Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][OH:5].C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH:3]([O:6][CH2:7][CH2:8][NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:4][O:5][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)NCCOC(CO)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCOC(COS(C)(=O)=O)COS(C)(=O)=O
Temperature: -3 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
A 20-L 4-neck round-bottom flask was flushed with N2, then charged a solution of tert-butyl 2-(1,3-dihydroxypropan-2-yloxy)ethylcarbamate (418 g, 1.8 mol, 1.0 eq) in dichloromethane (9000 mL, 21.5 v) and N,N-diisopropylethylamine (574 g, 4.4 mol, 2.5 eq). This is followed by dropwise addition of methanesulfonyl chloride (509 g, 4.4 mol, 2.5 eq) with stirring at −6-0° C. over 1 hour. The resulting mixture was stirred for 4 h at −6˜4° C., then washed with water (3×4000 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/EtOAc (1:1) to give 740 g (101.0%) of 2-(2-(tert-butoxycarbonylamino)ethoxy)propane-1,3-diyl dimethanesulfonate as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[N:10]=2)[N:5]=[CH:6][N:7]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(OCC)(=O)C.CCCCCC>C(O)C>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:8]2[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[N:10]=[C:3]3[C:2]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:7][CH:6]=[N:5][C:4]=23)=[CH:23][CH:22]=1
Reactant: Clc1ccc(-c2c3ncnc(Cl)c3nn2-c2ccccc2Cl)cc1
Reactant: C1CCNC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: Clc1ccc(-c2c3ncnc(N4CCCC4)c3nn2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
To a suspension of 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine I-2A-1c (40 mg, 0.1 mmol) in 5 ml ethanol was added pyrrolidine (711 mg, 10 mmol). The reaction mixture was stirred at room temperature for 1 hour and became homogeneous. After the reaction was complete (as monitored by TLC, ethyl acetate/hexane, 50/50), ethanol was removed under reduced pressure. The residue was redissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated. The crude product was purified by HPLC to give 3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-pyrrolidin-1-yl-2H-pyrazolo[4,3-d]pyrimidine 2A-1 (17 mg, 38.2%). MS: 410.2 (M+1)+; 1H NMR (400 MHz, CD2Cl2) δ 8.3 (s, 1H), 7.5 (m, 6H), 7.3 (d, J=8.7 Hz, 2H), 4.2 (t, J=6.3 Hz, 2H), 3.8 (t, J=7.1 Hz, 2H), 2.1 (m, 4H).
Reaction SMILES: BrC1C(OC)=CC=CN=1.C([Li])CCC.[Li].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(OCC)C.CCCCCC.O1CCCC1.O>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([CH2:23][OH:24])=[CH:25][CH:26]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: COc1cccnc1Br
Agent: [Li]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(CO)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 2-bromo-3-methoxypyridine (1.00 g) in diethylether (20 ml) was added a solution of n-butyllithium in hexane (1.6M, 3.7 ml) at -78° C., and the mixture was stirred for 1 hour to prepare the lithium salt, which was dropwise added to a solution of 4-nitrobenzaldehyde (0.81 g) in tetrahydrofuran (10 ml) cooled at -78° C. The mixture was stirred at -78° C. To the reaction mixture was added water to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. Under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate/hexane=1:3→1:1) to give 3-methoxypyridin-2-yl)-(4-nitrophenyl)methanol (742 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:15][O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Al](C)C.[CH3:20][O:21][C:22](=[O:43])[CH2:23][C@H:24]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(=O)=O.CC(C)=O.[F-].[Na+].O>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:36]([N:35]([CH2:15][C@@H:13]([OH:14])[CH2:12][O:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C@@H:24]([CH2:23][C:22]([O:21][CH3:20])=[O:43])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: COC(=O)C[C@H](NCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Al](C)C
Agent: O=C=O
Agent: [F-]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)C[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)C[C@@H](O)COS(=O)(=O)c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
To a solution of (2R)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (23.0 g, 0.101 mol) in 500 mL of methylene chloride was added 2.000 M of trimethylaluminum in Toluene (50.4 mL) at −78 Celsius, under an atmosphere of nitrogen. After stirred at −78 Celsius for 10 min, to the mixture was added a solution of (S)-2-benzylamino-succinic acid 1-benzyl ester 4-methyl ester (30.0 g, 0.0916 mol) in 150 mL of methylene chloride. The resulting reaction mixture was stirred at −78 Celsius for 30 min. The dry ice-acetone bath was changed to an ice-water bath to warm the mixture up to 0 Celsius. The mixture was stirred at 0 Celsius for 30 min. To the reaction mixture was added sodium fluoride (16.2 g, 0.385 mol) followed by Water (10.4 mL, 0.577 mol) at 0 Celsius. The resulting suspension was rapidly stirred for 1 h at 0 Celsius and filtered through a short column of Celite and the column was subsequently washed with 600 mL of methylene chloride. The combined filtrates were dried over sodium sulfate, concentrated to dry and purified by column purification (eluting with 0 to 30% EtOAc in hexane) to give the titled compound (43.0 g, 84.4%). MS (ESI): (M+H)+=556.1.
Reaction SMILES: Cl.[NH2:2][OH:3].O.[OH-].[Na+].[NH2:7][C:8]1[CH:13]=[C:12]([C:14](=O)[CH3:15])[CH:11]=[CH:10][N:9]=1>CO>[NH2:7][C:8]1[CH:13]=[C:12]([C:14](=[N:2][OH:3])[CH3:15])[CH:11]=[CH:10][N:9]=1
Reactant: NO
Reactant: CC(=O)c1ccnc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NO)c1ccnc(N)c1
Temperature: 0 °C

Procedure:
To a solution of 3.1 g. (45 mmoles) of hydroxylamine hydrochloride in 10 ml. of water was added 22.5 ml. of 2 N sodium hyroxide solution. To this solution was added 3.6 g. (26 mmoles) of 1-(2-amino-4-pyridyl)-1-ethanone and the mixture heated to the boiling point for 5 minutes. Methanol was added slowly until the mixture became homogeneous. Heating was continued until a precipitate began to form. The mixture was cooled to 0° C., and the resulting precipitate was filtered, washed with water and dried in vacuo. Recrystallization from ethyl acetate afforded 3.6 g. (92%) of the desired oxime, m.p. 215°-217° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.[CH2:14]([N:16]1[C:22]2[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:19][CH2:18][C:17]1=[O:37])[CH3:15].[N+:38]([C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[CH2:43]Br)([O-:40])=[O:39].O>C1COCC1>[CH3:28][O:27][C:25]1[C:24]([O:29][CH3:30])=[CH:23][C:22]2[N:16]([CH2:14][CH3:15])[C:17](=[O:37])[CH:18]([CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=3[N+:38]([O-:40])=[O:39])[N:19]=[C:20]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:21]=2[CH:26]=1
Reactant: CCN1C(=O)CN=C(c2ccccc2)c2cc(OC)c(OC)cc21
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1C(=O)C(Cc2ccccc2[N+](=O)[O-])N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of 920 μl (1.84 mmol) of 2M LDA/THF in 5 ml of anhydrous THF, add dropwise at −78° C. under an inert atmosphere a solution of 300 mg (0.92 mmol) of 1-ethyl-7,8-dimethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbd) in 2 ml of THF. Allow to equilibrate to room temperature for 30 minutes. Add dropwise at −30° C. a solution of 220 mg (1.01 mmol) of 2-nitrobenzyl bromide in 2 ml of THF. Stir at room temperature for 12 hours. Add 1 ml of H2O. Evaporate the THF. Purify by silica chromatography (AcOEt 1/hexane 4, 1/1, then AcOEt). Recrystallize in EtOH/cHexane. Yield: 35%. M: 158–160° C. 1H-NMR (DMSO, 300 MHz): d 0.87–0.91 (m, 3H, CH3), 3.61–3.99 (m, 10H, NCH+CHCH2+2OCH3), 4.35–4.40 (m, 1H, NCH), 6.60 (s, 1H Ar), 6.82 (s, 1 H Ar), 7.37–7.90 (m, 9H Ar). Mass: (M+H)+=460.88.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1.NN.[OH-].[K+].Cl>C(O)CO.O>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)O)c1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: Cc1cccc(C)c1COc1cccc(CCCC(=O)O)c1

Procedure:
A solution of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid (Step D, 3 g, 9.6 mmol), hydrazine (1.41 ml, 28.8 mmol) and potassium hydroxide (1.61 g, 28.8 mmol) in ethylene glycol (12 ml) was refluxed for 4 h, water (18 ml) and 6 N HCl (10 ml) were added to the reaction mixture. The crude reaction mixture was concentrated, and the residue was dissolved in EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The purification was done by flash chromatography on silica gel column (chloroform:methanol 95:5 spiked with acetic acid) to provide the title compound as a white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH:24]([C:25]2[NH:26][C:27]([CH3:36])=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:29]=2)[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=O)(C)(C)C>>[CH3:36][C:27]1[NH:26][C:25]([CH:24]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][NH:15]2)=[N:29][C:28]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1[nH]c(C2Cc3ccccc3CN2C(=O)OC(C)(C)C)nc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(C2Cc3ccccc3CN2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of TFA (5 mL) cooled to about 0° C. was added the compound prepared in Step A above (1.10 g, 2.82 mmol), and the reaction mixture stirred for about 30 minutes. The reaction mixture was then removed from the ice bath and allowed to warm to room temperature. Excess TFA was removed under a stream of N2. The residue was partitioned between saturated NaHCO3 and dichloromethane. The aqueous phase was washed with a second portion of dichloromethane and the organic phases combined. The combined organic phase was dried over Na2SO4, then filtered to yield the title product as a solution in dichloromethane, which was used without further purification or isolation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:24][O:25][C:26]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][C@@H:36]2[CH2:40][C@H:39]([O:41][C:42]3[CH:51]=[CH:50][C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:43]=3)[CH2:38][NH:37]2)=[N:32][CH:33]=1)=[O:27].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:24][O:25][C:26]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][C@@H:36]2[CH2:40][C@H:39]([O:41][C:42]3[CH:51]=[CH:50][C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:43]=3)[CH2:38][N:37]2[C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:32][CH:33]=1)=[O:27]
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2)nc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.1 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (89 mg, 0.283 mmol), methyl-2-[(2S,4S)-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxypyridine-5-carboxylate (107 mg, 0.78 mmol), EDC.HCl (81 mg, 0.425 mmol) and DMAP (52 mg, 0.425 mmol) in DMF (3 ml) was stirred at room temperature for 18 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was purified on TLC [CHCl3/MeOH (10/1)], to give 2-[(2S,4S)-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxy-5-pyridinecarboxylic acid methyl ester (193 mg, 100%) as a colorless amorphous. 1H-NMR (CDCl3) δ2.27 (d, J=3.2 Hz, 3H), 2.30 (m, 1H), 2.49 (dd, J=14.2, 2.0 Hz, 1H), 3.60 (d, J=3.9 Hz, 1H), 3.67 (d, J=5.9 Hz, 3H), 3.81 (s, 1H), 3.85 (s, 1H), 3.88 and 3.91 (s, 3H, amide isomers), 3.95 (m, 1H), 4.02-5.09 (m, 4H), 6.67 (d, J=8.8 Hz, 1H), 6.73-7.13 (m, 3H), 7.20-7.45 (m, 7H), 7.53 (t, J=7.8 Hz, 1H), 7.67-7.77 (m, 3H), 8.02-8.84 (m, 3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:51]=[CH:50][C:29]2[N:30]3[C:34]([CH2:35][NH:36][CH2:37][C:28]=2[CH:27]=1)=[N:33][N:32]=[C:31]3[CH:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[CH2:40][CH2:39]1.C(N(CC)CC)C.[CH3:59][N:60]([CH2:62][C:63](O)=[O:64])[CH3:61]>CN(C)C(=O)C>[Cl:25][C:26]1[CH:51]=[CH:50][C:29]2[N:30]3[C:34]([CH2:35][N:36]([C:63](=[O:64])[CH2:62][N:60]([CH3:61])[CH3:59])[CH2:37][C:28]=2[CH:27]=1)=[N:33][N:32]=[C:31]3[CH:38]1[CH2:39][CH2:40][N:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[CH2:42][CH2:43]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CN(C)CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 50 °C
Yield: 57.8 %

Procedure:
A solution of HBTU (152 mg, 0.38 mmol) in N,N-dimethylacetamide (1.9 ml) was added to a solution of the amine of example 4 (97 mg, 0.26 mmol), triethylamine (1.5 μl, cat.) and dimethylamino-acetic acid (36 mg, 0.26 mmol) in N,N-dimethylacetamide (2.5 ml) and heated to 50° C. for 2 hours. The mixture was cooled and the solvent evaporated under reduced pressure. The residue was partitioned between dichloromethane (10 ml) and 2M aqueous sodium hydroxide solution (10 ml). The organic phase was dried over magnesium sulphate before being evaporated under reduced pressure and purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (7:1:93) as eluant to afford the title compound (70 mg) as a brown foam.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][C:10]2[C:11]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:5]([NH2:6])=[C:4]([F:22])[CH:3]=1.[F:23][C:24]([F:34])([F:33])[C:25](=[O:32])[CH2:26][C:27](OCC)=[O:28].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:8]([O:9][C:10]2[C:11]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:5]([NH:6][C:27](=[O:28])[CH2:26][C:25]([C:24]([F:34])([F:33])[F:23])=[O:32])=[C:4]([F:22])[CH:3]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(N)c(F)cc1Cl
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)COc1ncccc1Oc1cc(NC(=O)CC(=O)C(F)(F)F)c(F)cc1Cl
Yield: 100.5 %

Procedure:
A mixture of 0.50 g of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}aniline, 0.28 g of ethyl trifluoroacetoacetate and 10 ml of toluene was subjected to azeotropic reaction with removing ethanol by passing through molecular sieves 5A for 3 hours. After cooling, the reaction solution was concentrated to obtain 0.71 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]trifluoroacetoacetamide.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:22][CH:21]([CH2:23][N:24]5[CH2:29][CH2:28][N:27]([CH:30]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]5)[O:20][C:19]4=[O:42])=[CH:14][CH:13]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C>CO>[C:7]([NH:8][C:9]([C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:22][CH:21]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH:30]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]3)[O:20][C:19]2=[O:42])=[CH:16][CH:17]=1)=[NH:10])(=[O:11])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(C(=O)OCC)N1CCN(CC2CN(c3ccc(C4=NOC(c5ccccc5)N4)cc3)C(=O)O2)CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CC(C(=O)OCC)N1CCN(CC2CN(c3ccc(C(=N)NC(=O)c4ccccc4)cc3)C(=O)O2)CC1

Procedure:
1,3 g 3-[4-(5-phenyl-1,2,4-oxadiazolin-3-yl)phenyl]-5-[4-(1,2-diethoxycarbonyl-ethyl)-piperazinomethyl]-oxazolidin-2-one [obtainable as described in Ex. 14] are dissolved in 50 ml methanol and hydrogenated on Raney nickel. The reaction mixture is then filtered and the filtrate is concentrated in vacuo. The product obtained is treated with 20 ml of ethyl acetate in the presence of heat and filtered off with suction after cooling. 3-[4-(N-benzoylamidino)-phenyl]-5-[4-(1,2-diethoxycarbonylethyl)-piperazinomethyl]-oxazolidin-2-one, m.p. 136°, is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O>C(Cl)(Cl)Cl>[C:15]1([C:13]2[N:1]=[C:2]3[N:6]([CH:12]=2)[C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[S:3]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc2c(s1)CCCC2
Reactant: O=C(CBr)c1ccccc1
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2cn3c4c(sc3n2)CCCC4)cc1

Procedure:
0.1 m. Quantities of 2-amino-4,5,6,7-tetrahydrobenzothiazole and α-bromoacetophenone in 100 ml. of chloroform are heated at reflux for 2 hours. After cooling, the solid is filtered off and slurried in 1 l. of water containing 40 g. of ammonium acetate. This suspension is heated to boiling over a 2-hour period and allowed to cool. The product is collected, washed with water and dried. The yield of product is 19.8 g. melting at 158°-160° C. and having the formula: ##STR20##
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17]([OH:19])=O.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:24]([F:23])([F:33])[F:34])=[CH:27][CH:28]=1)=[O:19]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CC#N
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Carbonyldiimidazole (2.367 g, 14.60 mmol) was added to a stirred solution of 2-bromoisonicotinic acid (2.4572 g, 12.16 mmol) in MeCN (30 mL) and the RM was stirred at RT for 3 h. 4-(trifluoromethoxy)aniline (2.467 mL, 18.25 mmol) was added and RM was stirred at RT overnight. and the mixture was treated with sat. aq. Na2CO3 (50 mL) and extracted with TBME. The combined extracts were washed with aq. HCl (pH=3), brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to a residue which was triturated with n-heptane and filtered to yield the title compound as a white solid. UPLC-MS (Condition 1) tR=1.55 min, m/z=360.9-362.9 [M+H]+, m/z=358.9-360.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.40 (d, J=8.56 Hz, 2H) 7.77-7.97 (m, 3H) 8.12 (s, 1H) 8.61 (d, J=5.14 Hz, 1H) 10.72 (s, 1H).
Reaction SMILES: [Li].[CH3:2]I.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12]23[CH2:27][CH:16]([N:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]2=O)[CH2:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][CH:11]=1.[BH4-].[Na+]>CCOCC.C1C=CC=CC=1.C(O)C.O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12]23[CH2:27][CH:16]([N:17]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:18]2[CH3:2])[CH2:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(C23CCCC(C2)N(Cc2ccccc2)C3=O)c1
Reactant: CI
Agent: [BH4-]
Agent: [Li]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: COc1cccc(C23CCCC(C2)N(Cc2ccccc2)C3C)c1
Reaction time: 0.83 h
Yield: 39.3 %

Procedure:
0.262 g of lithium is added to 10 ml of absolute ether in a nitrogen atmosphere, and a solution of 2.8 g of methyl iodide in 5 ml of absolute ether is added dropwise thereto at 0° to 5°C. The mixture is stirred at the same temperature for 50 minutes. Then, a solution of 1.5 g of 1-(3-methoxyphenyl)-6-benzyl-6-azabicyclo[3,2,1]octane- 7-one in 30 ml of absolute benzene is added dropwise to the mixture at 5° to 10°C in a nitrogen atmosphere. The mixture is stirred at room temperature overnight. After water is added to the mixture, the benzene-ether layer is washed with water, dried and then evaporated to remove solvent. The residue thus obtained is dissolved in 60 ml of ethanol, and 0.355 g of sodium borohydride is added to the ethanol solution at 8° to 10°C. The ethanol solution is stirred at room temperature for 2 hours. Then, the ethanol solution is concentrated under reduced pressure to remove solvent. water is added to the residue, and the aqueous mixture is extracted with ether. The ether extract is extracted with 10% aqueous hydrochloric acid. The aqueous extract is washed with ether, made alkaline with ammonia and again extracted with ether. The ether extract thus obtained is dried and evaporated to remove solvent. The residue is dissolved in 5 ml of chloroform. The chloroform solution is poured onto a column of 100 g of silica gel. Then, the column is eluted with a mixture of 2850 ml of chloroform and 150 ml of methanol. The effluent obtained is evaporated to remove solvent, whereby 0.59 g of 1-(3-methoxyphenyl)-6-benzyl-7-methyl-6-azabicyclo[3,2,1]octane is obtained. Picrate: M.p. 184°-186°C(recrystallized from methanol).
Reaction SMILES: Cl[C:2]1[C:7]2[S:8][C:9]([C:11]3[N:16]=[C:15]([CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[CH:13][CH:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:30]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([F:40])[CH:34]=1)([O-:32])=[O:31].CCN(CC)CC>C1(OC2C=CC=CC=2)C=CC=CC=1.C1COCC1.CCOC(C)=O>[F:40][C:35]1[CH:34]=[C:33]([N+:30]([O-:32])=[O:31])[CH:38]=[CH:37][C:36]=1[O:39][C:2]1[C:7]2[S:8][C:9]([C:11]3[N:16]=[C:15]([CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[CH:13][CH:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCCN(Cc1cccc(-c2cc3cccc(Cl)c3s2)n1)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCN(Cc1cccc(-c2cc3cccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
A solution of 57 (1.43 g, 3.3 mmol) and 2-fluoro-4-nitrophenol (3) (1.03 g, 6.61 mmol) in diphenyl ether (30 mL) were stirred overnight at 160° C. The reaction mixture was cooled down to room temperature, diluted with THF (30 mL), treated with Et3N (1.38 mL, 9.9 mmol) and Boc-anhydride (1.08 g, 4.95 mmol) and stirred at room temperature for 2 h. It was then diluted with EtOAc (100 mL) and washed with saturated NaHCO3 (100 mL). The organic phase was collected, dried over Na2SO4, filtered and concentrated. Obtained crude product was purified by flash chromatography (using the gradient 70-100% EtOAc in hexanes as an eluent), yielding 58 (850 mg, 47% yield). MS (m/z): 555.2 (M+1).