Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][C:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)([O:11][CH3:12])[C:7]([NH:9][NH2:10])=O.Cl.Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26](/[CH:36]=[CH:37]/[C:38](=[NH:42])OCC)[CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1.C(OCC)(=O)C.O>C(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2([O:11][CH3:12])[CH2:5][CH2:4][CH2:3][N:9]3[N:10]=[C:38](/[CH:37]=[CH:36]/[C:26]4[CH:27]=[CH:28][C:29]([N:30]5[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]5)=[C:24]([O:23][CH3:22])[CH:25]=4)[N:42]=[C:7]23)=[CH:14][CH:15]=1
Reactant: COC(CCCCl)(C(=O)NN)c1ccc(F)cc1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3(OC)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 75 °C
Reaction time: 24 h
Yield: 30.1 %

Procedure:
A solution of 5-chloro-2-(4-fluorophenyl)-2-methoxyvaleric acid hydrazide monohydrochloride (81 mg) and TEA (0.16 ml) in ethanol (1 ml) was added to a solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (94 mg) and TEA (0.16 ml) in ethanol (1 ml), and the reaction solution was stirred at 75° C. for 24 hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system) and again purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system) to obtain 36 mg of 8-(4-fluorophenyl)-8-methoxy-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine as a racemate. Then, the racemate was separated by CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the title optically active compound with a retention time of 15 minutes and negative optical rotation (14.2 mg, 100% ee) and the title optically active compound with a retention time of 18 minutes and positive optical rotation (14.3 mg, >99% ee).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44]OS(C)(=O)=O)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:50]1[CH2:54][CH2:53][NH:52][C:51]1=[O:55]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:20]([CH2:44][N:50]3[CH2:54][CH2:53][NH:52][C:51]3=[O:55])[CH2:21][N:22]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:23][CH:24]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C1NCCN1
Product: CC(C)(C)OC(=O)N1CC(CN2CCNC2=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 149(f), by reacting tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methanesulphonyloxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with imidazolidin-2-one there was obtained tert-butyl (3RS,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-(2-oxo-imidazolidin-1-ylmethyl)-piperidine-1-carboxylate as a yellowish oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>C1COCC1>[Cl:12][C:13]1[N:14]=[C:15]([CH2:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH:16]=[N:17][CH:18]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl methylcarbamate (prepared following a method substantially similar to the one described in JACS, 2003, 125, 7307-7312)(10.52 g, 80.21 mmol, 1.05 eq.) was dissolved in dry THF (120 mL) and cooled in an ice-bath. NaH (3.51 g, 87.84 mmol, 60%, 1.15 eq.) was added portionwise and the resultant suspension was stirred at RT for 1 hour. The suspension was cooled in an ice-bath and 2,6-dicloropyrazine (11.38 g, 76.39 mmol, 1 eq.) was added portionwise. The reaction mixture was stirred at RT overnight.
Reaction SMILES: C([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20])=[O:14])(=O)C1C=CC=CC=1>C(OCC)(=O)C.[H][H].[Pd]>[OH:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20])=[O:14]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)N2CCCC2=O)cc1OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N2CCCC2=O)cc1O
Temperature: 25 °C

Procedure:
150 mg of 1-(3-benzoyloxy-4-methoxybenzoyl)pyrrolin-2-one are dissolved in 100 ml of ethyl acetate and hydrogenated with hydrogen over 150 mg of 5% palladium/carbon at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated. The residue is stirred at room temperature in diethyl ether. After filtration, there is obtained 1-(3-hydroxy-4-methoxybenzoyl)-2-pyrrolidinone of melting point 122°-124° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH:20]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30]C)[C:14]3=[O:32])[CH:7]=2)[CH2:3][CH2:2]1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][NH:16][CH:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH:20]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[OH:30])[C:14]3=[O:32])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: COc1ccccc1C1CCCN1c1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1N1C=CNC(N2CCCC2c2ccccc2O)C1=O
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To N-cyclopropyl-3-(3-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 97, 0.993 g) in DCM (10 mL) was added boron tribromide (4.47 mL of a 1M solution in DCM) at 0° C. and the reaction stirred for 3 h. Further Boron tribromide (4.47 mL of a 1M solution in DCM) was added and the reaction stirred for 3 h. Ice was added followed by water and the aqueous layer extracted with DCM then EtOAc. The aqueous layer was neutralised to pH 7 and extracted with DCM then EtOAc and all the combined organics dried (Na2SO4) and the solvent removed to give the subtitle compound as a solid (0.786 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2ccc(Oc3ccccc3)cc2s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2ccc(Oc3ccccc3)cc2s1
Temperature: 100 °C
Yield: 7.1 %

Procedure:
To a solution of 2-methyl-6-phenoxy-benzothiazole (0.06 g, 0.24 mmol) in 5 ml of CCl4 was added NBS (0.039 g, 0.22 mmol) and AIBN (0.004 g, 0.024 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400M) using 1% ethyl acetate/hexane eluent to give the desired product (0.005 g, 6.3%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[C:14]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20][O:21][NH2:22])=[CH:18][CH:17]=1)#[N:15]>>[C:14]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20][O:21]/[N:22]=[C:10](/[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=2)\[CH3:11])=[CH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1ccc(CON)cc1
Reactant: COc1ccc(C(C)=O)cc1O
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2ccc(C#N)cc2)cc1O
Yield: 50.3 %

Procedure:
Acetophenone 12 (30 mg, 0.181 mmol) was condensed with O-(4-cyanobenzyl)hydroxylamine hydrochloride (35) (37 mg, 0.200 mmol) according to the general procedure II-B defined above. After being heated for 3 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing solid was filtered off and washed with cold isopropanol (3.0 mL) to afford the title compound CP30283 (27 mg, 51%) as a white solid, m.p. 125.9-129.7° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:14](=[O:15])[O:13][C:11](=[O:12])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+:17].C(O)(=O)C.CO>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][OH:15])[CH2:10][C:11]([O-:13])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2].[Na+:17]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(=O)OC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CO)CC(=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of Nα-(tert-butyloxycarbonyl)-D-aspartic anhydride (J. Med. Chem. 1996; 3842) (19 g, 88 mmol) in tetrahydrofuran (150 ml) was added dropwise to an ice-cooled suspension of sodium borohydride (3.4 g, 88 mmol) in tetrahydrofuran (75 ml), and once addition was complete, the mixture was stirred for a further 2 hours. Acetic acid (30 ml) was added dropwise and the mixture then evaporated under reduced pressure. The residue was partitioned between water (150 ml) and ether (150 ml) and 2N hydrochloric acid (20 ml) carefully added. The layers were separated, the aqueous phase further extracted with ether (2×150 ml), and the combined organic solutions dried (MgSO4) and evaporated under reduced pressure. The product was dissolved in 2N sodium hydroxide (50 ml), and the solution stirred for 1 hour. The mixture was washed with ether (2×50 ml), acidified with 2N hydrochloric acid (50 ml) and extracted with dichloromethane (4×100 ml). The combined dichloromethane extracts were dried (MgSO4) and evaporated under reduced pressure. The acid product (7.8 g, 35.6 mmol) was dissolved in methanol (100 ml) sodium hydroxide (1.42 g, 35.6 mmol) added, and the reaction stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure the residue azeotroped with toluene and then triturated with diisopropyl ether to afford the title compound as a white solid, 8.6 g; 1H NMR (DMSOd6, 400 MHz) δ: 1.38 (s, 9H), 2.17 (m, 2H), 3.21–3.50 (m, 3H), 6.74 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.NO.[OH-].[K+].CO>C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:23])=[O:2])=[CH:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)CCCCCSc1ccc(-c2ccc(Cl)cc2)cc1
Agent: NO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCCSc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 6-(4′-chloro-biphenyl-4-ylsulfanyl)-hexanoic acid methyl ester (1.0 g, 2.9 mmol) in distilled THF (20 mL) containing 50% aqueous hydroxylamine (1.9 mL, 28.8 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (5.0 mL, 1M, 5.0 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (20 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×40 mL) and the combined extracts were washed with brine (80 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (923 mg, 91%) as a white powder, mp 156-157° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>CC#N>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:15](=[O:16])[CH2:14][C:13](=[O:17])[CH3:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: Nc1ccc2[nH]nc(Br)c2c1
Reactant: C=C1CC(=O)O1
Solvent: CC#N
Product: CC(=O)CC(=O)Nc1ccc2[nH]nc(Br)c2c1
Temperature: 50 °C
Yield: 26 %

Procedure:
The product of Step (b) (4.00 g, 18.86 mmol, 1 equiv) was suspended In CH3CN (20 mL). In a separate flask, diketene (1.45 mL, 18.89 mmol, 1 equiv) was dissolved in CH3CN (10 mL) The diketene solution was added to the initial suspension, and the mixture was heated to 50° C. for 18 hours. The reaction mixture was cooled and concentrated en vacuo. The resulting residue was purified by flash chromatography to afford 1.47 g (26%) of the product as a pink solid.
Reaction SMILES: Cl.Cl.[F:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.Br[CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH2:12][CH2:11][CH2:10][N:6]1[CH2:7][CH2:8][CH:4]([F:3])[CH2:5]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: FC1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCN1CCC(F)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 3-Fluoro-pyrrolidine dihydrochloride salt (448 mg, 3.584 mmol) in anhydrous acetonitrile (24 mL) was treated with bromopropoxy-tert-butyldimethyl silane (0.83 mL) and then with K2CO3 (2.5 g, 5 equiv.). The reaction mixture was heated to 50° C. and stirred overnight. The reaction mixture was subsequently diluted with water (75 mL) and extracted with a 6:1 mixture of Hexane and diethyl ether (2×100 mL). The organic layer was washed with NaHCO3(aq) (100 mL) and brine (100 mL) then dried over anhydrous K2CO3. Following filtration and concentration of the filtrate in vacuo the crude product was purified by flash silica gel chromatography (MeOH:EtOAc, 1:20). By 1H NMR the resulting clear oil (0.8 g) was the desired 1-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-3-fluoro-pyrrolidine in a 10:1 ratio with the t-butyldimethylsilanol by-product. This residue was carried on without further purification.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[CH3:9][O:10][C:11]1[CH:17]=[C:16]([OH:18])[C:15]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:14][C:12]=1[OH:13].ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[O:32]1[C:21]([CH3:23])([CH3:22])[CH:20]1[CH2:19][C:15]1[C:16]([OH:18])=[CH:17][C:11]([O:10][CH3:9])=[C:12]([CH:14]=1)[OH:13]
Reactant: COc1cc(O)c(CC=C(C)C)cc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(O)c(CC2OC2(C)C)cc1O
Temperature: 5 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of 2-methoxy-5-(3-methyl-2-butenyl)hydroquinone diacetate (2.84 g) in dichloromethane (40 ml) was added m-chloroperbenzoic acid (2.09 g, 80% purity) in several portions at 5° C. After the addition, the mixture was stirred for one hour at 5° C., washed twice with a mixture of aqueous sodium bicarbonate solution and aqueous sodium thiosulfinate solution, dried, and concentrated in vacuo. The residue was crystallized from n-hexane to give 5-(2,3-epoxy-3-methylbutyl)-2-methoxyhydroquinone diacetate as a white solid (2.93 g).
Reaction SMILES: [CH3:1][CH:2]1[N:6]=[C:5]2[CH:7]=[CH:8][N:9]=[C:4]2[S:3]1.[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>>[CH3:1][CH:2]1[N+:6]([CH2:11][CH2:10][CH2:16][S:13]([O-:15])(=[O:14])=[O:12])=[C:5]2[CH:7]=[CH:8][N:9]=[C:4]2[S:3]1
Reactant: CC1N=C2C=CN=C2S1
Reactant: O=S1(=O)CCCO1
Product: CC1SC2=NC=CC2=[N+]1CCCS(=O)(=O)[O-]
Temperature: 130 °C
Yield: 92.2 %

Procedure:
2-Methylpyrrolo[3,2-d]thiazole (0.70 g) (5mmol) and 0.67 g of 1,3-propanesultone (5.5 mmol) were stirred with heating at 130° C. for 6 hours. After cooling, the crystals precipitated were filtered out and washed with acetone, thereby 1.2 g of 3-[2-methyl-1-pyrrolo[3,2-d]thiazolio]propanesulfonate was obtained (yield: 92%). 3-[5- Chloro-2-(3-sulfopropyl)thio-1-benzothiazolio]propanesulfonate (0.45 g) (1 mmol), 2 ml of dimethyl sulfoxide and 2 ml of acetonitrile were added to 0.26 g of the quaternary salt of 3-[2-methyl-1-pyrrolo[3,2-d]thiazolio]propanesulfonate (1 rmmol) and the mixture was stirred at 50° C. with adding 0.56 ml of triethylamine (4 mmol), followed by further stirring for 1 hour. The solution was concentrated, and then refined with column chromatography, thereby 0.10 g of the objective Methine Dye S-125 was obtained. Yield: 15%, ?max (MeOH)=447.5 nm.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:12][N:13]=[C:14]([C:18]1[N:19]=[C:20]([NH:23][CH:24]=[O:25])[S:21][CH:22]=1)[C:15]([OH:17])=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:26][CH:27]1[CH:32]=[C:31]([C:33]([OH:35])=[O:34])[N:30]2[C:36](=[O:39])[CH:37]([NH2:38])[C@H:29]2[S:28]1.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH3:26][CH:27]1[CH:32]=[C:31]([C:33]([OH:35])=[O:34])[N:30]2[C:36](=[O:39])[CH:37]([NH:38][C:15](=[O:17])[C:14](=[N:13][O:12][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:18]3[N:19]=[C:20]([NH:23][CH:24]=[O:25])[S:21][CH:22]=3)[C@H:29]2[S:28]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Reactant: CCCCCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: CCCCCCON=C(C(=O)O)c1csc(=NC=O)[nH]1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(NC=O)n1
Temperature: -20 °C

Procedure:
To a solution of N,N-dimethylformamide (1.23 g) and ethyl acetate (9 ml) was added dropwise phosphorus oxychloride (2.58 g) at -10° to -5° C. with stirring, and the mixture was stirred for 30 minute at the same temperature. To the mixture were added 2-hexyloxyimino-2-(2-formylaminothiazol-4-yl)acetic acid (syn isomer), which can be represented as 2-hexyloxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetic acid (syn isomer), (4.2 g) and ethyl acetate (33 ml), and the mixture was stirred for 30 minutes at -10° to -5° C. and then cooled to -20° C. Thus obtained solution was added to a solution, which was prepared by stirring a mixture of 2-methyl-7-amino-3-cephem-4-carboxylic acid (3 g) and trimethylsilylacetamide (11 g) in ethyl acetate (33 ml), with stirring under cooling to -10° C. The mixture was stirred for 30 minutes at -10° C. and thereto was added water 50 ml. The mixture was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous solution of sodium chloride and the precipitates were collected by filtration and then dried to give 2-methyl-7-[2-hexyloxyimino-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-hexyloxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (4.3 g). The filtrate was evaporated to give further the same object compound (1.15 g).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[NH2:7][C:8]1[C:9]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[CH:15][N:14]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]=2[N:11]=[CH:12][N:13]=1>O.C(O)(=O)C>[C:30]([N:14]1[C:10]2[N:11]=[CH:12][N:13]=[C:8]([NH2:7])[C:9]=2[C:16]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:2])=[CH:21][CH:22]=2)=[CH:15]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)n1cc(-c2ccc(Sc3ccccc3)cc2)c2c(N)ncnc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)n1cc(-c2ccc(S(=O)c3ccccc3)cc2)c2c(N)ncnc21

Procedure:
A solution of sodium periodate (0.60 g) dissolved in water (16 ml) was added to a solution of 4-amino-5-[4-(phenylthio)phenyl]-7-(tert-butyl)pyrrolo[2,3-d]pyrimidine (1.0 g) in glacial acetic acid (30 ml) with stirring whilst keeping the temperature below 5° C. The mixture was stirred for 66 hours at ambient temperature. The mixture was filtered and the filtrate was added to water (300 ml). This mixture was basified with solid sodium bicarbonate, filtered to remove a small amount of solid which was discarded and the filtrate extracted with ethyl acetate to give a residue which was purified by flash column chromatography on silica using ethyl acetate/triethylamine (9:1) as the mobile phase, to give a solid which was rechromatographed under the same conditions to give 7-tert-butyl-5-(4-phenylsulphinylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 180-182° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][C:16]([N:23]([CH2:28][CH2:29]C=C)[S:24]([CH3:27])(=[O:26])=[O:25])=[C:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=2)[O:13][C:12]=1[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)=[O:10]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][CH2:29][CH2:28][N:23]([C:16]1[N:15]=[C:14]2[O:13][C:12]([C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=3)=[C:11]([C:9](=[O:10])[NH:8][CH3:7])[C:19]2=[CH:18][C:17]=1[CH:20]1[CH2:22][CH2:21]1)[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: C=CC(=O)OC
Reactant: C=CCCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC=CC(=O)OC)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of Grubbs II catalyst (4.7 mg, 0.005 mmol, 0.05 equiv) in DCM (1.0 mL) was added methyl acrylate (95 mg, 1.1 mmol, 10 equiv) followed by a solution of 6-(But-3-enyl-methanesulfonyl-amino)-5-cyclopropyl-2-p-tolyl-furo[2,3-b]pyridine-3-carboxylic acid methylamide (50 mg, 0.11 mmol, 1.0 equiv) in DCM (1.0 mL). The solution was stirred at room temperature for 2 hours, after which the solvent was removed under vacuum. The residue was purified by silica gel column chromatography, EtOAc/heptane 70% to give product 35 mg. MS (ESI) m/z 512.6 (M+1). Retention time=1.50 min, Method LC-C8 broad range-NpH.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:18][S:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:19]3[CH2:22][CH:21]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)[CH2:20]3)=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: CSc1nn(-c2ccccc2)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCN(C2CNC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CSc1nn(-c2ccccc2)c2cc(N3CC(N4CCN(C(=O)OC(C)(C)C)CC4)C3)ccc12

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-bromo-3-(methylthio)-1-phenyl-1H-indazole (300 mg, 0.94 mmol, 1.00 equiv) in toluene (20 mL), tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate (270 mg, 1.12 mmol, 1.20 equiv), Cs2CO3 (430 mg, 1.32 mmol, 1.40 equiv), Pd(OAc)2 (a catalytic amount), BINAP (a catalytic amount). The resulting solution was heated to reflux overnight in an oil bath. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to yield tert-butyl 4-(1-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)azetidin-3-yl)piperazine-1-carboxylate as a yellow solid. MS: 480 (MH+).