Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:29]1([CH2:28][N:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@H:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:3]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:2]2=[O:1])[CH2:31][CH2:30]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a stirred solution of tert-butyl [(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67a) (190 mg, 0.536 mmol) in dry DMF (2 mL) under nitrogen was added (bromomethyl)cyclopropane (108 mg, 0.800 mmol) and powdered cesium carbonate (264 mg, 0.810 mmol). The mixture was stirred overnight at ambient temperature then diluted with water and extracted with ethyl acetate three times. The residue from the combined organic extracts was purified by flash chromatography on silica gel eluting with 6:1 (v/v) hexane:ethyl acetate to afford the title compound (201 mg, 92%) as a white solid. TLC Rf=0.31 (6:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ0.19 (m, 1H), 0.35-0.62 (m, 3H), 1.15 (m, 1H), 1.37 (s, 9H), 3.50 and 3.55 (dd, 1H, J=7.0 Hz), 4.12 and 4.17 (dd, 1H, J=7.0 Hz), 4.93 (m, 2H), 5.65 (d, 1H, J=7.0 Hz), 7.29 (m, 4H), 7.41 (m, 5H). MS APCI, m/z=309 (M-BOC). LC/MS: 3.08 min.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH:10]([N:24]([CH3:23])[S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH2:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNS(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C1CN(C(c2ccccc2)c2ccccc2)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a solution of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (WO 96/05193) (1.4 g) in dioxane (25 mL) were added N-methyl benzenesulphonamide (1.2 g) and caesium carbonate (2.6 g). The reaction mixture was heated to reflux for 3 h, then cooled to room temperature. Water (20 mL) was added to the resulting slurry, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organics were washed with brine, dried over magnesium sulphate, filtered and dried in vacuo to yield crude product. Chromatography on silica gel eluting with ethyl acetate:hexanes (2:3 by volume) yielded the title compound as a white foam (1.31 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([Br:26])=[CH:13][CH:14]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:7]([C:8]1[C:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([Br:26])=[CH:13][CH:14]=2)[CH:9]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27]
Reactant: CC(C)(C)OC(=O)Nc1cc2cc(Br)ccc2cc1OCc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1cc2cc(Br)ccc2cc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of (3-benzyloxy-7-bromonaphthalen-2-yl)-carbamic acid tert-butyl ester (38.65 g, 90.2 mmol) in DMF (300 mL) at 0° C. is added NaH (3.79 g, 99.3 mmol). To the solution is added methyl bromoacetate (10.3 mL, 108.2 mmol). The mixture is stirred for 10 min and then quenched with 1 N HCl. The solution is extracted with EtOAc and washed with 1 N HCl (3×) and sat. NaCl. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is recrystallized from EtOAc to afford [(3-benzyloxy-7-bromonaphthalen-2-yl)-tert-butoxycarbony-amino]-acetic acid methyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]3[O:28][CH2:27][CH2:26][N:25]4[C:21](=[N:22][C:23]([C:29](=[O:31])[NH2:30])=[CH:24]4)[C:20]=3[CH:32]=2)([OH:13])[CH2:9]1)=O)(C)(C)C.Cl.CC(=O)OCC>CO>[OH:13][C:10]1([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]3[O:28][CH2:27][CH2:26][N:25]4[CH:24]=[C:23]([C:29]([NH2:30])=[O:31])[N:22]=[C:21]4[C:20]=3[CH:32]=2)[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CCNC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
In a solution of 3-(2-Carbamoyl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-9-ylethynyl)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 0.1 mmol) in methanol (20 ml) was added HCl/EA (20 ml). The solution was stirred for 3 h at room temperature. The reaction mixture was purified by column to afford the titled compound (3.5 mg, 10%). 1HNMR (Methanol-d4, 400 MHz): δ 8.62 (d, J=2.0 Hz, 1H), 7.78 (s, 1H), 7.41 (dd, J=2.0, 8.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 4.52 (s, 4H), 3.54-3.40 (m, 4H), 2.43 (t, J=5.4 Hz, 2H), LCMS: 339.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH:36](Br)[CH2:37][CH3:38])[CH:30]=1>C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:35][CH:36]([CH2:37][CH3:38])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([OH:10])=[O:9])[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CCC(Br)Cc1cccc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(Cc1cccc(OC)c1)C(C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Phenylacetic acid (0.84 g, 6.07 mmol) was dissolved in THF (50 mL) and cooled in an ice bath. nBuLi (2.5 M in hexanes, 5.4 mL, 13.4 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 h, then at room temperature for 5 h. HMPA (0.25 mL) was added, and the stirring was continued for another 30 min. Cooled in an ice bath, a solution of 3-(2-bromobutyl)phenyl methyl ether (53) (1.77 g, 7.28 mmol) in THF (10 mL) was added dropwise. The resulting mixture was allowed to warm up to room temperature and stir at room temperature overnight, then heated at 50° C. for 1 h. Cooled and quenched with 0.5 N NaOH (25 mL), the mixture was again heated at 50° C. for 1 h. After cooled to room temperature and extracted with ether, the aqueous layer was acidified with 5 N HCl and extracted with CHCl3. The extracts were combined and washed with brine, dried (Na2SO4), filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by flash chromatography over SiO2 with CH2Cl2:Acetone (8:1) to give 0.81 g (45%) of the title compound (54) as a colorless viscous oil. 1HNMR indicated it was a mixture of two diastereomers with a ratio of 2:1.
Reaction SMILES: [NH2:1][C:2](=[O:11])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[SH:10].Cl[CH2:13][C:14](=[O:16])[CH3:15].[CH2:17](N(CC)CC)C>>[NH2:1][C:2](=[O:11])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]([CH3:17])[CH:6]1[S:10][CH2:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)CCl
Reactant: CCN(CC)CC
Reactant: NC(=O)CCn1ccnc1S
Product: CC(=O)CSC1N(C)C=CN1CCC(N)=O

Procedure:
In operations carried out in a manner similar to that described in Example I, 1-(3-amino-3-oxopropyl)imidazol-2-thiol was reacted first with chloroacetone in the presence of triethylamine to obtain 1-(3-amino-3-oxopropyl)-3-methyl-2[(2-oxopropyl)thio]-1H-imidazole, which then was reacted with methyl trifluoromethanesulfonate to obtain 1-(3-amino-3-oxopropyl)-3-methyl-2[(2-oxopropyl)thio]-1H-imidazolium trifluoromethanesulfonate which in turn was passed through a Dowex 1(Cl-) ion exchange column to obtain 1-(3-amino-3-oxopropyl)-3-methyl-2[(2-oxopropyl)thio]-1H-imidazolium chloride, m.p. 124°-125° C.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[N:11]([CH3:18])[C:10](=[O:19])[C:9]12[CH2:21][CH2:20]1)=O.CN(C=O)C.O.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[N:11]([CH3:18])[C:10](=[O:19])[C:9]12[CH2:20][CH2:21]1
Reactant: CN1C(=O)C2(CC2)c2cc(NC(=O)C(F)(F)F)c([N+](=O)[O-])cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CC2)c2cc(N)c([N+](=O)[O-])cc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 70.6 %

Procedure:
2,2,2-Trifluoro-N-(1′-methyl-6′-nitro-2′-oxo-spiro[cyclopropane-1,3′-indole]-5′-yl)-acetamide (2 g) is dissolved in MeOH (15 ml), DMF (10 ml) and water (6.1 ml). Freshly powdered K2CO3 (2.9 g; 21 mmol) is added and the reaction is stirred at 50° C. for 12 h. After completion of the reaction the mixture is poured into water and the precipitate is collected by filtration and washed with 2-propanol and tertbutylmethyl ether. The compound (1 g) is obtained as a red solid.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[CH:4]=[CH:5][C:6]([N+:32]([O-])=O)=[C:7]([CH:31]=1)[C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:9].[H][H]>CO.[Ni]>[NH2:32][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:35])[CH3:1])=[CH:31][C:7]=1[C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:17]1)=[O:9]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CN(C)c1ccc(N)c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Yield: 99.4 %

Procedure:
Step 2): A mixture of 5-dimethylamino-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)-methyl]benzamide (2.4 g, 5 mmol) and Raney Ni in methanol (50 ml) was hydrogenated at room temperature under stirring under 50 psi hydrogen pressure for 2 hours and then filtered. The filtrate was concentrated to give 2-amino-5-dimethylamino-N-[(1-diphenylmethylpiperidin-4-yl)-methyl]benzamide (2.2 g, 100%).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C@H:11]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.[NH:32]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@H:33]([C:41](O)=[O:42])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:40])[NH2:39].Cl.N1C=CC=CC=1.C(Cl)(=O)C(C)(C)C>CC(N(C)C)=O>[NH:32]([C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45])[C@H:33]([C:41]([NH:10][C@H:11]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:42])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:40]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)O
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
DMA, 1.00 equivalent of DIPEA and 1.00 equivalent of H-Trp-Pro-OH (Mw=301.3; purity=94.0%) were mixed at room temperature for at least 30 min until a solution was obtained and then the solution was cooled to 10±5° (solution No. 1). 1.00 equivalent of Z-Arg-OH.HCl (Mw=344.8) were added to DMA at room temperature until a clear solution was obtained (solution No. 2). While cooling solution No. 2 to −15±5° C., 1.05 equivalents pyridine (Mw=79.1; purity=99.0%) and 1.00 equivalent of DIPEA were added. Once this temperature was reached, 1.00 equivalent of pivaloyl chloride (PivCl) (Mw=120.58) was poured into the reaction mixture (solution No. 2) which was further activated for about 5 minutes. Finally, solution No. 1 was added to the activated solution No. 2 and the reaction mixture was further stirred for at least 1 hour while cooling was stopped and the reaction mixture allowed to warm up to room temperature.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]2[N:17]([S:18][CH3:19])[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[N:14]=2)=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:10][CH2:11]Cl)[CH3:9].[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:25]>>[ClH:1].[ClH:1].[ClH:1].[Cl:1][C:2]1[C:3]([C:13]2[N:17]([S:18][CH3:19])[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[N:14]=2)=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:10][CH2:11][N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:24][CH3:25])[CH3:9]
Reactant: CSn1c(-c2nccc(N(C)CCCl)c2Cl)nc2ccccc21
Reactant: CCNCc1ccccc1
Product: CCN(CCN(C)c1ccnc(-c2nc3ccccc3n2SC)c1Cl)Cc1ccccc1
Product: Cl

Procedure:
2-{3-Chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-pyridyl}-methylthio-1H-benzimidazole (500 mg/1.24 mmol) are heated in N-ethylbenzylamine (15 ml) at 140° C. for 4.5 h. Then the excess N-ethylbenzylamine is removed by distillation under high vacuum, and the residue is chromatographed on silica gel (dichloromethane/methanol 97/3 mixture which contains 1 ml of conc. NH3 ×aq./l). The collected pure fractions are concentrated together in vacuo and dissolved in a little methanol, and saturated ethereal hydrochloric acid (1 ml) and diisopropyl ether are added and the solid which precipitates thereby is filtered off and dried in vacuo. Yield: 200 mg (28%) of the title compound as a colorless solid of melting point >180° (decomposition).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[Br:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>[Pd]>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH:11][CH:12]([CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)=[O:14])(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 67.2 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.0 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-bromobenzenesulfonyl chloride (2.08 g) to obtain (RS)-2-(4-bromobenzenesulfonyl-amino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-(tetrahydro-pyran-2-yloxy)propanamide (1.58 g).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[Br:19][C:20]1[C:21]([CH3:27])=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C(Cl)Cl.CN(C=O)C>[Br:19][C:20]1[C:21]([CH3:27])=[C:22]([NH:23][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:3]=2[CH2:2][Br:1])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C(O)c1cc(F)ccc1CBr
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)c1cc(F)ccc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
A solution of crude 2-(bromomethyl)-5-fluorobenzoic acid (3.05 g, 13.1 mmol) in CH2Cl2 (50 mL) was treated with oxalyl chloride (1.66 g, 13.1 mmol) and 6 drops of DMF. The mixture was stirred at room temperature for 1 h, and then was concentrated. The residue was dissolved in CH2Cl2 (50 mL) and treated with 3-bromo-2-methylaniline (1.705 g, 9.16 mmol). The mixture was stirred at room temperature for 1 h, and then TEA (2.19 mL, 15.7 mmol) was added in portions. The mixture was stirred at room temperature for 2 h, then was diluted with CH2Cl2 (100 mL), washed with NaHCO3 (aq) and water, dried and concentrated. The residue was triturated with CH2Cl2 to provide the desired product as a white solid (0.9 g). The mother liquor was concentrated and the residue was again triturated with CH2Cl2 to provide additional desired product as a white solid (0.46 g). The mother liquor was concentrated and the residue was purified by column chromatography on silica gel, eluting with EtOAc-hexane (gradient from 0:100 to 30:70) to provide additional desired product as a pink solid (1.18 g) for a total of 2.54 g (48% yield). LCMS (M+H)+ m/z 400, 402, 404.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C@@H:14]2[CH2:19][O:18][C@@H:17]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:16][CH2:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(Br)CCCC1>>[CH:1]1([O:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][C@@H:14]3[CH2:19][O:18][C@@H:17]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:16][CH2:15]3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7][CH2:2]1
Reactant: CC(=O)NCCC[C@H]1OC[C@H](Oc2ccc(OCc3ccccc3)cc2)CO1
Agent: BrC1CCCC1
Product: CC(=O)NCCC[C@H]1OC[C@H](Oc2ccc(OC3CCCC3)cc2)CO1

Procedure:
trans-N-{3-[5-(4-Benzyloxyphenoxy)-[1,3]dioxan-2-yl]propyl}acetamide (24 mg, 0.062 mmol) was hydrogenated and reacted with cyclopentyl bromide in analogy to example 5. Yield: 6 mg (34%) M+H+: 364.21.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18](C=O)[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](Cl)(=[O:32])[CH3:31].[N:34]1C=CC=C[CH:35]=1>ClCCl>[CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH2:35][NH:34][C:30](=[O:32])[CH3:31])[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(C=O)nc12
Reactant: c1ccncc1
Solvent: ClCCl
Product: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CNC(C)=O)nc12
Reaction time: 2 h

Procedure:
0.5 g of 2-aminomethyl-6-benzyl-7-cyclopentyl-4-ethyl-imidazo[4.5-e]-s-triazolo[1.5-a]pyrimidin-5-one (for preparation see synthesis example II) are dissolved in 10 ml of dichloromethane and 0.2 ml of pyridine, and 0.1 ml of acetyl chloride is added dropwise whilst cooling. After 2 hours' stirring at constant temperature the mixture is diluted with 10 ml of dichloromethane for working up and washed twice with dilute aqueous hydrochloric acid. The organic phase is separated off, dried over magnesium sulphate and the solvent is distilled off in vacuo. 0.7 g of the title compound are left in the form of an amorphous colourless solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([C:10]([O:12]CC)=O)=[C:7](Cl)[N:8]=1.Cl.[CH2:16]([O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[NH:24])[CH:17]([CH3:19])[CH3:18]>C(N(CC)CC)C>[CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]2[C:10](=[O:12])[NH:25][C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[O:20][CH2:16][CH:17]([CH3:19])[CH3:18])=[N:24][C:7]=2[N:8]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: CC(C)COc1ccccc1C(=N)N
Agent: Cl
Solvent: CCN(CC)CC
Product: CSc1nnc2c(=O)[nH]c(-c3ccccc3OCC(C)C)nc2n1

Procedure:
In a similar manner to Example 18 reaction of 3-methylthio-5-chloro-6-carboethoxy-1,2,4-triazine (prepared from 3-methylthio-5-oxo-6-carboethoxy-4,5-dihydro-1,2,4-triazine, 1.5 g) with 2-isobutoxybenzamidine hydrochloride (2.37 g) and triethylamine (1.75 g) afforded the crude title compound (1.71 g). This was recrystallised from acetonitrile, then dissolved in chloroform, the organic solution was washed with 2 Normal hydrochloric acid (x 2), chloroform removed under reduced pressure and the residue recrystallised twice from ethanol to afford the title compound, 0.32 g, m.p. 237°-238° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([CH:13]=[CH2:14])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:21].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OOC(C)(C)C)(C)(C)C.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([CH:13]=[CH2:14])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:21])[CH:12]=1
Reactant: C=CC1(CCC(C)C)C(OC)=CCc2ccccc21
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(C)(C)OOC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CC1(CCC(C)C)C(OC)=CC(=O)c2ccccc21
Yield: 34 %

Procedure:
To a solution of Example 181B (0.13 g, 0.5 mmol) in benzene (5 mL) was added celite (0.13 g), pyridinium dichromate (0.38 g, 1.0 mmol), and a solution of 70% t-butyl peroxide in water (0.13 mL, 1.0 mmol). The heterogenous solution was filtered through celite. The filtrate was diluted with ethyl acetate (10 mL), washed with 5% Na2S2O5 (10 mL), dried (Na2SO4), and concentrated in vacuo. Column Chromatography on silica (20% dichloromethane/hexane-15% ethyl acetate/hexane) afforded product as a light yellow oil (46 mg, 35%). 1H NMR (300 MHz, CDCl3) δ ppm 0.51 (m, 1 H), 0.76 (m, 7 H), 1.37 (m, 1 H), 2.01 (m, 1 H), 2.33 (m, 1 H), 3.81 (s, 3 H), 5.12 (m, 2 H), 5.94 (m, 2 H), 7.37 (m, 2 H), 7.54 (m, 1 H), 8.18 (d, J=8.09 Hz, 1 H); MS m/z 270.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[NH:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[NH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)C(c1cccc(Cl)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)C(c1cccc(Cl)c1)CC2
Yield: 63 %

Procedure:
The title compound was synthesized from methyl 6-(3-chlorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.099 g, 0.36 mmol) and lithium hydroxide (0.151 g, 3.60 mmol in 2 mL water), according to General Procedure 7. A 1:2 mixture of methanol (MeOH) and THF (3-4 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford a light pink solid: 0.059 g (63% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.23 (ddt, J=13.18, 8.25, 5.25, 5.25 Hz, 1H), 2.62 (ddd, J=14.31, 8.70, 5.34 Hz, 1H), 2.74 (ddd, J=14.22, 8.63, 5.22 Hz, 1H), 2.89-2.99 (m, 1H), 4.25 (dd, J=8.57, 5.15 Hz, 1H), 6.68 (s, 1H), 7.02-7.05 (m, 1H), 7.10 (t, J=1.83 Hz, 1H), 7.18 (ddd, J=7.97, 2.04, 1.17 Hz, 1H), 7.25 (t, J=7.79 Hz, 1H); LCMS-MS (ESI−) 260.0 (M−H); HPLC (UV=100%), (ELSD=100%).