Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11](OCC)(=[O:14])[C:12]#[CH:13].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[OH:14][C:11]1[CH:12]=[CH:13][N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: C#CC(=O)OCC
Reactant: COc1ccc(NN)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(-n2ccc(O)n2)cc1
Reaction time: 12 h
Yield: 60.3 %

Procedure:
A solution of 72.7 g of 4-methoxyphenylhydrazine in 700 ml of tert-butanol was treated dropwise at 30° C. with 56.8 g of ethyl propiolate. A total of 118 g of potassium tert-butoxide was then introduced in portions with ice cooling into the mixture thus obtained. After 12 h at 25° C., the solvent was distilled off under reduced pressure and the residue thus obtained was taken up in water. The aqueous solution was washed with dichloromethane and then acidified with conc. acetic acid with cooling to a pH of 9, the product being deposited as a solid. After washing and drying, 60.3 g of the title compound (60% of theory) were obtained; m.p.: 167°-170° C.
Reaction SMILES: NC1C=CC(C)=C(C(C2C=CC(NC3C=CC(C(F)(F)F)=CC=3)=CC=2Cl)=O)C=1.[Cl:29][C:30]1[CH:35]=[C:34]([NH:36][C:37]2[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=2)[CH:33]=[CH:32][C:31]=1[C:44]([C:46]1[CH:51]=[C:50]([N+:52]([O-])=O)[CH:49]=[CH:48][C:47]=1[CH3:55])=[O:45]>>[NH2:52][C:50]1[CH:49]=[CH:48][C:47]([CH3:55])=[C:46]([C:44]([C:31]2[CH:32]=[CH:33][C:34]([NH:36][C:37]3[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=3)=[CH:35][C:30]=2[Cl:29])=[O:45])[CH:51]=1
Reactant: Cc1cccc(Nc2ccc(C(=O)c3cc([N+](=O)[O-])ccc3C)c(Cl)c2)c1
Agent: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: Cc1cccc(Nc2ccc(C(=O)c3cc(N)ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 415, using compound 463 (1.78 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:2 as the eluent to afford the title compound as yellow syrup.
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:20]=[CH:19][C:18]2[C:9](=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:13][CH:12]=3)[CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:10]1[C:11]2[C:16]([CH:17]=[C:18]3[C:9]=1[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:20]=[CH:19]3)=[CH:15][C:14]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:13][CH:12]=2
Reactant: BrBr
Reactant: CC(C)(C)c1ccc2cc3cc(C(C)(C)C)ccc3cc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc2c(Br)c3cc(C(C)(C)C)ccc3cc2c1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Bromine (3.02 g, 18.9 mmol) is added at 0° C. to a solution of 2,6-di-tert-butylanthracene (5.0 g, 17.2 mol) in carbontetrachloride (200 ml). The mixture is then stirred at 0° C. for 15 hours. After allowing to heat up to room temperature, half the amount of solvent is evaporated and the resulting mixture is poured into methanol. The precipitate is collected by filtration, recrystallized from n-hexane/methanol and the desired product is obtained as a white solid (1.13 g).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]=[N:11]2)=[O:7])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH2:12][NH:11]2)=[O:7])=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(=O)OCn2ncc(=O)[nH]c2=O)cc1
Agent: O=[Pt]
Solvent: CCO
Product: Cc1ccc(C(=O)OCN2NCC(=O)NC2=O)cc1

Procedure:
2-(4-Methylbenzoyloxymethyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (2.1 g) is dissolved in ethanol (100 ml), and the mixture is added with platinum oxide (400 mg) and stirred at room temperature for 3 hours in an atmosphere of hydrogen. After the completion of the reaction, the catalyst is filtered off, and the filtrate is concentrated in vacuo to give a pale yellow liquid. The liquid is purified by chromatography over silica gel using a mixture of chloroform/methanol as an eluent to give white crystals of 2-(4-methylbenzoyloxymethyl)-3,5-dioxo-hexahydro-1,2,4-triazine (Compound No. 73). The product is recrystallized from a mixture of ethanol/n-hexane. Yield, 1.35 g (62.2%). M.P., 163.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH2:38][C:39]1([CH2:44][OH:45])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:38][C:39]3([CH2:44][OH:45])[CH2:43][CH2:42][CH2:41][CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: NC1(CO)CCCC1
Product: O=C(Nc1ccc(Oc2ccnc(NC3(CO)CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 1-amino-cyclopentylmethanol according to conditions described in general procedure C. 1H NMR (400 MHz, DMSO-d6) δ 1.14 (s, 4 H), 1.58-1.61 (m, 10 H), 3.26-3.31 (m, 6 H), 6.27 (d, J=5.5 Hz, 1 H), 6.53 (s, 1 H), 6.95 (d, J=12.4 Hz, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.35 (d, J=7.7 Hz, 1 H), 7.44 (s, 1 H), 7.52-7.59 (m, 3 H), 7.78 (s, 1 H), 7.95-7.97 (m, 1 H), 8.16 (d, J=5.5 Hz, 1 H), 10.41 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[C:21]1([CH2:20][C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4ccccc4)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4-(bromomethyl)biphenyl in N,N-dimethylformamide. Trituration with diethyl ether provided an off-white solid. 1H NMR: δ 7.98 (s, 1H), 7.93, (dd, J=7.0, 2.0 Hz, 2H), 7.34-7.57 (m, 7H), 7.23-7.26 (m, 2H), 7.06 (dd, J=7.0, 2.0 Hz, 2H), 3.97 (A of AB, J=13.7 Hz, 1H), 3.92 (s, 3H), 3.39 (B of AB, J=13.7 Hz, 1H). MS (m/e): 452.1 (M−H)−. Anal: Calc for C23H19NO5S2.C3H7NO: 59.30% C, 4.98% H, 5.32% N; Found: 59.13% C, 4.89% H, 5.24% N. MP: 119-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([F:30])[C:3]=1[O:4][C:5]1[CH:21]=[CH:20][C:8]2[N:9]([CH3:19])[C:10](=[O:18])[C:11]([CH3:17])([C:13](=[N:15][OH:16])[CH3:14])[O:12][C:7]=2[CH:6]=1.[H-].[Na+].Br[CH2:34][CH3:35].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([F:30])[C:3]=1[O:4][C:5]1[CH:21]=[CH:20][C:8]2[N:9]([CH3:19])[C:10](=[O:18])[C:11]([CH3:17])([C:13](=[N:15][O:16][CH2:34][CH3:35])[CH3:14])[O:12][C:7]=2[CH:6]=1
Reactant: CCBr
Reactant: CC(=NO)C1(C)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCON=C(C)C1(C)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a DMF (10 ml) solution of 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-2-[1(hydroxyimino)ethyl]-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (Compound 101) (0.3 g) obtained in Example 16 was added, under ice-cooling, 60% sodium hydride (0.03 g), and after stirring for 20 minutes, bromoethane (0.1 g) was dropwise added thereto. After stirring for 2 hours, 1N hydrochloric acid was added and the mixture extracted twice with ethyl acetate (20 ml). The extract was then washed with water and with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was evaporated under a reduced pressure, and the residue purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=4/1) to give 0.3 g of the title compound (colorless oil).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.C1(C)C=CC=CC=1.Cl.[CH2:16]([NH:23][NH2:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH2:16]([NH:23]/[N:24]=[CH:2]/[C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNCc1ccccc1
Reactant: CCOC(=O)C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=N/NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
47% ethyl glyoxylate in toluene (polymer type) (29.2 g, 134.5 mmol) was dissolved in THF (200 ml), and to the solution was added benzylhydrazine monohydrochloride (21.3 g, 134.5 mmol) and triethylamine (20.6 ml, 148 mmol), and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 14.9 g of E-ethyl 2-(2-benzylhydrazono)acetate (mixture of E:Z=4:1) (yield: 53%) as oil.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:13](=[O:16])([O-])[O-:14].[Na+].[Na+]>COCCOC.O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:6]3[CH:11]=[CH:10][C:9]([C:13]([OH:14])=[O:16])=[CH:8][CH:7]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(-n2cncn2)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(O)c1ccc(-c2ccc(-n3cncn3)cc2)cc1
Yield: 184.5 %

Procedure:
4-(1,2,4-Triazol-1-yl)bromobenzene (340 mg, 1.5 mmol), 4-carboxylic acid benzene boronic acid (250 mg, 1.5 mmol), sodium carbonate (650 mg, 4 eq), tetrakis (triphenylphosphine)palladium(0) (50 mg) in DME (25 ml) and water (25 ml) was heated under argon at reflux for 24 h, cooled, evaporated to dryness under reduced pressure, partitioned between saturated aqueous sodium carbonate solution (50 ml) and ethyl acetate (50 ml), the aqueous extracts acidified with conc. HCl and dried in vacuo to afford the title compound as a pale yellow crystalline solid (367 mg, 92%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.Cl.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCC(Cl)(Cl)Cl>[C:9]([C:6]1[NH:5][C:4](=[O:7])[NH:3][C:2]=1[CH3:1])(=[O:16])[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: Cc1c[nH]c(=O)[nH]1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccncc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
In 80 ml tetrachloroethane are placed 3.87 g (39.5 mmole) 1,3-dihydro-4-methyl-2H-imidazole-2-one and 7 g (39.5 mmole) isonicotinoyl chloride hydrochloride. Aluminum chloride (26 g, 194 mmole) is added and the mixture is stirred at 85° C. for 3 hours. The tetrachloroethane is decanted from the reaction mixture and the residue is quenched with water and neutralized with sodium bicarbonate. The suspension is filtered and the filtrate evaporated to dryness. Chromatography over silica gel affords the title compound; m.p. 295°-96°.
Reaction SMILES: [Na+].[O:2]=[C:3]1[NH:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O-:23])=[O:22].[CH3:24]C(C)=O.[OH-].[K+].CI>O>[CH3:24][N:7]1[CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:3]1=[O:2]
Reactant: CC(C)=O
Reactant: O=C([O-])CCCCCCCn1c(-c2ccccc2)c[nH]c1=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: Cn1cc(-c2ccccc2)n(CCCCCCCC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.2 g of 8-(2-oxo-5-phenyl-4-imidazolin-1-yl) caprylic acid sodium salt (preparation see German patent application No. P 29 34 746.4) are suspended in 20 cc. of acetone together with 2.8 g of pulverized potassium hydroxide. The mixture is refluxed and converted into a homogenous solution by the addition of some drops of water. Thereafter, 2.8 g of methyliodide are added at boiling temperature, the mixture is refluxed for 30 minutes and cooled to room temperature. After cooling, so much of water is added that precipitated solids are dissolved. The solution is stirred at room temperature for 4 hours, is acidified and diluted with water until the crude acid is separated as oil. The oil is dissolved in a small amount of chloroform, the chloroform phase is washed with water several times and is finally extracted with 5% soda lye. The soda lye extract is washed with chloroform, the aqueous solution is acidified with dilute hydrochloric acid and is separated from the acid precipitated as an oil. Purification occurs by chromatography on silicic acid gel using a mixture of chloroform and methanol as eluant.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:9](=O)[O:10]C)=[C:6]([NH2:18])[N:5]=[C:4]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[N:20]=2)[N:3]=1>O1CCCC1>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[N:20]=2)[N:5]=[C:6]2[C:7]=1[N:8]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:9](=[O:10])[NH:18]2
Reactant: COC(=O)N(CC(F)(F)F)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: C1CCOC1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(CC(F)(F)F)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
Under an argon atmosphere, 2.100 g (4.282 mmol) of the compound from example 15A were dissolved in 235 ml of tetrahydrofuran and cooled to 0° C., and 10.705 ml (10.705 mmol) of a 1N solution of bis(trimethylsilyl)sodium amide in tetrahydrofuran were added dropwise. The mixture was stirred at 0° C. for 2 h and then at RT for 16 h. The tetrahydrofuran was partly concentrated in an argon stream and the precipitate was filtered off. 1.290 g of the title compound were obtained (66% of theory).
Reaction SMILES: [Cl-].[CH2:2]([O:5][C:6]1[CH:31]=[C:30]([CH3:32])[C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:8]([CH3:33])[C:7]=1[CH3:34])[CH2:3][CH3:4].[CH2:35]([O:37][C:38](=[O:49])[CH:39]=[C:40]([CH3:48])[CH:41]=[CH:42][CH:43]=[C:44]([CH:46]=O)[CH3:45])[CH3:36]>>[CH2:35]([O:37][C:38](=[O:49])[CH:39]=[C:40]([CH3:48])[CH:41]=[CH:42][CH:43]=[C:44]([CH3:46])[CH:45]=[CH:10][C:9]1[C:30]([CH3:32])=[CH:31][C:6]([O:5][CH2:2][CH2:3][CH3:4])=[C:7]([CH3:34])[C:8]=1[CH3:33])[CH3:36]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: CCCOc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: [Cl-]
Product: CCCOc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)OCC)c(C)c1C

Procedure:
4-propoxy-2,3,6-trimethyl-benzyl-triphenyl-phosphonium chloride is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to produce 9-(4-propoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester which is converted by the procedure of Example 7 to 9-(4-propoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid, m.p.: 200°-201° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.Cl[C:19]1[CH:35]=[C:23]2[N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:36])[N:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:16][O:17][C:19]1[CH:35]=[C:23]2[NH:24][CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:36])[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)cc2)c(F)c1
Product: O=c1nc(OCc2ccc(Oc3ccc(F)cc3)c(F)c2)cc2n1CCCN2

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E111 starting from (3-fluoro-4-(4-fluorophenoxyl)phenyl)methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:20][CH2:19]2)=[O:14])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCC(=O)O)cc1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(OCC(=O)NC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1
Reaction time: 12 h
Yield: 29.2 %

Procedure:
(4-Acetylphenyloxy)acetic acid (2.0 g) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (3.4 g) were suspended in DMF (50 mL), and triethylamine (2.9 mL), EDC hydrochloride (2.4 g) and HOBt (1.9 g) were added to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to crystallize to give the title compound (1.3 g) as a white solid. melting point: 113° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:4][C:3]=1[C:36]#[C:37][C:38]([OH:41])([CH3:40])[CH3:39].[CH:42]1[C:51]2[C:46](=[CH:47][C:48](B(O)O)=[CH:49][CH:50]=2)[CH:45]=[CH:44][N:43]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1>[OH:41][C:38]([CH3:40])([CH3:39])[C:37]#[C:36][C:3]1[N:4]=[C:5]([N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=2)[S:6][C:2]=1[C:48]1[CH:47]=[C:46]2[C:51](=[CH:50][CH:49]=1)[CH:42]=[N:43][CH:44]=[CH:45]2
Reactant: CC(C)(O)C#Cc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1Br
Reactant: OB(O)c1ccc2cnccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(O)C#Cc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1-c1ccc2cnccc2c1
Temperature: 120 °C
Yield: 37 %

Procedure:
(S)-tert-butyl 1-(N-(5-bromo-4-(3-hydroxy-3-methylbut-1-ynyl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.025 g, 0.038 mmol) was taken up in 1 mL of dioxane in a microwave safe tube. Isoquinolin-6-ylboronic acid (0.0098 g, 0.057 mmol), sodium carbonate, 2M in water (0.075 mL, 0.15 mmol), and tetrakistriphenylphosphine palladium (0) (0.0044 g, 0.0038 mmol) were added. The mixture was degassed with nitrogen and the tube was sealed. The tube was then heated to 120° C. in a Personal Chemistry microwave unit for 20 minutes. The mixture was diluted with 10 mL of EtOAc, washed with 5 mL of water and 5 mL of brine, and then dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (pipette column, 25% to 70% EtOAc/hexanes), afforded (S)-tert-butyl 1-(N-(4-(3-hydroxy-3-methylbut-1-ynyl)-5-(isoquinolin-6-yl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.010 g, 37% yield) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:13]=[CH:12]2.[CH2:25]([O:27][Si:28]([O:38][CH2:39][CH3:40])([O:35][CH2:36][CH3:37])[CH2:29][CH2:30][CH2:31][N:32]=[C:33]=[O:34])[CH3:26].C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(Cl)Cl>[CH2:36]([O:35][Si:28]([O:38][CH2:39][CH3:40])([O:27][CH2:25][CH3:26])[CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:13]=[CH:12]2)=[O:34])[CH3:37]
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Reactant: COC(=O)/C=C/c1ccc2cc(OCCCCCCO)ccc2c1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCl
Product: CCO[Si](CCCNC(=O)OCCCCCCOc1ccc2cc(/C=C/C(=O)OC)ccc2c1)(OCC)OCC
Temperature: 25 °C

Procedure:
A mixture of 500 mg of methyl (E)-3-[6-(6-hydroxyhexyloxy)naphthalen-2-yl]acrylate, 25 ml of methylene chloride, 0.376 ml of 3-triethoxysilanylpropyl isocyanate and 0.009 ml of dibutyltin dilaurate was heated under reflux for 3 hrs. Thereafter, a further 0.009 ml of dibutyltin dilaurate was added and the mixture was left to react under reflux for 16 hrs. Then, the reaction solution was cooled to room temperature, evaporated completely and the residue was chromatographed on 150 g of silica gel with ether/hexane. This gave 830 mg of methyl 3-{6-[6-(3-triethoxysilanylpropylcarbamoyloxy)hexyloxy]naphthalen-2-yl}acrylate as a colorless solid, λmax. (CH2Cl2): 326 nm (ε=26200).
Reaction SMILES: [C:1]([O:11]CC(N)CC)(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(OCC(N)CC)(=O)[C@@H](C1C=CC=CC=1)O.[OH-].[K+]>>[C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: CCC(N)COC(=O)[C@@H](O)c1ccccc1
Agent: CCC(N)COC(=O)[C@H](O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C(O)c1ccccc1

Procedure:
To a portion (1100 mls out of a total of 4800 mls) of the mother liquor plus methanol wash liquor obtained from resolution B, containing about 2.4 moles of a mixture of diastereomers, consisting of about 2.25 moles of (-)-2-amino-1-butanol L-(+)-mandelate and about 0.15 mole of (-)-2-amino-1-butanol D-(-)-mandelate, is added 180 grams of potassium hydroxide (88.8% real; 2.85 moles) to obtain a solution having an initial αD25°C. of +24.7° ("as is", 10 cm cell). The solution is then heated at 115°-116° C. under pressure (40 psi) for 4 hours to obtain a mandelic acid solution having an αD25°C. of -3.0° ("as is", 10 cm cell). The resulting solution is essentially racemized, the negative rotation being due to the presence of the (-)-2-amino-1-butanol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](O)=O)=[CH:2]1.[NH2:9][C:10]1[C:11](=[O:24])[N:12]([CH2:21][CH2:22][CH3:23])[C:13](=[O:20])[N:14]([CH2:17][CH2:18][CH3:19])[C:15]=1[NH2:16]>>[CH2:21]([N:12]1[C:11](=[O:24])[C:10]2[NH:9][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[N:16][C:15]=2[N:14]([CH2:17][CH2:18][CH3:19])[C:13]1=[O:20])[CH2:22][CH3:23]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)c1ccoc1
Product: CCCn1c(=O)c2[nH]c(-c3ccoc3)nc2n(CCC)c1=O

Procedure:
The starting 1,3-dipropyl-8-(3-furanyl)xanthine is prepared by a process analogous to that described in Example 2 above using 3-furoic acid and 5,6-diamino-1,3-dipropyluracil, mp 244°-245° C.