Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[CH3:6][CH:5]([CH3:7])[C@H:4]([NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:3]([OH:43])=[O:2]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(-c5ccccc5)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2cccc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 32.3 %

Procedure:
To 38 mg of (S)-3-methyl-2-{4′-[(3-methyl-4-phenyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid methyl ester dissolved in 0.5 mL of THF was added 2 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 4 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 12 mg of (S)-3-methyl-2-{4′-[(3-methyl-4-phenyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid, obtained as pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=13.6, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.2 (s, 3 H) 3.5 (m, 1 H) 7.2 (dd, J=7.3, 1.0 Hz, 1 H) 7.5 (m, 5 H) 7.6 (dd, J=8.3, 7.3 Hz, 1 H) 7.7 (dd, J=8.3, 1.0 Hz, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.8 (m, 4 H) 8.0 (m, 3 H) 10.6 (s, 1 H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[NH:24][C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:28]=2[N:29]=1>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[NH:24][C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH:34][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:31]=[CH:30][C:28]=2[N:29]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: O=C(Cl)c1ccccc1
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccccc5)cc4s3)c2cc1OC

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl ]benzamide was prepared from benzoyl chloride (14 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 40 mg, 87 mmol, 77%). LC/ESI-MS: m/z=458 [M+H]+; m/z=456 [M−H]−; Rt=3.13 min.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O-:17])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(C)C=CC(S(O)(=O)=O)=C[CH:19]=1>C(O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])Cc1ccc(Oc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Oc2ccccc2)cc1
Yield: 404.9 %

Procedure:
To a suspension of (4′-phenoxyphenyl)acetate acid (0.456 g) in 4 ml of ethanol is added para-toluensulfonic acid (0.076 g) and the resulting mixture is refluxed for 2 hours. The solvent is evaporated off, the residue is dissolved in diethyl ether and the organic phase is washed with saturated aqueous solution of sodium hydrogencarbonate and then with brine. The organic phase is dried over sodium sulfate and concentrated to dryness to give 0.458 g of the product as a brown oil.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][S:5][CH2:6][CH2:7][C:8]#[N:9].[C:11]([NH:14][C:15]([NH2:17])=[S:16])(=[NH:13])[NH2:12]>CC(C)=O>[C:8]([CH2:7][CH2:6][S:5][CH2:4][C:3]1[N:17]=[C:15]([N:14]=[C:11]([NH2:13])[NH2:12])[S:16][CH:2]=1)#[N:9]
Reactant: N=C(N)NC(N)=S
Reactant: N#CCCSCC(=O)CCl
Solvent: CC(C)=O
Product: N#CCCSCc1csc(N=C(N)N)n1
Temperature: 50 °C
Reaction time: 9 h
Yield: 84.4 %

Procedure:
To a solution of 8.9 g of 1-chloro-3-(2-cyanoethylthio)propanone in 100 ml of acetone is added 6.3 g of amidinothiourea and the reaction mixture is stirred at 50° C. for 9 hours. Also, the reaction mixture is concentrated under reduced pressure, made basic with saturated sodium carbonate solution, and extracted with chloroformmethanol (10:1) solution (170 ml×2). The combined organic layer is dried over anhydrous magnesium sulfate, and is concentrated in vacuo to give a solid, which is crystallized from acetone-hexane to afford 10.2 g of the title compound, m.p.: 125°-128° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccccn1
Product: CN(C)C=CC(=O)c1ccccn1

Procedure:
A solution of 250 ml of 2-acetylpyridine and 500 ml of N,N-dimethylformamide dimethyl acetal was heated on a steam bath for 6 hours. After concentrating the reaction solution under vacuum, 1 liter of hexane was added to the part crystalline residue. The product was collected as small crystalline particles which were washed with an additional liter of hexane. Air drying was followed by drying at 45° C. under vacuum, leaving 350.7 g of 3-dimethylamino-1-(2-pyridinyl)-2-propen-1-one.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12]([N:16]=[C:17]=[S:18])[CH2:13][CH2:14][CH3:15].O>CN(C)C=O>[CH2:12]([N:16]1[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=[C:17]1[SH:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN=C=S
Reactant: COC(=O)c1ccccc1N
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(S)nc2ccccc2c1=O
Reaction time: 8 h

Procedure:
A stirred mixture of 7.6 g (0.05 mole) methyl anthranilate and 5.8 g (0.05 mole) n-butyl isothiocyanate in 45 ml dimethylformamide was heated at reflux for 11/2 hours, stirred overnight, then heated for 6 hours and then stirred at ambient temperature over the weekend. The reaction mixture was poured into 200 ml water (at 20° C.) to give a precipitate. The mixture was chilled and then filtered. The precipitate was washed three times with water; the filtrate was set aside. A small amount of ethanol was drained through the filter cake once. The solid was washed twice with hexane and air-dried overnight to give the above-identified product, as a solid, melting point 167°-172° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)=[O:26].C(N(CC)CC)C>C(Cl)Cl.O.CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25](=[O:26])[CH2:24][NH:23][C:14]([CH:10]2[O:11][CH2:12][CH2:13][N:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:9]2)=[O:16])=[CH:32][CH:31]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Reactant: NCC(=O)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 125.3 %

Procedure:
To a mixture of 4-(phenylmethyl)-2-morpholinecarboxylic acid (1.61 g, 7.28 mmol) and DMF (0.1 mL) in CH2Cl2 (70 mL) was added oxalyl chloride (0.956 mL, 10.92 mmol) at 25° C. The mixture was stirred at this temperature for 1 hour and the mixture turned clear. The solvent and excess of oxalyl chloride were removed in vacuo, and the resulting residue was dissolved in CH2Cl2 (70 mL). 2-Amino-1-(4-chlorophenyl)ethanone (1.5 g, 7.28 mmol) and triethylamine (4.06 mL, 29.1 mmol) were added, and the resulting mixture was stirred overnight. Water (80 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×80 mL). The combined organics were washed with sat. NaHCO3 aq. (80 mL), then brine (2×80 mL), dried (MgSO4), and evaporated to get 3.4 g yellow residue, which was chromatographed (EtOAc-petroleum ether, 1:1) to afford the title compound (2.5 g). LC-MS (ES) m/z=373 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH:8]=[CH:7]1)=[O:5])[CH3:2].CCOC(C)=O>[Pd].CO>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C=Cc2ccsc2C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2ccsc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A mixture of 6-ethoxycarbonyl-6,7-dihydrobenzo[b]thiophene (1.00 g), 10% palladium on carbon (2.16 g), AcOEt (30 ml) and MeOH (10 ml) was stirred at r.t. under hydrogen atmosphere for 4 hours. After removal of insoluble solids, the filtrate was concentrated in vacuo to give 6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (0.96 g) as an oil.
Reaction SMILES: [H-].[Na+:2].[OH-].[OH-].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCCC1>[CH2:21]([O:20][C:18]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=[O:13])=[O:14])=[CH:8][CH:7]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+:2]
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)Oc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an aqueous solution (40 ml) of sodium hydride (3.8 g), sodium 4-hydroxybenzenesulfonate dihydroxide (20 g) and tetrahydrofuran (28 ml) was added. To the mixture, benzyl chloroformate (12.3 ml) was added at 0° C. The mixture was stirred for 1 hour at 0° C. and for 1 hour at room temperature. The reaction mixture was concentrated. The precipitated crystals was washed with water and dried to give the title compound (18.1 g) having the following physical data.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[Cl:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH:29]1[O:33][CH2:32][CH2:31][O:30]1.[O:34]1CCC[CH2:35]1>CCCCCC.O.C(O)(=O)C.CN(C)C=O>[Cl:21][C:22]1[C:23]([CH:29]2[O:30][CH2:31][CH2:32][O:33]2)=[CH:24][CH:25]=[C:26]([F:28])[C:27]=1[CH:35]=[O:34]
Reactant: C1CCOC1
Reactant: Fc1ccc(C2OCCO2)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1c(F)ccc(C2OCCO2)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (4.25 mL) in tetrahydrofuran (25 ml) was added dropwise 1.6 mol/L solution (18.9 mL) of n-butyllithium in hexane at −78° C., and the mixture was stirred at 0° C. for 1 hr. To the prepared lithium diisopropylamide was added dropwise a solution of 2-(2-chloro-4-fluorophenyl)-1,3-dioxolane (5.34 g) in tetrahydrofuran (25 mL) at −78° C. The mixture was stirred at the same temperature for 1 hr, and N,N-dimethylformamide (2.3 mL) was added thereto. The reaction mixture was stirred for 30 min, and acetic acid was added thereto. After the temperature of the reaction mixture was raised to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=9:1→1:1) and recrystallized from hexane to give the title compound as a colorless solid (yield: 3.96 g).
Reaction SMILES: C[O:2][C:3]1([O:9][CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:11][C:12]([O:15]O)([CH3:14])[CH3:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CS(C)=O>[CH3:10][O:9][C:3]1([O:2][O:15][C:12]([CH3:14])([CH3:13])[CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OO
Reactant: COC1(OC)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Product: COC1(OOC(C)(C)C)CCCCC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
A mixed solution consisting of 16.4 g of dimethyl sulfoxide and 1.2 g of p-toluenesulfonic acid was kept at 20° C., and another mixed solution consisting of 28.9 g of cyclohexanone-dimethylacetal and 18.5 g of 1,1-dimethylethyl hydroperoxide was dropwise added to the former mixed solution. The resulting solution has an acid concentration of 0.1 mol/kg of the solution. The solution was stirred at 20° C. for 3 hours to complete the reaction. Then, 20 ml of petroleum ether was added to the solution, and the resulting solution was washed with 10 ml of water, then with 50 ml of a 5% NaOH aqueous solution, and further with 20 ml of water 3 times, and then dried by means of anhydrous sodium sulfate. The solvent was distilled off from the dried solution under vacuum to obtain 26.1 g (yield: 57%) of crude 1-methoxy-1-(1,1-dimethylethylperoxy)cyclohexane having a purity of 89%. The resulting crude peroxyketal was distilled at 40°-45° C. under a vacuum of 1 mmHg to obtain a purified peroxyketal having a purity of 99%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.C[Si]([N-:39][Si](C)(C)C)(C)C.[Li+]>CC(OC)(C)C.COC1C=CC=C(OC)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH3:34][O:33][CH2:32][CH2:31][O:30][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH2:39])=[CH:3][C:4]=2[N:10]([C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:9]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COCCOc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: Cl[Pd+]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: NCCc1[c-]cccc1
Solvent: COC(C)(C)C
Product: COCCOc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(N)ncc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
6-chloro-3-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (500 mg, 1.064 mmol) and SPHOS Palladacycle (162 mg, 0.213 mmol) were mixed in a pressure release vial, degassed and backfilled with Nitrogen (3×), tetrahydrofuran (8 mL) was added, followed by the addition of lithium bis(trimethylsilyl)amide (1M) (2.128 mL, 2.128 mmol), the resultant mixture was degassed and backfilled with nitrogen (3×), and heated up to 60° C. for overnight. Hydrochloric acid 1M (2 mL) was added, and the mixture was stirred at room temperature for 2 h, the mixture was basified with aqueous sodium hydroxide (1M, ˜4 mL) to pH 9, and the mixture was extracted with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (saturated, lx 10 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc/isohexane=50%-100% to give 3-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (32B, 432 mg, 0.959 mmol, 90% yield) as a brown solid. MS: [M+H]+ m/z 451.
Reaction SMILES: C([O:4][CH2:5]/[CH:6]=[CH:7]/[CH2:8][N:9]1[C:14]([C:15](=[O:24])[C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[C:13]([CH2:25][CH3:26])[C:12](=[O:27])[NH:11][C:10]1=[O:28])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[OH:4][CH2:5]/[CH:6]=[CH:7]/[CH2:8][N:9]1[C:14]([C:15](=[O:24])[C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)=[C:13]([CH2:25][CH3:26])[C:12](=[O:27])[NH:11][C:10]1=[O:28]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)n(C/C=C/COC(C)=O)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(C/C=C/CO)c(=O)[nH]c1=O
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a stirred solution of 50 mg (0.13 mmol) of the compound obtained from Example 80 in 5 ml of methanol was added 20 mg (0.37 mmol) of sodium methoxide at room temperature. After 1 hour, the reaction mixture was neutralized with acetic acid and evaporated under reduced pressure to give a yellow-colored residue, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (4:1) as an eluent to afford 26 mg (yield 56%) of the title compound as a white solid.
Reaction SMILES: [K].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([SH:12])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1.F[C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH3:20])[CH:19]=1>CN1CCCC1=O>[CH3:11][O:10][C:8]1[CH:7]=[C:6]([S:12][C:14]2[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH3:20])[CH:19]=2)[CH:5]=[C:4]([O:3][CH3:2])[CH:9]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: COc1cc(S)cc(OC)c1
Agent: [K]
Solvent: CN1CCCC1=O
Product: COc1cc(OC)cc(Sc2ccc([N+](=O)[O-])c(C)c2)c1
Temperature: 160 °C
Reaction time: 5 h
Yield: 53.5 %

Procedure:
0.426 g (0.0021 mol) of 3,5-dimethoxythiophenol potassium salt was dissolved in 7 ml of 1-methyl-2-pyrrolidone, treated with 0.317 g (0.0021 mol) of 5-fluoro-2-nitrotoluene and a spatula tip of Cu powder and stirred at 160° C. for about 5 hrs. Thereafter, the reaction mixture was partitioned in water/diethyl ether and the organic phase was washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:9. There was obtained 0.343 g (55%) of 1-(3,5-dimethoxyphenylsulphanyl)-3-methyl-4-nitrobenzene as a yellow oil. MS (EI): me/e=305 (C15H15NO4S+).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH:6]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:26])([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][C:13]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:2]([CH3:4])[CH3:3].O.NN.[OH-].[K+].Cl>C(OCC)C.C(O)CO>[CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:26])([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][C:13]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)CCN2CC(C)C)c(OCc2ccccc2)c1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCO
Solvent: CCOCC
Solvent: O
Product: CCCCCCC(C)(C)c1ccc(C2CCCCN2CC(C)C)c(OCc2ccccc2)c1
Temperature: 100 °C

Procedure:
A mixture of 2.32 g (5 mmoles) of N-isobutyl-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidone, 10.2 ml hydrazine hydrate and 20 ml ethylene glycol is heated at 100° C. for one hour. The mixture is cooled to 60° C, and 4.05 g (72.3 mmoles) solid potassium hydroxide is added. After heating at 200° C. for two hours, the reaction mixture is cooled and added to 500 ml 1N hydrochloric acid and 300 ml ethyl ether. The ether layer is separated, washed with brine, sodium bicarbonate solution, dried over magnesium sulfate and the solvent evaporated at reduced pressure. The crude product is purified, if desired, by column chromatography on silica gel.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(#N)C.O>[O:28]1[CH2:29][CH2:30][N:25]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:18])[CH2:26][CH2:27]1
Reactant: C1COCCN1
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCOCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a stirred suspension of 1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.861 mmol) and potassium carbonate (1286 mg, 9.30 mmol) in acetonitrile (10 ml) was added morpholine (0.814 ml, 9.30 mmol) via a syringe. The resulting suspension was then stirred overnight at 75° C. in a sealed tube. The reaction mixture was then cooled to room temperature, diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in ethyl acetate, followed by 5% (2M NH3 in methanol) in dichloromethane, giving the desired 1-(3-morpholinopropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (560 mg, 1.754 mmol, 94% yield). 1H NMR (DMSO-d6) δ 8.14-8.10 (m, 2H), 7.40 (d, J=9 Hz, 1H), 3.95 (t, J=7.4 Hz, 2H), 3.58-3.54 (m, 4H), 3.03-2.97 (m, 2H), 2.64-2.59 (m, 2H), 2.33-2.28 (m, 6H), 1.74-1.64 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][C:6](=[O:10])[CH:7]=[N+]=[N-].[CH:20]1C=CC=CC=1>CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][C:6](=[O:10])[CH2:7][CH2:20][N:11]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:19]
Reactant: COC(=O)C(CC(=O)C=[N+]=[N-])NC(=O)OC(C)(C)C
Reactant: c1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Product: COC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a refluxing mixture of rhodium acetate dimer (0.0093 g, 0.02 mmol) and 40 mL of benzene was added dropwise a solution of 2-tert-butoxycarbonylamino-5-diazo-4-oxo-pentanoic acid methyl ester (0.60 g, 2.1 mmol) in 4.5 mL of benzene. After stirring for 2 h at reflux, the mixture was cooled to room temperature, concentrated in vacuo, and filtered through a small pad of silica gel eluting with 1:1 ethyl acetate-hexane. Concentration of the filtrate afforded 0.53 g of 4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([C:37](=[O:66])[NH:38][CH2:39][CH2:40][NH:41][C:42]([NH:44][CH:45]2[CH2:50][CH2:49][N:48]([C:51](=[O:65])[NH:52][CH:53]4[CH2:58][CH2:57][N:56]([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][N:60]=5)[CH2:55][CH2:54]4)[CH2:47][CH2:46]2)=[O:43])=[N:17][C:18]=3[NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:67])[C@@H:9]1[OH:68])(C)(C)C.[ClH:70]>CO.O1CCOCC1>[ClH:70].[ClH:70].[N:56]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][N:60]=2)[CH2:57][CH2:58][CH:53]([NH:52][C:51]([N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:42](=[O:43])[NH:41][CH2:40][CH2:39][NH:38][C:37]([C:16]3[N:15]=[C:14]4[C:19]([N:20]=[CH:21][N:13]4[C@@H:11]4[CH2:12][C@H:8]([NH2:7])[C@@H:9]([OH:68])[C@H:10]4[OH:67])=[C:18]([NH:22][CH2:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:17]=3)=[O:66])[CH2:50][CH2:49]2)=[O:65])[CH2:54][CH2:55]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(C(=O)NC5CCN(c6ccccn6)CC5)CC4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(C(=O)NC5CCN(c6ccccn6)CC5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of {(1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-(2-{3-[1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylcarbamoyl)-piperidin-4-yl]-ureido}-ethylcarbamoyl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-carbamic acid tert-butyl ester (76.7 mg, 81 μmol) in MeOH (0.5 ml) is treated with 4M HCl in dioxane (0.5 ml). After stirring at room temperature for 1 hour, the solvent is removed in vacuo to afford the title compound which is used crude in the next step.