Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[CH2:13][CH2:12][C:11](=S)[NH:10][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]1=[O:24].C(O)CCC.[N:39]1([CH2:45][CH2:46][C:47]([NH:49][NH2:50])=O)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[F:30][C:28]([F:31])([F:29])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:32])[F:1])[CH:27]=1)[CH2:6][N:7]1[CH2:13][CH2:12][C:11]2[N:10]([C:47]([CH2:46][CH2:45][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[N:49][N:50]=2)[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]1=[O:24]
Reactant: O=C1C(Cc2ccc(Cl)c(Cl)c2)NC(=S)CCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NNC(=O)CCN1CCOCC1
Solvent: CCCCO
Product: O=C1C(Cc2ccc(Cl)c(Cl)c2)n2c(CCN3CCOCC3)nnc2CCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 106 mg (0.2 mmol) (RS)-1-(3,5-bis-trifluoromethyl-benzyl)-3-(3,4-dichloro-benzyl)-5-thioxo-[1,4]diazepan-2-one in 1 ml of butan-1-ol 42 mg (0.24 mmol) of 3-morpholin-4-yl-propionic acid hydrazide was added. The reaction mixture was stirred at 130° C. overnight. After evaporation of the solvent in vacuum water (5 ml) was added and the mixture was extracted three times with ethyl acetate. The combined organic layers are dried (MgSO4) and concentrated. The residue was purified by column chromatography (SiO2, dichloromethane/methanol=95:5) to yield 77 mg (59.2%) of the title compound as a light yellow solid. MS m/e (%): 650.0 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:11]([O-])=O.[Na+].[OH-].[NH4+]>C(O)(=O)C.S(=O)(=O)(O)O.Cl>[Cl:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:11]
Reactant: CCc1ccc(N)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCc1ccc(NN)c(Cl)c1
Yield: 60.4 %

Procedure:
2-Chloro-4-ethylaniline [14.5 g; described by K. Altau, J. Chem. Eng. Data, 8, 122 (1963)] was dissolved, with stirring, in glacial acetic acid (113 ml). A solution of sodium nitrite (7.0 g) in concentrated sulphuric acid (55 ml) was then added at 55°-60° C. The solution thus obtained was cooled to 0°-5° C. and a solution of stannous chloride (70 g) in concentrated hydrochloric acid (80 ml) was added with vigorous stirring. A cream-coloured solid precipitated. The mixture was filtered and the solid obtained was added to a mixture of aqueous ammonium hydroxide solution and ice. The mixture thus obtained was extracted with diethyl ether (4×300 ml) and the combined ethereal extracts were dried over sodium sulphate, filtered and evaporated to dryness, to give 2-chloro-4-ethylphenylhydrazine (9.6 g), m.p. 55°-57° C., in the form of a cream-coloured solid.
Reaction SMILES: IC1N(S(C2C=CC(C)=CC=2)(=O)=O)C2N=CC=C(C#N)C=2C=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[N:44](S(C2C=CC(C)=CC=2)(=O)=O)[C:37]2[N:38]=[CH:39][CH:40]=[C:41]([C:42]#[N:43])[C:36]=2[CH:35]=1>C(OCC)(=O)C.CCCCCCC>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[NH:44][C:37]2[N:38]=[CH:39][CH:40]=[C:41]([C:42]#[N:43])[C:36]=2[CH:35]=1
Reactant: COc1ccc2[nH]cc(-c3cc4c(C#N)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Agent: Cc1ccc(S(=O)(=O)n2c(I)cc3c(C#N)ccnc32)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]cc(-c3cc4c(C#N)ccnc4[nH]3)c2c1

Procedure:
By proceeding in a similar manner to Reference Example 12(a) but using 2-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile [Reference Example 62(a)] there was prepared the title compound as a yellow solid, m.p. 303-304° C., TLC RF=0.07 (ethyl acetate/heptane 1:1) and 2-(5-methoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile [Reference Example 100] as a brown oil. MS: 443 (MH+). TLC: RF=0.38 (ethyl acetate/heptane 1:1).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][C:7]([NH:9][CH:10]1[C:20]2[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=2[C:18]2[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:28][CH3:29])[C:17]=2[O:26][CH3:27])[CH2:12][CH2:11]1)=[O:8].O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[S:2]([OH:5])([O:25][C:22]1[CH:23]=[CH:24][C:19]2[C:18]3[C:17]([O:26][CH3:27])=[C:16]([O:28][CH3:29])[C:15]([O:30][CH3:31])=[CH:14][C:13]=3[CH2:12][CH2:11][C@H:10]([NH:9][C:7](=[O:8])[CH3:6])[C:20]=2[CH:21]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OS(=O)(=O)O)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Chlorosulphonic acid (1 ml) was added at 0° C. in portions to a solution of pyridine (10 ml). After 15 minutes at 0° C., a solution of N-acetyl-colchicinol (1 g, 2.8 mmol) in pyridine (10 ml) was added. The solution was stirred overnight at ambient temperature. Water (30 ml) was added and the mixture was adjusted to pH8 by addition of sodium hydrogen carbonate. The aqueous layer was extracted with ether (3×20 ml) and purified on HP20SS resin, eluted with a 0–40% gradient of methanol/water. The volatiles were removed by evaporation to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl hydrogen sulphate as a white solid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5]1([N:11]2[C:15]([CH3:17])([CH3:16])[CH2:14][NH:13][C:12]2=[O:18])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.N1C=CC=CC=1>C(Cl)Cl>[CH:5]1([N:11]2[C:15]([CH3:16])([CH3:17])[CH2:14][N:13]([C:1]([Cl:4])=[O:2])[C:12]2=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(Cl)Cl
Reactant: CC1(C)CNC(=O)N1C1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CN(C(=O)Cl)C(=O)N1C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A 0° C. solution of phosgene (15% in toluene, 1.854 mL, 2.60 mmol) in DCM (10 mL) was treated drop-wise with a solution of 1-cyclohexyl-5,5-dimethylimidazolidin-2-one (0.34 g, 1.732 mmol) and pyridine (0.28 mL) in DCM (5 mL), stirred at 0° C. for 0.5 h, then concentrated to dryness to afford crude 3-cyclohexyl-4,4-dimethyl-2-oxoimidazolidine-1-carbonyl chloride (0.45 g, 100%) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[Li]CCCC.[CH3:25][N:26]([CH3:44])[S:27]([N:30]1[C:34]([CH:35]=[O:36])=[CH:33][N:32]=[C:31]1[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=[O:29])=[O:28]>C1COCC1>[CH3:25][N:26]([CH3:44])[S:27]([N:30]1[C:34]([CH:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[S:8][CH2:7][CH2:6][CH:5]3[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[OH:36])=[CH:33][N:32]=[C:31]1[Si:37]([C:40]([CH3:42])([CH3:41])[CH3:43])([CH3:39])[CH3:38])(=[O:28])=[O:29]
Reactant: CC(C)(C)[Si](C)(C)OC1CCSc2ccc(Br)cc21
Reactant: CN(C)S(=O)(=O)n1c(C=O)cnc1[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c(C(O)c2ccc3c(c2)C(O[Si](C)(C)C(C)(C)C)CCS3)cnc1[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of (6-bromo-thiochroman-4-yl-oxy)-tert-butyl-dimethyl-silane (Intermediate-K3) (2.74 g, 7.64 mmol) in THF (30 mL) was treated with nBuLi (3.1 mL of a 2.5 M soln) at −78° C. for 30 m. A solution of 2-(tert-butyl-dimethyl-silanyl)-5-formyl-imidazole-1-sulfonic acid dimethylamide (see the General Method above, Intermediate K1) (2.42 g, 7.63 mmol) in THF (10 mL) was added via cannula. After 15 m, the reaction mixture was allowed to warm to rt for 16 h. The mixture was quenched with water, washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by chromatography on silica gel with 20% EtOAc:hexane to afford 2-(tert-butyl-dimethyl-silanyl)-5-{[4-(tert-butyl-dimethyl-silanyloxy)-thiochroman-6-yl]-hydroxy-methyl}-imidazole-1-sulfonic acid dimethylamide (Intermediate K4) as an oil, 4.12 g.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([C:31](OCC)=[O:32])[N:23]=[C:22]2[CH2:36][CH2:37][CH3:38])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][OH:32])[N:23]=[C:22]2[CH2:36][CH2:37][CH3:38])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCCc1nc(CO)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 71.5 %

Procedure:
Following a procedure similar to that described in Example 1(b), 16.47 g of diethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-propylimidazole-4,5-dicarboxylate [prepared as described in step (a) above] were reduced, using 44.4 ml of a 1.5M solution of diisobutylaluminum hydride in tetrahydrofuran, to afford 10.83 g of the title compound as crystals, melting at 108°-110° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]=1[NH2:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:34]([O:36][CH2:37][C:38](Cl)=[O:39])[CH3:35]>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]=1[NH:26][C:38](=[O:39])[CH2:37][O:36][CH2:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NCCOCc2ccccc2)c(N)c(Oc2ccccc2)n1
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1c(NCCOCc2ccccc2)cc(C)nc1Oc1ccccc1
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
Under a nitrogen atmosphere, a solution of N4-[2-(benzyloxy)ethyl]-6-methyl-2-phenoxypyridine-3,4-diamine (3.80 g, 10.9 mmol), anhydrous dichloromethane (75 mL), and anhydrous triethylamine (1.8 mL, 13 mmol) was cooled to 5° C. Ethoxyacetyl chloride (1.40 g, 11.4 mmol) was then added over a period of 30 seconds, and the reaction was stirred for 20 minutes. The reaction mixture was washed with aqueous sodium bicarbonate (3×), and the combined aqueous washings were extracted with chloroform (3×). The combined organic solutions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a white powder. The powder was dried for three days under vacuum at room temperature to provide 4.01 g of N-{4-[2-(benzyloxy)ethylamino]-6-methyl-2-phenoxypyridin-3-yl}-2-ethoxyacetamide as a white solid.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:22][CH2:21][CH2:20][O:19][CH3:18])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: COCCN
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: COCCNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), 2-methyoxyethanamine (0.50 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 319 (M+, 0.3), 141 (17), 88 (bp), 72 (29), 58 (12), 56 (16).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])[C:15](=[O:28])[NH:14][CH2:13]2)=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])[C:15](=[O:28])[NH:14][CH2:13]2)=[O:9]
Reactant: C=COCCONC(=O)c1cc2c(cc1Nc1ccc(I)cc1F)C(=O)NC2
Agent: Cl
Solvent: CO
Product: O=C1NCc2cc(C(=O)NOCCO)c(Nc3ccc(I)cc3F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a solution of 6-(2-fluoro-4-iodo-phenylamino)-1-oxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide (100 mg, 0.20 mmol) in methanol (7 mL) was added hydrochloric acid (1 mL, 1M, 1 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and the resultant residue triturated with hot ethyl acetate. The product was collected by filtration to give the title compound as a pale beige solid (58 mg, 61%). LCMS (Method A): RT=7.64, M+H+=472. 1H NMR (DMSO-d6) 11.89 (1H, s), 9.00 (1H, s), 8.68 (1H, s), 7.68-7.62 (2H, m), 7.49-7.45 (1H, m), 7.24 (1H, s), 7.17 (1H, t, J=8.63 Hz), 4.69 (1H, s), 4.28 (2H, s), 3.89 (2H, t, J=4.82 Hz), 3.58 (2H, t, J=4.73 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]([NH:41][CH2:42][CH2:43][OH:44])=[O:40])[CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1>>[F:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]([NH:41][CH2:42][CH2:43][OH:44])=[O:40])[CH:26]=[CH:27][C:28]=1[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: COC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C
Product: COC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCO)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 26 %

Procedure:
Method as described for example 147 using (S)-methyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 26) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxyethyl)urea (intermediate 32) as starting materials. The crude reaction mixture was purified by SCX-2 cartridge (loaded in MeOH eluted with 2M methanolic ammonia). Ammonia eluent was concentrated in vacuo. Residue was then purified by prep. HPLC at high pH to afford a light brown solid (50 mg, 0.11 mmol, 26%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]([CH3:10])[CH2:8][OH:9])=[CH:4][CH:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>ClCCl>[CH3:13][S:14]([O:9][CH2:8][CH:7]([O:6][C:5]1[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:10])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)Oc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)Oc1ccc(F)cc1

Procedure:
As described in Example 56, 7.7 g of 2-(p-fluorophenoxy)-1-propanol is reacted with 8.8 ml of methanesulfonyl chloride in 400 ml of dichloromethane in the presence of 12.5 ml of triethylamine. The product is obtained as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22]Br)[C:8]2=[O:24])=[CH:4][CH:3]=1.[C-:27]#[N:28].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][C:27]#[N:28])[C:8]2=[O:24])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: COc1nn(-c2ccccc2CBr)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nn(-c2ccccc2CC#N)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 20 °C
Yield: 100.5 %

Procedure:
According to Scheme 9 Step 2: A mixture of 4-(4-chlorobenzyl)-2-(2-(bromomethyl)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione (70 mg, 0.16 mmol) in DMF (2 mL) and potassium cyanide (31 mg, 0.13 mmol) was stirred at 20° C. 12 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 10 g prepacked column, DCM/MeOH 99/1 to afford 2-(2-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetonitrile 4.167 (50 mg, Yield=81%) as a white oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH:34]1([N:37]([CH3:44])[CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][NH:40]2)[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:34]1([N:37]([CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH3:44])[CH2:35][CH2:36]1
Reactant: CN(C[C@H]1CCCN1)C1CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H]1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.5 %

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (146 mg, 0.29 mmol), cyclopropyl-methyl-(R)-1-pyrrolidin-2-ylmethyl-amine (71 mg, 0.46 mmol), HOBt (54 mg, 0.4 mmol), EDAC (74 mg, 0.39 mmol) and TEA (0.085 mL) in DMF (3 mL) was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate and extracted with DCM. The combined DCM was dried, concentrated and purified on a silica gel column to give 133 mg (71%) of the titled compound.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][CH:12]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:7][CH2:11][CH:12]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
To a solution of 0.6 g (3.7 mmol) of diethylamino-sulfur trifluoride in 5 ml dichloromethane cooled at -78° C. under nitrogen was added dropwise a solution of 1 g (3.4 mmol) of 2-hydroxymethyl-1,4-di-phenylmethyl piperazine in 5 ml dichloromethane. The temperature of the solution was allowed to warm to -50° C. in 30 mn then to 0° C. in 1 hr 30 min. The solution was stirred two more hours at room temperature and cooled back to +5° C. A few drops of aqueous saturated solution of sodium bicarbonate were added until basic pH. The organic layer was washed twice with water, dried over magnesium sulfate, the solvent removed to give 1.10 g of an oil which was purified by chromatography using dichloromethane/ethyl acetate (95:5) to afford 0.46 g (42%) of title compound.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[CH:7]1([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: C1=C(N2CCCCC2)c2ccccc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: CCOCC
Product: c1ccc2c(c1)CCCC2N1CCCCC1
Reaction time: 1 h

Procedure:
An ether solution of 48 g. of 1-piperidino-3,4-dihydronaphthalene as prepared above is treated with gaseous HCl to precipitate the salt. Rapid filtering to avoid hydrolysis by moisture followed by drying over potassium hydroxide in a vacuum dessicator provides a white powder salt which is added portionwise to an ether suspension of excess lithium aluminum hydride. After 1 hour of stirring, the excess reagent is decomposed by the catious dropwise addition of potassium carbonate solution until a granular white precipitate forms. Filtration and concentration leaves an oil which is fractionally distilled to yield 25 g. of 1-(1-tetrahydronaphthyl)piperidine collected at 102°-106° (0.3 mm.).
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)(=[O:7])=[O:6])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.C(N(CC)C(C)C)(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:35]2[NH:36][C:37]([NH2:40])=[N:38][N:39]=2)[CH:32]=[CH:33][CH:34]=1>>[CH:1]1([CH2:4][S:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:40][C:37]2[NH:36][C:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[CH:30]=3)=[N:39][N:38]=2)=[O:11])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cccc(-c2nnc(N)[nH]2)c1
Reactant: CC(C)(C(=O)O)S(=O)(=O)CC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COc1cccc(-c2nnc(NC(=O)C(C)(C)S(=O)(=O)CC3CC3)[nH]2)c1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
Activation of 0.46 g (2.23 mmol) of 2-cyclopropylmethanesulfonyl-2-methyl-propionic acid as the corresponding acid chloride is achieved by treatment with thionyl chloride (5 mL, 69 mmol) at 70° C. for 2 h. The reaction is cooled to room temperature and excess thionyl chloride is removed under reduced pressure. The crude acid chloride is dissolved in THF (5 mL) and N,N-diisopropylethylamine (0.54 mL, 5.64 mmol) is added followed by 0.3 g (2.6 mmol) of 5-(3-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylamine. After complete addition the reaction is heated to 70° C. for 36 h. The reaction is cooled to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in DCM (20 mL) and washed with saturated aqueous NaHCO3 solution (20 mL). The aqueous layer is back-extracted with DCM (2×20 mL). The combined organic layers are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residue is slurried in DCM/ether (1/1, 10 mL) to yield 0.398 g of 2-cyclopropylmethanesulfonyl-N-[5-(3-methoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-2-methyl-propionamide. Yield: 46%; ES-MS: m/z 379 [M+H]
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:8]1[N:12]([C@@H:13]2[O:19][C@H:18]([CH3:20])[C@@H:16]([OH:17])[C@H:14]2[OH:15])[C:11]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:10]=2[N:9]=1>C(Cl)Cl>[Cl:25][C:23]1[C:22]([Cl:26])=[CH:21][C:11]2[N:12]([C@@H:13]3[O:19][C@H:18]([CH3:20])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:8]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:9][C:10]=2[CH:24]=1
Reactant: NC1CCCC1
Reactant: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Product: C[C@H]1O[C@@H](n2c(NC3CCCC3)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Yield: 95.4 %

Procedure:
Following General Procedure V, cyclopentyl amine (Aldrich, 5 mL, 50.68 mmol), and 2-bromo-5,6-dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (250 mg, 0.65 mmol) reacted for 92 h. Purification on a silica gel column with 1:15 methanol:CH2Cl2 gave the title compound (238 mg, 0.62 mmol, 95%); MS (EI): m/z (rel. intensity) 386 (0.20, M+); 1H NMR (DMSO-d6) δ7.42 (s, 1H, Ar—H), 7.33 (s, 1H, Ar—H), 6.68 (d, 1H, NH, J=6.7 Hz), 5.71 (d, 1H, CH, J=6.8 Hz), 5.29 (m, 2H, overlapping OH), 4.32 (m, 1H. CH), 4.16 (m, 1H, CH), 3.92 (m, 1H, CH), 3.81 (m, 1H, CH), 1.95 (m, 2H, CH2), 1.70 (m, 2H, CH2), 1.56 (m, 4H, CH2), 1.38 (d, 3H, CH3, J=6.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[C:10]([N+:17]([O-:19])=[O:18])[C:9]2=[O:20])=[CH:5][CH:4]=1.C1(S(Cl)(=O)=O)C=CC=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[C:10]([N+:17]([O-:19])=[O:18])[C:9]2=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ccc(CCO)c([N+](=O)[O-])c2=O)cc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=Cc1ccn(Cc2ccc(OC)cc2)c(=O)c1[N+](=O)[O-]
Reaction time: 96 h
Yield: 83.3 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-4-hydroxyethyl-3-nitro-2-pyridone (0.35 g, 1.2 mmol) in pyridine (4 mL) was added benzenesulfonyl chloride (0.2 mL). After 4 days, the mixture was diluted with ethyl acetate, and washed with dilute hydrochloric acid. The aqueous phase was basified to pH 13 with aqueous KOH, and after 30 minutes was extracted with ethyl acetate. The organic phase was dried, filtered and evaporated to give 1-(4-methoxybenzyl)-4-vinyl-3-nitro-2-pyridone (0.29 g, 1.0 mmol, 83%).