Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OCC)(=O)C.O>CN(C=O)C>[Br:13][C:7]1[C:8]([F:9])=[C:2]([F:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(F)c(F)c1Br
Reaction time: 8 h

Procedure:
2-Bromo-3,4-difluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell et al. (Mitchell, R. H. et al., J. Org. Chem. 44: 4733 (1979)). To a solution of 4,5-difluoro-2-nitroaniline (500 mg, 2.87 mmol) in DMF (25 mL) under N2 was added all at once N-bromosuccinimide (511 mg, 2.87 mmol) in dry DMF (16 mL). The reaction was allowed to stir overnight. TLC (1:1 hexanes:ethyl acetate) showed still some starting material present. Additional N-bromosuccinimide (100 mg) was added and the reaction stirred another 12 h. The solution was then poured into 100 ml H2O and the resulting cloudy suspension extracted with 3×20 mL methylene chloride. The combined organic phases were washed with 4×25 mL H2O and 25 mL saturated NaCl solution and dried (MgSO4). The MgSO4 was vacuum filtered and the solvent rotary evaporated to yield a yellow brown oil which slowly crystallized to yield 700 mg (96%). 1H NMR (CDCl3) δ 6.70 (br s, 2H, NH2), 7.99 (m, 1H, H-5).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1N.N([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].[C-:24]#[N:25].[K+]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].CCOCC>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:24]#[N:25]
Reactant: [C-]#N
Reactant: Cc1cc(C(F)(F)F)ccc1N
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C(F)(F)F)ccc1C#N
Temperature: 5 °C
Yield: 88.4 %

Procedure:
Concentrated hydrochloric acid (16 mL) was added dropwise at a moderate rate to a heterogeneous mixture of 2-methyl-4-(trifluoromethyl)benzenamine (14 g, 80 mmol) and 120 mL of water while stirring vigorously. A thick suspension resulted which was stirred for 20 minutes, diluted with 280 mL of water and cooled to 5° C. A solution of sodium nitrite (5.5 g, 80 mmol) and 25 mL of water was added slowly to the reaction suspension. After stirring for 30 minutes at 5° C. a solution resulted which was stirred cold for 30 more minutes and then neutralized with potassium carbonate. This diazonium salt solution was then added portionwise via cannula to a stirred, 95° C. mixture of potassium cyanide (22 g, 0.34 mole), copper sulfate pentahydrate (20 g, 80 mmol) and 140 mL of water. After the addition the mixture was stirred for 30 minutes at 95° C. and then allowed to cool to room temperature. Ether was added and the heterogeneous mixture was filtered through celite. The solids were washed with ether, and the filtrate was partitioned. The aqueous phase was extracted with ether, and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to afford 13.1 g of the title compound as brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[C:23]([O:27][CH3:28])=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)cccc12
Reactant: COc1cccc(F)c1B(O)O
Product: COc1cccc(F)c1-c1cccc2c(N)c(C(=O)NC3CCC3)nnc12
Yield: 19.3 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclobutyl-cinnoline-3-carboxamide (145 mg) and 2-fluoro-6-methoxy-phenyl boronic acid (191 mg) were reacted to afford the title compound (32 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, 1H), 8.44 (m, 1H), 7.76 (m, 2H), 7.44 (m, 1H), 6.99 (d, 1H), 6.90 (t, 1H), 4.49 (m, 1H), 3.65 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=367 (M+H).
Reaction SMILES: [CH2:1]([CH:9]([C:15](OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].IC[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28]>>[F:31][C:26]([F:32])([C:27]([F:28])([F:29])[F:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:15][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C=CCCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: FC(F)(F)C(F)(F)CCCCCI
Product: C=CCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with the diethyl 2-(7-octenyl)malonate prepared in Example 5 and the 1-iodo-6,6,7,7,7-pentafluoroheptane prepared in Example 3, the same procedure as shown in Example 5 was repeated to give ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-9-decenoate.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:37])([CH3:36])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](S(C)(=O)=O)[N:18]=3)=[C:10]2[CH:9]=1)([CH3:4])[CH3:3].[BH4-].[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)C>[CH3:4][C:2]([Si:5]([CH3:37])([CH3:36])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)=[C:10]2[CH:9]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccn2nc(-c3cccc([N+](=O)[O-])c3)c(-c3ccnc(S(C)(=O)=O)n3)c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccn2nc(-c3cccc([N+](=O)[O-])c3)c(-c3ccncn3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a solution of 5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-3-[2-(methylsulfonyl)-4-pyrimidinyl]-2-(3-nitrophenyl)pyrazolo[1,5-a]pyridine (3.00 g, 5.56 mmol) in DCM (90 mL) and ethanol (90 mL), NaBH4 (526 mg, 13.9 mmol) was added one portion at rt. The mixture was stirred at rt for 1 h. The reaction mixture was poured into aq. 1N NaOH and extracted with DCM. The organic layer was combined, washed with brine and dried (Na2SO4). The solvent was evaporated under reduced pressure. Chromatography on silica gel eluting with DCM/EtOAc gradient (0-20% EtOAc) gave a pale yellow solid (1.87 g).
Reaction SMILES: ClC1C=C2C(C([C:12](=[O:19])[C:13]3[S:17][CH:16]=[C:15]([CH3:18])[CH:14]=3)C(=O)N2)=NC=1.ClC1C=C2C([CH2:25][C:26](=[O:30])N2)=NC=1.CC1C=C(C(Cl)=O)SC=1.[O-]CC.[Na+].N1C2C(=CC=CC=2)NC1=O>C(O)C>[CH2:26]([O:30][C:12]([C:13]1[S:17][CH:16]=[C:15]([CH3:18])[CH:14]=1)=[O:19])[CH3:25]
Reactant: O=C1Cc2ncc(Cl)cc2N1
Reactant: Cc1csc(C(=O)C2C(=O)Nc3cc(Cl)cnc32)c1
Agent: CC[O-]
Agent: Cc1csc(C(=O)Cl)c1
Agent: O=c1[nH]c2ccccc2[nH]1
Solvent: CCO
Product: CCOC(=O)c1cc(C)cs1

Procedure:
6-Chloro-3-(4-methyl-2-thenoyl)-4-azaoxindole was first prepared according to a variation of the procedure of Example 2B, using 6-chloro-4-azaoxindole (1.3 g, 7.71 mmol) sodium (1.75 g, 49.7 mmol), 4-methylthiophene-2-carbonyl chloride (1.93 g, 12.0 mmol) and ethanol (40 mL). Ethyl-4-methylthiophene-2-carboxylate was prepared in situ by addition of the acid chloride to the sodium ethoxide solution. The azaoxindole was added and the reaction carried out as in Example 1B. Yield: 1.64 g (46%) m.p.>250°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](Cl)=O.ClCC(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH2:23][Cl:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: O=C(Cl)CCl
Agent: O=C(O)CCl
Solvent: CC(=O)O
Product: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 5, 7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine (31.9 g., 0.1 mole) was reacted with chloroacetyl chloride (11.3 g. 0.1 mole) the resulting chloroacetic acid, 2-(7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl)hydrozide was cyclized in hot acetic acid to give 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. The analytical sample had a melting point of 195°-198° C. with decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH:24]=[O:25])[CH:7]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][OH:25])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CO)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To [3-(2-formyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (1 equivalent) in methanol was added sodium borohydride (1.2 equivalents), and the reaction was stirred at room temperature for 15 minutes. The mixture was then concentrated and partitioned between EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cccc2c(Oc3cccc(C(F)(F)F)c3)nccc12
Yield: 374 %

Procedure:
To a solution of 1-chloro-5-nitroisoquinoline (Step-1, Intermediate-1, 200 mg, 0.96 mmol) in CH3CN (2 mL) were added 3-(trifluoromethyl)phenol (233 mg, 1.4 mmol) and K2CO3 (265 mg, 1.92 mmol). The reaction mass was heated at reflux for 5 h and it was diluted with water and extracted with chloroform. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 1.2 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.82 (d, J=8.4 Hz, 1H), 8.58 (d, J=7.8 Hz, 1H), 8.17 (s, 2H), 7.76 (t, J=8.4 Hz, 1H), 7.61-7.47 (m, 4H); MS (m/z): 335.12 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:25])[CH3:22]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCCO
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCCO)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 4-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamino]-pentan-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[F:39].N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([S:40]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:41])=[O:42])[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(F)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-chloro-4-fluorobenzene-1-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[Cl:32])=[O:9])=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39]>>[Cl:32][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:21]=2)=[O:19])=[CH:16][C:11]=1[NH:10][C:8]([C:5]1[CH:6]=[N:7][C:2]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:40])[CH3:33])=[CH:3][CH:4]=1)=[O:9]
Reactant: CN(C)CCCCN
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1)c1ccnc(N2CCOCC2)c1
Product: CN(C)CCCCNc1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2Cl)cn1
Yield: 61 %

Procedure:
Using an analogous procedure to that described in Example 21, 6-chloro-N-[2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide was reacted with 4-dimethylaminobutylamine to give the title compound in 61% yield; NMR Spectrum: (DMSOd6) 1.49 (m, 4H), 2.09 (s, 6H), 2.19 (t, 2H), 3.51 (m, 4H), 3.71 (m, 4H), 6.49 (d, 1H), 7.1 (d, 1H), 7.23 (m, 2H), 7.5 (d, 1H), 7.68 (d, 1H), 7.89 (d, 1H), 8.06 (s, 1H), 8.27 (d, 1H), 8.64 (s, 1H), 9.64 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M+H+ 552 and 554.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=5)[CH2:22][CH2:21]4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(I)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: COc1cccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-methoxybenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 482.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH3:20].[OH-].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:19][CH3:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a mixture of 5-chlorosalicylic acid (20.0 g, 116 mmol) and potassium carbonate (48.4 g, 350 mmol) in acetonitrile (300 ml) was added iodoethane (24.0 ml, 299 mmol). The mixture was heated under reflux for 24 hours. After cooling to room temperature, the mixture was filtered through a pad of celite under suction and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (100 ml), washed with aqueous sodium hydroxide solution (1 M, 2×100 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (200 ml) and a solution of sodium hydroxide (10.7 g, 268 mmol) in water (50 ml) was added. The mixture was heated under reflux for 90 minutes. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in water (100 ml) and the solution was washed with diethyl ether (2×50 ml). The solution was adjusted to pH 2 by the careful addition of concentrated hydrochloric acid. After 60 minutes, the solid was filtered and dried under reduced pressure to provide 5-chloro-2-ethoxybenzoic acid (20.4 g, 90% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])[CH:4]=[CH:3]1.[H-].[Na+].I[CH3:34]>CN(C)C=O.O>[CH3:34][N:7]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])=[CH:6]1
Reactant: O=C1N(Cc2ccc(=O)[nH]c2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a cooled (0° C.) solution of 1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.07 g, 0.17 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added sodium hydride (60% in mineral oil, 0.01 g, 0.25 mmol). The mixture was stirred at ambient temperature for 1 h, and iodomethane (0.02 mL, 0.27 mmol) was added. The mixture was stirred at ambient temperature for 16 h, diluted with water (15 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers was washed with brine (35 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 10% to 30% gradient of acetone in dichloromethane to afford 1′-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.03 g, 42%) as a colorless solid: mp 205-207° C.; 1H NMR (300 MHz, CDCl3) δ7.40-7.34 (m, 2H), 7.33-7.26 (m, 1H), 7.21-7.16 (m, 1H), 7.11-7.04 (m, 1H), 6.91-6.85 (m, 1H), 6.60-6.54 (m, 1H), 6.50 (s, 1H), 6.12 (s, 1H), 4.77 (ABq, J=75.6, 9.0 Hz, 2H), 4.66 (ABq, J=58.2, 15.3 Hz, 2H), 4.22-4.08 (m, 4H), 3.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.7, 162.5, 155.2, 144.7, 141.5, 139.6, 138.3, 137.4, 132.2, 128.9, 124.3, 123.8, 121.3, 120.7, 114.0, 111.2, 108.5, 99.5, 79.8, 64.5, 63.9, 57.9, 40.8, 37.9; MS (ES+) m/z 416.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[NH:13][C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH2:27]([N:34]([CH2:36][CH2:37]Cl)[CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:37][CH2:36][N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:35])[C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Reactant: CN(CCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Yield: 69.6 %

Procedure:
A mixture of 3.0 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.9 g of 2-(N-benzyl-N-methylamino)ethyl chloride.hydrochloride, 3.3 g of potassium carbonate and 80 ml of acetone is refluxed for 20 hours. Insoluble materials are removed by filtration, and the filtrate is evaporated under reduced pressure to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and evaporated to remove solvent. 2.9 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[N:16]=CN(C)C)=[O:8])CCCCC1.F[C:22](F)(F)[C:23](O)=O>O>[N:12]1([NH:1][C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[NH2:16])=[O:8])[CH2:23][CH2:22][CH2:15][CH2:10][CH2:11]1
Reactant: CN(C)C=Nc1ccncc1OC(=O)N1CCCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ccncc1OC(=O)NN1CCCCC1

Procedure:
A mixture prepared from 4-[[(dimethylamino)methylene]amino]-3-pyridinol 1-piperdine carboxylate (3.4 g), trifluoroacetic acid (11 mL) and water (6 mL) was refluxed for a half hour. The reaction mixture was concentrated, dissolved in saturated NaHCO3 (50 mL) and extracted three times with ethyl acetate (450 mL). The extract was dried (MgSO4), concentrated, and triturated with diethyl ether/pentane (1:2) to yield 2.27 g of solid. This was recrystallized from ethyl acetate and dried under high vacuum and refluxing acetone for 4 hours to yield 1.58 g of crystals, m.p. 134° C. (dec.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:32]([CH3:46])[CH2:33][CH2:34][N:35]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:35][CH2:34][CH2:33][CH:32]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH2:12][CH2:13]1)[CH3:46]
Reactant: Cc1cccc(OC(c2ccc(C#N)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: Cc1cccc(OC(c2ccc(C#N)cc2)C2CCN(C(C)CCN)CC2)n1
Yield: 44.8 %

Procedure:
Using general procedure C with the above carbamate (1.2 g, 2.95 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (1.2 g, 5.60 mmol) followed by general procedure D afforded 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-methyl-pyridin-2-yloxy)-methyl]-benzonitrile (500 mg, 40% over 4 steps) as a white foam.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:35])[NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:14]3[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19](COCC[Si](C)(C)C)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH:10]=[CH:11][CH:12]=1)#[N:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(OCC)(=O)C>[C:1]([CH2:3][NH:4][C:5](=[O:35])[NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:14]3[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:10]=[CH:11][CH:12]=1)#[N:2]
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(NC(=O)NCC#N)c3)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(NC(=O)NCC#N)c3)c12
Temperature: 45 °C

Procedure:
Ethyl 4-(3-(3-(cyanomethyl)ureido)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (65.4 mg, 0.132 mmol) was mixed with 1 M TBAF in THF (2.64 mL, 2.64 mmol) and heated at 45° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with 0-20% MeOH/DCM to give ethyl 4-(3-(3-(cyanomethyl)ureido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (EST) calc'd for C18H17N6O3 [M+H]+: 365, found 365. 1H NMR (600 MHz, DMSO-D6) δ 12.96 (bs, 1H), 9.08 (s, 1H), 8.89 (s, 1H), 8.29 (s, 1H), 7.76 (s, 1H), 7.54 (d, J=8.21 Hz, 1H), 7.35 (t, J=7.63 Hz, 1H), 7.20 (d, J=7.63 Hz, 1H), 6.71 (d, J=5.28 Hz, 1H), 4.13 (d, J=5.87 Hz, 2H), 3.86 (q, J=6.8 Hz, 2H), 0.84 (t, J=7.04 Hz, 3H).