Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].O.O.O.C([O-])(=O)C.[Na+].[Cl:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH2:23]Cl.Cl>O.C(#N)C>[Cl:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH2:23][NH:9][C:6]1[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=S(=O)(O)c1ccc(NCc2ccc(Cl)cc2Cl)cc1
Yield: 55.3 %

Procedure:
To a mixture of 52.0 g (0.30 mole) of sulfanilic acid in 225 ml of warm water was added 83 g (0.61 mole) of sodium acetate trihydrate and 75 ml of acetonitrile. Then a solution of 37.1 g (0.19 mole) of 2,4-dichlorobenzyl chloride in 75 ml of acetonitrile was added and the resulting solution refluxed for 31/2 hrs, followed by the dropwise addition of 50 ml of conc. HCl while simultaneously removing 75 ml of acetonitrile by distillation. The reaction mixture was filtered while hot (80° C.) and the same purification sequence utilized as described in the previous example, which gave 34.91 g (55.3% yield) of purified 4-(((2,4-dichlorophenyl)methyl)amino)benzenesulfonic acid as a white powder having a melting point greater than 275° C.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[NH:14][C:13](=S)[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1.[Na+].[Cl-]>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)([C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[OH:28])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]([NH:1][NH2:2])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=S)N2
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(NN)=N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
Hydrazine (4.5 ml) was added at room temperature to a mixture of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepine-2(3H)-thione (described in Example B14) (0.0085 mol) in THF (50 ml). The mixture was stirred at room temperature for 30 min, poured out into ice water, saturated with NaCl and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 4.3 g (96.4%) of 5-(3-chlorophenyl)-α-(4-chlorophenyl)-2-hydrazino-3,5dihydro-α-(1-methyl-1H-imidazol-5-yl)-4,1-benzothiazepine-7-methanol.
Reaction SMILES: C([O:5][C:6](=[O:17])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][N:10]=1)(C)(C)C.[OH-].[K+].[CH3:20][C@H:21]1[N:26]([CH3:27])[C@@H:25]([CH3:28])[CH2:24][N:23]([C:29]2[CH:30]=[C:31]([C:35](=[O:37])[CH3:36])[CH:32]=[CH:33][CH:34]=2)[CH2:22]1>CCO>[O:37]=[C:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([N:23]2[CH2:22][C@H:21]([CH3:20])[N:26]([CH3:27])[C@H:25]([CH3:28])[CH2:24]2)[CH:30]=1)/[CH:36]=[CH:15]/[C:12]1[CH:13]=[CH:14][C:9](/[CH:8]=[CH:7]/[C:6]([OH:5])=[O:17])=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Reactant: CC(=O)c1cccc(N2C[C@@H](C)N(C)[C@@H](C)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1CN(c2cccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)c2)C[C@H](C)N1C
Temperature: 0 °C
Reaction time: 6 h
Yield: 96.9 %

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 168 mg, 0.718 mmol), 1.7 M KOH (0.674 ml) and 1-[3-((3R,5S)-3,4,5-trimethyl-piperazin-1-yl)-phenyl]-ethanone (described in Preparation 8, 188 mg, 0.764 mmol) in EtOH (7 ml) was stirred at 0° C. for 6 h. The resulting precipitate was filtered off and dissolved in DCM (5 ml) and TFA (1 ml). The mixture was stirred at room temperature for 4 h and then the solvent was removed in vacuo to give 282 mg of (E)-3-(5-{(E)-3-oxo-3-[3-((3R,5S)-3,4,5-trimethyl-piperazin-1-yl)-phenyl]-propenyl}-pyridin-2-yl)-acrylic acid as its bis-trifluoroacetate salt.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([O:20][C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1)([CH3:19])([CH3:18])[CH3:17].CN(C)[CH:29]=[O:30]>O1CCCC1.C(OCC)(=O)C.O>[C:16]([O:20][C:21]1[C:26]([CH:29]=[O:30])=[N:25][CH:24]=[CH:23][N:22]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CN(C)C=O
Reactant: CC(C)(C)Oc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1nccnc1C=O
Temperature: -50 °C
Reaction time: 0.42 h
Yield: 45 %

Procedure:
After dissolving 2.50 ml of 2,2,6,6-tetramethylpiperidine in 40 ml of tetrahydrofuran, the solution was cooled to −50° C. Next, 5.25 ml of n-butyllithium (2.6 M, n-hexane solution) was added dropwise thereto under a nitrogen atmosphere. The mixture was stirred for 25 minutes, cooled on ice, and stirred for an additional 35 minutes. It was then cooled to −78° C., and a solution of 1.89 g of 2-tert-butoxypyrazine [CAS No. 70090-30-1] in tetrahydrofuran (5 ml) was added dropwise. After stirring the mixture for 15 minutes, 1.25 ml of N, N-dimethylformamide was added dropwise. After 10 minutes, water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.00 g, 45% yield).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][N:13]([C:15]([O:19][N:20]1[N:28]=[N:27][C:22]2[CH:23]=[CH:24][CH:25]=[N:26][C:21]1=2)=[N+:16]([CH3:18])[CH3:17])[CH3:14].[F:29][P-:30]([F:35])([F:34])([F:33])([F:32])[F:31].CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:69])[C:57]4[C:61]([CH:62]=3)=[N:60][N:59](C3CCCCO3)[CH:58]=4)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:18][N:16]([C:15]([O:19][N:20]1[N:28]=[N:27][C:22]2[CH:23]=[CH:24][CH:25]=[N:26][C:21]1=2)=[N+:13]([CH3:14])[CH3:12])[CH3:17].[F:29][P-:30]([F:35])([F:34])([F:33])([F:32])[F:31].[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:69][C:9](=[O:11])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccccn1)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
2-Pyridylacetic acid hydrochloride (0.033 g, 0.191 mmol), HATU (0.084 g, 0.220 mmol) and DIPEA (0.130 ml, 0.764 mmol) were combined in DMF (3 ml) and stirred at 20° C. for 10 minutes. 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (0.07 g, 0.20 mmol) was added and the reaction was stirred for 5 h at 20° C. A second batch of 2-pyridylacetic acid hydrochloride (0.033 g, 0.191 mmol), HATU (0.084 g, 0.220 mmol) and DI PEA (0.130 ml, 0.764 mmol) in DMF (3 ml) was prepared and stirred at 20° C. for 10 minutes. It was added to the main reaction mixture and stirred for 3 days (weekend) at 20° C. The reaction mixture was applied to a 5 g NH2-SPE cartridge and eluted with 10% methanol in dichloromethane. The solvent was evaporated and the residue was purified by Mass Directed Auto Prep (Method B) to give the title compound (0.018 g).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]2=[O:17])(=[O:3])C.II.[OH-:21].[K+].[OH-].[Na+]>O.C(O)CO.N1C=CC=CC=1>[C:1]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]2=[O:17])([OH:3])=[O:21]
Reactant: [OH-]
Reactant: CC(=O)c1cc(C)c2c(c1C)C(=O)C(C)(C)CS2
Agent: II
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: OCCO
Product: Cc1cc(C(=O)O)c(C)c2c1SCC(C)(C)C2=O
Yield: 95 %

Procedure:
A mixture containing 10.8 g (41 mmol) of 6-acetyl-3,3,5,8-tetramethylthiochroman-4-one, 12.6 g (50 mmol) of iodine and 9.8 g (124 mmol) of pyridine was heated at 110~110° C. for 6 hours. After the completion of the reaction, excess pyridine was distilled off under reduced pressure, and to the residue were added 50 ml of ethylene glycol, 20 ml of water and 11 g (167 mmol) of potassium hydroxide. The mixture was refluxed under heat for 2 hours. After the reaction mixture was allowed to cool, 200 ml of a 1 wt % sodium hydroxide aqueous solution was added, and an aqueous layer was washed with chloroform twice and then acidified with a 5 wt % hydrochloric acid aqueous solution. A precipitated grey solid was collected by filtration under reduced pressure, washed with water and then dried under reduced pressure to give 10.3 g (yield 95%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[C:17]([O:21][C:22]([N:24]1[CH2:31][CH:30]2[O:32][CH:26]([CH2:27][NH:28][CH2:29]2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH:26]2[O:32][CH:30]([CH2:29][N:28]([CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=3)(=[O:8])=[O:7])[CH2:27]2)[CH2:31]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: N#Cc1ccc(S(=O)(=O)NCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCCNS(=O)(=O)c3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A suspension of N-(3-Bromo-propyl)-4-cyano-benzenesulfonamide (6.39 g, 0.021 mol; see step (i) above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4.32 g, 0.0189 mol see WO 01/28992) and dry K2CO3 (10.16 g, 0.0735 mol) in dry acetonitrile (70 ml) was stirred at 60° C. overnight under N2 atmosphere. The reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 50% ethyl acetate in petroleum ether, as eluent to give the sub-title compound (4.29 g) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[CH3:28][C:29]1[NH:30][C:31]([NH:34][CH:35]2[CH2:40][CH2:39][S:38][CH2:37][CH2:36]2)=[N:32][N:33]=1>>[F:27][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:18])[N:34]([CH:35]2[CH2:36][CH2:37][S:38][CH2:39][CH2:40]2)[C:31]2[N:32]([N:33]=[C:29]([CH3:28])[N:30]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: Cc1nnc(NC2CCSCC2)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCSCC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 53.4 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1.5 g) and 5-methyl-N-(tetrahydro-2H-thiopyran-4-yl)-4H-1,2,4-triazol-3-amine (0.4 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.54 g, 27%).
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:23][CH2:24][CH2:25][OH:26])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:30]>C1COCC1>[CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:23][CH2:24][CH2:25][O:26][CH3:30])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCCO)cc2cccnc12)C1CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,1-dimethylethyl cyclopropyl{[6-(3-hydroxypropyl)-8-quinolinyl]methyl}carbamate (1 eq.) from the previous step in THF (0.3 M) was added sodium hydride (60% (w/w) dispersion in paraffin oil, 1.2 eq.). The resulting suspension was stirred at RT for 15 min before iodomethane (1.4 eq.) was added. The now yellow solution was stirred at RT for 12 h before the reaction was quenched with the addition of 1 N aq. NaOH. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: C([Li])CCCCC.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH3:16])[C:10]=1[F:17].[CH2:18]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[CH3:19]>O1CCCC1>[CH2:18]([N:20]1[CH2:25][CH2:24][C:23]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH3:16])[C:10]=2[F:17])([OH:26])[CH2:22][CH2:21]1)[CH3:19]
Reactant: CSc1cccc(Br)c1F
Reactant: CCN1CCC(=O)CC1
Agent: [Li]CCCCCC
Solvent: C1CCOC1
Product: CCN1CCC(O)(c2cccc(SC)c2F)CC1

Procedure:
Preparation according to preparation 1 with the exception that n-hexyllitium was used instead of n-butyllithium: 1-bromo-2-fluoro-3-(methylthio)benzene (15 g, 67.8 mmol), dry tetrahydrofurane (70 ml), n-hexyllithium (2.3 M in hexane, 31 ml, 71 mmol), 1-ethylpiperidin-4-one (9.06 g, 71 mmol). Yield: 20.7 g. MS m/z (rel. intensity, 70 eV) 269 (M+, 49), 254 (bp), 236 (36), 56 (31), 84 (23).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][S:9]C1C=CC(O)=CC=1>>[CH3:8][S:9][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7]
Reactant: CSc1ccc(O)cc1
Reactant: Oc1ccccc1
Product: CSc1ccccc1O
Temperature: 25 °C
Yield: 41 %

Procedure:
The mixture was cooled to room temperature and filtered. The catalyst was washed several times with ether and allowed to dry. The filtrate and ether washings were combined, and volatiles were removed on a rotary flash evaporator. GC analysis indicated the presence of phenol (5.3 g. 42% recovered), ortho(methylthio)phenol (5.2 g. 41% yield), para-(methylthio)phenol (2.0 g, and di-(methylthio)phenols (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:28])[N:5]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25]CC)[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]2=[O:11].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:28])[N:5]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]2=[O:11]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)C[C@H](c1ccc(O)c(O)c1)N1C(=O)c2cccc(N)c2C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-4-amino-2-[1-(3-ethoxy-4-hydroxy-phenyl)-2-methanesulfonyl-ethyl]-isoindole-1,3-dione (0.55 mmol) in anhydrous CH2Cl2 at room temperature, is added AlCl3 (2.2 mmol). After stirring for 1 hour, water is added. The product is extracted into CH2Cl2, and the organic extract is dried over MgSO4. The solvent is removed to afford crude (S)-4-amino-2-[1-(3,4-dihydroxy-phenyl)-2-methanesulfonyl-ethyl]-iso indole-1,3-d lone. The product is purified by column chromatography or recrystallization.
Reaction SMILES: O[CH:2]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[NH:15][C:14]=1[C:24]1[CH:28]=[C:27]([CH3:29])[S:26][CH:25]=1)[C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.C(O)(=O)C>CO.C(OCC)(=O)C>[CH3:23][O:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([CH2:2][C:3]3[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=3)=[C:14]([C:24]3[CH:28]=[C:27]([CH3:29])[S:26][CH:25]=3)[NH:15]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(C(O)c2c(-c3csc(C)c3)[nH]c3cc(OC)ccc23)n1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cccc(Cc2c(-c3csc(C)c3)[nH]c3cc(OC)ccc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of methyl 6-{hydroxy-[6-methoxy-2-(5-methylthiophen-3-yl)-1H-indol-3-yl]methyl}pyridine-2-carboxylate (335 mg) and a boran-2-picoline complex (92.1 mg) in methanol (1.7 mL) was added acetic acid (1.7 mL), and this mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (255 mg). 1H-NMR (CDCl3) δ ppm: 2.48-2.53 (3H, m), 3.85 (3H, s), 4.05 (3H, s), 4.54 (2H, s), 6.74 (1H, dd, J=2.2, 8.6 Hz), 6.88 (1H, d, J=2.2 Hz), 6.96-7.01 (1H, m), 7.17-7.22 (2H, m), 7.29 (1H, d, J=8.6 Hz), 7.62 (1H, t, J=7.8 Hz), 7.93-7.98 (1H, m), 8.01 (1H, br s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)=[CH:4][CH:3]=1.C(=[NH:37])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH2:37][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=C1CN=C(c2ccc(Br)cc2)c2ccc3ccccc3c2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(C2=NCC(=O)Nc3c2ccc2ccccc32)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
5-(4-Bromophenyl)-1H-naphtho[1,2-e][1,4]diazepin-2(3H)-one (380 mg, 1.04 mmol), benzophenone imine (349 mg, 2.08 mmol), sodium tert-butoxide (200 mg, 2.08 mmol), palladium(II) acetate (23 mg, 0.104 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (60 mg, 0.208 mmol) were dissolved in anhydrous dioxane (5 mL), and the solution was stirred at 110° C. for 16 hours. The reaction mixture was left to cool, and then poured into water, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to give the title compound (154 mg, yield 49%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:8]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1nc(-c2ccc(Cl)s2)cs1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2ccc(Cl)s2)cs1

Procedure:
The title compound was prepared from 4-(5-chloro-2-thienyl)-1,3-thiazol-2-amine and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a beige solid (29.9 mg) with purity >90%: MS (pos) m/z 405.0, 407.0; HRMS m/z 403.9278 (calc. of monoisotopic mass for C14H10Cl2N2O2S3 gives 403.9281).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:1]([CH2:2][CH2:3][N:12]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][C:1]#[N:4])#[N:4]
Reactant: C=CC#N
Reactant: NCc1ccccc1
Product: N#CCCN(CCC#N)Cc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
18.58 g of acrylonitrile was added dropwise to an aqueous solution (80 mL) of 10.71 g of benzylamine at room temperature over 1 hour and 20 minutes. Thereafter, the mixture was heated and stirred at 70° C. for 8 hours. After the reaction mixture was concentrated to dryness, 100 mL of water was added thereto, followed by extraction of the mixture with ethyl acetate (150 mL). After the organic layer obtained was washed with water, it was dried with anhydrous magnesium sulfate. The solvent was distilled off to give 19.93 g of the title compound as a colorless oil.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=[O:11])[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]1=O)C.Cl.[NH2:21][OH:22]>CO>[OH:22][N:21]=[C:6]1[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C:10]2[O:11][N:2]=[CH:4][C:5]1=2
Reactant: CN(C)C=C1C(=O)CN(C(=O)OC(C)(C)C)CC1=O
Reactant: NO
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(=NO)c2cnoc2C1
Temperature: 20 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
12 mg (44.7 mmoles) of 1,1-dimethylethyl 4-[(dimethylamino)methylene]-3,5-dioxo-1-piperidinecarboxylate with 7.82 mg (112 mmoles) of hydroxylamine hydrochloride is introduced into 144 ml of methanol in a flask, the reaction medium is then agitated for 16 hours at 20° C. and then the solvent is evaporated off under reduced pressure. The mixture is poured into 10 ml of water followed by extracting with ethyl acetate (3×10 ml). The phases organic obtained are collected, dried over Na2SO4, filtered then the solvent is evaporated off under reduced pressure. 3.93 g of 1,1-dimethylethyl 4,7-dihydro-4-(hydroxyimino)-isoxazolo[5,4-c]pyridine-6(5H)-carboxylate, of molecular formula C11H15N3O4 is obtained (M=253.26 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])(C)(C)C.[Br:30][CH2:31][Si:32]([CH3:35])([CH3:34])Cl.O>C(OCC)C>[C:21]([O:20][C:18]([N:15]1[CH2:14][CH2:13][N:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]([Si:32]([CH2:31][Br:30])([CH3:35])[CH3:34])[CH:3]=2)[CH2:17][CH2:16]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Br)cc(C(F)(F)F)c2)CC1
Reactant: C[Si](C)(Cl)CBr
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)cc([Si](C)(C)CBr)c2)CC1
Temperature: -65 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-[3-bromo-5-(trifluoromethyl)-phenyl]-1-piperazine carboxylate (75 g, 183 mmoles) in diethyl ether, previously dried on molecular sieves, (1000 ml) was cooled to −65° C. and a 1.7M solution of tert-butyl lithium (215.6 ml, 366 mmoles) was added. After 30 minutes stirring bromomethyl-dimethyl-chlorosilane (49.9 ml, 366 mmoles) was added dropwise. After 2 hours stirring at −65° C., the reaction mixture was left at room temperature overnight. Water (600 ml) was added and the organic layer was washed with water, dried on MgSO4, filtered and evaporated.