Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.C(Cl)(Cl)(Cl)Cl.[Cl:11][C:12]1[CH:30]=[CH:29][CH:28]=[C:14]2[C:15]([N:17]([C:20]([CH:25]([CH3:27])[CH3:26])([CH3:24])[C:21]([NH2:23])=O)[C:18](=[O:19])[C:13]=12)=[O:16].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O>[Cl:11][C:12]1[CH:30]=[CH:29][CH:28]=[C:14]2[C:15]([N:17]([C:20]([CH:25]([CH3:27])[CH3:26])([CH3:24])[C:21]#[N:23])[C:18](=[O:19])[C:13]=12)=[O:16]
Reactant: CC(C)C(C)(C(N)=O)N1C(=O)c2cccc(Cl)c2C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)C(C)(C#N)N1C(=O)c2cccc(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To 60 ml. dry tetrahydrofuran, stirred and cooled to 0° C. is added dropwise 11.5 ml. titanium tetrachloride in 15 ml. dry carbon tetrachloride. To this cold mixture is added 8.82 grams of α-(3-chlorophthalimido)-α-isopropyl-α-methylacetamide in 50 ml. dry tetrahydrofuran, followed by 12.3 grams triethylamine in 20 ml. dry tetrahydrofuran. The reaction mixture is allowed to warm slowly to room temperature and kept overnight. Water is then added cautiously to the mixture while it is extracted three times with ether. The combined extracts are washed with water, dried, and evaporated. The residue is crystallized from ether-hexane to give 6.1 grams of the nitrile, melting point 71° C. to 72° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][C:10]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[C:9]([CH3:21])[C:8]=2[CH3:22])=[O:4].[OH-].[K+].O>CO>[C:16]([C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([CH3:22])[C:9]=1[CH3:21])[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][C:13]2=[O:15])(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)c1cc2c(=O)cc(C(=O)OC)[nH]c2c(C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(=O)c1cc2c(=O)cc(C(=O)O)[nH]c2c(C)c1C

Procedure:
6.1 g of 6-butyryl-7,8-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid methyl ester are heated under reflux for 4 hours together with 3.66 g of potassium hydroxide, 1.46 ml of water and 64.4 ml of methanol. The reaction mixture is concentrated to dryness by evaporation, partitioned between ethyl acetate and water, the aqueous phases are acidified and the precipitated crystals are filtered with suction and washed with water. The 6-butyryl-7,8-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid obtained in this manner melts at 267°-269° after recrystallisation from methanol/ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl>[Fe].O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Product: COc1ncc(Br)cc1N
Temperature: 22.5 °C
Reaction time: 1.75 h
Yield: 95.4 %

Procedure:
Iron powder (1.17 kg) was added to a suspension of 5-bromo-2-(methyloxy)-3-nitropyridine (1.36 kg) in IMS (6.1 L), stirred under nitrogen at 20-25° C. Water (0.8 L) was then added and the mixture cooled to less than 10° C. Aqueous hydrochloric acid (0.8 L concentrated hydrochloric acid and 0.8 L water) was then added to the reaction mixture, maintaining the temperature below 10-15° C. The suspension was warmed to 20-25° C. and then stirred at this temperature for 23 hours. The suspension was filtered, the filter cake washed with IMS (2×2.7 L) and the combined filtrates concentrated under vacuum. Water (4.1 L) was added slowly to the concentrated solution and the resulting suspension was held at 20-25° C. for 1.75 hours. The resultant suspension was filtered, washed with water (2×6.8 L) and the solid dried under vacuum to give the title compound as an off-white solid (1.13 kg).
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:37]([NH:44][C:45](=[O:51])[C@H:46]([CH:48]([CH3:50])[CH3:49])[NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:44]([CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:45](=[O:51])[C@H:46]([CH:48]([CH3:50])[CH3:49])[NH2:47])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 71.6 %

Procedure:
Using the procedure described in Example 3, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (109.1 mg, 0.37 mmol, 1.0 eq), triethylamine (156 uL, 1.12 mmol, 3.0 eq), and THF (1.5 mL), was treated with isobutyl chloroformate (53 uL, 0.41 mL, 1.1 eq), then with L-valine benzylamide (117.5 mg, 570 umol, 1.5 eq). Workup as before provided 127 mg (71%) of L-valine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide as a white foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[NH:5][C:4](=[O:13])[C:3]=1[N:14]=O>CN(C=O)C.O=[Pt]=O>[CH2:8]([N:7]1[C:2]([NH2:1])=[C:3]([NH2:14])[C:4](=[O:13])[NH:5][C:6]1=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCn1c(N)c(N=O)c(=O)[nH]c1=O
Agent: O=[Pt]=O
Solvent: CN(C)C=O
Product: CCCCn1c(N)c(N)c(=O)[nH]c1=O

Procedure:
52.8 g (0.27 mol) of 6-amino-1-butyl-5-nitroso-2,4-(1H,3H)-pyrimidinedione (IX) was dissolved in 1 l of DMF at 90° C. and catalytically hydrogenated in the presence of 0.1 g PtO2 for 18 hours and at room temperature and at a pressure of 200 KPa. The catalyst and the crystals were filtered off and washed with ethanol. Yield 36.6 g (67%) (X), NMR.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:7]1[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=1[S:5]2.[CH2:26]([O:28][CH2:29][CH2:30][O:31][C:32]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O)[CH3:27].[O-]CC.[Na+]>C(O)C>[CH2:26]([O:28][CH2:29][CH2:30][O:31][C:32]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:33]=1/[CH:34]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:5][C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[N:8]2[C:9](=[O:21])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1)[CH3:27]
Reactant: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: CCOCCOc1c(C=O)cccc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCCOc1c(/C=C/c2nc3sc4ccccc4n3c(=O)c2-c2ccc(C(F)(F)F)cc2)cccc1OC
Yield: 45.5 %

Procedure:
The title compound was synthesized by condensation of Intermediate 23 (250 mg, 0.690 mmol) with 2-(2-ethoxyethoxy)-3-methoxybenzaldehyde (204 mg, 0.970 mmol) in presence of sodium ethoxide (94 mg, 1.380 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to give 178 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.91 (t, J=6.9 Hz, 3H), 3.48-3.55 (m, 4H), 3.78 (s, 3H), 4.06 (br s, 2H), 6.81 (d, J=15.6 Hz, 1H), 6.92-6.94 (m, 1H), 7.00-7.02 (m, 1H), 7.55-7.57 (m, 2H), 7.61-7.64 (m, 2H), 7.84-7.87 (m, 2H), 8.07-8.09 (m, 1H), 8.23 (d, J=15.6 Hz, 1H), 8.84-8.87 (m, 1H); ESI-MS (m/z) 567.21 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:13]O>>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(N)cc1
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 4-aminophenylacetic acid (10 g, 66.2 mmol) in methanol (150 mL) at room temperature was added HCl conc. (37% 25 mL). The mixture became yellow and was stirred overnight. The reaction mixture was then quenched with a saturated aqueous solution of NaHCO3. The methanol was evaporated under reduced pressure and the aqueous layer was extracted several times with AcOEt. The combined organic extracts were dried over (MgSO4) and evaporated. The crude residue was purified by flash chromatography using hexane/AcOEt (4:1) as solvent mixture yielding 3 as a yellow oil (9.44 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][N:11]=[C:12]=[S:13].[N:14]#[C:15][NH2:16].C1CCN2C(=NCCC2)CC1>C(Cl)(Cl)Cl>[C:15]([NH:16][C:12]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])=[S:13])#[N:14]
Reactant: N#CN
Reactant: Cc1[nH]cnc1CSCCN=C=S
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Product: Cc1[nH]cnc1CSCCNC(=S)NC#N
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A solution of 2-(5-methylimidazol-4-ylmethylthio)ethylisothiocyanate [obtained from its hydrochloride (4.17 g)] in CHCl3 (20 ml) was added to a solution of cyanamide (1.05 g) and DBU (3.80 g) in CHCl3 (50 ml) and stirred overnight. After concentration, the residue was dissolved in water (30 ml) and washed with ether, decolorized with charcoal and acidified to pH 5 with 10% HCl under ice-cooling. The precipitate was filtered, washed with water and dried to give N-cyano-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]thiourea(mono-hydrate, 3.57 g). Yield 78.1%, m.p. 158°-161° C.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[OH:16][CH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[OH:16][CH2:17][C:18]1[CH:23]=[C:22]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1cccc(CO)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 3-hydroxymethylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H14N4O, 291. Found, 291.
Reaction SMILES: [Cl:1][C:2]1[CH:6]([O:7][Si](C(C)(C)C)(C)C)[CH2:5][C:4](=[O:15])[CH:3]=1.O1CCCC1.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CCOCC>[Cl:1][C:2]1[CH:6]([OH:7])[CH2:5][C:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([OH:15])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)C=C1Cl
Reactant: CCCCCCCC[Mg]Br
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC1(O)C=C(Cl)C(O)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
108 mg of 3-chloro-4-t-butyldimethylsilyloxy-2-cyclopentenone was dissolved in 4 ml of ether, and the solution was cooled to -78° C. Then, 0.79 ml of a 0.72 M tetrahydrofuran solution of octyl magnesium bromide was added. The mixture was stirred for 10 minutes, and water was added. The mixture was extracted with ether, and the extract was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting oily product was dissolved in 6 ml of tetrahydrofuran, and 1.1 ml of a 1 M tetrahydrofuran solution of tetrabutyl ammonium fluoride was added. The mixture was stirred for 2 days. A saturated aqueous solution of sodium chloride was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was chromatographed on a silica gel column to give 92 mg (yield 83%) of 2-chloro-4-octylcyclopent-2-ene-1,4-diol.
Reaction SMILES: [Na].N.[C:3]1([P:9](C2C=CC=CC=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].[NH4+].Br[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=1>>[C:10]1([P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(Br)n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: COc1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
2.7 g Sodium was added to 100 ml liquid ammonia at -80° C., and then 15.2 g of triphenylphosphine was added in 6 portions with stirring. The solution was slowly warmed to -40° C., kept at that temperature for 30 min, and then cooled again to -80° C. Then, 3.1 g of ammonium chloride was added to the stirred solution, followed by 10.9 g of 2-bromo-6-methoxypyridine in three portions. The cooling bath was removed and the ammonia was allowed to evaporate. The residue was worked up with water/dichloromethane as described in Preparation 1. Crystallization from hexane afforded 7 g of a somewhat impure product (characterized by 31P NMR: δp =-4.4 ppm) which was used as such in the following Examples.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C@H:6]([OH:22])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[OH:21])[CH2:3]1>[Pd]>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][C@H:6]([OH:22])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[OH:21])[CH2:3]1
Reactant: C[C@]12CC[C@H]3[C@@H]([C@@H](O)C=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: [Pd]
Product: C[C@]12CC[C@H](O)C[C@@H]1C[C@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
AET (I) is reduced by hydrogenation over a palladium on charcoal catalyst to yield 3β,7β,17β-trihydroxy-5α-androstane (CIX)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(#N)C.CCOC(C)=O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=3)[C:4](=[O:18])[CH:3]=2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 30 mL acetonitrile is added 0.22 mL (1.79 mmol) 1-bromomethyl-4-fluoro-benzene and 0.45 g (3.26 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT. 5.0 mL DMF is added and the reaction mixture is stirred additional 24 h at RT. The reaction mixture is diluted with 60 mL of EtOAc and is washed twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]([OH:17])=[C:15]([C:18]([CH3:20])=[O:19])[CH2:14][S:13]2)=[CH:8][CH:7]=1.S(Cl)(Cl)(=O)=O.O>C(O)(C)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][CH:14]=[C:15]([C:18]([CH3:20])=[O:19])[C:16]=2[OH:17])=[CH:10][CH:11]=1
Reactant: CC(=O)C1=C(O)C(c2ccc(Cl)cc2)SC1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CC(=O)c1csc(-c2ccc(Cl)cc2)c1O
Temperature: -35 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
A chloroform (100 mL) solution of 2-(4-chlorophenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (10.00 g, 37.29 mmol, purity: 95%) was cooled to −40° C., and to this solution, a chloroform (150 mL) solution of sulfuryl chloride (3.6 mL, 1.2 equivalent amounts) was dropwise added over a period of 50 minutes, followed by stirring at −35° C. for 40 minutes. The temperature of the solution was raised to −3° C., and water (20 mL) was dropwise added, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a saturated sodium hydrogencarbonate aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. The obtained crude product was suspended in isopropyl alcohol (100 mL) at room temperature, followed by stirring at 0° C. for 15 minutes. The formed crystals were subjected to filtration to give the desired product as a yellow solid (7.26 g, yield: 77%).
Reaction SMILES: FC(F)(F)C([O-])=O.[F:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH2+:17][CH2:16][C:15]2=[O:20])=[CH:11][CH:10]=1.[CH:23]([O:26][C:27]([C:29]1[C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28])([CH3:25])[CH3:24].C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH:23]([O:26][C:27]([C:29]1[C:34]([C:35]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:12]3[CH:21]=[CH:22][C:9]([F:8])=[CH:10][CH:11]=3)[C:15](=[O:20])[CH2:16]2)=[O:36])=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)OC(=O)c1ncccc1C(=O)O
Reactant: O=C1C[NH2+]CCN1Cc1ccc(F)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1ncccc1C(=O)N1CCN(Cc2ccc(F)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of 35 (1.46 g, 4.55 mmol) was dissolved in 20 mL of a 1:1 solution of CH2Cl2:DMF. To this solution was added 0.95 g (4.55 mmol) of 30, EDC (1.74 g, 9.10 mmol) and triethylamine (1.90 mL, 13.7 mmol). The solution was stirred at room temperature for 4 hours when the reaction was complete. The solution was diluted with CH2Cl2 and washed with water. The organic layer was subsequently washed with aq. saturated solution of NH4Cl and the solvent was removed. The yellow residue was purified by column chromatography using EtOAc-10% MeOH gradient to yield 1.8 g (100%) of the product 36 as a clear oil. EI MS (m/z) 400.5 [MH+], 422.3 [M+Na].
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:12]1[C:7]2[C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(-c2ccccc2-c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1ccc2c(c1)c1ccccc1c1ccccc21
Yield: 35 %

Procedure:
2.87 mmol of the o-terphenyl derivative, 0.14 mmol of Pd(OAc)2 and 5.7 mmol of K2CO3 are heated in 7 ml of DMA at 135° C. for 24 hours under a nitrogen atmosphere. The reaction mixture is cooled, treated with 5 ml of water and extracted with dichloromethane. The organic phase is dried, the solvent is removed under reduced pressure and the residue is purified by means of a short silica gel column (dichloromethane). After column chromatography (dichloromethane/hexane, 2:1), the desired triphenylene derivative (IIa) is obtained in from 35 to 40% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=O)[CH2:12][C:11](=[O:15])[N:10]([CH:16]3[CH2:18][CH2:17]3)[C:9]2=[O:19])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.BrC1C=CC(N2C(=O)C=C(Cl)N(C3CC3)C2=O)=CC=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([Cl:22])=[CH:12][C:11](=[O:15])[N:10]([CH:16]3[CH2:18][CH2:17]3)[C:9]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(=O)N(C2CC2)C(=O)N1c1ccc(Br)cc1
Agent: O=c1cc(Cl)n(C2CC2)c(=O)n1-c1ccc(Br)cc1
Solvent: O
Product: O=c1cc(Cl)n(-c2ccc(Br)cc2)c(=O)n1C1CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
To 1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine-2,4,6-trione 32 (11.8 g) obtained in Step 2 was added water (1.31 ml) and phosphorus oxychloride (17.0 ml) was added dropwise with stirring at room temperature. After the completion of the dropwise addition, the mixture was stirred at 110° C. for 3 hrs. After allowing to cool to room temperature, the reaction mixture was added to ice water by small portions and the mixture was stirred. The mixture was stirred at room temperature and extracted with chloroform. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=2:1→chloroform:acetone=30:1) to give a 1:1.4 mixture (11.6 g, yield 93%) of 1-(4-bromo-phenyl)-6-chloro-3-cyclopropyl-1H-pyrimidine-2,4-dione 33 and 3-(4-bromo-phenyl)-6-chloro-1-cyclopropyl-1H-pyrimidine-2,4-dione 34 as a pale-yellow foamy oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][NH:13][C:12]2=[O:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:17]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:21]([O:20][C:18]([CH:17]([N:13]1[CH2:14][CH:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:15])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)C(Br)c1ccccc1
Reactant: O=C(Cc1ccccc1)NC1CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC1CN(C(C(=O)OCc2ccccc2)c2ccccc2)C1=O

Procedure:
3-(2-Phenylacetamido)-2-azetidinone (816 mg.) and benzyl 2-bromo-2-phenylacetate (1.22 g.) were dissolved in N,N-dimethylformamide (20 ml.), and to the solution was added sodium hydride (50% oily) (210 mg.) in nitrogen atmosphere under ice-cooling while stirring, and then the reaction mixture was stirred for an hour at the same temperature. Ethyl acetate (150 ml.) was added to the reaction mixture, and the solution was washed with water, a sodium bicarbonate-saturated-aqueous solution and water respectively, and then dried over anhydrous magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give the yellow oily material (1.7 g.). The material was subjected to column chromatography using silica.gel (developer: chloroform) to give two isomers of 1-(α-benzyloxycarbonylbenzyl)-3-(2-phenyl)acetamido-2-azetidinone. Yield of the isomer A is 26 mg. and it of the isomer B is 65 mg.
Reaction SMILES: Cl.[OH2:2].N=[C:4]1[C:8]([CH3:15])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][C:6](=[S:16])[N:5]1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH3:15][C:8]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][C:6](=[S:16])[N:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]1=[O:2]
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=N
Reactant: O
Agent: Cl
Solvent: CO
Product: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
37% hydrochloric acid (5 ml) and water (1 ml) was added at room temperature with stirring to a solution of 4-imino-5-methyl-5-phenyl-3-phenylaminothiazolidine-2-thione (9.38 g) in methanol (50 ml). The solution was stirred for 24 hrs at room temperature. The solvent was then evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate-n-hexane, ⅓) to yield an oily 5-methyl-5-phenyl-3-phenylamino-2-thioxothiazolidin-4-one (7.02 g).
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:7][C:6]=1[F:20])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O1CCCC1>C(Cl)Cl>[C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[F:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(C)(C)C)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCC(=O)O)cc1F
Yield: 89 %

Procedure:
A mixture of tert-butyl (4-tert-butyl-3-fluorophenoxy)acetate (630 mg, 2.2 mmol), trifluoroacetic acid (3.0 ml), tetrahydrofuran (3.0 ml) and methylene dichloride (3.0 ml) was treated in the same procedure described in Example 3(c) to furnish 443 mg of the title compound which was used for further reaction without purification.