Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH:34]3[CH2:35][CH:36]([OH:38])[CH2:37][CH:30]2[CH2:31][O:32][CH2:33]3)[CH2:10]1)(=[O:8])=[O:7].[CH2:39]1COCC1.[H-].[Na+].IC>CO>[F:23][C:22]([F:25])([F:24])[C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:13][CH2:14][N:9]([S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:7])=[O:8])[CH2:10][C@@H:11]2[CH2:28][N:29]2[C@H:30]3[CH2:37][CH:36]([O:38][CH3:39])[CH2:35][C@@H:34]2[CH2:33][O:32][CH2:31]3)=[CH:16][CH:17]=1)([OH:27])[CH3:26]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2CC(O)C3)cc1)C(F)(F)F
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COC1C[C@H]2COC[C@@H](C1)N2C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 25-mL round-bottomed flask was charged with 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (50 mg, 0.087 mmol, Example 107) and THF (3 mL). Sodium hydride (60% dispersion in mineral oil, 34.7 mg, 0.869 mmol, Sigma-Aldrich, St. Louis, Mo.) was added at room temperature. After gas evolution had ceased iodomethane (0.054 mL, 0.87 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. The reaction was stirred at room temperature for 20 min, then MeOH (20 mL) was added and then the reaction concentrated onto silica gel and purified via column chromatography (12 g silica gel, 0 to 100% hexanes in EtOAc) to give 1,1,1-trifluoro-2-(4-((2S)-2-(((1R,5S)-7-methoxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (endo) (10 mg) as a mixture of two isomers.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)OC(=O)c2ccccc2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Benzoyl chloride (0.295 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 17 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.308 g, 91%). 1H NMR (Acetone d6, 400 MHz) δ 8.21-8.14 (m, 2H), 8.03 (d, J=9 Hz, 2H), 7.96 (d, J=9 Hz, 1H), 7.81 (t, J=8 Hz, 1H), 7.65-7.59 (m, 2H), 7.55-7.49 (m, 2H), 7.01 (d, J=9 Hz, 1H), 5.94-5.85 (m, 1H), 5.64 (dd, J=9 and 6 Hz, 1H), 5.48 (dd, J=5 and 8 Hz, 1H), 2.34 (s, 3H), 1.62 (d, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.S(O[CH2:22][CH:23]1[CH2:27][CH2:26][CH:25]([CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)[O:24]1)(C1C=CC(C)=CC=1)(=O)=O.COCCOCCOCCOC.[OH-].[Na+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][N:8]2[CH2:28][CH:25]3[O:24][CH:23]([CH2:27][CH2:26]3)[CH2:22]2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOCCOC
Product: Clc1ccc(CCN2CC3CCC(C2)O3)cc1
Temperature: 180 °C
Reaction time: 3 h

Procedure:
p-Chlorophenethylamine (0.643 mole, 100 grams) was added to a mixture of 2,5-bis(tosyloxymethyl)tetrahydrofuran (0.214 mole, 99.6 grams) and 200 ml of Ansul 161 (triethylene glycol dimethyl ether) and stirred the reaction mixture for 3 hours at 180° C. The reaction mixture was cooled to room temperature and neutralized with a methanolic sodium hydroxide solution (0.429 mole, 17.14 grams NaOH in 200 ml CH3OH) while stirring for 15 minutes. The solvents and excess starting amine were distilled from the reaction mixture under aspirator pressure. The residue was filtered collecting the sodium p-toluenesulfonate. The filtrate was distilled collecting one fraction (terminal pot temperature 280° C./0.1 mm Hg). The distillate which solidified was recrystallized from methanol obtaining 3-(p-chlorophenethyl)-8-oxa-3-azabicyclo(3.2.1)octane.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([CH:14]([CH2:17][CH:18]=[CH2:19])[CH2:15][OH:16])([CH3:13])[CH3:12].C(N(CC)CC)C.Cl>ClCCl>[CH:11]([CH:14]([CH2:17][CH:18]=[CH2:19])[CH:15]=[O:16])([CH3:13])[CH3:12]
Reactant: C=CCC(CO)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CCC(C=O)C(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Dimethyl sulfoxide (18.70 mL, 263.3 mmol) was added dropwise over 15 minutes to a dichloromethane (290 mL) solution of oxalic acid chloride (17.30 g, 136.3 mmol) cooled to −78° C., and the mixture was then stirred at −78° C. for 15 minutes. Subsequently, a dichloromethane (75 mL) solution of 2-isopropylpent-4-en-1-ol (11.30 g, 88.1 mmol) was added dropwise thereto over 30 minutes, and the mixture was stirred at −78° C. for 1 hour. Triethylamine (62.40 g, 616.7 mmol) was added dropwise thereto over 5 minutes, and the mixture was then stirred at room temperature for 2 hours. The mixture was neutralized with 2 N hydrochloric acid (320 mL). The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain a yellow oil substance as a mixture containing the compound of interest. This compound was used in the next reaction without being further purified.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][CH3:13].[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:9][NH:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]2[N:1]=[C:13]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:12]([CH3:29])[C:3]=2[CH:4]=1)=[O:7]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: CNC(=O)c1ccc(N)c(NC)c1
Solvent: ClCCCl
Product: CNC(=O)c1ccc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2c1
Yield: 2 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylic acid methylamide (11 mg) was prepared by following General Procedure D starting from 4-amino-N-methyl-3-methylamino-benzamide (298 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (303 mg), 1,1′-thiocarbonyl-diimidazole (329 mg), and EDC (398 mg). LC/MS: m/z 422.9. 1H NMR (DMSO-d6, 400 MHz): δ 8.39 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.69 (s, 1H), 7.54 (d, 1H), 7.45 (s, 1H), 7.33 (d, 1H), 6.73 (d, 1H), 3.63 (bs, 3H), 3.46 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=C)[N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.[O:14]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.ClCCl>[CH:8]([C:6]1[N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=[C:2]([CH3:1])[CH:7]=1)=[O:14]
Reactant: C=Cc1cc(C)cc(NC(C)=O)n1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1cc(C)cc(C=O)n1
Temperature: -80 °C
Reaction time: 0.08 h

Procedure:
5.0 g N-(4-methyl-6-vinyl-pyridin-2-yl)-acetamide (compound F5) are dissolved in a mixture of each 200 ml methanol and dichloromethane and cooled to −80° C. Subsequently, ozone is passed into the solution (flow 20-25 l/h ozone). After 5 min ozone treatment is stopped. Thereafter, nitrogen is applied for 5 min and 7.44 g of triphenylphosphane are added while stirring is continued. The solution is allowed to warm up to r.t. Subsequently, the volatile components are removed in vacuo and the residue is purified by chromatography on silica gel (eluent cyclohexane/ethyl acetate 3:1) to afford 2.72 g of the title compound as colourless solid. M.p. 202° C. GC-MS: 178.2 (M+). TLC: Rf=0.50 (cyclohexane/ethyl acetate 1:1). [Remark: Occasionally remaining traces of triphenylphosphine oxide can be removed by dissolving crude product in ethyl acetate followed by cooling to precipitate triphenylphosphine oxide.]
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:44][CH2:45][C:46]1[N:47]=[CH:48][N:49]([C:51]2[CH:56]=[CH:55][C:54]([N:57]3[CH2:62][CH2:61][CH2:60][CH2:59][C:58]3=[O:63])=[CH:53][CH:52]=2)[CH:50]=1>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:44][CH2:45][C:46]2[N:47]=[CH:48][N:49]([C:51]3[CH:52]=[CH:53][C:54]([N:57]4[CH2:62][CH2:61][CH2:60][CH2:59][C:58]4=[O:63])=[CH:55][CH:56]=3)[CH:50]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NCc1cn(-c2ccc(N3CCCCC3=O)cc2)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1cn(-c2ccc(N3CCCCC3=O)cc2)cn1)c1ccc(Cl)s1
Reaction time: 0.08 h
Yield: 60.3 %

Procedure:
To a solution of 5-chloro-thiophene-2-carboxylic acid 1-5 (43 mg, 0.26 mmol) and triethylamine (0.200 mL, 1.43 mmol) in DMF (2 mL), BOP (130 mg, 0.29 mmol) was added. After 5 min of stirring, the solution was added to a solid sample of 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)piperidin-2-one (54 mg, 0.18 mmol) in a flask. After being stirred at room temperature for 2 h, the mixture was purified by HPLC to give the titled compound (45 mg). MS 415.1 and 417.1 (M+H, Cl pattern).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]=C)(=[O:3])[CH3:2].[C:9]1([SiH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C>C1(C)C=CC=CC=1>[C:22]1([Si:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc([SiH](c2ccccc2)c2ccccc2)cc1
Reactant: C=CC=COC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OCC=C[Si](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 1-acetoxy-1,3-butadiene (0.1 mol), triphenylsilane (0.1 mol), and Rh2Cl2 (CO)4 (194.5 mg, 0.625 mol) in 100 mL of toluene was stirred at room temperature under argon for 3 days. The reaction mixture is treated with decolorizing charcoal, and the mixture boiled briefly. After cooling, the reaction mixture is filtered through Celite. Concentration of the solution will afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.II.[Cl:14]Cl>[Fe](Cl)(Cl)Cl>[Cl:14][C:3]1[CH:4]=[C:5]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: ClCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl[Fe](Cl)Cl
Agent: II
Product: Cc1ccc(S(=O)(=O)Cl)cc1Cl

Procedure:
576 g (3 mol) of 4-methylbenzenesulfonyl chloride are melted in a chlorination apparatus. After addition of 7 g of iron(III) chloride and 2 g of iodine, elemental chlorine is passed in (5 l Cl2 /h) at from 75° to 80° C. until 100% chlorination is achieved (GC analysis).
Reaction SMILES: [CH2:1]([C@@:3]1([CH:22](OCC)[O:23]CC)[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[NH:13][CH:12]=2)[C:4]1=[O:21])[CH3:2].C(O)(=O)C.O>C(Cl)(Cl)Cl>[CH2:1]([C@@:3]1([CH:22]=[O:23])[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[NH:13][CH:12]=2)[C:4]1=[O:21])[CH3:2]
Reactant: CCOC(OCC)[C@]1(CC)CCCN(CCc2c[nH]c3ccc(F)cc23)C1=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CC[C@@]1(C=O)CCCN(CCc2c[nH]c3ccc(F)cc23)C1=O

Procedure:
39.05 g of (S)-3-ethyl-3-diethoxymethyl-1-[2-(5-fluoro-indol-3-yl)-ethyl]-2-piperidone are mixed with 80 cc of 99% acetic acid and 20 cc of water. The mixture is heated to the boil for half an hour in an atmosphere of nitrogen. After cooling, the solvent is removed by evaporation; the oily residue is subsequently taken up twice in 50 cc amounts of toluene and again concentrated by evaporation in order to remove most of the water and acetic acid. After crystallization from ethyl acetate/hexane (1:2) at 0°, brownish crystals are obtained. M.P. 116°, [α]D20 = -31.5° (1%, CHCl3).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11](N2CCCCC2)=[O:12])=[CH:5][C:4]2[O:19][CH2:20][O:21][C:3]=2[CH:2]=1.[OH-:22].[K+].CO.Cl>O>[CH2:20]1[O:19][C:4]2[CH:5]=[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:12])=[O:22])[CH:1]=[CH:2][C:3]=2[O:21]1
Reactant: [OH-]
Reactant: O=C(/C=C/C=C/c1ccc2c(c1)OCO2)N1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/C=C/c1ccc2c(c1)OCO2

Procedure:
To piperine (1) (2 g, 0.7 mmol, 1 eq), 20% of methanolic KOH (100 ml) was added and refluxed for 2 days. After completion of the hydrolysis, methanol was removed under reduced pressure and a yellow coloured oily solid was obtained. This residue was dissolved in water (50 ml) and acidified with 6N HCl to pH<1 yielding a yellowish precipitate of piperinic acid. Recrystallization from methanol gave yellow needles (0.9 g, 60% yield). m.p. 206°-208° C. (Lit m.p. 217°-218° C.)1
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[N:17]1([C:22]2[CH:30]=[CH:29][C:25]([C:26]([O-])=[O:27])=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:23][CH:24]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C([O-])c1ccc(N2CCCC2)cc1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCCC4)cc3)cc2)cc1)c1ccc(N2CCCC2)cc1

Procedure:
Compound 324 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-pyrrolidinobenzoate. [M+H]+ calcd for C35H34N4O3: 559.27; found: 559.00.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1.Br[CH2:15][CH2:16][CH3:17].CC(N1CCCC(C(C)=O)=C1)C>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[N:9]([CH2:15][CH2:16][CH3:17])[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1
Reactant: CCCBr
Reactant: CC1(C)CC(=O)C2=C(C1)NCCC2
Agent: CC(=O)C1=CN(C(C)C)CCC1
Product: CCCN1CCCC2=C1CC(C)(C)CC2=O

Procedure:
7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinolin-5 (6H)-one [prepared by the method of Grob and Kiefer, Helv. Chim Acta., 48 799, (1964)] was reacted with 1-bromopropane according to the procedure of Part (b) of Example 1 to give 7,7-dimethyl-1,2,3,4,7, 8-hexahydro-1-propyl-quinolin-5(6H)-one (17) as an oil.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12](I)[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:12]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCI
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1cc(C=O)ccc1OC
Temperature: 25 °C

Procedure:
Isovanillin (6.00 g, 39.4 mM), butyl iodide (5.7 ml, 49.3 mM), and anhydrous potassium carbonate (6.8 g, 49.3 mM) were dissolved in dried dimethylformamide (50 ml) and stirred at room temperature for one night, then the solution was diluted with ethyl acetate (300 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to obtain a residue as a light yellow oil. The residue was purified by flash chromatography (SiO2: eluted by 20% ethyl acetate/hexane solution). The solvent was removed in vacuo and the resultant product was dried to obtain 3-butoxy-4-methoxy-3-benzaldehyde 8.09 g (yield 99.0%) as a light yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:20]([O-:22])=[O:21])[CH3:2].[N-:23]=[C:24]=[S:25]>>[CH2:8]([NH:23][C:24]([N:17]1[CH2:18][CH2:19][N:14]([C:8]2[C:7]3[C:12](=[CH:13][C:4]([NH:3][CH2:1][CH3:2])=[C:5]([N+:20]([O-:22])=[O:21])[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH2:15][CH2:16]1)=[S:25])[C:7]1[CH:12]=[CH:13][CH:4]=[CH:5][CH:6]=1
Reactant: CCNc1cc2ncnc(N3CCNCC3)c2cc1[N+](=O)[O-]
Reactant: [N-]=C=S
Product: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1[N+](=O)[O-]
Yield: 77 %

Procedure:
Substantially the same procedure as in Example 60 was repeated, except that 7-ethylamino-6-nitro-4-(1-piperazinyl)quinazoline obtained in Reference Example 5 (1) was used in place of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline, and the corresponding isothiocyanate was used in place of 4-phenoxyphenyl isocyanate, to give the desired compound.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[CH2:34]1C2C(=CC=CC=2)CC1CCO.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:34][CH:19]1[CH2:18][CH2:17][N:16]([C@H:27]1[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]1)[C:14](=[O:15])[NH:13][C:11]1[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: OCCC1Cc2ccccc2C1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCC2Cc3ccccc3C2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-indan-2-yl-ethanol (prepared as described in J. Med. Chem. 1994, 37, 13, 2071-2078) and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: CC([N:5]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[C:26]([C@@H:29]4[CH2:33][CH2:32][CH2:31][N:30]4[C:34](=[O:44])[C@@H:35]([NH:39][C:40]([O:42][CH3:43])=[O:41])[CH:36]([CH3:38])[CH3:37])[NH:27][CH:28]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])C(=O)[O-])(C)C.Cl>C(Cl)Cl>[NH2:5][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:25]=[C:26]([C@@H:29]4[CH2:33][CH2:32][CH2:31][N:30]4[C:34]([C@@H:35]([NH:39][C:40](=[O:41])[O:42][CH3:43])[CH:36]([CH3:38])[CH3:37])=[O:44])[NH:27][CH:28]=3)=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)CN(C(=O)[O-])C(C)(C)C)cc3)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)CN)cc3)cc2)c[nH]1)C(C)C

Procedure:
A solution of 1,1-dimethylethyl[2-(4′-{2-[(2S)-1-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2-pyrrolidinyl]-1H-imidazol-4-yl}-4-biphenylyl)-2-oxoethyl]carbamate (Intermediate 11) (3.8 g, 6.3 mmol) in DCM (40 mL) was treated with HCl (10 mL, 4M in dioxane) to give methyl {(1S)-1-[((2S)-2-{4-[4′-(aminoacetyl)-4-biphenylyl]-1H-imidazol-2-yl}-1-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate (Intermediate 1) as light yellow solid (3.5 g, quant.).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][CH:9]([CH3:17])[C:10](=[O:16])[CH2:11][C:12]([O:14]C)=O.C(N)CN.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH3:17][CH:9]([CH3:8])[C:10](=[O:16])[CH2:11][C:12]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14]
Reactant: Nc1ccccc1
Reactant: COC(=O)CC(=O)C(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: NCCN
Product: CC(C)C(=O)CC(=O)Nc1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 157.4 %

Procedure:
A three-necked, 12-L round-bottom flask equipped with a mechanical stirrer, a thermometer and set up for distillation is charged with 2.6 L of toluene, 1.73 kg (12 mol) of methyl 4-methyl-3-oxopentanoate and 72 g (1.18 mol) of ethylene diamine. The mixture is heated to 80° C. and charged with 0.49 kg of aniline. The mixture is brought to reflux and distillation started. After 40 minutes a further 0.245 kg of aniline is charged and at 40 minute intervals a further two portions of aniline (0.245 and 0.25 kg) are charged. Distillation is continued for a further one to five hours until a total of 985 mL of solvent is removed. The solution is stirred at room temperature for 16 hours and a further 550 mL of solvent is removed by vacuum distillation (using approximately 85 mm Hg). The mixture is cooled and 2 L of water is charged to provide an oil. The mixture is warmed to 40° C. and a further 1.0 L of water is charged. Seven hundred milliliters of toluene-water mixture is removed by vacuum distillation (approximately 20 mm Hg). Two liters of water is charged and the mixture is allowed to stand for 10 days. The product is isolated by filtration and washed with three portions of hexane. Drying in vacuo gives 1.7 kg of 4-methyl-3-oxo-N-phenylpentanamide as a hydrate; mp 46.5°-58.8° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[C:12]([O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1cccc(CO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCc1cccc(C(N)=O)n1

Procedure:
A mixture of 6-hydroxymethyl-2-pyridinecarboxamide (80 g) and acetic anhydride (198.8 ml) in tetrahydrofuran (800 ml) was heated under reflux for 24 hours. The reaction mixture was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 6 -acetoxymethyl-2-pyridinecarboxamide (93.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH3:16])[CH:3]=1.[CH:17]([Li])(CC)C.O.Cl.[O:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:11]([O:10][C:9](=[O:15])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH2:16][C:28](=[O:24])[CH2:27][CH:26]([CH3:17])[CH3:25])([CH3:12])([CH3:13])[CH3:14]
Reactant: C1CCOC1
Reactant: [Li]C(C)CC
Reactant: Cc1cc(Cl)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Product: CC(C)CC(=O)Cc1cc(Cl)ccc1NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (4-chloro-2-methyphenyl)carbamate (483 mg) in tetrahydrofuran (7 mL) was added dropwise sec-butyllithium (1.04 mol/L hexane-cyclohexane solution, 4.3 mL) at −40° C. under an argon atmosphere, and the mixture was stirred for 15 minutes. Then a solution of N-methoxy-N,3-methylbutylamide (319 mg) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at −40° C. for 15 minutes and at room temperature for 2 hours. Water and 1 mol/L hydrochloric acid were added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The aqueous layer was extracted once again with ethyl acetate. The combined organic layers were washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (282 mg).