Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:5][CH2:6]O)CCO.II.[C:10]1(=[O:16])O[C:13](=O)[CH:12]=[CH:11]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[N-:1]=[C:10]=[O:16].[N-:1]=[C:10]=[O:16].[C:17]1([CH2:27][C:6]2[CH:5]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCNCCO
Agent: II
Solvent: Cc1ccccc1
Product: [N-]=C=O
Product: c1ccc(Cc2ccccc2)cc1

Procedure:
The above amounts of diethanolamine and iodine were added to the above amount of soybean oil with stirring. The mixture was stirred for 22 hours at a temperature between about 180° F. and about 228° F. Then, the above amounts of maleic anhydride, toluene and p-toluenesulphonic acid were added with stirring. The mixture was refluxed for 10 hours using a Dean-Stark distilling trap, then distilled out of solvent to give a liquid soybean oil based polyol with a hydroxyl number of 54. A reaction mixture of about 10.00 grams of the polyol and the above indicated amount of diphenylmethane diisocyanate yielded a solid soybean oil based polyurethane material.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[C:10]([F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15]>C1COCC1>[F:13][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]2[C:11]=1[O:12][C:14](=[S:15])[NH:1]2
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(F)c(O)c1N
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c2oc(=S)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A mixture of methyl 2-amino-4-fluoro-3-hydroxybenzoate (1.5 g, 8.11 mmol) and 1,1′-thiocarbonyldiimidazole (1.46 g, 8.2 mmol) in THF (30 mL) was stirred at ambient temperature overnight, and at 50° C. for 6 h. The reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was washed with ether (3×50 mL) and dried to afford methyl 7-fluoro-2-thioxo-2,3-dihydrobenzoxazole-4-carboxylate (1.3 g, 70%) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.82-7.78 (m, 1H), 6.40 (t, J=9.0 Hz, 1H), 4.00 (s, 3H); (ESI+) m/z 228 (M+H).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:5])C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[NH2:17].O>ClCCl.CO>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:16]([C:18]3[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:17]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Reactant: CCOC(C)=NC(=O)c1ccc(F)cc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1nc(-c2ccc(F)cc2)n(-c2ccc(S(N)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 56.1 %

Procedure:
N-(1-ethoxy-ethylidene)-4-fluoro-benzamide 438 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(4-fluoro-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (391 mg, yield: 56%) was obtained as a solid phase.
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CC=1C(N[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=O.[N+:24]([C:27]1[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=1[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)([O-])=O.[C:40]1(C)C(C)=CC=CC=1>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:29]1[C:28]2[CH:36]=[CH:37][CH:38]=[CH:39][C:27]=2[N:24]=[C:40]1[C:13]1[CH:14]=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccccn1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccccc1Nc1ccccn1
Reactant: Cc1ccccc1C
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccn2)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
Suspending 5.5 g (15.0 mmol) of 2-(2-pyridylamino)-4′-bromobenzanilide obtained in the above step (2) into 60 milliliter of xylene, and adding 0.86 g (4.5 mmol) of p-toluenesulfonic acid 1 hydrate, the resultant solution was azeotropically dehydrated while refluxing with heating for 8 hours. The reacted solution was cooled down to room temperature, and the solvent was removed by distillation. Dissolving the resultant solid into ethyl acetate, and after sequentially washing with water, with 10% potassium carbonate aqueous solution and with saturated solution of sodium chloride, it was dried with sulfuric anhydride magnesium, followed by removing the solvent by distillation under reduced pressure, 3.5 g of 1-(2-pyridyl)-2-(4-bromophenyl)-1H-benzimidazole was obtained (yield: 67%).
Reaction SMILES: C([Cl:4])(=O)C.[OH:5][C@H:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]([NH:13]C(=O)OC(C)(C)C)[CH2:7]1>CO>[ClH:4].[NH2:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:6]([OH:5])[CH2:7]1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H](O)C1
Solvent: CO
Product: Cl
Product: N[C@@H]1CCCC[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To vigorously stirring methanol (60 mL) at 0° C. was added acetyl chloride (5.11 mL, 72.0 mmol) and the resulting mixture was allowed to stir for 30 min. tert-Butyl (1R,3S)-3-hydroxycycloheptylcarbamate (5500 mg, 23.98 mmol; synthesis described herein) was added and the resulting mixture was then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to an oil that was triturated with ethyl ether (100 mL) overnight. The solids were filtered, rinsed with diethyl ether, and dried under reduced pressure for a few hours to afford (1S,3R)-3-aminocycloheptanol hydrochloride (3780 mg, 22.82 mmol, 95% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (br. s., 3H), 4.69 (d, J=7.42 Hz, 1H), 3.64 (t, J=8.79 Hz, 1H), 3.07-3.21 (m, 1H), 2.05 (d, J=12.89 Hz, 1H), 1.69-1.94 (m, 2H), 1.28-1.68 (m, 7H). MS (ESI) m/z 130.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@@H:13]3[CH2:14][NH:15][CH2:16][CH2:17][N:12]3[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@@H:13]3[CH2:14][N:15]([C:23]([C:22]4[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=4)=[O:24])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(O[C@@H]2CCN3CCNC[C@@H]23)nc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCN2CC[C@@H](Oc3ccc(Cl)cn3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 100F (120 mg, 0.473 mmol) and 3-(trifluoromethyl)benzoyl chloride (118 mg, 0.568 mmol) in dichloromethane (1.5 mL) was added triethylamine (0.3 mL, 2.18 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=220 nm) to give the title compound 1H NMR (400 MHz, pyridine-4.90° C.) δ ppm 1.66-1.79 (m, 1 H), 2.18-2.44 (m, 4 H), 2.85-2.90 (m, 1 H), 2.92-3.13 (m, 3 H), 4.19 (br. s, 1 H), 4.58 (br. s, 1 H), 5.10-5.16 (m, 1 H), 6.64 (d, 1H, J=8 Hz), 7.40-7.50 (m, 2 H), 7.63-7.69 (m, 2 H), 7.87 (s, 1 H), 7.96 (s, 1 H); MS (DCI) m/z 426 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].[O-]CC.[Na+].C[O:19][C:20](=O)[CH2:21][C:22](=O)[C:23]([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([C:22]1[N:7]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:12])([F:13])[F:1])[NH:6][C:20](=[O:19])[CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: N=C(N)c1ccccc1C(F)(F)F
Reactant: COC(=O)CC(=O)C(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(=O)[nH]c(-c2ccccc2C(F)(F)F)n1
Yield: 32.4 %

Procedure:
A mixture of 2-trifluoromethylbenzamidine (1.12 g, 5 mmol), sodium ethoxide (1.02 g, 15 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid methyl ester (0.80 mL, 5 mmol) in ethanol (50 mL) and was heated at reflux for 16 hours. The reaction was cooled, concentrated, diluted with water and acidified with 2 N hydrochloric acid. This solution was extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, methanol:dichloromethane (2:98)] provided the title compound (0.48 g, 32% yield) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) δ12.8 (br s, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.78 (m, 2H), 7.71 (d, J=7.4 Hz, 1H), 6.24 (s, 1H), 1.20 (s, 9H) ppm; LC-MS 297.03 (M+H); Rt (Method A) 3.30 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[C@H:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P([N:37]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:37][C@H:10]1[C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cn2)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](c2ccc(F)cn2)C1
Temperature: 65 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of the compound (2.29 g) obtained in step 8 in toluene (24.0 mL) were added DPPA (2.44 g) and triethylamine (1.23 mL), and the mixture was stirred at 65° C. for 1 hr. The mixture was cooled to −10° C., 8N aqueous sodium hydroxide solution (9.23 mL) was added dropwise, and the mixture was stirred at −10° C. to 0° C. for 1.5 hr. The mixture was diluted with toluene, and extracted with water and 1N aqueous sodium hydroxide solution. The combined aqueous layer was extracted with ethyl acetate (4 times), dried and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.83 g, 88%) as a yellow oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([CH2:11][OH:12])[NH:2]1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C>ClCCl>[OH:12][CH2:11][C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][N:2]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1Cc2ccccc2C[C@H]1CO

Procedure:
This compound is obtained using a protocol from the literature (R. B. Kawthekar et al South Africa Journal of Chemistry 63, 195, 2009) starting from 15 g of (3S)-1,2,3,4-tetrahydroisoquinolin-3-ylmethanol (91.9 mmol) in the presence of benzyl chloroformate and triethylamine in solution in dichloromethane. After purification by chromatography over silica gel using petroleum ether and ethyl acetate as eluants, the title product is obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl.O>[C:12]([C:3]1[C:2]([NH:1][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1)(=[O:14])[CH3:13]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1N
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1cc(C(F)(F)F)cnc1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of 1-(3-amino-5-(trifluoromethyl)pyridin-2-yl)ethanone (0.87 g, 4.26 mmol, 1 eq.) in DCM (20 ml) were added TEA (0.65 ml, 4.69 mmol, 1.1 eq.) and ethyl 3-chloro-3-oxopropanoate (0.71 ml, 5.54 mmol, 1.3 eq.) at 0° C. The reaction mixture was stirred at RT for 3 h. Then the mixture was diluted with water (50 ml) and extracted with DCM (3×80 ml). The combined organic layers were washed with water (80 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to provide ethyl 3-(2-acetyl-5-(trifluoromethyl)pyridin-3-ylamino)-3-oxopropanoate (1.35 g, 4.24 mmol, 99%) which was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:38]2[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41](O)=[O:42])[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35].C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:37][O:36][C:32]1[CH:31]=[C:30]([C:38]2[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[O:42])[CH:29]=[C:28]([O:27][CH3:26])[C:33]=1[O:34][CH3:35]
Reactant: COc1cc(-c2cccc(C(=O)O)c2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2cccc(C(=O)N3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (226 mg), 3-(3,4,5-trimethoxyphenyl)benzoic acid (173 mg) and 4-(dimethylamino)pyridine (61 mg) were dissolved in dichloromethane (3 mL), and triethylamine (2.1 μL) was added to the solution. Water-soluble carbodiimide hydrochloride (115 mg) was added to the mixture at 0° C., and the resultant mixture was stirred for 2 hours at 0° C. and overnight at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the resultant mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=40:1) to obtain the title compound as a free base.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(N(CC)C(C)C)(C)C.[C:21]([NH:24][CH2:25][CH2:26][NH2:27])(=[O:23])[CH3:22]>C1COCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:27][CH2:26][CH2:25][NH:24][C:21](=[O:23])[CH3:22])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CC(=O)NCCN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g (15.5 mmol) 2,6-dichloro-3-nitropyridine in 50 mL of THF at −78° C. under Ar atmosphere was added 2.7 mL (15.5 mmol) of N,N-diisopropylethyl amine followed by 1.6 mL (15.5 mmol) of N-acetylethylenediamine. The mixture was stirred at −78° C. for 30 min, allowed to warm to room temperature, and stirred for 72 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with MeOH/dichloromethane gradient (1→10%) to provide N-(2-(6-chloro-3-nitropyridin-2-ylamino)ethyl)acetamide as pale yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[N:10]([CH2:26][C:27](=[O:36])[NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].B(Br)(Br)Br.O.[OH-].[Na+]>ClCCl>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:27]([CH2:26][N:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=[C:11]2[C:14](=[O:25])[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]2)=[O:36])=[N:30][CH:31]=1
Reactant: COC(=O)c1cccc2c1nc(C(=O)NC1CCN(C(C)C)CC1)n2CC(=O)Nc1ccc(Cl)cn1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
30 mg (0.058 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 3 mL dichloromethane and cooled to 0° C. 234 μl of a 1 M BBr3-solution (4 equiv.) in dichloromethane were carefully added and the resulting mixture was stirred at room temperature for 16 h. Under cooling 3 mL water were added dropwise followed by the addition of 0.7 mL of a 1 M NaOH-solution. The mixture was concentrated under reduced pressure. Purification by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid. The corresponding dihydrochloride was obtained by treatment of the product with a 0.1 M HCl-solution and following lyophilization. Yield: 26 mg MS (ES+): m/e=499, chloro pattern.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[N:4][CH:3]=1.[N:21]([O-])=O.[Na+].S(=O)(=O)(O)O.[OH-].[Na+]>O.CC(O)=O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:21]=[N:20][C:5]2=[N:4][CH:3]=1
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncccc2c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
To a 6° C. mixture of 6-bromo-N2-(quinolin-6-ylmethyl)pyrazine-2,3-diamine (16 g, 48 mmol), AcOH (97 mL) and H2O (97 mL) was added NaNO2 (4.0 g, 58 mmol) in H2O (12 mL) dropwise over 15 min. After 1.5 hours, a 1:1 mixture of concentrated sulfuric acid and water (6 mL) was added dropwise. After 1.5 hours, NaNO2 (0.5 g, 7 mmol) in H2O (2 mL) and a 1:1 mixture of concentrated sulfuric acid and water (5 mL) were added. The reaction was allowed to warm to room temperature overnight. The reaction was re-cooled in an ice bath and over a period of 1.5 hours, a 1:1 mixture of concentrated sulfuric acid and water (30 mL) and NaNO2 (1.5 g, 22 mmol) in H2O (5 mL) was added. Aqueous 3.75 M NaOH (210 mL) was added dropwise and the resulting suspension was filtered. The precipitate was washed sequentially with water and ether, then suspended in dichloromethane:ethanol (1:1) and filtered. The filtrate was washed sequentially with 1M aqueous Na2CO3 and brine, dried over Na2SO4, filtered and concentrated by rotary evaporation to afford 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (9.6 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].O>O1CCCC1>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24]
Reactant: Nc1ccc2ccccc2n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc2ccccc2n1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 2-aminoquinoline (1.00 g, 6.94 mmol) and pyridine (0.673 ml, 8.32 mmol) in tetrahydrofuran (23 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.15 ml, 8.32 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 908 mg (40.9%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C([Li])CCC.[C:14]12([C:24](Cl)=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.C(=O)(O)[O-].[Na+]>C1COCC1.CCCCCC.O>[C:14]12([C:24]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:25])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: OCc1ccncc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=C(OCc1ccncc1)C12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To 4-pyridylcarbinol (1.2 g, 11.0 mmol) in THF (40 ml) at -18° C. was added n-butyllithium (2.5 M, 4.2 ml, 10.5 mmol) in hexane dropwise with stirring. After 10 minutes a solution of 1-adamantanecarbonyl chloride (2.0 g, 10.0 mmol) in THF (10 ml) was added and stirring continued at room temperature for 30 minutes. The mixture was poured into water, basified with saturated aqueous sodium bicarbonate, and extracted with ether. The ether extracts were combined, dried (Na2CO3) and concentrated, Chromatography, on elution with petrol-ether-triethylamine 100:50:1, gave the title compound (0.95 g, 35%), which crystallised from 60-80 petrol, m.p. 57°-58° C., IR νmax 1730 cm-1 ; 1H-NMR(CDCl3) δ1.74 and 1.96 (12H, 2s, adamantyl CH2), 2.05 (3H, s, adamantyl CH), 5.12 (2H, s, OCH2), 7.24 (2H, d, J 5.7 Hz, Py 3 and 6H), 8.60 (2H, d, J 5.7 Hz, Py 2 and 6H). Anal. Calcd: C, 75.24; H, 7.80; N, 5.16. Found: C, 75.34; H, 7.92; N, 5.04%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>CN(C=O)C.[Na+].[Cl-].CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)CCN2CCN1CCCC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Under a nitrogen atmosphere 700 mg (3.46 mmol) 5-bromoindoline are added to a solution of 722 mg (4.16 mmol) N-(2-chloroethyl)-pyrrolidine hydrochloride and 1.19 mL (6.93 mmol) ethyldiisopropylamine in 10 mL DMF. The reaction solution is stirred for 21 h at RT and again combined with N-(2-chloroethyl)-pyrrolidine hydrochloride. The reaction solution is heated to 70° C. and stirred for 4 h at this temperature. The solvent is eliminated i.vac. and the residue taken up in 50 mL semisaturated NaCl solution and 50 mL EtOAc. The aqueous phase is extracted twice with 50 mL DCM, the combined organic extracts are dried over Na2SO4 and the solvent is eliminated i.vac.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[OH-].[K+].[O:13]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14]1>CO.O>[O:13]1[CH:17]=[CH:16][C:15]([CH:18]=[C:3]2[C:4](=[O:10])[CH:5]3[CH2:8][CH2:9][N:2]2[CH2:7][CH2:6]3)=[CH:14]1
Reactant: O=C1CN2CCC1CC2
Reactant: O=Cc1ccoc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2ccoc2)N2CCC1CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Furan-3-carboxaldehyde (2.83 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 ml water and cooled to 0° C. yielding 2-((3-furyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Furyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (2.1 g, 100 mmol) was dissolved in methanol (100 ml) and 10% palladium on charcoal (0.2 g) was carefully added under nitrogen. The suspension was hydrogenated at 50 psig in a Parr hydrogenation apparatus for 8 hrs followed by quenching of the catalyst with a small amount of chloroform. The entire slurry was filtered through a pad of Celite filter aid followed by additional washing of the pad with methanol. Rotary evaporation of the pooled solvents gave the desired product, 2-((3-oxolanyl)methyl)-1-azabicyclo[2.2.2]octan-3-one, as a clear oil that solidified upon cooling (2.05 g, 96.7%).