Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:3][CH2:4][OH:5])[NH2:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:17]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=3)[C:16](=[O:27])[C:15](=O)[CH:14]2[C:29](=O)[CH2:30][CH3:31])=[CH:9][CH:8]=1.CC(O)=O.S(=O)(=O)(O)N>CO>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:14]3[C:29]([CH2:30][CH3:31])=[N:2][N:1]([CH2:3][CH2:4][OH:5])[C:15]=3[C:16](=[O:27])[N:17]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:9][CH:8]=1
Reactant: NNCCO
Reactant: CCC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Agent: NS(=O)(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: CCc1nn(CCO)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 90 °C
Yield: 45 %

Procedure:
To a solution of 2-hydrazinylethanol (76 mg, 1.0 mmol) in MeOH (2 mL) was added 5-(4-chlorophenyl)-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-propionylpyrrolidine-2,3-dione (Step 60.1) (204 mg, 0.5 mmol) and the reaction mixture was heated for 1 hr at 70° C. and for 0.5 hr at 90° C. in the MW. The volume of MeOH was reduced to 1 mL and AcOH (2 mL) and sulfamic acid (97 mg, 1.0 mmol) were added. The reaction mixture was heated for 1 h at 110° C. in the MW. The reaction mixture was concentrated under reduced pressure. The residue was basified with 20% K2CO3 solution and extracted with EtOAc. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was first purified by silica gel column chromatography (hexane/EtOAc/MeOH 80:20:2 to 0:10:1) then further purified by preparative achiral SFC (column Propyl-pyridyl-urea, gradient 15-20% in 6 min_total 11 min) to afford the title product (97 mg, 0.225 mmol, 45% yield) as colorless foam. tR: 0.84 min (LC-MS 2); ESI-MS: 427 [M+H]+ (LC-MS 2); Rf=0.21 (EtOAc/MeOH 9:1); 1H NMR (400 MHz, CDCl3) δ ppm 0.91 (t, J=7.6 Hz, 3H) 2.01 (s, 3H) 2.25-2.48 (m, 2H) 3.37 (s, 3H) 3.44 (t, J=6.3 Hz, 1H) 3.95-4.05 (m, 2H) 4.43 (dd, J=5.6, 3.7 Hz, 2H) 5.50 (s, 1H) 6.91-7.03 (m, 4H) 7.25 (d, J=8.3 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:49]([NH:57][C:58]1[CH:70]=[C:69](Br)[CH:68]=[CH:67][C:59]=1[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:49]([NH:57][C:58]1[CH:70]=[C:69]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:68]=[CH:67][C:59]=1[C:60]([O:62][C:63]([CH3:65])([CH3:66])[CH3:64])=[O:61])(=[O:56])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(Oc2cccc([N+](=O)[O-])c2)cc1NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
31 mg of 3-nitrophenol, 79 mg of tripotassium phosphate, 4.7 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl and 6.8 mg of tris(dibenzylideneacetone)dipalladium(0) were added to 1.4 mL of toluene solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 4.7 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl and 6.8 mg of tris(dibenzylideneacetone)dipalladium(0) were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 1 hour. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane; ethyl acetate=10:1) to obtain tert-butyl 2-(benzamido)-4-(3-nitrophenoxy)benzoate.
Reaction SMILES: NC1C(N)=C(C)C=CC=1.N[CH:11]([CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)N.NC1C=CC(C(C)C2C=CC=CC=2)=C(N)C=1N>>[CH3:11][CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(N)C(c1ccccc1)c1ccccc1
Agent: CC(c1ccccc1)c1ccc(N)c(N)c1N
Agent: Cc1cccc(N)c1N
Product: CC(c1ccccc1)c1ccccc1

Procedure:
3(a) An aromatic polyamine mixture made up of 2.6% of diaminotoluene (isomer mixture), 6.2% of diaminomethyl diphenylmethane (isomer mixture containing more than 90% of diamines of the type containing one amino substituent on each aromatic ring) and 91.2% of triamino-methyl diphenyl methane (isomer mixture containing more than 90% of triamines with one amino group on the unsubstituted aromatic ring and two amino groups on the methyl-substitued aromatic ring) was obtained by the nitration of methyl diphenyl methane, followed by catalytic hydrogenation using Raney nickel in accordance with European Patent Application No. 46,917. 350 g of this polyamine mixture were hydrogenated at 200° C./275 bars in accordance with Example 1(a) in the presence of 35 g of ruthenium (5%)/aluminum oxide supported catalyst and 35 g of ammonia in a 0.7 liter stirrer-equipped autoclave. After distillation twice, the hydrogenation product which was 91% triaminomethyl dicyclohexyl methane corresponding to formula (I) (R=CH3), and 9% diaminomethyl dicyclohexyl methane, was isolated in a yield of 69.2 g (B.p. 132°-148° C./0.1 mbar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.CC(O)C.C(=O)=O.C([Li])CCC.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](=[O:42])N(OC)C)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CCCCCC>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](=[O:42])[C:7]2[CH:6]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:4]=[CH:3][C:2]=2[F:1])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(C(F)(F)F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.3 %

Procedure:
A solution of 4-fluorobenzotrifluoride (25 g, 0.152M) in anhydrous THF (300 mi) was cooled to −60° C. (IPA/CO2 bath) and treated with n-butyl lithium (84 mL of a 2.0M solution in Hexane, 0.168M-1.1 eq) with a maximum rate so not to exceed 60° C. The reaction was stirred for 3 hours (temperature maintained) and then treated with a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (51.86 g, 0.190M-1.25 eq, in 130 mL of anhydrous THF) with a maximum rate so as not to exceed −55° C. The mixture was stirred for a further two hours before allowing to warm to room temperature and stirred for 0.5 hours. The reaction was quenched with saturated ammonium chloride solution (75 mL) and the THF removed under reduced pressure. The residue was dissolved in ethylacetate (800 mL), washed with 1N Hydrochloric acid (400 ml), 5% aq NaHCO3 (400 mL), water (400 mL) and brine (400 mL) successively. The organics were dried over MgSO4, filtered and concentrated to give a brown oil, which on triturating in ethyl acetate gave a white solid 27.6 g (48%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:28][CH2:27][C:13]3([O:18][CH2:17][CH2:16][N:15]([C:19]([C:21]4[N:22]=[C:23]([CH3:26])[S:24][CH:25]=4)=[O:20])[CH2:14]3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:26][C:23]1[S:24][CH:25]=[C:21]([C:19]([N:15]2[CH2:14][C:13]3([CH2:27][CH2:28][N:10]([CH2:9][CH2:8][O:7][C:6]4[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:30][CH:29]=4)[CH2:11][CH2:12]3)[O:18][CH2:17][CH2:16]2)=[O:20])[N:22]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CO)cc4)CC3)C2)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(C=O)cc4)CC3)C2)cs1

Procedure:
Manganese dioxide (0.65 g) was added to a solution of (9-(2-(4-(hydroxymethyl)phenoxy)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4-yl)methanone (0.32 g) (example 1, step i) in DCM (20 mL) and the resulting black suspension heated under reflux for 1 h. After cooling the reaction mixture was passed through a pad of Celite. The pad was washed with DCM (2×30 mL) and the combined filtrate and washings evaporated in vacuo to give the subtitled compound as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:16]O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[N:11]([CH:12]=[N:13][CH:14]=[CH:15]3)[N:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON=C(Cc1ccncn1)c1cccc(Cl)c1
Agent: Cl[Fe]Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Clc1cccc(-c2cc3ccncn3n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
To a cold (0° C.) solution of 1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethanone oxime (5.0 g, 20.2 mmol) in ethylene glycol dimethyl ether (50 mL) was added trifluoroacetic anhydride (2.85 ml, 20.2 mmol) dropwise). The reaction mixture was warmed to room temperature and stirred 10 minutes then recooled to 0° C. A solution of triethylamine (5.63 mL, 40.4 mmol) in ethylene glycol dimethyl ether was added and the resultant solution was stirred at room temperature 1.5 hours. Iron (II) chloride (25 mg, 0.20 mmol) was added and the reaction mixture was refluxed 3 hours. The reaction mixture was cooled to room temperature and the excess ethylene glycol dimethyl ether was removed in vacuo. The resultant oil was chromatographed (9:1 to 4:1 hexanes:ethyl acetate) to provide 2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidine (3.2 g, 69%) as a pale yellow solid. Rf 0.27 (4:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 9.25 (s, 1H), 8.00 (s, 1H), 7.88–7.81 (m, 2H), 7.46–7.39 (m, 3H), 6.81 (s, 1H); MS m/z 230 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([OH:22])=O)[CH:4]=1.S(Cl)(Cl)=O.C1C=CC=CC=1.[C:33]1([NH:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C.CN(C=O)C>[C:33]1([NH:39][NH:40][C:20]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[N:6]=2)=[O:22])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reactant: NNc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NNc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.4 g (0.00128 mol) of 4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxylic acid was mixed with 0.3 g (0.00128×2.0 mol) of thionyl chloride and then with about 10 ml of benzene and a small amount of DMF, followed by treating the obtained mixture under reflux for about 30 minutes. The reaction solution was concentrated and mixed with methylene chloride and then with 0.34 g (0.00128×2.5 mol) of phenyl hydrazine, followed by stirring at room temperature for about one hour. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>O1CCCC1>[F:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([NH:11][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:24]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ncccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ncccn1
Reaction time: 0.17 h
Yield: 25 %

Procedure:
LiHMDS (1.0 M in tetrahydrofuran, 27.4 ml, 27.4 mmol) was added to 2-aminopyrimidine (1.43 g, 15.0 mmol) in tetrahydrofuran (50.0 ml) and stirred for 10 min. 2,4-Difluoronitrobenzene (1.50 ml, 13.7 mmol) was added and the reaction stirred for a further 15 min. The reaction mixture was quenched with water then poured into sodium bicarbonate (dilute aqueous) and the aqueous layer extracted with EtOAc (×3). The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by chromatography (SiO2, 0-100% EtOAc/cyclohexane) to yield the title compound (800 mg, 3.42 mmol, 25%). 1H NMR (CDCl3, 400 MHz): δ 8.94 (1H, dd, J 12.3, 2.4 Hz), 8.62 (2H, d, J=4.8 Hz), 8.36 (1H, dd, J 9.4, 6.1 Hz), 7.08 (1H, t, J=4.8 Hz), 6.88 (1H, ddd, J 9.6, 7.2, 2.8 Hz).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH2:30][OH:31])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[CH:30]=[O:31])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(hydroxymethyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (510 mg, 1.017 mmol) in CH2Cl2 (20 mL) at 0° C. under N2, was added Dess-Martin periodinane (647 mg, 1.526 mmol) portionwise. The reaction was stirred at 0° C. for 1 h. The reaction was carefully quenched with saturated NaHCO3 and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzaldehyde as a white solid. LCMS calc.=500.1; found=500.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 10.29 (s, 1 H); 8.04 (d, J=7.8 Hz, 1 H); 7.93 (s, 1 H); 7.85 (d, J=8.0 Hz, 1 H); 7.83 (s, 1 H); 7.82 (s, 2 H); 5.77 (d, J=7.9 Hz, 1 H); 5.11 (d, J=16.5 Hz, 1 H); 4.94 (d, J=16.5 Hz, 1 H); 4.23-4.18 (m, 1 H); 0.84 (d, J=6.5 Hz, 3 H).
Reaction SMILES: [OH:1][C@@H:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][C@@H:2]([CH3:11])[C:3]([N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: C[C@H](O)C(=O)N1CCOCC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A mixture of (S)-ethyl lactate (75 g) and morpholine (164 g) was heated at 80° C. for 64 hours. The reaction solution was concentrated and the residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=4/1 to ethyl acetate) to give 4-[(S)-2-hydroxypropionyl]-morpholine (69.4 g) as a pale yellow oily substance. p-Toluenesulfonic acid monohydrate (0.82 g) was added to a solution of 4-[(S)-2-hydroxypropionyl]morpholine (69.4 g) in dichloromethane (300 ml), to which 3,4-dihydro-2H-pyran (40.3 g) was added dropwise at ice-bath temperature. The reaction solution was stirred at 0° C. for 30 minutes and washed with a 5% aqueous solution of sodium bicarbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=8/1 to ethyl acetate) to give 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (89.1 g) as a pale yellow oily substance.
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[C:13]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:14][CH:15]=[CH:16][C:3]1=2.[OH2:22].NN.[OH-].[Na+].Cl>C(O)C.O.C(O)COCCO>[CH:16]1[C:3]2[CH2:2][CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[C:13]([CH:17]([CH3:21])[C:18]([OH:22])=[O:19])=[CH:14][CH:15]=1
Reactant: CC(C(N)=O)c1cccc2c1Oc1ccccc1CC2=O
Reactant: O
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: OCCOCCO
Solvent: CCO
Product: CC(C(=O)O)c1cccc2c1Oc1ccccc1CC2
Reaction time: 8 h

Procedure:
To 80 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-4-yl)-propionamide in 4 ml of ethanol was added 0.3 ml of hydrazine hydrate and the mixture was refluxed with stirring for 8 hours. The solvent was distilled off to obtain pale yellow oil, to which were added 3 ml of diethylene glycol and 400 mg of sodium hydroxide, and the resulting mixture was stirred at 125° C. for 1 hour. To the mixture was added water and the resulting solution was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was extracted with saturated sodium hydrogencarbonate solution. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain pale yellow crystals, which were recrystallized from benzene-n-hexane, and there was obtained 37 mg of 2-(10,11-dihydro dibenzo[b,f]oxepin-4-yl)-propionic acid as pale yellow crystals having a melting point of 133°-133.5° C.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH3:24])[CH:15]=2)=[O:12])[CH2:4]1.[CH:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:36]([N:37]=[C:38]=[O:39])=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=1>C1COCC1>[C:31]1([C:28]2[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=2)[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=1[NH:37][C:38](=[O:39])[N:2]([CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH3:24])[CH:15]=2)=[O:12])[CH2:4]1)[CH3:1]
Reactant: CNC1CCN(CCNC(=O)Nc2cc(C)nc3ccccc23)C1
Reactant: O=C=Nc1ccccc1-c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(N(C)C(=O)Nc3ccccc3-c3ccccc3)C2)c2ccccc2n1
Reaction time: 18 h

Procedure:
To a solution of 1-[2-(3-methylamino-pyrrolidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea (0.03 mmol) in THF (0.3 mL) is added a solution of 2-biphenyl isocyanate (0.09 mmol) in THF (0.6 mL). The reaction is allowed to stir for 18 h, and then is quenched with water (0.1 mL), and stirred for an additional 0.5 h. The reaction mixture is evaporated. The residue is taken up in a mixture of formic acid/TFA (1:1; 1 mL), and purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([N+:18]([O-])=O)=[CH:13][N:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl.[N:22]([O-])=O.[Na+].[N+]([O-])([O-])=O.[Na+].CC([O-])=O.[K+]>CC(O)=O.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[C:15]3[CH:17]=[N:22][NH:18][C:14]3=[CH:13][N:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=N[O-]
Reactant: Cc1cc(Oc2ccc(F)cc2C#N)ncc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1cc(F)ccc1Oc1cc2cn[nH]c2cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
Intermediate (1u) (0.25 g, 1.03 mmol) and NH4BF4 (0.22 g, 2.06 mmol) were dissolved in 10 mL of mixed solvent of AcOH/water (2:1) and cooled to 0° C., and followed by addition of concentrated HCl (0.43 mL, 5.16 mmol) and NaNO2 (0.078 g, 1.13 mmol) to the solution at 0° C. The color of the solution immediately turned into yellow as sodium nitrate was added. The reaction mixture was then allowed to warm to room temperature. After stirring 2 hours, the solvent was removed under reduced pressure and azeotroped with toluene three times to removed the water, to give a pale yellow crude solid. The solid was dissolved in 10 mL of EtOAc and KOAc was added to the solution. The color of suspension turned into deep orange in 30 minutes and then stirred an additional hour. The white inorganic salt was removed by filtration and washed with EtOAc. The combined filtrate was diluted with EtOAc to 100 mL of total volume and transferred to a separatory funnel, washed with sat. NaHCO3 (10 mL) and brine, dried over MgSO4, filtered and evaporated to obtain a deep orange colored solid. The crude solid was purified on silica gel with EtOAc/hexane (2:3) to afford an orange yellow colored solid (2u) (0.23 g, 88% yield over 2 steps). 1HNMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.15 (s, 1H), 7.30-7.34 (m, 2H), 7.32-7.22 (m, 2H), 7.12 (dd, J=9.4, 4.7 Hz, 1H) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.[ClH:21]>C(OCC)(=O)C>[ClH:21].[ClH:21].[CH2:14]([NH:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(CNC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of (R)-3-benzylaminopyrrolidine-1-carboxylic acid tert-butyl ester (15.3 g, 55.4 mmol) in ethyl acetate (100 ml) was added 12% hydrogen chloride in ethyl acetate (100 ml) at 5° C. The mixture was stirred for 2 hours at room temperature. The precipitated crystals were collected by filtration and washed with ethyl acetate to afford benzylpyrrolidin-3-yl-amine dihydrochloride (6.0 g, 51%) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[C:16]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:16]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][CH2:24][N:25]([C:8]([NH:7][C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:26][CH2:27]2)[CH:17]=1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnn1)N1CCN(c2cccc(-c3ccccc3)c2)CC1
Yield: 20 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (250 mg, 0.923 mmol), 1-biphenyl-3-ylpiperazine (200 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 12 hours. Water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the titled compound 60.3 mg (20.0%) as solid product.