Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][C@H:7](/[C:32](/[CH3:40])=[CH:33]/[C:34]1[N:35]=[C:36]([CH3:39])[S:37][CH:38]=1)[CH2:8][C@@H:9]1[O:11][C@:10]1([CH2:26][O:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:12][CH2:13][CH2:14][C@H:15]([CH3:25])[CH2:16][O:17][Si](C(C)(C)C)(C)C)([CH3:4])([CH3:3])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C([O-])(O)=O.[Na+].CC(OC)(C)C>C(Cl)Cl.CO>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][C@H:7](/[C:32](/[CH3:40])=[CH:33]/[C:34]1[N:35]=[C:36]([CH3:39])[S:37][CH:38]=1)[CH2:8][C@@H:9]1[O:11][C@:10]1([CH2:26][O:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH2:12][CH2:13][CH2:14][C@H:15]([CH3:25])[CH2:16][OH:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C(=C\c1csc(C)n1)[C@H](C[C@@H]1O[C@@]1(CCC[C@H](C)CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O)O[Si](C)(C)C(C)(C)C
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: COC(C)(C)C
Product: C/C(=C\c1csc(C)n1)[C@H](C[C@@H]1O[C@@]1(CCC[C@H](C)CO)COS(C)(=O)=O)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
The crude TBDMS ether XVI (3.79 g, 5.7 mmol) was dissolved in a mixture of CH2Cl2 and CH3OH (1:1 v/v) (140 ml) and treated at 0° C. with 1.33 g (5.73 mmol) of 10-camphorsulfonic acid. The reaction mixture was stirred for 1 h at 0° C. After completion of the deprotection 20 ml of saturated aqueous NaHCO3 were added along with 20 ml of TBME. The layers were separated and the aqueous layer was extracted with TBME (2×20 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (2×20 ml), brine (20 ml), dried over MgSO4 and concentrated under reduced pressure. The crude product XVII (3.11 g) obtained as a yellowish oil was used for the next step without further purification. Rf=0.28 (SiO2, 1:1 heptane-AcOEt).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[NH2:18])[S:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[C:35](O)=[O:36]>O>[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[C:35]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=1[C:14]1[S:13][C:10]2[C:9]([N:15]=1)=[CH:8][C:7]([CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[CH:12][N:11]=2)=[O:36]
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)O
Reactant: Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 5-methyl-2-phenyloxazole-4-carboxylic acid. The product was isolated by precipitation by the addition of water, triturated with hot methanol and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C28H25N5O2S: 495.17. Found (M+H)+ m/z=496.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:20]=[C:19]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[NH:18][C:15]1[CH:14]=[CH:13][C:12]2[N:8]=[CH:9][NH:10][C:11]=2[C:16]=1[CH3:17])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1c(NC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)ccc2c1ncn2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(NC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)ccc2nc[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a cold (0° C.) solution of 874 mg of 1-(tert-butoxycarbonyl)-5-[N2, N3-bis(benzyloxycarbonyl)guanidino]-4-methylbenzimidazole in 2 mL of methylene chloride is added 2 mL of trifluoroacetic acid. The resulting solution is stirred at room temperature for 30 minutes, then rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with 20% methanol/chloroform followed by recrystallization from hexanes/methylene chloride to provide 573 mg of 5-[N2,N3-bis(benzyloxycarbonyl)guanidino]-4-methylbenzimidazole as a white solid.
Reaction SMILES: [CH2:1]([C:5]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]2[CH2:10][N:11]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24]C(=O)OC(C)(C)C)=[O:15])[CH2:12][CH2:13][C:8]=2[C:7](=[O:32])[O:6]1)[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:14]([N:11]1[CH2:12][CH2:13][C:8]2[C:7](=[O:32])[O:6][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:9]=2[CH2:10]1)=[O:15]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1NC(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1N)CC2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To an ice-cold solution of tert-butyl 2-((3-isobutyl-1-oxo-3-phenyl-1,3,4,5,6,7-hexahydrofuro[3,4-c]pyridine-5-carboxamido)methyl)phenylcarbamate (62 mg, 0.119 mmol) in dichloromethane (5 mL) was added TFA (1 mL). The reaction mixture stirred at 0° C. for 5 hours and concentrated to dryness to provide crude N-(2-aminobenzyl)-3-isobutyl-1-oxo-3-phenyl-3,4,6,7-tetrahydrofuro[3,4-c]pyridine-5(1H)-carboxamide. The residue was added to a solution of 2-phenylacetic acid (32 mg, 0.238 mmol), BOP (79 mg, 0.179 mmol), and N,N′-diisopropylethylamine (62 mg, 0.477 mmol) in dichloromethane (5 mL), and stirred at room temperature for 16 hours. The crude reaction mixture was concentrated to dryness and purified by column chromatography (12 g, SiO2, 0 to 100% ethyl acetate in hexanes) to provide 3-isobutyl-1-oxo-3-phenyl-N-(2-(2-phenylacetamido)benzyl)-3,4,6,7-tetrahydrofuro[3,4-c]pyridine-5(1H)-carboxamide (66 mg, 93%) as a colorless oil: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.81-0.98 (m, 6H), 1.65 (dd, J=11.87, 6.59 Hz, 1H), 1.73-1.84 (m, 1H), 2.24-2.47 (m, 4H), 3.30 (dt, J=13.19, 6.22 Hz, 1H), 3.52 (dt, J=13.56, 5.09 Hz, 1H), 3.75 (s, 2H), 3.91 (d, J=18.84 Hz, 1H), 4.21-4.48 (m, 2H), 5.22 (br. s., 1H), 6.97-7.09 (m, 1H), 6.99-7.10 (m, 1H), 7.18 (d, J=6.78 Hz, 1H), 7.23-7.47 (m, 9H), 7.75 (br. s., 1H), 7.96 (d, J=7.91 Hz, 1H), 9.65 (br. s., 1H); MS m/z 538 (M+H)+, 560 (M+23)+, 536 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:3]2[N:14]=[N:13][N:12]([C@@H:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[OH:20])[C:4]=2[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=1.[F:21][C:22]1[CH:23]=[C:24]([C@@H:29]2[CH2:31][C@H:30]2[NH2:32])[CH:25]=[CH:26][C:27]=1[F:28].O[C@H]([C@@H](O)C([O-])=O)C([O-])=O>>[F:21][C:22]1[CH:23]=[C:24]([CH:29]2[CH2:31][CH:30]2[NH:32][C:2]2[C:3]3[N:14]=[N:13][N:12]([CH:15]4[CH2:19][CH2:18][CH2:17][CH:16]4[OH:20])[C:4]=3[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: N[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Reactant: CCCSc1nc(Cl)c2nnn([C@@H]3CCC[C@H]3O)c2n1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Product: CCCSc1nc(NC2CC2c2ccc(F)c(F)c2)c2nnn(C3CCCC3O)c2n1

Procedure:
Prepared using the product from Example 13 step b) (0.15 g) and (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine, (2R,3R)-2,3-dihydroxybutanedioate (1:1) (0.20 g) (prepared as described in WO 9905143) by the method of Example 13, step c). Purified by chromatography (SiO2, ethyl acetate:dichloromethane 1:9 as eluant) to afford the title (0.12 g).
Reaction SMILES: N[C@H](C(O)=O)C([SH:6])(C)C.C[Si](C)(C)S[Si](C)(C)C.C[O-].[Na+].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:48]=[CH:47][C:32]3[N:33]=[C:34]([C:39]4[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=4)[C:42]#[N:43])[CH2:35][C:36](=[O:38])[NH:37][C:31]=3[CH:30]=2)=[CH:25][CH:24]=1>CN1CCN(C)C1=O.O>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:48]=[CH:47][C:32]3[N:33]=[C:34]([C:39]4[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=4)[C:42]([NH2:43])=[S:6])[CH2:35][C:36](=[O:38])[NH:37][C:31]=3[CH:30]=2)=[CH:27][CH:28]=1
Reactant: N#Cc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Reactant: CC(C)(S)[C@H](N)C(=O)O
Agent: C[O-]
Agent: C[Si](C)(C)S[Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: NC(=S)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Reaction time: 0.08 h

Procedure:
Preparation of 4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiobenzamides (according to Pen-Yuan Lin et al. Synthesis 1992, 1219]: To a solution of hexamethyldisilthiane (1.45 g, 8.0 mmol) in 1,3-dimethyl-2-imidazolidinone (8 mL) was added at 23° C. sodium methoxide (0.31 g, 6.8 mmol). The mixture was stirred for 5 min. and the blue solution formed was then added to a solution of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 57) (1.42 g, 4 mmol) in 1,3-dimethyl-2-imidazolidinone (12 mL). The mixture was stirred for 3 h at 23° C. and then poured into water (100 mL). Stirring was continued for 0.5 h and the precipitate was isolated by filtration and triturated with ethyl acetate (50 mL) to give the title compound as light yellow solid (1.38 g).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16])([O-:11])=[O:10].C(O)(=O)C>N1C=CC=CC=1.CCOC(C)=O>[N+:9]([C:12]1[CH:13]=[C:14]([C:15]2[O:16][C:2]3[C:7]([N:8]=2)=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:18]=[CH:19][CH:20]=1)([O-:11])=[O:10]
Reactant: Nc1cccnc1Cl
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(-c2nc3cccnc3o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
2-Chloropyridin-3-amine (3.20 g, 0.025 mol) was suspended in 15 mL of pyridine and added slowly to a suspension of 3-nitrobenzoyl chloride (4.64 g, 0.025 mol) in 15 mL of pyridine in an ice bath. The reaction mixture was slowly warmed to room temperature and stirred overnight. The next day, the reaction mixture was cooled in an ice bath and 30 mL of glacial acetic acid was added slowly. The resulting mixture was diluted with 200 mL of EtOAc and washed with water (3×20 mL). The organic layer was then dried (Na2SO4) and concentrated. The resulting residue was mixed with 10 mL of PPA and stirred at 160 degree for 6 hours. The reaction mixture was then poured carefully into 150 mL of water. The pH was brought to about 5 with solid NaOH and the solids were collected by filtration and dried. This material was mixed with 50 mL of MeOH and filtered. The filtrate was concentrated to afford 2.1 g of 2-(3-nitrophenyl)oxazolo[5,4-b]pyridine (35% yield) (MS, M++H=242).
Reaction SMILES: C[CH2:2][C:3]([O:5][CH2:6][CH:7]([O:14]C(CC)=O)[CH2:8][O:9]C(CC)=O)=[O:4].CC(=O)OCC(COC(=O)C)OC(=O)C.C[O-].[Na+]>>[CH3:2][C:3]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][OH:9])=[O:4]
Reactant: CCC(=O)OCC(COC(=O)CC)OC(=O)CC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)OCC(COC(C)=O)OC(C)=O
Product: CC(=O)OCC(O)CO
Reaction time: 0.29 h

Procedure:
Acetoglyceride fat mixtures are prepared using the interesterification procedure of Example 1, except that the interesterification mixture contains hydrogenated canola with both tripropionin (1.25 moles, 2.25 moles and 6 moles per mole hydrogenated canola) and triacetin (in the same proportions), the reaction temperature is 120° to 125° C., and 0.2 to 0.5% sodium methoxide is employed. Though reactions are run for about 5 to 30 minutes, most are complete in less than 10 minutes. The samples are steam deodorized after interesterification as set out in Example 1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].C(N([CH2:13][CH3:14])CC)C.C([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])#N>ClCCl>[CH2:20]([O:19][C:17]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:17]([O:19][CH2:20][C:14]1[CH:13]=[CH:23][CH:22]=[CH:21][CH:26]=1)=[O:18])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCN(CC)CC
Reactant: NCCNCCN
Reactant: N#CC(=O)OCc1ccccc1
Solvent: ClCCl
Product: O=C(NCCNCCNC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
51.5 g (500 mmol) of diethylenetriamine and 139 ml (1 mol) of triethylamine are dissolved in dichloromethane and mixed at -20° C. with 161 g of benzyl cyanoformate (Fluka) in dichloromethane and then stirred overnight at room temperature. After the reaction is completed, concentration by evaporation is performed during draw-off, the residue is taken up in diethyl ether, the organic phase is washed with sodium carbonate solution and dried with sodium sulfate. The filtrate is mixed with hexane, the precipitate is filtered out and dried.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[BrH:14]>O.S>[Br:14][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cccnc1CO
Reactant: Br
Agent: O=N[O-]
Agent: S
Agent: [Na+]
Solvent: O
Product: OCc1ncccc1Br

Procedure:
A solution sodium nitrite (2.38 g.) in water (10 ml.) was added dropwise to a stirred mixture of 3-amino-2-hydroxymethylpyridine (4.8 g.) in aqueous hydrobromic acid (48%, 10 ml) and water (5 ml) at 0°-5° C. This solution of the diazonium salt was added to a hot solution of cuprous bromide (2.5 g.) in 60% hydrobromic acid and following cessation of nitrogen evolution the mixture was heated on the steam bath for 0.5 hours, diluted with water and saturated with hydrogen sulphide. Filtration, concentration to low bulk and extraction with chloroform yielded 3-bromo-2-hydroxymethyl-pyridine (4.8 g.). This was dissolved in aqueous hydrobromic acid (48%, 50 ml.), cysteamine hydrochloride (3.22 g.) added and the solution obtained was heated under reflux for 6 hours. Concentration, followed by recrystallisation from aqueous ethanol afforded 2-((2-aminoethyl)-thiomethyl)-thiomethyl)-3-bromopyridine dihydrobromide (6.1 g.), m.p. 252°-254°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:3]=1.[ClH:15].[H][H]>CCO.CCOC(C)=O.[Pd]>[ClH:15].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:3]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(F)cc1-n1cccn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCc1ccc(F)cc1-n1cccn1
Reaction time: 20 h
Yield: 58.6 %

Procedure:
To a solution of 4-fluoro-2-pyrazol-1-yl-benzonitrile (500 mg, 2.67 mmol) in EtOH (10 mL) and EtOAc (10 mL) was added conc-HCl (0.25 mL, 3 mmol) and 10% Pd—C (100 mg). The mixture was hydrogenated at 1 atmosphere hydrogen for 20 h. To the mixture was added additional conc-HCl (0.15 mL) and 10% Pd—C (100 mg) and the mixture was further hydrogenated for additional 20 h. The mixture was filtered over Celite, washed with EtOH, and the combined filtrate and washings were concentrated in vacuo. The residual material was triturated with EtOH to obtain 356 mg of the title compound as the hydrochloride salt as an off-white crystalline solid: HPLC rt=1.01 min. LC/MS m/z 192 (M+H); 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.99 (2H, s, 7-CH2), 6.63 (1H, t, J=2 Hz, 9-CH), 7.40 (1H, dt, J=8.5, 2.5 Hz, 5-CH), 7.54 (1H, dd, J=10, 2.5 Hz, 3-CH) 7.81 (1H, dd, J=8.5, 6 Hz, 6-CH), 7.86 (1H, d, J=1.5 Hz, 10-CH) 8.35 (1H, d, J=2 Hz, 8-CH), 8.54 (3H, br.s, NH3+); 13C NMR (DMSO-d6, 125.8 Hz) δ ppm 38.8 (7-CH2), 107.7 (9-CH2), 111.6 (d, J=25 Hz, 3-CH), 114.6 (d, J=21 Hz, 5-CH), 123.7 (d, J=3 Hz, 1-C), 131.7 (8-CH), 134.0 (d, J=9 Hz, 6-CH), 140.4 (d, J=11 Hz, 2-C), 141.5 (10-CH), 161.9 (d, J=247 Hz, 6-CF); HRMS (ESI) calcd for C10H11FN3 (M+H) 192.0937, found 192.0930 (δ-3.6 ppm).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=S)[CH3:2].Cl.Cl.[NH2:17][CH:18]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:19]([NH:21][C:22]1([C:32]#[N:33])[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:23]1)=[O:20]>>[CH2:1]([O:3][C:4](=[O:14])[N:5]=[C:6]([NH:17][CH:18]([C:19](=[O:20])[NH:21][C:22]1([C:32]#[N:33])[CH2:26][CH2:25][N:24]([CH:27]([CH2:28][CH3:29])[CH2:30][CH3:31])[CH2:23]1)[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCC(CC)N1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)C1
Reactant: CCOC(=O)NC(=S)N1CCOCC1
Agent: Cl
Product: CCOC(=O)N=C(NC(CC1CCCCC1)C(=O)NC1(C#N)CCN(C(CC)CC)C1)N1CCOCC1

Procedure:
The title compound was prepared starting from (Morpholine-4-carbothioyl)-carbamic acid ethyl ester and 2-amino-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 76, step b,. MS, m/z 519=M+1.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.Cl[C:7]([O:9][CH2:10][CH3:11])=O.COC1C=CC([C:20]2[C:25]([S:26]([NH2:29])(=[O:28])=[O:27])=CC=[CH:22][C:21]=2[CH2:30][C@H:31]([NH2:33])[CH3:32])=CC=1.Cl>C(Cl)Cl.C(N(CC)CC)C>[Br:1][CH2:2][C:3]([NH:33][C@H:31]([CH3:32])[CH2:30][C:21]1[CH:22]=[CH:11][C:10]([O:9][CH3:7])=[C:25]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:20]=1)=[O:5]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)CBr
Reactant: COc1ccc(-c2c(C[C@@H](C)N)cccc2S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C[C@@H](C)NC(=O)CBr)cc1S(N)(=O)=O
Temperature: -42.5 °C
Reaction time: 4 h
Yield: 117 %

Procedure:
Bromoacetic acid (3.4 g) was dissolved in 50 ml of methylene chloride. 2.3 g of triethyamine was added to the resultant solution and cooled to −40 to −45° C. Then, 2.66 g of ethyl chloroformate was added dropwise to the resultant solution and stirred at −40 to −45° C. for 4 hours. 3.0 g of (R)-2-(4-methoxyphenyl-3-aminosulfonyl-phenyl)-1-methylethylamine was added to the resultant product and stirred at −40 to −45° C. for 1.5 hours. Then, 50 ml of 10% HCl were added to the resultant solution and stirred. The organic layer was separated and washed with 50 ml of 10% K2CO3 solution and dried over MgSO4, and then, filtered and concentrated. The obtained concentrate was dissolved in methanol and recrystallized with hexane to obtain the title compound as a white solid (4.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH3:31])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CB1OB(C)OB(C)O1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2c(cc1C1CCN(C(=O)OC(C)(C)C)CC1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A degassed mixture of 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.167 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.042 g, 0.334 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloride dichloromethane complex (0.027 g, 0.033 mmol) and K2CO3 (0.046 g, 0.334 mmol) in dioxane (1 mL) and water (0.2 mL) was heated to reflux for 8 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative-TLC (eluting with 50% EtOAc in petroleum ether) to give 4-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.03 g, 43%) as a pale white solid. LC/MS (Table 1, Method 3) Rt=1.415 min.; MS m/z: 415 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C>ClCCl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:24][CH2:25][N:26]([S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:27][CH2:28]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCN(c2ccc(F)cc2F)CC1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a stirred solution of naphthalene-2-sulfonyl chloride (350 mg, 1.54 mmol) and 1-(2,4-difluorophenyl)piperazine (305.0 mg, 1.54 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (0.670 mL, 3.85 mmol). The mixture was stirred for 30 minutes. Reaction was complete as determined by TLC. The reaction mixture was purified via flash column chromatography to afford 1-(2,4-difluorophenyl)-4-(2-naphthylsulfonyl)piperazine in 55% yield (327 mg) as white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10]([CH2:12][C:13]3[N:14]=[CH:15][N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=3)[C:9](=[O:37])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38]C#N>>[CH3:38][N:14]1[C:13]([CH2:12][N:10]2[CH2:11][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][C:9]2=[O:37])=[CH:17][N:16]=[CH:15]1
Reactant: CC#N
Reactant: O=C1CC(c2ccccc2)CN1Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: Cn1cncc1CN1CC(c2ccccc2)CC1=O
Temperature: 25 °C

Procedure:
In a 50 ml, three-necked flask fitted with a magnetic stirrer, under inert atmosphere, 4-phenyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x44 (2 g, 4.1 mmol) is dissolved in CH3CN (20 ml) and Mel (283 μL, 4.5 mmol) is added. The mixture is stirred at room temperature and two additional portions of Mel (283 μl and 500 μl) are added after 40 h and 46 h. After stirring for 16 h at room temperature, the mixture is concentrated and dissolved in a 1/1 mixture of AcOH and water. After stirring at room temperature for 48 h, the mixture is filtered and evaporated to dryness (by azeotropic distillation with toluene). The residue is dissolved in a solution of HCl at pH 1 (25 ml) and extracted with CH2Cl2 (3×50 ml). The aqueous phase is brought at pH 10 by adding solid K2CO3 and extracted again with CH2Cl2 (3×50 ml). Combined organic phases are dried over MgSO4, filtered and concentrated to give 1 g of crude product which is purified by chromatography on silicagel (60 g of SiO2, CH2Cl2/EtOH/NH4OH: 94/5.4/0.6 (v/v/v)) to give 0.5 g of 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one. This free base is treated with a 3.6 M solution of HCl (5 ml), and the resulting solid is recrystallized in CH3CN to lead to 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one hydrochloride 119.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:20][C:21]1[CH:51]=[CH:50][C:24]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([N:35]3[CH2:44][CH2:43][C:42]4[C:37](=[CH:38][CH:39]=[C:40]([OH:45])[CH:41]=4)[CH:36]3[C:46]([O:48][CH3:49])=[O:47])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1.[N:52]1([CH2:58][CH2:59]O)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([N:35]3[CH2:44][CH2:43][C:42]4[C:37](=[CH:38][CH:39]=[C:40]([O:45][CH2:59][CH2:58][N:52]5[CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)[CH:41]=4)[CH:36]3[C:46]([O:48][CH3:49])=[O:47])(=[O:33])=[O:34])=[CH:30][CH:31]=2)=[CH:50][CH:51]=1
Reactant: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1c2ccc(OCCN3CCOCC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 53 %

Procedure:
667 mg (2.0 mmol) of polymer-bound PPh3 (3 mmol/g) are introduced into 2 ml of THF and, at room temperature, 229 mg (0.5 mmol) of methyl 2-[4-(4-fluorophenoxy)-benzenesulfonyl]-6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate (3B), 242 μl (2.0 mmol) of 2-morpholin-4-ylethanol and 311 μl (2.0 mmol) of DEAD are added. After one hour, the mixture is filtered and the filtrate is concentrated in vacuo. The residue is chromatographed on silica gel (dichloromethane→dichloromethane/methanol 98:2), resulting in 53% of the title compound.