Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[H-].[Na+].[CH3:14]I.CO>C1COCC1.O>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:14])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CI
Reactant: CCc1cccc(NC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1cccc(N(C)C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A solution of m-ethylphenylcyanamide (1.46 g, 10 mmol) and sodium hydride (480 mg, 20 mmol, pre-washed thrice with hexane) in anhydrous THF (10 ml) was heated at 80-85° C. for 2.5 hours. After it was allowed to cool to room temperature, methyl iodide (3.5 g, 25 mmol) was added and stirring was continued at room temperature for 2 hours. Methanol (10 ml) followed by water (20 ml) were added and then extracted with dichloromethane (3×25 ml). Concentration of the organic layer followed by quick flash chromatography afforded the title compound (960 mg, 60%) as a colorless liquid: IR (film): 2220, 3400 cm−1.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl.O>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([CH2:8][NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:17][CH:16]=2)=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(CNc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(CNc3ccccc3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
4-((Phenylamino)methyl)benzoic acid (150 mg, 0.66 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (301 mg, 0.79 mmol) and triethylamine (2 mL) were dissolved in dichloromethane (20 mL). The mixture was stirred for 0.5 hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (100 mg, 0.66 mmol) was added to the mixture. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-((phenylamino)methyl)benzamide (100 mg, 42%). LRMS (M+H+) m/z: calcd 361.18. found 361. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, CD3OD): δ 7.75 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.06-7.04 (m, 2H), 6.60-6.58 (m, 3H), 6.11 (s, 1H), 4.49 (s, 2H), 4.37 (s, 2H), 2.36 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].O>CN(C=O)C>[Si:12]([O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(F)ccc1F
Reaction time: 0.5 h
Yield: 94020.3 %

Procedure:
To a stirred solution of 2,5-difluorophenol (15.1 g, 116 mmol) in DMF (100 ml) was added sodium hydride (60% W/W dispersion in mineral oil; 5.13 g, 139 mmol) with ice-cooling. After stirring for 30 min, tert-butyldimethylsilyl chloride (17.5 g, 0.116 mmol) was added and stirring was continued for an additional 1 hr. The mixture was poured into water (200 ml) and extracted with ether (300 ml). The extract was washed with brine (200 ml), dried (sodium sulfate) and solvent removed by evaporation to give 26.65 g (94%) of the titled compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br-].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[Zn+].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>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]=1[C:19]1[S:18][CH:22]=[CH:21][CH:20]=1
Reactant: [Zn+]c1cccs1
Reactant: COC(=O)c1cc(Br)c(C(=O)OC)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2cccs2)c(C(=O)OC)cc1-c1cccs1
Temperature: 67 °C
Yield: 87.2 %

Procedure:
Dimethyl 2,5-dibromoterephthalate (6.09 g, 17.30 mmol) is dissolved in anhydrous THF (100 cm3), followed by the addition of 2-thienylzinc bromide (0.50 M in THF, 90 cm3, 45.0 mmol) and Pd(PPh3)4 (0.50 g, 0.43 mmol). The mixture is heated at 67° C. for 2 hours. After cooling, the reaction mixture is poured into water. The precipitate is collected by filtration and washed with water, methanol and diethyl ether then dried in vacuo, to yield the product as a pale yellow solid (5.41 g, 87%). 1H NMR (300 MHz, CDCl3): δ(ppm) 7.82 (s, 2H, Ar—H), 7.40 (dd, J=4.8 and 1.4 Hz, 2H, Ar—H), 7.07-7.12 (m, 4H, Ar—H), 3.78 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ(ppm) 168.1 (C═O), 140.3 (q), 133.6 (q), 133.4 (q), 131.9 (CH), 127.5 (CH), 127.0 (CH), 126.7 (CH), 52.6 (CH3); MS (m/e): 358 (M+, 100%), 327, 299, 240, 195.
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[N:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[O:22][CH3:23])[N:9]=1.[S-2].[Na+].[Na+]>O>[Cl:7][C:8]1[N:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[O:22][CH3:23])[N:9]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)n1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(N)ccc1-n1cnc(Cl)n1
Temperature: 75 °C
Yield: 72.8 %

Procedure:
Step E (3): Water (8 mL) and dioxane (8 mL) were added to a mixture of 3-chloro-1-(2-methoxy-4-nitrophenyl)-1H-1,2,4-triazole (0.900 g, 3.53 mmol) and sodium sulfide (1.379 g, 17.67 mmol) in a 20 mL vial. The vial was capped and heated at 70-80° C. for 24 hours. The mixture was cooled to rt, poured into water (300 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (577 mg, 73%) as a brown solid. LC-MS (M+H)+ 225.1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10](I)(I)[I:11]>O1CCCC1.[Cl-].[Cr+2].[Cl-]>[I:11]/[CH:10]=[CH:6]/[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: IC(I)I
Agent: [Cr+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Brc1ccc(/C=C/I)cc1
Reaction time: 1 h

Procedure:
To a heterogeneous mixture of chromium (II) chloride (3.98 g, 32.4 mmol) in tetrahydrofuran (40 mL) at 0° C. was added via Syringe pump over 1 hour (in the total absence of light) 4-bromo-benzaldehyde (1.00 g, 5.40 mol) and iodoform (4.25 g, 10.8 mmol) combined as a homogeneous solution in tetrahydrofuran (20 mL). The cold bath was removed, whereupon a quantitative reaction as indicated occurred within 1 hour. The reaction mixture was diluted with 1:1 ether-hexanes (200 mL) then filtered through a short pad of silica gel, concentrated to a solid tainted with residual iodoform.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[CH3:19][CH:20]1[N:25]([CH2:26][CH2:27][NH2:28])[CH:24]([CH3:29])[CH2:23][O:22][CH2:21]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:28][CH2:27][CH2:26][N:25]1[CH:24]([CH3:29])[CH2:23][O:22][CH2:21][CH:20]1[CH3:19])=[O:18]
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: CC1COCC(C)N1CCN
Product: CC1COCC(C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and 2-(3,5-dimethylmorpholino)ethylamine [see Preparation 12]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 95:5, by volume dichloromethane:methanol to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2 -[2-(3,5-dimethylmorpholino)ethyl]-2-piperidinecarboxamide as a solid.
Reaction SMILES: I[C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][NH:5][CH:6]=1.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>O1CCCC1.[Pd+2].[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:13]([C:9]1[CH:8]=[C:7]([C:3]2[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:6][NH:5][N:4]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Reaction time: 4 h

Procedure:
415 mg (1.32 mmol) of 4-iodo-3-(3-nitrophenyl)-1H-pyrazole (prepared as described in Example 27) were dissolved in 15 ml of dry tetrahydrofuran and 494 μL (3.42 mmol) of triethylamine, 80 mg (0.106 mmol) of palladium(II)-bis(triphenylphosphine) dichloride, 26 mg (0.166 mmol) of cuprous iodide and 406 μL (2.9 mmol) of trimethylsilylacetylene were added consecutively in a nitrogen atmosphere. The reaction was refluxed under stirring for 4 hours. The solvent was then removed in vacuo and the residue re-dissolved with dichloromethane and washed with water. The organic phase was dried over sodium sulphate and evaporated, affording, after trituration with diisopropylether, 300 mg (80%) of the title compound, that was employed for the next step without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[H][H]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: OCC#Cc1ccc(Br)cc1
Reactant: [H][H]
Solvent: CCO
Solvent: Cc1ccccc1
Product: OCCCc1ccc(Br)cc1
Yield: 81.1 %

Procedure:
To a solution under inert gas of 36.4 g of 3-(4-bromophenyl)-2-propynol (stage A) in 200 ml of ethanol at 5% of toluene, is added 200 ml of toluene, 7.9 g of Wilkinson's reagent and hydrogen at 1900 mbar for 5 hours. It is evaporated at reduced pressure until the obtainment of 45.9 g of raw product that is purified by chromatography on silica by eluting with the compound CH2Cl2/AcOEt 95/5. 30.1 g of expected product is obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:23]([F:24])=[C:22]([F:25])[C:8]2[N:9]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[CH3:21])C[O:11][C:12](=[O:13])[C:7]=2[CH:6]=1)=[O:4].OCC(CO)O.Cl>C1COCC1>[F:24][C:23]1[C:22]([F:25])=[C:8]([NH:9][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[CH3:21])[C:7]([C:12]([OH:13])=[O:11])=[CH:6][C:5]=1[C:3]([NH:2][CH3:1])=[O:4]
Reactant: CNC(=O)c1cc2c(c(F)c1F)N(c1ccc(I)cc1C)COC2=O
Agent: Cl
Solvent: OCC(O)CO
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C(=O)O)c(Nc2ccc(I)cc2C)c(F)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.2 %

Procedure:
To a suspension of 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid methylamide in THF (10 mL) is added polymer bound glycerol, (0.33 g, 200–400 mesh) and 10 mL of 1.0 M HCl solution. After stirring for 48 hours at room temperature, the resin is filtered off and the filtrate is transferred to a separatory funnel and partitioned with ethyl acetate. The organics are washed twice with 1.0 M HCl, twice with saturated brine solution, collected, dried over Na2SO4, filtered and concentrated in vacuo affording 4,5-difluoro-6-(-4-iodo-2-methyl-phenylamino)-N-methyl-isophthalamic acid (0.11 g, 76.2%); mp 254–259° C.; 1H NMR (400 MHz; DMSO-d6) 9.31 (s, 1H), 8.19 (s, 1H), 8.07 (d, 1H, J=7.2), 7.56 (s, 1H), 6.69 (t, 1H, J=5.6), 2.74 (d, 3H, J=4.4), 2.20 (s, 3H); MS (APCI)m+1=447; Anal.calcd/found for C16H13F2IN2O3, C 43.07/43.26, H 2.94/3.07. N 6.28/6.10.
Reaction SMILES: [OH:1][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:25]O)=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[CH2:25][O:1][CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)=[CH:22][CH:23]=1
Reactant: OCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=c1[nH]c2c([nH]c1=O)C(O)c1ccccc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: O=c1[nH]c2c([nH]c1=O)C(OCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1)c1ccccc1-2
Yield: 17.5 %

Procedure:
A suspension of 9-hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione. 1H2O (0.50 g, 2.13 mmol) in acetic acid (30 ml), 2,2-bis(4-chlorophenyl)ethanol (2.84 g, 10.65 mmol) and p-toluensulfonic acid (20 mg) was refluxed for 21 hours. The reaction mixture was evaporated in vacuo to dryness, the residue was suspended in ethanol (40 ml) and the precipitate was filtered off and washed with ethanol and dried to give 0.39 g of the crude product, which was recrystallized from ethanol to yield 0.174 g (17.5%) of the title compound. M.p. 234°-237° C. 1 -NMR (DMSO-d6, δ): 3.68 (t, 1H), 4.0 (t, 1H), 4.27 (t, 1H), 5.23 (s, 1H), 7.1-7.5 (m, 12H), 11.98 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:37])[N:13]2[C:16](=[C:33]([OH:36])[CH2:34]Cl)[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[OH:40]>O1CCCC1>[O:1]([CH2:8][C:9]([NH:10][CH:11]1[C:12](=[O:37])[N:13]2[C:16]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:33]([OH:36])[CH2:34][S:15][C@H:14]12)=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(=C(O)CCl)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: CO
Agent: Cl
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice cooled solution of diphenylmethyl α-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-chloro-1-hydroxyethylidene)acetate (36 mg) in a mixture of methanol and tetrahydrofuran (1:1) (1.1 ml) is added 1 N-hydrochloric acid (0.39 ml), warmed to the room temperature, and the mixture is stirred for 1.5 hours. The reaction mixture is poured into ice water, and is extracted with methylene chloride. The extract solution is washed with 5% aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate, and evaporated. Purification of the obtained residue by thin-layer chromatography using a mixture of benzene and ethyl acetate (3:2) gives diphenylmethyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate (6 mg). m.p. 125°-126° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:22](OC)(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[SH:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:30]=[C:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[S:25][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])=[O:14])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: C[Si](C)(C)CCOC(=O)CCCCc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOC(=O)CCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 26.1 %

Procedure:
2-(Trimethylsilyl)ethyl 5-(6-cyano-2-pyridyl)valerate (1.0 g, 3.3 mmol) and methyl thiosalicylate (0.85 g, 5.0 mmol) were dissolved in toluene (4 ml), and triethylamine (0.85 ml, 8.4 mmol) was added thereto. The reaction mixture was refluxed for 10 hrs and subjected to a silica gel (75 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give the titled compound (0.38 g, 27%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH3:16][O:17][CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:20]1[CH2:21][CH2:22][CH2:23][C@@H:19]1[CH2:18][O:17][CH3:16])=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: COC[C@H]1CCCN1
Product: COC[C@H]1CCCN1C(=O)c1cnoc1-c1ccccc1Cl

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and (R)-2-methoxymethyl-pyrrolidine (6.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (8.5 mg). Calcd for C16H17ClN2O3: 320.0928, found 320.0924.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH3:11])[C:3]=12.[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]c2ncnc(Cl)c12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (150.4 mg, 0.89 mmol, Example 3) and potassium carbonate (187 mg, 1.35 mmol) in dimethylformamide (6 mL) was added iodomethane (225 mg, 1.59 mmol, Aldrich). The reaction mixture was stirred at room temperature for 2 hours before it was diluted with ethyl acetate, washed with water, brine, dried and concentrated. The crude product was purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 162.3 mg).
Reaction SMILES: [H][H].[Si]([O:10][C@H:11]([C@H:14]1[C@@H:17]([CH2:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[S:20])[NH:16][C:15]1=[O:27])[CH2:12][CH3:13])(C(C)(C)C)(C)C.N1C=CN=C1.[CH2:33]([Si:35](Cl)([CH2:38][CH3:39])[CH2:36][CH3:37])[CH3:34]>C(#N)C.C(OCC)(=O)C.CN(C)C=O>[CH2:33]([Si:35]([CH2:38][CH3:39])([CH2:36][CH3:37])[O:10][C@H:11]([C@H:14]1[C@@H:17]([CH2:18][C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[S:20])[NH:16][C:15]1=[O:27])[CH2:12][CH3:13])[CH3:34]
Reactant: CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@@H]1CC(=S)c1ccccc1
Reactant: CC[Si](Cl)(CC)CC
Reactant: [H][H]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC[C@H](O[Si](CC)(CC)CC)[C@@H]1C(=O)N[C@@H]1CC(=S)c1ccccc1
Reaction time: 2 h
Yield: 69.4 %

Procedure:
An aqueous solution of hydrogen fluroride (46%, 2.53 ml) was added to a solution of the compound (2.29 g, 5.8 mmol) prepared in Example 7 in acetonitrile (40 ml) at room temperature in an argon atmosphere. After stirring for two hours at this temperature, the mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a de-protected compound as an oily substance. Imidazole (579 mg, 8.5 mmol) and triethylsilyl chloride (1.24 ml, 7.4 mmol) were added to the solution of this de-protected compound in N,N-dimethylformamide (10 ml) at room temperature, followed by stirring for 10 minutes at the same temperature. After the reaction, the reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of potassium hydrogen sulfate, a saturated aqueous solution of sodium hydrogencarbonate, and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1), to obtain 1.52 g (yield 67%) of the title compound as a light yellow oily substance.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2.Br[CH2:16][CH2:17][O:18][CH3:19].[OH-:20].[Na+]>CN(C)C=O>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:16][CH2:17][O:18][CH3:19])[CH:10]=2)[C:5]=1[OH:20]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: COCCBr
Reactant: [OH-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(O)c(Br)ccc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium hydride (60%, 5.3 g, 134 mmol) was added in small portions to a mixture of 6-bromo-2-naphthol (25.0 g, 112 mmol), 2-bromoethylmethylether (17.1 g, 123 mmol) and dimethylformamide (150 ml). The mixture was stirred at room temperature for 5 h. Aqueous sodium hydroxide (200 ml, 1 M) was added, and the mixture was allowed to stir overnight. The crystals were filtered. Yield 28.2 g, 89%. Mp 54–55° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:21]=[CH:20][C:13]3[O:14][CH:15]([CH2:18][OH:19])[CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:22]#[N:23])=[C:4]([SH:24])[N:3]=1.[OH:25][CH2:26][CH2:27]Br.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:21]=[CH:20][C:13]3[O:14][CH:15]([CH2:18][OH:19])[CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:22]#[N:23])=[C:4]([S:24][CH2:27][CH2:26][OH:25])[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc2c(c1)OCC(CO)O2
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCCO)c(C#N)c1-c1ccc2c(c1)OCC(CO)O2

Procedure:
30 mg (0.09 mmol) of 2-amino-6-sulfanyl-4-[2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-3,5-pyridinedicarbonitrile [prepared analogously to Dyachenko et al., Russian Journal of Chemistry 33 (7), 1014–1017 (1997); 34 (4), 557–563 (1998)], 22 mg (0.18 mmol) of 2-hydroxyethyl bromide and 29 mg (0.35 mmol) of sodium bicarbonate are stirred in 1.5 ml of DMF at room temperature overnight. The reaction solution is purified directly by preparative HPLC on reversed-phase silica gel.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[S:16][C:17]1[N:18]([CH2:25][C@:26]2([CH3:29])[CH2:28][O:27]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1.[N:30]1([C:36]([O:38][CH2:39][CH:40]=[CH:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O>C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[S:16][C:17]1[N:18]([CH2:25][C@:26]([OH:27])([CH3:29])[CH2:28][N:33]2[CH2:32][CH2:31][N:30]([C:36]([O:38][CH2:39][CH:40]=[CH:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]([F:50])([F:51])[F:49])=[CH:44][CH:43]=3)=[O:37])[CH2:35][CH2:34]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Sc2c(Cl)cccc2[N+](=O)[O-])CO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Sc1c(Cl)cccc1[N+](=O)[O-]
Yield: 89.5 %

Procedure:
N,N-Dimethylformamide (0.25 ml) solution of (R)-2-(2-chloro-6-nitrophenylthio)-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole (55 mg) and 3-(4-trifluoromethylphenyl)-2-propenyl piperazin-1-carboxylate (51 mg) was stirred at 60° C. for 1 day. To the reaction mixture was added water and ethyl acetate, the organic layer was taken by separation. The ethyl acetate layer was washed with water and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/methanol=30/1), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[2-(2-chloro-6-nitrophenylthio)-4-nitroimidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate (91 mg, yield: 87%) as yellow amorphous product.