Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([C:9](=[O:23])[CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]3[CH2:20][CH2:21][N:22]=[C:12]23)=[CH:7][CH:6]=1.[ClH:26]>CO>[ClH:26].[OH:23][CH:9]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:25][CH:24]=1)[CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]2[CH2:20][CH2:21][N:22]=[C:12]12
Reactant: COc1ccc(C(=O)CN2C3=NCCN3c3ccccc32)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(O)CN2C3=NCCN3c3ccccc32)cc1
Reaction time: 4 h

Procedure:
Add 0.3 g (7.5 mmol) of sodium borohydride bit by bit to a suspension of 2.41 g (7 mmol) of 9-(4'-methoxyphenacyl)-2,3-dihydroimidazo[1,2-a]benzimidazole--described in Example 6--in 15 ml of methanol over a period of thirty minutes at room temperature. Continue stirring for a further four hours and leave until the next day. Subsequently, add 10 ml of 10% hydrochloric acid until a pH of 2-3 is obtained, and evaporate the methanol. Treat the residue with an ammonium hydroxide solution and extract with chloroform. Recrystallise the residue. The title compound is obtained in the form of a base. Dissolve in hot ethanol and add ethereal hydrogen chloride. Allow to cool, suction-filter, and wash with ether. The title compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([C:12](=[NH:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C([O:32][C:33](=O)[CH:34]([C:36](Cl)=[O:37])[CH3:35])C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:12]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:33](=[O:32])[C:34]([CH3:35])=[C:36]([OH:37])[N:21]=1)[CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)Cl
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(O)nc(C(NC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a stirred solution of [(R)-1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid t-butyl ester (16.37 g, 53.6 mMol) in CH2Cl2 (150 mL) with cooling, at 0° C. was added Et3N (9 mL, 64.3 mMol) followed by 2-chlorocarbonyl-propionic acid ethyl ester (10 g, 60.8 mMol) dropwise over 15 minutes. The reaction was allowed to warm to RT and stirred for 4 h, poured into a separatory funnel, washed with water, brine, dried (Na2SO4), and evaporated to dryness under vacuum. The unpurified acylamidine (˜90% pure by LCMS, MS (ES) m/e (M+H)+ 434.4) was taken up in DMF (150 mL) and heated to 100° C. with stirring for 18 h. The reaction was concentrated under vacuum and purified by flash chromatography (90:10:1, CH2Cl2:EtOAc:HOAc) then (30:70:1, EtOAc:hexane:HOAc) to give the title compound (8.42 g, 41%) as an off-white solid: MS (ES) m/e 388.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])=[C:13]3[NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28][CH2:27]2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[NH2:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([NH:25][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:4]4[CH:5]=[C:6]([F:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=4)[CH:11]=3)[N:16]=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:23][CH2:24]2)=[O:21])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (20 mg, 0.036 mmol) was reacted with TFA (2 mL) to afford the desired product (14.5 mg, 32%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.13 (s, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.02 (dd, J=8.7, 1.9 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.56-7.53 (m, 1H), 7.46 (dd, J=11.6, 2.2 Hz, 1H), 4.17-4.11 (m, 1H), 3.28-3.19 (m, 1H), 2.88-2.81 (m, 1H), 2.36 (d, J=12.8 Hz, 2H), 2.18 (d, J=12.2 Hz, 2H), 1.68 (q, J=10.6 Hz, 2H), 1.61-1.50 (m, 2H), 1.23-1.17 (m, 2H), 1.14-1.08 (m, 2H); ESI MS m/z 454 [C25H25ClFN3O2+H]+; HPLC 99.0% (AUC), tR=10.52 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.[OH-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:15])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCOCC2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 74 %

Procedure:
1-(tert-Butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (Bionet Co., 1.0 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (733 mg), 1-hydroxybenzotriazole (370 mg), morpholine (1 g) and triethylamine (0.76 ml) were dissolved in dimethylformamide (6 ml), and the mixture was stirred at room temperature for 10 hr. After completion of the reaction, 1N sodium hydroxide was added thereto. The precipitated solid was collected by filtration to give 4-(morpholin-4-ylcarbonyl)-4-phenyl-1-piperidinecarboxylic acid tert-butyl ester (907 mg, yield ds89%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl.[NH:18]1[CH2:22][CH2:21][C@@H:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19]1.C(N(CC)CC)C.[Cl-].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CN(C)C=O.O.C(OCC)(=O)C>[N:23]1([C@@H:20]2[CH2:21][CH2:22][N:18]([C:2]3[S:3][C:4]4[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=4[N:6]=3)[CH2:19]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)c1ccc2nc(Cl)sc2c1
Reactant: C1CCN([C@@H]2CCNC2)CC1
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of ethyl 2-chlorobenzo[d]thiazole-6-carboxylate (1.62 g, 6.72 mmol), (R)-1-(pyrrolidin-3-yl)piperidine dihydrochloride (Reference Example 5c, 1.80 g, 7.94 mmol), and triethylamine (5.11 mL, 36.66 mmol) in N,N-dimethylformamide (19 mL) was stirred at ambient temperature for 17 hours. According to TLC (100% ethyl acetate) the spot for starting chloride was replaced by a much lower Rf, ninhydrin-positive spot. The reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with brine (2×200 mL) then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on an Analogix IF-280 (Analogix SF40-120 g, 99:1 ethyl acetate/methanol). Fractions containing product were combined and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 8.34 (d, J=1.7 Hz, 1H), 7.96 (dd, J=1.7 Hz, 8.5, 1H), 7.49 (d, J=8.6 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.82 (dt, J=8.8, 18.3 Hz, 2H), 3.63-3.50 (m, 1H), 3.41 (t, J=9.3 Hz, 1H), 3.16-3.02 (m, 1H), 2.67-2.43 (m, 4H), 2.43-2.30 (m, 1H), 2.11-1.93 (m, 1H), 1.72-1.59 (m, 4H), 1.58-1.45 (m, 2H), 1.39 (t, J=7.1 Hz, 3H); MS (DCI/NH3) m/z 360 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=[O:9])=[O:2].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:11]([O:9][C:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[CH:1]=[O:2])=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccsc1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccsc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Formyl-2-thiophenecarboxylic acid (4.68 g) was dissolved in N,N-dimethylformamide (30 ml), and benzyl bromide (3.9 ml) and potassium carbonate (4.15 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water, and then extracted with diethyl ether. The extract was washed with 5% potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 3-formyl-2-thiophenecarboxylic acid benzyl ester (2.65 g). 3-Formyl-2-thiophenecarboxylic acid benzyl ester (2.65 g) was dissolved in ethanol (50 ml), and hydroxylamine hydrochloride (0.83 g) and pyridine (0.97 ml) were added. The mixture was stirred under reflux for 3 hours, and concentrated under reduced pressure. The residue was poured into water, and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-aldoxime-2-thiophenecarboxylic acid benzyl ester (2.61 g). This product was dissolved in acetic anhydride (20 ml), and the mixture was stirred at 160° C. for 10 hours. The mixture was cooled, poured into water (100 ml) and extracted with diethyl ether. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-cyano-2-thiophenecarboxylic acid benzyl ester (2.01 g). This product was dissolved in tetrahydrofuran (40 ml), and 5% Pd--C (wet) (0.25 g) was added. The mixture was hydrogenated at room temperature under atmospheric pressure for 72 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give 3-cyano-2-thiophenecarboxylic acid (0.98 g) as crystals.
Reaction SMILES: [CH:1]1([CH2:8][S:9]([O-:12])(=O)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].S(Cl)([Cl:16])=O>>[CH:1]1([CH2:8][S:9]([Cl:16])(=[O:12])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])CC1CCCCCC1
Agent: [Na+]
Product: O=S(=O)(Cl)CC1CCCCCC1

Procedure:
The subtitle compound was prepared by the method of Preparation 58 from sodium cycloheptylmethanesulfonate [Preparation 67] and thionyl chloride, to afford cycloheptylmethanesulfonyl chloride as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:15]I.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5](=[O:8])[N:6]([CH3:15])[CH:7]=1
Reactant: CI
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(Br)cc(C(F)(F)F)c1=O
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (6 g, 25 mmol) stirred at rt in THF (5 mL) was added NaH (1.5 g, 37 mmol, 60% in mineral oil). After stirring for 30 min, methyl iodide (7.1 g, 50 mmol) was added. After stirring at rt for 3 h, the reaction mixture was treated with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (6 g, 97%) as a tan solid. The solid was carried forward without any further purification. 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J=2.0 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 3.60 (s, 3H). LCMS (M+H)+=256.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:4]1[C:5]2([CH2:10][NH:9][CH2:8][CH2:7][O:6]2)[CH2:1][CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCOC2(CCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CCC2(C1)CNCCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 173.4 %

Procedure:
To a of solution 1,1-dimethylethyl 6-oxa-9-azaspiro[4.5]decane-9-carboxylate (200 mg, 0.829 mmol, available from Tyger Scientific Inc) in DCM (3 ml) was added trifluoroacetic acid (TFA) (0.5 ml). The resulting colourless yellow solution was stirred at room temperature for 24 hr. The solvent was evaporated to give the title compound as a grey oil (203 mg).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:25]4[N:29](COCC[Si](C)(C)C)[C:28]5[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=5[N:26]=4)[C:13](=[O:24])[N:14](COCC[Si](C)(C)C)[N:15]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.C(O)C>Cl.O1CCOCC1>[NH:29]1[C:28]2[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=2[N:26]=[C:25]1[C:12]1[C:13](=[O:24])[NH:14][N:15]=[C:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)[CH:11]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccnc(C3CC3)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2ccnc(C3CC3)n2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
27 mg of 6-(2-cyclopropylpyrimidin-4-yl)-2-(2-trimethylsilanylethoxymethyl)-4-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2H-pyridazin-3-one are dissolved in 2.5 ml of 4M hydrochloric acid solution in dioxane and 1 ml of ethanol and stirred at room temperature for 2 days. The solvent is then distilled off, and the residue is dissolved in 2 ml of dichloromethane and 1 ml of trifluoroacetic acid and again stirred at room temperature for 3 h. Distillation off is then repeated, and the residue is dissolved in 1 ml of 2M sodium hydroxide solution and 2 ml of water, and the mixture is stirred at room temperature for 10 h. For workup, it is neutralized with 2M hydrochloric acid, the volatile components are distilled off, and the crude product is purified by RP HPLC (acetonitrile (+0.05% HCOOH)/water (+0.05% HCOOH)).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([NH2:11])=[C:6]([NH2:12])[CH:5]=1.[OH-].[K+].CCO[C:18]([S-])=[S:19].[K+].C(O)(=O)C>C(O)(C)C.O>[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]2[N:11]=[C:18]([SH:19])[NH:12][C:6]=2[CH:5]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(F)c(F)cc1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)O
Product: Fc1cc2nc(S)[nH]c2cc1F

Procedure:
40.7 g of 4,5-difluoro-o-phenylenediamine dihydrochloride were suspended in 655 ml of isopropanol. A solution of 22.5 g of potassium hydroxide in 250 ml of water was added dropwise thereto while stirring and the mixture was treated with 39.7 g of potassium ethyl xanthogenate, whereupon the solution was boiled at reflux overnight, then diluted with 300 ml of water and made neutral with glacial acetic acid. The resulting suspension was stirred at 60°-70° for an additional hour. The isopropanol was largely removed from the mixture in a vacuum. After the addition of 1 liter of water, the solid was filtered off washed with water and then dissolved in ether. The solution was then extracted with 1.2 liters of water, treated with active charcoal, dried and evaporated in a vacuum. The residue was suspended in petroleum etber (low boiling) and filtered off. There was obtained 5,6-difluoro-2-benzimidazolethiol of melting point above 300°.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:7]([CH3:14])[CH:6]=[C:5]([CH3:15])[C:3]=1[NH2:4].N1C=CC=CC=1.[C:22]1([S:28]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36](Cl)=[O:37])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>ClCCl>[C:22]1([S:28]([N:31]2[CH2:35][CH2:34][CH2:33][C@H:32]2[C:36]([NH:4][C:3]2[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:2]=2[CH3:1])=[O:37])(=[O:29])=[O:30])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)C1CCCN1S(=O)(=O)c1ccccc1
Reactant: Cc1cc(C)c(N2CCCC2)c(C)c1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(N2CCCC2)c(C)c1NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of the 2,4,6-trimethyl-3-pyrrolidin-1-ylaniline (220 mg, 1.00 mmol) in of anhydrous dichloromethane (20 mL), were added pyridine (0.100 mL, 1.3 mmol) and 1-benzenesulfonyl-pyrrolidine-2-carbonyl chloride (0.297 g, 1.0 mmol). The reaction mixture was stirred overnight at room temperature. The solution was acidified with HCl (1N, 20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (10 mL) and dried over magnesium sulfate (MgSO4). The organic layers were filtered and concentrated under reduced pressure to give a brown solid. The residue was further purified by flash chromatography (silica gel) using 95-5% hexane/ethyl acetate as the mobile phase (gradient) and semi-preparative HPLC to give ′1-(Phenylsulfonyl)-N-(2,4,6-trimethyl-3-pyrrolidin-1-ylphenyl)prolinamide (157 mg) as an off-white solid. MS m/z (M+H)+: calculated (m/z) 442.22, found (m/z) 442.25.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH2:14][NH2:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O=[C:28]([CH3:40])[CH2:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH2:36])=[O:35].C([BH3-])#N.[Na+]>CO>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][NH:15][CH:28]([CH3:40])[CH2:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:33]([C:34](=[O:35])[NH2:36])[CH:32]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)CCc1cccc(C(N)=O)c1
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(CCc1cccc(C(N)=O)c1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 15 h
Yield: 81.1 %

Procedure:
2.61 g of 3,4-dibenzyloxyphenethylamine hydrochloride and 2.70 g of 3-(3'-oxobutyl)benzamide were dissolved in 50 ml of methanol, to which was added 0.47 g of sodium cyanoborohydride. The reaction was allowed to stand at room temperature for 15 hours. Then, the solvent was distilled off and the residue was extracted with 300 ml of ethyl acetate. The organic phase was washed with water and dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel chromatography (solvent chloroform:ethanol:acetic acid=90:8:2) to obtain 2.91 g of N-[2-(3,4-dibenzyloxyphenyl)ethyl]-1-methyl-3-(3-carbamoylphenyl)propylamine as a viscous oil.
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1(C(OC(C)(C)C)=O)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCNCC1)[C@](O)(c1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a stirred solution of (R)-cyclopentylhydroxyphenyl acetic acid (10.0 g, 45.4 mmol) in DCM (200 mL) was added t-butyl 1-piperazinecarboxylate (8.5 g, 45.4 mmol). Into the reaction was added DIPEA (23.7 mL, 13.6 mmol), HOBt (10.4 g, 68.1 mmol), and then EDCI (10.4 g, 54.5 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then washed with 1N NaOH (300 mL), 1N HCl (300 mL) then saturated aqueous NaCl (300 mL). The organic layer was then removed, dried over MgSO4 and then filtered. The solvent was removed under reduced pressure. A solution of 20% TFA/DCM was added to the crude material, and the resulting mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure. DCM (300 mL) was added and the mixture was washed with saturated sodium bicarbonate (300 mL). The organic layer was then removed, dried over MgSO4 and filtered. The crude material was purified via silica gel chromatography (10% MeOH/DCM w/1% NH3 (aq)) to afford the title compound as a white powder (9.0 g, 31.2 mmol).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C([O:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]([CH2:37][CH3:38])([CH2:35][CH3:36])[C:31]([O:33][CH3:34])=[O:32])[CH2:25][CH2:24]1)=O)(C)(C)C>>[CH2:35]([C:30]([CH2:29][N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][NH:21][C:19]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2=[O:13])=[O:18])[CH2:28][CH2:27]1)([CH2:37][CH3:38])[C:31]([O:33][CH3:34])=[O:32])[CH3:36]
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Reactant: CCC(CC)(CN1CCC(CNC(=O)OC(C)(C)C)CC1)C(=O)OC
Product: CCC(CC)(CN1CCC(CNC(=O)n2c(=O)n(C(C)C)c3ccccc32)CC1)C(=O)OC

Procedure:
The title compound was prepared according to the procedure described in Step 2 of Example 8 from 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and Methyl 2-[(4-{[(tert-butoxycarbonyl)amino}methyl}piperidin-1-yl)methyl]-2-ethylbutanoate (step 1 of Example 13).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][C:12](=O)[CH2:13]2>C1COCC1>[CH3:7][N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][CH2:12][CH2:13]2
Reactant: CN1C2CCC1CC(=O)NC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C2CCNCC1CC2
Reaction time: 0.5 h

Procedure:
Neat LAH (0.5 g, 13.17 mmol) was added in small portions to a stirred solution of 9-methyl-3,9-diazabicyclo[4.2.1]nonan-4-one (1.0 g, 6.48 mmol) in THF (40 ml) and the mixture was heated at reflux under nitrogen for 3-4 h. Reaction mixture was cooled in ace bath and quenched by consecutive addition of water (0.5 ml), 15% NaOH (1.5 ml) and water (0.5 ml) and then stirred for 30 min. Precipitated sodium aluminate was filtered off and the filtrate was dried over MgSO4, filtered and evaporated to dryness to afford 9-methyl-3,9-diazabicyclo[4.2.1]nonane as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.08-1.67 (m, 4H) 1.74-1.92 (m, 1H) 2.01-2.31 (m, 2H) 2.41-2.46 (m, 3H) 2.66 (dd, J=13.09, 2.01 Hz, 1H) 2.77-3.00 (m,2H) 3.07-3.36 (m, 2H) 3.50-4.06 (m, 1H).
Reaction SMILES: [CH2:1]([CH:8]1[NH:12]C(=O)N[C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:15].[Na+]>O.CCOCCO>[NH2:12][CH:8]([C:9]([OH:14])=[O:15])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C1NC(=O)C(Cc2ccccc2)N1
Agent: [Na+]
Solvent: O
Solvent: CCOCCO
Product: NC(Cc1ccccc1)C(=O)O
Reaction time: 48 h
Yield: 77 %

Procedure:
95.1 g (0.5 mole) of 5-benzyl-hydantoine are dissolved in a solution of 87 g of sodium hydroxide and 400 ml of water, whereupon 300 ml of cellosolve are added. The reaction mixture is heated to boiling for 48 hours, the water and the cellosolve are distilled off in vacuo (30 Hgmm, 80° C.), the solid residue is dissolved in a small amount of water and acidified with concentrated hydrochloric acid (pH 2). The solution is treated with activated charcoal and the pH is adjusted to 6 with a concentrated ammonium hydroxide solution. The mixture is allowed to stand for some hours at 5° C. The precipitated product is filtered off, washed with cold water and cold ethanol. Thus 63.4 g of the desired airdry compound are obtained, yield 77%, mp.: 245°-255° C. Purity: 97.9% according to HPLC.