Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37](=[O:51])[O:38][C@H:39]([CH2:41][CH2:42][O:43][Si](C(C)(C)C)(C)C)[CH3:40].O>O1CCCC1>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([B:27]2[O:31][C:30]([CH3:32])([CH3:33])[C:29]([CH3:34])([CH3:35])[O:28]2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37](=[O:51])[O:38][C@H:39]([CH2:41][CH2:42][OH:43])[CH3:40]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)O[C@@H](C)CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)O[C@@H](C)CCO
Yield: 146.6 %

Procedure:
To (S)-4-(tert-butyldimethylsilyloxy)butan-2-ol (1.649 mmol, 337 mg) in dichloromethane (4 ml) were added mol sieves (4A), 2-(4-isocyanato-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.374 mmol, 378 mg) and 4-dimethylaminopyridine (0.275 mmol, 33.6 mg) were added and the mixture was stirred at 40° C. (oil bath temperature) for 18 hours. The mol sieves were removed by filtration and the filtrate washed with water, dried (sodium sulfate) and concentrated in vacuo to give a crude product which was purified by column chromatography (silica gel, heptanes with gradient 10% to 50% of ethyl acetate) to afford (S)-4-(tert-butyldimethylsilyloxy)butan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (443 mg). Tetrabutylammonium fluoride (1M in tetrahydrofuran, 1.22 mmol, 1.22 ml) was added to (S)-4-(tert-butyldimethylsilyloxy)butan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (240 mg) in tetrahydrofuran (1 ml) at room temperature. After 20 hours water was added to the reaction mixture, extracted with dichloromethane, the organic extract dried (sodium sulfate) and concentration in vacuo to yield (S)-4-hydroxybutan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (268 mg) which was used in the next step without further purification.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:10][CH2:9][C:7]([C:3]1[S:2][CH:6]=[CH:5][CH:4]=1)=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NCC(=O)c1cccs1)c1ccccc1
Yield: 94 %

Procedure:
5 g of N-[(2-thienylcarbonyl)methyl]amine hydrochloride, 10 g of sodium bicarbonate and 3.9 g of benzoyl chloride are treated in the same manner as described in Preparation 1-(3). 6.4 g of N-benzoyl-N-[(2-thienylcarbonyl)methyl]amine are thereby obtained. Yield: 93.3%
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])[CH2:3][CH2:2]1.S(Cl)([Cl:26])=O>C(Cl)Cl.CN(C=O)C>[Cl:26][CH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[C:7]([C:4]2[CH2:3][CH2:2][O:1][CH2:6][CH:5]=2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCOCC2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2=CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.3 %

Procedure:
To a solution of 66.46G (39.3 mg, 0.13 mmol) in dry DCM (1.0 mL) and dry DMF (0.010 mL) was added thionyl chloride (0.020 mL, 0.27 mmol) at 0° C. The resulting solution was warmed to room temperature and monitored with TLC and LCMS. After 45 minutes, the reaction was concentrated and then purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 66.46H (39.5 mg, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.39 (3H, m), 7.02 (1H, t, J=8.8 Hz), 6.85 (2H, m), 5.57 (1H, s), 4.64 (2H, s), 4.13 (2H, q, J=2.7 Hz), 3.80 (3H, s), 3.70 (2H, t, J=5.3 Hz), 2.14 (2H, dd, J=4.5, 2.5 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[F:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=O.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[F:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=C(O)c1ccncc1F
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(-c2ccncc2F)nc2cc(C(F)(F)F)cnc21
Temperature: 120 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
A mixture of 5.51 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 6.10 g of 3-fluoroisonicotinic acid, 8.28 g of WSC and 58 ml of pyridine was stirred for 3 hours while heating at 120° C. After cooling down to room temperature, water was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 6.77 g of 2-(3-fluoropyridin-4-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as present active compound 36).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:18]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C.Br[CH2:35][CH2:36][O:37][CH3:38]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:35][CH2:36][O:37][CH3:38])[CH2:21][CH2:20]3)[CH:18]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(C(N)=O)c(Nc2cnn(C3CCNCC3)c2)nc1Cl
Reactant: COCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(N)=O)c(Nc2cnn(C3CCN(CCOC)CC3)c2)nc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-6-ethyl-3-{[1-(piperidin-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide (350 mg), diisopropylethylamine (685 μL), and N,N-dimethylformamide (3.5 mL) was added 2-bromoethylmethyl ether (282 μL), followed by reacting at 60° C. for 2 hours. The mixture was subjected to liquid separation by the addition of ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=99:1-90:10) to obtain 5-chloro-6-ethyl-3-({1-[1-(2-methoxyethyl)piperidin-4-yl]-1H-pyrazol-4-yl}amino)pyrazine-2-carboxamide (225 mg) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.[C:11](O)(=O)[CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>O.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:9][C:5]2=[N:4][C:3]=1[CH3:10]
Reactant: CCCCC(=O)O
Reactant: Cc1nc(N)c(N)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc2nc(C)c(Br)cc2[nH]1
Temperature: 110 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
9.0 g (44.6 mmole) of the compound obtained in step 3 and 5.5 g (58 mmole) of valeric acid were mixed with 30 ml of polyphosphoric acid and stirred for 3 hours at 110° C. The reaction solution was dissolved in a mixture of 50 ml of cold water and 50 ml of THF and the resulting solution was neutralized to Ph 8 with cold 40% aqueous NaOH solution with stirring vigorously and extracted with ethyl acetate (50 ml×3). Thereafter, the organic layer was dried over Na2SO4, concentrated under reduced pressure and recrystallized from hexane-methylene chloride to obtain 9.8 g of the title compound (yield 82%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>C(O)CCC>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CN)cc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1
Solvent: CCCCO
Product: COc1ccc(CNc2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cc1

Procedure:
A mixture of 2-bromo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (5.55 g, 15 mmol) and 4-methoxybenzylamine (5.9 mL, 45 mmol) in n-butanol (15 mL) was refluxed for 2 days. Evaporated to dryness, diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as an orange oil (6.409 g, 100%). MS (ISP) 427.3 [(M+H)+].
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.C(OC(Cl)=O)C(C)C.CN1CCOCC1.[CH3:28][S:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:52])[C@H:35]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[N:36](C(OC(C)(C)C)=O)[CH3:37]>ClCCl>[CH3:28][S:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:52])[C@H:35]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[N:36]([C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CSCCCNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CSCCCNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
BOC-Gly-OH (0.69 g) was dissolved in dichloromethane (10 ml) and cooled at -20°. Isobutylchloroformate (0.53 g) and NMM (0.4 g) were added with stirring. After 2 minutes Cl-H2+MePhe-NHTmp (1.2 g) and NMM (0.4 g) were added and the reaction mixture was allowed to attain room temperature. The stirring was continued for additional 3 hours when the reaction was worked up as described for (II). The dipeptide amide (IV) was obtained as a gum.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=1)[CH:5]([CH3:7])[CH3:6].Cl>C1COCC1.O>[CH2:4]([C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: CCOC(=O)c1csc(CC(C)C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1nc(C(=O)O)cs1
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (4.1 g) was added to a solution of ethyl 2-isobutylthiazole-4-carboxylate (example 72, step c) (5.2 g) in a mixture of THF (80 mL) and water (20 mL). The resulting mixture was stirred overnight. The reaction was carefully acidified with concentrated hydrochloric acid (10 mL) and the volatiles evaporated. The resulting aqueous mixture was poured into brine (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic solutions were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a white solid. Yield 3.8 g.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[Cl:13][C:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][N:15]=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:20][C:19]1[C:14]([Cl:13])=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cccnc1Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1cccnc1Cl)c1ccccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A solution of 2-nitrobenzoylchloride (7.2 g) in 100 ml toluene was added dropwise to a stirring solution of 2-chloro-3-amino-pyridine (10.0 g) in 100 ml toluene. After the entire amount was added, the mixture was heated to 80° C. for 120 min. After the reaction mixture was cooled down and the resulting 2-nitro-N-(2-chloro-pyridin-3-yl)-benzamide was isolated by filtration. Yield 10.0 g, mp 158-161° C.
Reaction SMILES: [N:1]([O-:3])=O.[K+].[CH3:5][O:6][C:7]1[CH:36]=[CH:35][C:10]([CH2:11][N:12]([CH:19]([OH:34])[C@H:20]2[O:26][C@:24]([CH2:27][CH2:28][CH2:29][CH3:30])([OH:25])[C@H:23]([OH:31])[C@@H:22]([OH:32])[C@@H:21]2[OH:33])[C:13](=[O:18])[NH:14][CH2:15][CH2:16][Cl:17])=[CH:9][CH:8]=1>O1CCCC1.Cl>[CH3:5][O:6][C:7]1[CH:36]=[CH:35][C:10]([CH2:11][N:12]([CH:19]([OH:34])[C@H:20]2[O:26][C@:24]([CH2:27][CH2:28][CH2:29][CH3:30])([OH:25])[C@H:23]([OH:31])[C@@H:22]([OH:32])[C@@H:21]2[OH:33])[C:13](=[O:18])[N:14]([CH2:15][CH2:16][Cl:17])[N:1]=[O:3])=[CH:9][CH:8]=1
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(Cc2ccc(OC)cc2)C(=O)NCCCl)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC[C@]1(O)O[C@H](C(O)N(Cc2ccc(OC)cc2)C(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
Potassium nitrite (2 g) was added at 0° to 5° C. to a solution of the above synthesized 3-(p-methoxybenzyl)-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (3.85 g, 8.35 mmol) in a mixture of tetrahydrofuran (100 ml) and 10% hydrochloric acid (10 ml). After stirring at the same temperature for 10 minutes, the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, vacuum-concentrated at 25° C., and purified by column chromatography (packing: Kiesel gel 60; eluent: chloroform/methanol 10:1). Thus, 2.35 g of 3-(p-methoxybenzyl)-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea was obtained; yield 57.4%, m.p. 86°-88° C., [α]D20 +61.5° (C 1.0, methanol).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:15]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C[C@H]1CCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)C[C@H]1CCCN1c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.5 %

Procedure:
To a solution of 2.0 g (0.012 mole) of D-beta-homoproline hydrochloride in 20 mL of methanol was added slowly 1.8 mL (0.024 mole) of thionyl chloride at 0 degrees. The mixture was stirred overnight, then concentrated under reduced pressure. The solid was slurried in ether, and collected by filtration to give 2.2 g of (2R)-pyrrolidin-2-yl-acetic acid methyl ester hydrochloride as a white solid. A solution of 2.2 g (0.012 mole) of (2R)-pyrrolidin-2-yl-acetic acid methyl ester hydrochloride in 3 mL of chloroform was added over 5 minutes to a cooled (0 degrees) mixture of 2.34 g (0.012 mole) of 2,4-dichloro-5-nitro-pyrimidine, 5.1 g (0.060 mole) of sodium bicarbonate and 25 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-70:30) gave 3.3 g of [(R)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-pyrrolidin-2-yl]-acetic acid methyl ester (IV-102) as a yellow thick oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[OH-].[Na+]>C1C=CC=CC=1>[CH2:10]([O:9][C:8]([NH:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]1[O:1][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(N[C@H]1CCC[C@@H]1O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a mixture of benzyl [(1S,2S)-2-hydroxycyclopentyl]carbamate (1.3 g) and benzene (13 ml) were added, tert-butyl bromoacetate (3.2 g), hydrogen tetrabutyl ammonium sulfate (0.46 g), and a 50% aqueous NaOH solution (13 ml) under ice-cooling, followed by stirring under ice-cooling for 1 hour and further at room temperature for 2 hours. The reaction mixture was poured into ice-water, extracted with ethyl acetate, then washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→7:1→5:1) to obtain tert-butyl {[(1S,2S)-2-{[(benzyloxy)carbonyl]amino}cyclopentyl]oxy}acetate (1.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12](=[O:41])[C@@H:13]2[CH2:17][C@@H:16]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[C:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:20]=3)[CH2:15][N:14]2[C:37]([NH:39][NH2:40])=[O:38])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[CH:42](=O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl>CO.C1COCC1>[CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12](=[O:41])[C@@H:13]2[CH2:17][C@@H:16]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[C:21]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:20]=3)[CH2:15][N:14]2[C:37]([NH:39][NH:40][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:38])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NN)C(=O)OCC
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NNCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
To a solution of compound 105 (0.037 mmol) in MeOH:THF (4:1) was added benzaldehyde (0.0448 mmol). The solution was stirred at RT for 18 hrs. Borane-pyridine complex (0.37 mmol) was added followed by HCl (37%, 400 μl). The solution was stirred for 1.5 hrs and then filtrated and concentrated to dryness. The crude material was dissolved in MeOH and purified by Prep LCMS which gave the title compound (0.01 mmol). Purity by HPLC>95%. M+H+650.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:26])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([Cl:26])=[O:8])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Product: NS(=O)(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1Oc1ccccc1

Procedure:
A mixture of 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid (5 g) and thionyl chloride (50 ml) was heated on a steam bath for 5 hours. After evaporation in vacuo to dryness, the compound was obtained as a crude product, which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:18](=O)[CH3:19])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)(O)[O-].[Na+].S(O)(O)(=O)=O.[CH3:31][O:32][C:33](=[NH:35])[NH2:34]>CN(C)C=O.O>[CH3:31][O:32][C:33]1[NH:35][C:18]([CH3:19])=[C:11]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:34]=1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)C
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Temperature: 60 °C
Yield: 67 %

Procedure:
A reaction mixture containing 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, 1-methylethyl ester (10.0 g, 36.0 mmol), sodium bicarbonate (8.40 g, 108 mmol), and O-methylpseudourea hydrogen sulfate (8.06 g, 46.8 mmol) in dimethylformamide (54 ml) was heated at 60° C. under argon for about 21/2 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water (six times) and saturated sodium chloride, dried (potassium carbonate) and evaporated. The residue was passed through a short pad of silica gel and crystallized from isopropyl ether/hexanes to give the title compound as yellow crystals (8.04 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Mg].[CH2:11]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:22][CH2:21][C:20]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)([OH:23])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Mg]
Product: OC1(c2cc(F)cc(F)c2)CCN(Cc2ccccc2)C1

Procedure:
Preparation according to Preparation 1: 1-Bromo-3,5-difluorobenzene (2.0 g, 10.3 mmol), magnesium turnings (0.25 g, 10.3 mmol), 1-benzylpyrrolidin-3-one (1.65 g, 9.3 mmol). Purification using flash chromatography on silica gel (ethyl acetate/isooctane, 1:4 to 1:1). Yield: 0.81 g. MS m/z (rel. intensity, 70 eV) 289 (M+, 2), 198 (26), 133 (32), 132 (23), 91 (bp). The enantiomers were separated by HPLC on Kromasil 5-Cellucoat (heptane/2-propanol/diethyl amine, 99:1:0.1): (+)-enantiomer (0.23 g). [α]D=+28.3° (methanol). MS m/z (rel. intensity, 70 eV) 289 (M+, 5), 198 (48), 133 (48), 132 (37), 91 (bp). (−)-enantiomer (0.35 g). [α]D=−28.1° (methanol). MS m/z (rel. intensity, 70 eV) 289 (M+, 9), 198 (58), 133 (48), 132 (40), 91 (bp).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][C:13]([OH:15])=O)[C:10](=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1.[ClH:41].[CH2:42]([O:44][C:45](=[O:49])[CH2:46][NH:47][CH3:48])[CH3:43]>>[ClH:41].[O:1]=[C:2]1[N:11]([CH2:12][C:13]([N:47]([CH2:46][C:45]([O:44][CH2:42][CH3:43])=[O:49])[CH3:48])=[O:15])[C:10](=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][CH2:22]1
Reactant: O=C(O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Reactant: CCOC(=O)CNC
Agent: Cl
Product: CCOC(=O)CN(C)C(=O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Yield: 79.2 %

Procedure:
Using the method similar to that in Example 109 and starting from 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-acetic acid (1.20 g, 2.22 mmol) obtained in Example 50, and also using sarcosine ethyl ester hydrochloride (408 mg, 2.66 mmol) instead of glycine methyl ester hydrochloride, the ethyl ester of the title compound (1.19 g 83%) was obtained as an oil.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].CC(C)([O-])C.[K+].Cl[C:13]1[C:18]([C:19]#[N:20])=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([C:27]#[N:28])=[C:15]([S:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[S:34][CH:35]=2)[N:14]=1>CN(C=O)C>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:33]2[S:34][CH:35]=[C:31]([CH2:30][S:29][C:15]3[C:16]([C:27]#[N:28])=[C:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:18]([C:19]#[N:20])=[C:13]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[N:14]=3)[N:32]=2)=[CH:37][CH:38]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Reactant: OCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCCCO)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Reaction time: 0.25 h

Procedure:
68 μl (0.939 mmol) of 1,3-propanediol are initially charged in 2 ml of DMF, 38 mg (0.344 mmol) of potassium tert-butoxide are added and the mixture is stirred for 15 minutes, after which 150 mg (0.313 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-phenylpyridine-3,5-dicarbonitrile, dissolved in 2 ml of DMF, are added. The reaction mixture is stirred at room temperature for 1 hour and then purified by preparative HPLC (acetonitrile/water: 10:90→95:5, with 0.1% TFA added). This gives 98 mg (59% of theory) of the target compound.