Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:13]=3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[F:26][C:27]1[N:32]=[C:31]([N:33]([C:41]2[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[CH:29][C:28]=1[CH:48]=[O:49].O>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:13]=3[C:12]([CH:48]([OH:49])[C:28]3[CH:29]=[CH:30][C:31]([N:33]([C:41]4[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=4)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:32][C:27]=3[F:26])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2c(Cl)ncnc21
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cn1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(Cl)c34)c(F)n2)cn1
Temperature: -5 °C

Procedure:
To a solution of 7-(benzenesulfonyl)-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine (1, 0.43 g, 1.01 mmol) in Tetrahydrofuran (5 mL) at −30° C. under nitrogen was added 2.0 M Isopropylmagnesium Chloride in Tetrahydrofuran (0.5 ml) slowly. The reaction was allowed to warm to −5° C. in 75 minutes. Then, the reaction was cooled to −45° C., followed by adding tert-butyl N-(6-fluoro-5-formyl-2-pyridyl)-N-(6-methyl-3-pyridyl)carbamate (84, 0.24 g, 0.72 mmol) in THF (3.0 mL). The reaction was allowed to warm to room temperature in around 2 hours. The reaction was poured in to water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, purified with silica gel column chromatography eluting with 20%-100% ethyl acetate in hexane to give product (85, 0.41 g, 90.6%). MS (ESI) [M+H+]+=625.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([CH3:10])[CH2:5]1.[CH2:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[CH3:12]>>[CH2:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH:4]3[O:8][C:7](=[O:9])[N:6]([CH3:10])[CH2:5]3)[CH2:24][CH2:25]2)=[CH:18][CH:19]=1)[CH3:12]
Reactant: CN1CC(CCCl)OC1=O
Reactant: CCNc1ccc(N2CCNCC2)cc1
Product: CCNc1ccc(N2CCN(CCC3CN(C)C(=O)O3)CC2)cc1

Procedure:
Following the procedure of Example 2, the title compound is prepared from 5-(2-chloroethyl)-3-methyl-2-oxazolidinone and 1-(4-ethylaminophenyl)piperazine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=3)[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.4) (0.41 g, 1.5 mmol) and commercially available 3-bromo-benzene-boronic acid (0.33 g, 1.64 mmol) according to the general procedure IIb. Obtained as a light yellow solid (0.30 g, 51%). MS (ISP) 394.0 [(M+H)+]; mp 130° C.
Reaction SMILES: [CH:1]1([CH2:9][OH:10])[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[CH2:3][NH:2]1.CCN(C(C)C)C(C)C.[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:25]([CH:29]=1)[C:26](O)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:10][CH2:9][CH:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:26]([C:25]1[CH:29]=[C:21]([CH3:20])[CH:22]=[CH:23][C:24]=1[N:30]1[N:34]=[CH:33][CH:32]=[N:31]1)=[O:27]
Reactant: OCC1NCC2CCCC21
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CO)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the carbamate above in DCM was added TFA (1:1 v/v). The reaction was stirred at rt for 30 min before being concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with satd. aq. NaHCO3, brine, dried (MgSO4), and concentrated to afford (octahydrocyclopenta[c]pyrrol-1-yl)methanol as a pale yellow oil. To a solution of (octahydrocyclopenta[c]pyrrol-1-yl)methanol (1 equiv.) from the previous step in DMF was added DIPEA (2 equiv.) followed by 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (1.5 equiv.) and HATU (2 equiv.). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1 M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound as a clear oil. MS (ESI) 326 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].I[C:23]1[CH:24]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:26](=[O:29])[NH:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[N:8]=[CH:9][C:10]([C:23]2[CH:24]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:26](=[O:29])[NH:27][CH:28]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1cc(I)c[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2c[nH]c(=O)c(C(=O)OC)c2)cn1
Temperature: 25 °C

Procedure:
A solution of N-ethyl-N′-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea (Intermediate 1, 200 mg, 0.69 mmol), methyl 5-iodo-2-oxo-1,2-dihydro-3-pyridinecarboxylate (174 mg, 0.62 mmol), Tetrakispalladium (72.2 mg, 0.06 mmol), and cesium carbonate (224 mg, 0.69 mmol) in dioxane (4 mL) and water (1.000 mL) was heated to 100° C. in microwave for 1 h. The reaction mixture was filtered through Celite and washed with methanol. The resulting solution was concentrated under reduced pressure to give a yellow solid. The solid was triturated with acetone, then collected by filtration and added to hot acetone/water. The solution was cooled to room temperature, and the solid that formed was collected by filtration and placed under high vacuum to remove residual solvent (58 mg). MS (ESP): 317 (M+H+) for C15H16N4O4.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH2:10][CH2:11][CH:12]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[N:14]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:13]1=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F-].[K+].[Br-].[Br:41][CH:42]([CH2:49][CH3:50])[CH2:43][CH2:44][N+:45]([CH3:48])([CH3:47])[CH3:46]>C(#N)C>[Br-:41].[F:29][C:26]1[CH:25]=[CH:24][C:23]([N:14]2[C:13](=[O:30])[CH:12]([CH2:11][CH2:10][CH:9]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:15]2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:50][CH2:49][CH2:42][CH2:43][CH2:44][N+:45]([CH3:48])([CH3:47])[CH3:46])=[CH:18][CH:17]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(O)cc1)c1ccc(F)cc1
Reactant: CCC(Br)CC[N+](C)(C)C
Agent: [Br-]
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(OCCCCC[N+](C)(C)C)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
370 mg of 3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 3 ml of absolute acetonitrile. 300 mg of KF.alumina (1.15 mol/100 g) and 375 mg of (3-bromopentyl)-trimethylammonium bromide are then added. The reaction mixture is stirred at room temperature overnight and then filtered. The mother liquor is concentrated using a rotary evaporator and the residue is purified using a 5 g SiO2 cartridge (dichloromethane/methanol 4:1). The product is obtained as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:41]=[CH:40][C:15]([C:16]([NH:18][CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])=[O:17])=[CH:14][CH:13]=1)=[O:10].[CH3:42][NH:43][CH2:44][CH2:45][OH:46].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][NH:18][C:16](=[O:17])[C:15]3[CH:40]=[CH:41][C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]([CH2:44][CH2:45][OH:46])[CH3:42])=[CH:13][CH:14]=3)[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Reactant: CNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(NC(=O)CCCCCCCN(C)CCO)cc1
Temperature: 85 °C

Procedure:
4-[(8-Bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (100 mg, 0.16 mmol, e.g. which can optionally be as prepared in Intermediate 11) was dissolved in N,N-dimethylformamide (4 ml). To one-quarter of this solution, i.e. containing 4-[(8-bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (25 mg, 0.04 mmol) in N,N-dimethylformamide (1 ml), was added 2-(methylamino)ethanol (0.0064 ml (6.4 microliters), 0.08 mmol, 2 equivalents, commercially available e.g. from Aldrich) followed by N,N-diisopropylethylamine (0.04 ml, about 6 equivalents). The reaction mixture was heated at 85° C. for 16 hours. The solvent was evaporated and the residue was purified by eluting through a 5 g silica SPE cartridge, with dichloromethane containing 20% methanol and 1% triethylamine as the eluent, to give the title compound (18.7 mg), in the form of a cream foam, initially thought to be in the form of the “free base”. LCMS showed MH+=622; TRET=2.20 min. However, later re-inspection of the 1H NMR spectrum suggests that the product was isolated as a salt e.g. a mono-salt (presumed to be a hydrobromide salt), e.g. from the signals of protons adjacent to the (2-hydroxyethyl)(methyl)amino group.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:14]1.[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[N:14]1[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1c(N=C2NC3(CCCC3)CS2)ccc([N+](=O)[O-])c1C
Reactant: BrC1CCCC1
Product: Cc1c(N=C2SCC3(CCCC3)N2C2CCCC2)ccc([N+](=O)[O-])c1C

Procedure:
2,3-Dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, Step 1. The acetamide was converted to 2,3-dimethyl-4-nitroaniline, then deprotected according to Method A2a, Step 2. The aniline was converted to 2,-dimethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2,3dimethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2,3-dimethyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[C:28]([F:41])[CH:27]=2)[CH:19]=1.SCC(O)=O.O.[OH-].[Li+]>CN(C)C=O>[CH3:17][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[C:28]([F:41])[CH:27]=2)[CH:19]=1
Reactant: Cc1cc(OCCN2CCCC2=O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCN2CCCC2=O)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)OC(C)(C)C)c(F)c2)c1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of tert-butyl 3-(4-{({2′,6′-dimethyl-4′-[2-(2-oxopyrrolidin-1-yl)ethoxy]biphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate (0.91 g, 1.23 mmol) and mercaptoacetic acid (0.26 mL, 3.68 mmol) in N,N-dimethylformamide (9 mL) was added lithium hydroxide monohydrate (0.31 g, 7.38 mmol) under stirring at room temperature, and the mixture was stirred at the same temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and to the residue was added brine. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate-=5/1-ethyl acetate) to give the title compound (0.51 g, yield 74%) as a colorless amorphous powder.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:12]3[C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[S:15][C:11]=3[C:10](=[O:20])[N:9]([OH:21])[C:8]2=[O:22])=[CH:4][CH:3]=1.[C:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:12]4[C:13]5[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=5[S:15][C:11]=4[C:10](=[O:20])[N:9]([OH:21])[C:8]3=[O:22])=[CH:23][CH:24]=2)=[CH:30][CH:29]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: O=c1c2sc3ccccc3c2n(Cc2ccc(Br)cc2)c(=O)n1O
Product: CC(=O)c1ccc(-c2ccc(Cn3c(=O)n(O)c(=O)c4sc5ccccc5c43)cc2)cc1

Procedure:
1-(4-Bromo-benzyl)-3-hydroxy-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was treated with 4-acetylphenylboronic acid according to general procedure C. The title compound was obtained as a yellow solid following purification by preparative HPLC. 1H NMR (d6-DMSO, 300 MHz) δ 2.63 (s, 3H); 5.80 (s, 2H); 7.70-8.20 (m, 12H); Ret. time=2.89, m/z=441.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:28]=[C:29]([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)=[S:37])=[O:34]
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[CH:14](OCC)(OCC)OCC>FC(F)(F)C(O)=O>[CH3:14][NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: CCOC(OCC)OCC
Reactant: C=CCOC(=O)c1cccc(N)c1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)c1cccc(NC)c1
Yield: 17 %

Procedure:
Allyl 3-aminobenzoate (5 g, 28.2 mN) was dissolved in triethyl orthoformate (50 ml) and trifluoroacetic acid (5 drops) was added. The solution was stirred and refluxed up through 3a molecular sieves for 5 hours. Solvent was removed, and the residue dissolved in ethanol (50 ml), followed by the addition of acetic acid (8.08 ml) and sodium cyanoborohydride (6.85 g, 0.108 M) in several portions. The mixture was stirred at ambient temperature for 16 hours, and solvent removed. The residue was dissolved in diethyl ether, washed with water, brine, and dried over MgSO4. Crude product was purified by chromatography on silica, eluting with a gradient from dichloromethane to dichloromethane/ethyl acetate (95:5), to give allyl 3-methylaminobenzoate (0.93 g, 17%). Nmr (CDCl3): δ 2.88 (s, 3H); 4.81 (dt, 2H); 5.23-5.45 (m, 2H); 5.94-6.13 (m, 1H); 6.83 (dd, 1H); 7.25 (dd, 1H); 7.33 (t, 1H); 7.43 (dm, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[NH:19])([O-:18])=[O:17]
Reactant: NCCNCc1ncccn1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCNCc1ncccn1)N[N+](=O)[O-]

Procedure:
Reaction of N-(2-pyrimidylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-pyrimidylmethylamino)-ethyl]guanidine. Similarly, from the same starting material, according to the procedure of Example 2(iii), there is produced N-methyl-N'-nitro-N"-[2(2-pyrimidyl-methylamino)ethyl]guanidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.CN(C=O)C.Cl>O.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>[CH3:10][O:11][C:12](=[O:24])[CH:13]=[CH:14][C:15]1[CH:16]=[CH:17][C:18]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])=[CH:19][CH:20]=1
Reactant: COC(=O)/C=C/c1ccc(B(O)O)cc1
Reactant: Cc1cc(O)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(-c2ccc(O)cc2C)cc1
Temperature: 80 °C
Yield: 20 %

Procedure:
A mixture of 4-bromo-3-methyl-phenol (460 mg, 2.01 mmol), [4-(E-3-methoxy-3-oxo-1-propen-1-yl)phenyl]boronic acid (486 mg, 2.21 mmol), tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.201 mmol) cesium carbonate (1.31 g, 4.02 mmol) and DMF (4.8 mL) is heated to 80° C. for 4.5 hours. The reaction is cooled to room temperature and diluted with water and acidified with 1 N HCl. The resulting solution is extracted with ether. The combined organic layers are dried over anhydrous magnesium sulfate and are purified via flash chromatography eluting with 15% ethyl acetate/heptane to give the title compound (108 mg, 20%). ES/MS m/e 267.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:9](O)=[N:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6][C:5]=2[N:15]=1.O.P(Cl)(Cl)([Cl:19])=O>>[Cl:1][C:2]1[S:3][C:4]2[C:9]([Cl:19])=[N:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6][C:5]=2[N:15]=1
Reactant: Oc1nc(C(F)(F)F)nc2nc(Cl)sc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: FC(F)(F)c1nc(Cl)c2sc(Cl)nc2n1

Procedure:
To a solution of the compound (1.35 g) obtained in Step 7 in phosphorus oxychloride (20 ml) was added water (190 mg) with stirring under ice-cooling, and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and partitioned by adding chloroform and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10) to give the title compound (1.17 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: c1ccc(NC2CCCCC2)cc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Clc1ncc(Br)c(N(c2ccccc2)C2CCCCC2)n1
Temperature: 120 °C
Yield: 20.4 %

Procedure:
5-Bromo-2,4-dichloro-pyrimidine (2.17 ml, 17.14 mmol) and cyclohexyl-phenyl-amine (2.0 g, 11.43 mmol) were dissolved in N-methylpyrrolidone (NMP) (25 ml), and this reaction was heated to 120° C. for 24 hours. The reaction was cooled to room temperature and diluted with ethyl acetate, washed with water and brine. The organic phase was dried using sodium sulfate and concentrated. Purification by flash chromatography (ethyl acetate/hexane) gave compound 37 as a yellow solid (855 mg, 24%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.27 (1 H, s), 7.41 (3 H, m), 7.21 (2 H, m), 4.62 (1 H, m), 1.93 (2 H, d, J=10 Hz), 1.75 (2 H, d, J=10 Hz), 1.58 (1 H, d, J=10 Hz), 1.34 (2 H, m), 1.15 (2 H, m), 0.91 (1 H, m).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[N:3]=[S:4](Cl)([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[C:23]1([O:29][S:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)(=[N:3][Si:2]([CH3:1])([CH3:14])[CH3:15])=[O:5])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: C[Si](C)(C)N=S(=O)(Cl)c1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N=S(=O)(Oc1ccccc1)c1ccc(F)cc1
Yield: 15 %

Procedure:
The reactants used in the general procedure were sulfonimidoyl chloride (7c), triethylamine (0.0936 mol, 13.3 ml), phenol (0.0934 mol, 8.79 g). Boiling range of product: 125°-131° C./0.25 mm. Yield: 15%. 1H NMR signals (90 MHz, CH3CN): 0.24 (s, 9H), 6.83-7.57 (m, 7H), and 7.83-8.1 (m, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([O:15][C:16](=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCCCCCC(=O)NCCCCC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1I
Product: CCCCCCCc1nc2ccccc2n1CCCCC(=O)OC(C)(C)C
Yield: 21.5 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and 5-octanoylamino-pentanoic acid tert-butyl ester (180 mg, 0.6 mmol) yielded the title compound as yellowy oil (40 mg, 38%). 1H NMR (DMSO) δ 0.86 (t, J=6.8Hz, 3H), 1.22-1.86 (m, 23H), 2.27 (t, J=7.3, 2H), 3.14 (t, J=7.8Hz, 2H), 4.43 (t, J=7.2Hz), 7.49-7.54 (m, 2H), 7.77 (d, J=8.8Hz, 1H), 7.93 (d, J=8.8Hz).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Reactant: NNc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and phenylhydrazine according to the method described for example 43. MS: M=393.1 (M+H)+