Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[Br:18]Br.C([O-])(=O)C.[Na+]>CCCCCC.C(O)(=O)C.O>[Br:18][C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)OCCCO2
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Brc1ccc2c(c1)OCCCO2
Reaction time: 24 h

Procedure:
To a mixture of 3,4-dihydro-2H-1,5-benzodioxepine (8.86 g) and sodium carbonate (9.4 g) in hexane (100 ml) was added dropwise at room temperature a solution of bromine. (3.0 ml) in hexane (30 ml) for 2.5 hours, and the mixture was stirred for 24 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give orange oil. To the obtained oil (13.39 g) in acetic acid (50 ml) was added sodium acetate (4.1 g), and then was added dropwise a solution of bromine (1.3 ml) in acetic acid (25 ml) for 1 hour. The mixture was stirred for 24 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane=1:4) to give orange oil of 7-bromo-3,4-dihydro-2H-1,5-benzodioxepine (13.17 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[OH-].[K+].[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>O.O1CCOCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)O)C(=O)O

Procedure:
14.7 g (0.1 Mol) of H-D-Glu-OH was dissolved in 200 ml of distilled water, and the pH was adjusted to 10.2 with 0.1M potassium hydroxide. 33.0 g (0.3 Mol) of BOC2O in dioxane was added with intensive mixing. The pH was controlled using pH-stat. After completion of the reaction, the mixture was transferred to a separating funnel, and extraction was carried out from the alkaline solution with ethyl acetate (3×150 ml). The pH of the aqueous phase was adjusted to 3.0 using 0.2% sulphuric acid, and Boc-D-Glu-OH was extracted from the organic phase (3×200 ml). The organic phase was washed three times with 200 ml of Na2SO4 saturated solution to neutral pH, and dried over Na2SO4, and evaporated to oil under vacuum. The yield was 16.7 g (68%).
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]2)=[N:7][CH:6]=1>C(Cl)Cl>[ClH:3].[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([Cl:3])=[O:23])[CH2:17][CH2:16]2)=[N:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN(c2ncnc3ccccc23)CC1
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)C1CCN(c2ncnc3ccccc23)CC1
Reaction time: 2 h
Yield: 74.9 %

Procedure:
Thionyl chloride (1.37 mL, 18.8 mmol) was added to a suspension of 1-quinazolin-4-yl-piperidine-4-carboxylic acid (2.20 g, 8.55 mmol) in DCM (40 mL), which results in a clear solution. After being stirred for 2 hours, a precipitate forms and was filtered off to give 1-quinazolin-4-yl-piperidine-4-carbonyl chloride hydrochloride as a white solid (2.0 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH3:22][N:23]([CH3:43])[C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[C:29]2[S:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:40]3[CH2:41][CH2:42][N:37]([S:34]([C:29]4[C:30]5[C:25](=[C:24]([N:23]([CH3:43])[CH3:22])[CH:33]=[CH:32][CH:31]=5)[CH:26]=[CH:27][CH:28]=4)(=[O:36])=[O:35])[CH2:38][CH2:39]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)N3CCNCC3)cccc12
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: CN(C)c1cccc2c(S(=O)(=O)N3CCN(C(=O)Oc4ccc(Oc5ccc(C(F)(F)F)cn5)cc4)CC3)cccc12
Yield: 32 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperazine and purified by flash chromatography (ethyl acetate—heptane 1:4), yield 32%. Pale crystals, HPLC-MS: m/z: 601(M+1) at Rt=5.2 min.; m.p. ° C.; IR (KBr): ν 1723 (C═O) cm−1.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:13]=O)[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(O)C>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:13]=[N:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([F:15])[CH:17]=2)[CH:3]=1
Reactant: COC(=O)c1cc(C)c(C)cc1C=O
Reactant: Nc1cccc(F)c1
Solvent: CCO
Product: COC(=O)c1cc(C)c(C)cc1C=Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
To a solution of the product of above-mentioned (25-a) (0.64 g, 3.3 mmol) in absolute ethanol (16 ml) was added 3-fluoroaniline (0.37 g, 3.3 mmol), and stirred at 25° C. for 2 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform) to give 0.45 g of methyl 4,5-dimethyl-2-{[(3-fluorophenyl)imino]methyl}benzoate.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.FC(F)(F)C(O)=[O:41]>ClCCl>[NH:9]1[CH2:8][CH2:7][C:6](=[C:5]2[CH:2]=[CH:21][CH:20]=[C:19]([O:41][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:4]2[CH3:3])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(O)c2)CC1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C(Oc2ccccc2)=CC=CC1=C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A slurry of tert-butyl 4-(3-hydroxybenzylidene)piperidine-1-carboxylate (500 mg, 1.73 mmol), phenylboronic acid (418 mg, 3.43 mmol), cupric acetate (314 mg, 1.73 mmol), triethyl amine (1.21 mL 1.8 mmol), and 4 Å powdered sieves (300 mg) in dichloromethane (15 mL) was stirred 18 h at ambient temperature. The reaction mixture was diluted with additional solvent and filtered to remove solid material, washed successively with 1N NaOH and brine, and dried over Na2SO4 to provide a brown oil. This material was purified by column chromatography (1:4 ethyl acetate:heptane) to provide the intermediate Boc-protected material (190 mg, 33%). This material was dissolved in dichloromethane (20 mL) and stirred with trifluoroacetic acid (1 mL) for 3 d at ambient temperature. The reaction was concentrated to a foam that was dissolved in toluene and re-evaporated to give the title compound which was used in the next reaction.
Reaction SMILES: [CH3:1][N:2]([S:17]([CH3:20])(=[O:19])=[O:18])[C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9].[OH-].[K+].CO.Cl>O1CCCC1>[CH3:16][O:15][C:13]([C:5]1[CH:6]=[C:7]([CH:12]=[C:3]([N:2]([CH3:1])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:4]=1)[C:8]([OH:10])=[O:9])=[O:14]
Reactant: COC(=O)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A mixture of dimethyl 5-[methyl(methylsulfonyl)amino]isophthalate obtained in Reference Example 5 36.0 g (119 mmol), potassium hydroxide 8.71 g (155 mmol), methanol (360 mL) and tetrahydrofuran (240 mL) was stirred at 90° C. for 1.5 hours. To a mixture of 1N hydrochloric acid (200 mL) and ice water (500 mL) was added the reaction mixture dropwise, and the precipitated solid was collected by filtering, and dried under vacuum to give 32.4 g (113 mmol) of the title compound (yield: 95%).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(B(O)O)c(C)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+]
Product: Cc1ccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c(C)c1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2,4-dimethylphenyl)boronic acid (209 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 177 mg, 56%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[C:18]([C:20]1[N:24]([CH3:25])[C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[N:21]=1)=[O:19].[H-].[Na+].[CH3:32][CH:33]([SH:35])[CH3:34]>O1CCCC1>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([S:35][CH:33]([CH3:34])[CH3:32])=[C:3]([C:18]([C:20]3[N:24]([CH3:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=3)=[O:19])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: CC(C)S
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(C(=O)c3nc4ccccc4n3C)sc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(C(=O)c3nc4ccccc4n3C)sc21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Prepared according to the method described in Example 37 step d from 5-bromo-3-methyl-6-[(1-methyl-1H-benzimidazol-2-yl)carbonyl]-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.2 g), sodium hydride (0.12 g) and 2-propanethiol (0.26 ml) in dry tetrahydrofuran (150 ml) with stirring at room temperature for 19 hours. The residue was purified by flash silica chromatography eluting with a gradient of 20-50% ethyl acetate in isohexane to give the title compound as a yellow solid (0.92 g).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.[Li]CCCC.CC[O:29][C:30]([CH:32]([F:34])[F:33])=O>C1COCC1>[Br:1][C:2]1[S:3][C:4]([C:30](=[O:29])[CH:32]([F:34])[F:33])=[CH:5][CH:6]=1
Reactant: Brc1cccs1
Reactant: CCOC(=O)C(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)s1)C(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A solution of 2-bromothiophene (0.5 g, 3.00 mmol) in dry THF (5 mL) was cooled to −78° C. and freshly prepared lithium diisopropylamide (prepared from diisopropyl amine (0.5 mL, 3.60 mmol) and nBuLi (2.3 mL, 3.60 mmol, 1.6M in THF) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h. Ethyl difluoro acetate (409 mg, 3.30 mmol) was added dropwise at −78° C. and the reaction mixture was stirred for 1 h, then slowly warmed up to room temperature and quenched with saturated NH4Cl solution. The organic product was extracted with EtOAc and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to get 1-(5-bromothiophen-2-yl)-2,2-difluoroethanone (500 mg, yield 69%). 1H NMR (400 MHz, CDCl3) δ 7.77-7.75 (m, 1H), 7.21-7.20 (d, J=4.1 Hz, 1H), 6.27-6.00 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)=[CH:23][CH:22]=1.[C:36](#[N:38])C>>[CH3:34][C:29]1([CH3:35])[C:30]([CH3:33])([CH3:32])[O:31][B:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][O:1][C:2]3[CH:10]=[CH:9][C:5]4[N:6]=[C:7]([C:36]#[N:38])[S:8][C:4]=4[CH:3]=3)=[CH:22][CH:23]=2)[O:28]1
Reactant: CC#N
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: Oc1ccc2ncsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC1(C)OB(c2ccc(COc3ccc4nc(C#N)sc4c3)cc2)OC1(C)C
Yield: 72 %

Procedure:
A mixture of 6-hydroxybenzothiazole (0.5 g, 2.84 mmol), potassium carbonate (0.78 g, 5.68 mmol) and potassium iodide (0.94 g, 5.68 mmol) in acetonitrile was heated to reflux for 1 hour. 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.93 g, 3.12 mmol) was added, and the reaction mixture was refluxed overnight. After cooling down, the suspension was extracted with ethyl acetate/water and the residue was purified with flash chromatography to give the product as a white solid (0.8 g, 72%). 1H NMR (300 MHz, CD2Cl2, δ): 8.11 (d, J=9.0 Hz, 1H), 7.81 (d, J=9.0 Hz, 2H), 7.47 (m, 3H), 7.34 (dd, J=9.0 Hz, 1H), 5.22 (s, 2H), 1.35 (s, 9H); MS (ESI) m/z 393.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O-:18])(=[S:17])[CH3:16].[K+].[Na+].[I-]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:17][C:15](=[O:18])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 173821.91 %

Procedure:
To a solution of 6.9 g (0.02 mol) of 4-bromo-piperidine-1-carboxylic acid tert-butyl ester in DMF (18 mL) are added 5.25 g (0.012 mmol) potassium thioacetate, followed by a catalytic amount of NaI (0.35 g, 10 mol %) at room temperature. After complete addition, the reaction is heated to 50° C. for 20 h. The reaction mixture is partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer is dried over Na2SO4, filtered and the solvent is removed under reduced pressure to afford 5.41 g of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester as a brown oil. Yield: 81%; ES-MS: m/z 245 [M+H—CH3], 160 [M+H—O5H9O2]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.37-1.64 (11 H, m), 1.78-1.99 (2 H, m), 2.25-2.35 (3 H, m), 3.06 (2 H, ddd, J=13.63, 10.43, 3.05 Hz), 3.61 (1 H, tt, J=10.28, 4.04 Hz), 3.76-3.96 (2 H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=3[N:11]=[C:10]2[SH:19])=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=3[N:11]=[C:10]2[S:19][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6][CH:7]=1
Reactant: Fc1ccc2c(c1)nc(S)n2Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCSc1nc2cc(F)ccc2n1Cc1ccc(Cl)cc1

Procedure:
9 g of 1-(4-chlorophenylmethyl)-2-mercapto-5-fluorobenzimidazole, prepared in Example 15, and 4.4 ml of ethyl 4-bromobutyrate are refluxed for 5 hours in 100 ml of acetone in the presence of 6.3 g of potassium carbonate. The solvent is evaporated off under vacuum, the residue is taken up with water and then extracted with ethyl acetate and the extract is washed with a dilute solution of sodium hydroxide. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give 11.9 g of ethyl 4-[1-(4-chlorobenzyl)-5-fluorobenzimidazol-2-yl]mercaptobutanoate in the form of an oil, which is used as such for the next step.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)N.[CH3:13][CH:14]([C:23](=O)[CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:21])=[O:20]>C(O)(=O)C>[CH3:24][C:23]1[C:14]([CH3:13])([CH2:15][CH2:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:21])=[O:20])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:7]=2)[N:1]=1
Reactant: CC(=O)C(C)CCCCS(=O)(=O)O
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
4-Hydrazinobenzenesulphonic acid (7.5 g), 5-methyl-6-oxoheptane-1-sulphonic acid (11.0 g) and acetic acid (50 ml) were heated under reflux under nitrogen for 6 hrs, during which time all of the suspended solid dissolved. The solvent was then evaporated under vacuum and the residue triturated with 2-propanol at 80° C. to give a light brown solid in suspension. The mixture was allowed to cool to ambient temperature, the solid collected by filtration, washed with 2-propanol and diethyl ether and dried under vacuum. The product was purified by HPLC, collecting the major peak detected at 270 nm. (Phenomenex Jupiter 15μ C18 300A, 250×50 mm. 100 ml/min. 0.5 g per run. Eluant isocratic water+0.1% TFA). Product fractions were pooled and evaporated to give 11.1 g.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH2:18]([O:20][C:21](=[O:25])[CH:22]=[N+]=[N-])[CH3:19].B(F)(F)F.CCOCC>CCOCC>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:4][CH2:3][CH:22]1[C:21]([O:20][CH2:18][CH3:19])=[O:25]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A dry 500 ml 3-neck flask was charged with benzyl 4-oxo-1-piperidinecarboxylate (35.08 g, 150 mmol). It was dissolved in 130 ml Et2O and cooled to −45° C. Ethyldiazoacetate (20.5 ml, 195 mmol) and boron trifluoride ethyl ether (19.4 ml, 158 mmol) were added simultaneously by syringe pump over 45 minutes. The temperature was kept below −25° C. The reaction was stirred for 30 minutes longer, and then quenched with sat. NaHCO3. The ice bath was removed. The reaction was diluted with EtOAc (250 ml) and H2O (150 ml). The layers were separated, and the organic phase was dried over MgSO4. It was concentrated under reduced pressure to an orange oil. The product was purified by flash chromatography (silica gel, 40% EtOAc/hexane), yielding product as pale yellow oil (42.1 g, 88%). 1H NMR (CDCl3) δ 7.39-7.31, 5.15-5.12, 4.42-4.17, 3.96-3.83, 3.75-3.70, 3.65, 3.54-3.37, 2.08-2.03, 1.29-1.24; IR (liq.) 1743, 1702, 1476, 1455, 1443, 1425, 1371, 1318, 1295, 1238, 1213, 1178, 1098, 1068, 1028 cm−1.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[CH3:13][S:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)[CH:22]=2)[NH:17][C:16]1=[O:29].[O:30]1[C:34]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][C:39](=[O:44])[CH2:38]3)=[CH:33][N:32]=[CH:31]1.[CH2:45]([O:47][CH:48]=[C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([C:58]3[O:62][CH:61]=[N:60][CH:59]=3)[CH:56]=2)[NH:51][C:50]1=[O:63])[CH3:46].[CH3:64][N:65]([CH3:76])[S:66]([C:69]1[CH:74]=[CH:73][C:72]([NH2:75])=[CH:71][CH:70]=1)(=[O:68])=[O:67]>>[CH3:13][S:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)[CH:22]=2)[NH:17][C:16]1=[O:29].[O:30]1[C:34]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][C:39](=[O:44])[CH2:38]3)=[CH:33][N:32]=[CH:31]1.[CH2:45]([O:47][CH:48]=[C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([C:58]3[O:62][CH:61]=[N:60][CH:59]=3)[CH:56]=2)[NH:51][C:50]1=[O:63])[CH3:46].[CH3:64][N:65]([CH3:76])[S:66]([C:69]1[CH:74]=[CH:73][C:72]([NH:75][CH:20]=[C:21]2[C:11]3[C:9](=[CH:8][CH:7]=[C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)[CH:12]=3)[NH:10][C:24]2=[O:28])=[CH:71][CH:70]=1)(=[O:67])=[O:68]
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Reactant: Nc1ccc(-c2cnco2)cc1
Agent: CCOC=C1C(=O)Nc2ccc(-c3cnco3)cc21
Agent: CSC1C(=O)Nc2ccc(-c3cnco3)cc21
Agent: O=C1Cc2cc(-c3cnco3)ccc2N1
Product: CN(C)S(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc(-c4cnco4)cc32)cc1

Procedure:
3-Methylsulfanyl-5-oxazol-5-yl-1,3-dihydro-indol-2one was prepared from 4-oxazol-5-yl-aniline according to Procedure D: 1H NMR (DMSO-d6): δ 10.7 (s, 1H), 8.3 (s, 1H), 7.5 (s, 3H), 6.9 (d, 1H), 4.5 (s, 1H), 2.0 (s, 3H); APCI−MS m/z 247 (M+H)+. 5-Oxazol-5yl-1,3-dihydro-indol-2-one was prepared from 3-methylsulfanyl-5-oxazol-5-yl-1,3-dihydro-indol-2-one according to Procedure D: 1H NMR (DMSO-d6): δ 10.5 (s, 1H), 8.3 (s, 1H), 7.5 (m, 3H), 6,8 (d, 1H), 3.5 (s, 2H); APCI−MS m/z 201 (M+H)+. 3-Ethoxymethylene-5-oxazol-5-yl-1,3-dihydro-indol-2-one was prepared from 5-oxazol-5-yl-1,3-dihydro-indol-2-one according to Procedure I: 1H NMR (DMSO-d6): 810.43 (s, 1H), 8.37 (s, 1H), 7.76 (s, 1H), 7.51 (m, 2H), 6.90, (d, 1H), 4.43 (q, 2H), 1.4 (t, 3H): APCI−MS m/z 255 (M−H)+. The title compound was prepared in 36% yield from 3-ethoxymethylene-5-oxazol-5-yl-1,3-dihydro-indol-2-one and N,N-dimethyl-4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 10.9 ( d, 1H), 10.8 (s, 1H), 8.8 (d, 1H), 8.4 (s, 1H), 8.0 (s, 1H), 7.7 (br d, 4H), 7.5 (m, 2H), 7.0 (d, 1H), 2.6 (s, 6H); APCI−MS m/z 409 (M−H)−.
Reaction SMILES: [CH3:1][S:2]([O-])(=O)=O.[NH2:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[CH:16]1[CH:20]2[O:21][CH2:22]C(O)[CH:19]2[O:18][CH2:17]1>>[NH2:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[CH:20]2[O:21][CH2:22][C@H:1]([SH:2])[CH:19]2[O:18][CH2:17]1
Reactant: CS(=O)(=O)[O-]
Reactant: Nc1ncnc2c1ncn2C1COC2C(O)COC21
Product: Nc1ncnc2c1ncn2[C@@H]1COC2C1OC[C@@H]2S

Procedure:
In an analogous manner to Example 3 the title compound is prepared from the methanesulfonate derivative of 6-(6-amino-purin-9-yl)-hexahydro-furo[3,2-b]furan-3-ol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:15].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH3:15])[N:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(Cl)c1ccccn1
Reactant: Brc1cnc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccccn1)n1ncc2ncc(Br)cc21
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To an ice-cooled solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (0.60 g, 3.0 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (60%, 488 mg, 12.2 mmol). After 30 min, 2-(1-chloroethyl)pyridine (1.73 g, 12.2 mmol) was added to reaction mixture, and the resulting suspension was warmed to 27° C. After 17 h, the reaction mixture was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (3×30 mL). The organic extracts were concentrated in vacuo. Purification by flash column chromatography (6→15% ethyl acetate in petroleum ether) afforded 6-bromo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[4,3-b]pyridine (450 mg, 49% yield). LRMS (ESI): [MH]+=304.6.