Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[C:23]3[C:24]([OH:28])=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O:32][C@@H:33]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@@H:34]1OC(=N)C(Cl)(Cl)Cl)(=[O:31])[CH3:30].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[C:29]([O:32][C@@H:33]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:34]1[O:28][C:24]1[C:23]2[C:19]([CH2:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])=[CH:12][CH:13]=3)=[CH:20][O:21][C:22]=2[CH:27]=[CH:26][CH:25]=1)(=[O:31])[CH3:30]
Reactant: O=C(OCc1ccccc1)c1ccc(CCc2coc3cccc(O)c23)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(C(=O)OCc5ccccc5)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
3-[2-(4-Benzyloxycarbonylphenyl)ethyl]-4-hydroxybenzofuran (0.26 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.41 g) were dissolved in dichloromethane (5 mL)-ethyl acetate (3 mL). To the solution was added boron trifluoride-diethyl ether complex (0.44 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous, sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2-2/3) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-benzyloxycarbonylphenyl)ethyl]-benzofuran (0.44 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added 10% palladium-carbon powder (0.2 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14](O)[C:15](F)(F)F)[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3C)[CH2:26][CH2:27][OH:28])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N(C3CC3)[C:46](=[O:51])N(CC(O)=O)N=2)=CC=1.NC(C1C=CC=C(OC)C=1)CCO>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:29]3[CH:30]=[CH:31][CH:32]=[C:33]([O:51][CH3:46])[CH:34]=3)[CH2:26][CH2:27][OH:28])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: Cc1ccccc1C(CCO)NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Agent: COc1cccc(C(N)CCO)c1
Product: COc1cccc(C(CCO)NC(=O)Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)c1

Procedure:
In the same way as for the compound from Example 86, 30 mg (0.10 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for preparation see WO 2007/134862, Example 88A) and 20 mg (0.11 mmol) of 3-amino-3-(3-methoxyphenyl)propan-1-ol were reacted. This gave 30 mg (63% of theory) of the target compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:12]2[CH:13]=[C:14]([CH2:17]N3C(C(NCC)=O)=C(Cl)N=C3CCCC)[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1C1C=CC=CC=1C1N=NN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)N=1.Br[C:64]1[CH:74]=[CH:73][CH:72]=[CH:71][C:65]=1[C:66]([O:68][CH2:69][CH3:70])=[O:67]>COCCOC.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.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][C:9]([C:64]3[CH:74]=[CH:73][CH:72]=[CH:71][C:65]=3[C:66]([O:68][CH2:69][CH3:70])=[O:67])=[CH:8][C:12]=2[CH:13]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: CCCCc1nc(Cl)c(C(=O)NCC)n1Cc1ccc2oc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(Br)c2c1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCOC(=O)c1ccccc1-c1cc2cc(C)ccc2o1
Temperature: 25 °C
Yield: 313.2 %

Procedure:
Sodium carbonate (1N; 60 ml) was added to a mixture of Intermediate 1 (4.7 g), ethyl 2-bromobenzoate (5.89 g) and tetrakis- triphenylphosphine palladium (0) (0.88 g) in DME (100 ml). The mixture was heated at reflux for 18 h, cooled to room temperature and then concentrated in vacuo. The residue was extracted with ether (3×100 ml) and the combined extracts washed with brine (1×100 ml) and dried. The solvent was evaporated to give a brown oil (5 g) which was purified by column chromatography eluting with System A (1:20) to give the title compound as a pale yellow oil (2.89 g).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:8]=1I.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>CCCCCC.C1COCC1.CCOC(C)=O.Cl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:8]=1[B:17]([OH:22])[OH:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOc1ccc(Cl)c(I)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(Cl)c(B(O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
Add, dropwise, 5.5 mL (8.8 mmol) of a 1.6N solution of butyllithium in hexane in the space of 30 min to a solution of 2.38 g (8.4 mmol) of 1-chloro-2-iodo-4-ethoxybenzene in 50 mL of anhydrous THF cooled under argon to −78° C. After 2 h at −70° C., add 1.74 g (9.2 mmol) of triisopropyl borate and stir the reaction mixture for 3 h at room temperature, then distribute in 200 mL of EtOAc/HCl aq 5N 1:1 mixture. Wash the organic phase with 50 mL of water, dry over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a DCM/methanol gradient from 0 to 10% of methanol. After concentration under reduced pressure, we obtain 990 mg of (2-chloro-5-ethoxyphenyl)boronic acid, in the form of oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:27]=[C:26]([N:28]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[S:29]([CH3:32])(=[O:31])=[O:30])[C:25]([CH:42]4[CH2:44][CH2:43]4)=[CH:24][C:18]=3[C:19]=2[C:20](OC)=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]3[CH:27]=[C:26]([N:28]([CH2:33][C:34]4[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)[S:29]([CH3:32])(=[O:31])=[O:30])[C:25]([CH:42]4[CH2:43][CH2:44]4)=[CH:24][C:18]=3[C:19]=2[CH2:20][OH:21])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)oc2cc(N(Cc3ccc(OC)cc3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN(c2cc3oc(-c4ccc(OCc5ccccc5)cc4)c(CO)c3cc2C2CC2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A solution of Example 18H (4.34 g, 7.09 mmol) in tetrahydrofuran (20 mL) at 5° C. under nitrogen was treated dropwise with a solution of 1 M lithium aluminum hydride (7.1 mL, 7.1 mmol). The reaction mixture was stirred for two hours at ambient temperature, and treated sequentially and dropwise with water (0.29 mL), 15% aqueous sodium hydroxide (0.29 mL) and water (0.875 mL). The resulting slurry was stirred for 20 minutes, diluted with ethyl acetate and filtered through diatomaceous earth. The diatomaceous earth was rinsed with ethyl acetate, and the combined filtrate was concentrated to an oil. The oil was diluted with dichloromethane and hexane and concentrated once again to give the title compound as a yellow foam (4.08 g, 99%). MS (ESI+) m/z 601 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[O:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.CN(C1CCCCC1)C1CCCCC1.Cl[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:7]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1cc(Cl)cc2cn[nH]c12
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(C=O)c2n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5-Chloro-1H-indazole-7-carbaldehyde (5.6 g, 31.0 mmol) and N-methyldicyclohexylamine (9 mL, 41.9 mmol) were suspended in tetrahydrofuran (100 mL), cooled to 0° C., and treated with (2-(chloromethoxy)ethyl)trimethylsilane (8.3 mL, 46.5 mmol). Cooling was removed and stirring continued for 4 h. The reaction was poured into ethyl acetate, washed with water (3×), 1 M potassium bisulfate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (25% ethyl acetate/hexanes) gave 5.6 g (58%) as a faint yellow oil. 1H-NMR (CDCl3, 300 MHz) δ 10.50 (s, 1H), 8.21 (s, 1H), 7.94 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 5.78 (s, 2H), 3.62-3.67 (m, 2H), 0.90-0.96 (m, 2H), 0.05 (s, 9H). Mass spec.: 332.98 (MNa)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]([C@@:15]1([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14].I[CH3:34].[NH4+].[Cl-]>C1COCC1>[CH3:11][O:12][C:13]([C@@:15]1([CH2:29][CH:30]([CH3:32])[CH3:31])[CH:19]([CH3:34])[C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14]
Reactant: COC(=O)[C@@]1(CC(C)C)CC(=O)N(c2c(C)cccc2C)C1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@]1(CC(C)C)CN(c2c(C)cccc2C)C(=O)C1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.7 %

Procedure:
LHMDS (1 M solution in THF, 1.78 mL, 1.78 mmol) was added slowly to a cooled (−50° C.) solution of (S)-1-(2,6-dimethylphenyl)-3-isobutyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step e, 450 mg, 1.48 mmol) in THF (10 mL). After 5 min, iodomethane (185 μL, 2.97 mmol) was added at −50° C. and the resulting reaction mixture was immediately warmed to room temperature and stirred further for 2 h. Saturated aqueous NH4Cl solution (25 mL) was added, and the solution was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2, 20→60% MTBE/hexanes) to give (S)-1-(2,6-dimethylphenyl)-3-isobutyl-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (130 mg, 28% yield). LC-MS: R, (retention time): 2.68 min, MS: (ES) m/z 318.2 (M+H+).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][SH:7])(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.[CH3:19][N:20]([CH3:49])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[CH:33]=[C:32]([CH2:43]OS(C)(=O)=O)[N:31]=2)=[CH:26][CH:25]=1)=[O:22]>C(#N)C>[CH3:49][N:20]([CH3:19])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([CH2:43][S:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:33]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[N:35]=2)=[CH:26][CH:25]=1)=[O:22]
Reactant: CC(=O)NCCS
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(=O)NCCSCc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-Acetylcysteamine (0.064 mL) was dissolved in acetonitrile (5 mL). DBU (0.141 mL) was then added to the solution and was allowed to stir at RT for 5 minutes. 1,1-Dimethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]urea (154 mg) was suspended in acetonitrile (5 mL) and added to the thiol. The reaction was left to stir at RT of 1 hour then concentrated in vacuo to give the desired material.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[S:4]([NH2:7])(=[O:6])=[O:5].[C:22](OC)(OC)(OC)[O:23][CH3:24].C(O)(=O)C>O1CCOCC1>[CH3:22][O:23][C:24]1[O:1][C:2]([CH3:21])([CH3:20])[CH:3]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:12][CH:13]=2)[S:4](=[O:5])(=[O:6])[N:7]=1
Reactant: CC(C)(O)C(c1ccc(N2CCOCC2)cc1)S(N)(=O)=O
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC1=NS(=O)(=O)C(c2ccc(N3CCOCC3)cc2)C(C)(C)O1

Procedure:
2-Hydroxy-2-methyl-1-(4-morpholin-4-ylphenyl)propane-1-sulfonamide (41 mg) was stirred with tetramethyl orthocarbonate (0.2 ml), glacial acetic acid (0.01 ml) and dioxane (0.1 ml) at 90° C. for 4 hours. The solvents were removed under reduced pressure and the residue was used further without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](=[NH:29])[NH:24][O:25][C:26](=O)C)=[CH:13][CH:12]=2)[C:8]2[C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(=S)=[S:39].[H-].[Na+]>CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][O:25][C:26](=[S:39])[N:29]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: S=C=S
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=N)NOC(C)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nc(=S)o[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a mixture of methyl 2-butyl-1-[[2'-(acetoxycarbamimidoyl)biphenyl-4-yl)methyl]benzimidazole-7-carboxylate (2.0 g) and CS2 (1.5 g) in DMF (12 ml) was added sodium hydride (60% in oil, 0.56 g) during a period of 10 minutes and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-water and the pH of the solution was adjusted to 3. The mixture was extracted with ethylacetate and the extract was washed with water, dried, and concentrated to dryness. The residue was crystallized from chloroform-methanol to afford pale yellow prisms (0.64 g, 32%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][S:4][C:3]1=[S:8].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1[OH:18])[CH:13]=O.N1CCCCC1>C(O)(=O)C>[OH:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:5]2[S:4][C:3](=[S:8])[N:2]([CH3:1])[C:6]2=[O:7])[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1[OH:18]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CN1C(=O)CSC1=S
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CN1C(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)SC1=S
Temperature: 100 °C

Procedure:
A solution containing 0.74 g (0.005 mol) of 3-methyl-2-thioxothiazolidin-4-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde, 0.05 ml of piperidine in 10 ml of acetic acid was heated for 8 h at 100° C. The product was filtered and washed with 2-propanol. Yield 0.87 g (56%), mp 274-276° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:26]([CH:28]4[CH2:30][CH2:29]4)=[O:27])[CH:13]=[C:14]([O:16]CC4C=CC(OC)=CC=4)[CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:26]([CH:28]4[CH2:29][CH2:30]4)=[O:27])[CH:13]=[C:14]([OH:16])[CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(COc2cc(C(=O)C3CC3)cc(-c3ccc4c(c3)OCO4)c2)cc1
Solvent: CC(=O)O
Product: O=C(c1cc(O)cc(-c2ccc3c(c2)OCO3)c1)C1CC1
Temperature: 100 °C
Yield: 78.7 %

Procedure:
[3-Benzo[1,3]dioxol-5-yl-5-(4-methoxy-benzyloxy)-phenyl]-cyclopropyl-methanone (250 mg) was dissolved in glacial acetic acid (3 mL) and heated at 100° C. overnight. The solvent was removed under reduced pressure and the residue was purified on a silica gel column using ethyl acetate and hexanes to yield 138 mg of the title compound (79% yield). HRMS calcd for C17H14O4 [M+H]+ 283.0965, observed 283.0964.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[CH:15][CH:14]=1
Reactant: C1COCCN1
Reactant: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccnc(Br)c3)sc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccnc(N4CCOCC4)c3)sc12
Temperature: 140 °C
Yield: 49.7 %

Procedure:
A stirred suspension of 200 mg (0.44 mmol) 2-bromo-N-{4-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-benzothiazol-2-yl}-isonicotinamide, 0.38 ml (4.43 mmol) morpholine and 289 mg (0.89 mmol) cesium carbonate in 5 ml N-methylpyrrolidone in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140° C. for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate) followed by trituration in ether afforded 100 mg (49%) N-{4-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-benzothiazol-2-yl}-2-morpholin-4-yl-isonicotinamide as a light yellow crystalline solid. ES-MS m/e (%): 458 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]([F:30])([F:29])[CH2:26]CI>C(#N)C>[F:24][C:25]([F:30])([F:29])[CH2:26][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1
Reactant: FC(F)(F)CCI
Reactant: Oc1c(C2CCNCC2)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Oc1c(C2CCN(CC(F)(F)F)CC2)cccc1C(F)(F)F

Procedure:
Preparation according to Example 1: 2-piperidin-4-yl-6-(trifluoromethyl)phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1,1,1-trifluoro-3-iodopropane (0.01 ml). MS m/z (relative intensity, 70 eV) 341 (M+, 40), 258 (bp), 195 (25), 167 (28), 152 (56).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([C:25](OCC)=[O:26])=[C:22]([CH3:24])[N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1.O.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([CH2:25][OH:26])=[C:22]([CH3:24])[N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1sc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)nc1C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)sc1CO
Temperature: 25 °C
Reaction time: 27 h

Procedure:
To a solution of ethyl 2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylate (Example 2) (0.1 g, 0.22 mmol) in THF was added a 1M solution of DIBAL-H in toluene (2.76 mL, 6 eq) and the reaction was stirred to room temperature for 27 hours. Ether was added followed by solid NH4Cl. After 30 min, water was added and the mixture was filtered. The aqueous phase was extracted with ether, dried over sodium sulphate and evaporated. After purification by flash chromatography, eluting with DCM/MeOH 95/5, and crystallisation from acetonitrile, the title compound was obtained as a white solid (3 mg, 3%). HRMS calculated for C16H15Cl2N5O2S (M+H)+412.0402, found: 412.0409, Rt: 2.65 min. MP: 161.8° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[CH:30]=[CH:29][C:18]3=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:22]=[C:17]3[C:16](=[O:31])[C:15]=2[CH:32]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[OH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[CH:30]=[CH:29][C:18]3=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:22]=[C:17]3[C:16](=[O:31])[C:15]=2[CH:32]=1
Reactant: Cn1cc(-c2cnc3ccc4ccc(CCO[Si](C)(C)C(C)(C)C)cc4c(=O)c3c2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3ccc4ccc(CCO)cc4c(=O)c3c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (5 mg, 0.011 mmol) was dissolved in 0.5 mL of tetrahydrofuran. Tetrabutylammonium fluoride (0.013 mL of 1.0M in THF, 0.013 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate and brine and washed with brine twice. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via reverse phase HPLC (10-70% acetonitrile/water gradient, 0.05% trifluoroacetic acid modifier) afforded the title compound. 1H NMR (600 MHz, CDCl3) δ 9.01 (d, 1H); 8.58 (s, 1H); 8.16 (d, 1H); 7.92 (s, 1H); 7.81 (s, 1H); 7.59 (dd, 1H); 7.56 (d, 1H); 7.35 (d, 1H); 7.24 (d, 1H); 3.99 (s, 3H); 3.96 (t, 2H); 3.03 (t, 2H). Hydroxyl proton was not observed. LRMS (APCI) calc'd for (C20H18N3O2) [M+H]+, 332.1; found 332.1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:20][C@H:19]([CH2:21][O:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:9]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@@H:8]2[F:31])[CH:5]=[N:4][C:3]=1[C:32](=[O:35])[CH2:33]Cl.[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:6]([C@@H:7]2[O:20][C@H:19]([CH2:21][O:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:9]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@@H:8]2[F:31])[CH:5]=[N:4][C:3]=1[C:32](=[O:35])[CH2:33][N:36]=[N+:37]=[N-:38]
Reactant: Nc1c(C(=O)CCl)ncn1[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c1N
Yield: 94 %

Procedure:
Compound (16) obtained in step (7) above (185 mg) was dissolved in N,N-dimethylformamide (3.7 ml), to which was then added sodium azide (37 mg), and the resultant mixture was stirred at room temperature for 1 hour to effect the desired reaction in order to convert the chloro group of compound (16) into azido group and thus to produce the titled compound (17). The reaction solution was concentrated and the residue obtained was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate and then concentrated to yield a yellow syrup. This syrup was purified by silica gel column chromatography (developer solvent:toluene-ethyl acetate, 1:1), to give the titled compound (17) as a colorless solid (176 mg). Yield: 94%.