Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH:55]1([C:58]2N=C(N)[S:60][N:59]=2)[CH2:57][CH2:56]1>ClCCl>[CH:55]1([C:58]2[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]3[CH2:20][C:19]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])=[CH:18][C:17]3=[O:29])[CH2:12][CH:13]([CH3:14])[CH3:15])[S:60][N:59]=2)[CH2:57][CH2:56]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: Nc1nc(C2CC2)ns1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1nc(C2CC2)ns1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 95 mg, 0.29 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62 mg, 0.32 mmol) and 1-hydroxybenzotriazole (41 mg, 0.30 mmol). The resulting solution was stirred for 5 min before 3-cyclopropyl-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.35 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water gradient) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (3-cyclopropyl-[1,2,4]thiadiazol-5-yl)-amide (42 mg, 32%) as a light orange solid: HR-ES-MS m/z calculated for C21H23ClN4O3S [M+H]+ 447.1252, observed 447.1252; 1H NMR (300 MHz, DMSO-d6) ppm 0.84-0.97 (m, 2H), 0.91 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.97-1.06 (m, 2H), 1.39-1.56 (m, 1H), 1.55-1.75 (m, 1H), 1.76-1.97 (m, 1H), 2.07-2.24 (m, 1H), 4.28 (d, J=18.4 Hz, 1H), 4.51 (d, J=18.4 Hz, 1H), 4.82 (s, 1H), 4.99 (dd, J=11.0, 4.4 Hz, 1H), 7.37 (td, J=8.0, 1.3 Hz, 1H), 7.47 (td, J=8.0, 1.1 Hz, 1H), 7.54 (dd, J=8.0, 1.3 Hz, 1H), 7.66 (dd, J=8.0, 1.1 Hz, 1H), 13.26 (s, 1H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[CH3:9][C:10]([NH:18][C:19]([C:21]1[N:22]=[C:23]([S:29][CH3:30])[S:24][C:25]=1[C:26]([OH:28])=[O:27])=[O:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11]>CN(C=O)C>[CH3:11][C:10]([NH:18][C:19]([C:21]1[N:22]=[C:23]([S:29][CH3:30])[S:24][C:25]=1[C:26]([O:28][CH3:1])=[O:27])=[O:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CSc1nc(C(=O)NC(C)(C)c2ccccc2)c(C(=O)O)s1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1sc(SC)nc1C(=O)NC(C)(C)c1ccccc1
Temperature: 85 °C

Procedure:
Potassium carbonate (0.37 g) and iodomethane (0.17 ml) were added to a solution of 4-{[(1-methyl-1-phenylethyl)amino]carbonyl}-2-(methylthio)-1,3-thiazole-5-carboxylic acid (Intermediate 14; 0.9 g) in DMF (20 ml) and heated in a sealed tube at an external temperature of 85° C. for 30 min. The reaction mixture was concentrated to remove DMF and partitioned with EtOAc and water. The combined organic extracts were washed with water, dried with MgSO4, and concentrated to an orange solid (0.63 g). NMR: 1.60-1.65 (m, 6H), 2.76 (s, 3H), 3.78-3.83 (m, 3H), 7.22 (d, J=7.16 Hz, 1H), 7.33 (t, J=7.63 Hz, 2H), 7.46 (d, J=7.35 Hz, 2H), 8.75 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1.O>O1CCCC1>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1
Reactant: CC(C)=CCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
To a solution of 3-methyl-2-buten-1-ol (780 mg, 9 mmol) and sodiumhydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 0.3 h. Water was added and the mixture was extracted with ether. The etherphase was dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[F:34])C(C1C=CC=CC=1)=O>FC(F)(F)C(O)=O>[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[F:34])[C:1]([OH:4])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccccc1)c1ccc(F)c(F)c1
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(F)c(F)c1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
2.5 g of sodium percarbonate were added over 1 h to a solution of 2.2 g (10 mmol) of 3,4-difluorobenzophenone and 20 ml of trifluoroacetic acid (0° C.) and the temperature was then allowed to rise to 20° C. The mixture was stirred for 16 h at this temperature and 50 g of ice were then added. The mixture was subsequently extracted twice with dichloromethane and the organic phases were washed (NaHCO3) until the washings were neutral. The solvent was then removed. Working-up as described in Example 22 gave 1.2 g (7.6 mmol, 76%) of 3,4-difluorobenzoic acid, which can be obtained analytically pure from water (melting point 113°-120.5° C.).
Reaction SMILES: S(=O)(=O)(O)O.C(Cl)(Cl)(Cl)Cl.[CH:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH:12]1O)[CH2:18]2.[CH:22]([OH:24])=[O:23]>>[CH:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH:12]1[C:22]([OH:24])=[O:23])[CH2:18]2
Reactant: OC1C2CC3CC(C2)CC1C3
Reactant: O=CO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C1C2CC3CC(C2)CC1C3
Temperature: 0 °C
Yield: 5 %

Procedure:
Concentrated sulfuric acid (50 mL) and carbon tetrachloride (100 mL) were combined, cooled to 0° C. and vigorously stirred. Adamantan-2-ol (451 mg) was dissolved in 96% formic acid (6 mL) and the solution was added to the sulfuric acid over 1 hour. The reaction continued to stir at 0° C. for 90 min after which it was added to 300 mL of ice. The layers were separated and the aqueous layer was extracted with 50 mL carbon tetrachloride (2×). The organic layers were combined and extracted with 1N NaOH. The aqueous portion was extracted with methylene chloride (4×) then acidified with 5N HCl. The solution turned white and was cooled on ice. Filtration provided the desired adamantane-2-carboxylic acid (contaminated with about 5% adamantane-1-carboxylic acid) as a white powder.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[H][H].O>CN(C)C=O>[C:1]([C:5]1[C:6]([O:17][CH2:2][CH2:1][CH2:5][CH3:12])=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(C=O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 85 °C
Yield: 217.8 %

Procedure:
4.0 g of 3,5-di-tert.-butyl-2-hydroxybenzaldehyde (CAS # 37942-07-7) was dissolved in dimethylformamide (DMF). This was treated with 0.89 g of sodium hydride (50% in oil suspension) and stirred at 25° C. until hydrogen was no longer evolved. To this was added 2.01 ml n-bromobutane and the mixture was heated to 85° C. for 14 hr. This was cooled and poured into water. The aqueous was extracted with ether. The ether layer was washed with water, dried (MgSO4), and solvent was removed. Purification was accomplished by florsil column chromatography (15% ether/hexane) to give 5.4 g of 3,5-di-tert.-butyl-2-butyloxybenzaldehyde; 1H NMR (CDCl3) δ 10.31 (s, 1H,aldehyde), 7.70 (dd,4H,aromatics), 3.94 (t,2H,—OCH2—).
Reaction SMILES: [C:1]1([C:7](=NN)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)=[N+]=[N-])C=CC=CC=1.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33]>[Hg]=O>[CH2:36]([O:35][C:31]([CH:32]1[CH2:33][C:7]1([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:34])[CH3:37]
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: O=[Hg]
Agent: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1CC1(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 95.9 %

Procedure:
Diphenylketone hydrazone (3.92 g, 20 mmol) was mixed with yellow mercury oxide (4.33 g, 20 mmol) in 40 mL petroleum. The mixture was stirred at the temperature less than 20° C. for 16 hours. The deep red solution of diphenyl diazomethane in petroleum was added into ethyl acrylate (6.0 g, 60 mmol) at 50° C. in ten minutes. When the red colour fade off the solvent and excess of ethyl acrylate were removed under reduced pressure and the crude product obtained was further purified over silica chromatography to furnish 2,2-diphenylcyclopropanyl carboxylate ethyl ester 5.11 g (96% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): 7.36-7.17 (10H, m), 4.00-3.83 (2H, m), 2.54 (1H, dd, J=8.3, 6.0 Hz), 2.17 (1H, dd, J=1H, dd, 6.0, 4.8 Hz), 1.59 (1H, dd, J=8.3, 4.8 Hz), 1.01 (3H, t, J=7.1 Hz).
Reaction SMILES: [C:1](=[C:4]1[NH:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].[H-].[Na+].[CH2:13](Br)[CH2:14][CH2:15][CH3:16]>CN(C)C=O>[CH2:13]([N:6]1[C:5](=[O:10])[C:4](=[C:1]([CH3:3])[CH3:2])[NH:8][C:7]1=[O:9])[CH2:14][CH2:15][CH3:16]
Reactant: CC(C)=C1NC(=O)NC1=O
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)NC(=C(C)C)C1=O
Temperature: 50 °C
Yield: 84.1 %

Procedure:
5-Isopropylidenehydantoin (5.6 g 0.04 mole) Journal of the Chemical Society, 2265 (1955) was added to a stirred suspension of sodium hydride (2.0 g 50% dispersion-oil removed by washing with light petroleum) in dry dimethylformamide (50 ml) and the mixture then heated at 50° C. for 15 minutes after which time a cream coloured solid separated. The mixture was cooled to room-temperature, a solution of n-butyl bromide (6.0 g 0.044 mole) in dry dimethylformamide (25 ml) added and the mixture heated at 80° C. for 4 hours. The mixture was cooled to room temperature and evaporated to dryness in a rotary evaporator under reduced pressure. The residue was dissolved in water (200 ml) and extracted with ether (3×50 ml). The ethereal solution was dried (MgSO4) and the solvent removed to yield a solid (6.6 g) which was crystallised from light petroleum (b.p. 60°-80° C.) to yield the title compound as needles, m.p. 130° C. Yield=4.3 g=55%.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH:23]=O.O>CO>[F:18][C:19]([F:32])([F:33])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=1)[CH2:23][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: O
Solvent: CO
Product: C[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a solution of the amine (4) (107 mg, 0.41 mmol) and 3,5-bis(trifluoromethyl)benzaldehyde (90 μL, 0.54 mmol) in methanol (4 mL) was added borane-pyridine complex (130 μL, 1.24 mmol) at 40° C. and the resulting mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (6) as a white solid (132 mg, Yield: 66%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17](C)=[CH:18]C=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C([Li])CCC.CC1[O:42]C(C=O)=C(C)N=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[O:42][C:17]([CH3:18])=[N:16][C:15]=3[CH3:21])[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1
Reactant: Cc1nc(C)c(C=O)o1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a 50 mL flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.5 g, 3.48 mmol, Intermediate 47: step d) was added THF (65 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. which remained homogeneous and then n-butyllithium (2.5 M in hexanes, 1.62 mL, 4.04 mmol) was added drop wise. The color of the solution became a dark opaque reddish-brown color. After 2 minutes, 2,4-dimethyloxazole-5-carbaldehyde (520 mg, 4.16 mmol, in 3 mL THF) was introduced and the color of the mixture went from an opaque dark brown to a light yellow homogeneous color within about 1 minute. After 25 minutes the mixture was quenched with aqueous NH4Cl. The reaction was diluted further with water and extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a light yellowish foam. The crude material was chromatographed on silica gel (10% CH3CN-DCM grading to 30% CH3CN containing 1% MeOH) to provide the title compound as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4](Cl)[N:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[K+]>C(O)C>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: CCCNc1cc(Cl)nc(N)[n+]1[O-]
Reactant: C1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCNc1cc(N2CCCCC2)nc(N)[n+]1[O-]
Reaction time: 1 h
Yield: 38.3 %

Procedure:
2 g of 2-amino-4-propylamino-6-chloropyrimidine 3-oxide, prepared according to the first two stages of the process of Example 1, are suspended in 20 ml of ethanol. 1.75 g of piperidine are added. The reaction mixture is refluxed for 19 hours. After it has returned to room temperature, 660 mg of potassium hydroxide are added as a solution in 10 ml of ethanol. After 1 hour's stirring the mixture is filtered on paper. The filtrates are evaporated to dryness. The residue is recrystallized from 25 ml of acetone. 950 mg of 2-amino-4-propylamino-6-piperidinopyrimidine 3-oxide are obtained.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.O.[NH2:18][NH2:19]>O>[CH3:12][N:9]1[CH2:10][CH2:11][CH:6]([C:4]2[C:3]3[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:19][N:18]=2)[CH2:7][CH2:8]1
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Reactant: NN
Solvent: O
Product: CN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 23.7 %

Procedure:
An autoclave was charged with 10.0 g of 4-(2-fluorobenzoyl)-1-methylpiperidine and 14 ml of hydrazine hydrate. The reaction was heated at 150° for 20 hrs, cooled, and poured into water. The resultant solid was collected. The solid was recrystallized twice from toluene to yield 2.4 g (23.7%) of product, mp 168°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25](O)=[O:26])=[CH:22][CH:23]=2)[C:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:28])[CH2:17][C:16]1([CH3:36])[CH3:35])(=[O:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:12]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:26])=[CH:22][CH:23]=2)[C:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:28])[CH2:17][C:16]1([CH3:36])[CH3:35])(=[O:14])[CH3:13]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1ccc(CCN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)c2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc1

Procedure:
Condensation of 2-(4-methoxyphenyl)ethylamine (6.1 mg) with 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid (10 mg), under the agency of HATU (23 mg) and N,N-diisopropylethylamine (19 l)) in dichloromethane (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)([CH3:6])[C:3]#[C:4][CH3:5].C(C1(C2C=CC(OC)=C(C=2)[CH:25]=[O:26])CC1)#N>>[CH3:6][C:2]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[C:11]([CH:12]=1)[CH:25]=[O:26])([CH3:1])[C:3]#[C:4][CH3:5]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Reactant: CC#CC(C)(C)c1ccc(OC)cc1
Product: CC#CC(C)(C)c1ccc(OC)c(C=O)c1

Procedure:
This compound was prepared from Compound 54 in the same manner of Compound 2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[I-].[N:23]1([C:33](N2C=C[N+](C)=C2)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2[C:8](=[O:12])[O:9][C:10]3[C:5]([C:6]=2[CH3:21])=[CH:4][CH:3]=[C:2]([O:1][C:33]([N:23]2[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]2)=[O:34])[CH:11]=3)=[CH:14][CH:15]=1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)cc1
Agent: [I-]
Product: COc1ccc(-c2c(C)c3ccc(OC(=O)N4CCCc5ccccc54)cc3oc2=O)cc1
Yield: 58.9 %

Procedure:
The title compound (130 mg, 59% yield, white solid) was prepared from 7-hydroxy-3-(4-methoxy-phenyl)-4-methyl-chromen-2-one (141 mg, 0.50 mmol) and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (188 mg, 0.51 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH:21]2[CH2:29][C:28]3[C:23](=[CH:24][C:25](F)=[CH:26][CH:27]=3)[C:22]2=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:32][OH:33].Cl.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[N:32][OH:33])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OC2Cc3ccc(F)cc3C2=O)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OC2Cc3ccccc3C2=NO)C1
Temperature: 100 °C

Procedure:
The title compound of Step A was dissolved into MeOH (2 mL), then NH2OH HCl (1 mmol) and K2CO3 (2 mmol) were added. The mixture was heated at 100° C. using a microwave reactor for 1 h. The mixture was cooled to rt and purified by PTLC providing the title compound (120 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2CC(N2CCOCC2)=S)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22]([OH:25])(=[O:24])[CH3:23]>Cl>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:23][C:22]([OH:25])=[O:24])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: S=C(Cc1ccccc1N1CCOCC1)N1CCOCC1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)Cc1ccccc1N1CCOCC1

Procedure:
A solution of N-[[2-(4-morpholinyl)-phenyl]thioacetyl]morpholine (2.78 g) in a mixture of acetic acid (25 cc) and 37% hydrochloric acid (25 cc) is refluxed for 8 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in ethyl acetate (20 cc) and normal sodium hydroxide solution (20 cc). The aqueous phase is acidified to pH 5 with acetic acid and then extracted with ethyl acetate (20 cc). This organic phase is washed with water (2×4 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 2-[2-(4-Morpholinyl)phenyl]acetic acid (0.48 g) melting at 128° C. is obtained.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].CN(/[CH:12]=[N:13]/[C:14]1[C:15]([C:26]([O:28]C)=O)=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:24][CH3:25])=[CH:19][CH:18]=2)C.C(O)(=O)C>O1CCCC1>[CH3:25][O:24][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]=[C:15]3[C:14](=[CH:23][C:22]=2[CH:21]=1)[NH:13][CH:12]=[C:7]([C:6]#[N:8])[C:26]3=[O:28]
Reactant: COC(=O)c1cc2ccc(OC)cc2cc1/N=C/N(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2cc3c(=O)c(C#N)c[nH]c3cc2c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.81 mL (7.03 mmol) of n-butyllithium (2.5M in hexane) in 2.0 mL of tetrahydrofuran at −78° C. is added dropwise a solution of 0.448 mL (8.44 mmol) of acetonitrile in 4.4 mL of tetrahydrofuran. After completion of addition, the suspension is stirred for 10 minutes. To this is added 804.5 mg (2.81 mmol) of methyl 3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate in 18 mL of tetrahydrofuran dropwise. The resulting reaction mixture is stirred at −78° C. for 1 hour and at −5° C. for 1 hour. The reaction mixture is again cooled to −78° C. and 4.0 mL (69.9 mmol) of acetic acid is added dropwise. The reaction mixture is warmed up to room temperature and stirred overnight. The precipitate is collected by filtration and washed sequentially with water, acetonitrile and methanol. After drying in vacuo, this yields 468.6 mg (67%) of 8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a yellow solid, mp>265° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH:12]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH2:12][CH2:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC=C[C@@H]2CCC[C@H](c3cccc(F)c3)N12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@@H]2CCC[C@H](c3cccc(F)c3)N12
Yield: 82.6 %

Procedure:
Platinum oxide (20 mg) was added to a solution of (6R*,9aS*)-6-(3-fluorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (460 mg) in methanol (10 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 383 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [PH4+].[Li]CCCC.[O:7]1[CH2:12][CH2:11][CH2:10][C:9](=O)[CH2:8]1.[CH2:14]1C[O:17][CH2:16][CH2:15]1>>[O:7]1[CH2:12][CH2:11][CH2:10][C:9](=[CH:14][CH2:15][CH2:16][OH:17])[CH2:8]1
Reactant: C1CCOC1
Reactant: O=C1CCCOC1
Agent: [Li]CCCC
Agent: [PH4+]
Product: OCCC=C1CCCOC1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a suspension of the phosphonium salt (69 g, 1.5 eg) in dry THF (1100 mL) at 0° C. under nitrogen atmosphere was added n-BuLi (2.5 M, 111 mL, 0.413 mol). The solution was stirred for 1 hr, followed by addition of dihydro-2H-pyran-3(4H)-one (11.5 g, 0.115 mol). Stirring was continued at rt overnight. The mixture was quenched by sat. aq. NH4Cl, and then filtered. The filtrate was dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified through column chromatography to give 3-(dihydro-2H-pyran-3(4H)-ylidene)propan-1-ol (11.2 g, 69%). 1H NMR (CD3OD) δ 4.2-3.9 (d, 2H), 3.8-3.5 (m, 4H), 2.4-2.2 (m, 4H), 5.3-5.2 (d, 1H), 2.1-1.8 (s, 1H), 1.8-1.6 (m, 2H).