Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10](N3CCNCC3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:5]=2[N:4]=1.[CH3:38][S:39]([Cl:42])(=[O:41])=[O:40].[C:43]([O-:46])([O-])=O.[K+].[K+].Cl>C(Cl)Cl.CO.C(Cl)Cl.CCOC(C)=O>[ClH:42].[F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([O:46][CH:43]3[CH2:6][CH2:5][N:4]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:3][CH2:2]3)[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CCCOc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCCOc1cccc2c1nc(C(F)F)n2-c1nc(OC2CCN(S(C)(=O)=O)CC2)nc(N2CCOCC2)n1
Yield: 71 %

Procedure:
Reaction of N-[3-({2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine from the previous step with methanesulphonyl chloride and powdered K2CO3 in CH2Cl2, followed by chromatography on alumina eluting with CH2Cl2/EtOAc (1:1) g, and acidification with HCl in MeOH gave N-[3-({2-(difluoromethyl)-1-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine hydrochloride in 71% yield: 1H NMR (DMSO-d6) δ 10.07 (br s, exchangeable with D2O, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.73 (t, JHF=52.7 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 5.27-5.21 (m, 1H), 4.34 (t, J=6.1 Hz, 2H), 3.86-3.85 (m, 4H), 3.74-3.71 (m, 4H), 3.44-3.38 (m, 2H), 3.20-3.14 2.93 (s, 3H), 2.82 (s, 6H), (m 2H), 2.28-2.26 (m, 2H), 2.15-2.10 (m, 2H); Anal. Calcd. for C26H29ClF2N8O5S.0.75 H2O: C, 47.3; H, 5.9; Cl, 5.4; N, 17.0. Found: C, 47.3; H, 5.8; Cl, 5.4; N, 17.0%.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH3:14][CH2:15][C@:16]12[CH2:32][C@:31]([OH:37])([C:33]([O:35][CH3:36])=[O:34])[N:30]3[C:22]4=[C:23]([CH2:38][CH2:39][N:20]([C@@H:21]14)[CH2:19][CH2:18][CH2:17]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=13>C(O)C.C(Cl)(Cl)Cl>[CH3:14][CH2:15][C@:16]12[CH2:32][C@:31]([OH:37])([C:33]([O:35][CH3:36])=[O:34])[N:30]3[C:22]4=[C:23]([CH2:38][CH2:39][N:20]([C@@H:21]14)[CH2:19][CH2:18][CH2:17]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=13.[C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([O-:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CC[C@]12CCCN3CCc4c(n(c5ccccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(=O)Oc1ccccc1C(=O)[O-]
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A solution of 3.6 g (2.10-` moles) of acetylsalicylic acid in 30 mls of ethanol is added to a solution of 7.08 g (2.10-2 moles) of vincamine in 80 mls of ethanol and 60 mls of CHCl3. The mixture is maintained under stirring at 70° C. for 10 minutes and then concentrated to 60 mls. The residue is taken with ethanol (70 mls) and the solvent is evaporated to a final volume of 15 mls.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([CH3:17])([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[CH3:5].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][C:29]=1[O:38][CH3:39].C(Cl)CCl.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([CH2:1][NH:2][CH2:3][C:4]([CH3:17])([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)[CH3:5])=[O:36])=[CH:30][C:29]=1[O:38][CH3:39]
Reactant: CNCC(C)(C)Oc1ccc(C(=O)OC)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1ccc(OC(C)(C)CNCC(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 44.3 %

Procedure:
To a stirred mixture of methyl 4-(1-methylamino-2-methyl-2-propoxy)benzoate (200 mg, 0.84 mmol), 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetic acid (268 mg, 0.84 mmol), 4-DMAP (125 mg, 1.0 mmol) in DMF (5 mL) was added EDC (220 mg, 1.14 mmol) at ambient temp. The resulting mixture was stirred for a further 10 hr at ambient temp. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated. The residual gum was triturated with CH2Cl2 and Et2O to give 200 mg (44.1%) methyl 4-[[1-[4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetyl]methylamino]-2-methyl-2-propoxy]benzoate as a crystalline material. 1H-NMR (CDCl3) δ1.36 and 1.31 (each s, 6H), 3.24-3.88 (series of s, 13 H), 6.65-8.20 (series of m, 14H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[C:12]1(=O)OCC[O:13]1.C(OCC)(=O)C.O>C1(C)C=CC=CC=1>[CH2:5]([C@@H:2]1[CH2:3][O:4][C:12](=[O:13])[NH:1]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1OCCO1
Reactant: N[C@@H](CO)Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1N[C@H](Cc2ccccc2)CO1
Yield: 78.2 %

Procedure:
3 g of (R)-(+)-2-amino-3-phenylpropanol and 1.8 g of ethylene carbonate in 50 ml toluene in a round bottom flask equipped with a Dean-Stark trap was refluxed for 24 hrs. The reaction mixture was poured into ethyl acetate/water mixture and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water, followed by brine, dried and concentrated. Kugelrohr distillation at 150°-160° C./0.5 mm Hg provided 2.75 g (75%) of an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[OH:11][C:12]1[CH:21]=[C:20]([CH3:22])[C:15]2[NH:16][C:17](=[O:19])[O:18][C:14]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([O:11][C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)[CH:7]=1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1

Procedure:
0.19 g (1.01 mmol) 4,6-dichloro-2-methoxypyrimidine, 0.18 g (1.04 mmol) 6-hydroxy-4-methyl-3H-benzoxazol-2-one and 0.15 g (1.09 mmol) potassium carbonate in 1.5 mL DMF were stirred for 2 h at RT. Then water was added and the precipitate formed was suction filtered, washed and dried.
Reaction SMILES: C[Sn](C)(C)C.[C@@H:6]1([N:14]2[CH:18]=[C:17](I)[CH:16]=[C:15]2[N+:20]([O-:22])=[O:21])[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[CH2:7]1.[C:23]1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C@@H:6]1([N:14]2[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]2[N+:20]([O-:22])=[O:21])[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[CH2:7]1
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Sn](C)(C)C
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])n([C@H]2C[C@H](O)[C@@H](CO)O2)c1
Yield: 150 %

Procedure:
Tetramethyltin (287 μL, 2 mmol) was added to a DMF (2 mL) solution containing 1-(2-deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (142 mg, 0.4 mmol), bis(triphenylphosphine)palladium(II) dichloride (14 mg, 0.02 mmol), and triphenylarsine (12 mg, 0.04 mmol), followed by reaction at 60° C. for 2 days. The reaction solution was separated between ethyl acetate (50 mL) and water (50 mL). The organic layer was concentrated and purified by HPLC to yield 1-(2-deoxy-β-D-ribofuranosyl)-4-methyl-2-nitropyrrole (15 mg, 0.06 mmol, 15%).
Reaction SMILES: [C:1]([CH2:5][CH:6]([F:8])[F:7])([F:4])([F:3])[F:2].[Cl:9]Cl>>[C:1]([CH2:5][C:6]([Cl:9])([F:8])[F:7])([F:4])([F:3])[F:2]
Reactant: ClCl
Reactant: FC(F)CC(F)(F)F
Product: FC(F)(F)CC(F)(F)Cl
Temperature: 0 °C

Procedure:
The reactor described above was cooled and maintained at about 0° C. during the photochlorination reaction. Initially, the reactor was purged of air using nitrogen. Chlorine gas was then introduced to displace the nitrogen. Thereafter, 335 g (2.5 mol) of CF3CH2CHF2 (HFC-245fa) was charged to the reactor. A total of 208 g (2.9 mol) of chlorine gas was bubbled into the CF3CH2CHF2 over a period of about 24 hours while the reactants were being irradiated. At the end of the 24 hour period, GC analysis indicated a 96% conversion of HFC-245fa (retention time 1.9 min) to the desired product HCFC-235fa (retention time 2.1 min). The reaction mixture was washed with 100 mL of a cooled (about 2° C.) solution of aqueous sodium bisulfite (10 wt. %) and distilled (boiling point=26-28° C.) to afford 383 g CF3CH2CF2Cl (yield, 91%). Absent cooling of the wash solution, loss of product by vaporization has been observed due to a slight exotherm during the washing step. No multichlorinated products were detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([CH3:12])[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:6]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 21 %

Procedure:
3,4-Dichlorobenzoyl chloride (60 mg, 0.29 mmol, CAS RN 2905-60-4) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (45 mg, 0.23 mmol, example 1, intermediate a) and DIPEA (79 μL, 0.45 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the product as a waxy solid (18 mg, 21%). MS (ESI): m/z=371.0 [M+H]+.
Reaction SMILES: C(OC[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11]C=1)=[CH2:8])(=O)C.S(=O)(=O)(O)O.C(OCCC(C1C=CC=CC=1)=C)(=[O:22])C.S(=O)(=O)(O)O.[OH-].[Na+].[CH2:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH:7]([CH:9]1[CH2:14][CH:13]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:12]=[CH:11][O:22]1)([CH3:6])[CH3:8]
Reactant: C=C(CCOC(C)=O)c1ccccc1
Reactant: C1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C1CC(c2ccccc2)C=CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 500 ml three neck reaction flask equipped with stirrer, thermometer, reflux condenser and addition funnel is placed 72 gms (1 mole) of isobutyl aldehyde. The isobutyl aldehyde is heated to 66° C (reflux) and from the additional funnel, over a period of 1 hour, is added a mixture of 204 g (1 mole) of 3-phenyl-3-buten-1-yl acetate and 1 g concentrated sulfuric acid. During addition of the 3-phenyl-3-buten-1-yl acetate/sulfuric acid mixture, the reaction mass temperature increases to 80°-85° C. At the end of the addition of the mixture, the reaction mass is stirred for a period of three hours at 80°-85° C. The reaction mass is then cooled to room temperature and 100 ml of a 10% aqueous sodium hydroxide solution is added thereto with stirring, followed by 100 ml cyclohexane. The resulting mixture is transferred to a separatory funnel and the aqueous layer is removed. The organic, layer is then washed with one 100 ml portion of 10% aqueous sodium chloride. The organic layer is then stripped of solvent and rushed over. To the rushed over material 4.5 gms Primol®, 0.5 gms triethanolamine and 0.1 gms of Ionox® is added. The resulting material is then distilled in an 8 plate vigreux column yielding the following fractions:
Reaction SMILES: [NH2-].[Na+].C[C:4](=[O:7])[CH2:5][CH3:6].C[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=O.[CH3:16]C(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.S(=O)(=O)(O)O>O>[CH3:14][O:13][CH:11]([C:10](=[O:9])[CH2:15][C:4](=[O:7])[CH2:5][CH3:6])[CH3:16]
Reactant: CCC(C)=O
Reactant: COC(=O)C(C)OC
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=S(=O)(O)O
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Product: CCC(=O)CC(=O)C(C)OC
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
In a 200 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel was placed 8.00 g (205 mmol) of sodium amide, and the flask was purged with argon. Then, 50 mL of toluene was placed in the flask. Subsequently, 15.0 g (208 mmol) of 2-butanone was slowly dropped into the ice-cooled mixture in the flask, and the resulting mixture was stirred for 10 minutes. The mixture was cooled to 5° C., and Into the cooled mixture was further dropped 8.50 g (72 mmol) of methyl 2-methoxypropionate (prepared by the method of Reference Example 1), and the mixture was stirred for 30 minutes for carrying out a reaction. After the reaction was complete, 40 mL of water was placed in the flask under cooling with ice. The aqueous portion was taken out, made acetic with 2.5 mol/L sulfuric acid, and subjected to extraction with diethyl ether. The diethyl ether extract was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and distilled under reduced pressure (32° C., 26.6 Pa) to give 5.60 g (yield: 49%) of 2-methoxy-3,5-heptanedione as colorless liquid.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]([CH2:17][N:18]2C(=O)C3C(=CC=CC=3)C2=O)[CH:8]=[N:9][C:10]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]>CO>[Cl:4][C:5]1[CH:6]=[C:7]([CH2:17][NH2:18])[CH:8]=[N:9][C:10]=1[O:11][CH2:12][C:13]([F:14])([F:15])[F:16]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(OCC(F)(F)F)c(Cl)c1
Agent: NN
Solvent: CO
Solvent: O
Product: NCc1cnc(OCC(F)(F)F)c(Cl)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 111.3 %

Procedure:
Hydrazine monohydrate (0.04 mL, 0.84 mmol) is added to a solution of 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (210 mg, 0.56 mmol, Step-3) in methanol (10 mL) and stirred for 20 hours at 50° C. After removal of the solvent, the residue is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mL×3) and dried over sodium sulfate, and concentrated in vacuo to give 0.15 g (>99% yield) of the title compound as colorless oil. This material is used for the next reaction without further purification.
Reaction SMILES: [CH:1]1([N:4]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)(=[O:33])=[O:32])[C:5]2[CH:6]=[C:7]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:8]=[C:9]3[C:13]=2[N:12](C(OC(C)(C)C)=O)[CH:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH2:3][CH2:2]1>C(OCC)(=O)C.Cl>[CH:1]1([N:4]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)(=[O:33])=[O:32])[C:5]2[CH:6]=[C:7]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:8]=[C:9]3[C:13]=2[NH:12][CH:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1Cc2cc(OCCOC)cc(N(C3CC3)S(=O)(=O)c3ccccn3)c2N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1Cc2cc(OCCOC)cc(N(C3CC3)S(=O)(=O)c3ccccn3)c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
1-tert-Butyl 2-ethyl 7-[cyclopropyl(pyridin-2-ylsulfonyl)amino]-5-(2-methoxyethoxy)indoline-1,2-dicarboxylate (1.70 g) was added to 4N hydogen chloride-ethyl acetate solution (50 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.34 g, yield 96%) as a pale-yellow amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:68]([O:75][CH2:76][C@@H:77]([C:79]([OH:81])=[O:80])[NH2:78])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:78][C@H:77]([C:79]([OH:81])=[O:80])[CH2:76][O:75][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine, (20.3 mg, 0.038 mmol) in DMF (2 ml) was added N-methylmorpholine (15 μl, 0.14 mmol). TBTU (14.8 mg, 0.046 mmol) was added the mixture was stirred at 30° C. for 1.5 hours. O-benzyl-L-serine (8.8 mg, 0.045 mmol) was added and the mixture was stirred overnight. The formation of the ketone of the title compound was confirmed. M/z: 718.04 (M+1) and 716.02 (M−1). Methanol (3 ml) and sodium borohydride (10.3 mg, 0.27 mmol) were added and the mixture was stirred for 1.5 hours. Ammonium acetate (20 mg) was added and the methanol was removed under reduced pressure. The remaining DMF-solution was purified by preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 45% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The combined organic phases were concentrated and the residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained as a white solid (2.3 mg, 8.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:23]([OH:26])[C:24]#[CH:25]>O1CCCC1.C(OCC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:25]#[C:24][CH2:23][OH:26])=[CH:3][CH:4]=1
Reactant: C#CCO
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: OCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a degassed solution of 1-bromo-4-trifluoromethylbenzene (5.62 g, 25 mmol) in tetrahydrofuran (25 ml) was added in the following order: copper(I) iodide (143 mg, 0.75 mL), tetrakis(triphenylphosphine)palladium (0.85 g, 7.5 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.55 g, 30 mmol). The resulting mixture was degassed one more time, cooled in an ice bath and a solution of propargyl alcohol (1.68 g, 30 mmol) in tetrahydrofuran (5 mL) was added over period of 10 min. The reaction mixture was slowly heated up to 55° C. and then stirred at this temperature for 3 h and then at ambient temperature overnight. The mixture was diluted with diethyl ether (100 mL), washed with water (50 mL), 5% hydrochloric acid (35 mL) and saturated aqueous solution of sodium hydrogen carbonate (30 mL). The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, dichloromethane) affording 3-(4-trifluoromethylphenyl)prop-2-yn-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(O)[CH2:42][CH2:41]C[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:41][CH2:42][CH2:37][CH2:38][CH2:39]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCCCC1
Reactant: COc1cc2ncnc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3cc(C)c(NC(=O)OC4CCCCC4)cc3C)c2cc1OC
Yield: 83.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclohexanol (23 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (58 mg, yield 74%).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=O)C1C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:47][C:48](OC2C=CC=CC=2)=[O:49])[C:34](=[CH:45][CH:46]=1)[C:35](OCC1C=CC=CC=1)=[O:36]>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:34]([C:35](=[O:36])[N:28]([S:25]([C:14]3[CH:13]=[C:12]([NH2:11])[C:17](=[CH:16][CH:15]=3)[C:18]([OH:20])=[O:19])(=[O:26])=[O:27])[C:48](=[O:49])[NH:47]2)=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Reactant: COc1ccc(C(=O)OCc2ccccc2)c(NC(=O)Oc2ccccc2)c1
Product: COc1ccc2c(=O)n(S(=O)(=O)c3ccc(C(=O)O)c(N)c3)c(=O)[nH]c2c1
Yield: 3.1 %

Procedure:
500 mg (1.23 mmol) of 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 460 mg (1.22 mmol) of benzyl 4-methoxy-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 15 mg (yield 3.1%: 4 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.82 (3H, s), 6.58 (1H, s) 6.80 (1H, d), 7.16 (1H, d), 7.56 (1H, s), 7.80 (1H, d) 7.90 (1H, d), 11.49 (1H, s).