Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[OH:10].S(=O)(=O)(O)O.O.C(#[N:20])C>>[NH2:20][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10]
Reactant: O[C@@H]1Cc2ccccc2[C@H]1O
Reactant: CC#N
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 40 ml of acetonitrile, 3.0 g (20.1 mmol) of trans-(-)-1,2-indandiol (I': trans-configuration: 98.0%; cis-configuration: 2.0%; optical purity: 100% e.e.) was dissolved. At room temperature, 3.2 g (31.7 mmol) of 97% sulfuric acid was dropwise added thereto in a period of 30 minutes. After the resulting mixture was stirred at room temperature for 1 hour, the compound (I') disappeared from an HPLC. To the reaction liquid, 20 ml of water was added. Immediately thereafter, the mixture was heated and 42 ml of an acetonitrile/water azeotrope was distilled off under normal pressure. Then, the mixture was subjected to a reflux for 1.5 hours to complete the reaction. The reaction liquid was cooled to room temperature and washed twice with 10 ml of dichloromethane. Then, its pH was adjusted to 10.5 by an addition of an aqueous solution of 25% sodium hydroxide. The grayish white scaly crystal deposited thereby was filtered off under reduced pressure, washed with a small quantity of water, and then dried under reduced pressure to yield 1.77 g of cis-(-)-1-aminoindan-2-ol (V) as a primary crystal. Then, the mother liquid after the deposition of the crystal was extracted with dichloromethane and the extracted phase was concentrated to yield 0.69 g of the compound (V) as a secondary crystal.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH:6]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.N1C=CC=CC=1.Cl.N1C=CC=CC=1>C1C=CC=CC=1>[C:2](=[O:3])([O:14][CH:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:4][CH3:5]
Reactant: OC1CCCCCCC1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)OC1CCCCCCC1
Reaction time: 12 h

Procedure:
18.9 gm of methyl chloroformate were added drop-by-drop under agitation to a solution of 25.6 gm of cyclooctanol and 15.8 gm of absolute pyridine in 150 ml of dry benzene under external cooling at 0° to 5° C. After the methyl chloroformate had been added, agitation was continued for 12 hours at room temperature. Then, the benzene phase was drawn off from the precipitated pyridine hydrochloride, and washed with diluted hydrochloric acid, sodium hydroxide solution and water, and dried. After the solvent had been distilled off, the raw ester was distilled in vacuo by means of a Vigreux column. A colorless liquid was obtained which had a herbal, very natural and complex fragrance which is distinguished by a strong and long-clinging flowery jasmine scent.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([I:1])=[N:3]2)=[N:14][CH:15]=1
Reactant: Fc1ccc(F)nc1
Reactant: CCOC(=O)c1c[nH]nc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2ccc(F)cn2)nc1I
Temperature: 100 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of ethyl 3-iodo-1H-pyrazole-4-carboxylate (8.5 g, 32.0 mmol) in DMF (160 mL) was added 2,5-difluoropyridine (11.0 g, 96.0 mmol) and potassium carbonate (13.3 g, 96.0 mmol). The mixture was stirred at 100° C. in a sealed reaction flask. After 18 h, the mixture was cooled to ambient temperature and ethyl acetate and water were added. The solid in the organic layer was filtered off and the filtrate was dried over MgSO4, filtered and concentrated. The product was recrystallized using ethyl acetate and ether to give 6.5 g of the title compound. The solution from recrystallization was concentrated and purified by silica gel chromatography (100% dichloromethane→98% dichloromethane/methanol) gave 0.8 g of the title compound (7.3 g total). MS 361.8 (M+1).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].Br[CH2:26][C:27]#[N:28].O>O1CCCC1>[C:27]([CH2:26][CH:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:16])#[N:28]
Reactant: O=C1CC(c2ccccc2)(c2ccccc2)c2ccccc21
Reactant: N#CCBr
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCC1C(=O)c2ccccc2C1(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Spiro[3,3-diphenyl-2,3-dihydro(1H)indene-1,3′-2′-cyanooxirane] (Compound 5) and 2-cyanomethyl-3,3-diphenylindanone (Compound 9) were synthesized as follows: 3,3-diphenylindanone (Compound 2), 5.0 g (0.0176 mole) and 2.62 g (0.0229 mole) of potassium hydride were stirred at room temperature in 40 mL of tetrahydrofuran. After the gas evolution subsided (approx. 45 min), 1.5 mL (0.0215 mole) of bromoacetonitrile was added. The dark red mixture was stirred for 1 hour and then 50 mL of water was added. The mixture was extracted three times with 75 mL of ethyl acetate. The combined organic extracts were concentrated in vacuo, loaded onto a silica gel column and eluted with 10% ethyl acetate in hexane. Three fractions were collected. After evaporation of the solvent, the first fraction yielded unreacted starting material (3.5 g). The second fraction yielded 0.49 g (9% yield) of spiro[3,3-diphenyl-2,3-dihydro(1H)indene-1,3′-2′-cyanooxirane] (Compound 5) as a white solid. The third fraction yielded 1.05 g (18% yield) of 2-cyanomethyl-3,3-diphenylindanone (Compound 9) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH2:26]([OH:32])[C@H:27]([OH:31])[C:28]([OH:30])=[O:29].C(O)(C(F)(F)F)=O>C1COCC1>[C:28]([CH:27]([OH:31])[CH2:26][O:32][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:25])=[O:19])([OH:30])=[O:29]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Reactant: O=C(O)[C@@H](O)CO
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)C(=O)O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.1 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1h-pyrrol-2-yl)-meth-(z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indole-2-one (166 mg, 0.5 mmol), L-glyceric acid (432 mg, 1.5 mmol), and TFA (399 mg, 3.5 mmol) in 3 mL of THF was stirred at room temperature for 4 h and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:4) followed by 1% of acetic acid in ethylacetate-hexane (1:1) to afford 15 mg (8%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-carboxy-2-hydroxy-ethyl ester as a red solid. MS m/z (relative intensity, %) 371 (100, [M+1]+.).
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH:6]=[CH:7][CH2:8]1)[CH2:4][CH:3]([NH2:10])[CH2:2]2.[H][H]>C(O)C.[C].[Pd]>[CH:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH:3]([NH2:10])[CH2:2]2
Reactant: [H][H]
Reactant: NC1CC2C=CCC(C1)C2
Agent: [Pd]
Solvent: CCO
Product: NC1CC2CCCC(C1)C2

Procedure:
To bicyclo[3.3.1]non-6-en-3-amine (100 mg, 0.729 mmol) in ethanol (3 mL), 10% palladium-carbon (10 mg) was added in a nitrogen stream, and the reaction solution was stirred in a hydrogen stream at room temperature for 1 day. After completion of the reaction, the reaction solution was filtered through celite and the filtrate was evaporated under reduced pressure. The resulting crude reaction product was used for the next step without to further purification (98.5 mg).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14](C(O)=O)[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.COC1N=[C:53]([O:55]C)[N:52]=[C:51]([N+:57]2(C)[CH2:62][CH2:61]OCC2)[N:50]=1.S(O)(O)(=O)=O.N1C=CN=C1N>C(#N)C>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14]([C:53]([NH:52][C:51]3[NH:50][CH:61]=[CH:62][N:57]=3)=[O:55])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: CN1CCOCC1
Solvent: CC#N
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ncc[nH]2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
To a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (121 mg, 0.225 mmol) in acetonitrile (4 mL) at 0° C. was added 4-methylmorpholine (0.087 mL, 0.788 mmol), followed by 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (DMTMM) (89 mg, 0.270 mmol). The solution was stirred for 15 min, and then 1H-imidazol-2-amine sulfate (38.7 mg, 0.293 mmol) was added. The reaction mixture was warmed up to room temperature and stirred overnight. The solvent was evaporated and the residue was purified by RP-HPLC to provide phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[(1H-imidazol-2-ylamino)carbonyl]-1-pyrazolidinecarboxylate as a colorless gum (39 mg, 29%)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(O)CCCCl
Product: CCCCCC(CCCCl)OC(C)=O

Procedure:
A mixture of 1-chloro-4-nonanol (111.99 g.; 0.627 mole) and acetic anhydride (128.0 g.; 1.254 moles) is heated on a steam bath for 11/2 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of 3-fluoro-4-nitrophenol (2.56 g), potassium carbonate (4.5 g) and iodomethane (4.63 g) in N,N-dimethyl-formamide (15 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was washed with diethyl ether. The extract was washed with water twice, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-fluoro-4-nitroanisole (2.56 g). This material was dissolved in 1,2-dichloroethane (13 mL). To the solution was added chlorosulfonic acid (1.3 mL), and the mixture was heated for reflux for 4 hours. The reaction mixture was diluted with methylene chloride, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (0.51 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH2:26])[CH:21]1[O:25][CH2:24][CH2:23][CH2:22]1>>[O:25]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:20][NH:26][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Reactant: NCC1CCCO1
Product: O=C(Nc1nc2cccc(NCC3CCCO3)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and tetrahydrofurfurylamine (1.0 mL) as a white powder (32 mg, 52%). HPLC, Rt: 2.34 min. (purity 91.7%). LC/MS, M+(ESI): 339.0, M−(ESI): 338.1.
Reaction SMILES: C([O:8][C:9](=[O:35])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:34])[C@H:16]([CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)[NH:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[S:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:35])=[O:8])=[O:34])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)([C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=1)(=[O:19])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)O)cc1

Procedure:
In 150 ml of methanol was dissolved 13.5 g of compound (49) and the compound was catalytically reduced for 5 hours in the presence of 10% palladium-carbon. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue thus formed was dissolved in ethyl acetate and extracted thrice each time with an aqueous sodium hydrogen carbonate solution. The extracts were combined with each other and washed once with ethyl acetate. After acidifying the aqueous layer with 1N hydrochloric acid, the desired compound was extracted with ethyl acetate. Thus, 2.0 g of Nα -t-butyloxycarbonyl-Nim -tosyl-L-histidyl-L-proline (50) was obtained as a foamy product. Also, from the organic layer formed after extracting the product with an aqueous sodium hydrogencarbonate solution, 9.1 g of the starting material (49) was recovered.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:45]=[CH:44][CH:43]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: CCc1cc(C(=O)O)n(C)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C)n1
Yield: 61.7 %

Procedure:
In the same manner as in Example 18-4 and using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (212 mg, 1.37 mmol), tetrahydrofuran (10 mL), oxalyl chloride (180 μL, 2.07 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (296 mg, 0.950 mmol), N,N-dimethylformamide (2 drops) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (261 mg, 61%) was obtained as a white solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[H][H]>[Pd].C(O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: [H][H]
Reactant: C1=CC2CC1CC2Cn1ccnc1
Agent: [Pd]
Solvent: CCO
Product: c1cn(CC2CC3CCC2C3)cn1

Procedure:
A mixture of 1-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)imidazole (2.0 g, 11.48 mmol) and palladium on charcoal (0.2 g, 10%) in dry ethanol was shaken in an atmosphere of hydrogen for 4.5 h. The reaction mixture was the filtered through Hyflo-Supercel, and the filtrate was concentrated under reduced pressure to afford a colourless oil. Distillation of the oil afforded 1-(bicyclo[2.2.1]heptan-2-ylmethyl)imidazole as a colourless oil, b.p. 82°-84°/0.15 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:13][N:14]([C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCNC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 4-nitrobenzoic acid (16.7 g), ethyl 3-(methylamino)propanoate (13.1 g), 1-hydroxybenzotriazole monohydrate (18.4 g), and N,N-dimethylformamide (200 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.0 g), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (28.0 g, 100%) as an oil.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([O:27][C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[NH:32][C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)[CH:20]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:26][O:25][C:23]1[N:24]=[C:19]([N:14]2[CH2:13][CH2:12][C:5]3([O:4][C:3](=[O:17])[NH:2][C:7]4[N:8]=[CH:9][CH:10]=[CH:11][C:6]3=4)[CH2:16][CH2:15]2)[CH:20]=[C:21]([O:27][C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[NH:32][C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)[N:22]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: COc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(Oc2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC3(CC2)OC(=O)Nc2ncccc23)n1

Procedure:
58 mg (0.23 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 70 mg (0.20 mmol) 6-(6-chloro-2-methoxypyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 0.10 mL DIPEA (0.57 mmol) in 1.0 mL DMF were stirred for 3 h at 90° C. The reaction mixture was mixed with water, the precipitate w suction filtered, washed and dried. The residue was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](O)=[O:21])=[C:8]2[CH3:27])=[CH:4][CH:3]=1.S(C)C.Cl.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[CH2:20][OH:21])=[C:8]2[CH3:27])=[CH:28][CH:29]=1
Reactant: COc1ccc2c(c1)c(-c1ccccc1C(=O)O)c(C)n2Cc1ccc(Br)cc1
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(-c1ccccc1CO)c(C)n2Cc1ccc(Br)cc1
Yield: 99 %

Procedure:
A solution of the acid from Step 1 (300 mg, 0.66 mmol) and BH3 Σ SMe2 (0.1 mL, 1 mmol) in THF (3 mL) was gently refluxed for 2 h. The cooled mixture was poured over icy dilute HCl and ethyl acetate. The organic layer was washed with brine and dried with MgSO4. Removal of the solvents yielded essentially pure product (285 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=[O:5].[CH:7](=O)[C:8]1[C:9]([O:14][CH3:15])=[CH:10][CH:11]=[CH:12][CH:13]=1>O>[CH:7](=[CH:3][C:4](=[O:5])[CH3:6])[C:8]1[C:9]([O:14][CH3:15])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccccc1C=O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1C=CC(C)=O
Reaction time: 2 h

Procedure:
o-Anisalacetone is prepared by adding 70 ml of 10% aqueous sodium hydroxide to 7.7 moles of acetone, 280 ml of water, and 2.8 moles of o-anisaldehyde, slowly with cooling to maintain the temperature in the range of 25°-31° C. Another 2 hours stirring followed by acidification, separation of layers, dehydration with acid in benzene at reflux, and finally distillation at reduced pressure gives the crude o-anisalacetone.
Reaction SMILES: FC(F)(F)C(O)=[O:4].O.C(O)(=O)/C=C\C(O)=O.[F:17][C:18]1[CH:19]=[CH:20][C:21]2=[C:22]([CH:52]=1)[O:23][CH2:24][C:25]1[CH:51]=[CH:50][CH:49]=[CH:48][C:26]=1/[C:27]/2=[CH:28]\[C:29]1[CH:47]=[CH:46][C:32]2[N:33]([C@@H:39]3[C@@H:43]([OH:44])[CH2:42][N:41]([CH3:45])[CH2:40]3)/[C:34](=[N:36]/[C:37]#[N:38])/[NH:35][C:31]=2[CH:30]=1.[OH-].[Na+]>C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]2=[C:22]([CH:52]=1)[O:23][CH2:24][C:25]1[CH:51]=[CH:50][CH:49]=[CH:48][C:26]=1/[C:27]/2=[CH:28]\[C:29]1[CH:47]=[CH:46][C:32]2[N:33]([C@@H:39]3[C@@H:43]([OH:44])[CH2:42][N:41]([CH3:45])[CH2:40]3)/[C:34](=[N:36]/[C:37]([NH2:38])=[O:4])/[NH:35][C:31]=2[CH:30]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1C[C@H](O)[C@@H](n2/c(=N/C#N)[nH]c3cc(/C=C4\c5ccccc5COc5cc(F)ccc54)ccc32)C1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C[C@H](O)[C@@H](n2/c(=N/C(N)=O)[nH]c3cc(/C=C4\c5ccccc5COc5cc(F)ccc54)ccc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a mixture of trifluoroacetic acid (30 mL) and water (6.0 eq, 100 mmol, 1.81 mL) in an ice bath add (E)-N-(5-((E)-(3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-1-((3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)cyanamide maleate (16.73 mmol, 10.00 g). Allow the resulting suspension to warm up to room temperature and stir for 2 h. Dilute the solution with ethyl acetate (250 mL), cool the mixture in an ice bath for 30 min, and treat with 5 N sodium hydroxide to pH=11. Wash the organic layer with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography eluting with 2.5 to 5% methanol in ethyl acetate to obtain a white solid. Dry in a vacuum oven at 40° C. overnight to obtain the title compound (6.74 g, 81%). LC-MS m/z 500.2 [M+H]+.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].C[NH-].C1C=CC2N(O)N=[N:57][C:55]=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CO>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:55][NH-:57]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[NH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 50 mg of Z-Phe-His-OH, 28 mg of H-Leu-Val-methyl amide, 18 mg of HOBt and 31 mg of DCCI, the title compound is obtained after flash chromatography (35 g of silica gel 60, 40-63 μm, eluant system methylene chloride/methanol/concentrated ammonia 700:50:1). Rf (B2)=0.43, Rf (S10)=0.68.