Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:26]([N:33]1C=CN=C1)(N1C=CN=C1)=[O:27].[C:38]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])(=[O:41])[NH:39]N.O>CN(C)C=O>[NH:33]([C:26]([O:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)=[CH:15][N:14]=2)=[CH:23][CH:22]=1)=[O:27])[NH:39][C:38]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CO)cc3)nc2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(COC(=O)NNC(=O)OC(C)(C)C)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
To a suspension of (4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)methanol (115.3 mg, 0.340 mmol) in anhydrous N,N-dimethylformamide (1.5 ml) was added 1,1′-carbonyldiimidazole (83.1 mg, 0.513 mmol), and the mixture was stirred at room temperature for 1.5 hrs. tert-Butyl carbazate (137.5 mg, 1.040 mmol) was added, and the mixture was stirred at room temperature 7 hrs. tert-Butyl carbazate (134.8 mg, 1.020 mmol) was added, and the mixture was stirred at room temperature for 16 hrs. tert-Butyl carbazate (135.7 mg, 1.027 mmol) was further added, and the mixture was stirred at 50° C. for 8 hrs. Water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was suspended in dichloromethane (15 ml), collected by filtration, washed with dichloromethane and dried under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane=1:20). The fraction containing the target product was concentrated and the obtained solid was suspended in a mixture of ethyl acetate (1 ml) and diisopropyl ether (4 ml), collected by filtration and dried under reduced pressure to give 4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}benzyl tert-butyl hydrazine-1,2-dicarboxylate (148.6 mg, yield 87.9%) as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[Cl:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][C:14]2[N:19]=[C:18]([OH:20])[C:17]([NH:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[C:16]([OH:31])[N:15]=2)=[CH:11][CH:10]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[NH:19][C:18](=[O:20])[C:17]3[N:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[O:31][C:16]=3[N:15]=2)=[CH:32][CH:33]=1
Reactant: O=C(Nc1c(O)nc(Cc2ccc(Cl)cc2)nc1O)c1cccc(F)c1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(Cc2ccc(Cl)cc2)nc2oc(-c3cccc(F)c3)nc12
Temperature: 60 °C
Reaction time: 20 h
Yield: 6.1 %

Procedure:
7.4 g of phosphorus pentachloride were added at 60° C. to a suspension of 8.9 g of N-[2-(4-chloro-benzyl)-4,6-dihydroxy-pyrimidin-5-yl]-3-fluoro-benzamide hydrochloride in 100 ml of dry chloroform. After heating at 60° C. for several hours, 5.5 g of phosphorus oxychloride were added and the reaction mixture was stirred at 75° C. for 20 h. After cooling to room temperature, the precipitate was filtered off and purified by silica gel chromatography (gradient from ethyl acetate to dichloromethane to dichloromethane/methanol 3:1). The product fractions were evaporated and the residue washed with chloroform and water and dried in an infrared dryer until constant weight to give 0.47 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:4]=1[C:5](O)=[O:6].ClC1C=CC=CC=1.S(C)C>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[C:4]=1[CH2:5][OH:6]
Reactant: COc1cccc(C(F)(F)F)c1C(=O)O
Solvent: CSC
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: COc1cccc(C(F)(F)F)c1CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Into a 100-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 2-methoxy-6-(trifluoromethyl)benzoic acid (2.2 g, 9.99 mmol, 1.00 equiv), chlorobenzene (20 mL). This was followed by the addition of BH3.SMe2(2M in tetrahydrofuran) (15.0 mL) dropwise with stirring at 0° C. The mixture was stirred 15 min at 0° C. Then the resulting solution was stirred for 2 h at 80° C. and continued stirring for 18 h at 130° C. in an oil bath. The reaction progress was monitored by TLC (PE:EtOAc=4:1). The reaction was then quenched by the addition of 20 mL of water, extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 1.9 g (92%) of [2-methoxy-6-(trifluoromethyl)phenyl]methanol as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[CH3:22][CH2:23][OH:24]>>[C:23]([C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[NH:9][CH:8]=[C:7]2[C:1]1[CH2:6][CH2:5][CH:4]([NH:17][CH2:21][CH2:20][C:19]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:18]=2)[CH2:3][CH:2]=1)(=[O:24])[CH3:22]
Reactant: CCO
Reactant: C1CCNC1
Reactant: O=C1CCC(NCCc2ccccc2)CC1
Product: CC(=O)c1ccc2[nH]cc(C3=CCC(NCCc4ccccc4)CC3)c2c1
Yield: 96 %

Procedure:
5-Acetyl-1-H-indole1 (3.18 g, 0.02 mol), 4-[(2-phenylethyl)amino]cyclohexanone (5.2 g, 0.024 mol) and pyrrolidine (5 mL) were dissolved in EtOH (30 mL) and refluxed for 48 h. The solvent was removed in vacuo. Silica gel chromatography (20-100% EtOAc gradient in hexane followed by 5-20% MeOH gradient in EtOAc) of the residue yielded the product (6.93 g, 96%). Treatment of this material with fumaric acid in MeOH afforded the fumarate salt which was recrystallized from MeOH/EtOAc (2.6 g, 30.5%): mp 266°-269° C. Anal. Calcd for C24H26N2).0.7 C4H4O4 : C 73.25; H 6.84; N 6.37. Found: C 73.20; H6.60; N6.37. Prepared according to the procedure reported in CA 54 12098e.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[N+:9]([C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([O-:11])=[O:10].C(N(C(C)C)CC)(C)C>[Cl-].[Cl-].[Zn+2].C(#N)C>[N+:9]([C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14]([O:16][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1)=[O:15])([O-:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: O=C1C=C(Cl)CCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c([N+](=O)[O-])c1
Temperature: 45 °C
Yield: 50.5 %

Procedure:
To a mixture of 157 mg (1.15 mmol) of 3-chlorocyclohex-2-en-1-one (prepared as described in Synthesis (1974), (1), 47-8), 16 mg (0.12 mmol) of ZnCl2, 297 mg (1.15 mmol) of 2-nitro-4-methylsulfonylbenzoic acid and 3 ml of anhydrous acetonitrile there are added dropwise, under a nitrogen atmosphere, over the course of 15 minutes, 166 mg (1.27 mmol) of diisopropylethylamine. A further 2 ml of acetonitrile are then added and the reaction mixture is maintained at a temperature of 45° C. for 18 hours in an oil bath, with stirring. The reaction mixture is then heated up again and maintained at reflux temperature for 40 hours. The reaction mixture is then brought to ambient temperature and the solvent is removed in vacuo. 25 ml of dichloromethane and 0.35 g of 36% hydrochloric acid in 5 ml of water are then added and the phases are separated. The organic phase is washed twice with 10 ml of water, dried using magnesium sulfate and concentrated in vacuo. 197 mg of 3-(2-nitro-4-methylsulfonyl-phenylcarbonyloxy)-cyclohex-2-en-1-one are obtained in the form of a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH:16]1([CH2:22][NH2:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:23][CH2:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: NCC1CCCCC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCC1CCCCC1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and cyclohexanemethylamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[N:36]=[C:35]([CH3:47])[CH:34]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[N:36]=[C:35]([CH3:47])[CH:34]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (257 mg, 1.0 mmol) and (RS)-3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K64) (426 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (460 mg, 76%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:18](=[O:25])[O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])[CH2:10][C:11]([O:13][C:14]([CH3:17])(C)C)=[O:12])=O)(C)(C)C.[CH:26](N(C(C)C)CC)(C)C.Cl[C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37].[Cl-].[NH4+]>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH2:39]([O:38][C:36]([NH:8][C@H:9]([C:18](=[O:25])[O:19][CH2:20][C:21]([Cl:22])([Cl:23])[Cl:24])[CH2:10][C:11]([O:13][CH2:14][CH:17]=[CH2:26])=[O:12])=[O:37])[CH:40]=[CH2:41]
Reactant: C=CCOC(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)C[C@H](NC(=O)OCC=C)C(=O)OCC(Cl)(Cl)Cl
Reaction time: 1 h
Yield: 66.8 %

Procedure:
tert-Butyl (S)-3-[(tert-butyl)oxycarbonylamino]-4-oxo-4-(2,2,2-trichloroethoxy)butyrate (605 mg, 1.48 mmol) obtained from Example 20-(1) was dissolved in trifluoroacetic acid (2.5 ml) followed by stirring for 1 hour. The mixture was diluted with toluene, and the solvent was distilled off under reduced pressure. The obtained white powder was suspended in dichloromethane (5 ml), and diisopropylethylamine (1.8 ml, 10 mmol) and allyl chloroformate (624 mg, 5.18 mmol) were added thereto at room temperature. The mixture was stirred for 1 hour, then a saturated aqueous solution of ammonium chloride was added thereto, and the product was extracted with ethyl acetate. The organic layer was washed successively with water and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel (25 g) column (eluent; hexane:ethyl acetate=4:1) to afford the title compound (384 mg, 67% yield) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@:10]([CH2:14][NH2:15])([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([N:28]([CH3:36])[C:29](=[O:35])[C@@H:30]3[CH2:34][C@@H:31]32)=[CH:26][C:25]=1[CH:37]=O.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@:10]([CH2:14][NH:15][CH2:37][C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][C:24]=3[O:23][CH3:22])[C@H:31]3[CH2:34][C@H:30]3[C:29](=[O:35])[N:28]4[CH3:36])([CH2:11]2)[C@@H:9]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)[C@@H]1C[C@H]21
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@]2(CN)[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1CNC[C@@]13C[C@@H]1CN(C(=O)OC(C)(C)C)[C@H]3c1ccccc1)N(C)C(=O)[C@@H]1C[C@H]21
Reaction time: 3 h
Yield: 104.5 %

Procedure:
Racemic Intermediate 21, one enantiomer being (1R,2S,5S)-1-aminomethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.055 g, 0.19 mmol) was combined with (1aR,7bS)-6-methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde (0.046 g, 0.20 mmol) in methylene chloride (3 mL) and the mixture was stirred for 3.0 hours. APCI mass spec showed complete imine formation (m+1: 503). Methanol (1.0 mL) and sodium triacetoxyborohydride (0.053 g, 0.25 mmol) were added and the reaction allowed to stir for 16 hours. The solvent was removed at reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution and methylene chloride, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a white foam (0.10 g, quantitative crude yield). This material was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]([O:19]C)=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+]>C(O)C>[OH2:2].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:17]([OH:19])=[O:18])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O
Product: O=C(O)C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 127.1 %

Procedure:
A mixture of intermediate (1) (0.026 mole) and KOH (0.13 mole) in ethanol (150 ml) was stirred at room temperature for 18 hours, heated at 50° C. for 2.5 hours and cooled to room temperature. The precipitate was filtered off, stirred in 2-propanol, filtered off, washed three times with 2-propanol and dried. This fraction was stirred and refluxed in 2-propanol. HCl/2-propanol 6N (19.94 ml) was added. The mixture was stirred and refluxed, filtered warm and stirred in water (350 ml). The precipitate was filtered off and dried, yielding 5.94 g of (±)-4-(4-nitrophenyl)-α-phenyl-1-piperazineacetic acid monohydrate (intermediate 2).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].[BrH:12]>C(O)(=O)C.ClCCl>[C:3]([O:10][C@@H:9]1[C@@H:7]([O:8][C:5](=[O:6])[CH3:7])[C@H:5]([O:6][C:9](=[O:10])[CH3:11])[C@@H:3]([CH3:2])[O:4][C@@H:11]1[Br:12])(=[O:4])[CH3:2]
Reactant: C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)O[C@H](C)[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
In a 10 mL round bottom flask containing 10 mL of glacial acetic acid was placed 6-deoxyglucose (332.3 mg) and the reaction was cooled to 0° C. Hydrobromic acid in glacial acetic acid (5 mL of a 30 wt. % solution) was added dropwise. The reaction was stirred for 4 hours. The reaction was diluted with 100 mL of dichloromethane and washed with 50 mL ice water and then 50 mL of cold saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and filtered. The solvent was removed in vacuo to yield the title compound as a yellow solid (636.5 mg, 85.4%) and the product was used without further purification as in Example 1. MS (FAB) calculated for C12H17O7Br (M−Br) 273.1, found 273.1.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:14]([Cl:16])=[CH:13][C:12](=O)[CH2:11][C:10]=3[C:9]3([CH2:21][NH:20][C:19](=[O:22])[NH:18]3)[C:8]2=[O:23])=[C:4]([F:26])[CH:3]=1.Cl.[OH-:28].C[N+](C(C1C=CC=CC=1)C)(C)C>CO>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:16])[C:9]3([C:21](=[O:28])[NH:20][C:19](=[O:22])[NH:18]3)[C:8]2=[O:23])=[C:4]([F:26])[CH:3]=1
Reactant: O=C1C=C(Cl)C2=C(C1)C1(CNC(=O)N1)C(=O)N2Cc1ccc(Br)cc1F
Reactant: [OH-]
Agent: CC(c1ccccc1)[N+](C)(C)C
Agent: Cl
Solvent: CO
Product: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Br)cc1F)c1c(Cl)cccc12
Temperature: 70 °C
Reaction time: 48 h

Procedure:
(±)-1'-(4-Bromo-2-fluorobenzyl)-7'-chloro-spiro[imidazoline-4,3'-indoline]-2,2',5'-trione (64.4 g.) was dissolved in a 0.253 M solution of (-)-N,N,N-trimethyl-(1-phenylethyl)ammonium hydroxide in methanol (581 ml.). The solution was filtered and the filtrate was evaporated. The residue was dissolved in 2-methoxyethanol (132 ml.). The solution was warmed to 70° C. and then diluted with 1,2-dimethoxyethane (440 ml.) previously warmed to 70° C. The clear solution was stored at 0° C. for 48 hours and the crystals of the quaternary ammonium salt were collected by filtration [27 g.; [α]D23 +21.1°, c. 0.93, MeOH)]. This product was recrystallised from 2-methoxyethanol (55.3 ml.) and 1,2-dimethoxyethane (184 ml.) to give crystals [20 g.; [α]D23 +22° (c.1.11, MeOH)]. A third recrystallisation gave crystals [15.8 g.; [α]D23 +21.9° (c.1.12 MeOH)]. The crystalline salt (15.8 g.) thus obtained was dissolved in methanol (50 ml.) and treated with 0.25 M aqueous hydrochloric acid (105 ml.). The solution was chilled at 0° C. overnight and the solid removed by filtration, washed with water and dried over phosphorus pentoxide under vacuum to give the (+)-enantiomer of 1'-[4-bromo-2-fluorobenzyl]-7'-chloro-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (9.1 g.), m.p. 260°-262° C., [α]D23 +17.9° (c. 0.89, MeOH).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[K].[S:15]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1)(=[O:18])(=[O:17])[NH2:16]>CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:16][S:15]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH:7]=1
Reactant: Clc1cc(Cl)nc(N2CCCC2)n1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: [K]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N3CCCC3)n2)cc1
Yield: 58.9 %

Procedure:
0.58 g (0.00266 mol) of 4,6-dichloro-2-pyrrolidin-1-yl-pyrimidine and 1.36 g (0.00539 mol) of N-(4-sulfamoyl-phenyl)-acetamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was made acid with 4N HCl and extracted with ethyl acetate. Both organic phases were combined and concentrated. The residue was recrystallized from a small amount of ethanol and the mother liquor was chromatographed over silica gel with cyclohexane/ ethyl acetate 2:1 as the eluent. There was obtained a total of 0.62 g (66%) of N-[4-(6-chloro-2-pyrrolidin-1-yl-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide as whitish crystals; m.p. 229-233° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].[C:28](O)(=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32].Cl.CN(C)CCCN=C=N.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH:24][C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Reactant: C=CCCC(=O)O
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Yield: 97.7 %

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg), 4-pentenoic acid (33 mg), N-ethyl-N,-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg), 1-hydroxybenzotriazole (64 mg) and N,N-dimethylformamide (1.5 ml) was stirred for 2 hours at ambient temperature. Water was added thereto, and the mixture was extracted with methylene chloride three times. The organic layers were combined, washed with water four times and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:methanol =30:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(4-pentenoylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (172 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[Si](C#N)(C)(C)C.[N:26]1([C:31](N2C=CN=C2)=[O:32])C=CN=[CH:27]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:16]([C:15]4[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=4)[CH2:27][NH:26][C:31]3=[O:32])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2ccc(Cl)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 4-chlorobenzaldehyde (0.56 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA 1.93 mL, 13.9 mmol), di-(imidazol-1-yl)methanone (1.12 g, 6.9 mmol) as described in method 2. Yield: 0.045 g (3.6%); MS m/z 313.1 (M+H)+; 1H NMR (400 MHz, DMSO-D6): δ 3.04-3.08 (m, H); 3.79-3.84 (m, H); 5.49-5.52 (m, H); 6.93 (s, H); 7.33-7.38 (m, 5H); 7.19-7.22 (m, H); 7.51 (d, H, J=1.7 Hz); 8.05 (s, H); 12.22 (br s, H), HPLC (λ=214 nm, [B]: rt 9.62 min (99.7%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.COC(=O)C(O)C(C)C.[C:35]([O:39][C:40](=[O:44])[C@H:41](O)[CH3:42])([CH3:38])([CH3:37])[CH3:36].CO>C(OCC)(=O)C>[C:35]([O:39][C:40](=[O:44])[C@@H:41]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH3:42])([CH3:38])([CH3:37])[CH3:36]
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: COC(=O)C(O)C(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)OC(C)(C)C

Procedure:
Following the procedure of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol and 2-hydroxy-3-methyl-butyric acid methyl ester and (R)-2-hydroxy-propionic acid tert-butyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give (S)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid tert-butyl ester as a yellow oil contaminated with triphenylphosphine oxide. LCMS: RT=3.86 min, [M+H]+=480