Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].O=O.[O:4]=[C:5]([CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[NH:14][C:13]([C:18]34[CH2:25][CH:24]5[CH2:26][CH:20]([CH2:21][CH:22]3[CH2:23]5)[CH2:19]4)=[N:12][C:11]=2[N:10]([CH2:27][CH2:28][CH3:29])[C:8]1=[O:9]>CN(C)C=O.[Pd](Cl)Cl>[O:4]=[C:5]([CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[NH:14][C:13]([C:18]34[CH2:25][CH:24]5[CH2:26][CH:20]([CH2:21][CH:22]3[CH2:23]5)[CH2:19]4)=[N:12][C:11]=2[N:10]([CH2:27][CH2:28][CH3:29])[C:8]1=[O:9].[O:1]=[CH:30][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[NH:14][C:13]([C:18]34[CH2:25][CH:24]5[CH2:26][CH:20]([CH2:21][CH:22]3[CH2:23]5)[CH2:19]4)=[N:12][C:11]=2[N:10]([CH2:27][CH2:28][CH3:29])[C:8]1=[O:9]
Reactant: O
Agent: Cl[Pd]Cl
Agent: CCCn1c(=O)n(CC(C)=O)c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Agent: O=O
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(CCC=O)c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Temperature: 0 °C
Yield: 27 %

Procedure:
A solution of 35.0 mg (0.10 mmol) of Compound J obtained in Reference Example 4 in 3 ml of N,N-dimethylformamide was added dropwise to a mixture of 0.5 ml-N,N-dimethylformamide and 0.5 ml-water containing 3.6 mg (0.02 mmol) of palladium chloride and 2.7 mg (0.02 mmol) of cupric chloride. The reaction mixture was stirred at 50° C. for 2 hours in an oxygen atmosphere, poured into 20 ml of ice water, extracted three times with chloroform. The extracts were washed with water, and with a saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 10.4 mg (yield 28%) of 1-(2-oxopropyl)-8-(3-tricyclo[3.3.1.03,7 ]nonyl)-3-propylxanthine (Compound 9) and 9.9 mg (yield 27%) of Compound 11, as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([OH:41])=O)=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.N1C(F)=NC(F)=NC=1[F:44].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:44])=[O:41])=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2Oc2ccc(C(=O)O)cc2)N1
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2Oc2ccc(C(=O)F)cc2)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(4-hydroxycarbonyl-phenoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.28 mmol) in dichloromethane (50 mL) at 0° C. was added cyanuric fluoride (120 mg, 0.88 mmol) (Alfa) and pyridine (100 mg, 1.3 mmol). After the mixture was stirred at 0° C. for 2 h, the mixture was partitioned between H2O and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO4, concentrated to give racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(4-fluorocarbonyl-phenoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow foam and used for the next step without further purification (Yield: 0. 18 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(Cl)cc(OC)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(Cl)cc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methyl 2-amino-5-chloro-3-methoxybenzoate (770 mg, 3.57 mmol) was suspended in tetrahydrofuran (20 mL), 2M sodium hydroxide (5 mL) was added and the mixture was stirred at ambient temperature for 20 hours. The solution was concentrated in vacuo, then partitioned between ethyl acetate and 1M hydrochloric acid. The organic layer was washed with water, then brine, dried with sodium sulfate, decanted and concentrated in vacuo to yield 2-amino-5-chloro-3-methoxybenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[N:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][C:36]=1[CH3:37])[CH2:6][N:7]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.[OH-].[Na+:45]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[N:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][C:36]=1[CH3:37])[CH2:6][N:7]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:20][C:21]([CH3:26])([CH3:25])[C:22]([O-:24])=[O:23])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.[Na+:45]
Reactant: COc1cc(Cn2c3ccccc3c3c(OC(C)(C)C(=O)O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cc(Cn2c3ccccc3c3c(OC(C)(C)C(=O)[O-])cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 0.5 h

Procedure:
1.88 g of 2-{9-[3-methoxy-4-((5-methyl-2-phenyl-oxazole-4-yl)methoxy)-benzyl]-9H-carbazole-4-yloxy}-2-methyl-propionic acid was suspended in 30 mL of 2-propanol, and dissolved at 70° C. 3.3 mL of 1 N sodium hydroxide solution was added thereto and stirred for 0.5 hour. The reaction mixture was allowed to cool, the precipitate crystal was isolated by filtration, washed with 2-propanol, dried under reduced pressure, and 1.66 g of the subject compound was prepared as white crystal.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:7]1(=[O:13])[NH:11][C:10](=[O:12])[CH:9]=[CH:8]1.C(N(CC)CC)C.CO>CN(C)C=O.C(Cl)(Cl)Cl.CCCCCC>[CH2:5]([O:4][C:2]([N:11]1[C:7](=[O:13])[CH:8]=[CH:9][C:10]1=[O:12])=[O:3])[CH3:6]
Reactant: O=C1C=CC(=O)N1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
Ethyl chloroformate (0.38 ml, 4 mmol) was added dropwise to a stirred solution maleimide (0.3 g, 3 mmol) and triethylamine (0.5 ml, 3.5 mmol) in dimethylformamide (2 ml) at 0-5° C. The reaction mixture was allowed to warm to room temperature and stand for 4 h. Methyl alcohol (1 ml) was added, diluted with chloroform (20 ml) and washed with water (3×10 ml). The chloroform solution was dried (Na2SO4) and concentrated in vacuum. The residue was purified in chloroform and hexane on a silica gel column to give N-ethoxycarbonyl-maleimide (yield 41%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([F:11])=[C:4](F)[C:3]=1[F:13].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[F:10][C:6]1[C:5]([F:11])=[C:4]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])[C:3]([F:13])=[C:2]([F:1])[C:7]=1[CH:8]=[O:9]
Reactant: OCC(F)(F)F
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=Cc1c(F)c(F)c(OCC(F)(F)F)c(F)c1F

Procedure:
Pentafluorobenzaldehyde (Oakwood Products, cat. #002835, 19.6 g, 0.1 mol) and tetrabutylammonium hydrogensulfate, Bu4NHSO4 (50 mg, 0.0015 mol) are dissolved in 500 ml CH2Cl2. 2,2,2-Trifluoroethanol (10.0 g, 0.01 mol) is added and the mixture is stirred and cooled in an ice-bath. Sodium hydroxide pellets (4.0 g, 0.01 mol) are dissolved in 100 ml of water and slowly added to the mixture with a dropping funnel. The temperature of the mixture is monitored. The rate of addition controlled to keep the temperature below 5° C. After addition is complete the mixture is stirred for an additional 2 h at 5° C. and then transferred to a separatory funnel. The organic layer is separated and dried with Na2SO4. The solvent is evaporated using a rotovap and the residual oil is fractionally distilled with a short path apparatus. The fraction with a boiling range of 105-108° C. contains the desired compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:19])[C:9]=1[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])=[CH:2][CH3:3].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:19][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]=[CH:2][CH3:3])[C:9]=2[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[O:11])[N:23]=1
Reactant: CC=Cc1cccc(O)c1C(=O)OCC[Si](C)(C)C
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC=Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OCC[Si](C)(C)C
Yield: 43.6 %

Procedure:
In a 50 ml round bottom-flask, there were charged 2-trimethylsilylethyl 6-(1-propenyl)salicylate (3.1 g, 11.0 mmol), 4,6-dimethoxy-2-methylsulfonylpyrimidine (2.4 g, 11.0 mmol), potassium carbonate (1.8 g, 13.0 mmol) and 10 ml of N,N-dimethylformamide (hereinafter referred to as "DMF"), and the resultant mixture was reacted for 1 hour at 80° C. After cooling the reaction mixture, DMF was distilled off under reduced pressure, and the residue thus obtained was dissolved in ethyl acetate, washed with water and a saturated salt water, dried with anhydrous sodium sulfate and concentrated. The resultant residue was purified by silica gel column chromatography to obtain 2.0 g (yield: 47.6%) of the aimed product (colorless transparent viscous liquid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH3:25][S:26][CH2:27][C:28]#[CH:29]>C(NCC)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:29]#[C:28][CH2:27][S:26][CH3:25])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C#CCSC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CSCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 5 h

Procedure:
A mixture of N-[(4-Chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example No. 5 (1.57 g), propargyl methyl sulfide (0.355 g, 4.12 mmol), copper iodide (0.125 g), and dichlorobis(triphenylphosphine)palladium (II) (0.462 g) in diethylamine (38 mL) are stirred at room temperature overnight. An additional 0.092 g of propargyl methyl sulfide is added, and the mixture is stirred another 5 h. The reaction mixture was then concentrated in vacuo, and the residue is suspended in water (100 mL) and extracted with three portions of EtOAc. The combined organic layers are then dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (elution with 5-10%MeOH/CH2Cl2) yielded the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:15])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[N+]([O-])=O.[OH-].[Na+].O.[CH2:19]([OH:22])[CH:20]=[CH2:21]>>[CH2:19]([O:22][C:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N+:4]([O-:15])=[CH:3][C:2]=1[CH3:1])[CH:20]=[CH2:21]
Reactant: Cc1c[n+]([O-])c2c(c1[N+](=O)[O-])CCCC2
Reactant: C=CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOc1c(C)c[n+]([O-])c2c1CCCC2
Reaction time: 3 h

Procedure:
2.0 Grams of 3-methyl-4-nitro-5,6,7,8tetrahydroquinoline-N-oxide was dissolved in allyl alcohol. Then 0.6 g of sodium hydroxide was added thereto, and the mixture was stirred at 70°-80° C. for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, to the residue thus obtained was added water, and was extracted with chloroform. The chloroform layer was washed with an aqueous solution saturated with sodium chloride, then dried with anhydrous magnsium sulfate. Chloroform was removed by evaporation under reduced pressure to obtain 1.4 g of 4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide in the form of brown oily substance.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Reaction time: 1.25 h
Yield: 87 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.3 g) in methylene chloride (40 ml) were added anisole (3.3 g) and trifluoroacetic acid (8.7 g) under ice-cooling with stirring, and the stirring was continued at ambient temperature for 75 minutes. After evaporation of the reaction mixture, to the residue was added water and ethyl acetate, followed by adjusting to pH 7 with a saturated aqueous solution of sodium bicarbonate. To the separated aqueous solution was added ethyl acetate, followed by adjusting to pH 2 with 10% hydrochloric acid. The ethyl acetate layer was separated out, washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a residue, which was washed with diethyl ether to obtain 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:23]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)=[CH:26][CH:25]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(OCCN2CCCCC2)cc1
Reactant: Nc1cc(Cl)cnc1N
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cnc2[nH]c(-c3ccc(OCCN4CCCCC4)cc3)nc2c1
Temperature: 80 °C
Yield: 3.4 %

Procedure:
5-Chloropyridin-2,3-diamine (0.200 g, 1.39 mmol) was dissolved in DMF (5 ml). Iron(III)chloride hexahydrate (0.025 g, 0.092 mmol) was added and the mixture heated to 80° C. 4-(2-Piperidin-1-ylethoxy)benzaldehyde (0.33 g, 1.41 mmol) dissolved in DMF (2 ml) was added dropwise, and the reaction mixture was heated at 120° C. for 5 h with air bubbling through the solution. The DMF was removed by evaporation and the solid residue was washed with 1M NaOH and diethyl ether. The crude product was purified by column chromatography (EtOAc/heptane, 1:1), giving the title product (0.017 g, 3%).
Reaction SMILES: [C:1]([S:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([F:11])[CH:5]=1)#[N:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1CCCCC1.C1(C)C=CC=CC=1>[C:1]([S:3][C:4]1[CH:10]=[C:9]2[C:7](=[C:6]([F:11])[CH:5]=1)[N:8]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]2[OH:14])#[N:2]
Reactant: N#CSc1ccc(N)c(F)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: CCOC(=O)c1cnc2c(F)cc(SC#N)cc2c1O
Temperature: 130 °C
Yield: 25.6 %

Procedure:
A mixture of 48 g of 4-(cyanosulfanyl)-2-fluoroaniline and 57.7 g of diethyl ethoxymethylenemalonate is stirred at 130° C. After 1.5 h the mixture is diluted with 200 mL of a 1:1 mixture of cyclohexane and toluene. The mixture is cooled to 0° C. and the precipitate collected by filtration. It is washed with two 75 mL portions of a 1:1 mixture of cyclohexane and toluene, dried in a stream of air, and then it dissolved in 400 mL of diphenyl ether. The mixture is refluxed for 1 h and then cooled to 25° C. It is diluted with 1 L of 1:1 toluene/cyclohexane and the precipitate collected by filtration. The solid is dried in a stream of air to give 20 g of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH:4]=[C:5]([C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][N:18]2[CH3:21])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH:5]([C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][N:18]2[CH3:21])=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNC(=O)C=C(c1ccccc1)c1ccc2ccn(C)c2c1
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNC(=O)CC(c1ccccc1)c1ccc2ccn(C)c2c1

Procedure:
N-Methyl-3-(1-methyl-1H-indol-6-yl)-3-phenyl-propionamide CXLV was prepared from N-Methyl-3-(1-methyl-1H-indol-6-yl)-3-phenyl-acrylamide using the procedure described above for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (Example 4).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.O.[C:27](OCC)(=[O:29])C.Cl>C[O-].[Na+].CN(C)C=O>[CH3:27][O:29][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCCCBr)cc2)cc1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
A solution of 4-[4-(8-Bromooctyloxy)phenyl]benzoic acid (1 g) in a mixture of sodium methylate (28% solution in methanol) (10 ml) and N,N-dimethylformamide (5 ml) was refluxed for 5 hours. The reaction mixture was added to a mixture of water and ethyl acetate and adjusted to pH 2.0 with conc. HCl. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-(8-Methoxyoctyloxy)phenyl]benzoic acid (0.77 g).
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.CO>C(#N)C>[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]([N:11]1[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][C@H:10]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](c2ccccc2)N1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)N1[C@@H](c2ccccc2)CC[C@H]1C(=O)OC(C)(C)C
Yield: 80.3 %

Procedure:
tert-Butyl (2S,5R)-1-(2-tert-butoxycarbonylaminoacetyl)-5-phenylprolinate may be obtained as per Example 2 B, but starting from a solution containing 8 g of tert-butyl (2S,5R)-5-phenylprolinate, 5.7 g of 2-tert-butoxycarbonylaminoacetic acid and 6.7 g of N,N'-dicyclohexylcarbodiimide in 75 cm3 of anhydrous acetonitrile. 10.5 g of tert-butyl (2S,5R)-1-(2-tert-butoxycarbonylaminoacetyl)-5-phenylprolinate, melting at 136° C., [α]D20 +19.1°±0.8° (C=0.64; methanol), are thus obtained.
Reaction SMILES: [CH2:1]([N:5]([CH2:41][CH2:42][CH2:43][CH3:44])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:16][CH:15]=2)=[C:8]([O:39][CH3:40])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[CH2:41]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][OH:21])=[CH:18][CH:19]=2)=[C:8]([O:39][CH3:40])[CH:7]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(CO)cc2)c(OC)c1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
In 50 ml of tetrahydrofuran was dissolved 3.9 g (6.44 mmol) of dibutyl[4-[2-[4-(tert-butyldiphenylsiloxymethyl)phenyl]vinyl]-3-methoxyphenyl]amine, and 20 ml of tetrabutylammonium fluoride (1 mol solution in tetrahydrofuran) was added dropwise thereto with stirring at room temperature. The mixture was stirred for 2.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.28 g of a yellow liquid (yield: 96.4%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f2) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[C:7]([C:14]([NH:16][CH3:17])=[O:15])[C:6]=2[CH:18]=1.CCN=C=NCCCN(C)C.[C:36](O)(=[O:38])[CH3:37]>CN(C=O)C>[C:36]([NH:13][NH:12][C:10]([C:8]1[O:9][C:5]2[CH:4]=[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:21])=[O:22])[C:2]([Br:1])=[CH:18][C:6]=2[C:7]=1[C:14]([NH:16][CH3:17])=[O:15])=[O:11])(=[O:38])[CH3:37]
Reactant: CC(=O)O
Reactant: CNC(=O)c1c(C(=O)NN)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C(=O)NNC(C)=O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
A mixture of compound 5-bromo-2-(hydrazinecarbonyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (210 mg, 0.50 mmol), EDCI (384 mg, 2.0 mmol) and acetic acid (60 mg, 1.0 mmol) in DMF (5 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue diluted with water, and the resulting solid was filtered to give the product 2-(2-acetylhydrazinecarbonyl)-5-bromo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (146 mg, yield: 63%). 1H-NMR (DMSO-d6, 400 MHz) δ 11.25 (br s, 1H), 10.22 (s, 1H), 9.68 (br s, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 3.20 (s, 3H), 3.17 (s, 3H), 2.83 (d, J=4.4 Hz, 3H), 1.92 (s, 2H). MS (M+H)+: 461/463.