Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[O:28]1[CH2:33]CC(O)[CH2:30][CH2:29]1>>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:30][CH2:29][O:28][CH2:33][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCOCC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Product: O=C(OC1CCOCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
A mixture of 3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 mg of powdered potassium cyanide and 10 g (100 mmol) of tetrahydro-2H-pyran-4-ol is heated at 140° for 20 hours, whereupon the excess tetrahydro-2H-pyran-4-ol is distilled off and the residue is taken up in chloroform. The solution is washed with water, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate there is obtained tetrahydro-2H pyran-4-yl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 226°-227°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=O.CC(OC(C)=O)=O>>[CH2:16]([O:15][C:11](=[O:14])/[CH:12]=[CH:1]/[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[CH3:17]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)C=O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)/C=C/c1ccc(C(=O)O)cn1
Temperature: 130 °C
Yield: 145.7 %

Procedure:
6-Methylnicotinic acid (5 g, 36 mmol) and ethyl glyoxalate (50% solution in toluene—8.7 mL, 44 mmol) were added to Ac2O (25 mL) and stirred under a nitrogen atmosphere. The reaction was heated at 130° C. for 3 h then allowed to cool to RT over 17 h. The reaction was then quenched with water (10 mL) and concentrated to dryness in vacuo to afford the product as a brown solid (11.6 g, >100%). m/z=222 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[O:5].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(Cl)cc1)NC(c1ccccc1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[phenyl-(4-trifluoromethyl-phenyl)-methyl]-acetamide hydrochloride (example 3.2) and 4-chlorobenzoic acid.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:21])[NH2:20]>[Ni].[Pd]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][N:18]([CH2:2][CH:3]([OH:4])[CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[C:19](=[NH:20])[NH2:21]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: [Ni]
Agent: [Pd]
Product: N=C(N)N(CCC[C@H](NCC(O)C(O)C(O)C(O)CO)C(=O)O)CC(O)C(O)C(O)C(O)CO

Procedure:
The manufacture took place by reductive amination of D-glucose and L-(+)-arginine in the molar ratio 2:1 using Raney nickel or palladium/activated carbon (10%) as a catalyst in the temperature range from 50° to 70° C. As a reaction product a light-yellow resin was obtained.
Reaction SMILES: [CH3:1][N:2]([S:25]([CH3:28])(=[O:27])=[O:26])[C:3]1[CH:4]=[C:5]([C:21]([O:23]C)=[O:22])[C:6]2[CH2:7][CH2:8][N:9]([CH:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10](=[O:13])[C:11]=2[CH:12]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][N:2]([S:25]([CH3:28])(=[O:26])=[O:27])[C:3]1[CH:4]=[C:5]([C:21]([OH:23])=[O:22])[C:6]2[CH2:7][CH2:8][N:9]([CH:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10](=[O:13])[C:11]=2[CH:12]=1
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(N(C)S(C)(=O)=O)cc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCC(CCC)N1CCc2c(C(=O)O)cc(N(C)S(C)(=O)=O)cc2C1=O
Yield: 96.5 %

Procedure:
0.25 g of methyl 7-[methyl(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate is dissolved in 5 cm3 of dioxane at a temperature close to 20° C. 1.52 cm3 of a 1M aqueous solution of sodium hydroxide are added, then the reaction mixture is heated at a temperature close to 60° C. for 1 h. The dioxane contained in the reaction mixture is concentrated using a rotary evaporator under reduced pressure (5 kPa). 20 cm3 of ethyl ether and 10 cm3 of water are added to the residue obtained. After decanting, the aqueous phase is acidified with 1.6 cm3 of a 1M aqueous solution of hydrochloric acid. The aqueous phase is extracted with 20 cm3 of dichloromethane. After decanting, the organic phase is dried over magnesium sulfate, filtered then concentrated using a rotary evaporator under reduced pressure (5 kPa). 0.233 g of 7-[methyl(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid is obtained in the form of a pale pink powder.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][O:16]2)([C:12]#[N:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].N.O>CO.[Ni]>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:12][NH2:13])([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][O:16]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(C#N)(CC2CCCO2)CC1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)N1CCC(CN)(CC2CCCO2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a heavy wall flask was placed 1-(ethylsulfonyl)-4-(tetrahydrofuran-2-ylmethyl)piperidine-4-carbonitrile (15, 2 g, 6.98 mmol) and 2N ammonia in methanol (50 ml). To this was added commercially available Raney nickel slurry in water (1.8 g, 20.94 mmol) and the solution agitated under hydrogen atmosphere (45 psi) at room temp for 12 hours. The catalyst was filtered off using celite and washed with MeOH (200 ml) and the combined organics concentrated in vacuo to give 1-[1-(ethylsulfonyl)-4-(tetrahydrofuran-2-ylmethyl)piperidin-4-yl]methanamine (16) as a clear semi-solid. MS 291 (M+1)
Reaction SMILES: [N:1]1([C:14]([O:16][CH2:17][CH:18]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:13][C@H:7]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.ClCCl>[N:1]1([C:14]([O:16][CH2:17][CH:18]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:13][C@H:7]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])[CH2:6][C@H:2]1[C:3]([O:5][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)O[C@@H]1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reaction time: 1 h

Procedure:
65 mmol of N,N-dicyclohexylcarbodiimide are added to a mixture containing 61 mmol of Fmoc-Hyp(tBu)-OH, 65 mmol of benzyl alcohol and 27 mmol of 4-dimethylaminopyridine in 150 ml of dichloromethane cooled on an ice bath. After one hour at 0° C., the mixture is adjusted to room temperature and left stirring for 18 hours. The dicyclohexylurea precipitate is filtered and the filtrate is evaporated. The residual oil is taken up in ethyl acetate. The solution is washed with 5% sodium bicarbonate, with 5% citric acid and then with a saturated sodium chloride solution. After drying and evaporation, the expected product is obtained in the form of an oil.
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.[CH2:24]([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH3:28].N12CCCN=C1CCCCC2>CN(C)C=O>[CH2:24]([S:29]([NH:32][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([N:2]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH3:1])[CH:4]=1)(=[O:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CN(Cc1ccc(Cl)cc1Cl)c1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CCCCCS(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(N(C)Cc2ccc(Cl)cc2Cl)c1
Reaction time: 1 h
Yield: 51.8 %

Procedure:
N,N′-carbonyldiimidazole (0.776 g) was added to a mixture of 0.85 g of 3-(N-methyl-2,4-dichlorobenzylamino)-4-nitrobenzoic acid and 10 ml N,N-dimethylformamide at room temperature, and the mixture was stirred for 1 hour. 1-Pentanesulfonamide (0.724 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.729 g) were then added thereto, and the resulting mixture was stirred at 100° C. for 21 hours. The mixture was concentrated, and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with water, concentrated, and purified by silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 1:1 to 0:1). The desired fractions were collected and concentrated. The concentrate was re-dissolved in ethyl acetate, washed twice with diluted hydrochloric acid and subsequently with a solution of sodium hydrogen carbonate. The organic layer was dried and concentrated to give 0.605 g of N-(n-pentanesulfonyl)-3-(N-methy-2,4-dichlorobenzylamino)-4-nitrobenzamide. This product was used immediately in the next reaction step.
Reaction SMILES: [NH2:1][C@@H:2](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:21]#[C:22]Br.N>CO>[N+:13]([C:10]1[CH:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C@H:2]2[CH2:3][O:4][C:22]([NH2:21])=[N:1]2)=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: N[C@@H](/C=C/c1ccc([N+](=O)[O-])cc1)CO
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC1=N[C@@H](/C=C/c2ccc([N+](=O)[O-])cc2)CO1
Reaction time: 48 h
Yield: 33.9 %

Procedure:
To a solution of (E)-(S)-2-amino-4-(4-nitro-phenyl)-but-3-en-1-ol (2.5 g) in methanol (90 ml) at room temperature was added sodium acetate (3.0 g) followed by a solution of cyanogen bromide (1.65 g) in methanol (10 ml) dropwise over 15 minutes. The reaction mixture was stirred for 2 days, then 25% aqueous ammonia (8.2 ml) was added and the solution stirred for 1 hour at room temperature. The solvent was evaporated in vacuo and the residue purified by Isco chromatography (column: Silicycle Si-Amine, AcOEt) to give (S)-4-[(E)-2-(4-nitro-phenyl)-vinyl]-4,5-dihydro-oxazol-2-ylamine (950 mg) as a yellow oil. MS (ISP): 234.1 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)(=[O:4])[CH:2]=[CH2:3].[Cl:13][C:14]1[S:18][N:17]=[C:16]([OH:19])[CH:15]=1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[S:18][N:17]([CH2:3][CH2:2][C:1]([C:5]2[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=2)=[O:4])[C:16](=[O:19])[CH:15]=1
Reactant: C=CC(=O)C1=CC(=O)C=CC1=O
Reactant: Oc1cc(Cl)sn1
Solvent: Cc1ccccc1
Product: O=C1C=CC(=O)C(C(=O)CCn2sc(Cl)cc2=O)=C1

Procedure:
A stirred solution of 2-acryloyl-1,4-benzoquinone (1.0 g, 0.007 mole) and 5-chloro-3-hydroxyisothiazole (0.81 g, 0.006 mole) in 20 ml of toluene was heated at 80° C. for 4 hours. Upon cooling, the precipitate which formed during the reaction period was removed by filtration and recrystallized from ethyl acetate/acetone mixture. A gray/tan solid was obtained; 0.85 g; mp 181°-183° C.; IR (KBR) 1635 cm-1 (broad); NMR (acetone-d6) δ7.35 (s, 1H); 7.15 (d, 1H); 6.85 (d, 1H); 6.35 (s, 1H); 4.2 (t, 2H); 3.52 (t, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[N:12][NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:26]1CCOCC1>COCCOC>[C:1]1([CH2:7][C:8](=[N:12][NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[C:9]([NH2:26])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)C(Cc1ccccc1)=NNc1nc(-c2ccccc2)cs1
Solvent: COCCOC
Product: NC(=O)C(Cc1ccccc1)=NNc1nc(-c2ccccc2)cs1
Reaction time: 0.33 h

Procedure:
To a solution of 3-Phenyl-2-[(4-phenyl-thiazol-2-yl)-hydrazono]-propionic acid (4b) (1.0 mmol, 337 mg) in DME (5 mL) at −15° C., were added NMM (1.1 mmol, 121 μL), then IBCF (1.1 mmol, 147 μL). Then, a solution of NH4OH concentrated was added and the mixture was stirred for 20 minutes. 5 mL of water was added and the precipitate was filtered and washed with H2O and hexane to give the desired product.
Reaction SMILES: [O:1]=[C:2]([N:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:3][NH:4][C:5]1[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1.[C:29](Cl)(=[O:34])[CH2:30][C:31](Cl)=[O:32]>C1COCC1>[O:1]=[C:2]([N:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:31](=[O:32])[CH2:30][C:29]1=[O:34]
Reactant: O=C(CNc1ccccc1Nc1ccccc1)N1CCCCc2ccccc21
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: O=C(CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 100 mL of THF at 0° C. was added dropwise over 20 min simultaneously a solution of 8.0 g of the N1-[2-oxo-2-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)ethyl]-N2-phenylbenzene-1,2-diamine (8.0 g, 21.5 mM) in 100 mL of THF and solution of malonyl dichloride (2.40 mL, 25.8 mM) in 100 mL of THF. The resulting solution was stirred at RT for 20 h and the solvent removed in vacuo. The resultant material was purified by silica gel flash column chromatography using hexanes/EtOAc 1/1 and the combined filtrates evaporated in vacuo to give 7.5 g of product.
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([S:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)OC2=O)=CC=1>CS(C)=O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([S:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1ccc(N2C[C@H](CN3CCC(Sc4ccc(C(C)(C)C)cc4)CC3)OC2=O)cc1
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(SC2CCNCC2)cc1

Procedure:
3-p-methoxyphenyl-5(S)-[(4-p-tertbutylphenylthiopiperidino)methyl]-2-oxazolidinone (hydrochloride), m.p. 231°-234°; [α]D =-30.9° (DMSO);
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([CH3:16])[CH3:15].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH3:15][C:8]1([CH3:16])[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([O:4][CH2:3][CH2:2][N:31]3[CH2:32][CH2:33][N:28]([CH2:27][C:18]4[CH:19]=[CH:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:17]=4)[CH2:29][CH2:30]3)[CH:6]=2)[NH:10][C:9]1=[O:14]
Reactant: c1ccc2nc(CN3CCNCC3)ccc2c1
Reactant: CC1(C)C(=O)Nc2ccc(OCCCl)cc21
Solvent: ClC(Cl)Cl
Product: CC1(C)C(=O)Nc2ccc(OCCN3CCN(Cc4ccc5ccccc5n4)CC3)cc21
Temperature: 150 °C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
5-(2-Chloroethoxy)-3,3-dimethyl-2,3-dihydroindol-2-one (182 mg, 3.0 mmol) and N--(2-quinolylmethyl)piperazine (690 mg, 3.0 mmol) were mixed, followed by stirring at 150° C. for 3 hours under an argon gas stream. The resulting mixture was allowed to cool down, and was then dissolved in chloroform. The thus-obtained solution was washed with water and then dried over anhydrous sodium sulfate. After the solution was concentrated under reduced pressure, the residue was purified by chromatography on a silica gel column while using chloroform-methanol (10:1) as an eluent. Fractions containing the target compound were collected and then concentrated under reduced pressure. The concentrate was crystallized from n-hexane and was then recrystallized from ethyl acetate-ethyl ether, whereby 240 mg of the title compound were obtained as pale yellow powder (yield: 73%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:18])[CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1)([OH:3])=[O:2]>O>[CH3:18][CH:13]1[CH2:14][C:15](=[O:17])[C:9]2[CH:10]=[C:5]([CH2:4][C:1]([OH:3])=[O:2])[CH:6]=[CH:7][C:8]=2[CH2:11][CH2:12]1
Reactant: CC(CCc1ccc(CC(=O)O)cc1)CC(=O)O
Solvent: O
Product: CC1CCc2ccc(CC(=O)O)cc2C(=O)C1

Procedure:
17.8 g of 5-(4-carboxymethylphenyl)-3-methylvaleric acid are added at 100°, while stirring, to 200 g of polyphosphoric acid. The reaction mixture is stirred at 100° for a further hour, is cooled to about 60°, and 100 cc of water are added dropwise thereto. The reaction mixture is then poured on ice, extracted with methylene chloride, the methylene chloride extract is washed with water and dried over sodium sulphate. The 6,7,8,9-tetrahydro-7-methyl-9-oxo-5H-benzocycloheptene-2-acetic acid, obtained after concentrating the solvent, is purified by chromatography on silica gel. The title compound has a M.P. of 105°-107° (from acetonitrile). The cyclohexylammonium salt form of the title compound has a M.P. of 135°-137° (from acetonitrile).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.C(N(CC)CC)C.C(O)C=[C:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH:27]=[CH:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:5]([O:4][CH2:2][CH:1]=[C:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH:27]=[CH:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1)(=[O:6])[CH3:7]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=CCO)CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC=C1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
0.24 ml of acetanhydride, 0.36 ml of triethylamine and 50 mg of 4-dimethylaminopyridine are added to 400 mg of the pregna-1,4,17(20)-triene-21-ol-3-one produced in accordance with Example 1 in 10 ml of absolute methylene chloride, followed by stirring for 30 minutes at 0° C. A thin-layer chromatogram shows that the reaction is quantitative after this period. The reaction solution is successively washed with ice-cold dilute HCl, NaHCO3 solution and finally with water. The CH2Cl2 phase is dried over Na2SO4, the drying agent is filtered off and the residue is concentrated to dryness. The residue is substantially pure product in a yield of more than 90%. 1H-NMR (80 MHz, COCl3 ; δ-value):
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[CH3:13]>[C].[Pd].C(O)C>[F:1][CH:2]([F:14])[O:3][C:4]1[C:5]([CH3:13])=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10]
Reactant: Cc1c(OC(F)F)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cccc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A mixture of the above-prepared 1-difluoromethoxy-2-methyl-3-nitrobenzene (described in Reference Preparation example 3) 7.50 g, palladium-carbon (palladium 5%) 0.8 g and ethanol 80 ml was stirred at room temperature under hydrogen atmosphere for eight hours. The reaction mixture was filtered and the filtrate was concentrated to give 3-difluoromethoxy-2-methylaniline 6.4 g.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([C:18](=[O:32])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:13]=2[CH3:33])=[CH:8][CH:7]=1)=[O:5])C>C1COCC1.[OH-].[Na+]>[CH3:33][C:13]1[CH:14]=[CH:15][C:16]([C:18](=[O:32])[NH:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[CH:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2cc(C(=O)Nc3ccc(N4CCOCC4)cc3)ccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
2′-Methyl-5′-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-carboxylic acid ethyl ester (0.89 g) in THF (10 ml) and 0.5M NaOH (15 m) was heated to 100° C. for 3 hours then cooled to room temperature. THF was evaporated and the residue extracted with dichloromethane. The aqueous layer was acidified to pH 1 and a grey solid precipitated which was collected by filtration and dried (0.74 g).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:15][CH2:14][CH2:13][C@H:10]1[CH2:11][OH:12])=[O:8].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>C(#N)C.C1(C)C(S(O)(=O)=O)=CC=CC=1.N1C=CC=CC=1>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:15][CH2:14][CH2:13][C@H:10]1[CH2:11][O:12][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1)=[O:8]
Reactant: C1=COCCC1
Reactant: O=C1CC[C@@H](C(=O)N2CCC[C@H]2CO)N1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C1CC[C@@H](C(=O)N2CCC[C@H]2COC2CCCCO2)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 109.9 %

Procedure:
The thus obtained L-pyroglutamyl-L-prolinol (110 g, 0.519 mol) and dihydropyran (220 g, 2.62 mol) are dissolved in acetonitrile (2.75 l), and pyridine toluenesulfonate (11 g) is added under water-cooling. The mixture is stirred at room temperature for two days, and the reaction liquid is concentrated under reduced pressure, dissolved again in methylene chloride (1.5 l) and washed successively with 5% potassium carbonate (1 l) and water (1 l). The methylene chloride layer is dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to dryness under reduced pressure to give N-pyroglutamyl-O-tetrahydropyranyl-L-prolinol (169 g, 110%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][NH2:22])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O>[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][NH:22][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH3:19]
Reactant: CCCCC(CC)CN
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCC(CC)CNc1nc(C)[nH]c2cc(-c3ccccc3)nc1-2
Yield: 62.5 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70.0 mg, 0.29 mmol), 2-ethylhexylamine (Aldrich Chemical Company) (0.24 mL, 1.44 mmol) and K2CO3 (0.40 g, 2.87 mmol) in H2O (2 mL) to give 61 mg (63%) of the title compound as a white solid. An analytical sample was obtained by recrystallization from i-PrOH. Mp: 288-289° C. (dec.).1H NMR (CDCl3; 500 MHz): δ 0.72-0.78 (m, 6), 1.15-1.34 (m, 9), 2.62 (s, 3), 3.56 (dd, 2, J=5.3, 7.6), 6.71 (s, 2), 7.17-7.24 (m, 3), 7.59 (d, 2, J=7.6), 12.78 (br s, 1). MS m/z: 337 (M+1), 335 (M−1). HRMS: Calcd for M+H: 337.2392. Found: 337.2397.