Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3].[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][CH:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3]
Reactant: CC(Cl)c1nc2ccccc2[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(C)c1nc2ccccc2[nH]1

Procedure:
2-(1-chloroethyl)-1H-benzo[d]imidazole (0.39 g) and 25 wt % solution of Sodium Methoxide in Methanol (0.96 mL) in 10 mL of Methanol was heated for 20 minutes at 150° C. in a microwave synthesizer. The reaction mixture was extracted with EtOAc and sat NH4 chloride. The organic layer was dried, filtered and concentrated to afford crude 2-(1-methoxyethyl)-1H-benzo[d]imidazole in quantitative yield.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:15][CH2:16][C:11]=2[C:10]([NH2:25])=[N:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].ClC[CH2:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:39][CH2:38]1)=O>>[NH2:25][C:10]1[C:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:13](=[O:24])[C:12]=2[N:8]([C:6](=[O:5])[CH2:34][CH2:35][N:37]2[CH2:42][CH2:41][N:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:39][CH2:38]2)[N:9]=1
Reactant: Cc1ccc(N2CCc3c(N)nn(C(=O)OC(C)(C)C)c3C2=O)cc1
Reactant: O=C(CCCl)N1CCN(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(c5ccccc5)CC4)c3C2=O)cc1

Procedure:
A target compound (77.8 mg, 0.169 mmol, 44.7%) was yielded as liquid in the same manner as Example 1 by reacting 1-N-t-butoxycarbonyl-3-amino-4,5,6,7-tetrahydro-6-N-(p-tolyl)pyrazolo[3,4-c]pyridin-7-one (130 mg, 0.379 mmol) with potassium carbonate (57.6 mg, 0.417 mmol) and 3-chloro-1-(4-phenylpiperazin-1-yl)propan-1-one (100.6 mg, 0.398 mmol).
Reaction SMILES: O.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([OH:13])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1.CN(C)C=O.O.ON1C2C=CC=CC=2N=N1>O>[NH:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]=[C:3]1[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1)=[O:13]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3nc4ccccc4[nH]3)cc2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.1 %

Procedure:
1H-Benzimidazole-2-carboxylic acid monohydrate (14 mg, 0.077 mmol), 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (23 mg, 0.072 mmol) obtained in Example 1, (3), dimethylformamide (1.4 mL), and 1-hydroxybenzotriazole monohydrate (11 mg, 0.08 mmol) were mixed, and the mixture was stirred at room temperature for 3 hours. This reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogencarbonate, and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), and then recrystallized from ethyl acetate/hexane to give the title compound (15 mg, yield 43%) as slightly yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([SH:9])[N:3]=1.CN1C(=O)CCC1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>[OH-].[Na+]>[C:18]1([CH2:17][S:9][C:4]2[N:5]=[C:6]([OH:8])[CH:7]=[C:2]([OH:1])[N:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(O)nc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Oc1cc(O)nc(SCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4,6-dihydroxy-2-mercaptopyrimidine (100 g) in 5M NaOH (360 ml) was added first NMP (200 ml), then benzyl bromide (90 ml) dropwise over 2 hours. The reaction was stirred at room temperature for 24 hours, then acidified to pH 2 with conc HCl (100 ml) added dropwise over 2 hours at −5° C. to give a pink precipitate. This was isolated by decanting off the solution followed by trituration with diethyl ether (1 liter) to give the subtitled product as a white powder after filtration and drying (210 g).
Reaction SMILES: CO[C:3]1[CH2:4][C:5]2([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[BH4-].[Na+]>C(O)C>[C:5]12([CH2:13][CH2:14][CH:15]([OH:18])[CH2:16][CH2:17]1)[C:6]1[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:12][CH2:3][CH2:4]2
Reactant: COC1=Cc2ccccc2C2(CCC(=O)CC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCC2(CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a partial solution of 5.10 g. (0.038 M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r) (prepared as in Example 16A) in 105 ml. of 95% ethanol, 2.59 g. of sodium borohydride is added and the mixture stirred at room temperature for about 4 hours. Most of the solvent is removed under vacuum and water added to the residue. The material that precipitates is extracted with ether and the combined extracts washed with water and brine and evaporated to dryness. The residue is recrystallized once from Skellysolve B and then chromatographed over a column containing 500 ml. of silica gel with elution by 10% acetone:Skellysolve B. On the basis of TLC the less polar fractions are combined and recrystallized from benzene:cyclohexane to give a small amount of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s), having a melting point of 144.5° to 146° C., and an NMR spectrum suggesting that the compound has the hydroxy substituent in the axial position.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[N:4]=[CH:3]1.[Br:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15](F)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:21]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][C:5]=3[CH:10]=2)[CH:22]=1
Reactant: Cn1cnc2cc(O)ccc21
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Br)cc1Oc1ccc2c(c1)ncn2C
Temperature: 90 °C

Procedure:
1-methyl-1H-benzo[d]imidazol-5-ol (296 mg), methyl 4-bromo-2-fluorobenzoate (311 mg) and potassium carbonate (553 mg) were combined in dimethylsulfoxide and heated to 90° C. overnight. The reaction mixture was diluted with ethyl acetate and washed thoroughly with water and with brine, dried over MgSO4, filtered and concentrated.
Reaction SMILES: C(O)=O.[C:4](OC(=O)C)(=O)C.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19]>C1COCC1>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH3:4])=[CH:14][C:13]=1[F:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)c(F)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: CNc1ccc(Cl)c(F)c1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
Formic acid (1.76 ml) was added to acetic acid anhydride (0.91 ml) at 0° C. The solution was stirred for 10 min at this temperature. The reaction was heated under nitrogen to 55° C. for 2 h. The reaction mixture was cooled to 0° C. 4-Chloro-3-fluoroaniline (1.07 g) dissolved in THF (2 ml) was added and the reaction was stirred over night at RT. The solvent was evaporated in vacuo. The residue was dissolved in THF (4 ml). The solution was cooled to 0° C. and borane tetrahydrofuran complex 1M in THF (16.2 ml) was added slowly. Strong gas evolution was observed. The reaction was heated to reflux for 3 h, then cooled to 0° C. and MeOH (4 ml) was added dropwise. The reaction was stirred for 1 h and 1M aq HCl solution (6 ml) was added. The reaction was stirred over night at RT. The solvent was removed in vacuo and the pH of the aqueous layer was adjusted to 9 with 2N aq NaOH solution. The reaction mixture was extracted twice with diethyl ether and the combined organic layers were dried over sodium sulfate, filtered and the solvent was removed in vacuo to yield (4-chloro-3-fluoro-phenyl)-methyl-amine (1150 mg, 98%) as a light brown oil. 1HNMR (DMSO-d6, 300 MHz): δ 2.65 (d, J=5.1 Hz, 3H), 6.15 (d, J=5.1 Hz, 1H), 6.20 (dd, J=3.0 and J=8.4 Hz, 1H), 6.45 (dd, J=2.4 and 12.3 Hz, 1H), 7.18 (t, J=8.7 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1)=[O:8])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1)=[O:8]
Reactant: [H][H]
Reactant: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)c1
Yield: 79.9 %

Procedure:
Ethanol (50 ml) is added to 10% Pd-C (0.1 g) and thereto is added 1-[4-(3-nitrobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.73 g). The mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. After completion of the reduction, 10% Pd-C is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is extracted with dichloromethane and the extract is dried over magnesium sulfate. The solvent is distilled off under reduced pressure and recrystallized from methanol to give 1-[4-(3-aminobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.54 g) as white powder, m.p. 205.5-206.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=4[CH:15]=3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=4[CH:15]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C#N)cc4)on3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(CN)cc4)on3)ccc21

Procedure:
0.95 g (2.7 millimoles) of 5-(4-cyanophenyl)-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-isoxazole (Example 19) were added a little at a time, at room temperature, to a suspension of 0.28 g (7.4 millimoles) of lithium aluminum hydride in 30 ml of dry ether. The mixture was then refluxed for 3 hours and cooled, after which hydrolysis was carried out carefully with water, the phases were separated, the aqueous phase was extracted again with ether and the combined organic extracts were dried over sodium sulfate and evaporated down. 0.9 g of the title compound of melting point 138°-143° C. remained as the residue.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][C:43]=1[OH:44])[C:8]([NH:10][C@H:11]([B:28]1[O:36][CH:35]2[C:30]([CH3:40])([CH:31]3[CH2:37][CH:33]([CH2:34]2)[C:32]3([CH3:39])[CH3:38])[O:29]1)[CH2:12][C:13]1[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:52][CH2:53][NH:54]C(=O)OC(C)(C)C.O>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][C:43]=1[O:44][CH2:52][CH2:53][NH2:54])[C:8]([NH:10][C@H:11]([B:28]1[O:36][CH:35]2[C:30]([CH3:40])([CH:31]3[CH2:37][CH:33]([CH2:34]2)[C:32]3([CH3:39])[CH3:38])[O:29]1)[CH2:12][C:13]1[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:9])(=[O:3])[CH3:2]
Reactant: COc1c(C[C@H](NC(=O)c2ccc(O)c(OC(C)=O)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C[C@H](NC(=O)c2ccc(OCCN)c(OC(C)=O)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-((2R)-2-(3-acetoxy-4-hydroxybenzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate (100 mg from step 1) in DMF (3 mL) was added K2CO3 (100 mg) followed by tert-butyl 2-bromoethylcarbamate (100 mg). The resulting reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with EtOAc three times. The combined organic phases were dried and concentrated to afford the product which was carried on to the next step without further purification.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:3]#[C:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[OH:1][CH:2]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.5 g (93 mmol) of methyl 4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate, 200 ml of methanol and 20 ml of a methanolic sodium hydroxide solution (2N) were introduced into a round-bottomed flask. The reaction mixture was stirred at room temperature for 8 hours and evaporated and the residue was taken up in water and acidified with hydrochloric acid. Extraction was carried out with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was recrystallized from a cyclohexane/isopropyl ether mixture and 1.7 g (50% of the expected acid, with a melting point of 134°-135° C., was recovered.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.C[O:22][C:23](=[O:30])[C:24]([NH2:29])([CH2:27][CH3:28])[CH2:25][CH3:26]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:29][C:24]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:23]([OH:30])=[O:22])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CCC(N)(CC)C(=O)OC
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CCC(CC)(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)O

Procedure:
The title compound can e.g. be synthesized by: i) coupling of 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) with 2-amino-2-ethyl-butyric acid methyl ester (CAN 70974-26-4) in analogy to Example 1; and ii) saponification of the ester group in analogy to the conditions described in Example 48 e), MS (EI): m/e=396.1 [M−H]−.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[F:11][C:12]([F:17])([F:16])[C:13](O)=O>>[I:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:13]([C:12]([F:17])([F:16])[F:11])[N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CNc1ncc(I)cc1N
Product: Cn1c(C(F)(F)F)nc2cc(I)cnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.50 g of 5-iodo-N2-methylpyridine-2,3-diamine and 6 ml of trifluoroacetic acid was stirred at room temperature for 1 hour, and then stirred under heat-reflux for 9 hours. The cooled reaction mixture was concentrated under reduced pressure, then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.57 g of 6-iodo-3-methyl-2-trifluoromethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)[CH:12]=2)=[CH:7][C:6]=1[F:35])=[O:4].Cl.[NH2:37][OH:38].C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19](=[N:37][OH:38])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)[CH:12]=2)=[CH:7][C:6]=1[F:35])=[O:4]
Reactant: NO
Reactant: COC(=O)c1ccc(-c2cccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)c2)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(-c2cccc(C(CC(=NO)c3ccnc(C)c3)c3ccccc3C)c2)cc1F

Procedure:
In analogy to example 74, step 7, from 3-fluoro-3′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid methyl ester and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (4.4:1) as a white foam, MS (ESI+): m/z=483.2 ([M+H]+).
Reaction SMILES: C[O:2][C:3]([C:5]1(/[CH:11]=[CH:12]/[C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C@H:23]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:24])=[N:20]3)=[CH:15][CH:14]=2)[CH2:10][O:9][CH2:8][CH2:7][O:6]1)=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[C:29]([O:28][C:26]([NH:25][C@@H:23]([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][C:13](/[CH:12]=[CH:11]/[C:5]3([C:3]([OH:4])=[O:2])[CH2:10][O:9][CH2:8][CH2:7][O:6]3)=[CH:14][CH:15]=2)[N:20]=1)[CH3:24])=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)COCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C3(C(=O)O)COCCO3)cc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A solution of 2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-[1,4]dioxane-2-carboxylic acid methyl ester (157 mg, 0.35 mmol) in tetrahydrofuran (6 mL) was stirred at 5° C. under nitrogen. A solution of lithium hydroxide monohydrate (30 mg, 0.71 mmol) in water (1.5 mL) was added and the reaction mixture was stirred at room temperature for 18 h. The majority of the organic solvent was evaporated. The solution was acidified to pH 2 with 2 M hydrochloric acid and the mixture was extracted with dichloromethane. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford the title compound (149 mg, 100%) as a pale yellow foam and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 429.1 [M+H], Tr=1.87 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](OC(C1C(N)SC2=CC=CC=12)=O)C.S(Cl)(Cl)=O>CO>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOC(=O)C1=C2C=CC=C2SC1N
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 15 h

Procedure:
5-Chloro-2-nitro-benzoic acid (compound A′) (5.0 g) was dissolved in methanol (150 ml). Thionyl chloride (9.5 ml) was added to the solution at 0° C., and the mixture was heated under reflux with stirring for 15 hr. After the completion of the reaction, distilled water was added thereto at 0° C., and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with distilled water and saturated brine, was dried over sodium sulfate, and was then concentrated to give 5-chloro-2-nitro-benzoic acid methyl ester as a useful intermediate (12.9 g, yield 92%).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>C(#N)C.[C-]#N.[Zn+2].[C-]#N>[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15]([CH:8]1[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]1=[O:7])=[O:16]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1C(=O)C(C(=O)c2ccc(Cl)cc2Cl)C(=O)N(C)C1=O
Yield: 80.2 %

Procedure:
1,3-Dimethylbarbituric acid (15.6 g, 0.1 mole), 2,4-dichlorobenzoyl chloride (20.9 g, 0.1 mole) and zinc cyanide (12.9 g, 0.11 mole) were combined in acetonitrile (175 ml). Triethylamine (10.1 g, 0.12 mole) was slowly added with cooling. The reaction mixture was then heated at reflux for one hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid. The resulting product precipitate was filtered and washed with ether to afford 26.4 grams of the desired product, m.p. 123°-127° C. (80.2% yield). The structure was confirmed by instrumental analysis.
Reaction SMILES: C([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH2:16][CH:17]=[CH2:18])[C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)C.B(F)(F)F.O.[OH-].[Na+]>ClCCl>[C:19]([C:6]1[C:7]2[CH2:16][CH:17]([CH3:18])[O:15][C:8]=2[CH:9]=[C:10]([C:11]([CH3:14])([CH3:12])[CH3:13])[C:5]=1[OH:4])([CH3:20])([CH3:21])[CH3:22]
Reactant: C=CCc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
4-Acetoxy-3,5-di-tert-butyl-2-(2-propenyl)phenol (1.0 g, 3.3 mmol) was dissolved in dichloromethane (10 ml) and BF3 etherate (0.7 ml) was added dropwise to the solution under a nitrogen atmosphere. The mixture was stirred for 24 h at room temperature and, thereafter, water was added and the mixture was extracted with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was dissolved in tetrahydrofuran (5 ml) and the solution was added dropwise to a suspension of lithium aluminum hydride (76 mg) in tetrahydrofuran (5 ml) that had been prepared under a nitrogen atmosphere. After refluxing for 3 h, the reaction mixture was cooled to room temperature and water was added dropwise. Following the addition of 1N aqueous sodium hydroxide, the mixture was subjected to extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4,6-di-tert-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran [450 mg (yield, 52%)].