Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C([C:6]1[CH:18]=[CH:17][C:9]([O:10][C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)(=O)C.S([O-])([O-])=O.[Na+].[Na+]>O.C(O)=O>[C:12]([O:14][C:6]1[CH:7]=[CH:8][C:9]([O:10][C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:17][CH:18]=1)(=[O:13])[CH3:11]
Reactant: COC(=O)[C@@H](C)Oc1ccc(C(C)=O)cc1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: COC(=O)[C@@H](C)Oc1ccc(OC(C)=O)cc1
Temperature: 35 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
54.4 g (0.48 mol) of a 30% strength solution of hydrogen peroxide in water was added dropwise to the solution of 88.93 g (0.4 mol) of methyl (R)-2-(4-acetylphenoxy)propionate in 356 g of formic acid at 35° C. over the course of 1 h. After stirring at 35° C. for 5 hours, the excess hydrogen peroxide was decomposed with 5 g of sodium sulfite. The mixture was finally concentrated under reduced pressure and subjected to a short-path distillation at 150°-160° C. under 0.5 mbar. Yield: 96% (94-95% enantiomeric excess).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1Br
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1Br
Temperature: 25 °C
Yield: 98.1 %

Procedure:
1-Bromo-2-methoxy-benzene (1.87 g, 10.0 mmol) was dissolved in chloroform (5 mL) and the solution was cooled in an ice-salt bath to −5° C. to 0° C. The cooled solution was carefully charged with chlorosulfonic acid (2.0 mL, 30.0 mmol) over 30 minutes and the mixture was allowed to warm to room temperature over 1 hour. The mixture then was poured onto chopped ice and transferred to a separatory funnel. The aqueous layer was separated and extracted (×2). The combined organic layers were dried and concentrated to give 3-bromo-4-methoxyphenylsulfonyl chloride (2.80 g, 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[CH2:15]([CH:17]([NH2:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH3:16].C1(C)C=CC=CC=1.C(C(N1C(=O)C2=C(N=[N+]=[N-])C=CC=C2C1=O)CCCCCCCCC(C)(C)CO)C>CN(C)C=O>[CH2:15]([CH:17]([N:31]1[C:10](=[O:11])[C:5]2=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]1=[O:9])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH3:16]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CCC(N)CCCCCCCCC(C)(C)CO
Agent: CCC(CCCCCCCCC(C)(C)CO)N1C(=O)c2cccc(N=[N+]=[N-])c2C1=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCC(CCCCCCCCC(C)(C)CO)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 99.9 %

Procedure:
The starting material used in the above example can be prepared as follows: A mixture of 9.6 g (0.05 mol) of 3-nitrophthalic anhydride, 12.9 g (0.055 mol) of 1-ethyl-10,10-dimethyl-11-hydroxy-1-aminoundecane, 150 ml of toluene and 250 ml of dimethylformamide is heated to the boil, the water formed being removed azeotropically. The reaction mixture is then evaporated to dryness. The residue is dissolved in 150 ml of methylene chloride and the solution is extracted with three times 50 ml of 10% sodium carbonate solution. The methylene chloride solution is then dried over anhydrous sodium sulphate and evaporated. 20.9 g (about 100% of theory) of N-(1-ethyl-10,10-dimethyl-11-hydroxyundecyl)-3-nitrophthalimide are obtained in the form of a viscous oil which gradually crystallises after standing for several weeks; melting point 66°-68° C.
Reaction SMILES: I[C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])#[CH:22].[NH4+].[Cl-]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:8]1([C:3]2[N:4]=[C:5]([NH2:7])[S:6][C:2]=2[C:22]#[C:21][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1nc(-c2ccccc2)c(I)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1sc(N)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a stream of Ar the above prepared 5-iodo-4-phenyl-thiazol-2-ylamine (1.60 g, 5.29 mmol) was dissolved in 30 mL of acetonitrile and treated successively with triethylamine (2.09 mL, 3 eq.), Cul (0.096 g, 0.1 eq.), (Ph3P)2PdCl2 (0.353 g, 0.1 eq. and ethynyltrimethylsilane (2.09 mL, 3 eq.). The flask was closed with a septum and allowed to stir for 15 h at ambient temperature. The reaction mixture was then poured onto icewater/NH4Cl, twofold extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/ethyl acetate=8/2) yielded finally 1.075 g of the title compound as brown foam. MS (ISP): 273.3 [M+H]+.
Reaction SMILES: ClCl.IC1N=C(N)C2N=CN(C=2N=1)[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1[OH:13].[Cl:23][C:24]1[N:25]=[C:26]([NH2:42])[C:27]2[N:28]=[CH:29][N:30]([C:40]=2[N:41]=1)[C@@H:31]1[O:39][C@H:36]([CH2:37]Cl)[C@@H:34]([OH:35])[C@H:32]1[OH:33]>>[Cl:23][C:24]1[N:25]=[C:26]([NH2:42])[C:27]2[N:28]=[CH:29][N:30]([C:40]=2[N:41]=1)[C@@H:31]1[O:39][C@H:36]([CH2:37][OH:13])[C@@H:34]([OH:35])[C@H:32]1[OH:33]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Agent: ClCl
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
In yet another route the 5′-substituent was introduced prior to C2-substitution to circumvent all problems met in the previous routes. The method of Robins20 yielded 5′-deoxy-2-iodo-5′-chloroadenosine from 2-iodoadenosine (1). However, besides the 5′-hydroxyl group, also the 2-iodo group of 1 was replaced by chlorine to some extent, and a mixture of 5′-deoxy-2-iodo-5′-chloroadenosine with 2,5′-dichloro-5′-deoxyadenosine was obtained. Separation of the two products by column chromatography proved impossible. Thus, it was necessary to go further back in the synthesis route, since pure 2,5′-dichloro-5′-deoxyadenosine, obtained by chlorination of 2-chloroadenosine, failed to react with ethanethiol under different conditions (either with KOtBu in MeOH at different temperatures that all regained starting material, or in 2 M NaOH at elevated temperatures yielding the 2,5′-diethylthio substituted derivatives). Finally, in Scheme 1 the successful synthesis of the desired compounds is depicted. The 5′-substituents were introduced at guanosine, which is also the precursor of 2-iodoadenosine (1). Although more laborious, this route starts with the introduction of the 5′-alkylthio substituents at guanosine to circumvent all described problems. Chlorination20 of guanosine gave 5′-chloro-5′-deoxy-guanosine (16) in 93% yield. Compound 16 was reacted with the appropriate thiol in 2 M NaOH1,5 and the 2′- and 3′-hydroxyl groups of compounds 17–20 were subsequently protected to yield the 2′,3′-O-acetyl-5′-(alkylthio)-substituted derivatives 21–24. Several laboratories have described chlorination on the 6-position of purine nucleosides with phosphoryl chloride (POCl3).18,21 To prevent decomposition of the starting materials, the chemicals used were either properly dried or freshly distilled, and compounds 25–28 were obtained in reasonable to good yields (40%–74%). Subsequently, the 2-amino group of compounds 25–28 was replaced by iodine. The method used26 was a variation of the originally diazotization-iodine substitution procedure.22 With this efficient method 29–32 were obtained in good yields (71–82%). Stirring 29–32 in ethanol freshly saturated with NH3 readily removed the protecting groups and slowly aminated the 6-position to give the intermediates 33–36. NMR showed that amination at the 6-position needed stirring at room temperature for at least two days. Subsequent introduction of the C2-substituents was done as described above,7,8 and compounds 37–40 and 45–48 were obtained in good yields.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[NH:29][CH2:30][C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=3[CH3:21])[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Cc1cccc(NCc2nnn(C)n2)c1C
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2cccc(C)c2C)[C@H]1O
Yield: 47 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (300 mg, 1.07 mmol) obtained in step 1 of example 2 and N-(2,3-dimethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (253 mg, yield: 47%).
Reaction SMILES: [F-].C([N+](C[CH2:16][CH2:17][CH3:18])(CCCC)CCCC)CCC.C(OC1(O[Si](C)(C)C)CC1)C.C1(P(=[CH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>C1COCC1.C(OCC)C>[C:16]1(=[CH:49][C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[CH2:17][CH2:18]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC1(O[Si](C)(C)C)CC1
Agent: O=C(O)c1ccccc1
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
At room temperature, 55 ml (55 mmol) of a 1 M solution of tetra-n-butylammonium fluoride in THF were added dropwise to a solution of 9.65 g (55.34 mmol) of [(1-ethoxycyclopropyl)oxy](trimethyl)silane, 25 g (66.41 mmol) of tert-butyl (triphenyl-λ5-phosphanylidene)-acetate and 8.11 g (66.41 mmol) of benzoic acid in 240 ml of THF. After 1 h of stirring, the reaction mixture was heated to 80° C. and stirred at this temperature for 2 h. Using a rotary evaporator, the solvent was then distilled off (200 mbar, bath temperature 40° C.). The residue obtained was taken up in diethyl ether and the mixture was cooled to 4° C. and allowed to stand at this temperature for 1 h. The resulting precipitate (triphenylphosphane oxide) was filtered off. Using a rotary evaporator, the filtrate was then freed from the solvent. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 3.58 g (42% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[CH:34]([NH2:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([NH:37][CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N(C)C)cc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with isopropylamine, HATU and DIPEA in THF to give 339 as a colorless solid after reverse phase HPLC. MS: (ESI+) 526.1
Reaction SMILES: [C:1]([CH:7]([OH:13])[CH2:8][CH:9]([OH:12])[CH2:10][OH:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.O>[Si:19]([CH:10]([OH:11])[CH:9]([OH:12])[CH2:8][CH:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[OH:13])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)C(O)CC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C(=O)C(O)CC(O)C(O)[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of 1 (70 g, 0.368 mol) in CH2Cl2 (2.0 L) is added imidazole (31.3 g, 0.46 mol) and tert-butyldimethylsilyl chloride (58.2 g, 0.386 mol) and stirred at room temperature for 3 h. The reaction mixture is diluted with water, the organic layer separated and washed with water and brine and then dried over MgSO4. After filtration, the filtrate is concentrated and the residue is purified on a silica gel column using ethyl acetate:hexanes as eluent to give 91.2 g (81%) of product as an oil: 1H NMR (DMSO-d6): δ 4.66 (d, J=5.2 Hz, 1H), 4.14-3.90 (m, 2H), 3.54-3.25 (m, 3H), 1.84-1.72 (m, 1H), 1.51-1.39 (m, 1H), 1.10 (s, 9H), 0.83 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: [C:1](O)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][CH2:9][CH:10]([OH:13])[CH2:11][NH2:12]>O>[C:2]([C:1]1[NH:8][CH2:9][CH:10]([OH:13])[CH2:11][N:12]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: NCC(O)CN
Reactant: CC(C)(C)C(=O)O
Solvent: O
Product: CC(C)(C)C1=NCC(O)CN1
Temperature: 0 °C
Yield: 62 %

Procedure:
The feed solution was comprised of 41.4 percent pivalic acid, 43.9 percent 1,3-diamino-2-propanol, and 14.6 percent water, corresponding to a 1/1.2/2 molar ratio, and was kept warm on a hot plate stirrer and pumped through a heated line to the catalyst bed. Pivalic acid (167.4 g, 1.64 mol), 1,3-diamino-2-propanol (177.5 g, 1.97 mol), and water (59.0 g, 3.28 mol) were pumped as a single feed to the alumina bed held at 275° C., at a rate of 1.5 g/min. A preheater tube held at 250° C. served to vaporize the feed components. A nitrogen flow rate of 210 mL/min was applied to the reactor during the run. The reactor effluent was condensed with a hot water condenser to prevent crystallization. The product consisted of an orange oil containing crystalline solid and was stripped on a rotary evaporator to remove water. A roughly equal volume of acetonitrile was added, the slurry cooled to 0° C., and crystalline product was collected on a filter and dried in a vacuum oven at 60° C. to give 139.2 g of 2-t-butyl-5-hydroxy-1,4,5,6-tetrahydropyrimidine as a first crop. The mother liquor was reduced in volume to give an orange oil and placed in an oven at 80° C. overnight. After addition of acetonitrile to the resulting solid and filtration as above, an additional 60.1 g solid was obtained, which was 84 percent pure, most of the remainder being uncyclized materials. The total of 189.7 g of 2-t-butyl-5-hydroxy-1,4,5,6-tetrahydropyrimidine represented a 74 percent isolated yield based on pivalic acid, and a 62 percent yield based on 1,3-diamino-2-propanol. A pure sample was prepared by recrystallization from warm CH3CN: mp 212°-214° C. (corrected, decomp); 1H NMR (D2O/CD3CN) δ 3.9 (m, 1H), 3.1 (apparent dt, 2H), 2.9 (apparent dd, 2H), 1.0 ppm (s, 3H); 13C NMR {1H} (D2O/CD3CN) δ 168.7 (1 C), 60.0 (1 C), 47.0 (2 C), 37.0 (1 C), 27.7 ppm (3 C); Anal. Calcd for C8H16N2O: C, 61.50; H, 10.32; N, 17.93. Found: C, 61.57; H, 10.50; N, 18.01.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1.[SH:20][CH:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3]([S:20][CH:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cn1
Reactant: CCC(S)C(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(Sc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br)C(C)=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
73 mg (0.2 mmol) of 5-(5-bromo-4-chloro-pyrimidin-2-ylamino)-pyridine-2-sulfonic acid amide and 32 mg (0.27 mmol) of 3-mercapto-2-pentanone are dissolved in 4 ml of DMF p.a. After 0.038 ml (0.27 mmol) of triethylamine is added, it is allowed to stir for 2 hours at room temperature and for 3 hours at 50° C. After concentration by evaporation, it is flashed with dichloromethane/MeOH (9:1).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[N:7][C:8]([S:12][CH2:13][CH3:14])=[N:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16].N1C=CC=CC=1.C>[OH-].[Na+]>[S:16]=[C:2]1[C:11]2[C:6](=[N:7][C:8]([S:12][CH2:13][CH3:14])=[N:9][CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCSc1ncc2c(=O)[nH]cnc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCSc1ncc2c(=S)[nH]cnc2n1
Yield: 95.9 %

Procedure:
A mixture of 4-oxo-7-ethylthio-3H-pyrimido[4,5-d]pyrimidine (1.33 g, 6.7 mmol), P2S5 (1.48 g, 6.6 mmol) and pyridine (15 mL) is refluxed under N2 for 3 h. The pyridine is then stripped under reduced pressure, and the residue is dissolved in NaOH solution (0.5M, 75 mL) and boiled with charcoal. After filtration, the filtrate is neutralized with acetic acid to generate a gold brown solid. Buchner filtration and drying in a vacuum oven affords 4-thiono-7-ethylthio-3H-pyrimido[4,5-d]pyrimidine (1.42 g, 95%). 1H NMR (DMSO) δ 9.47 (1H, s), 8.46 (1H, s), 3.20 (2H, q, J=7.3 Hz), 1.35 (3H, t, J=7.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[N:9]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].I[CH3:22]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[N:9]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:10](=[O:12])[N:11]([CH3:22])[C:7]=2[CH:6]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)n(C)c(=O)n2C1CCC1
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of 1-cyclobutyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester (17.01 g, 69.1 mmol) in methyl sulfoxide (60 ml) was added sodium hydride (2.76 g as a 60% dispersion in oil, 69 mmol). The reaction mixture was stirred for 30 minutes prior to the dropwise addition of iodomethane (4.3 ml, 69.1 mmol). The reaction was stirred for 1 hour, was diluted with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 17.76 g of 1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>>[OH:16][C@@H:7]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CC=Cc1ccccc1
Reactant: COP([O-])OC
Agent: Cl
Product: COP(=O)(OC)[C@H](O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then, cinnamaldehyde (0.40 mmol) was added thereto. After reacting for 81 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S,E)-1-hydroxy-3-phenyl-2-propenylphosphonate as a final product in a yield of 85%. The chemical reaction in this Example is shown in chemical formula 34. ##STR28##
Reaction SMILES: [OH:1][C@@H:2]1[C@H:15]2[C@@H:6]([CH2:7][CH2:8][C:9]3[C@:14]2([CH3:16])[CH2:13][CH:12]([CH:17]=O)[C:11](=O)[CH:10]=3)[C@@H:5]2[CH2:20][CH2:21][C@:22]3([C:26]4([CH2:30][O:29][CH2:28][O:27]4)[O:25][CH2:24][O:23]3)[C@@:4]2([CH3:31])[CH2:3]1.[F:32][C:33]1[CH:34]=[C:35]([NH:40][NH2:41])[CH:36]=[C:37]([F:39])[CH:38]=1>>[F:32][C:33]1[CH:34]=[C:35]([N:40]2[C:11]3[CH:10]=[C:9]4[CH2:8][CH2:7][C@@H:6]5[C@@H:15]([C@@:14]4([CH3:16])[CH2:13][C:12]=3[CH:17]=[N:41]2)[C@@H:2]([OH:1])[CH2:3][C@:4]2([CH3:31])[C@:22]3([CH2:21][CH2:20][C@@H:5]52)[C:26]2([CH2:30][O:29][CH2:28][O:27]2)[O:25][CH2:24][O:23]3)[CH:36]=[C:37]([F:39])[CH:38]=1
Reactant: NNc1cc(F)cc(F)c1
Reactant: C[C@]12CC(C=O)C(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@@]21OCOC12COCO2
Product: C[C@]12Cc3cnn(-c4cc(F)cc(F)c4)c3C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@@]21OCOC12COCO2

Procedure:
The compound was prepared from (8S,9S,10R,11S,13S,14S,17R)-11-hydroxy-10,13-dimethyl-3-oxo-1,2,3,6,7,8,9,10,11,12,13,14,15,16-tetradecahydrodispiro[cyclopenta[a]phenanthrene-17,4′-[1,3]dioxolane-5′,4″[1,3]dioxolane]-2-carbaldehyde and (3,5-difluorophenyl)hydrazine according to the procedure for Intermediate 50. APCI-MS m/z: 541 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39])=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1[CH:34]=[C:35]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:11])([F:12])[F:13])=[C:4]([Cl:27])[CH:3]=2)[CH:36]=[CH:37][C:38]=1[F:39])=[O:32])[CH3:29]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
The title compound was prepared in analogy to Example 117 from 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 116, step 8) by Suzuki coupling with 3-ethoxycarbonyl-4-fluoro-phenylboronic acid [CAS Reg. No. 874219-36-0]. MS (m/e)=552.3 [M+H+], MS (m/e)=506.1 [(M−CH3CH2O−)+].
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[CH:7][CH:8]=2)[N:3]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:27][Cr](O[Cr]([O-])(=O)=O)(=O)=O.CN(C=O)C>O>[Cl:1][C:2]1[C:11]([C:12]([OH:27])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccc(Cl)cc2nc1Cl
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc2ccc(Cl)cc2nc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
A dry reaction flask equipped with a magnetic stirring bar and a rubber septum was charged with 2,7-dichloro-3-formylquinoline 3 (1.1 g, 5 mmol), PDC (3.76 g, 10 mmol) and dry DMF (5 mL) and stirred at room temperature for 24 h. The reaction mixture was diluted with water (500 mL), filtered, the filtrate was saturated with NaCl and the resulting aqueous solution was extracted with EtOAc (3×200 mL). The EtOAc extract was dried over anhydrous Na2SO4 and solvent was removed to give 1.02 g (85%) of the desired 2,7-dichloroquinoline-3-carboxylic acid 4. TLC Rf: 0.12 (20% MeOH/EtOAc); 1H NMR (acetone d6): 8.96 (s, 1H); 8.22 (d, 1H, J=9.0 Hz), 8.04 (d, 1H, J=1.8 Hz), 7.97 (bs, 1H), 7.74 (dd, 1H, J=1.8 and 8.7 Hz); LCMS (ret. time): 25.15 min.; MS (m/z): 241 (MH+).