Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C@H:7]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:26]([O:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C@H:7]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8]2)=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(C[C@H]2CCc3ccccc3O2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C[C@H]2CCc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
(R)-(-)-3,4-Dihydro-2-(4-hydroxybenzyl)-2H-benzopyran (5.0 g, 20 mmol), 4-dimethylaminopyridine (240 mg, 2 mmol), triethylamine (2.6 g, 25 mmol) and acetic anhydride (2.9 g, 28 mmol) were dissolved in methylene chloride (75 ml) and stirred at room temperature for 2 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue purified on silica gel using hexanes/ethyl acetate (3:1) as eluent to afford an oil which was crystallized from hexanes to yield 4.0 g of the title product, m.p. 64°-65° C.; [α]D -98.9° (c 1.3, MeOH);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.[H-].[Na+].[CH3:12]I.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH3:12])[CH:7]=1
Reactant: OCc1cncc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-bromo-5-hydroxymethylpyridine (379 mg, 2.0 mmol) in dry tetrahydrofuran (10 mL) was treated at ambient temperature with sodium hydride (160 mg, 4.0 mmol, 60% dispersion in mineral oil). After stirring 5 min at ambient temperature, the opaque, yellow mixture was treated with methyl iodide (342 mg, 2.4 mmol). After stirring 2 h at ambient temperature, the mixture was added to cold water (30 mL) and extracted with diethyl ether (3×20 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to an orange oil (429 mg). Purification by column chromatography on silica gel, eluting with 15% (v/v) ethyl acetate in hexane afforded 266 mg (65.3%) of 3-bromo-5-methoxymethylpyridine as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9](N(CC=C)CC=C)=[C:8]([N+:22]([O-:24])=[O:23])[CH:7]=1)[CH2:2][CH3:3].[Cl:26]C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1[N+]([O-])=O.C(O)CC>S(=O)(=O)(O)O.O>[CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([Cl:26])=[C:8]([N+:22]([O-:24])=[O:23])[CH:7]=1)[CH2:2][CH3:3]
Reactant: C=CCN(CC=C)c1c([N+](=O)[O-])cc(C(=O)OCCC)cc1[N+](=O)[O-]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: CCCO
Solvent: O
Product: CCCOC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1

Procedure:
According to a preferred form of realization of the process of the present invention n-propyl-4-diallylamino-3,5-dinitro-benzoate may be prepared by reacting 1 mole of 4-chloro-3,5-dinitro-benzoic acid with 1.25 moles of n-propanol at a temperature between 85° C. and 90° C., in the presence of a sulfuric acid catalyst, whereby the water formed is removed by azeotropic distillation with benzene. The distillation of water having been completed (5-7 hours) the reaction mixture, is cooled and the n-propyl-4-chloro-3,5-dinitro-benzoate is isolated. This compound is reacted with a 1.1 molar amount of diallyl amine at a temperature between 70° C. and 80° C., in an aqueous melt in the presence of 0.1 mole of 75% phosphoric acid and 1.05 moles of a 10% sodium hydroxide solution as acid binding agent. The reaction mixture is allowed to sedimentate, the organic phase is poured into water and the crystalline n-propyl-4-diallylamino-3,5-dinitro-benzoate is isolated.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH2:18])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.Br[CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2c1cnn2C1CCCCO1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(O[C@H]2CCC[C@@H](N3CCCC3)C2)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
Under nitrogen, the cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.304 mmol) obtained in Example 724 was dissolved in N,N-dimethylacetamide (3 ml), followed by adding thereto 1,4-dibromobutane (36 μl, 0.304 mmol) and potassium carbonate (105 mg, 0.759 mmol), and the resulting mixture was stirred at 80° C. for 1.5 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extraction with chloroform (twice). The combined chloroform layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/2) to obtain 4-methyl-5-[(cis-3-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole (64 mg, yield 55.0%) as light-yellow tar.
Reaction SMILES: [C:1]([S:4][CH:5]([C:21]1[N:22]=[CH:23][N:24](C(OC(C)(C)C)=O)[CH:25]=1)[CH2:6][C:7]([N:9]1[CH2:20][CH2:19][CH2:18][C@H:10]1[C:11]([O:13]C(C)(C)C)=[O:12])=[O:8])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.[ClH:41]>C(Cl)Cl>[ClH:41].[C:1]([S:4][CH:5]([C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[CH2:6][C:7]([N:9]1[CH2:20][CH2:19][CH2:18][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)c1cn(C(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)c1c[nH]cn1
Reaction time: 5 h

Procedure:
A solution of 2.8 g (5.99 mmol) of (±)-1-[3-(acetylthio)-3-[1-[(1,1-dimethylethoxy)carbonyl]-1H-imidazol-4-yl]-1-oxopropyl]-L-proline, 1,1-dimethylethyl ester in 125 ml of CH2Cl2 and 6.5 ml (59.9 mmol) of anisole is cooled in an ice-water bath under nitrogen and saturated with HCl. The cold bath is removed and the stoppered flask is kept at ambient temperature for five hours. The reaction mixture is then concentrated in vacuo and the residue partitioned between 40 ml of water and 40 ml of diethyl ether. The organic solution is extracted with 20 ml more of water and the combined aqueous extracts lyophillized to afford 1.9 g of a glassy solid. This material is chromatographed on about 600 ml of LH-20 eluted with water. Pooling of the product fractions (R=0.36 on silica gel; 4:1:1:1, n-butanol:pyridine:acetic acid:water) yielded 1.9 g of product (±)-1-[3-(acetylthio)-3-(1H-imidazol-4-yl)-1-oxopropyl]-L-proline, hydrochloride.
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][C@@H:11]2[N:12]([CH3:23])[C:13]3[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[C@H:10]2[CH:9]1Br)=O)(C)(C)C.[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH2:30]>>[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH:30][C:16]1[CH:15]=[C:14]([C:19]([F:21])([F:22])[F:20])[C:13]2[N:12]([CH3:23])[C@H:11]3[CH2:24][CH2:25][NH:8][CH2:9][C@H:10]3[C:18]=2[CH:17]=1
Reactant: CN1c2c(cccc2C(F)(F)F)[C@H]2C(Br)N(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: Nc1ccc(F)cc1F
Product: CN1c2c(cc(Nc3ccc(F)cc3F)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general coupling procedure as a yellow solid (21 mg, 55%) from (4aS,9bR)-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45, 41 mg, 0.095 mmol) and 2,4-difluoroaniline (39 mg, 0.30 mmol). MS (APCI): 384 (base, M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:25](OC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:14]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CNc2ccccc2)COC1(C)C
Reactant: COC(OC)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CN(Cc2ccccc2)c2ccccc2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-phenylaminomethyl-oxazolidine-3-carboxylic acid tert-butyl ester (495 mg; example 2.a) at r.t. in 1,2-dichloroethane (10 ml) under an argon atmosphere were added benzaldehyde dimethyl acetal (0.37 ml), trifluoroacetic acid (0.13 ml) and sodium triacetoxyborohydride (571 mg). The mixture was stirred at room temperature overnight. The mixture was directly adsorbed on silica gel and purified by chromatography (SiO2; gradient:heptane->heptane/EtOAc 7:3) to give (S)-4-[(benzyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (492 mg, 77%) as a colourless viscous oil. MS (ISP): 397.4 ([M+H]+)
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[OH-].[Na+].[Cl:12][CH:13]([Cl:18])[C:14](OC)=O>C(O)C>[Cl:12][CH:13]([Cl:18])[C:14]1[N:9]=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1
Reactant: Nc1cccc[n+]1N
Reactant: COC(=O)C(Cl)Cl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ClC(Cl)c1nc2ccccn2n1
Reaction time: 4 h

Procedure:
A solution of 24 g of 1,2-diaminopyridinium iodide and 6.6 g. of sodium hydroxide in 200 ml of ethanol was stirred at 50°-60° C. for 1 hour. To the reaction mixture was added 17.2 g of methyl dichloroacetate and the mixture was refluxed with stirring for 4 hours. The mixture was concentrated under reduced pressure, water was added and extracted with chloroform.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[CH:16]=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[O:14][CH:15]=[CH:16][C:17]=4[CH2:18]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: c1cc2c(o1)CCNC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2occc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][N:8]1[C:12]([NH2:13])=[CH:11][C:10]([CH3:14])=[N:9]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[CH3:7][N:8]1[C:12]([NH:13][C:15](=[O:17])[CH3:16])=[CH:11][C:10]([CH3:14])=[N:9]1
Reactant: Cc1cc(N)n(C)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C)nn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Pyridine (7.1 mL, 90 mmol) was added to a solution of 2,5-dimethyl-2H-pyrazol-3-ylamine (10 g, 90 mmol) in acetic anhydride (46 mL) at 0° C. and the resulting mixture was stirred at room temperature for 30 min. The solvent was removed under vacuum to yield the title compound as a brownish liquid (13.7 g, yield: 100%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([Cl:52])[CH:48]=[CH:47][C:46]=1[F:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([F:53])=[CH:47][CH:48]=[C:49]([Cl:52])[C:50]=3[Cl:51])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Fc1ccc(Cl)c(Cl)c1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(F)ccc(Cl)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloro-1-fluorobenzene and isolated as white solid. MS (m/e): 459.3 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH2:20]([O:19][C:17]([N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([OH:8])[CH:2]1[CH3:1])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1NCCCC1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C(O)CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
To a solution of 1.4 g (9.232 mmol) 2-methyl-piperidin-3-ol (CAS: 4766-56-7) in 9.8 ml dichloromethane under argon at room temperature, was added 2.57 ml (18.46 mmol) triethylamine. The mixture was stirred for 15 minutes and then cooled to 0° C. 1.37 ml (9.232 mmol) benzyl chloroformate was added dropwise. The reaction mixture was allowed to come to room temperature and the stirring was continued overnight. The mixture was extracted three times with water and the combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified with flash column chromatography on silica gel (Eluent: Heptane/ethyl acetate 0 to 30) to provide 800 mg (34.8%) of the title compound as a colorless oil. MS (m/e): 272.4 (M+Na+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:19])[C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CO)N(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 50 °C

Procedure:
A solution of 2A (2 g, 7.2 mmol) in DMF (20 mL) was added with an. K2CO3 (1.5 mol eq, 1.49 g) and, after few minutes, iodomethane (1.2 mol eq, 0.8 ml) was added and the mixture heated at 50° C. for 12 h. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase extracted with EtOAc (3×40 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to obtain 3A as a pale yellow oil (2.3 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 2.82 (s, 3H), 3.50 (s, 3H), 3.69 (m, 3H), 4.60 (t, 1H, J=6), 5.12 (t, 1H, J=6.1), 7.44 (m, 2H), 7.83 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23][CH2:22]2)=[O:20])[CH:5]=[C:6]([F:18])[C:7]=1[NH:8]CC1C=CC(OC)=CC=1.C(O)(=O)C>CO.[Pd]>[NH2:8][C:7]1[C:6]([F:18])=[CH:5][C:4]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH2:26]2)=[O:20])=[CH:3][C:2]=1[F:1]
Reactant: CCN1CCN(C(=O)c2cc(F)c(NCc3ccc(OC)cc3)c(F)c2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCN(C(=O)c2cc(F)c(N)c(F)c2)CC1
Reaction time: 24 h
Yield: 90.6 %

Procedure:
To a solution of [3,5-difluoro-4-(4-methoxy-benzylamino)-phenyl]-(4-ethyl-piperazin-1-yl)-methanone (11.8 g, 30.4 mmol) obtained in Step C in methanol (150 ml), palladium black was added, followed by stirring for 24 hours under a hydrogen gas atmosphere. Acetic acid (15 ml) was added, followed by further stirring for 17 hours at room temperature. This was filtered through Celite, and the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 10/1), to obtain the desired compound as a brown solid (7.42 g, 91%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[CH:11]([O:22]CC1C=CC(OC)=CC=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:7])=[O:6].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[CH:11]([OH:22])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(COC(C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(COS(=O)(=O)CCCCl)C(O)C(=O)OCc1ccccc1
Yield: 66 %

Procedure:
Following the general procedure for the oxidative cleavage of (4-methoxy)benzyl ethers of Description 19 phenylmethyl (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethyl-butanoate (32a) (0.22 g, 0.4 mmol) dissolved in a mixture of dichloromethane (DCM) and water (10:1) (3 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (200 mg, 0.87 mmol). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 100 mg (60% yield) of the title compound (32b) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ=0.95 (s, 3H), 1.08 (s, 3H), 2.27-2.34 (m, 2H), 3.04 (d, J=6.0 Hz, 1H), 3.26-3.29 (m, 2H), 3.65-3.69 (m, 2H), 3.97 (d, J=8.8 Hz, 1H), 4.08 (d, J=5.6 Hz, 1H), 4.16 (d, J=9.6 Hz, 1H), 5.24 (d, J=12.4 Hz, 1H), 5.28 (d, J=12.4 Hz, 1H), 7.36-7.38 (m, 5H) ppm. MS (ESI) m/z: 379.03 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][S:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>C(#N)C.O>[CH3:20][N:21]([CH3:25])[C:22](=[O:23])[O:1][C:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][S:4][N:3]=1
Reactant: Oc1nsnc1Oc1ccccc1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C)C(=O)Oc1nsnc1Oc1ccccc1
Yield: 95.7 %

Procedure:
In acetonitrile were suspended 0.80 g of 3-hydroxy-4-phenoxy-1,2,5-thiadiazole and 0.46 g of potassium carbonate and after adding 0.36 g of dimethylcarbamoyl chloride to the suspension, the mixture was refluxed for 12 hours. After allowing to cool, the reaction mixture was poured in water and extracted with ether. The ether layer was washed twice each time with a diluted aqueous solution of sodium hydroxide, water, and then a saturated aqueous sodium chloride solution. The ether layer thus washed was dried with anhydrous magnesium sulfate, concentrated, and thereafter purified by silica gel column chromatography to provide 0.85 g of 3-phenoxy-1,2,5-thiadiazol-4-yl N,N-dimethylcarbamate.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:22]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])[CH3:23]>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[CH2:22][CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Reactant: CCc1ccccc1N
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1CC
Yield: 69.4 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (3.69 g, 9.84 mmol) and 2-ethylaniline (1.55 g, 12.8 mmol) in acetonitrile (20 ml) was refluxed for 6 h. The solution was evaporated. Chromatography (SiO2 ; CH2Cl2 :MeOH 97:3) gave 2.79 g (69%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]([OH:19])=O)[S:11]3)=[CH:4][CH:3]=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(CC)CC)C>CN(C=O)C>[CH3:20][N:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17]([C:12]1[S:11][C:10]2=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:15][N:14]2[C:13]=1[CH3:16])=[O:19]
Reactant: CNc1ccccc1
Reactant: Cc1c(C(=O)O)sc2nc(-c3ccc(F)cc3)cn12
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N(C)c2ccccc2)sc2nc(-c3ccc(F)cc3)cn12
Yield: 13.7 %

Procedure:
6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid (example 7, 50 mg, 0.18 mmol) N-methyl-phenyl-amine (29.15 mg, 0.27 mmol), TOTU (63.32 mg, 0.2 mmol) and triethylamine (100.6 μl, 0.72 mmol) in 3 ml DMF were stirred at RT for 8 hours. The mixture was evaporated. Ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 9 mg (14%) of the desired product. MS: M+H+=365.94.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:10]=1[CH:11]=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:9]1[C:10]2[CH:11]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:17][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCl
Reactant: O=Cc1c(O)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cccc2o1
Temperature: 25 °C

Procedure:
Ethyl chloroacetate (8.0 mL, 1.3 eq.) was added to a mixture of 2-chloro-6-hydroxy-benzaldehyde (Example 1a), 9.0 g, 57 mmol) and potassium carbonate (16.0 g, 114 mmol) in DMF (100 mL) at rt. The reaction mixture was heated at +120° C. for 1.5 h, cooled to room temperature and filtered through a short bed of Celite. The filtrate was acidified to pH 2 with 5 M HCl and the solution was extracted with dichloromethane (2×100 mL). The combined organic extracts was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography by using hexane/ethyl acetate (9/1) as eluent to give the title compound. Yield: 10 g (77%). 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (t, 3H) 4.56 (q, 2H) 7.29-7.32 (m, 1H) 7.35-7.40 (m, 1H) 7.49-7.52 (m, 1H) 7.60 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]([OH:11])[OH:10])=O.[OH-].[Na+].[N+:14]([CH3:17])([O-:16])=[O:15].Cl>O>[N+:14]([CH2:17][CH:1]1[O:11][B:9]([OH:10])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]1=2)([O-:16])=[O:15]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])CC1OB(O)c2ccccc21
Temperature: 25 °C
Yield: 87.1 %

Procedure:
2-Formylphenylboronic acid (25 g, 0.167 mol) was added to a cooled solution of sodium hydroxide (7.0 g, 0.175 mol, 1.05 eq) in 83 mL of water at 10° C. Nitromethane (10.17 g, 1 eq) was added to this solution and then warmed to room temperature with stirring. This mixture was stirred for 3.5 hours. The reaction was then cooled in an ice bath and acidified with 3M HCl to a pH of 2. A white precipitate was collected and filtered, washed with water and air dried to obtain 28 g (87%) of 3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (off-white solid).