Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][CH:22](O)[C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][CH:24]=3)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[C:5]1([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][CH:22]([Cl:3])[C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][CH:24]=3)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)[C@H]1CN(CCCc2ccccc2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CN(CCCc2ccccc2)CC[C@H]1CCC(Cl)c1ccnc2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.46 cm3 of thionyl chloride was added dropwise to a solution of 1 g of methyl (3R,4R)-1-(3-phenylpropyl)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)-propyl]piperidine-3-carboxylate in 15 cm3 of chloroform while maintaining the temperature at 0° C. The reaction mixture was allowed to return to a temperature in the region of 20° C. with stirring over 2 hours. The reaction mixture was subsequently concentrated under reduced pressure (5 kPa) at a temperature in the region of 50° C. The residue was dissolved in 30 cm3 of distilled water and the aqueous phase was washed with 15 cm3 of dichloromethane, then basified to pH 9 with solid potassium carbonate and, finally, extracted with 3 times 20 cm3 of dichloromethane. The organic phases were combined, washed with 2 times 20 cm3 of distilled water, and dried over magnesium sulfate. After filtering and then concentrating under reduced pressure (5 kPa) at a temperature in the region of 45° C., 1.16 g of methyl (3R,4R)-1-(3-phenylpropyl)-4-[3-(R,S)-chloro-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate were obtained in the form of a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.[OH-].[K+]>CCO>[C:1]([O:5][C:6](=[O:17])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:32]/[C:31]([C:28]2[CH:27]=[CH:26][C:25]([N:22]3[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]3)=[CH:30][CH:29]=2)=[O:33])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCN(C)CC2)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)OC(C)(C)C)nc3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.7 %

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (261 mg, 1.12 mmol), 1-[4-(4-methyl-piperazin-1-yl)-phenyl]-ethanone (246 mg, 1.2 mmol) and KOH (125 mg, 2.24 mmol) in 10 ml of EtOH was stirred at room temperature for 24 hours, observing the formation of a precipitate. The solid was then filtered off through a Buchner funnel to obtain 222 mg of (E)-3-(5-{(E)-3-[4-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([OH:30])=O)[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10].C[N:33](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([NH2:33])=[O:30])[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C
Yield: 57 %

Procedure:
To a mixture of (2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (0.25 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (0.13 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.16 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=10:0-8:2), and the obtained pale-brown solid was washed with ethyl acetate-hexane to give the title compound (143 mg, yield 57%) as pale-brown crystals. MS: 459 (MH+). melting point 227-228° C.
Reaction SMILES: C(O[C:4]1[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=[C:6]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:5]=12)C.O.[NH2:19][NH2:20]>CO>[CH2:16]([N:13]1[C:6]2=[N:7][CH:8]=[C:9]([C:10]([NH2:12])=[O:11])[C:4]([NH:19][NH2:20])=[C:5]2[CH:15]=[N:14]1)[CH3:17]
Reactant: NN
Reactant: CCOc1c(C(N)=O)cnc2c1cnn2CC
Solvent: CO
Solvent: O
Product: CCn1ncc2c(NN)c(C(N)=O)cnc21
Reaction time: 72 h

Procedure:
To 3.6 g. of 4-ethoxy-1-ethyl-1H-pyrazolo-[3,4-b]pyridine-5-carboxamide [J. Het. Chem. 9, 235 (1972)] (0.0154 mol.), dissolved in 100 ml. of hot methanol, are added 0.83g. of hydrazine hydrate (98%). On allowing the reaction mixture to stand for 3 days, 2.15g. of 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxamide crystallize out. Work up of the mother liquor gives another 0.9g., total yield 3.05g. (90%). The product is recrystallized from ethanol, m.p. 201°-202° (dec.).
Reaction SMILES: [Na].[NH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[C:21](OCC)(=[O:28])[CH2:22][C:23](OCC)=[O:24].Cl>C(O)C.O>[OH:24][C:23]1[CH:22]=[C:21]([OH:28])[N:7]2[N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:4]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:3]2[N:2]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Oc1cc(O)n2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2n1
Yield: 65.2 %

Procedure:
To a solution of sodium (51 mg) in dry ethanol (3 ml) was added 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (254 mg) and diethyl malonate (176 mg). The mixture was refluxed for 5 hours and cooled. To the reaction mixture were added 1N-hydrochloric acid (4 ml) and water (6 ml). The separated solid was collected, washed with water and dried to give 5,7-dihydroxy-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (210 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:17])[CH2:13][CH:12](Br)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=2)[O:5]1.[N:18]1[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([OH:25])[N:19]=1>CS(C)=O>[CH3:3][C:4]1([CH3:17])[CH2:13][CH:12]([O:24][C:23]2[N:18]=[N:19][C:20]([OH:25])=[CH:21][CH:22]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=2)[O:5]1
Reactant: Oc1ccc(O)nn1
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CC(Oc2ccc(O)nn2)c2cc(C#N)ccc2O1
Reaction time: 72 h

Procedure:
1.2 g of 80% NaH are added to a solution of 2.66 g of 2,2-dimethyl-4-bromo-6-cyanochroman (m.p. 89-92°; obtainable by reduction of 2,2-dimethyl-6-cyano-4-chroma-none with NaBH4 in CH3OH to give oily 2,2-dimethyl-6-cyano-4-chromanol and reaction with PBr3 in toluene at 20°) and 2.5 g of pyridazine-3,6-diol in 70 ml of DMSO and the mixture is stirred at 20° for 3days. After customary working up, 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-cyanochroman, m.p. 221-224°, is obtained.
Reaction SMILES: [CH2:1]1[O:15][C:14]2[C:3](=[CH:4][C:5]3[O:10][CH2:9][CH:8]([CH2:11][NH2:12])[O:7][C:6]=3[CH:13]=2)[O:2]1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:26]1[C:27]2[C:22](=[C:21]([O:20][CH2:19][CH2:18][CH2:17][NH:12][CH2:11][CH:8]3[O:7][C:6]4[CH:13]=[C:14]5[O:15][CH2:1][O:2][C:3]5=[CH:4][C:5]=4[O:10][CH2:9]3)[CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: NCC1COc2cc3c(cc2O1)OCO3
Reactant: BrCCCOc1cccc2ncccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(OCCCNCC2COc3cc4c(cc3O2)OCO4)c2cccnc2c1
Temperature: 80 °C
Yield: 38.6 %

Procedure:
2,3-Dihydro-6,7-methylenedioxy-1,4-benzodioxin-2-methanamine (2.3 g, 11 mmole), 5-(3-bromopropoxy)quinoline (2.54 g, 9.2 mmole), and diisopropylethylamine (2.6 g, 20 mmole) were combined in 100 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 500 ml of dichloromethane. The mixture was washed with 250 ml each of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 250 g of silica gel using 2% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue (2.0 g) recrystallized from 50 ml of ethanol with the addition of 6 ml of 4N isopropanolic HCl to give 1.4 g of the title compound as an orange solid dihydrochloride, one-quarter hydrate, m.p. 140°-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:27])[CH2:14][S:13](=[O:16])(=[O:15])[C:12]([CH3:18])([CH3:17])[C:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:10]2)[C:5]([F:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:38](Br)[CH:39]=[CH2:40]>C1COCC1>[CH2:40]([C@H:14]1[S:13](=[O:15])(=[O:16])[C:12]([CH3:18])([CH3:17])[C:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:10][C@@:9]1([C:4]1[C:5]([F:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:27])[CH:39]=[CH2:38]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)CS(=O)(=O)C1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@@](C)(c2cc(Br)cnc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
To a solution of (R)-tert-butyl (5-(5-bromo-2-fluoropyridin-3-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (1.02 g, 2.197 mmol) in THF (13 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (1 M in THF, 13.2 mL, 13.2 mmol) dropwise. The solution was stirred at −78° C. for 30 min and allyl bromide (0.570 mL, 6.59 mmol) was added. The reaction mixture was stirred at −78° C. for 70 min, quenched with saturated NH4Cl, warmed to room temperature and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, concentrated. Purification by flash column chromatography on silica gel (40 g, 10% to 40% EtOAc in hexanes) gave tert-butyl ((5R,6R)-6-allyl-5-(5-bromo-2-fluoropyridin-3-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.703 g, 1.39 mmol, 63% yield) as a white solid, LC/MS (ESI+) m/z=504 (M+H); and tert-butyl ((5R,6S)-6-allyl-5-(5-bromo-2-fluoropyridin-3-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.280 g, 0.555 mmol, 25% yield) as white solid, LC/MS (ESI+) m/z=504 (M+H). The two products were recombined and used in the next step.
Reaction SMILES: C([Li])CCC.[C:6](=[N:19][C:20]1[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=1[F:27])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:28][S:29]C.[Cl-].[NH4+]>O1CCCC1.O>[C:6](=[N:19][C:20]1[CH:25]=[C:24]([S:29][CH3:28])[CH:23]=[CH:22][C:21]=1[F:27])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSC
Reactant: Fc1ccc(Br)cc1N=C(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(F)c(N=C(c2ccccc2)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
2.2 mL n-butyl lithium (2.66 M hexane solution) was added dropwise to a solution of 1.85 g benzhydrylidene-(5-bromo-2-fluorophenyl)-amine (compound in Production Example 336) in 10 mL tetrahydrofuran at −70° C., then the mixture was stirred for 15 minutes, a solution of 0.53 mL methyl sulfide in 5 mL tetrahydrofuran was added dropwise thereto, and the mixture was stirred at 0° C. for 2 hours. An aqueous saturated ammonium chloride solution was added thereto, and the reaction mixture was diluted with water, extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1.24 g of the title compound (colorless oil).
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[N:9]=1>O1CCCC1>[C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([S:4][CH:1]([CH3:3])[CH3:2])[N:9]=1)#[N:15]
Reactant: N#Cc1cccc(Cl)n1
Reactant: CC(C)S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Sc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
Isopropyl mercaptan (0.60 g, 7.9 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7 mmol). The reaction mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give the titled compound (1.40 g, ca. 100%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[N:7][C:8]([CH:11]=[CH:12][C:13]3[CH:14]=[C:15]([C@H:19]([S:32][CH2:33][C:34]4([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH2:36][CH2:35]4)[CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([OH:31])([CH3:30])[CH3:29])[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[C:6]2=[N:7][C:8]([CH2:11][CH2:12][C:13]3[CH:14]=[C:15]([C@H:19]([S:32][CH2:33][C:34]4([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH2:36][CH2:35]4)[CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([OH:31])([CH3:30])[CH3:29])[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(C=Cc3ccc4scc(Cl)c4n3)c2)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(CCc3ccc4scc(Cl)c4n3)c2)CC1
Reaction time: 5 h
Yield: 39.7 %

Procedure:
To a solution of the olefin of Step 18 of Example 1 (270 mg, 0.456 mmol) in THF at 0° C. was added BH3 in THF (1M) (1.36 mL, 1.37 mmol). The mixture was stirred for 5 hr. at room temperature. Addition of 25% aq. NH4OAc and extraction with EtOAc followed by purification by flash chromatography (15% EtOAc in toluene) afforded 110 mg (41%)of the saturated compound.
Reaction SMILES: [NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([O:22]CC1C=CC=CC=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1>CO.O.[Pd]>[NH:1]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
12 g of Boc-Tyr-(D)Ala-Gly-OBzl are dissolved in a mixture of methanol/H2O (9:1) and hydrogenated in the presence of Pd-C at normal pressure and room temperature. The mixture is filtered off from the catalyst, reduced in volume and crystallised from methanol/CH2Cl2 /ether. Decomp. 110°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[N:8]([C@H:17]2[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]2)[C:7]1=[O:24].[C:30](O)(=[O:32])[CH3:31].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:30]([O:23][C@@H:20]1[CH2:19][CH2:18][C@H:17]([N:8]2[C:9]3=[N:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[C:14]3[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:2]([Cl:1])[CH:3]=3)[C:7]2=[O:24])[CH2:22][CH2:21]1)(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ncc(C#N)cc32)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@@H](OC(C)=O)CC3)c3ncc(C#N)cc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-chloro-4-methoxybenzyl)-6-cyano-3-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (500 mg), acetic acid (76.9 mg) and diethyl azodicarboxylate (221 mg) in anhydrous tetrahydrofuran (5 mL) was added triphenylphosphine (334 mg). The mixture was stirred at ambient temperature for overnight. The mixture was evaporated in vacuo, and the residue was purified by a silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (3:1) to give 3-(cis-4-acetoxycyclohexyl)-1-(3-chloro-4-methoxybenzyl)-6-cyano-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (150 mg) as a pale yellow gum.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[C:3]1=[O:9].O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:20].[Mg+2].C(=O)(O)[O-].[Na+]>CO.O>[CH3:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[O:20][C:3]1=[O:9]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CC1CCCC(C)C1=O
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1CCCC(C)C(=O)O1
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A 250 mL round bottom flask was charged with 2,6-dimethylcyclohexanone (2.162 mL, 2.0 g, 15.85 mmol) and 126 mL of a 1:1 methanol/water mixture. The solution stirred as magnesium monoperoxyphthalate hexahydrate (MMPP, 15.68 g, 31.7 mmol) and sodium bicarbonate (2.66 g, 31.7 mmol) were added. The reaction proceeded overnight at room temperature with stirring. The following day the crude product was extracted into ethyl acetate, washed sequentially with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulfate before concentrating in vacuo to give 1.07 g (47.5% yield) of 3,7-dimethyloxepan-2-one (61) as a clear, colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13](O)[CH3:14])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C1(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)C=CC=CC=1.O>C1(C)C=CC=CC=1>[N:35]([CH:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:9]=1)[CH3:14])=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(N=[N+]=[N-])c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
To the product from Example 164b (0.30 g, 1.0 mmol) in toluene (20 mL) was added diphenylphosphoryl azide (0.36 g 6.26 mmol), followed by 1,8-diazabicyclo[4.3.0]undec-7-ene (0.19 g, 1.3 mmol). The mixture is stirred at 25° C. for 18 h. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers are washed with 5% HCl, sat. NaCl (1×), dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by silica gel chromatography, eluting with hexanes/ethyl acetate/methanol (85:15:5) to provide the title compound (300 mg, 94%).
Reaction SMILES: O.NN.[CH3:4][N:5]1[C:9]([CH3:10])=[CH:8][N:7]([N:11]=CC2C=NC=CC=2)[C:6]1=[O:19]>CO>[NH2:11][N:7]1[CH:8]=[C:9]([CH3:10])[N:5]([CH3:4])[C:6]1=[O:19]
Reactant: Cc1cn(N=Cc2cccnc2)c(=O)n1C
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cn(N)c(=O)n1C

Procedure:
2 g of hydrazine hydrate are added to a solution of 2 g of 3,4-dimethyl-1-(pyridin-3-ylmethyleneamino)-2,3-dihydroimidazol-2-one in 12 ml of methanol and the suspension is boiled under reflux for 6 hours, then concentrated by evaporation and chromatographed on silica gel. 1 g of pyridine-3-carbaldehyde hydrazone and 0.7 g of the title compound having a melting point of 115-119° are thus obtained.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:40][CH2:41][CH3:42])[C:18]2[C:27]3[CH:26]=[C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][C:33]4=[O:37])[CH:24]=[CH:23][C:22]=3[N+:21]([O-])=[CH:20][C:19]=2[N:39]=1)[CH3:13].[OH-].[NH4+:44]>ClCCl>[NH2:44][C:20]1[C:19]2[N:39]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:40][CH2:41][CH3:42])[C:18]=2[C:27]2[CH:26]=[C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][C:33]3=[O:37])[CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: [NH4+]
Reactant: CCCn1c(COCC)nc2c[n+]([O-])c3ccc(OCCCN4CCCC4=O)cc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCCN4CCCC4=O)cc3c21
Reaction time: 16 h

Procedure:
p-Toluenesulfonyl chloride (0.700 g, 3.66 mmol) was added to a stirred mixture of 1-(3-{[2-(ethoxymethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}propyl)pyrrolidin-2-one (1.56 g, 3.66 mmol), ammonium hydroxide (24 mL), and dichloromethane (36 mL) at room temperature. After 16 hours, the layers were separated and the aqueous layer was extracted with dichloromethane (3×50 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallization from acetonitrile afforded 0.759 g of 1-(3-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}propyl)pyrrolidin-2-one as off-white needles, mp 188.5-190° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:10](O)=[O:11].O>C1(C)C=CC=CC=1>[N:1]1([CH:10]=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=CN1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of indoline (47.4 g, 398 mmol) and formic acid (30 g, 652 mmol, 1.64 eq.) in toluene (175 mL) was heated at reflux with azeotropic removal of water. After 3 h, the reaction mixture was cooled to RT. The solution was washed with water and brine, dried over Na2SO4 and concentrated. The residue was triturated with TBME and heptanes. The precipitate was filtered off, washed with heptanes and pentane and dried in vacuo at 45° C. for 4 h. Yield: 50.46 g, (86%).