Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][C:25]=1[S:34]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (1 g, 5.37 mmol) in DCM (40 ml) was added DIPEA (1.969 ml, 11.28 mmol) and then 2-bromo-5-(trifluoromethyl)benzenesulfonyl chloride (1.737 g, 5.37 mmol). The mixture was stirred for 1 h 20 min at room temperature before it was washed with water (50 ml), dried on a phase separation cartridge and concentrated under vacuum.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13]C(=O)OCC2C=CC=CC=2)[CH2:8]1.CO.C(Cl)Cl>CO.[Pd]>[NH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH2:8]1
Reactant: O=C(N[C@H]1CCC[C@@H](N2CCCC2=O)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: N[C@H]1CCC[C@@H](N2CCCC2=O)C1
Reaction time: 1.75 h

Procedure:
A degassed solution of benzyl (1S,3R)-3-(2-oxopyrrolidin-1-yl)cyclohexylcarbamate, 45b, (0.165 g, 0.522 mmol) and Pd on C (10% wet, Degussa, 0.050 g, 0.024 mmol) in MeOH (15 mL) was placed under H2 atm (balloon). After 105 min, TLC (10% MeOH-DCM) indicated complete consumption of starting material. H2 was removed and the solution filtered and concentrated in vacuo. The crude product was azeotroped with CH3CN (2×) to remove any residual MeOH and provided the desired product (96 mg): FIA (M+H+) 183.27
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[N:6]1.C(=O)([O-])[O-].[K+].[K+].[N+:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])([O-:18])=[O:17]>>[N:5]1([CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[N+:16]([O-:18])=[O:17])[CH:9]=[CH:8][CH:7]=[N:6]1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: NCCCn1cccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NCCCn1cccn1)c1ccccc1[N+](=O)[O-]

Procedure:
The subtitled compound was prepared substantially in accordance with the method detailed in Example 24A using 6.0 g (0.030 mol) of N-(3-aminopropyl)pyrazole, 8.5 g of potassium carbonate and 2.65 g (O.013 mol) of o-nitrobenzoyl chloride with the exception that the final product was purified by crystallization from a cyanomethane/diethyl ether solution, followed by recrystallization from an ethanol/diethyl ether solution, to provide 6.62 g of the desired subtitled intermediate (m.p. 78°-81° C.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]([OH:23])=O)[S:20][C:13]=13)=[CH:6][CH:5]=2.[NH:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[C:29]([OH:32])([CH3:31])[CH3:30]>>[OH:32][C:29]([C@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:21]([C:19]1[S:20][C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:12]=2[NH:11][C:7]2[CH:6]=[C:5]3[C:4](=[CH:9][CH:8]=2)[NH:3][C:2]([CH3:10])=[CH:1]3)[CH:18]=1)=[O:23])([CH3:31])[CH3:30]
Reactant: Cc1cc2cc(Nc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Reactant: CC(C)(O)[C@H]1CCCN1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC[C@@H]5C(C)(C)O)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carboxylic acid and (R)-2-pyrrolidin-2-yl-propan-2-ol by a procedure analogous to Example 21B. MS: 435.2; HPLC Rf: 4.656 min.; HPLC purity: 97%.
Reaction SMILES: C([O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([CH3:18])=[N:15][C:14]=2[CH:19]=1)=[O:8])(=O)C.C([O-])(=O)C.[Na+]>CO>[OH:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([CH3:18])=[N:15][C:14]=2[CH:19]=1)=[O:8]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ccc2oc(C)nc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cc(NC(=O)c3ccccc3O)ccc2o1
Reaction time: 2 h
Yield: 83.9 %

Procedure:
5-(2-Acetoxybenzamido)-2-methylbenzoxazole (10.0 g, 0.032 mol) was combined with sodium acetate (3.5 g, 0.043 mol) in 100 mL of MeOH and the solution was heated to reflux for 2.5 hr. The heat source was removed and after standing for 2 hours the mixture was chilled in a refrigerator overnight. The solid was collected and dried affording 7.2 g (84% yield) of product; m.p. 202°-206° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[NH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Product: O=C(Cc1ccc(Br)cc1F)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 36 %

Procedure:
Following the procedure outlined for Example 627, (2-(4-bromo-2-fluorophenyl)acetic acid) (10.8 g, 30.7 mmol) reacted with (S)-(+)-4-benzyl-2-oxazolidinone (5.44 g, 30.7 mmol) to obtain the desired product (4.5 g, 36%) as white solid. ESI MS nm/393 [C18H15BrFNO3+H]+
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:40])[C:19]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)=O)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:42][O:43][NH2:44].N1C=CC=CC=1>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:40])[C:19](=[N:44][O:43][CH3:42])[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CON
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(C(=O)Nc1cc(C(C)(C)C)nn1-c1ccc(C)cc1)c1ccc(OCCN2CCOCC2)c2ccccc12
Temperature: 45 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
Compound 13 (10 mg, 0.018 mmol) and methoxyamine hydrochloride (50 eqv., 0.92 mmol, 77 mg) were dissolved in 2 mL of EtOH. Pyridine (0.1 mL) was added and the mixture was stirred at 45° C. for 12 h. The solvent was then removed in vacuo and the crude solid was purified via LCMS to yield 8 mg of a white solid (76% yield; mixture of isomers). Expected mass=569. Observed mass=570.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]([NH2:16])([CH3:15])[CH3:14]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][C:13]([CH3:15])([CH3:14])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)N
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-bromobenzene-1-sulfonyl chloride (2 g, 7.83 mmol, 1.0 eq) and 2-methylpropan-2-amine (1.72 g, 23.5 mmol, 3.0 eq) in dioxane (50 mL) was stirred at room temperature for 1 hours and filtered. The filtrate was concentrated in vacuo to afford 3-bromo-N-tert-butylbenzenesulfonamide (all for the next step). LCMS: 291.9, 293.9 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:35]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:44]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH:33]=[O:44])[N:25]=[C:24]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:35]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O
Reactant: CCOC(=O)c1c(C)nc(-c2ccc(C(=O)OC)cc2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C=O)nc(-c2ccc(C(=O)OC)cc2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-(4-(methoxycarbonyl)phenyl)-6-methylpyrimidine-5-carboxylate (0.63 g, 1.06 mmol) was dissolved in dioxane (10 mL), SeO2 (0.6 g, 5.4 mmol) and water (0.096 mL) were added and the reaction mixture heated at 100° C. for 3.5 hours. The reaction mixture was concentrated in vacuum and the mixture loaded on to a column of silica gel and eluted with MeOH, dichloromethane as eluent, to give the desired compound (0.52 g). 1HNMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 9.53 (s, 1H), 8.56 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 4.39 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.41 (s, 2H), 3.26 (m, 4H), 2.35 (m, 4H)), 1.39 (s, 9H), 1.36 (t, J=6.8 Hz, 3H); MS m/z 636.5 (M+1).
Reaction SMILES: C([O:4][CH2:5][C@@:6]1([CH2:20][O:19][C@H:18]([CH2:21][O:22]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@@H:8]1[O:9]C(=O)C)[OH:7])(=O)C.C[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:20]1[O:19][C@H:18]([CH2:21][OH:22])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@:6]1([OH:7])[CH2:5][OH:4]
Reactant: CC(=O)OC[C@H]1OC[C@@](O)(COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: OC[C@H]1OC[C@@](O)(CO)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
1,3,4,6-Tetra-O-acetyl-2,5-O-methylene-D-mannitol 17 (2.8 kg, 7.73 mol) was added to chloroform (14 lit.) in 25 lit. round bottom flask with mechanical stirring. The reaction mixture was cooled to 0° C., and 0.5% NaOMe solution (6.5 lit.) was added slowly. The reaction mixture was stirred for 3 hours . The solid was filtered and dried to provide 1.0 kg (67%) of 2,5-O-methylene-D-mannitol 18, m.p. 172°-173° C., [α]D−52° (c 1.18, CHCl3), TLC (silica gel), 1:4, methanol:chloroform, Rf=0.8. 1H NMR (D20): δ 3.42 (m, 2H), 3.72 (m, 4 H), 3.97 (m, 2 H), 4.91 (s, 2 H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN1C(=O)CCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:30]2[CH2:31][CH2:32][N:27]([C:25]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:26])[CH2:28][CH2:29]2)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Reactant: O=C(c1ccccc1)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 25 °C
Yield: 1362.5 %

Procedure:
A solution of N-benzyl-5-bromo-2-nitrobenzenamine (50 mg, 0.16 mmol) and phenyl(piperazin-1-yl)methanone (93 mg, 0.48 mmol) in NMP (1 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish (4-(3-(benzylamino)-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (520 mg, 2.18 mmol), 92% yield. 1H NMR (500 MHz, CDCl3) d (ppm) 8.85 (m, 1H), 8.14 (d, J=9.5 Hz, 1H), 7.51-7.3 (m, 10H), 6.24 (dd, J=2.5 Hz, 10 Hz, 1H), 5.88 (d, J=2.5 Hz, 1H), 4.55 (d, J=5 Hz, 2H) 3.9-3.2 (m, 8H).+ESI HRMS (calcd for C24H24N4O3Na, M+Na) 439.1746, found 439.1741
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[N:14](C)[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[C:5]([CH3:20])[CH:4]=1.Cl.O1CCC[CH2:23]1>>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:13]([CH3:23])[N:14]=2)=[C:5]([CH3:20])[CH:4]=1
Reactant: C1CCOC1
Reactant: COc1cc(C)c(-c2cc(C(F)(F)F)nn2C)cc1C
Agent: Cl
Product: COc1cc(C)c(-c2cc(C(F)(F)F)n(C)n2)cc1C

Procedure:
A mixture of 5-(4-methoxy-2,5-dimethyl-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (described in Reference preparation example 84) 3.2 g, 6N aqueous hydrochloric acid solution 5.3 ml and tetrahydrofuran 50 ml was stirred with heating under reflux for one hour. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-methoxy-2,5-dimethyl-phenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole 3 g.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]#[CH:15])=[O:12])=[CH:7][C:6]=1[N+:16]([O-])=O)(=[O:3])[CH3:2].CO>[Fe].O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]#[CH:15])=[O:12])=[CH:7][C:6]=1[NH2:16])(=[O:3])[CH3:2]
Reactant: C#CCS(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CO
Solvent: O
Product: C#CCS(=O)c1ccc(NC(C)=O)c(N)c1

Procedure:
2 G. of 1-acetamido-2-nitro-4-propargylsulfinylbenzene is treated in a refluxing mixture of 160 ml. methanol and 40 ml. water with 4 g. iron powder (added in two portions) and 1 g. ferrous sulfate for four hours. The mixture is filtered, and the filtrated concentrated. The residue is dissolved in chloroform and washed with water, then the solvent evaporated affording 1-acetamido-2-amino-4-propargylsulfinylbenzene.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[CH:24]1[C:29](O)=[CH:28][CH:27]=[C:26]([CH3:31])[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C1COCC1>[CH3:31][C:26]1[CH:27]=[CH:28][C:29]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH2:10]3)=[CH:22][CH:23]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCO)cc2)CC1
Reactant: Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(OCCc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 85 h
Yield: 63.7 %

Procedure:
To a THF (40 mL) solution of tert-butyl 4-[4-(2-hydroxyethyl)benzyl]piperazine-1-carboxylate (4.74 g) and p-cresol (1.76 g) were added triphenylphosphine (4.27 g) and 2.2 M solution of DEAD in toluene (7.40 mL) at 0° C. After stirring at room temperature for 85 hours, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1 to 1/2), then the concentrated eluate was diluted with CH2Cl2, and washed with 5 M NaOH and saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure to give tert-butyl 4-{4-[2-(4-methylphenoxy)ethyl]benzyl}piperazine-1-carboxylate as a yellow solid (3.87 g).
Reaction SMILES: NCCCN1C2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])C=2N=C1CCOC.C1(N=C=[O:31])CCCCC1>>[CH:11]1([NH:10][C:9](=[O:31])[NH2:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C=NC1CCCCC1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: NC(=O)NC1CCCCC1

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin4-amine (1.50 g, 5.01 mmol) was reacted with cyclohexyl isocyanate (780 mg, 5.51 mmol) to provide 1.02 g of N-l3-[4amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl)-N′-cyclohexylurea as a solid, m.p. 179-180° C. Analysis: Calculated for C23H32N6O2. 0.75H2O: %C, 63.06; %H, 7.71; %N, 19.18; Found: %C, 62.74; %H, 7.57; %N, 19.16.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36]O)[CH2:31][CH2:30]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:36][CH2:35][N:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(OCCN2CCOCC2)ccc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.9 %

Procedure:
A flask was charged with 4-bromo-3-fluorophenol (4.999 g, 26.2 mmol) and triphenylphosphine (10.298 g, 39.3 mmol). Methylene chloride (120 mL) was added followed by 2-morpholinoethanol (4 mL, 33.0 mmol) and the solution was stirred on an ice water bath to cool. After 5 minutes, diisopropyl azodicarboxylate (7.6 ml, 39.1 mmol) was added over 6 to 8 minutes. The reaction was left stirring on the cold bath to slowly warm to room temperature overnight. The reaction was concentrated and the residue purified by flash chromatography (25% to 100% EtOAc in hexanes) to provide the product as a colorless oil (2.621 g, 33%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]CC)=[CH:12][CH:11]=2)[CH:3]=1.BrB(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
At −78° C., to a stirred solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (8.47 g, 0.026 mol) (according to the synthesis procedure in the reference: Journal of Medicinal Chemistry, 2008, 51, 1145-1149) in dichloromethane (250 mL) was added slowly a solution of tribromoborane in dichloromethane (8 mL, 4 M) in drops, the mixture was stirred at −78° C. for further 30 minutes and then 1 hour at room temperature. Saturated aqueous sodium bicarbonate (200 mL) was added dropwise, the mixture was extracted for 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine for one time, dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:1) to afford the target compound.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH2:16][OH:17])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[NH:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH2:16][OH:17])[CH2:9]1
Reactant: OCCNCC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCCNCC1CCNC1
Yield: 57.5 %

Procedure:
A mixture of 32.32 g of 2-[[[1-(phenylmethyl)3-pyrrolidinyl]methyl]amino]ethanol, 330 ml of methanol and 3 g of 20% palladium on charcoal was shaken in an atmosphere of hydrogen at about 50 psi and at room temperature for 18 hours. The solvents were then removed at reduced pressure. The residue was distilled under vacuum (bp 129°-131° C. 1.5 mm Hg) to give 11.43 g of 2-[(3-pyrrolidinyl methyl)amino] ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH2:22])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:22][CH3:23])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A mixture of 7-(benzyloxy)-9H-carbazol-2-amine (150 mg, 0.52 mmol), paraformaldehyde (78 mg, 2.6 mmol), and NaOMe (900 mg, 25% MeOH solution, 4.16 mmol) in 15 mL of MeOH was heated at reflux for 2 h under Ar atmosphere and cooled to rt. To this mixture was added NaBH4 (98 mg, 2.6 mmol) and the mixture was heated at reflux for 2 h. After cooling to rt, the mixture was quenched onto ice (30 g). It was extracted with EtOAc (3×50 mL) and the combined organic phase was dried over MgSO4 and concentrated. The crude product was purified with chromatography (hexane/EtOAc) to afford 7-(benzyloxy)-N-methyl-9H-carbazol-2-amine as a light-brown solid (130 mg, 82%). 1H NMR (400 MHz, acetone-d6) δ 9.78 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.37 (m, 2H), 7.32-7.28 (m, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.78 (dd, J=8.4, 2.4 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.49 (dd, J=8.4, 2.4 Hz, 1H), 5.13 (s, 2H), 4.96 (s, 1H), 2.82 (s, 3H); MS (ESI) m/z 303 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:23][C:24]([O:26][CH2:27]C)=[O:25]>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][N:11]1[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc(COCC2CN2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CC1COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of 2-[(benzyloxy)methyl]aziridine (0.42 g, 2.57 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.90 mmol) in dichloromethane (15 mL) under an atmosphere of nitrogen, ethyl bromoacetate (0.39, 2.5 mmol) was added over a period of 1 h. The resultant mixture was allowed to slowly warm up to room temperature and stirred overnight. The resultant mixture was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a mixture of 70% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[C:22]([CH2:21][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16])([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccccc1O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1-c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
A dispersion of 530 mg of 60% sodium hydride in mineral oil and 10 ml of DMF is treated, dropwise, with a solution of 1.50 g (6.6 mmol) of 5-(2-hydroxyphenyl)-6-methyl-2-oxo1,2-dihydro-3-pyridinecarbonitrile in 20 ml of DMF. The reaction is stirred 30 min at RT, then cooled in an ice bath and 1.11 g (6.6 mmol) of ethyl bromoacetate in 30 ml of DMF is added dropwise. The reaction is allowed to slowly come to RT and stirred overnight under N2. The mixture is concentrated under vacuum, the residue taken up in 80 ml of water and extracted with EtOAc. The aqueous phase is acidified to pH=5 with 10% HCl and extracted with EtOAc (4×80 ml). The combined EtOAc extracts are dried (MgSO4) and the solvent removed to leave an orange solid. This solid is recrystallized from EtOAc to give 740 mg of 5-(2-carboethoxymethoxyphenyl)-6-methyl-2-oxo-1,2 -dihydro-3-pyridinecarbonitrile as a yellow solid, m.p. 188°-190° C. Yield, 37%. 1H-NMR (d6 -DMSO): δ1.20 (t,3H): 2.18 (s,3H); 4.15 (q,2H); 4.80 (s,2H); 7.0 (q,2H); 7.20 (d,1H); 7.35 (t,1H); 8.00 (s,1H).