Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)=[O:11].[CH3:38][O:39][CH2:40][CH2:41][CH2:42]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH3:38][O:39][CH2:40][CH2:41][CH2:42][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:36])[CH3:37])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][NH:15][CH2:14]1)=[O:11]
Reactant: COCCCO
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 27.2 %

Procedure:
tert-Butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (700 mg), 3-methoxypropan-1-ol (123 mg) and triphenylphosphine (465 mg) were dissolved in THF (20 ml), diisopropyl azodicarboxylate (40% toluene solution: 896 mg) was added, and the mixture was stirred at room temperature for 60 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was saturated aqueous sodium hydrogen carbonate and saturated washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:3) was concentrated under reduced pressure. The obtained substance was dissolved in ethyl acetate (3 ml), 4M hydrogen chloride-ethyl acetate (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:0) and ethyl acetate-methanol (93:7) was concentrated under reduced pressure. The obtained substance was dissolved in ethyl acetate (10 ml), sulfuric acid (42 mg) was added, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml), and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-methanol to give the object product (180 mg) as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:13][C:12]=2[F:24])[CH2:7][CH2:6]1)[CH3:2].[Cl:26]N1C(=O)CCC1=O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[C:12]([F:24])=[CH:13][C:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:15][C:16]=2[Cl:26])[CH2:9][CH2:10]1)[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)OC(C)(C)C)cc2F)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2c(F)cc(C(=O)OC(C)(C)C)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
To a solution of 0.50 g of N-(4-tert-butoxycarbonyl-2-fluorophenyl)isonipecotic acid ethyl ester in 5 ml of DMF, 0.21 g of N-chlorosuccinimide was added, and the mixture was stirred at room temperature for 1 day. After the evaporation of the solvent, the residue was purified by silica gel column chromatography (eluent: hexane-EtOAc=5:1˜1:1) to obtain 0.51 g of N-(4-tert-butoxycarbonyl-2-chloro-6-fluorophenyl)isonipecotic acid ethyl ester.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>C1COCC1.C(OC(=O)C)C>[CH:5]1([CH2:4][N:10]2[CH2:11][CH2:12][CH:7]([OH:6])[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: OC1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1CCN(CC2CC2)CC1
Reaction time: 8 h
Yield: 46.7 %

Procedure:
Add bromomethylcyclopropane (2.025 g, 15 mmol) to a solution of 4-hydroxypiperidine (3.035 g, 30 mmol) in THF (10 mL) and stir the mixture overnight. Dilute the mixture with ethylacetate, wash with saturated NaHCO3 solution, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel, eluting with 8% 2M NH3-methanol in CH2Cl2) provides 1.087 g (47%) of the title compound: mass spectrum (ion spray): m/z=156.2 (M+1); 1H NMR (CDCl3, ppm): 3.60 (m, 1H), 2.81 (m, 2H), 2.16 (d, 1H), 2.10 (m, 3H), 1.84 (m, 2H), 1.53 (m, 3H), 0.79 (m, 1H), 0.44 (m, 2H), 0.00 (m, 2H).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]2[N:27]([C@H:28]3[CH2:32][CH2:31][NH:30][CH2:29]3)[CH:26]=[N:25][N:24]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C1COCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]2[N:27]([C@H:28]3[CH2:32][CH2:31][N:30]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:29]3)[CH:26]=[N:25][N:24]=2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nncn2[C@H]2CCNC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nncn2[C@H]2CCN(S(C)(=O)=O)C2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To 4-tert-butyl-N-[4-chloro-2-((S)-4-pyrrolidin-3-yl-4H-[1,2,4]triazol-3-yl)phenyl]-benzenesulfonamide hydrochloride (0.25 g, 0.505 mmol) in THF (8 mL) was added pyridine (0.60 mL, 7.4 mmol). The resultant solution was stirred for 20 minutes at room temperature. The reaction mixture was subsequently cooled to 0° C., methanesulfonyl chloride (0.595 mL, 7.6 mmol) was added, and the mixture was stirred overnight at room temperature. The following day, the volatiles were evaporated and the resultant residue was adsorbed onto silica gel and purified by automated normal-phase chromatography (using 50→100% EtOAc in hexanes) to obtain the title compound (0.183 g) in 67.5% yield: MS (ES) M+H expected 538.0, found 538.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH2:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:16][C:8]12[CH2:14][CH:12]3[CH2:11][CH:10]([CH2:15][C:6]([C:4]([O:3][CH3:2])=[O:5])([CH2:13]3)[CH2:7]1)[CH2:9]2)=[O:22]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C12CC3CC(CC(NC(=O)c4cccc(Cl)c4)(C3)C1)C2
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 3-amino-adamantane-1-carboxylic acid methyl ester HCl salt (Hermogenes N. J. et al.; U.S. Pat. No. 7,947,680 B2) (160 mg, 0.65 mmol) and 3-chlorobenzoic acid (130 mg, 0.78 mmol) in DMF (5 mL) was added DIEA (340 mg, 2.6 mmol) and HATU (300 mg, 0.78 mmol) under N2. After stirring at room temperature for an hour, the reaction was quenched with brine, the aqueous layer was extracted with ethyl acetate (3×20 mL), and the combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1) to afford 220 mg (97%) of the title compound, methyl 3[(3-chlorobenzoyl)amino]adamantane-1-carboxylate, as a white solid. ESI-MS m/z: 348 (M+H)+.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>O1CCCC1.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccccc1)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 0.701 ml, 1.10 mmol) was added to a tetrahydrofuran (5 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (303 mg, 1.00 mmol) obtained in Example 5. The temperature of the resulting mixture was raised to room temperature and then stirred for 10 minutes. After cooling the reaction mixture to −78° C., benzoyl chloride (0.140 ml, 1.20 mmol) was added thereto dropwise. The reaction mixture was stirred at −78° C. for 30 minutes. The temperature of the mixture was then raised to OC over 3 hours. After addition of 1N hydrochloric acid (2.0 ml), the mixture was extracted with ethyl acetate. The extracts were combined, washed successively with water, a saturated aqueous solution of sodium bicarbonate, and brine, dried over MgSO4, and then concentrated. The residue was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane). The solid thus obtained was washed with hexane, whereby the title compound (200 mg, 49%) was obtained as a colorless solid.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]C.[H-].[Na+]>>[C:1]([O:6][CH2:7][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: COC(=O)C(C)O
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)C(C)O
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Behenyl Lactate was prepared by reacting methyl lactate (Aldrich Chemical Company, Inc. of Milwaukee, Wis.) with Lanette 22 (behenyl alcohol, 90%, Henkel Corp. of Ambler, Pa.) in a transesterification reaction according to the following method: 0.2 g sodium hydride (60% in mineral oil) was added to 32.6 grams Lanette 22 at 70° C. in a 3-neck 250 ml glass flask purged with nitrogen and inserted with overhead stirrer, Dean Stark trap, thermometer, and condenser. To this was slowly added 9.4 g of methyl lactate and the contents were slowly heated to 160° C. and held at that temperature for one hour. At this temperature over 2 ml of methanol was collected. The contents were heated to 200° C. with a nitrogen sweep to remove any volatile components. After approximately 15 minutes at 200° C. the contents were cooled. Upon cooling the product crystallized and had a melting point of approximately 57° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][C:8](=[O:12])[CH:9](Br)[CH3:10].[CH3:13][O:14][C:15]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[C:16]=1/[CH:17]=[CH:18]/[S:19]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([NH2:29])[CH:28]=1)(=[O:21])=[O:20]>CO>[CH3:13][O:14][C:15]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[C:16]=1/[CH:17]=[CH:18]/[S:19]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([NH:29][CH:9]([CH3:10])[C:8]([O:7][CH3:6])=[O:12])[CH:28]=1)(=[O:21])=[O:20]
Reactant: COC(=O)C(C)Br
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(N)c2)c(OC)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)Nc1cc(CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)ccc1OC
Temperature: 25 °C

Procedure:
Sodium acetate (0.4 mol) was dissolved in methanol (200 mL). Methyl-2-bromopropionate (40 mmol) was added and the resulting mixture was heated at reflux for 10 min. The heated mixture was cooled to room temperature (25° C.), and (E)-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxybenzenamine (0.1 mol) was added. The resulting mixture was heated at reflux for 1 h. The hot reaction mixture was allowed to cool to room temperature (25° C.), and then poured into ice water (500 mL). A solid precipitate formed. The precipitate was separated by filtration and recrystallized from ethanol to provide the desired methyl(E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)propanoate.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])=[CH:6][C:5]=1[N+:20]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:34]([N:41]1[C:45](=[O:46])[C:44](=[C:47]2[N:51]([CH3:52])[C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[S:48]2)[S:43][CH2+:42]1SC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([N:41]1[C:45](=[O:46])[C:44](=[C:47]2[N:51]([CH3:52])[C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[S:48]2)[S:43][C:42]1=[N:20][C:5]1[CH:6]=[C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])[CH:8]=[CH:9][C:4]=1[NH:3][CH2:1][CH3:2])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCNc1ccc(NC(=O)N2CCN(C)CC2)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)N2CCN(C)CC2)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4-methylpiperazine-1-carboxylic acid (4-ethylamino-3-nitro-phenyl)amide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. MS(ESI): 614 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]([NH:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[O:12])=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]2=[O:33])[CH2:20][CH2:19]1.[CH:34]1(N2C(C(O)=O)=NC3C2=NC=NC=3N2CCC(N3C4C=CC=CC=4NC3=O)CC2)C[CH2:35]1.C1(N)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[CH:1]1([N:2]2[C:10]([C:11]([NH:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:12])=[N:9][C:8]3[C:3]2=[N:4][CH:5]=[N:6][C:7]=3[N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]3=[O:33])[CH2:20][CH2:19]2)[CH2:35][CH2:34]1
Reactant: Cn1c(C(=O)NCC2CC2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Reactant: O=C(O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(NCC1CC1)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C1CC1

Procedure:
9-Cyclopropyl-N-(cyclopropylmethyl)-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide was prepared in the same manner as 9-methyl-N-(cyclopropylmethyl)-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide. The 9-cyclopropyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid (0.09 g, 0.21 mmol) was treated with cycloproplyamine (0.305 g, 0.429 g mmol, 0.037 mL), HATU (0.163 g, 0.429 mmol), diisopropylethylamine (0.110 g, 0.858 mmol, 0.149 mL) and DMA (8 mL) at room temperature for 18 hours. Purification by preparative reverse phase HPLC (eluting with 0.01% aqueous ammonium acetate and acetonitrile) yielded 0.057 g of 9-cyclopropyl-N-(cyclopropylmethyl)-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.50 (broad s, 1H), 8.63 (t, 1H), 8.07 (s, 1H), 6.98 (m, 1H), 6.6.716 (m, 3H), 5.11 (broad s, 2H), 4.30 (m, 1H), 3.38 (m, 1H), 3.13 (dd, 1H), 2.93 (t,4H), 2.07 (t, 2H), 1.63 (m, 2H), 0.83 (m, 4H), 0.18 (m, 2H), 0.02 (m, 2H).MS (EI) for C25H28N8O2: 473 (MH+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:18])[CH2:16][OH:17])[CH2:6]1)(=[O:3])[CH3:2].[C:28](OC)(=[O:34])[CH2:29][C:30]([O:32][CH3:33])=[O:31].[Cl-].[Ca+2].[Cl-]>C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:18])[CH2:16][O:17][C:28](=[O:34])[CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(=O)CO)[C@@]4(C)CC[C@@H]32)C1
Reactant: COC(=O)CC(=O)OC
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 160 °C

Procedure:
A mixture of 200 mg of 3β-acetoxy-21-hydroxypregn-5-en-20-one, 10 ml of dimethyl malonate and 2.0 g of calcium chloride was heated in an oil-bath having a temperature of 84° C. for 4 days under nitrogen whereupon 20 ml of toluene was added. The reaction was then arranged for distillation at atmospheric pressure and the bath temperature was raised to 160° C. during 1.5 hours. Subsequently the temperature of the bath temperature was lowered to 84° and the mixture was subjected to distillation at high vacuum for 1.5 hours. The resulting solid residue was dissolved in 15 ml of ether, 2.5 ml of hexane and some charcoal was added. Filtration through diatomaceous earth, followed by concentration of the filtrate with intermittent addition of hexane and ether gave a suspension which after filtration gave 3β-acetoxy-21-[methoxycarbonyl]acetoxy-pregn-5-en-20-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH3:20])[C:13](=S)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CI.[CH3:24][C:25]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:26]=1[NH2:27]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH3:20])[C:13](=[N:27][C:26]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:25]=3[CH3:24])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCn1c(-c2ccc(OC)c(OC)c2)cc(=S)n(C)c1=O
Solvent: C1CCOC1
Solvent: CI
Product: CCn1c(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Yield: 37 %

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-thioxo-2(1H)-pyrimidinone (0.59 g) in tetrahydrofuran (50 ml) was added methyl iodide (10 ml) and the mixture was refluxed for 90 minutes. The precipitate was added to 2,4,6-trimethylaniline (2 g) and the mixture was heated at 110°-120° C. for 3 hours. The reaction mixture was washed with a mixture of hexane and diisopropyl ether to remove excess 2,4,6-trimethylaniline. The resulting precipitate was collected by filtration and then dissolved in chloroform. The solution was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure to give crude product, which was purified by silica gel column chromatography to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.29 g); mp 57°-61° C. Thus obtained compound was recrystallized from a mixture of ethanol and water (3:1) to give the desired compound as crystals. mp 116°-118° C.
Reaction SMILES: [C:1](=[O:4])([O-:3])O.[Na+].[C:6](=O)([O:14]C1C=CC=CC=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:6]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:14])[C:1]([O:3][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Product: O=C(Oc1ccccc1)C(=O)Oc1ccccc1

Procedure:
400 parts of an aqueous solution of sodium hydrogencarbonate having a pH of 10 were added to 200 parts of diphenyl carbonate, obtained through the decarbonylation reaction of diphenyl oxalate using triphenyl phosphine oxide and oxalyl chloride as catalysts, the mixture was heated to 90° C. and stirred for 1 hour. To the obtained heavy solution (diphenyl carbonate layer) was further added 400 parts of distilled water, and the resulting mixture was heated to 90° C. and stirred for 1 hour to obtain diphenyl carbonate containing 10.3 ppm of hydrolyzable chlorine. An ester interchange reaction between this diphenyl carbonate and bisphenol A was carried out in the same manner as in Example 1 except that a disodium salt of bisphenol A was used in place of sodium hydroxide as an ester interchange catalyst in an amount of 2.0×10−6 mole, in terms of sodium, based on bisphenol A, to synthesize polycarbonate. The conditions and results are shown in Tables III-A and III-B below.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[CH2:39][NH2:40].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:5]3[C:3](=[O:2])[N:40]4[CH2:39][C@H:35]5[CH2:36][CH2:37][CH2:38][N:34]5[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: NC[C@H]1CCCN1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C[C@H]3CCCN3[C@@H]1C2
Yield: 91.8 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (60 mg, 0.13 mmol) and [(2R)-2-pyrrolidinylmethyl]amine (100 mg, 1.0 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4aS,13aR)-N-[(4-fluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide (60 mg, 91%). This material was hydrogenated in a second step as described in example Z-2 to give (4aS,13aR)-N-[(4-fluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide (21 mg, 42%) as a white solid. 1H NMR (CDCl3) δ 11.72 (m, 1H), 1.37 (m, 1H), 8.33 (s, 1H), 7.29 (m, 2H), 6.97 (m, 2H), 4.57 (m, 2H), 4.52 (m, 1H), 4.24-4.19 (m, 2H), 3.87-8.76 (m, 2H), 3.14-3.07 (m, 2H), 2.82 (m, 1H), 2.11-1.89 (m, 3H), 1.68 (m, 1H); ES+ MS: 413 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1N
Temperature: 90 °C

Procedure:
A DME/water solution (40 mL, 3/1) containing methyl 2-amino-5-bromobenzoate (2.5 g, 12.3 mmol), K2CO3 (4.0 g, 24.6 mmol), 4-(trifluoromethoxy)phenyl boronic acid (3.8 g, 18.5 mmol) and Pd(PPh3)4 (0.712 g, 0.62 mmol) was heated at 90° C. under an argon atmosphere. After approximately 1 hour the solution was cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was washed with water, brine and dried over Na2SO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 8.12 (d, J=2.2 Hz, 1H); 7.57 (d, J=8.5 Hz, 2H); 7.52 (dd, J=2.2, 8.5 Hz, 1H); 7.28 (d, J=8.5 Hz, 2H); 6.77 (d, J=8.5 Hz, 1H); 5.84 (broad s, 2H); 3.94 (s, 3H). LCMS1 3.91 min. (M+H)=312