Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)([O-])=O.[Cl-].[NH4+]>O.[Fe]>[N:9]1([C:5]2[S:6][CH:7]=[CH:8][C:4]=2[NH2:1])[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: O=[N+]([O-])c1ccsc1-n1cncn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1ccsc1-n1cncn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
A mixture of 1-(3-nitrothiophen-2-yl)-1H-1,2,4-triazole (462 mg, 2.35 mmol), iron (1.31 g, 23.5 mmol) and ammonium chloride (163 mg, 3.06 mmol) in water (5 mL) was stirred at 100° C. for 18 h. The resulting suspension was filtered through a pad of diatomaceous earth and the filtrate was basified with aqueous NaOH. The aqueous solution was extracted with methylene chloride and the organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum to give 2-(1H-1,2,4-triazol-1-yl)thiophen-3-amine (314 mg, 1.89 mmol, 80%). Retention time (min)=0.454, method [1], MS (ESI) 167.0 (M+H).
Reaction SMILES: [CH:1]([O:4][S:5]([CH2:8][CH3:9])(=[O:7])=[O:6])([CH3:3])[CH3:2].C([Li])CCC.[P:15](Cl)([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16].Cl>O1CCCC1>[CH:1]([O:4][S:5]([CH:8]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[CH3:9])(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCS(=O)(=O)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C)S(=O)(=O)OC(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 58.3 %

Procedure:
A solution of ethanesulfonic acid isopropyl ester (1.0 g, 6.6 mmol) in tetrahydrofuran (15 mL) was cooled to −78° C., and n-butyllithium (1.57 M, 4.6 mL, 7.2 mmol) was added. After stirring at −78° C. for 20 minutes, diethyl chlorophosphate (0.52 mL, 3.6 mmol) was added to the reaction mixture, and the mixture was further stirred for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60) to give the title compound (0.61 g, 2.1 mmol, 58%).
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:29])[C:22]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:30])C1C=CC=CC=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3].C(OCC)C>C(O)(C(F)(F)F)=O>[Br:29][C:21]1[C:22]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:30]
Reactant: O=C1c2cccc3c(N4CCCCC4)c(Br)cc(c23)C(=O)N1OCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Agent: [B+3]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2cccc3c(N4CCCCC4)c(Br)cc(c23)C(=O)N1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
To a solution of 2-benzyloxy-5-bromo-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.27 g, 0.58 mmol, from Example T1-A) in TFA (5 mL) at 0° C. was added a 1.0 M solution of boron tris(trifluoroacetate) in TFA (3 mL). The reaction was stirred at 0° C. for 2 hours. Ethyl ether was added forming a precipitate which was collected by filtration. The solid was taken up in chloroform, the organic layer washed with water, dried, filtered, and evaporated under reduced pressure to give 0.060 g of the title compound as the TFA salt, mp>250° C.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])=[O:22])=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(Cl)cc1)[C@@H]1CCCN1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)N2CCC[C@H]2C(=O)c2ccc(Cl)cc2)c(C(F)F)n1
Reaction time: 3 h
Yield: 97.3 %

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (1.94 g; 10.0 mmol) in dichloromethane (5 ml) was added dropwise to a stirred suspension of (4-chloro-phenyl)-(S)-pyrrolidin-2-yl-methanone hydrochloride (2.46 g; 10.0 mmol), which was prepared as described in example P16, and triethylamine (3.0 g; 30.0 mmol) in dichloromethane (25 ml). Dichloromethane (40 ml) was added to the mixture. The ice bath was removed and reaction mixture was allowed stirring for 3 hours. The reaction mixture was washed with 1M NaOH (20 ml), 1M HCl (20 ml) and saturated NaCl (20 ml) and then dried over Na2SO4. After removal of the solvent, the residue was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:19). 3.58 g (97.3% of theory) of (4-chloro-phenyl)-[(S)-1-(3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl)-pyrrolidin-2-yl]-methanone was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.91-1.98 (m, 1H), 2.02-2.16 (m, 2H), 2.33-2.42 (m, 1H), 3.75-3.85 (m, 2H), 3.97 (s, 3H, NCH3), 5.61-5.65 (m, 1H), 6.99-7.28 (t, 1H, CHF2), 7.45-7.47 (d, 2H, Ar—H), 7.73 (s, 1H) 7.96-7.98 (d, 2H, Ar—H). MS [M+H]+ 368/370.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[CH3:13])=[O:5])#[N:2].[C:14](=S)=[S:15].[H-].[Na+].CI.[CH3:21][S:22]([CH3:24])=O>O>[CH3:21][S:22][C:24]([S:15][CH3:14])=[C:3]([C:4](=[O:5])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[CH3:13])[C:1]#[N:2]
Reactant: S=C=S
Reactant: CS(C)=O
Reactant: Cc1ccc(C)c(C(=O)CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CSC(SC)=C(C#N)C(=O)c1cc(C)ccc1C
Temperature: 18 °C
Reaction time: 1 h

Procedure:
A solution of 4.96 g (28.6 mmol) of 2-cyano-2′,5′-dimethylacetophenone in 120 mL of dry dimethyl sulfoxide and 3.43 mL (57.3 mmol) of carbon disulfide in a flame-dried 3-neck round bottom flask under dry nitrogen was stirred at 15-18° C. while 1.41 g (58.7 mmol) of oil free sodium hydride was added in 5 portions. The resulting deep red solution was stirred for 1 hour at 18° C. and then cooled to 15° C. whereupon 3.92 mL (8.95 g, 63.0 mmol) of methyl iodide was added dropwise. The temperature rose to about 22° C. during the addition. After stirring for 2 hours at room temperature, the reaction mixture was poured into cold water and the aqueous layer was extracted three times with ethyl acetate. The combined extracts were washed three times with water and then dried with brine and magnesium sulfate. Evaporation gave 8.96 g of the title compound as a heavy orange oil which crystallized in the refrigerator. The analytical sample crystallized from ethanol, m.p. 74.5-75.5° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.N1C=CC=N1.C(N(CC)CC)C.[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][C:44]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:45])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1cn[nH]c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OC(=O)C1CCCCC1
Yield: 54 %

Procedure:
As a starting material, 4-methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide corresponding to pyrazole derivative (I-H) was used. 0.4 Gram (1.1 mmol) thereof was dissolved in 4 ml of methylene chloride, and 0.22 g (2.2 mmol) of triethylamine as a base and 0.19 g (1.3 mmol) of cyclohexylcarbonyl chloride corresponding to compound B-A-Hal as a reaction reagent were added. The mixture was allowed to react at room temperature for 8 hours. A saturated sodium carbonate aqueous solution was added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate. An organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant oil was purified by flush column chromatography (Wako Gel C-300; hexane/ethyl acetate=1:1) to give 0.28 g (yield 54%) of 4-methoxy-5-methyl-6-(5-cyclohexylcarbonyloxy-1-ethylpyrazol-4-yl)carbonylthiochroman-1,1-dioxide.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH2:11]Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C-:18]#[N:19].[K+]>O1CCOCC1.C(O)C.O>[C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH2:11][C:18]#[N:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(CCl)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: COc1c(CC#N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a mixed solution of 5-tert-butyl-1-(chloromethyl)-2-methoxy-3-nitrobenzene (1.93 g, 7.49 mmol) in dioxane (5.0 mL), ethanol (5.0 mL) and water (2.5 mL), potassium cyanide (0.980 g, 15.0 mmol) was added, and the mixture was stirred for 2 hours under reflux. After cooling the mixture to room temperature and evaporated under reduced pressure and water was added to the residue. The resultant was extracted with ethyl acetate and then dried over anhydrous sodium sulfate, evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-30/70) to obtain 1.84 g of the captioned compound (99% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][O:20]2)=[CH:15][C:14]=1[CH3:22])(=[O:12])=[O:11].[CH3:27][C:28]1([NH2:32])[CH2:31][O:30][CH2:29]1>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:20])[CH2:21][NH:32][C:28]2([CH3:27])[CH2:31][O:30][CH2:29]2)=[CH:15][C:14]=1[CH3:22])(=[O:11])=[O:12]
Reactant: CC1(N)COC1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)cc2C)c(C)c1
Solvent: CCO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CNC3(C)COC3)cc2C)c(C)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-(2,4-dimethylphenyl)-N-isobutyl-2-methyl-4-(oxiran-2-yl)benzenesulfonamide (20 mg, 0.054 mmol) in ethanol at 25° C. was added 3-methyloxetan-3-amine (5.08 mg, 0.058 mmol). The reaction mixture was then stirred at 50° C. for 18 hours. Another portion of 3-methyloxetan-3-amine (5.08 mg, 0.058 mmol) was then added and the reaction stirred for a further 8 hours at 50° C. The reaction mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 5.2 mg. LCMS [LCMS2] Rt 1.23 min, m/z (ES+) 461 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18]CCOC3CCCCO3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=[O:65])=CC=1.[NH+]1[CH:74]=[CH:73]C=CC=1>CO>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH:73]([OH:65])[CH3:74])[CH:11]=2)[N:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: c1cc[nH+]cc1
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCCOC3CCCCO3)c2)n1
Solvent: CO
Product: CC(O)COc1cc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)ccc1Cl
Yield: 90.3 %

Procedure:
A solution of Intermediate 75c (247 mg, 0.31 mmol) and pyridinium p-toluenesulphonate (233 mg, 0.93 mmol) in methanol (14 mL) was stirred at 40-45° C. for 18.5 h. The cooled mixture was concentrated in vacuo, diluted with sat. sodium hydrogen carbonate solution and extracted with DCM (3×15 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-12% MeOH in DCM, to give the product (199.7 mg, 99%). Part of this (50 mg) was further purified by HPLC (XBridge C18 column, 30-90% MeCN in H2O, 0.1% NH4OH) to give the title compound (35 mg). LCMS (Method 5): Rt 4.53 min, m/z 713.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.57-1.65 (2H, m), 1.68-1.77 (4H, m), 1.80-1.94 (4H, m), 1.97-2.17 (2H, m), 3.07-3.17 (4H, m), 3.48-3.64 (2H, q, J=6.2 Hz), 4.09-4-20 (2H, t, J=6.52 Hz), 4.48-4.58 (1H, t, J=5.7), 4.76-4.84 (1H, m), 5.54 (1H, t, J=4.3 Hz), 6.34 (1H, s), 7.05-7.11 (2H, m), 7.16 (1H, dd, J=2.0, 9.9 Hz), 7.21-7.41 (5H, m), 7.54 (1H, d, J=8.5 Hz), 7.59-7.65 (2H, m), 8.14 (1H, br s).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=O.[N-:19]=[N+]=[N-].[Na+]>C(O)CO>[N:19]1[O:18][N:16]=[C:3]2[CH:4]=[C:5]([C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])[CH:14]=[CH:15][C:2]=12
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)N1CCCCC1
Agent: [Na+]
Solvent: OCCO
Product: O=C(c1ccc2nonc2c1)N1CCCCC1
Temperature: 50 °C
Yield: 74.7 %

Procedure:
4—Chloro-3-nitro-benzoylpiperidine (539.2 g, 2.00 mol) was dissolved in 2.93 L ethylene glycol in a 5-L flask with stirring and heating to 50 ° C. To this solution, sodium azide (137.0 g, 2.10 moles) was added in portions over 40 min. When the addition was complete, the temperature was increased to 120 ° C. during 2.5 hr and maintained at this temperature for 3 hr. The solution was allowed to cool to 50 ° C, at which time additional sodium azide (65.3 g, 1.00 moles) was added over 5 min. The temperature was increased to 25 120 ° C. during 2.5 hr and maintained at this temperature for 4.5 hr until gas evolution had ceased. The solution was allowed to cool to room temperature, at which time the mixture was partitioned between water and ethyl acetate (1.5 L each). The aqueous phase was extracted three times with ethyl acetate (300 mL). The combined organic phases were washed with 30 mL water, twice with saturated NaCl (200 mL), and finally dried over anhydrous Na2SO2. The filtered solution was evaporated to yield 345.5 g of crude 1-(benzofurazan-5-ylcarbonyl)piperidine.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:7])=[O:6].[CH3:24][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Br:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:24])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:6])=[O:7]
Reactant: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N(CCO)CCBr
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N(CCO)CCBr)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-{[(2-bromoethyl)(2-hydroxyethyl)amino]sulfonyl}-5-hydroxy-1H-indole-2-carboxamide, described in Step B of Example 51, in 2:1 dichloromethane/MeOH was added excess trimethylsilyldiazomethane (solution in hexane). After stirring at room temperature for 16 hours, the mixture was concentrated in vacuo. Purification by preparative reversed phase HPLC afforded the titled product. HRMS (ES) exact mass calculated for C14H18BrN3O5S (M+H+): 420.0224. Found 420.0221.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Br)[C:8]([N+:12]([O-])=O)=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)[CH3:17]>CC#N>[C:1]([C:5]1[CH:10]=[C:9]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH2:16][CH3:17])[CH:24]=2)[C:8]([NH2:12])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Reactant: CCOc1cccc(B(O)O)c1
Solvent: CC#N
Product: CCOc1cccc(-c2cc(C(C)(C)C)c(O)cc2N)c1

Procedure:
2-tert-Butyl-4-(3-ethoxyphenyl)-5-aminophenol (C-16) was synthesized following the general scheme above starting from 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) and 3-ethoxyphenyl boronic acid. HPLC ret. time 2.77 min, 10-99% CH3CN, 5 min run; ESI-MS 286.1 m/z (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([OH:9])[CH3:8])[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=1)[C:14]([NH:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1)=[O:15]>C(#N)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=1)[C:14]([NH:16][C:17]1[C:18]([N:1]2[CH2:6][CH2:5][CH:4]([CH:7]([OH:9])[CH3:8])[CH2:3][CH2:2]2)=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1)=[O:15]
Reactant: O=C(Nc1cc(Cl)cnc1Cl)c1cccc(Cl)c1
Reactant: CC(O)C1CCNCC1
Solvent: CC#N
Product: CC(O)C1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 0.200 g (1.55 mmol) of 1-piperidin-4-yl-ethanol and 0.200 g (0.663 mmol) of 3-chloro-N-(2,5-dichloro-pyridin-3-yl)-benzamide in acetonitrile (10 mL) is heated at 175 C in a microwave reactor for 14 hours. The mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to give 0.170 g (65.0%) of 3-chloro-N-[5′-chloro-4-(1-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-benzamide as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:32]=[CH:31][C:12]3[N:13]([CH3:30])[C:14]([N:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:33](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:33])[C:9]2[CH:32]=[CH:31][C:12]3[N:13]([CH3:30])[C:14]([N:16]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1c(N(C(=O)OC(C)(C)C)c2ccccc2)nc2cc(Nc3ccnc(Cl)n3)ccc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc2c(c1)nc(N(C(=O)OC(C)(C)C)c1ccccc1)n2C)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
Tert-butyl 5-[(2-chloropyrimidin-4-yl)amino]-1-methyl-1H-benzimidazol-2-yl(phenyl)carbamate (0.97 g, 2.2 mmol) was dissolved in DMF (10 ml) and cesium carbonate (2.15 g, 6.6 mmol) was added. After 15 min, iodomethane (0.20 ml, 3.3 mmol) was added, and the reaction was stirred at rt. After TLC showed the starting material to be consumed, the reaction was diluted with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4 and concentrated to a red foam. The crude material was purified through silica gel to give the title compound as a white solid (0.80 g. 78% over two steps). 1H NMR (300 MHz, d6-DMSO) δ 7.90 (d, J=6.3 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.38 (m, 4H), 7.25-7.29 (m, 2H), 6.17 (d, J=5.7 Hz, 1H), 3.78 (s, 3H), 3.41 (s, 3H), 1.41 (s, 9H). MS (ESI) m/z=465 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26](OCC)=[O:27]>CN(C=O)C>[CH:26]([NH:1][C:2]1[CH:3]=[C:4]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1)=[O:27]
Reactant: CCOC=O
Reactant: Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Solvent: CN(C)C=O
Product: O=CNc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 29 from (Z)-3-[1-(3-aminophenylamino)-1-phenyl-methylidene]-2-indolinone and ethyl formate in DMF.
Reaction SMILES: [I-].[CH2:2]([N+:9]1(C)[CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:20][CH3:21])=[C:14]([O:18][CH3:19])[CH:15]=2)[CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[CH3:19][O:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:20][CH3:21])[CH2:10][N:9]([CH3:2])[CH2:17]2
Reactant: COc1cc2c(cc1OC)C[N+](C)(Cc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Agent: [I-]
Solvent: CO
Product: COc1cc2c(cc1OC)CN(C)C2

Procedure:
1.0 g (2.43 mmol) of N-benzyl-5,6-dimethoxy-N-methylisoindolinium iodide was dissolved in 40 ml of a 50% methanol aqueous solution, and 300 mg of a 10% palladium carbon catalyst was added. Then, the catalytic reduction was conducted at 50° C. for 6 hours in a hydrogen gas stream. After filtering off the catalyst, methanol was distilled off under reduced pressure, and the residual solution was adjusted to strongly alkaline by an addition of a 50% sodium hydroxide aqueous solution. Then, the solution was extracted twice with methylene chloride. The extract solution was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 200 mg of the above identified compound.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O)(C)(C)C.[CH:13]1([N:19]=[C:20]=NC2CCCCC2)CCCC[CH2:14]1.CN(C1C=CC=CN=1)C.[NH2:37][C:38]1[N:47]=[C:46]([C:48]([N:50]2[CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH2:51]2)=[O:49])[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[S:65](N(CCO)C)(=[O:67])=[O:66])[CH:44]=2)[N:39]=1>C1COCC1>[NH2:8][CH2:9][C:10]([O:12][CH2:14][CH2:13][NH:19][CH2:20][S:65]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=1[C:43]1[CH:44]=[C:45]2[C:40](=[CH:41][CH:42]=1)[N:39]=[C:38]([NH2:37])[N:47]=[C:46]2[C:48]([N:50]1[CH2:51][C:52]2[C:57](=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:58]1)=[O:49])(=[O:66])=[O:67])=[O:11]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN(CCO)S(=O)(=O)c1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: NCC(=O)OCCNCS(=O)(=O)c1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Reaction time: 2 h

Procedure:
56 mg of tert-butoxycarbonylaminoacetic acid, 33 mg of N,N′-dicyclohexylcarbodiimide and 2 mg of dimethylaminopyridine (DMAP) are added to a solution of 80 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-N-(2-hydroxyethyl)-N-methylbenzenesulfonamide in 1 ml of THF. After 120 min, the mixture is evaporated in vacuo, the residue is taken up in 1 ml of DCM:TFA (1:1) with cooling, and the mixture is stirred for 30 min. The mixture is evaporated to dryness in vacuo, the residue is taken up in 500 μl of DMSO and purified by column chromatography on a reversed phase.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[C:2]#[CH:3].O.Cl([O-])=[O:14].[Na+]>C1COCC1>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([OH:14])=[O:9])=[CH:10][CH:11]=1)[C:2]#[CH:3]
Reactant: C#CCc1ccc(C=O)cc1
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 4-prop-2-ynyl-benzaldehyde (10 mmol) in THF (30 ml), amidosurfulic acid (16 mmol) and water (15 ml) solution of sodium chlorite (30 mmol) are added. The reaction mixture is stirred at room temperature for 2 h. Water is added and then aqueous layer is extracted with two 50 ml portions of CH2Cl2. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to give crude product which is purified by silica gel column chromatography. Yield: 62%. Rf=0.44 (n-hexane:AcOEt=7:3)