Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:10][C:11](=[O:21])[N:12]([CH3:20])[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:10]1[C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:12]([CH3:20])[C:11]1=[O:21]
Reactant: Cn1c(-c2ccccc2)c(-c2ccccc2)[nH]c1=O
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(C)c1=O

Procedure:
The product is produced as described in example 1 from 2.4 g of NaH (80% suspension in mineral oil), 20 g of 4.5-diphenyl-1-methyl-4-imidazolin-2-one, 160 cc. of DMF, 19 g of 8-bromocaprylic acid methyl ester and 2.4 g of NaJ.
Reaction SMILES: S[CH2:2][C:3]([OH:5])=O.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)[S:23]([O-])(=O)=O.[F:29][C:30]([F:60])([C:56]([F:59])([F:58])[F:57])[C:31]([F:55])([F:54])[C:32]([F:53])([F:52])[C:33]([F:51])([F:50])[C:34]([F:49])([F:48])[C:35]([F:47])([F:46])[C:36]([F:45])([F:44])[I+]C1C=CC=CC=1>C(Cl)Cl>[F:29][C:30]([F:60])([C:56]([F:59])([F:58])[F:57])[C:31]([F:55])([F:54])[C:32]([F:53])([F:52])[C:33]([F:51])([F:50])[C:34]([F:49])([F:48])[C:35]([F:47])([F:46])[C:36]([F:45])([F:44])[CH2:2][C:3]([OH:5])=[S:23]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: O=C(O)CS
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[I+]c1ccccc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: OC(=S)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
2.0 ml of methylene chloride, 0.03 ml (0.42 mmol) of mercaptoacetic acid and 80 mg (0.39 mmol) of 2,6-di-tert-butyl-4-methylpyridine were charged in a flask, and 290 mg (0.38 mmol) of heptadecafluoro-n-octylphenyliodonium trifluoromethanesulfonate was added thereto in small portions while stirring at room temperature, followed by stirring for 20 minutes at room temperature. The resulting precipitate was filtered, subjected to silica gel chromatography and, after eluting iodobenzene with pentane, the desired product was eluted with diethyl ether. Diethyl ether was distilled off from the eluate to obtain heptadecafluoro-n-octylthioacetic acid as white crystals. A sample of the product was purified by gas chromatography. Yield, 88%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=4[O:35][CH2:36][CH3:37])=[O:24])[NH:12][C@H:11]3[CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:5]2=[CH:4][CH:3]=1.CC[N:46]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C=O)C>[C:30]([C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:38][C:39]([CH3:40])([CH3:41])[CH3:42])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:43])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])=[C:27]([O:35][CH2:36][CH3:37])[CH:28]=1)(=[O:32])[NH2:46]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 80 °C

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-ethoxy-benzoic acid (0.1 g, 0.17 mmol) prepared in Example 130 in anhydrous DMF (2 mL) were added EDCI (64 mg, 0.33 mmol), HOBt (45 mg, 0.33 mmol), NH4Cl (89 mg, 1.67 mmol), and triethylamine (34 mg, 0.33 mmol) sequentially. The reaction mixture was heated at 80° C. for 1 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25-100% EtOAc in hexanes) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-ethoxy-phenyl)-amide as a off white solid (37 mg, 35%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1ccncc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Intermediate 1B, 1-(4-(benzyloxy)phenyl)-2-(pyridin-4-yl)ethanone (5.22 g, 17.21 mmol) and solvent THF (60 mL) were added to 20% Pd(OH)2—C, wet (1.044 g, 7.43 mmol) in a 250 mL stainless steel pressure bottle. The reaction mixture was stirred for 3 hr at 30 psi and ambient temperature. HPLC indicated that both starting material and product were present, so MeOH (10 mL) was added and the reaction was run for an additional 1 h. The reaction mixture was filtered through a nylon membrane and the filtrate was concentrated under reduced pressure to give a pale yellow solid (3.13 g, 85% yield). Much of the yellow color was removed by rinsing with MeOH. After the MeOH rinses, the solid was rinsed with Et2O, then dried in a vacuum oven at 50° C. for 4 hours. This vacuum-dried sample weighed 2.071 g (56.4%). 1H NMR (300 MHz, DMSO-d6) δ 10.38 (br s, 1H), 8.52-8.45 (m, 2H), 7.96-7.89 (m, 2H), 7.29-7.24 (m, 2H), 6.90-6.83 (m, 2H), 4.35 (s, 2H). MS (DCI—NH3) m/z=214 (M+H)+, m/z=231 (M+NH4)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13]C)=[O:12])[CH:2]=[CH2:3].[OH-].[Li+]>O1CCCC1.O>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCc1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of the Methyl 2-allylphenylacetate (Step 1, 0.400 mg. 2.10 mmol) in tetrahydrofurane (10 mL) was added Lithium hydroxide (0.097 g, 2.31 mmol) in water (10 mL). The solution was stirred at room temperature for 3 h and was concentrated in vacuo. Water (40 mL) was added and the pH was adjusted to 1. The solution was extracted with dichloromethane and the combined organic layers were dried and concentrated to give 2-allyl phenyl acetic acid (yellow oil, 363 mg, 98%); C11H12O2; MW: 176.22; ES− 175; IR 1702 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.16-7.38 (4H, m), 5.99 (1H, m), 5.11 (1H, m), 5.04 (1H, m), 3.73 (2H, s), 3.47 (2H, dt) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[CH:4][C:3]=1[O:17][CH3:18].C([Mg]Cl)C.[CH3:23][N:24]1[C:28]([C:29](OC)=[O:30])=[CH:27][C:26]2[CH:33]=[CH:34][S:35][C:25]1=2>O1CCCC1.[Cl-].[Na+].O>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([B:8]2[O:9][C:10]([CH3:12])([CH3:11])[C:13]([CH3:14])([CH3:15])[O:16]2)[CH:6]=[CH:7][C:2]=1[NH:1][C:29]([C:28]1[N:24]([CH3:23])[C:25]2[S:35][CH:34]=[CH:33][C:26]=2[CH:27]=1)=[O:30]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: COC(=O)c1cc2ccsc2n1C
Agent: CC[Mg]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccsc2n1C
Temperature: 25 °C
Yield: 32.5 %

Procedure:
To 4-amino-3-methoxyphenylboronic acid pinacol ester (1340 mg, 5.38 mmol) in tetrahydrofuran (20 ml) under a nitrogen atmosphere was added slowly a 2M solution of ethylmagnesium chloride in tetrahydrofuran (2.69 ml, 5.38 mmol) and the resulting solution was heated at reflux for one hour. Methyl 6-methyl-6H-thieno[2,3-b]pyrrole-5-carboxylate (500 mg, 2.56 mmol) was added and the reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled to room temperature and poured in brine. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed subsequently with water and brine. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; heptane with gradient of 0 to 50% of ethyl acetate). The product was dissolved in hot dichloromethane and the remaining solids were removed by filtration. The filtrate was concentrated, the residue dissolved in hot dichloromethane and diethylether was added. The formed solids were collected by filtration, washed with diethylether and dried to yield N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-methyl-6H-thieno[2,3-b]pyrrole-5-carboxamide (343 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[H-].[Na+].[C:23]([O:27][C:28]([N:30]1[C:38]2[N:33]([C:34](=[O:40])[N:35]=[C:36](Cl)[CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:36]3[CH:37]=[C:38]4[N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:31][CH2:32][N:33]4[C:34](=[O:40])[N:35]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methanol, NaH and tert-butyl-7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32](C)=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[Cl:36]C1C=CC=CC=1S(N=C=O)(=O)=O>>[Cl:36][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[S:26]([NH:25][C:23]([NH:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:15][CH:16]=1)=[O:24])(=[O:28])=[O:27]
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 10 of Example 1 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9 of Example 1) and 2-chlorobenzenesulfonyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH2:11][O:10]1.S(=O)(=O)(O)[OH:19].N>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH2:11][OH:10])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: Clc1ccc(C2(Cn3ccnc3)CO2)c(Cl)c1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: CCOC(C)=O
Product: OCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
A mixture of 2-(2,4-dichlorophenyl)-2-(imidazol-1-yl)methyloxirane (170.4 g; Japanese Patent Publications (unexamined) Nos. 12372/1981 and 106666/1982) and a 25% aqueous sulfuric acid solution (1193 g) was stirred at 80°-85° C. for 5 hours. To the reaction mixture, ethyl acetate (405 ml) and a 28% aqueous ammonia solution (520 ml) were added dropwise at 0°-10° C., and then the mixture was stirred for 1 hour at the same temperature. The resulting precipitate was collected by filtration and dried at 80° C. (10 mmHg) for 5 hours to give 2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2,3-propanediol. Yield, 146 g; 80.3%. M.P., 123.5°-124.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13](Br)=[CH:14][CH:15]=2)[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[N:7]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.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>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:8]1[C:9]([C:11]2[S:12][C:13]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=3)=[CH:14][CH:15]=2)=[CH:10][C:6]([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:24])=[N:7]1
Reactant: COC(=O)COc1cc(-c2ccc(Br)s2)n(-c2ccccc2Cl)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
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: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Temperature: 70 °C
Yield: 44.5 %

Procedure:
To a solution of [5-(5-bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-1H-pyrazol-3-yloxy]-acetic acid methyl ester (1.43 g, 3.33 mmol) in anhydrous THF (13.0 mL) was added sequentially 3-methylsulfonylphenylboronic acid (0.80 g, 4.0 mmol), Pd(PPh3)4 (192 mg, 0.17 mmol), Na2CO3 (1.06 g, 10.0 mmol) and water (1.0 mL). The reaction mixture was heated to reflux at 70° C. for overnight. The solvent was evaporated and the crude residue was purified by flash column chromatography with 50% ethyl acetate in hexane, resulting the product methyl {1-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazol-3-yloxy}acetate (0.746 g, 45% yield). 1H-NMR (CDCl3): δ 8.17 (m, 1H), 7.83 (m, 2H), 7.55 (m, 3H), 7.40 (m, 3H), 7.33 (m, 1H), 5.91 (s, 1H), 4.70 (s, 2H), 3.81 (s, 3H), 3.09 (s, 3H). MS (ES): 503 [M+H]+.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([O:10]CCCl)=O)CCC.[Li+].[BH4-].Cl>C1COCC1.CCCCCC>[CH2:6]([C:6]1[CH:5]=[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:14][C:7]=1[CH2:8][OH:10])[CH2:5][CH2:16][CH3:15]
Reactant: CCCCc1cc(C(=O)OCCCl)ccc1-c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCc1cc(-c2ccccc2)ccc1CO

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 2-chloroethyl 3-butyl-4-phenylbenzoate (570 mg, 1.80 mmol), THF (9 mL) and LiBH4 (9 mL of a 2M solution in THF, 18 mmol). This mixture was heated at reflux for 18 h. The cooled reaction mixture was treated with 1N HCl and extracted with EtOAc. The combined EtOAc extracts were washed with H2O and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chiromatographed on silica gel using 20% EtOAc in hexane as eluant to afford the title compound as a crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Li]CCCC.O1CCCC1.[CH:21]([N:24]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:25](=[O:34])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)([CH3:23])[CH3:22]>C(OCC)C.C1COCC1.C(OCC)C>[CH:35]1([N:24]([CH:21]([CH3:23])[CH3:22])[C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([CH:30]([OH:31])[C:2]3[CH:7]=[CH:6][C:5]4[O:8][CH2:9][O:10][C:4]=4[CH:3]=3)=[CH:32][CH:33]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)N(C(=O)c1ccc(C=O)cc1)C1CCCCC1
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc(C(O)c2ccc3c(c2)OCO3)cc1)C1CCCCC1
Temperature: -20 °C

Procedure:
To a stirred solution of 4-bromo-1,2-(methylenedioxy)benzene (1.00 g, 6.0 mmol) in ethyl ether (30 mL) at 0° under an argon atmosphere is added n-BuLi (3.75 mL of 1.6 M solution in hexane). Tetrahydrofuran (10 mL) is added. The reaction mixture is cooled to -20° C. and a solution of terephthalaldehydic acid N-isopropyl-N-cyclohexyl amide (0.82 g, 3.0 mmol) in THF: ethyl ether (4:3, 35 mL) is added rapidly. The reaction is followed by thin layer chromatography until complete. The reaction is quenched at -15° C. by adding water (50 mL) and 1N HCl(20 mL). The reaction is further diluted with water (300 mL) and extracted three times with EtOAc (50 mL portions). The combined extracts are washed twice with saturated NaCl solution and dried (MgSO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. The crude product is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([CH2:10][I:11])[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2].C[C:22](OC(C)=O)=[O:23].N1C=CC=C[CH:29]=1>>[CH3:19][C:18]1[C:16](=[O:17])[NH:15][C:13](=[O:14])[N:12]([C@@H:7]2[O:8][C@:9]([C:10]#[CH:29])([CH2:22][OH:23])[CH:5]=[CH:6]2)[CH:20]=1.[C:1]([O:4][C@H:5]1[C@@H:9]([CH2:10][I:11])[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Agent: CC(=O)O[C@@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CI
Product: C#C[C@@]1(CO)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
TKD-4-114 (2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine, 4′-ethynyl-d4T) was synthesized by a series of reactions shown in Scheme B, starting from compound 6 which was prepared according to the published procedure: B. V. Joshi and C. B. Reese, Tetrahedron Lett., 32, 2371-2374 (1992). 1-(3-O-Acetyl-2,5-dideoxy-5-iodo-β-D-threo-pentofuranosyl)-thymine (7) A mixture of 6 (5.3 g, 15.05 mmol) and Ac2O (4.3 mL, 45.15 mmol) in pyridine (30 mL) was stirred at room temperature for 13 h. The reaction mixture was partitioned between CHCl3/saturated aqueous NaHCO3 (250 mL×3/50 mL). Silica gel column chromatography (hexane/EtOAc=1/1-1/2) of the organic layer gave 7 (5.53 g, 93%) as a foam: 1H NMR (CDCl3) δ 1.96 (3H, s, Me), 2.11 (3H, s, Ac), 2.11-2.16 (1H, m, H-2′a), 2.82 (1H, ddd, Jgem=15.8 Hz, J1′,2′b=8.0 Hz and J2′b,3′=5.7 Hz, H-2′b), 3.32-3.39 (2H, m, H-5′), 4.28 (1H, dt, J3′,4′=3.3 Hz and J4′,5′=7.1 Hz, H-4′), 5.48 (1H, dd, J2′b,3′=5.7 Hz and J3′,4′=3.3 Hz H-3′), 6.30 (1H, dd, J1′,2′a=2.8 Hz and J1′,2′b=8.0 Hz, H-1′), 7.38 (1H, d, J6,Me=0.7 Hz, H-6), 8.59 (1H, br, NH); FAB-MS m/z 395 (M++H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([C:13]3[S:14][C:15]([C:18]4[CH:23]=[C:22]([NH:24][C:25]5[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=5)[CH:21]=[C:20]([CH3:35])[CH:19]=4)=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO.C(OCC)(=O)C.O>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]([C:13]3[S:14][C:15]([C:18]4[CH:23]=[C:22]([NH:24][C:25]5[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=5)[CH:21]=[C:20]([CH3:35])[CH:19]=4)=[CH:16][N:17]=3)[OH:12])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(=O)C3CCC4(CC3)OCCO4)s2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)C3CCC4(CC3)OCCO4)s2)c1
Reaction time: 1 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]dec-8-yl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanone (Ex 1-20) (100 mg, 0.20 mmol) in methanol (5 mL) was added sodium borohydride (22.5 mg, 0.60 mmol). After one hour, water was carefully added and then diluted with ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel (0-100% ethyl acetate gradient with hexanes) afforded 1,4-dioxaspiro[4.5]dec-8-yl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanol. MS ESI calc'd. for C24H26F3N4O3S [M+H]+ 507. found 507. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.83 (d, J=4.9, 1H), 7.97-7.94 (m, 2H), 7.45 (s, 1H), 7.27 (d, J=4.9, 1H), 7.15 (s, 1H), 6.18 (d, J=5.1, 1H), 4.61 (t, J=5.1, 1H), 3.80 (s, 4H), 2.30 (s, 3H), 1.84-1.72 (m, 1H), 1.71-1.61 (m, 2H), 1.61-1.51 (m, 2H), 1.52-1.28 (m, 4H). rhSyk=++.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16](O)([CH3:17])[O:15][C:14](=O)[C:13]=2[C:20]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=2[F:28])=[CH:8][CH:7]=1)#[CH:5]>C(O)CCC>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH3:17])=[N:3][NH:2][C:14](=[O:15])[C:13]=2[C:20]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=2[F:28])=[CH:8][CH:7]=1)#[CH:5]
Reactant: NN
Reactant: C#Cc1ccc(C2=C(c3c(F)cc(F)cc3F)C(=O)OC2(C)O)cc1
Solvent: O
Solvent: CCCCO
Product: C#Cc1ccc(-c2c(C)n[nH]c(=O)c2-c2c(F)cc(F)cc2F)cc1

Procedure:
Hydrazine hydrate (0.17 g) is added to a solution of 0.87 g 4-(4-ethynylphenyl)-5-hydroxy-5-methyl-3-(2,4,6-trifluorophenyl)-5H-furan-2-one in 5 ml of 1-butanol and this mixture is heated for 4 h to 120° C. The reaction mixture is evaporated under reduced pressure and the residue is purified by chromatography on silica gel, using a mixture of toluene/ethyl acetate 5:1 as eluent to obtain 5-(4-ethynylphenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one (Compound No. 1) as colourless crystals, m.p. 252-254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26](I)[CH3:27]>CN(C=O)C.C(OCC)(=O)C>[CH2:26]([N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[C@@H:12]([CH:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[CH3:27]
Reactant: CCI
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN([C@H](C(=O)OC)C(C)O)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Compound 9C (3 g, 8.94 mmol) dissolved in DMF (15 ml) was added with K2CO3 (1.1 equiv., 1.36 g) and ethyl iodide (1.1 equiv., 1 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 2.8 g of a semisolid. Yield=97%. 1HNMR (DMSO, 200 MHz) δ 1.00 (3H, d, J=6.2 Hz), 1.26 (3H, t, J=7 Hz), 3.32 (3H, s), 3.34 (2H, m), 4.02 (1H, bs), 4.23 (1H, m), 5.14 (1H, d, J=4.4 Hz), 7.62 (2H, m), 7.76 (2H, m)