Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C[O-].[Na+].[C:5]([C:7]1[C:16]([C:17]#[N:18])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)#[N:6].[NH3:19]>CO>[NH:18]=[C:17]1[C:16]2[CH:15]=[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[CH:8][C:7]=2[C:5](=[NH:19])[NH:6]1
Reactant: N#Cc1cc2ccccc2cc1C#N
Reactant: N
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: N=C1NC(=N)c2cc3ccccc3cc21
Yield: 86 %

Procedure:
Next, in an atmosphere of nitrogen, 0.64 g (28 mmoles) of metallic sodium was added in five portions to 90 ml of anhydrous methanol to prepare a methanolic solution of sodium methoxide. To the methanolic solution was added 10.2 g (57.3 mmoles) of 2,3-dicyanonaphthalene. While thoroughly stirring the mixture, anhydrous ammonia gas was bubbled into the mixture slowly over a period of about one hour at room temperature. Then, the mixture was heated under reflux for about 3 hours while bubbling anhydrous ammonia gas. After cooling the mixture, the deposited yellow-colored solid product was collected by filtration, thoroughly washed with methanol and dried in vacuum. Thus, about 9.5 g (86%) of 1,3-diiminobenzo(f)isoindoline was obtained as a yellow colored solid. It was used in the subsequent reaction without purification.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[H-].[Na+].Br[C:29]1[N:30]([CH2:37][C@:38]2([CH3:41])[CH2:40][O:39]2)[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[N:33]=1>CN(C=O)C>[CH3:40][C@@:38]1([CH2:41][O:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:11][CH2:10][CH:9]([O:8][C:7]4[CH:22]=[CH:23][C:4]([O:3][C:2]([F:1])([F:24])[F:25])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[O:39][C:29]2=[N:33][C:32]([N+:34]([O-:36])=[O:35])=[CH:31][N:30]2[CH2:37]1
Reactant: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COc2ccc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 72.5 °C
Reaction time: 0.33 h
Yield: 32.7 %

Procedure:
4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (693 mg, 1.96 mmol) was dissolved in N,N′-dimethylformamide (3 ml), and sodium hydride (86 mg, 2.16 mmol) was added while cooling on ice followed by stirring at 70-75° C. for 20 minutes. The mixture was cooled on ice. To the solution, a solution prepared by dissolving (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (720 mg, 2.75 mmol) in N,N′-dimethylformamide (3 ml) was added followed by stirring at 70-75° C. for 20 minutes. The reaction mixture was allowed to return to room temperature, ice water (25 ml) was added, and the resultant solution was extracted with methylene chloride (50 ml) three times. The organic phases were combined, washed with water 3 times, and dried over magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=3/1). Recrystallization from ethyl acetate/isopropyl ether gave (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (343 mg, 33%) as a light yellow powder.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH:44]2[CH2:49][CH2:48][N:47]([C:32]([N:12]3[C@@:13]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)([CH3:24])[C@@:14]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=4)([CH3:16])[N:15]=[C:11]3[C:8]3[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=3[O:35][CH2:36][CH3:37])=[O:33])[CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CCN(C2CCNCC2)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCCC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with [1,4′]-bipiperidinyl (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H50Cl2N5O2 [(M+H)+] 690.3336, observed 690.334.
Reaction SMILES: [CH:1]1([N:5]2[CH2:18][CH2:17][C:8]3[NH:9][C:10]4[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][C:15]=4[C:7]=3[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH:1]1([N:5]2[CH2:18][CH2:17][C:8]3[N:9]([CH2:27][CH2:26][C:23]4[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=4)[C:10]4[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][C:15]=4[C:7]=3[CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C1CCC1)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C2CCC2)C1

Procedure:
The title compound is prepared from a mixture of 2-cyclobutyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:34])[C:17]([N:19]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:20][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:22][CH3:23])=[O:18])[CH:8]=2)[N:3]=1.C(O)(=[O:37])C>>[CH3:34][N:16]([CH2:15][CH2:14][CH2:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:37])[CH:11]=[CH:10]2)[C:17]([N:19]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:20][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:22][CH3:23])=[O:18]
Reactant: CC(=O)O
Reactant: CCC(CN(C(=O)N(C)CCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1)OC(C)=O
Product: CCC(CN(C(=O)N(C)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1)OC(C)=O

Procedure:
To acetic acid (100 ml) is added 2-chloro-6-{3-[1-methyl-3-cyclohexyl-3-(2-acetyloxybutyl)ureido]propoxy}quinoline (5.5 g), and the mixture is refluxed for 4 hours. The mixture is concentrated under reduced pressure to remove the acetic acid, and the residue is dissolved in methylene chloride and washed with a saturated aqueous sodium hydrogen carbonate solution. The mixture is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol=20:1), and recrystallized from methylene chloride-diethyl ether to give 6-{3-[1-methyl-3-cyclohexyl-3-(2-acetyloxybutyl)ureido]propoxy}carbostyril (2.7 g) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[CH3:15][S:12]([C:4]1[CH:5]=[C:6]([CH:11]=[C:2]([N:1]2[CH:18]=[CH:22][CH:21]=[CH:20]2)[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:14])=[O:13]
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1cc(N)cc(S(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(-n2cccc2)cc(S(C)(=O)=O)c1

Procedure:
The mixture of methyl 5-amino-3-methylsulfonylbenzoate (1.5 g) and 2,5-dimethoxytetrahydrofuran (1.3 ml) in acetic acid (4.5 ml) was heated under reflux for 2 hours under stirring. After cooling, the mixture was poured into a mixture of ethyl acetate and water, and adjusted to pH 8 with 20% aqueous potassium carbonate solution. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with diisopropyl ether to give methyl 3-methylsulfonyl-5-(pyrrol-1-yl)benzoate (1.58 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:15])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and t-butylamine (36 mg, 0.39 mmol). The title compound was obtained as a solid (25 mg, 15% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.57 (1H, s), 8.23 (1H, s), 1.31 (9H, s). MS m/z: 404.09, 406.07 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.O>CN(C=O)C.C(NCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[CH:19][C:4]=2[CH:3]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Oc1ccc(Cl)cc1I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Reaction time: 1 h
Yield: 49.6 %

Procedure:
A solution of 4-Chloro-2-Iodophenol [71643-66-8] (1.0 g, 3.9 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and Cul (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried, concentrated to give a solid which was triturated with MeOH, filtered to give a solid (0.5 g, 50%): Mp=183–185° C.; 1H NMR (CDCl3) δ 7.76 (d, 2 H, J=8.0 Hz), 7.50 (d, 1 H, J=1.6 Hz), 7.39 (d, 1 H, J=8.3 Hz), 7.20–7.18 (m, 1 H), 6.97 (d, 2 H, J=8.3 Hz), 6.82 (s, 1 H), 3.86 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)cc1F
Temperature: 50 °C
Yield: 92.8 %

Procedure:
Combine methyl 3-fluorobiphenyl-4-carboxylate (8.18 g, 35.5 mmol), THF (225 mL), and 1.0 M aqueous sodium hydroxide (225 mL). Heat at 50° C. for 8 h. Cool to room temperature, add 1.0 M aqueous hydrochloric acid (300 mL), and extract with 2×200 mL ethyl acetate. Separate the organic phase, dry over MgSO4, filter, and evaporate in vacuo to afford 7.12 g (93%) of 3-fluorobiphenyl-4-carboxylic acid as a white solid. 1H NMR (d6-DMSO, 300 MHz) 13.22 (br s, 1H), 7.93 (t, J=8.1 Hz, 1H), 7.74-7.78 (m, 2H), 7.60-7.66 (m, 2H), 7.40-7.52 (m, 3H); IR (cm−1, KBr): 3035, 2666, 2575, 1699, 1621, 1563, 1408, 1298, 1265, 1193, 904; Anal calc'd for C13H9FO2: C 72.22, H 4.20; Found: C 72.18, H 4.35.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO.[H][H]>C(Cl)Cl.[Ru]>[OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCCCCCCCCCCCC(=O)CC(=O)OC
Reactant: [H][H]
Agent: [Ru]
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCCCCCC[C@@H](O)CC(=O)OC
Yield: 95 %

Procedure:
Into a 200-ml autoclave (made of Hastelloy) were introduced 50 g of the methyl 3-oxooctadecanoate obtained above and 50 ml of methanol. The atmosphere in the autoclave was replaced with nitrogen gas. Thereto was added a solution prepared by dissolving 325 mg of Ru2Cl4 ((+)-(T)BINAP)2Et3N as a ruthenium-optically active phosphine complex in 3.8 ml of methylene chloride. Asymmetric hydrogenation was conducted at 65° C. and a hydrogen pressure of 30 atm. After the reaction mixture was thus reacted for 12 hours, it was taken out of the autoclave. The reaction product was recrystallized from methanol to obtain 47.8 g of methyl (R)-3-hydroxyoctadecanoate. Yield, 95%.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]([CH3:33])[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=[C:13]([O:15]CC2C=CC=CC=2)[CH:14]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[OH:15][C:13]1[CH:12]=[C:11]([CH:23]([CH3:33])[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]=[C:9]([OH:8])[CH:14]=1
Reactant: CC(CCOc1ccccc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(CCOc1ccccc1)c1cc(O)cc(O)c1
Reaction time: 2 h

Procedure:
A solution of 3-(3,5-dibenzyloxyphenyl)-1-phenoxybutane (14.7 g., 133.5 mM) in a mixture of ethyl acetate (110 ml.), ethanol (110 ml.) and concentrated hydrochloric acid (0.7 ml.) is hydrogenated for 2 hours under 60 p.s.i. hydrogen in the preseence of 10% palladium-on-carbon (1.5 g.). Removal of the catalyst by filtration and concentration of the filtrate gives an oil. The oil is purified by chromatography on silica gel (100 g.) and eluting with benzene-ethyl acetate consisting of 0-10% ethyl acetate. The middle fractions are combined and concentrated to give the title product: 7.8 g. (80%), as an oil.
Reaction SMILES: CO[C:3](=[O:22])[C@H:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:5][C:6]([NH:8][C:9]1[S:10][C:11](=[S:14])[NH:12][N:13]=1)=[O:7].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOC(C)=O>[S:14]=[C:11]1[S:10][C:9]([NH:8][C:6]([NH:5][C@@H:4]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:3]([NH:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])=[O:7])=[N:13][NH:12]1
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1n[nH]c(=S)s1
Solvent: CCOC(C)=O
Product: O=C(Nc1n[nH]c(=S)s1)N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1

Procedure:
A solution of N-[[(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino]carbonyl]-L-phenylalanine methyl ester (EXAMPLE 1, 200 mg, 0.591 mmol) and benzylamine (1.0 mL) is stirred for 3 days at room temperature. The mixture is diluted with EtOAc and washed several times with 10% HCl and brine. The organic layer is dried (MgSO4), filtered, and concentrated to give 214 mg of the amide. Recrystallization from hot CH2Cl2 /hexane gives 150 mg (61%) of the title compound as a white solid (mp 198°-200° C.). Occasionally this reaction is carried out in EtOH or MeOH, especially when the amine used is methylamine. The solution is concentrated (if necessary) and either triturated with ether to give a solid (and remove excess amine) or partitioned between EtOAc and dilute HCl. Purification by flash chromatography and recrystallization is usually sufficient to provide analytically pure material.
Reaction SMILES: Cl.C([N:9]1[C:13]([CH2:14][CH2:15][C:16](O)([CH2:27][CH2:28][C:29]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:36])[CH2:17][CH2:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])=[CH:12][N:11]=[CH:10]1)C1C=CC=CC=1.S([O-])(O)(=O)=O.[K+]>C(O)C>[CH3:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:19]=1[CH2:18][CH2:17][CH:16]([CH2:27][CH2:28][C:29]1[C:30]([CH3:36])=[CH:31][CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:15][CH2:14][C:13]1[N:9]=[CH:10][NH:11][CH:12]=1
Reactant: Cc1cccc(C)c1CCC(O)(CCc1c(C)cccc1C)CCc1cncn1Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Product: Cc1cccc(C)c1CCC(CCc1c[nH]cn1)CCc1c(C)cccc1C
Temperature: 150 °C

Procedure:
4,0 g of 1-benzyl-5-[5-(2,6-dimethylphenyl)-3-hydroxy-3-(2,6-dimethylphenylethyl)pentyl]-1H-imidazole hydrochloride and 20 g of kalium hydrogen sulfate is combined and the mixture is heated for 6 hours at 150° C. Ethanol (40 ml) is added and the mixture is filtered. 20 ml of conc. hydrochloric acid is added and the mixture is hydrogenated palladium on carbon (10%) as catalyst until the hydrogen consumption ceases. The reaction mixture is filtered, water is added and the mixture is made alkaline with sodium hydroxide. The product is then extracted into toluene, which is washed with water, and evaporated to dryness. The residue which is the product as base, is converted to nitrate with nitric acid in water. M.p. 147°-150° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:31])OCC(Cl)(Cl)Cl)[C:5]=1[CH3:32])(=[O:3])[CH3:2].[OH:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24]([NH:37][CH2:36][CH2:35][CH2:34][OH:33])=[O:31])[C:5]=1[CH3:32])(=[O:3])[CH3:2]
Reactant: NCCCO
Reactant: CC(=O)c1c(C)c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Product: CC(=O)c1c(C)c(NC(=O)NCCCO)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 59 %

Procedure:
Using 2,2,2-trichloroethyl (7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 206 and 3-hydroxypropylamine, the title compound was obtained in the same as manner as in Example 143. Yield: 59%.
Reaction SMILES: O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]2)=[C:13]([C@H:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C)CC2)c1Br
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(C)CC2)c1Br
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
The 2.0 mL of benzo[d][1,3,2]dioxaborole (2.3 g, 9.56 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-oxoacetate (1.9 g, 4.78 mmol) and 1.9 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (530 mg, 1.9 mmol) in toluene (45 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3, diluted with EtOAc, and stirred for 30 min. The organic layer was washed with sat'd Na2CO3 solution, brine and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-30% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate 1.9 g (100%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 5.94 (s, 1H), 4.94 (dt, J=12.3, 6.3 Hz, 1H), 3.57 (t, J=11.0 Hz, 1H), 3.34 (t, J=11.4 Hz 1H), 2.86 (d, J=11 Hz, 1H), 2.76 (d, J=11.0 Hz, 1H), 2.51 (s, 3H), 2.37 (s, 3H), 1.64-1.56 (m, 2H), 1.43 (br. s, 1H), 1.29-1.25 (m, 2H), 1.14 (d, J=6.2 Hz, 3H), 1.07 (d, J=6.2 Hz, 3H), 0.95 (d, J=6.2 Hz, 3H). UPLC (M+H)=401.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([NH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1.[C:25]12[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=1)[NH:30]C(=O)O[C:26]2=[O:27]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:23][C:26](=[O:27])[C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:7]=1
Reactant: COC(=O)C(N)Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: c1ccncc1
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)NC(=O)c1ccccc1N
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture of the title G compound, 3-(3-benzyloxy-4-nitro-phenyl)-2-amino-propionic acid methyl ester (597 mg, 1.7 mmol), isatoic anhydride (278 mg, 1.7 mmol) and pyridine (5 mL) is heated with stirring at 80° C. for 7 h and allowed to cool to RT overnight. The mixture is evaporated to dryness, the residue is dissolved in EtOAc and the solution is washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The residue is purified by chromatography (silica gel column, 3×20 cm, on EtOAc-hexane-methanol, 8:12:2) to give 2-(2-amino-benzoylamino)-3-(3-benzyloxy-4-nitro-phenyl)-propionic acid methyl ester: 1H-NMR δ 7.815 (d, 1H), 6.294 (s, 1H), 6.825 (d, 1H), 7.384-7.206 (m, 7H), 6.699-6.577 (m, 3H), 5.532 (br s, 2H), 5.093-5.039 (m, 3H), 3.749 s, 3H), 3.403-3.175 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[N:9]([CH:10](O)[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3].S(Cl)([Cl:41])=O.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:5][C@H:6]1[N:9]([CH:10]([Cl:41])[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(O)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(Cl)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of diphenylmethyl α-[4(R)-acetonyloxy-3(R)-phenylacetamido-2-oxo-azetidin-1-yl]glycolate (2.136 g) in anhydrous methylene chloride (20 ml) are added thionyl chloride (0.90 ml) and pyridine (0.33 ml) with stirring at 0° C. After stirring for 1 hour at 0° C., the mixture is poured into ice water, and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give the crude product of a mixture of epimers at position α.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[C:14]([O:21][CH3:22])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN(C=O)C>[CH3:22][O:21][C:14]1[C:13]([O:12][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: COc1c(O)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C=O)cccc1Oc1cc(C)ccc1[N+](=O)[O-]
Yield: 78.3 %

Procedure:
2-Fluoro-4-methyl-1-nitrobenzene (0.25 g, 1.6 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.25 g, 1.6 mmol) and cesium carbonate (0.54 g, 1.6 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 20 h. The reaction mixture was cooled, poured into 0.1N sodium hydroxide solution and extracted with diethyl ether. The ether layer was separated, washed with 0.1N sodium hydroxide solution (4×), water (4×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to give 2-methoxy-3-(5-methyl-2-nitrophenoxy)benzaldehyde (0.36 g, 77%) as a brown oil, which was used without further purification.