Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])(C1C=CC(C)=CC=1)(=O)=O.[S-:21][C:22]#[N:23].[K+]>CN(C)C=O>[S:21]([CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14][S:15]([NH2:18])(=[O:16])=[O:17])[C:22]#[N:23]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)CS(N)(=O)=O)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CSC#N)CS(N)(=O)=O
Yield: 21.7 %

Procedure:
A solution of 6.2 g of 3-tosyloxy-2,2-dimethyl-1-propanesulfonamide and 3.75 g of potassium thiocyanate in 30 ml of dimethylformamide was stirred at 130°-140° C. for 6 hours, and then concentrated to dryness. A mixture of dichloromethane and methanol (9:1)was added to the residue, followed by filtration to remove insoluble material. The filtrate was concentrated and the residue was subjected to a column chromatography, eluting with chloroform-ethyl acetate (2:1). The relevant fractions were concentrated to obtain 0.87 g of 3-thiocyanato-2,2-dimethyl-1-propanesulfonamide as yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:38]=[N+:39]=[N-:40].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]4[NH:40][N:39]=[N:38][N:24]=4)=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:9]1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(OCC#N)cc3)cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(OCc4nnn[nH]4)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1-benzyl-3-pentyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.252 g, 0.520 mmol) was reacted with NaN3 (0.169 g, 2.6 mmol) and NH4Cl (0.139 g, 2.6 mmol) in DMF (5 ml) to give the product (0.137 g, 0.260 mmol, 50%) as a white solid, mp 165-168° C. 1H NMR (DMSO-d6) δ 0.76 (t, J=7.0 Hz, 3H), 1.15-1.22 (m, 4H), 1.53-1.59 (m, 2H), 2.68 (t, J=7.5 Hz, 2H), 5.27 (s, 2H), 5.52 (s, 2H), 6.83 (d, J=7.2 Hz, 2H), 7.13-7.16 (m, 3H), 7.20 (t, J=6.9 Hz, 2H), 7.34-7.38 (m, 4H), 7.43 (t, J=7.0 Hz, 1H), 7.48 (t, J=6.9 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.77 (S; 1H), 16.79 (broad s, 1H); IR (solid) 3030, 2920, 2850, 1605, 1520, 1480, 1260 and 1240 cm−1; [ESI(−)], m/z 527 (M−H)−; Anal. Calcd. for C34H33N5O: C, 77.39; H, 6.30; N, 13.27; Found: C, 77.34; H, 6.33; N, 13.30.
Reaction SMILES: [CH3:1][S-:2].[Na+].O1CCCC1.[CH:9]([O:12][N:13]=[C:14]([N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)[C:15](=[N:21][O:22][CH:23]([CH3:25])[CH3:24])N1C=NC=N1)([CH3:11])[CH3:10]>O>[CH3:1][S:2][C:15](=[N:21][O:22][CH:23]([CH3:25])[CH3:24])[C:14]([N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)=[N:13][O:12][CH:9]([CH3:11])[CH3:10]
Reactant: C[S-]
Reactant: CC(C)ON=C(C(=NOC(C)C)n1cncn1)n1cncn1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSC(=NOC(C)C)C(=NOC(C)C)n1cncn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
Sodium thiomethoxide was added to 5 ml of a tetrahydrofuran solution (which was under heating and refluxing) containing 0.35 g (1.14 mmol) of the 1,2-diisopropoxyimino-1,2-bis(1H-1,2,4-triazol-1-yl)ethane produced in Example 6, with confirming a reaction by thin-layer chromatography. Then, stirring was conducted for 5 hours. The reaction mixture was cooled to room temperature and poured into water, followed by extraction with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elutant:ethyl acetate/hexane=1/2) to obtain 0.17 g (yield: 52%) of a title compound.
Reaction SMILES: C(OC1C=C2C(=CC=1)NC=C2CC[N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])C1C=CC=CC=1.C([Si](OS(C(F)(F)F)(=O)=O)(C(C)C)C(C)C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[C:21]1(=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28](=[O:29])[NH:20]1
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine a mixture of an oil dispersion of KH (40%, 1 g) in 30 mL anhydrous THF and a suspension of 2-(2-(5-benzyloxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione (1.2 g, 3 mmol) in 30 mL THF portionwise. Stir for 1 hour at ambient temperature, cooled to 0° C., add triisopropylsilyltrifluoromethanesulfonate (1.85 g, 6 mmol) and stir an additional 1 hour at ambient temperature. Pour the reaction into a rapidly stirring solution of saturated NaHCO3 and extract with 2×50 mL EtOAc. Combine the organic layer, day over MgSO4 and concentrate to dryness and chromatograph on silica get eluting with 1% MeOH in CHCl3 to give 2-(2-5-benzyloxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione as an oil.
Reaction SMILES: [C:1]([S@:5]([N:7]=[C:8]([C:10]1[N:15]=[C:14]2[CH:16]=[CH:17][N:18](C(OC(C)(C)C)=O)[C:13]2=[CH:12][CH:11]=1)[CH3:9])=[O:6])([CH3:4])([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[NH:18]1[C:13]2[C:14](=[N:15][C:10]([C@@H:8]([NH:7][S@@:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[O:6])[CH3:9])=[CH:11][CH:12]=2)[CH:16]=[CH:17]1
Reactant: CC(=N[S@](=O)C(C)(C)C)c1ccc2c(ccn2C(=O)OC(C)(C)C)n1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](N[S@](=O)C(C)(C)C)c1ccc2[nH]ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a solution of (R)-tert-butyl 5-(1-(tert-butylsulfinylimino)ethyl)-1H-pyrrolo[3,2-b]-pyridine-1-carboxylate (1.18 g, 3.25 mmol) in anhydrous THF (21.1 mL) at 0° C. was added dropwise L-selectride (1.0 mol/L) in THF (4.9 mL). The resultant orange reaction mixture was warmed to RT and stirred under N2 for 3 h. The solvent was removed in vacuo, and the crude product was purified by SiO2 chromatography eluting with MeOH/EtOAc+1% TEA to afford 700 mg (81.3%) of (R)—N—((S)-1-(1H-pyrrolo[3,2-b]-pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide as a foam (95% ee). The enantiomers were separated via chiral SFC chromatography to give 597.0 mg (100% ee) of (R)—N—((S)-1-(1H-pyrrolo[3,2-b]-pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide: 1H NMR (400 MHz, MeOD) δ 7.79 (d, J=8.5 Hz, 1H), 7.55 (d, J=3.3 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.58 (d, J=3.1 Hz, 1H), 4.73-4.66 (m, 1H), 1.63 (d, J=6.9 Hz, 3H), 1.19 (s, 9H); MS (ESI) m/z: 266.3 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:15][C:8]2=[CH:9][N:10]=[C:11]([O:13][CH3:14])[CH:12]=[C:7]2[C:6]=1[C:16]1[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:4].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:15]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[F:24])[C:8]2=[CH:9][N:10]=[C:11]([O:13][CH3:14])[CH:12]=[C:7]2[C:6]=1[C:16]1[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:4]
Reactant: Fc1ccccc1CCl
Reactant: COC(=O)c1[nH]c2cnc(OC)cc2c1-c1cccnc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2cccnc2OC)c2cc(OC)ncc2n1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.5 %

Procedure:
5-methoxy-3-(2-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid methyl ester C4 (0.07 g, 0.22 mmol) was diluted with DMF (2 mL) and to the resulting solution was added 2-fluorobenzyl chloride (0.048 g, 0.33 mmol) and cesium carbonate (0.107 g, 0.33 mmol). The resulting suspension was allowed to stir at room temperature for 24 hours, then ethyl acetate (50 mL) and water (20 mL) were added to the reaction mixture and the layers were separated. The organic layer was sequentially washed with aqueous saturated sodium bicarbonate solution (10 mL), water (10 mL) and saturated brine (10 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo to provide a crude residue which was purified using flash chromatography to provide 1-(2-Fluoro-benzyl)-5-methoxy-3-(2-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid methyl ester C5 (0.07 g, 75%) MS: 422.20 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:8][C:5]2=[N+:6]([O-:29])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ncc(F)cc32)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2cc(F)c[n+]3[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.1 %

Procedure:
To a solution of 6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridine (18 g, 62 mmol) in DCM (300 mL) was added MCPBA (16 g, 93 mmol). The mixture was stirred at RT overnight and then concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with DCM:MeOH (30:1) to afford 23 g (100%) of 6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridine 4-oxide as a solid. MS (ESI) m/z: 307.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH:11]=[O:12])[CH:3]=1.[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][OH:12])[CH:3]=1
Reactant: O=Cc1cc(Cl)c2c(c1)OCO2
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCc1cc(Cl)c2c(c1)OCO2
Reaction time: 0.5 h

Procedure:
To a solution of 7-chlorobenzo[d][1,3]dioxole-5-carbaldehyde (6.0 g, 33 mmol) in THF (50 mL) was added NaBH4 (2.5 g, 64 mmol)) in portion at 0° C. The mixture was stirred at this temperature for 30 min and then poured into aqueous NH4Cl solution. The organic layer was separated, and the aqueous phase was extracted with EtOAc (50 mL×3). The combined extracts were dried over Na2SO4 and evaporated under reduced pressure to afford (7-chlorobenzo[d][1,3]dioxol-5-yl)methanol, which was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:31][CH2:32][CH2:33][CH2:34]Br>C(#N)C>[Br:31][CH2:32][CH2:33][CH2:34][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1
Reactant: BrCCCBr
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(-c2cc(NCCCBr)c3cc(OC)ccc3c2)n1
Temperature: 65 °C
Reaction time: 10 h

Procedure:
A mixture of 4-(4-amino-6-methoxy-2-naphthyl)-N-methylpyrimidin-2-amine (33), synthesized according to General Procedure B Steps 1-3 (1.00 g, 3.2 mmol) and acetonitrile (10 mL) was treated with N,N-diisopropylethylamine (1.2 mL, 7.1 mmol) followed by 1,3-dibromopropane (7.3 mL, 71.4 mmol). The resulting mixture was stirred at 65° C. for 10 h. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated (rotary). The crude compound was purified by column chromatography (silica gel) using 75% ethyl acetate/hexanes as the eluent to afford 4-(4-((3-bromopropyl)amino)-6-methoxynaphthalen-2-yl)-N-methylpyrimidin-2-amine (189) (0.55 g). LC/MS (m/z): 402 [M+H]
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][NH:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][N:25]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:24]1
Reactant: CC1CNCC1CN
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC1CN
Temperature: 25 °C
Reaction time: 7 h
Yield: 33 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.6 g), anhydrous acetonitrile (5 ml), 3-aminomethyl-4-methylpyrrolidine (0.27 g) and 1,8-diazabicyclo[5,4,0]-7-undecene (DBU; 0.3 g) was refluxed for an hour and then stirred at room temperature for 7 hours. The resulting precipitate was collected by filtration and recrystallized from chloroform-methanol-concentrated aqueous ammonia (10:10:1) to give the title compound (0.26 g) as colorless prisms, mp 235°-238° C.
Reaction SMILES: [CH2:1]([CH:4]1[NH:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([NH2:16])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C([C@@H]1N[C@@H](C2C=CC=CC=2)[C@@H](N)CC1)CC.C([C@H]1N[C@H](C2C=CC=CC=2)[C@H](N)CC1)CC.[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[CH:61]=O)[N:57]([CH3:63])[C:56](=[O:64])[CH2:55][CH2:54]2>>[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[CH2:61][NH:16][CH:7]1[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[NH:9][CH:8]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[N:57]([CH3:63])[C:56](=[O:64])[CH2:55][CH2:54]2
Reactant: CCCC1CCC(N)C(c2ccccc2)N1
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)CC2
Agent: CCC[C@@H]1CC[C@@H](N)[C@@H](c2ccccc2)N1
Agent: CCC[C@H]1CC[C@H](N)[C@H](c2ccccc2)N1
Product: CCCC1CCC(NCc2cc3c(cc2OC)CCC(=O)N3C)C(c2ccccc2)N1

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-propyl-2-phenyl-piperidin-3-ylamine [or (2S,3S,6S)-6-propyl-2-phenyl-piperidin-3-ylamine or (2R,3R,6R)-6-propyl-2-phenyl-piperidin-3-ylamine] with 6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:29]([O-])=O)=[CH:4][C:5]([O:26][CH2:27][CH3:28])=[C:6]([CH:25]=1)[C:7]([NH:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12]1)=[O:8].C(O)C>C(OCC)(=O)C>[NH2:29][C:3]1[C:2]([Cl:1])=[CH:25][C:6]([C:7]([NH:9][CH2:10][CH:11]2[O:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:12]2)=[O:8])=[C:5]([O:26][CH2:27][CH3:28])[CH:4]=1
Reactant: CCOc1cc([N+](=O)[O-])c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: 70 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
Stannous chloride dihydrate (5.4 g) is added to a stirred mixture of 5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-4-nitrobenzamide (2.2 g), ethanol (30 ml), and ethyl acetate (30 ml). The reaction mixture is stirred at 70° C. for 2 hours and concentrated. The residue is basified with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue is recrystallized from ethanol to give the title compound (1.1 g), mp 151°-153° C.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([NH2:14])[CH3:13]>>[CH2:12]([NH:14][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH3:13]
Reactant: CCN
Reactant: O=C(O)c1ccc(I)cc1F
Product: CCNc1cc(I)ccc1C(=O)O
Temperature: 125 °C
Reaction time: 24 h

Procedure:
3.5 g (13.16 mmol) of 2-fluoro-4-iodobenzoic acid were mixed to a 16.11 ml solution of ethylamine (70% in water) in a sealed tube. The reaction vessel was heated and stirred at 125° C. during 24 hours. Nitrogen was bubbled through the reaction mixture to eliminate the excess of ethylamine. The reaction mixture was than poured into an iced water solution and the mixture acidified to pH=3-4 with acetic acid. The resulting white solid was then filtered off, washed with water and dried to give 2.2 g (7.55 mmol).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:25])(=[N:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:18])[CH:12]=2)=[CH:5][C:4]=1[N:26]=[CH:27][N:28](C)[CH3:29])#N.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.ClCCl.CO>CO>[CH2:23]([O:22][C:20]([N:19]=[S:17]([CH3:25])([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][NH:9][C:6]2[CH:5]=[C:4]3[C:3]([C:29]([NH:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[N:28][CH:27]=[N:26]3)=[CH:8][CH:7]=2)[CH:12]=1)=[O:18])=[O:21])[CH3:24]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(CNc2ccc(C#N)c(N=CN(C)C)c2)c1
Reactant: Nc1cccnc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1cccc(CNc2ccc3c(Nc4cccnc4)ncnc3c2)c1
Yield: 68 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylamino}phenyl)-N,N-dimethylformimidamide (50 mg, 0.12 mmol) with 3-aminopyridine (14 mg, 0.14 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 68% yield (38 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1>N1C=CC=CC=1.Cl>[Br:8][C:9]1[CH:10]=[C:11]([S:15]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CCN(S(=O)(=O)c2cccc(Br)c2)CC1

Procedure:
A solution of 1-methylpiperazine (0.072 ml, 0.65 mmol) and 3-bromobenzene-1-sulfonyl chloride (0.2 g, 0.78 mmol) in pyridine (3 ml) is stirred at room temperature for 2 hours. The reaction mixture is diluted with 2M HCl, and extracted with DCM. The aqueous layer is made basic with 2M NaOH, and is extracted with DCM. The DCM layers are combined, dried (MgSO4) and the solvent removed in vacuo to afford the title compound as an orange oil. [M+H]+ 345.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[CH:21]=[CH:20][C:19]4[C:18]([NH2:22])=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]=3)[C:4]=2[O:3]1.[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>>[CH3:23][N:24]([CH3:29])[S:25]([NH:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[CH:21][C:12]([NH:11][C:10]1[C:4]3[O:3][CH:2]([CH3:1])[CH2:6][C:5]=3[CH:7]=[CH:8][CH:9]=1)=[N:13]2)(=[O:27])=[O:26]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC1Cc2cccc(Nc3ccc4c(N)cccc4n3)c2O1
Product: CC1Cc2cccc(Nc3ccc4c(NS(=O)(=O)N(C)C)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=399.1 (M+H+), was prepared in accordance with the general method of example 19 from N2-(2-methyl-2,3-dihydro-benzofuran-7-yl)-quinoline-2,5-diamine and dimethylsulfamoyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[OH:14])(=O)[CH3:2].C(O)(=O)C>CO.[C].[Pd]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[OH:14])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1ccc(NC(C)=O)cc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.8 %

Procedure:
To a solution of N-(4-acetyl-3-hydroxyphenyl)acetamide (4.0 g, 20.7 mmol) in methanol (50 mL)/acetic acid (50 mL) was added 10% palladium-carbon powder (2.0 g), and the mixture was stirred at room temperature for 6 hr under a hydrogen atmosphere of 2.8 pressure. 10% Palladium-carbon powder was filtered off by celite filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was washed with diisopropyl ether/hexane (1:1) to give the title compound (3.07 g, 83%) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1([CH3:21])[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[Na+].[K+].[Br-]>CN(C=O)C.O>[CH3:21][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 18 h

Procedure:
4-Nitrobenzyl chloride (5.0 g, 29.1 mmole) and sodium p-toluenesulfinate (6.8 g, 37.9 mmole) were dissolved in 50 mL of dry DMF. The mixture was stirred at about 23° for about 18 hours then diluted with water. The sulfone crystallized from the aqueous mixture and was filtered. The sulfone was purified by recrystallization from ethanol to give a pale yellow crystalline solid, mp 188°-190° (7.6 g, 25.9 mmole, 89%): IR (KBr) 2994, 1598, 1514, 1490, 1342, 1312, 1304, 1148, 824 cm-1 ; 1H NMR (CDCl3) δ 2.44 (s, 3H), 4.38 (s, 2H), 7.27 (m, 4H), 7.53 (d, J=8.3 Hz, 2H), 8.13 (d, J=8.3 Hz, 2H); MS m/e 292 (MH+).
Reaction SMILES: [C:1]([C:9]1([CH3:12])[CH2:11][O:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14]([CH3:16])=[O:15].B(F)(F)F.CCOCC.[OH-].[Na+]>O>[C:1]([C:9]1([CH3:12])[CH2:11][O:10][C:14]([CH3:16])([CH3:13])[O:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C(=O)c2ccccc2)CO1
Reactant: CC(C)=O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC1(C)OCC(C)(C(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
16.2 g (0.1 mol) of 2-benzoyl-2-methyloxirane (see Example 1) are dissolved in 35 g (0.6 mol) of acetone, and a solution of 1.42 g (0.01 mol) of boron trifluoride-etherate in 35 g (0.6 mol) of acetone is then added dropwise while the mixture is cooled by means of an ice bath. The mixture is then stirred for 2 hours at room temperature and is then heated under reflux for 5 hours. The reaction solution is cooled, rendered alkaline, with cooling, by means of 50 ml of saturated methanolic sodium hydroxide solution, and diluted with 200 ml of water. The product is extracted with ether. The ether solution is dried with potassium carbonate and concentrated. The residue is distilled in vacuo at 95° C. and 0.5° mbar. The distillate is purified by mediumpressure chromatography, a colourless oil being obtained.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:27]([CH3:29])[CH3:28].C(Cl)Cl.CCOCC.CO>CN(C)C=O>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:27]([CH3:29])[CH3:28])=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[N:3]=1
Reactant: Cc1ccc(CNc2nc(F)nc3[nH]cnc23)cn1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(CNc2nc(F)nc3c2ncn3C(C)C)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2-fluoro-N-(6-methylpyridin-3-yl)methyl-9H-purin-6-amine (0.3 g, 1.17 mmol) in dimethylformamide (10 ml) at room temperature under an argon atmosphere, was added powdered, anhydrous K2CO3 (0.8 g, 5 eq, 5.85 mmol), followed by 2-bromopropane (1.15 ml, 11.7 mmol). The reaction mixture was stirred at room temperature for 24 h, when DCM:ether:MeOH (55:40:5), indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between EtOAc (100 ml) and water (100 ml). The aqueous phase was extracted with more EtOAc (2×50 ml) and the combined organic phase washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel flash column chromatography, eluted with CHCl3:MeOH (98:2) to afford the title compound as a slightly yellow film (195 mg, 55%). δH (CDCl3, 250 MHz) 1.52 (6 H, d, J 7.5, CH[CH3]2), 2.5 (3 H, s, CH3), 4.76-4.6 (3 H, m, NHCH2 and CHMe2), 7.06 (1 H, d, J 2.5, ArH), 7.35 (1 H, s, br, NH), 7.56 (2 H, s, br, ArH), 8.47 (1 H, s, br, ArH); δC (CDCl3, 250 MHz) 157.6 (C), 156.32 (C), 156 (C), 148.47 (CH), 137.72 (CH), 136.08 (CH), 130.83 (C), 123.11 (CH), 118.2 (C), 47.38 (CH), 43.2 (CH2), 23.99 (CH3), 22.5 (2×CH3); m/z 301.2 (M+H)