Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[F:6][C:7]1[CH:8]=[C:9]([CH:11]=[C:12]([F:14])[CH:13]=1)[NH2:10]>Cl.O>[F:6][C:7]1[CH:13]=[C:12]([F:14])[CH:11]=[C:9]2[C:8]=1[CH:1]=[CH:2][C:3]([CH3:4])=[N:10]2
Reactant: Nc1cc(F)cc(F)c1
Reactant: C/C=C/C=O
Agent: Cl
Solvent: O
Product: Cc1ccc2c(F)cc(F)cc2n1
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
Crotonaldehyde (28 mL, 0.33 mol) was added dropwise to a refluxing solution of 3,5-difluoroaniline (10.75 g, 0.083 mol) in 5 N hydrochloric acid (450 mL) and reflux was continued for a further 0.5 h. Reaction mixture was cooled, diluted with water (200 mL) and washed with ether (200 mL). The aqueous layer was basified (pH 14) with 50% NaOH (aq) and extracted into MDC (3×200 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a dark oil which was purified by chromatography on silica gel (˜100 g) with 50-100% ethyl acetate in hexane gradient elution to give 5,7-difluoro-2-methylquinoline as a brown solid (6.57 g, 44%). A mixture of 5,7-difluoro-2-methylquinoline (1.0 g, 5.6 mmol) and sodium methoxide (1.69 g, 30 mmol) in methanol (50 mL), was stirred at reflux for 18 h, cooled, and most of the methanol removed in vacuo. The residue was partitioned between ethyl acetate (100 mL), and water (100 mL). The organic phase was dried (Na2SO4) and evaporated in vacuo to give a brown oil which was purified by chromatography on silica gel (˜60 g) with 20-30% ethyl acetate hexane gradient elution to give a yellow solid (0.57 g) which was suspended in 48% HBr (aq) (5 mL) and heated at reflux for 18 h. Reaction mixture was cooled and evaporated in vacuo to give the title compound as a brown solid (0.67 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5]([N+:27]([O-])=O)=[CH:4][CH:3]=1.[NH2:30][C:31]1[N:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CS(C)=O.CO>[NH2:30][C:31]1[C:32]([C:33]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[C:6]3=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=[C:5]3[N:27]=2)=[CH:35][CH:36]=[CH:37][N:38]=1
Reactant: Nc1ncccc1C=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Nc3nc(Cl)ccc3[N+](=O)[O-])cc2)CCC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Temperature: 100 °C
Yield: 21.2 %

Procedure:
To a suspension of tert-butyl (1-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}cyclobutyl)carbamate (10 g, 24 mmol) in DMSO/MeOH (4:1, 200 mL), were added 2-aminonicotinaldehyde (3.5 g, 29 mmol) and sodium dithionite (16 g, 93 mmol) and the mixture was heated for 48 h at 100° C. The mixture was poured into water and the solid was collected by filtration. The solid was purified by silica gel column chromatography (dichloromethane/ethyl acetate, 10:0 to 0:10) to give the titled compound as a white solid (2.5 g, 21%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].O.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24](Cl)=[O:25]>O1CCOCC1>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:25]
Reactant: NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 43 gm (20.1 millimols) of 4-[2-Aminoethyl]-4'-hydroxy-biphenyl in a mixture of 8.5 gm (21.3 millimols) of sodium hydroxide, 270 ml of water and 100 ml of dioxane, was acylated with 41.5 gm (20.1 millimols) of 2-methoxy-5-chloro-benzoyl chloride at 0° C. After stirring at room temperature for 2 hours, the mixture was extracted with chloroform, and the organic phase was dried over sodium sulfate. After distilling off the extracting agent, 72 gm (94% of theory) of a light yellow oil were obtained. This oil crystallized slowly and was uniform in the thin-layer chromatogram (silicagel; eluant: benzene/ethyl acetate = 7:2). After purification by column chromatography on silicagel with benzene/ethyl acetate as the eluant, the oil crystallized slowly. M.p. 169° C
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH:7]=[CH:6]2)[CH2:4][CH2:3][CH2:2]1>CC(=O)OCC.[Pd]>[CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C=CC2(CCCC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of spiro[4.5]dec-6-en-8-one (1.58 g, 10.5 mmol, prepared according to a literature procedure (N. R. Natale, R. O. Hutchins, Org. Prep. Proc. Int. 9 (1977) 103-108)) in EA (12 mL), Pd/C (75 mg, 10% Pd) is added. The mixture is stirred at rt under 1 bar of H2 for 90 min before it is filtered over celite. The solvent of the filtrate is evaporated to give spiro[4.5]decan-8-one (1.56 g) as an almost colourless liquid; 1H NMR (CDCl3): δ 2.36 (t, J=7.0 Hz, 4H), 1.75 (t, J=7.0 Hz, 4H), 1.70-1.65 (m, 4H), 1.62-1.50 (m, 4H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([NH:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1O>O1CCCC1>[CH:43]1[C:44]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[CH:41][C:42]=1[O:33][C:32](=[O:34])[C@H:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:22]
Reactant: Oc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1ccc2ccccc2c1
Reaction time: 12 h

Procedure:
6.2 g of dicyclohexylcarbodiimide are added to a solution of 7.8 g of tert.-butyoxycarbonyl-L-phenylalanine and 5.3 g of β-naphthol in 50 ml of absolute tetrahydrofurane at 0° C. and the reaction mixture was kept at 4° C. for 12 hours. The dicyclohexylurea which had precipitated was then separated off by filtration and the filtrate was evaporated to dryness in vacuo. The crystalline residue was recrystallised twice from ethyl acetate/cyclohexane and finally from acetonitrile. 8.5 g (73% of theory) of melting point 118°-119° C. were obtained.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[C:14]([S:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23]CC)=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[C:14]([S:19][C:20]([CH3:27])([CH3:26])[C:21]([OH:23])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C)Sc1ncccc1-c1ccc(C#N)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Sc1ncccc1-c1ccc(C#N)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 2-(3-(4-cyanonaphthalen-1-yl)pyridin-2-ylthio)-2-methylpropanoate (121 mg, 0.32 mmol) in a mixture of aqueous sodium hydroxide solution (1M, 2 mL) and methanol (5 mL) was stirred at room temperature for 5 hours. Methanol was partially removed and the resulting residue acidified causing precipitation of the product 2-(3-(4-cyanonaphthalen-1-yl)pyridin-2-ylthio)-2-methylpropanoic acid. Solid product was isolated by filtration and dried under vacuum (0.065 g, 0.187 mmol, 60%).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:8]3[C:7]([OH:22])=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[N:11]=[CH:10][C:9]=3[N:12]=2)=[CH:20][CH:19]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(F)cc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccc(F)cc3)sc2c1O
Temperature: 120 °C
Yield: 76 %

Procedure:
A mixture of 2-(4-fluoro-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (81 mg, 0.25 mmol) and glycine (190 mg, 5.07 mmol) in 0.5 M sodium methoxide/methanol (4.0 mL) was heated at 120° C. using a CEM microwave reactor for 1H before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (50 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a brown solid (66 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.28 (br s, 1H), 9.44 (br s, 1H), 8.91 (s, 1H), 8.21 (m, 2H), 7.45 (m, 2H), 4.03 (d, J=6.2 Hz, 2H); MS: (+) m/z 348.00 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21](N=[N+]=[N-])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]>C(O)C.[C].[Pd]>[CH2:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:20][CH:19]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(N=[N+]=[N-])c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(Cc2ccccc2)cc1
Reaction time: 6 h
Yield: 98.3 %

Procedure:
[4-(2-Ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)phenyl]phenylmethylazide (0.580 g, 1.46 mmol) obtained in Step 1 was dissolved in ethanol (30 mL), and the flask was filled with argon. 10% Palladium-carbon (50% wet, 0.311 g) was added to the solution, followed by stirring for 6 hours under hydrogen atmosphere. The unsoluble material was filtered out through Celite, and washed with ethanol. The filtrate was combined and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether-hexane to obtain Compound 4 (0.510 g, yield 94%).
Reaction SMILES: [C:1]([C:3]1[C:8]2[NH:9][C:10]3[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:14][C:15]=3[C:7]=2[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[C:35](=[O:36])[C:34]4[C:29](=[C:30]([F:37])[CH:31]=[CH:32][CH:33]=4)[N:28]=[CH:27]3)[C:21]=2[CH3:38])=[N:5][CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:40]>>[CH3:19][O:18][C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:7]3[C:6]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[C:35](=[O:36])[C:34]6[C:29](=[C:30]([F:37])[CH:31]=[CH:32][CH:33]=6)[N:28]=[CH:27]5)[C:21]=4[CH3:38])=[N:5][CH:4]=[C:3]([C:1](=[O:40])[NH2:2])[C:8]=3[NH:9][C:10]=2[CH:11]=1)=[O:17]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)cnc(-c3cccc(-n4cnc5c(F)cccc5c4=O)c3C)c12
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cnc(-c3cccc(-n4cnc5c(F)cccc5c4=O)c3C)c12
Temperature: 60 °C

Procedure:
A stirred mixture of methyl 4-cyano-1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate (0.172 g, 0.342 mmol) and 90% aqueous Sulfuric acid (2.000 ml, 36.8 mmol) was heated at 60° C. for 15-30 minutes. LC-MS showed complete conversion to the desired product plus the corresponding carboxylic acid as a minor product. The reaction mixture was cooled to 0° C. and carefully neutralized to approx. pH=5-6 with 50% NaOH solution then stirred overnight. The reaction mixture was filtered and the residue dried under vacuum overnight to give methyl-4-carbamoyl-1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate as a tan solid. [0.143 g, 0.274 mmol, 80% yield] The product had an HPLC Retention Time=2.798 minutes[mixture of isomers] [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 522.4.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C(C)=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Yield: 72.8 %

Procedure:
Under a nitrogen atmosphere, a xylene solution (65 mL) of tert-butyl 4-amino-piperidine-1-carboxylate (1.00 g, 5.00 mmol), 4-bromo-1-fluorobenzene (0.500 mL, 4.57 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (360 mg, 1.00 mmol), and tris(dibenzylideneacetone)dipalladium (0) (209 mg, 0.250 mmol) was stirred at 140° C. for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate=100/0→70/30 (v/v)) to obtain the title compound (980 mg, yield 66%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.[ClH:26].O>O1CCOCC1>[Cl:26][CH2:14][CH2:13][C:12](=[O:15])[C@@H:11]1[C@:16]2([CH3:25])[C@H:8]([C@H:7]3[C@H:19]([C:18](=[O:24])[CH2:17]2)[C@:20]2([CH3:23])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:22][CH2:21]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: Cl
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: C1COCCO1
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCCl)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 2 h

Procedure:
3α-Hydroxy-21-methylene-5α-pregnane-11,20-dione (500 mg) was dissolved in dioxan (40 ml) and dry hydrogen chloride passed through the solution for 1 hour. The mixture was left to stand for a further 2 hours, then poured into water and the sticky solid extracted into ether. The extracts were washed with saturated sodium bicarbonate, water and then dried over anhydrous sodium sulphate. After evaporation and trituration of the resulting foam with ether/petrol the title compound (375 mg) was obtained as a white solid. m.p. 110°-112° with gas evolution [α]D + 100° (c = 1.06).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[OH:25])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([C:6]1[CH:7]=[C:8]([C:9](=[O:10])[CH2:22][CH2:23][CH2:18][C:19]([C:22]2[CH:21]=[C:20]([CH3:24])[C:19]([OH:25])=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:23]=2)=[O:25])[CH:21]=[C:20]([CH3:24])[C:5]=1[OH:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: O=C(Cl)CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(=O)CCCC(=O)c2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
27 g (200 mmol) of aluminium chloride, 6.5 ml (50 mmol) of glutaric acid chloride and 250 ml of methylene chloride are initially introduced into a 500 ml three-necked round-bottomed flask. The suspension is cooled to -60° C. and a solution of 18 g (110 mmol) of 2-tert-butyl-6-methylphenol in 30 ml of methylene chloride is added dropwise in the course of about 30-40 minutes. The hydrochloric acid gas which evolves is collected in water. The reaction mixture is stirred at -50° C. for 30 minutes and is then poured onto ice. After addition of 20 ml of concentrated hydrochloric acid, the mixture is stirred for about 10 minutes. The phases are separated and the organic phase is dried over sodium sulfate and freed from the solvent on a rotary evaporator. The 20 g of crude product thus obtained are purified by column chromatography (SiO2, toluene/ethyl acetate 19:1). 12 g (56% of theory) of 1,5-di(3'-tert-butyl-5'-methyl-4'-hydroxyphenyl)-1,5-pentanedione of melting point 156°-158° C. result. The vibration band of the CO groups in the infra-red spectrum appears at 1663.7 cm-1.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[C:17](=[O:18])[N:16]([CH3:19])[C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[C:13]([C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH2:31])=[CH:26][CH:25]=2)=[N:12]1)C1C=CC=CC=1.Br>>[NH2:10][CH:11]1[C:17](=[O:18])[N:16]([CH3:19])[C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[C:13]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH2:31])=[O:32])=[CH:28][CH:29]=2)=[N:12]1
Reactant: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccc(C(N)=O)cc2)c2ccccc21
Agent: Br
Product: CN1C(=O)C(N)N=C(c2ccc(C(N)=O)cc2)c2ccccc21
Temperature: 0 °C
Yield: 79.3 %

Procedure:
To the product from Step 2C (400 mg, 0.9 mmol.) was added hydrogen bromide (45 wt % in acetic acid, 2 ml) and the mixture stirred until dissolution was complete (30 minutes). After this time, the orange solution was poured into ice cold ether (20 ml) and vigorously stirred for 10 minutes. The resulting precipitate was filtered and washed with cold ether to give the title compound (220 mg, 80%) as the hydrobromide salt.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][OH:13]>S(=O)(=O)(O)O.[Pd]>[CH3:12][O:13][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([NH2:9])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1ccc(C)c([N+](=O)[O-])c1
Reactant: CO
Agent: [Pd]
Agent: O=S(=O)(O)O
Product: COc1cc(C)c(N)cc1C
Yield: 66 %

Procedure:
2,5-Dimethylnitrobenzene, (46.8 ml, 0.35 mol) was dissolved in sulfuric acid (47.1 ml)/methanol (650 ml) and then 5% palladium on carbon (50% hydrate, 0.35 g) was added. The mixture was allowed to react for 3 hours under hydrogen atmosphere at the pressure of 5 atms at 40° C. After cooling, the catalyst was removed, and methanol was removed under reduced pressure. The residue was poured into a 25% aqueous ammonia solution with cooling on ice, and extracted with toluene. The extract was washed with 5% sodium hydrosulfite, dried over sodium sulfate and purified by column chromatography on a small amount of silica gel (toluene:ethyl acetate=1:1). The solvent was removed under reduced pressure and crystallization from hexane yielded 35.0 g of the title compound.
Reaction SMILES: FC(F)C1NC2C=CC=CC=2N=1.FC(F)C1NC2C(O[SiH3])=C(C(C)(C)C)C(C)=C(C)C=2N=1.[F:33][CH:34]([F:72])[C:35]1[N:39]([C:40]2[N:45]=[C:44]([N:46]3[CH2:51][CH2:50][O:49][C@@H:48]([CH3:52])[C@H:47]3[CH3:53])[N:43]=[C:42]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)[N:41]=2)[C:38]2[CH:60]=[CH:61][C:62]([O:64][Si](C(C)(C)C)(C)C)=[CH:63][C:37]=2[N:36]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[F:72][CH:34]([F:33])[C:35]1[N:39]([C:40]2[N:45]=[C:44]([N:46]3[CH2:51][CH2:50][O:49][C@@H:48]([CH3:52])[C@H:47]3[CH3:53])[N:43]=[C:42]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)[N:41]=2)[C:38]2[CH:60]=[CH:61][C:62]([OH:64])=[CH:63][C:37]=2[N:36]=1
Reactant: C[C@@H]1OCCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4cc(O[Si](C)(C)C(C)(C)C)ccc43)n2)[C@@H]1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1c(C(C)(C)C)c(O[SiH3])c2[nH]c(C(F)F)nc2c1C
Agent: FC(F)c1nc2ccccc2[nH]1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1OCCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4cc(O)ccc43)n2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
In accordance with the procedure of the Example 4 except that 2-difluoromethylbenzimidazole in (1) of the Example 4 was replaced by 2-difluoromethyl-5-tert-butyldimethyl-silyloxybenzimidazole, obtained was 2-(2-difluoromethyl-5-tert-butyldimethylsilyloxybenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine. 120 mg (0.22 mmol) of the obtained compound dissolved in THF (2 ml) was added with a solution of tetrabutylammoniumfluoride (1 M) in THF (0.5 ml) and stirred at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 75 mg (yield: 79%) of the titled compound as colorless crystals.
Reaction SMILES: C([C:4]1[S:8][C:7]2[S:9][C:10]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:11][C:6]=2[CH:5]=1)(O)=O.C>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.[Cu]>[S:9]1[C:7]2[S:8][CH:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[C:12]([C:14]1[CH:15]=[C:16]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: CC(C(=O)O)c1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Agent: [Cu]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CC(C(=O)O)c1cccc(C(=O)c2cc3ccsc3s2)c1
Temperature: 250 °C
Yield: 61 %

Procedure:
2-{3-(5-Carboxy-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionic acid (14 g), copper powder (1.5 g) and copper turnings (1.5 g) are suspended in diphenyl ether (60 cc) and heated at 250° C. for 30 minutes. After cooling, the reaction mixture is diluted with methylene chloride (100 cc), decolourizing charcoal (1 g) is added and the mixture is filtered. The filtrate is extracted three times with a 10% (w/v) aqueous solution of sodium carbonate (total 150 cc), and then washed twice with distilled water (total 100 cc). The combined aqueous phases are acidified to pH 1 by the addition of 12 N concentrated hydrochloric acid and extracted four times with methylene chloride (total 200 cc). The combined methylene chloride solutions are washed three times with distilled water (total 90 cc), dried over anhydrous sodium sulphate and evaporated. Crude 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionic acid (7.5 g) in the form of an oil is thus obtained.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:3][CH:2]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: COC(=O)CCNC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCNC(=O)[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of (R)-tert-butyl 3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoate (40 mg, 0.094 mmol) in DCM (0.5 mL), TFA (0.15 mL) is added at room temperature. The mixture is allowed to stir for 2 hours, and then concentrated under reduced pressure to give (R)-3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoic acid (33.5 mg, 96%). HPLC retention time=1.20 minutes (condition A); MS (m+1)=370.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.21-2.29 (m, 1 H) 2.38-2.45 (m, 1 H) 2.62-2.66 (m, 1 H) 2.75-3.00 (m, 4 H) 3.29-3.37 (m, 1 H) 3.45-3.53 (m, 4 H) 6.12 (br s, 1 H) 7.23 (d, J=8 Hz, 2 H) 7.32-7.35 (m, 1 H) 7.41-7.45 (m, 2 H) 7.53 (d, J=8.1 Hz, 2 H) 7.56-7.59 (m, 2 H).