1-methoxycarbonylmethyl-2-naphthyl 4-aminoiminomethylaminobenzoate.dimethanesulfonate, followed by stirring for 3 hours at 60° C. Then, 700 mg of active carbon was added to the reaction mixture, followed by stirring for 30 minutes at room temperature. Insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. To the residue was added 30 ml of water to dissolve the residue. The solution was added dropwise to 150 ml of acetone, followed by stirring for 1 hour under cooling with ice. Then, the precipitate was collected by filtration and washed with a small amount of acetone to obtain 580 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[N:4][CH:3]=1>CCO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncn1CCCN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: Cc1cncn1CCCN
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
2-(3-(5-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione (i.e. 8.92 mmol, 1 eq.) and hydzine monohydrate (17.84 mmol, 2 eq.) were dissolved in dry EtOH (50 mL). The mixture was kept under reflux over night, then mixture was concentrated down to a volume of 25 mL. After that hydrochloric acid (conc., 55 mL) was added and the mixture was heated up to 50° C. for and kept at this temperature for 30 min. The formed precipitate was filtered off. The filtrate was cooled down to 0° C. and solid NaOH was added until a final pH-value of 10-12 is reached. The aqueous solution was extracted by means of CHCl3 (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed. The product was purified by means of flash-chromatography using silica gel and a CHCl3/MeOH-gradient.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][S:5][CH:6]=1.I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:11][CH3:12])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: Cc1cscc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cscc1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Methyl-3-thiophenecarboxylic acid (1.42 g) (synthesized in accordance with the method described in J. Org. Chem., 51, 230 (1986)) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (0.8 ml) and potassium carbonate (1.38 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water. and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 4-methyl-3-thiophenecarboxylate (1.7 g). Ethyl 4-methyl-3-thiophenecarboxylate (1.7 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.2 ml) in acetonitrile (20 ml) was added. The mixture was stirred at room temperature for 1 hour, and then 10% aqueous sodium thiosulfate (100 ml) was added and stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of ethyl 5-chloro-4-methyl-3-thiophenecarboxylate and ethyl 2,5-dichloro-4-methyl-3-thiophenecarboxylate. The mixture of ethyl 5-chloro-4-methyl-3-thiophenecarboxylate and 2,5-dichloro-4-methyl-3-thiophenecarboxylate was dissolved in ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (20 ml) was added. The mixture was stirred at room temperature for 2 hours, and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of 5-chloro-4-methyl-3-thiophenecarboxylic acid and 2,5-dichloro-4-methyl-3-thiophenecarboxylic acid. The mixture was suspended in toluene (15 ml). Oxalyl chloride (1.31 ml) was added dropwise and then N,N-dimethylformamide (1 drop) was added. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (5 ml) and added dropwise into a mixture of 25% aqueous ammonia solution (16 ml) and ethyl acetate (50 ml) with stirring under ice-cooling. The resulting mixture was stirred at room temperature for 10 minutes. The organic layer was collected and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-4-methyl-3-thiophenecarboxamide (0.83 g) and 2,5-dichloro-4-methyl-3-thiophenecarboxamide (0.61 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9]C(=O)C)=[C:4]([C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:16]=[CH:15][CH:14]=2)[CH:3]=1.Cl.C(=O)([O-])O.[Na+].[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CC(=O)Nc1cc(C)c(Br)cc1-c1ccnn1C1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(N)c(-c2ccnn2C2CCOCC2)cc1Br
Temperature: 120 °C
Reaction time: 0.67 h
Yield: 95.5 %

Procedure:
A mixture of 3.96 g of N-{4-bromo-5-methyl-2-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]phenyl}acetamide and 18 mL of 12 M hydrochloric acid was stirred at 120° C. for 40 minutes. The reaction mixture was cooled to room temperature, then poured into a mixture of a saturated aqueous sodium hydrogen carbonate solution/ethyl acetate, and adjusted to pH 10 with a 6 M aqueous sodium hydroxide solution. The aqueous layer was separated, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 3.36 g of 4-bromo-5-methyl-2-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]aniline.