Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])([O-:3])=[O:2].[C:12]([N:17]=[C:18]([CH:22]1[CH2:24][CH2:23]1)OCC)(OCC)=[O:13]>CO.C(Cl)Cl>[CH:22]1([C:18]2[NH:17][C:12](=[O:13])[N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[N:11]=2)[CH2:24][CH2:23]1
Reactant: NNc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)N=C(OCC)C1CC1
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(C2CC2)nn1-c1ccccc1[N+](=O)[O-]
Yield: 69 %

Procedure:
By the procedure of Example 4, Step C, 2-nitrophenylhydrazine was reacted with ethyl N-(carbethoxy)cyclopropanecarboximidate. After work-up, the residue was purified by flash chromatography on silica gel (150 mL for 2.0 mmole, eluted with 1.5% MeOH/CH2Cl2) to give the desired material as a yellow foam in 69% yield, homogeneous by TLC in 5% MeOH/CH2Cl2, mass spectrum (FAB) m/e 247 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4N(CC(F)(F)F)N=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=CC2C3N=C(C(N)=O)SC=3CCOC=2C=1.[NH:44]([CH2:46][CH:47]([OH:49])[CH3:48])[NH2:45]>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:44]([CH2:46][CH:47]([OH:49])[CH3:48])[N:45]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(O)CNN
Agent: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(O)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with 1-hydrazino-propan-2-ol to give 1-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propan-2-ol. MS (ESI+) 407.0/409.0.
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][CH:9]([CH2:19][N:20]([CH2:33][C:34]([OH:36])=[O:35])[CH2:21][CH2:22][CH2:23][N:24]([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][C:26]([OH:28])=[O:27])[N:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O>[Pd].CC#N>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:19][N:20]([CH2:33][C:34]([OH:36])=[O:35])[CH2:21][CH2:22][CH2:23][N:24]([CH2:25][C:26]([OH:28])=[O:27])[CH2:29][C:30]([OH:32])=[O:31])[N:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][C:12]([OH:14])=[O:13])=[CH:37][CH:38]=1
Reactant: O=C(O)CN(CCCN(CC(=O)O)CC(Cc1ccc([N+](=O)[O-])cc1)N(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Pd]
Solvent: CC#N
Product: Nc1ccc(CC(CN(CCCN(CC(=O)O)CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 82.4 %

Procedure:
1.03 g (1.25 mmol) of NO2-Bz-TTDA was dissolved into 50 mL of CH3CN, and was mixed with 24.8 mg of Pd/C to form a reaction solution. The reaction solution was charged into a reactor. The reactor was vacuumed for 3 minutes, followed by introducing H2 therein to adjust the pressure to 1.5 kg/cm2, allowing reaction to take place by stirring at room temperature for 4 hours, and evaporating when the pressure in the reactor was kept constant to form a crude product. The crude product was purified using silica column chromatography (eluent: CH2Cl2/CH3OH=19/1) so as to obtain a product of 0.82 g (1.03 mmol, 82.4%) of NH2-Bz-TTDA.
Reaction SMILES: ClC(=C)C#[N:4].[N:6]1([CH:14]2[CH2:21]CC[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:13]CCCCCN1>C(#N)C>[C:21]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[CH:13][N:6]=1)#[N:4]
Reactant: C1CCCC(N2CCCCCCN2)CCC1
Reactant: C=C(Cl)C#N
Solvent: CC#N
Product: Cc1ccc(C#N)nc1

Procedure:
19.6 g of 1-dimethyl-1-aza-3-methyl-1,3-butadiene, 17.5 g of 2-chloroacrylonitrile and 33.6 g of diazabicyclooctane (DABCO) are heated in 200 ml of acetonitrile for 30 hours to reflux. The reaction mixture is concentrated by evaporation and the residue is slightly acidified with 1N HCl and extracted with chloroform. The organic extract is dried and concentrated by evaporation and the residue is distilled. b.p. (6·10-3 bar) 63°-69° C. The distillate is digested with petroleum ether. The title compound is isolated in the form of crystals with a melting point of 72°-74° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccco1
Reactant: Fc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(-c2ccco2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of 1-bromo-4-fluorobenzene (3.0 g, 17.14 mmol) in dioxane (100.0 mL) and water (3.0 mL) was added (furan-2-yl)boronic acid (5.76 g, 51.48 mmol), K3PO4 (10.76 g, 50.69 mmol) and Pd(PPh3)4 (980 mg, 0.85 mmol) with stirring for 2 h at 90° C. in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified via silica gel chromatography (1% ethyl acetate in petroleum ether) to afford 2-(4-fluorophenyl)furan as colorless oil (2.5 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[C:15](OC(=O)C)(=[O:17])[CH3:16]>S(=O)(=O)(O)O.[N+](C1C=CC=CC=1)([O-])=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:15](=[O:17])[CH3:16])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1cc(Cl)c(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 27 h

Procedure:
In 28 ml of acetic anhydride was dissolved 50.0 g of 2,6-dichlorophenol and, one or two drops of conc. sulfuric acid were added to the solution The mixture was reacted at 130° C. for 10 minutes to effect acetylation After the reaction, the reaction solution was poured onto 300 ml of ice water and the mixture was extracted with ethyl acetate After drying the ethyl acetate phase over anhydrous magnesium sulfate overnight, the ethyl acetate phase was concentrated to give 58.2 g of colorless oily substance. Next, the oily substance was dissolved in 150 ml of nitrobenzene and 56 8 g of powdery aluminum chloride was gradually added to the solution. The reaction was carried out at 60° to 70° C. for 27 hours to effect Fries rearrangement. After completion of the reaction, the reaction solution was poured onto 1 liter of cold dil. hydrochloric acid and the organic phase was separated from the aqueous phase. The organic phase was extracted with 2N sodium hydroxide aqueous solution After the extraction, the solution was rendered acidic by adding 5N hydrochloric acid thereto followed by extracting with ethyl acetate. After drying over anhydrous magnesium sulfate, the ethyl acetate phase was concentrated to give 38.5 g of 2,6-dichloro-4-acetylphenol as crude crystals. The crystals were recrystallized from hot ethyl acetate to give 19.9 g of pure white 2,6-dichloro-4-acetylphenol. 2,6-dichloro-4-acetylphenol (3,5-dichloro-4-hydroxyacetophenone): C8H6Cl2O2
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([F:10])[CH:4]=1.CC([O-])(C)C.[K+].[O:17]1[CH2:22][CH2:21][CH2:20][O:19][CH:18]1[C:23]1[N:28]=[CH:27][C:26]([C:29]2[S:37][C:36]3[C:31](=[N:32][CH:33]=[CH:34][C:35]=3Cl)[CH:30]=2)=[CH:25][CH:24]=1.O>CS(C)=O>[O:17]1[CH2:22][CH2:21][CH2:20][O:19][CH:18]1[C:23]1[N:28]=[CH:27][C:26]([C:29]2[S:37][C:36]3[C:31](=[N:32][CH:33]=[CH:34][C:35]=3[O:9][C:6]3[CH:7]=[CH:8][C:3]([NH2:2])=[CH:4][C:5]=3[F:10])[CH:30]=2)=[CH:25][CH:24]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCCO4)nc3)sc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)nc4)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a stirred solution of 4-amino-2-fluorophenol hydrochloride (5.79 g, 35.4 mmol) in DMSO (40 mL) was added t-BuOK (8.66 g, 77.0 mmol). After 30 min, chloride 279 (10.70 g, 32.2 mmol) was added and the reaction mixture was heated at 100° C. for 1.5 h. More solution of 4-amino-2-fluorophenol HCl (860 mg, 7.70 mmol) and t-BuOK (0.86 g, 7.70 mmol) in DMSO (4 mL) was added to the reaction mixture that was heated at 100° C. for an additional 15 min. The reaction mixture was then poured into water (300 mL) to form a precipitate that was collected by filtration, dried under vacuum and triturated with MTBE to afford the title compound 280 (12.39 g, 29.3 mmol, 91% yield) as a beige solid. MS (m/z): 424.39 (M+H).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30]>>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1)(=[O:30])=[O:31]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(S(=O)(=O)c4ccc5ccccc5c4)CC3)cccc2n1
Yield: 58 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-naphthalene-sulfonyl chloride (79.8 mg; 0.41 mmol) to obtain 50.0 mg. (58% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.31 (br s, 1H), 8.23 (m, 2H), 8.13 (m, 1H), 7.84 (m, 1H), 7.77 (m, 2H), 7.37 (m, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.83 (m, 2H), 5.90 (br s, 2H), 3.82 (br d, J=11.2 Hz, 2H), 3.11 (br d, J=12.0 Hz, 2H), 2.87 (m, 2H), 2.64 (m, 2H). ESIMS+436.0 m/z
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][CH:27]=O)=[CH:22][CH:21]=2)[C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH:18]=O)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:18][NH:17][C:14]1[CH:13]=[CH:12][C:11]([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([NH:3][CH3:1])=[CH:9][CH:8]=2)[C:20]2[CH:25]=[CH:24][C:23]([NH:26][CH3:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: O=CNc1ccc(C(c2ccc(NC=O)cc2)c2ccc(NC=O)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(C(c2ccc(NC)cc2)c2ccc(NC)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 70.3 %

Procedure:
The tris(4-formylaminophenyl)methane (130 mg) obtained in Reference Example 31 was dissolved in tetrahydrofuran (5 ml), after which lithium aluminum hydride (66.1 mg) was added under a nitrogen atmosphere at 5° C., the temperature was raised to room temperature, and the mixture was stirred for 19 hours. Water (5 ml) was added to the reaction mixture at 5° C., and stirring was continued for 10 minutes. The reaction mixture was filtered with celite and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (Kiesel-gel 60, 240-400 mesh) and elution was performed with a mixed solvent of chloroform:methanol=98:2 to obtain 81.1 mg of the title compound as a yellow oily substance (70% yield).
Reaction SMILES: Cl.[C:2](=N)([NH2:4])[CH3:3].[NH:6]([C:8]([C:10]1[C:14]([CH3:15])=[CH:13][S:12][C:11]=1[NH:16][C:17](=[O:30])[CH2:18][N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][C:20]1=[O:29])=O)[NH2:7]>>[CH3:15][C:14]1[C:10]([C:8]2[NH:6][N:7]=[C:2]([CH3:3])[N:4]=2)=[C:11]([NH:16][C:17](=[O:30])[CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][C:20]2=[O:29])[S:12][CH:13]=1
Reactant: Cc1csc(NC(=O)CN2C(=O)CCc3ccccc32)c1C(=O)NN
Reactant: CC(=N)N
Agent: Cl
Product: Cc1n[nH]c(-c2c(C)csc2NC(=O)CN2C(=O)CCc3ccccc32)n1

Procedure:
The title compound was prepared from acetimidamide hydrochloride (55 mg, 0.590 mmol) and N-(3-(hydrazinecarbonyl)-4-methylthiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide (141 mg, 0.393 mmol) according to the procedure of Example 1.11.2, above. Retention time (min)=4.106, method [7], MS(ESI) 382.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 12.07 (s, 1H), 7.23-7.31 (m, 2H), 7.05-7.23 (m, 2H), 6.57 (s, 1H), 4.86 (s, 2H), 3.02-3.07 (m, 2H), 2.84-2.87 (m, 2H), 2.41 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=O.Cl.[NH2:14]O.C([O-])(=O)C.[Na+]>C(O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][NH2:14]
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NCc1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-chloro-1H-indole-3-carbaldehyde (0.690 g; 3.76 mmol), hydroxylamine hydrochloride (0.366 g; 5.27 mmol) and sodium acetate (0.463 g; 5.65 mmol) in ethanol (10 mL) was stirred at reflux for 3.5 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and brine and extracted with ethyl acetate. The solvent was evaporated and the resulting residue (crude oxime) was dissolved in glacial acetic acid (30 mL). Zinc dust (1.48 g; 22.59 mmol) was added to the solution, and the mixture was stirred overnight at room temperature. The suspension was filtered through Celite, the cake was washed with ethyl acetate, and the organic solution was concentrated under reduced pressure. An aqueous solution of sodium carbonate was added to the residue and the resulting mixture was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered, and concentrated to afford the (5-chloro-1H-indol-3-yl)methanamine as a brown solid, which was used without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][SH:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][CH2:22][C:23]([C:25]([C:27]1[CH:28]=[CH:29][C:30]([O:35][CH2:36][C:37](O)=[O:38])=[C:31]([Cl:34])[C:32]=1[Cl:33])=[O:26])=[CH2:24]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][S:17][C:37](=[O:38])[CH2:36][O:35][C:30]1[CH:29]=[CH:28][C:27]([C:25](=[O:26])[C:23](=[CH2:24])[CH2:22][CH3:21])=[C:32]([Cl:33])[C:31]=1[Cl:34])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C=C(CC)C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: CC(CS)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Solvent: ClCCl
Product: C=C(CC)C(=O)c1ccc(OCC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C2CCCC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing 19.2 g (63.8 mmol) of N-(3-mercapto-2-methylpropanoyl)-N-cyclopentylglycine t-butyl ester and 19.3 g (63.7 mmol) of ethacrynic acid in 20 ml of methylene chloride at 0° C. was added a solution of 13.2 g (64.0 mmol) of N,N-dicyclohexylcarbodiimide in 20 ml of methylene chloride. The solution was allowed to warm to room temperature and to stir overnight. The solution was filtered and the filtrate was concentrated in vacuo. Purification of the product by HPLC [10% ethyl acetate in hexanes] afforded N-[3-[2,3-dichloro-4-(2-methylene-1-oxobutyl) phenoxy] acetylthio-2-methylpropanoyl]-N-cyclopentyl glycine t-butyl ester as a viscous oil.
Reaction SMILES: [C:1]1([P:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=CC(O)=[CH:18][CH:17]=1.C(O)C>>[C:1]1([P:7]([O:11][C:12]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:13]=2)[O:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(OCC)c1ccccc1
Reactant: COc1ccc(O)cc1
Solvent: CCO
Product: CCOP(Oc1ccc(OC)cc1)c1ccccc1
Temperature: 160 °C

Procedure:
99 g (0.5 mol) of diethyl phenylphosphonite and 62 g (0.5 mol) of 4-methoxyphenol were mixed and heated with stirring at 415 mbar. Ethanol distilled off at 115° C. via a small column. The temperature was then increased stepwise to 160° C., and the vacuum was simultaneously increased to 70 mbar. In total, 21.5 g (0.467 mol) of ethanol distilled off. The batch was then cooled and distilled. After a first fraction of 29 g, which essentially contained the unreacted starting materials, 103 g were obtained having a boiling point from 135° to 138° C. at 0.1 to 0.2 mbar. The yield was thus 75% of theory.
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([N:26]([CH2:33][CH3:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:2]=[CH:3][C:4]([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([N:26]([CH2:33][CH3:34])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)N(CC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(c1ccccc1)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
Ethyl 3-[4-[2-(biphenyl-4-carbonylamino)ethoxy]phenyl]-2-(N-ethyl-N-phenylamino)propionate, which is the product of Example 181, is hydrolyzed by sodium hydroxide in methanol to give the title compound.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:8]1[C:19](OCC)=[O:20])([CH3:4])[CH3:3].OC[C@@H]1[C@@H](C)CCN1C(OC(C)(C)C)=O>>[CH3:4][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C@@H:8]1[CH2:19][OH:20])([CH3:1])[CH3:3]
Reactant: CCOC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO

Procedure:
The title compound was prepared from 1-(1,1-dimethylethyl) 2-ethyl(2S,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1,2-pyrrolidinedicarboxylate using the methods used for preparation of 1,1-dimethylethyl(2S,3S)-2-(hydroxymethyl)-3-methyl-1-pyrrolidinecarboxylate. 1H NMR (400 MHz, DMSO-D6) δ ppm—0.0 (m, 6 H) 0.8 (m, 9 H) 1.0 (m, 1 H) 1.4 (m, 9 H) 1.6 (m, 1 H) 3.1 (m, 1 H) 3.2 (m, 2 H) 3.5 (m, 2 H) 4.3 (m, 1 H) 4.8 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOC(C)=O.[Pd]>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH2:10])[C:3]=1[NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc([N+](=O)[O-])c(Nc2ccccc2)c1Br
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(Nc2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a solution of (2-bromo-3-methoxy-6-nitro-phenyl)-phenylamine (470 mg, 1.81 mmol) in EtOAc (15 mL) was added palladium on carbon (100 mg, 10% by wt) and the reaction mixture stirred at RT under an atmosphere of hydrogen for 16 h. The reaction mixture was filtered and the filtrate concentrated in vacuo to give the title compound as a yellow solid (426 mg, 100%). 1H NMR 400 MHz δ (CDCl3): 7.24-7.17 (2H, m), 6.89-6.83 (1H, m), 6.74-6.72 (1H, m), 6.68-6.63 (2H, m), 5.48 (1H, br s), 3.85 (3H, s).
Reaction SMILES: CS(C)=O.[CH3:5][O:6][C:7](=[O:23])[CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:21][OH:22].FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:5][O:6][C:7](=[O:23])[CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH:15]1[CH:21]=[O:22]
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1CO
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: COC(=O)CCCC#CCN1C(=O)CCCC1C=O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
1-(3-(Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 530 mg, 2.76 mmol) and DMSO (0.26 mL, 3.68 mmol) were added sequentially to a solution of 7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (246 mg, 0.92 mmol) in benzene (7.0 mL) at rt. The mixture was cooled to 0° C. and pyridinium trifluoroacetate (196 mg, 1.01 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 2.5 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×5 mL). The combined benzene phases were concentrated in vacuo to afford crude 7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester that was used without further purification.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9]([C:11]1[C:16](O)=[C:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=1[CH3:21])=[O:10])[CH3:7]>>[CH2:6]([O:8][C:9]([C:11]1[C:16]([Cl:3])=[C:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=1[CH3:21])=[O:10])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)c(C)c(=O)n(C)c1C
Product: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Phosphorous oxychloride (20.0 mL, 216 mmol) was added to 4-hydroxy-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester and heated to 80° C. After two hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was poured onto ice and, carefully neutralized with saturated NaHCO3, and diluted with EtOAc. After stirring for 16 hours, the organic layer was separated and the aqueous layer was reextracted with EtOAc repeatedly. The pH of the aqueous layer was adjusted to pH 11 with saturated K2CO3 and extracted with EtOAc (2×). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give 3.42 g (89%) clean desired product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]([O:19]C)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:21]>CO>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]([NH2:21])=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)CN1C(=O)CC[C@@H]1CO[Si](C)(C)C(C)(C)C
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CC(N)=O
Reaction time: 8 h

Procedure:
To a solution of the compound 66 (13.7 g) in methanol (91 mL) was added 28% ammonia (91 mL) at room temperature and the solution was stirred overnight. The reaction solution was concentrated. Brine and ethyl acetate were added thereto and the solution was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:methanol=1:0→97:3→95:5→90:10) to give the title compound (10.1 g) having the following physical data.