Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH:31]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[C:32]([F:35])([F:34])[F:33])=[N+]=[N-].C(Cl)CCl.[C:49]([N:56]1[CH2:63][CH2:62][CH2:61][C@H:57]1[C:58](O)=[O:59])([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C1C=NC2N(O)N=NC=2C=1>O.CN(C=O)C>[Cl:30][C:28]1[CH:27]=[CH:26][C:25]([CH:31]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:32]([F:35])([F:34])[F:33])=[C:24]([CH:29]=1)[CH2:23][NH:20][C:58](=[O:59])[C@@H:57]1[CH2:61][CH2:62][CH2:63][N:56]1[C:49]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:50]
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CN=[N+]=[N-])C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2cccnc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (0.157 mg, 0.60 mmol) was added to a stirred solution of N-{1-[2-(azidomethyl)-4-chlorophenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine (0.199 mg, 0.538 mmol) in water (1 mL) and water (30 μL). After 16 h the volatiles were evaporated in vacuo, the residue was dissolved in methanol (1 mL), potassium hydroxide (1 pellet) was added and the mixture was stirred at 60° C. for 15 min. The reaction mixture was then cooled and partitioned between ether and water. The organic layer was dried (Na2SO4) and evaporated to a gum. EDC (154.7 mg, 0.81 mmol) was added to a stirred mixture of this crude amine, N-Boc-L-proline (115.8 mg, 0.54 mmol) and HOAT (36.6 mg, 0.27 mmol) in DMF (3 mL). After 16 h, the mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography on silica gel (eluting with EtOAc/CHCl3, 1:5) to give N-(5-chloro-2-{1-[(4-methoxyphenyl)amino]-2,2,2-trifluoroethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamide (196 m g) as a glass: MS: 542.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH2:19][CH3:20])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[AlH3].C1COCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH2:19][CH3:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN1CCCC1CNC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: [AlH3]
Solvent: C1CCOC1
Product: CCN1CCCC1CNCCc1ccc(Cl)c(Cl)c1
Yield: 99.7 %

Procedure:
The title compound of Example 15 (base) (6.39 g, 20.3 mmol) was reduced with a 1.0M solution of AlH3 in THF (60 mL, 60 mmol, 3 eq) as described in Example 8 to give the crude product as a colorless oil (6.1 g, quantitative). The oxalate salt (6.5 g, 80% ) crystallized from 2-propanol/MeOH (1:1): mp 181°-182° C. (dec); 1H-NMR (CDCl3) ∂7.35 (d, J=8.1 Hz, 1H), 7.31 (d, J=1.8 Hz, 1H), 7.05 (dd, J=1.8, 8.1 Hz, 1H), 3.14 (m, 1H), 2.80-2.91 (m, 2H), 2.67-2.80 (complex m, 4H), 2.58 (m, 1H), 2.48 (m, 1H), 2.24 (m, 1H), 2.15 (q, J=8.6 Hz, 1H), 1.89 (m, 1H), 1.73 (m, 2H), 1.60 (m, 2H° ), 1.07 (t, J=8.6 Hz, 3H); CIMS (MH+ calcd for C15H22Cl2N2): 301. Found (MH+): 301; Anal. (calcd for C17H24Cl2N2O·0.5H2O): C,H,N.
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:17]1[CH2:20][CH:19]([OH:21])[CH2:18]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:17]2[CH2:20][CH:19]([OH:21])[CH2:18]2)=[CH:4][CH:5]=1
Reactant: OC1CNC1
Reactant: Clc1ccc(C(Br)c2ccc(Cl)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reaction time: 1.5 h

Procedure:
The reaction mixture of 22.30 g (70.5 mmol) of 1-[bromo(4-chlorophenyl)methyl]-4-chlorobenzene, 5.67 g (77.6 mmol) of azetidin-3-ol (2) and 18.4 mL (105.75 mmol) of DIEA in 250 mL of acetonitrile was rapidly stirred for 1.5 h at rt to 91° C., Reaction mixture was concentrated to remove solvents and residue was purified by silica gel chromatography with hexanes/ethyl acetate/ammonia (2M in MeOH)=100/30/0.5 to afford the title compound; 1H-NMR(CDCl3) δ 2.03 (br s, 1H), 2.81 (m, 2H), 3.55 (m, 2H), 4.34 (s, 1H), 4.50 (m, 1H), 7.29 (m, 4H), 7.34 (m, 4H).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[CH:20][S:21][CH:22]=1)=[O:17].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[N+:1]([O:4][CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[CH:20][S:21][CH:22]=1)=[O:17])([O-:3])=[O:2]
Reactant: O=C(NCCO)c1cscn1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(NCCO[N+](=O)[O-])c1cscn1
Temperature: 5 °C

Procedure:
Fuming nitric acid (12.8 ml) was added dropwise to acetic anhydride (27.4 ml) with stirring and ice-sodium chloride cooling at 10° C. for 1 minute, and the mixture was stirred for 10 minutes at the same temperature. Continuously, a solution of N-(2-hydroxyethyl)-4-thiazolecarboxamide (25.0 g) in dry chloroform (35 ml) was added dropwise thereto with stirring and cooling at 5° C. for 10 minutes and the mixture was stirred for hour at the same temperature. The reaction mixture was poured into a mixture of sodium bicarbonate (100 g) and ice-water (1.0 kg) and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residual solid was recrystallized from a mixture of diisopropyl ether and methanol (3:2) to give colorless crystals of N-(2-nitrooxyethyl)-4-thiazolecarboxamide (10.17 g).
Reaction SMILES: [CH3:1][N:2]([C:7]1[C:12]([CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:11][CH:10]=[CH:9][N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:14][CH2:13][C:12]1[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(c1ncccc1CNC(=O)OC(C)(C)C)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1ncccc1CN)S(C)(=O)=O
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
To a 25 mL round bottom flask charged with tert-butyl (2-(N-methylmethylsulfonamido)pyridin-3-yl)methylcarbamate (118 mg, 0.26 mmol) was added a 40% solution of TFA in CH2Cl2 (4 mL). The resulting mixture was stirred for 20 min, then the volatiles were evaporated. Toluene (4 mL) was added to the crude followed by evaporation. This procedure was repeated once. A solution of the crude residue in CH2Cl2 (4 mL) was treated with Amberlyst A-21 (1.8 g) and stirred for 30 min. The Amberlyst A-21 resin was filtered off and washed with CH2Cl2 (20 mL). The volatiles were evaporated to yield N-(3-(aminomethyl)pyridin-2-yl)-N-methylmethanesulfonamide (50 mg, 0.23 mmol, 88%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:4][C:5](F)=[CH:6][CH:7]=1.[CH3:18][O-:19].[Na+]>CO.[Cl-].[Na+].O>[F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:4][C:5]([O:19][CH3:18])=[CH:6][CH:7]=1
Reactant: Fc1cccc(CNc2nc(F)ccc2F)c1
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(F)c(NCc2cccc(F)c2)n1
Temperature: 150 °C
Yield: 62.2 %

Procedure:
3,6-difluoro-N-(3-fluorobenzyl)pyridine-2-amine (0.5209 g, 2.19 mmol), was dissolved in anhydrous MeOH (6.6 mL) and placed under argon. This mixture then was treated with sodium methoxide (0.500 mL, 0.473 g, 2.19 mmol, 25% in MeOH) by slow addition. The resulting mixture was then heated in the microwave at 150° C. for four 30 min. The reaction mixture was then poured into brine (25 mL). This mixture was extracted with EtOAc (3×25 mL), the combined extracts were washed with brine (1×25 mL) and dried (Na2SO4). After filtration the solvent removed in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 100 hexanes to 25 EtOAc/75 hexanes afforded 0.3408 g (62%) of 3-fluoro-N-(3-fluorobenzyl)-6-methoxypyridin-2-amine. LCMS (m/z): 251.1 (MH+), retention time=1.07 min.
Reaction SMILES: [NH2:1][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].[Cl:14]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cccc(OC)c1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc(OC)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To methyl 2-amino-3-methoxybenzoate (750 mg, 4.1 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added N-chlorosuccinimide (580 mg, 4.35 mmol) and this mixture was stirred at ambient temperature for 2 hours. The temperature was increased to 60° C. for 4 hours. The deep red solution was cooled, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, then brine, dried with sodium sulfate, decanted and concentrated to yield crude methyl 2-amino-5-chloro-3-methoxybenzoate (0.85 g, 95%). MS (m/z): 216.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[CH:8]=[C:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2)=[O:6].C(N(C(C)C)CC)(C)C.[CH2:36]([C:40]1[CH:45]=[CH:44][C:43]([CH:46]([C:48]2[CH:53]=[CH:52][C:51]([CH2:54][CH:55]([CH3:57])[CH3:56])=[CH:50][CH:49]=2)Cl)=[CH:42][CH:41]=1)[CH:37]([CH3:39])[CH3:38]>C(Cl)Cl>[CH2:54]([C:51]1[CH:52]=[CH:53][C:48]([CH:46]([NH:1][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=2)[C:5]([C:7]2[CH:8]=[C:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)=[O:6])[C:43]2[CH:44]=[CH:45][C:40]([CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:41][CH:42]=2)=[CH:49][CH:50]=1)[CH:55]([CH3:57])[CH3:56]
Reactant: CCOC(=O)CCCc1cc(C(=O)c2cccc(N)c2)c2ccccn12
Reactant: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCc1cc(C(=O)c2cccc(NC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)c2)c2ccccn12
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a stirred solution of ethyl 4-[1-(3-aminobenzoyl)indolizin-3-yl]butyrate (320 mg) in methylene chloride (10 ml) was added diisopropylethylamine (0.22 ml) and bis(4-isobutylphenyl)chloromethane (340 mg) in methylene chloride (5 ml) at room temperature. After stirring for 18 hours, the reaction mixture was evaporated and extracted with ether. The organic layers were washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (methylene chloride:ethyl acetate=20:1) to give ethyl 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indolizin-3-yl]butyrate (279 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:26]1([CH2:32][C:33]([Cl:35])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>ClCCl>[ClH:35].[C:26]1([CH2:32][C:33]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[ClH:35]
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(-c2cc(CN3CCN(C(=O)Cc4ccccc4)CC3)ccn2)cc(OC)c1OC
Product: Cl
Reaction time: 1 h

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) was dissolved in dichloromethane (0.9 mL), and to the solution phenylacetyl chloride (60 mg) was added, and the mixture was stirred for 1 hour under ice cooling. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to conduct extraction with chloroform. The resultant organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to obtain the title compound in the form of a hydrochloride.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6]CN.N[C@H:13](C(O)=O)CCCNC(=N)N.N[C@H](C(O)=O)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:2][C@H:3]([C:9]([O:11][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:10])[CH2:4][CH:5]([CH3:6])[CH3:13]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)C[C@H](N)C(=O)OCc1ccccc1

Procedure:
Amino acid analysis (after hydrolyzed in 6 N--HCl at 110° C. for 24 hours) (Parenthesized are the theoretical data.): Lys 0.84 (1); Glu 1.02 (1); Leu 1.00 (1); Tyr 0.92 (1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:12](=O)([O:18]C(C)(C)C)[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.O.C(OCC)C>[C:14]([O:13][C:12]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: Nc1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-aminobenzyl alcohol (2.00 g, 16.2 mmol) in 10 mL of dioxane was added a solution of sodium hydroxide (0.65 g, 16 mmol) in 40 mL of water at room temperature. After addition of di-tert-butyl carbonate (4.95 g, 22.7 mmol), the reaction mixture was stirred at room temperature overnight. The mixture was diluted with diethyl ether, and the solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain crude 4-(tert-butoxycarbonylamino)benzyl alcohol.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[C:18]2[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=2)[CH2:4][CH2:3]1.[F:24][C:25]1C=CC(C(Cl)=O)=[CH:27][C:26]=1[Cl:34].C(N(CC)CC)C.[CH2:42]1[CH2:46][O:45][CH2:44][CH2:43]1>>[Cl:34][C:26]1[C:25]([F:24])=[C:42]([CH:43]=[CH:44][CH:27]=1)[C:46]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([F:1])[CH2:3][CH2:4]2)=[C:12]([C:18]2[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=2)[CH:13]=1)=[O:45]
Reactant: C1CCOC1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCC(F)CC1
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(Cl)c2F)ccc1OCCN1CCC(F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture of 4-[2-(4-fluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (80 mg, 0.25 mmol), 4-fluoro-3-chlorobenzoyl chloride (48 mg, 0.25 mmol), and triethylamine (0.3 mL) in THF (3 mL) was stirred at r.t. for 10 min. The solvent was concentrate in vacuo and the crude was purified by HPLC to give the title compound (58 mg, 50%) as a white solid as TFA salt. 1H NMR (acetone-d6, 400 MHz) δ 2.02-2.24 (m, 4H), 3.08-3.18 (m, 2H), 3.32-3.42 (m, 2H), 3.63 (t, J=4.55 Hz, 2H), 3.80 (s, 3H), 4.59 (t, J=4.55 Hz, 2H); 4.91-5.03 (m, 1H), 6.30 (d, J=1.77 Hz, 1H), 7.23 (d, J=8.84 Hz, 1H), 7.43-7.51 (m, 2H), 7.81 (t, J=2.27 Hz, 1H), 7.91-7.97 (m, 1H), 8.02-8.08 (n, 1H), 8.18 (dd, J=2.53, 7.33 Hz, 1H), 9.71 (s, 1H). Exact mass calculated for C24H25ClF2N4O2 503.1. found 504.1/506.1 (MH+).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[C:19]2[N:24]=[C:23]([CH:25]=O)[CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:27]([C:30]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([CH3:39])[CH3:38])[C:31]=1[NH2:32])([CH3:29])[CH3:28].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH:1]1([NH:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[C:19]2[N:24]=[C:23](/[CH:25]=[N:32]/[C:31]3[C:33]([CH:37]([CH3:38])[CH3:39])=[CH:34][CH:35]=[CH:36][C:30]=3[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc(-c2c(CNC3CCCCC3)ccc3ccccc23)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)c1cccc(C(C)C)c1/N=C/c1cccc(-c2c(CNC3CCCCC3)ccc3ccccc23)n1
Temperature: 25 °C

Procedure:
A solution of 9.80 g (28.0 mmol) of 6-{2-[(cyclohexylamino)methyl]-1-naphthyl}pyridine-2-carbaldehyde, 5.55 g (31.0 mmol) of 2,6-diisopropylaniline, 0.1 g of TsOH in 100 ml of dry ethanol was refluxed for 10 h in argon atmosphere. The resulting mixture was cooled to room temperature and then evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexane-ethyl acetate-triethylamine=10:1:1, vol.). Yield 10.8 g (77%) of yellow powder. Anal. Calc for C35H41N3: C 83.45; H 8.20; N 8.34. Found: C 83.59; H 8.06; N 8.41.1H NMR (CDCl3): δ 8.39 (m, 1H, 3-H in Py), 8.35 (s, 1H, CHN), 8.00 (m, 1H, 4-H in Py), 7.87-7.92 (m, 2H, 4,8-H in naphthyl), 7.63 (m, 1H, 3-H in naphthyl), 7.54 (m, 1H, 3-H in Py), 7.37-7.47 (m, 3H, 5-H in Py and 6,7-H in naphthyl), 7.09-7.17 (m, 3H, 3,4,5-H in naphthyl), 3.69 (m, 2H, CH2N), 3.01 (sept, J=6.8 Hz, 2H, CH in 2,6-diisopropylphenyl), 2.29 (m, 1H, CH in Cy), 1.61-1.72 (m, 4H, Cy), 1.52-1.54 (m, 2H, Cy), 1.19 (d, J=6.8 Hz, 12H, CH3 in 2,6-diisopropylphenyl), 1.09-1.11 (m, 2H, Cy), 0.94-0.99 (m, 2H, Cy).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:47]1([NH2:53])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>CN(C=O)C>[CH:47]1([NH:53][C:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:4][CH:5]=2)=[O:11])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
To 6-(trifluoromethyl)-3-pyridinecarboxylic acid (2.0 g, 10.5 mmol) in DMF (10 mL) was added HATU (4.18 g, 11.0 mmol) followed by Hunig's base (1.83 mL, 10.5 mmol). After 15 minutes, cyclohexylamine (2.40 mL, 20.9 mmol) was added, and the reaction mixture was stirred for 45 minutes at room temperature. The reaction was poured onto water (˜300 mL). After 5 minutes, the resulting aqueous mixture was filtered, and the white solid was air dried for ˜15 minutes to afford the title compound (2.57 g). LC-MS (ES) m/z=273 [M+H]+.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[CH3:7][NH:8][C:9](=[O:19])[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([CH3:18])[CH:12]=1.N1C=CC=CC=1>O>[CH3:7][NH:8][C:9](=[O:19])[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[C:13]([CH3:18])[CH:12]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Solvent: O
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(OC(=O)NC)cc1C
Reaction time: 1 h

Procedure:
Ethanesulfonyl chloride (2.2g., 0.0171 mole) was added dropwise to a stirred solution of 3-methyl-4-aminophenyl N-methylcarbamate (3.0g., 0.0166 mole) in 20 ml. of pyridine. The temperature rose to a maximum of 38° C. and then subsided. Stirring was continued at ambient temperature for one hour, and the reaction mixture poured into excess water to give an insoluble precipitate. Recrystallization from ethanol-water gave the product as a beige powder, m.p. 146.5°-48.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([O:20][CH2:21][C:22](O)=O)[CH3:19]>>[CH3:16][C:14]([CH3:15])([OH:17])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:19]1[CH2:18][O:20][CH2:21][CH3:22]
Reactant: CCOCC(=O)O
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Yield: 6 %

Procedure:
Using the general method of Example 91, 3-amino-4-(2-hydroxy-2-methylpropylamino)quinoline (46.2 g. 0.20 mol) was reacted with ethoxyacetic acid (62.5 g, 0.6 mol) to provide 53.6 g of crude product as a greyish solid. A small amount was recrystallized from toluene to provide 3.6 g of a colorless solid, m.p. 117-120° C. Analysis: Calculated: %C, 68.2; %H, 7.1; %N, 14.0; Found: %C, 68.5; %H, 7.1; %N, 14.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1.C([O-])([O-])=O.[K+].[K+]>CCO>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:8]1
Reactant: C1CNCCN1
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1cnc(N2CCNCC2)cn1

Procedure:
A mixture of 3 g of piperazine, 1.04 ml of 2-chloropyrazine and 1.85 g of K2CO3 in 100 ml of EtOH is refluxed for 48 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in water and basified to pH 10 by addition of 10% NaOH, and extracted with chloroform, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 1.8 g of the expected product are obtained after crystallization from hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22](OC(C)(C)C)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][N:34]([CH3:50])[CH2:35][CH2:36][O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42](C(O)=O)=[CH:41]2.CCN=C=NCCCN(C)C>CC(N(C)C)=O.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22]([C:42]3[NH:43][C:44]4[C:40]([CH:41]=3)=[CH:39][C:38]([O:37][CH2:36][CH2:35][N:34]([CH3:50])[CH3:33])=[CH:46][CH:45]=4)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(OCc1ccccc1)c1ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(OCc3ccccc3)c3ncccc43)cc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
A suspension of 14 (0.20 g, 0.47 mmol) in cooled (0° C.) dioxane (5 mL) was saturated with HCl, allowed to warm to r.t. over 2 h and evaporated. 5-[2-(Dimethylamino)ethoxy]-1-H-indole-2-carboxylic acid hydrochloride (0.13 g, 0.47 mmol) [Milbank et al., J. Med. Chem., 1999, 42, 649], EDCI (0.27 g, 1.42 mmol) and DMA (3 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 20 h. The mixture was partitioned between EtOAc and 5% NaHCO3 solution. The aqueous layer was extracted with EtOAc (×3). The EtOAc extracts were dried (brine, Na2SO4). Flash chromatography (Alumina, EtOAc/MeOH; 49:1, then 9:1) gave 2-[(2-{[5-(benzyloxy)-1-(chloromethyl)-1,2-dihydro-3H-pyrrolo[3,2-f]quinolin-3-yl]carbonyl}-1H-indol-5-yl)oxy]-N,N-dimethylethanamine (17b) (0.22 g, 84%) as a yellow solid: mp 176–179° C.; 1H NMR [(CD3)2SO]δ 11.68 (s, 1 H), 8.79 (dd, J=4.1, 1.5 Hz, 1 H), 8.41 (dd, J=8.6, 1.5 Hz, 1 H), 8.29 (s, 1 H ), 7.56 (m, 3 H), 7.40 (m, 4 H), 7.17 (d, J=2.3 Hz, 1 H ), 7.11 (d, J=1.5 Hz, 1 H), 6.92 (dd, J=9.0, 2.4 Hz, 1 H), 5.32 (s, 2 H), 4.82 (dd, J=10.7, 9.6 Hz, 1 H), 4.58 (dd, J=10.9, 2.1 Hz, 1 H), 4.32 (m, 1 H), 4.05 (t, J=5.7 Hz, 2 H), 4.04 (m, 1 H), 3.93 (dd, J=11.2, 6.9 Hz, 1 H), 2.65 (t, J=5.8 Hz, 2 H), 2.23 (s, 6H); 13C NMR [(CD3)2SO]δ 160.3, 154.5, 153.0, 147.3, 142.3, 137.4, 136.7, 131.6, 131.3, 130.6,128.4, 127.9, 127.7, 127.4, 125.1, 122.4, 116.2, 116.0, 113.1, 105.5, 103.1, 102.0, 70.0, 66.9, 66.2, 57.8, 54.9, 47.7, 45.5, 40.7.