Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[OH:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([C@@H:27]2[CH2:31][C@H:30]([S:32]CC3C=CC(OC)=CC=3)[CH2:29][N:28]2[CH3:42])=[O:26])[CH2:21][CH2:20]1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:32][C@@H:30]1[CH2:29][N:28]([CH3:42])[C@H:27]([C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][OH:16])[CH2:24][CH2:23]2)=[O:26])[CH2:31]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 ml of trifluoroacetic acid and 520 μl of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 1150 mg of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl)-4-(4-methoxybenzylthio)-1-methylpyrrolidine [prepared as described in step (i) above] in 3 ml of anisole, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, to give 1680 mg of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](O)=[CH:6][CH:7]=1.ClC1C=CC=CC=1.C([O-])(=O)C.[K+].[N+:22]([O-])(OCCC(C)C)=O>C(OC(=O)C)(=O)C>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[N:22]1
Reactant: Cc1cc(O)ccc1N
Reactant: CC(C)CCO[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: Clc1ccccc1
Product: c1ccc2[nH]ncc2c1

Procedure:
4-Amino-m-cresol is suspended in acetic anhydride and chlorobenzene in the presence of potassium acetate, isoamyl nitrate is added to the suspension at 70° C. to 100° C., preferably about 80° C., and the mixture is stirred to form an indazole skeleton. The intermediate thus obtained is dissolved in hydrochloric acid-methanol, and the mixture is preferably stirred at room temperature to deacetylate the compound.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]([OH:18])[CH2:15][C:16]#[CH:17]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:18][CH2:14][CH2:15][C:16]#[C:17][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(OC)c1Br
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(OC)c1C#CCCO
Yield: 14.7 %

Procedure:
A mixture of methyl 2-bromo-3-methoxybenzoate (0.4 g, 1.63 mmol), Pd(PPh3)2Cl2 (0.057 g, 0.082 mmol), copper (I) iodide (0.031 g, 0.16 mmol) and 3-butyn-1-ol (0.173 ml, 2.28 mmol) were stirred in trietylamine (5 ml) at 80° C. for 20 h. The solvent was concentrated under vacuum, and the residue was partitioned between ethyl acetate (15 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using hexanes:ethyl acetate 2:1 as eluent to afford methyl 2-(4-hydroxybut-1-yn-1-yl)-3-(methyloxy)benzoate (0.056 g; 15% yield). MS (EI) for C13H14O4: 235 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[CH2:12][NH:13][C@@H:14]([CH:17]3[CH:22]4[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]4)[CH2:18]3)[C:15](=[O:16])[N:7]3[C:8]=2[C:4]=1[CH:5]=[CH:6]3.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:1][CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[CH2:12][NH:13][C@@H:14]([CH:17]3[CH:22]4[CH2:21][CH2:20][N:19]([CH2:24][CH2:23]4)[CH2:18]3)[C:15](=[O:16])[N:7]3[C:8]=2[C:4]=1[CH:5]=[CH:6]3)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1[C@H](C2CN3CCC2CC3)NCc2ccc(CO)c3ccn1c23
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc2c3c1ccn3C(=O)[C@H](C1CN3CCC1CC3)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
4-(Dimethylamino)pyridine (13 mg, 0.05 mmol) was added to a solution of (S)-7-(hydroxymethyl)-2-(quinuclidin-3-yl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-1(2H)-one from Step B above in a mixture of acetic anhydride (0.1 ml, 1.2 mmol) and pyridine (3 ml). The mixture was stirred overnight at room temperature, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-(1-oxo-2-(quinuclidin-3-yl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)methyl acetate (124 mg, 71%) as a white solid: MS (ESI+) m/z 368 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[OH-].[Li+:33]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[Li+:33]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)[O-])cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 40 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of methyl 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 46)(1.63 g, 3.84 mmol) in MeOH (20 mL) was added lithium hydroxide (4.61 mL, 4.61 mmol). The resulting mixture was stirred at 40° C. for 6 h, whereupon it was concentrated under reduced pressure to give lithium 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (1.65 g, 100%) which was not purified but directly used in the subsequent step. LCMS (Formate, 2 min), Rt=0.87 min, MH+=411.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:21]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])[C:22]=2[N:23]=[CH:24][N:25]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:21]2[CH:29]=[CH:28][N+:27]([O-:9])=[C:26]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])[C:22]=2[N:23]=[CH:24][N:25]=1
Reactant: Fc1ccc(-c2ncnc3c(-c4c(F)cccc4F)nccc23)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc2c(-c3ccc(F)cc3Cl)ncnc2c1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
Meta-chloroperbenzoic acid (77%) (30 mg, 0.13 mmol) was added portionwise to a solution of the title compound from Example 25 (50 mg, 0.13 mmol) in dichloromethane (2.5 mL) at 0° C. and the reaction mixture was stirred overnight at room temperature. Then, more dichloromethane was added (50 mL) and the solution was washed with 1N NaOH (2×30 ml) and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield an oil which was purified by column chromatography on silica gel, using hexane/ethyl acetate (5:1) as eluent, to yield the title compound (24 mg, 46%) as an off-white solid.
Reaction SMILES: [ClH:1].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)[CH2:14][CH2:15]2)=[CH:22][CH:21]=1
Reactant: c1ccc2cc(CC3CCNCC3)ccc2c1
Reactant: Fc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(OCCN2CCC(Cc3ccc4ccccc4c3)CC2)cc1

Procedure:
The title compound was prepared from 4-((2-naphthyl)methyl)piperidine hydrochloride (150 mg, 573 μmol), 2-(4-fluorophenoxy)ethyl bromide (132 mg, 602 μmol) and K2CO3 (162 mg, 1.17 mmol) as a colorless solid (126 mg): mp 170-172° C.; 1H NMR (CDCl3) 1.60-1.92 (m, 3H), 2.02-2.41 (m, 2H), 2.65-2.90 (m, 4H), 3.45-3.55 (m, 2H), 3.60-3.71 (m, 2H), 4.51 (t, J=4.2 Hz, 2H), 6.77-7.01 (m, 4H), 7.25 (d, J=6.0 Hz, 1H), 7.40-7.51 (m, 2H), 7.57 (s, 1H), 7.72-7.84 (m, 3H) 12.64 (bs, 1H). Anal. Calcd for C24H27ClFNO: C, 72.08; H, 6.80; N, 3.50. Found: C, 71.73; H, 6.64; N, 3.34.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:17]([C:18]([OH:20])=O)=[CH:16][C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.C(N(CC)CC)C.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][O:37][CH2:38][CH2:39][OH:40])=[C:32]([F:41])[CH:31]=1>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C.O>[F:41][C:32]1[CH:31]=[C:30]([CH2:29][NH:28][C:18]([C:17]2[C:8]([CH3:7])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)=[O:20])[CH:35]=[CH:34][C:33]=1[CH2:36][O:37][CH2:38][CH2:39][OH:40]
Reactant: NCc1ccc(COCCO)c(F)c1
Reactant: Cc1nc2ncccc2cc1C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2ncccc2cc1C(=O)NCc1ccc(COCCO)c(F)c1
Reaction time: 1.5 h
Yield: 36.1 %

Procedure:
45 μl oxalyl chloride (0.53 mmol) was added to a mixture of 50 mg 2-methyl-1,8-naphthyridine-3-carboxylic acid (0.27 mmol) in 3 ml CH2Cl2 with one drop DMF. The reaction mixture was stirred for 1.5 h and then evaporated to dryness under reduced pressure. The residue was dissolved in 3 ml CH2Cl2. 4 mg DMAP (0.03 mmol) and 188 μl triethyl amine (1.35 mmol) were added to the solution followed by 54 mg 2-[[4-(aminomethyl)-2-fluoro-phenyl]methoxy]ethanol (0.27 mmol). The reaction mixture was stirred for 4 h and then diluted with water. The phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (SiO2, CH2Cl2/MeOH 20:1) gave 36 mg (36%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[NH:9][C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15])[CH3:2].[CH2:17](C1C([N+]([O-])=O)=CC2NC(=O)COC=2C=1)[CH3:18].C([Mg]Br)C>>[CH2:1]([C:3]1[C:8]2[NH:9][C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[C:4]=1[N+:14]([O-:16])=[O:15])[CH3:2]
Reactant: CCc1cc2c(cc1[N+](=O)[O-])NC(=O)CO2
Reactant: CCc1c([N+](=O)[O-])ccc2c1NC(=O)CO2
Agent: CC[Mg]Br
Product: CCc1cc2c(c(CC)c1[N+](=O)[O-])NC(=O)CO2

Procedure:
The title compound is synthesized from either 5-ethyl-6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine or from 7-ethyl-6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine and ethyl magnesium bromide, using the procedure illustrated in Example 37.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[O:27][C@@H:28]3[CH2:32][CH2:31][O:30][CH2:29]3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5])C.[Li+].[OH-]>C(O)C>[F:26][C:24]1[CH:23]=[CH:22][C:21]([O:27][C@@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)=[C:20]([CH:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:12]2[CH:13]=[CH:14][C:9]3[N:10]([C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=3)[CH:11]=2)[CH:25]=1
Reactant: CCOC(=O)c1cnc2ccc(N3CCCC3c3cc(F)ccc3O[C@@H]3CCOC3)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2ccc(N3CCCC3c3cc(F)ccc3O[C@@H]3CCOC3)cn12
Temperature: 85 °C
Reaction time: 5 h
Yield: 3.7 %

Procedure:
To stirred solution of Ethyl-6-(2-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (1.15 g, 26.18 mmol) in ethanol was added 1M LiOH (2.3 ml) solution and stirred for 5 h at 85° C. Solvent was removed under reduced pressure and residue was dissolved in water, extracted unwanted impurities with diethyl ether and water was acidified with 2N HCl and solid was collected by filtration. Solid was dried under high vacuum to afford 6-(2-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid as pale yellow solid (400 mg, yield: 37.7%), MS (ESI): 412.1 (M+H).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:42])[CH2:7][C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH:24]=2)[N:13]=1>O.C1COCC1>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([N:23]2[CH:24]=[C:20]([NH:19][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:38]=[CH:39][CH:40]=[CH:41][C:8]=4[CH2:7][C:6]([OH:42])=[O:5])[C:17]([CH3:18])=[CH:16][N:15]=3)[CH:21]=[N:22]2)[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1CCc1ccccc1CC(=O)O
Temperature: 40 °C

Procedure:
LiOH.H2O (0.302 g, 7.20 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (A126) (0.077 g, 0.14 mmol) in H2O (1 mL) and THF (10 mL) and the resulting mixture was heated to 40° C. for 18 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (100 mL), washed with aqueous 2 M HCl (50 mL), water (100 mL), brine (50 mL) and dried over MgSO4. The volatiles were removed in vacuo to give the title compound A127 as a pale yellow solid (0.068 g, 91%); LCMS-A: rt 5.366 min; m/z 521 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[C:6]([Cl:12])[CH:5]=1)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+].C(Cl)(Cl)[Cl:19]>>[NH2:11][C:7]1[C:8]([Cl:10])=[N:9][C:4]([C:1](=[O:3])[CH2:2][Cl:19])=[CH:5][C:6]=1[Cl:12]
Reactant: CC(=O)c1cc(Cl)c(N)c(Cl)n1
Reactant: ClC(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1c(Cl)cc(C(=O)CCl)nc1Cl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
14 g (68.3 mmol) of 6-acetyl-3-amino-2,4-dichloropyridine are dissolved in 70 ml of dry CHCl3 and then a solution of 5.5 ml (68.4 mmol) of SO2Cl2 in 70 ml of dry CHCl3 is added dropwise and the mixture is stirred for two hours at 40° C. For working up, it is poured into 250 ml of NaHCO3 solution, and the organic phase is separated off and extracted once more using 100 ml of CHCl3. The combined organic phases are dried using Na2SO4 and evaporated.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C:6]=2[S:5][C:4]=1[NH:19][C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:19][C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])#[N:2]
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCNC2
Reaction time: 2 h

Procedure:
To a solution of the intermediate isolated in Step B in 100 mL of dichloromethane was added 25 mL of trifluoroacetic acid. After 2 h at ambient temperature, the reaction was diluted with an equal volume of saturated aqueous NAHCO3. The mixture was extracted twice with dichloromethane, and the combined organic layers were dried (Na2SO4) and concentrated in vacuo, affording the title compound.
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[H-].[Na+]>C1COCC1>[N:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9][C:5]=1[CH2:4][N:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=[C:5]1[CH2:4][Cl:3]
Reactant: ClCc1nc2ccccc2[nH]1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ClCc1nc2ccccc2n1Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22165.7 %

Procedure:
To a three-necked, 12 L flask, flushed with N2, 2-(chloromethyl)benzimidazole (75 g, 0.45 mmol) and THF (10 L) were added, and the slurry was stirred for one hour at room temperature. Using an ice bath, the slurry was cooled to 0° C. and NaH (5.7 g, 95%, 0.23 mmol) was added. The slurry temperature increased to 4.5° C. The reaction mixture was stirred for 3 h and quenched with 150 g of silica gel. The slurry was concentrated to dryness under reduced pressure and purified using column chromatography (loaded with 40% EtOAc/hexanes, the eluting solvent started with 40% EtOAc/hexanes to end with 75% EtOAc/hexanes). 14.8 g of 1-benzimidazolylmethyl-2-(chloromethyl)benzimidazole 1 was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](OCC)=O)[CH3:2].[CH2:24]([NH2:27])[CH2:25][NH2:26].C[Al](C)C.O>C1(C)C=CC=CC=1.CO>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][CH:7]([C:8]1[NH:26][CH2:25][CH2:24][N:27]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccccc1)Oc1ccccc1OCC
Reactant: NCCN
Agent: C[Al](C)C
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccccc1OC(Cc1ccccc1)C1=NCCN1
Temperature: 25 °C

Procedure:
A mixture of 6.28 g (0.02 m) of ethyl 2-(2-ethoxy-phenoxy)-3-phenylpropionate, 1.93 g (0.033 m) ethylenediamine and 150 ml of dry toluene was stirred at room temperature and 17 ml of a 2 m solution of trimethylaluminum in toluene was added dropwise. After stirring 10 minutes, the mixture was heated at reflux for 3 hours, then cooled in an ice bath. Water (10 ml) was added followed by 20 ml methanol and the mixture heated on a steam bath for 0.5 hours. Solids were filtered and the solvent evaporated. The solid residue was recrystallized from cyclohexane to give 3.53 g, melting point 95-97° C. Anal., Calcd. for C19H22N2O2 : C=73.52; H=7.14; N=9.0,
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([OH:31])=O)[C:20]3=[O:32])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.Cl.CN.C[CH2:37][N:38]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.O>[C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([NH:38][CH3:37])=[O:31])[C:20]3=[O:32])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O=C(O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.1 %

Procedure:
(R)-2-{3-[1-(Acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzoimidazol-1-yl}acetic acid (1 g, 2.3 mmol) was dissolved in DMF (10 ml). Methylamine hydrochloride (0.17 g, 2.5 mmol), WSC•HCl (0.53 g, 2.7 mmol), HOBt (0.43 g, 2.8 mmol) and triethylamine (0.7 ml, 5 mmol) were added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.7 g) as pale-yellow crystals.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([N:7]2[NH:12][N:11]=[N:10][C:8]2=[O:9])[C:4]([Cl:13])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH:20]1([N:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[CH3:31][CH2:30][N:26]([C:27]([N:10]1[N:11]=[N:12][N:7]([C:5]2[C:4]([Cl:13])=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:8]1=[O:9])=[O:28])[CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=c1nn[nH]n1-c1ccccc1Cl
Reactant: CCN(C(=O)Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(C(=O)n1nnn(-c2ccccc2Cl)c1=O)C1CCCCC1
Yield: 84.9 %

Procedure:
1-(2-chlorophenyl)-5(4H)-tetrazolinone (2 g) and potassium carbonate (1.68 g) were suspended in acetonitrile (30 ml), followed by fifteen minutes heating under refluxing. After cooling, N-cyclohexyl-N-ethylcarbamoyl chloride (2.31 g) was added to the reaction mixture, followed by a further five-hour heating under refluxing. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure, and the resulting residue was subjected to flush column chromatography (hexane:ethylacetate=5:2), to obtain the desired 1-(2-chlorophenyl)-4-(N-cyclohexyl-N-ethylcarbamoyl)- 5(4H)-tetrazolinone (3.02 g) having a m.p. in the range of from 77.5° to 79.5° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-oxoazepane-1-carboxylate (0.60 g, 2.81 mmol), in MeOH (11 mL) was cooled to 0° C. NaBH4 (0.266 g, 7.03 mmol) was added and the mixture was slowly warmed to ambient temperature where the reaction stirred overnight. The mixture was concentrated in vacuo and the residue was taken up in EtOAc (20 mL) and saturated aqueous NH4Cl solution (20 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine and dried over Na2SO4, then filtered and concentrated. The product was isolated as a thick colorless oil that solidified overnight to a white solid.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:26]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[CH:26]1([S:31]([N:18]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH2:25])[C:24]=3[C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:15][CH:14]=3)=[CH:17]2)(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=S(=O)(Cl)C1CCCC1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2S(=O)(=O)C1CCCC1
Reaction time: 72 h

Procedure:
Sodium hydride (0.132 g of a 60% dispersion in mineral oil) was added to a solution of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (1.0 g) in dry dimethylformamide (30 ml) with stirring under nitrogen. The mixture was stirred for 30 minutes and then cyclopentanesulphonyl chloride (0.558 g, prepared as described in J.O.C.1952, 17, 1529-1533) in dry dimethylformamide (5 ml) was added dropwise. The mixture was allowed to stand for 72 hours and then evaporated under vacuum. The residue was triturated with water and filtered to give a solid which was washed well with water, then stirred with ethyl acetate then filtered. The filtrate was purified by flash column chromatography on silica using ethyl acetate as the mobile phase. Appropriate fractions were collected and evaporated to give 7-cyclopentanesulphonyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 188-188.5° C.
Reaction SMILES: O.NN.F[C:5]1[C:10]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[C:7]([N+:18]([O-])=O)[C:6]=1[NH2:21]>C(O)C>[CH:17]1([N:14]2[CH2:15][CH2:16][N:11]([C:10]3[CH:5]=[C:6]([NH2:21])[C:7]([NH2:18])=[CH:8][CH:9]=3)[CH2:12][CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:10]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N
Temperature: 25 °C

Procedure:
Hydrazine monohydrate (0.13 mL, 2.7 mmol) was added to a solution of phthalimide 1 (134 mg, 0.39 mmol) in ethanol (4 mL). The reaction was maintained overnight at rt and then was filtered through Celite. The filter cake was rinse with EtOAc (3×) and the organic portions were combined and concentrated to give diamine 2 which was carried forward without further purification: LCMS m/z 215.1 (MH+), tR=1.77 min.