Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[C:21](N)[C:4]=2[N:3]=1.N([O-])=[O:30].[Na+].C([O-])(O)=O.[Na+]>O.CO.OS(O)(=O)=O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:20]=[C:21]([OH:30])[C:4]=2[N:3]=1
Reactant: O=N[O-]
Reactant: Cc1nc2c(N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc2c(O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-methyl-6-morpholino-1-(naphthalen-1-ylmethyl)-1H-benzo[d]imidazol-4-amine (842 mg) in H2O (20 mL), MeOH (1 mL) and conc. H2SO4 (3 mL) was added aqueous NaNO2 (344 mg) solution drop-wise at 0° C. The mixture was stirred at 0° C. for 15 min and then stirred at reflux temperature for 1 h. The mixture was cooled to room temperature and the pH neutralized with aqueous NaHCO3 solution. It was extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo. The residue was then purified by silica gel chromatography eluted with MeOH:DCM=1:60 and then by Prep-HPLC to afford crude desired product LC-MS: m/e=374 [M+1]+ containing an impurity that was removed by the two-step sequence described below.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18]Cl)[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:17]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(CSc2ccc([N+](=O)[O-])cc2)cs1
Yield: 99.4 %

Procedure:
A mixture of 4-nitrothiophenol (9.3 g), 2-amino-4-chloromethylthiazole hydrochloride (11 g) and potassium carbonate (20 g) in N,N-dimethylformamide (200 ml) was heated at 85°-90° C. for 5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-4-(4-nitrophenylthiomethyl)thiazole (15.80 g, yield: 98.6%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH:21]([C:24](=O)[CH3:25])[CH2:20][CH2:19][CH2:18][C:8]=2[N:9](C(OC(C)(C)C)=O)[CH:10]=1)=[O:5])[CH3:2].Cl.[NH2:28]O>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22]3[O:23][N:28]=[C:24]([CH3:25])[C:21]=3[CH2:20][CH2:19][CH2:18][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(C(C)=O)CCC2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2c1-c1onc(C)c1CCC2
Temperature: 100 °C
Yield: 76 %

Procedure:
In a sealed tube were 5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.1 mmol) and hydroxylamine hydrochloride (2.2 mmol) and 10 mL EtOH. The mixture is heated at 100° C. for 16 hours. The solvent is evaporated in vacuo and the residue is taken up in CH2Cl2 and washed two times with NaHCO3 (aq). The organic layer is dried over Na2SO4 and evaporated in vacuo and the residue chromatographed using 10% MeOH in CH2Cl2 as mobile phase to yield 3-methyl-4,5,6,7-tetrahydro-1-oxa-2,7-diaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester as a white solid (76%). 1H NMR (CDCl3+CD3OD) 1.3 (t, 3H), 1.90-1.98 (m, 2H), 2.10 (s, 3H), 2.35 (t, 2H), 2.75-2.82 (m, 2H), 4.21 (q, 2H), 7.15 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:19]([N:21]([CH2:36][CH3:37])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:36]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:37]
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(OC)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.3 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (94 mg, 78%).
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.[Cl:18][C:19]1[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[C:21](Cl)[N:20]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:18][C:19]1[N:20]=[C:21]([N:4]2[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH:3]2[C:7]([O:9][CH3:10])=[O:8])[CH:22]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[N:24]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2C(=O)OC)nc(Cl)n1
Temperature: 50 °C

Procedure:
A mixture of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate (5.133 g, 21.01 mmol), methyl 2,6-dichloropyrimidine-4-carboxylate (4.354 g, 21.03 mmol), and iPr2NEt (4.0 mL, 23.0 mmol) in acetonitrile (50 mL) was heated at 50° C. for 4 h. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 20-70% EtOAc in hexanes. The product fractions were evaporated in vacuo to give 1-tert-butyl 3-methyl 4-(2-chloro-6-(methoxycarbonyl)pyrimidin-4-yl)piperazine-1,3-dicarboxylate as a very pale yellow powder (6.626 g, 15.97 mmol, 76% yield). LC/MS: m/z=415.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:3]=2[OH:2])[CH2:14][CH2:15]1)[CH2:20][CH3:21]
Reactant: CCCN1CCC(c2cccc(C(F)(F)F)c2OC)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCN1CCC(c2cccc(C(F)(F)F)c2O)CC1
Reaction time: 2 h

Procedure:
4-[2-methoxy-3-(trifluoromethyl)phenyl]-1-propylpiperidine (0.18 g, 0.6 mmol) and pyridine hydrochloride (2 g) was heated to 190° C. and stirred for 2 h. Aqueous sodium carbonate (10%, 50 ml) and ethyl acetate (50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phase was dried (MgSO4) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethyl acetate/methanol, 1:1) gave the title compound: 0.17 g (98%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 218-220° C. MS m/z (relative intensity, 70 eV) 287 (M+, 10), 259 (14), 258 (bp), 238 (15), 195 (19).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(#N)C>[Br:9][C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(Cl)n1
Solvent: CC#N
Product: Nc1ccc(Br)c(Cl)n1
Reaction time: 13 h
Yield: 86.8 %

Procedure:
6-Chloropyridin-2-amine (2.0 g) was dissolved in acetonitrile (40 ml). N-Bromosuccinimide (3.1 g) was added and the mixture was stirred under shading at room temperature for 13 hours. The reaction solution was concentrated and the resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (2.8 g).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17]2.C1OCCOCCOCCOCCOCCOC1>C(#N)C>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([O:24][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH:18]=[CH:17]2
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CC#N
Product: N#Cc1ccc([N+](=O)[O-])cc1Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
After heating to reflux 2-fluoro-4-nitrobenzonitrile (1 g), 6-bromo-2-naphthol (1.41 g), potassium fluoride/alumina (0.7 g) and 18-crown-6 (0.16 g) in acetonitrile, the mixture was reacted for 12 hours. It was then cooled to room temperature, the insoluble portion was filtered using celite, the ethyl acetate layer was washed with water and saturated saline and then dried over magnesium sulfate, and the solvent was distilled off. Methanol was added to the residue for crystallization to obtain 1.43 g of 2-(6-bromo-2-naphthyloxy)-4-nitrobenzonitrile.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[Na+].[Cl:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11]>C1(C)C=CC=CC=1>[Cl:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:11]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(C)(C)CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A slurry of sodium tert-butoxide (195.3 g, 2.03 mol) in 800 mL of dry toluene was cooled to 0° C. in an ice bath. To the stirred slurry was added 3-chloropivaloyl chloride (XIII) (300.0 g 1.94 mol) dropwise at a rate sufficient to maintain the reaction temperature below 10° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, the mixture extracted with ether, and the ether layer washed with water and saturated NaHCO3. After drying over MgSO4, the solution was filtered and concentrated to give the product as an amber oil. 1H NMR (CDCl3) δ 1.24 (s,6H), 1.46 (s,9H), 3.57 (s,2H); 13C NMR (CDCl3) δ 22.96, 27.70, 44.80, 53.32, 80.87, 174.5.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:17](I)[CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:13]([O:15][CH3:16])=[O:14])[C:2]=1[O:1][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)c1cc2ccccc2c(C)c1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1c(C(=O)OC)cc2ccccc2c1C
Temperature: 60 °C
Reaction time: 120 h

Procedure:
3-Hydroxy-4-methyl-2-naphthoic acid was prepared according to a literature procedure (Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol. 2 (1979), 786; Farmaco, Ed. Sci. 33 (1978), 822) and esterified with methanol using standard conditions to give methyl 3-hydroxy-4-methyl-2-naphthoate. A suspension of 300 mg (1.39 mmol) of this ester, 263 mg (1.55 mmol) propyl iodide, and 215 mg (1.55 mmol) of dry potassium carbonate in 60 ml of absolute butanone was stirred at 60° C. for 5 days. After addition of the same amounts of propyl iodide and potassium carbonate stirring was continued at 60° C. for another 2 days. The inorganic salts were filtered off, washed with acetone, and together with a small amount of silica gel the filtrate was evaporated to dryness. The remaining powder was applied to column chromatography on silica gel using hexane followed by a hexane/tert.-butylmethylether gradient up to 9:1.
Reaction SMILES: [S:1]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15](=[O:22])[CH2:14][CH2:13][CH2:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:33])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1.C(NC(C)C)(C)C.C([Li])CCC>[F:33][CH:14]1[C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])[CH2:12][CH2:13]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(S(=O)(=O)N2CCC(F)C(=O)c3ccccc32)cc1
Temperature: -78 °C
Yield: 78.6 %

Procedure:
In 150 ml of tetrahydrofuran was dissolved 3.55 ml of diisopropylamine, and 14.9 ml of n-butyllithium was added dropwise while stirring at -78° C. in an atmosphere of argon. After 30 minutes of stirring under ice-cooling, the reaction mixture was cooled to -78° C., 60 ml of tetrahydrofuran solution containing 6.39 g of 1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one was added dropwise thereto and the resulting mixture was stirred for 30 minutes. Then, 90 ml of tetrahydrofuran solution containing 8.94 g of N-fluorobenzenesulfonimide was added dropwise, and the mixture was stirred for 1 hour while gradually increasing the temperature to 0° C. After adding saturated ammonium chloride aqueous solution to the reaction solution, the mixture was concentrated under a reduced pressure. Ethyl acetate was added thereto to separate the water layer, and the organic layer was washed with saturated sodium thiosulfate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in that order. The organic layer was then dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting residue was applied to silica gel column chromatography, which was eluted with chloroform to obtain 5.31 g of 4-fluoro-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[N:43]1([C:48](N)=[O:49])[CH:47]=[CH:46][N:45]=[CH:44]1>>[C:31]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:29][NH:28][C:9]2[N:8]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][C:48]([NH:43][CH2:47][CH2:46][N:45]3[CH2:38][CH2:37][CH:30]([CH:31]([CH3:36])[CH3:32])[CH2:29][CH2:44]3)=[O:49])=[O:6])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(=O)n1ccnc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCCN4CCC(C(C)C)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
Prepared from N-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 10) and N-[2-4-isopropyl-1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (Preparation 22) by a similar method to Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([O:20][CH3:21])[N:13]=1)[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]2=[O:25].Cl.Cl.[NH2:30][CH:31]1[CH2:34][NH:33][CH2:32]1.CN1CCCC1>C(#N)C>[NH2:30][CH:31]1[CH2:34][N:33]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:25])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][N:10]3[C:12]3[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([O:20][CH3:21])[N:13]=3)=[CH:5][C:4]=2[F:26])[CH2:32]1
Reactant: NC1CNC1
Reactant: COc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CC#N
Product: COc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Yield: 33.1 %

Procedure:
To 500 mg of acetonitrile were added 75 mg of 8-chloro-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 65 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was heated under reflux for 1 hour. The precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 28 mg of the title compound as a colorless powder. 5 Melting point: 171 to 175° C.
Reaction SMILES: C(OC(=O)[N:7]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:8][CH2:9][NH:10][CH2:11][C:12]1([C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:33][C:28]1[CH:27]=[C:26]([NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]2([C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=3)[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CN1CCC(CNCCN(C(=O)OC(C)(C)C)c2ccc(F)c(F)c2)(c2ccc(I)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CNCCNc2ccc(F)c(F)c2)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a stirred solution of (3,4-difluoro-phenyl)-(2-{[4-(4-iodo-phenyl)-1-methyl-piperidin-4-ylmethyl]-amino}-ethyl)-carbamic acid tert-butyl ester (2.03 g, 3.47 mmol) in CH2Cl2 (25 mL) at 0° C. was added TFA (6 mL, to give a 25% v/v solution). The mixture was stirred and warmed to room temperature for 4 h. The solvent was removed by rotary evaporation and the residue was dissolved in EtOAc (50 mL) and washed with 10% aqueous NaHCO3 (2×50 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give N-(3,4-difluoro-phenyl)—N′-[4-(4-iodo-phenyl)-1-methyl-piperidin-4-ylmethyl]-ethane-1,2-diamine (1.20 g, 96%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na].Br[CH2:11][CH2:12][CH3:13]>C(O)CC>[CH3:8][C:3]1[C:2]([O:1][CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCCBr
Reactant: Cc1ncccc1O
Agent: [Na]
Solvent: CCCO
Product: CCCOc1cccnc1C

Procedure:
3-Hydroxy-2-methylpyridine (50 g) was added to a solution of sodium (11.6 g) in propan-1-ol (250 ml) and the mixture treated with 1-bromopropane (51 ml) in propan-1-ol (50 ml) to give 2-methyl-3-propoxypyridine, b.p. 96°-104° C. (30 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:30])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([C:21](=O)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:30])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(Oc2ccc(OC)c(C(=O)c3ccc(F)cc3)c2)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)c(Oc2ccc(OC)c(Cc3ccc(F)cc3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a stirred solution of methyl 3,5-dichloro-4-[3′-(4-fluorobenzoyl)-4′-methoxyphenoxy]benzoate (350 mg, 0.78 mmol) and TFA (2 mL) in CH2Cl2 (50 mL) at room temperature was added triethylsilane (0.5 mL, 3.1 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with water (25 mL) and extracted with ether (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with hexanes, filtered and dried under reduced pressure to afford methyl 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]benzoate as a brown solid (0.31 g, 92%): mp 108-110° C.; 1H NMR (300 MHz, CDCl3): δ 7.98 (s, 2H), 7.06 (dd, J=6.0, 9.0 Hz, 2H), 6.88 (t, J=8.7 Hz, 2H), 6.70 (d, J=9.0 Hz, 1H), 6.58 (d, J=3.0 Hz, 1H), 6.48 (dd, J=3.3, 9.0 Hz, 1H), 3.89 (s, 3H), 3.83 (s, 2H), 3.71 (s, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (2:8); Rf=0.8.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:15])[CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8].Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].Cl>CS(C)=O>[CH3:15][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]([O:8][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCC(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
70 ml of dimethylsulfoxide were added over 10 minutes at 60°-65° C. to a mixture of 20 ml of dimethylsulfoxide and 9.2 g of sodium hydride in a 50% oil disperson and after cooling the mixture to 25° C., 17.28 g of N,N-dimethyl-3-phenyl-3-hydroxy-propanamine were added thereto. The temperature returned to room temperature and 25.2 g of o-chloro-nitrobenzene were added thereto. The mixture was held at 25° C. for one hour and was then extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness to obtain 41 g of raw product which was taken up twice in 100 ml of N hydrochloric acid. The neutral fraction was extracted twice with 400 ml of ether and the aqueous phase was made alkaline by addition of 50 ml of sodium hydroxide solution. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and treated with activated carbon. The mixture was filtered and the filtrate was evaporated to dryness to obtain 22 g of N,N-dimethyl-γ-(2-nitrophenoxy)-benzene-propanamine.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42])=[CH:35][C:34]=4[CH3:44])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=O)(C)(C)C.C(Cl)(Cl)[Cl:46].[ClH:49].O1CCOCC1>O1CCOCC1>[ClH:46].[ClH:49].[NH2:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42])=[CH:35][C:34]=4[CH3:44])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11]
Reactant: Cc1cc(/C=C/C(=O)O)cnc1N1CCN(c2ncc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cn2)CC1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(/C=C/C(=O)O)cnc1N1CCN(c2ncc(-c3cccc(CN(C)C(=O)CN)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2E)-3-[6-(4-{5-[3-({[N-(tert-Butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-methylpyridin-3-yl]acrylic acid (147 mg) was dissolved in dioxane (3 ml), and CHCl3 (1 ml) and 4 M hydrogen chloride/dioxane (1 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain (2E)-3-(6-{-4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-5-methylpyridin-3-yl)acrylic acid dihydrochloride (130 mg).