Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:11]2[C:10]3[S:12][C:13]([CH:15](Br)[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=O)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]([NH2:29])=[S:28].C(O)C>>[N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[N:26]=[C:27]([NH2:29])[S:28][C:16]=4[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1Cl)C(Br)c1cc2c(s1)-c1ncccc1OCC2
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(-c2cc3c(s2)-c2ncccc2OCC3)c(-c2ccccc2Cl)s1

Procedure:
6,7-Dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl-(2-chlorophenyl)-2-bromoethanone from Example 37 (100.0 mg, 0.230 mmol) and thiourea (20.14 mg, 0.264 mmol) were heated in ethanol (5 mL, 80 mmol) for 1 hour. The solvent was evaporated to half of the volume, whereupon the product crystallized upon standing. The product 165 was collected by filtration and washed with cold ethanol (yield 43 mg, 45%). 1H NMR (400 MHz, DMSO) δ 8.15 (d, J=3.2, 1H), 7.66 (d, J=8.2, 1H), 7.54 (t, J=7.6, 2H), 7.47 (t, J=7.4, 1H), 7.36 (d, J=8.1, 1H), 7.16 (dd, J=4.5, 8.1, 1H), 6.73 (s, 1H), 5.80-4.90 (m, 2H), 4.24 (t, J=4.7, 2H), 3.04 (t, J=4.7, 2H). MS (ESI+) 412.1
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[F:13])[CH3:2]>C1COCC1.[Pd]>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[F:13])[CH3:15]
Reactant: CCN(CC)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N,N-diethyl-2-fluoro-4-nitroaniline (4.00 g, 18.84 mmol) in THF (50 mL) was added Pd/C (1.50 g). The reaction mixture was stirred at rt under H2 for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound as an offwhite solid (3.20 g, 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[N:11][CH:12]=[C:13](Br)[C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C]=O.[Cl-].[NH4+].[C:58]([O:61][CH2:62]C)(=[O:60])C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CO>[CH3:62][O:61][C:58](=[O:60])[C:13]1[C:14]([OH:15])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([CH3:17])=[N:11][CH:12]=1
Reactant: Cc1ncc(Br)c(O)c1OCc1ccccc1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(C)c(OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of the compound 4 (88 g, 300 mmol), palladium acetate (13.4 g, 60 mmol) and 1,3-bis(diphenylphosphino)propane (30.8 g, 516 mmol) in dimethylformamide (660 ml) were added methanol (264 ml) and triethylamine (210 ml, 1.5 mol) at room temperature. The interior of a reaction vessel was replaced with carbon monoxide, and the material was stirred at room temperature for 30 minutes, and stirred at 80 degree for 18 hours. A vessel to which ethyl acetate (1500 ml), an aqueous saturated ammonium chloride solution (1500 ml) and water (1500 ml) had been added was stirred under ice-cooling, and the reaction solution was added thereto. Precipitates were filtered, and washed with water (300 ml), ethyl acetate (300 ml) and diethyl ether (300 ml) to obtain 5-benzyloxy-4-hydroxy-6-methyl-nicotinic acid methyl ester 5 (44.9 g, 55%) as a colorless crystal.
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.[O-:11][P:12]([O:15][P:16]([O-:19])([O-:18])=[O:17])(=[O:14])[O-:13].[Na+].[Na+].[Na+].[Na+].[CH2:24]([N:28]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>O.[NH+]1C=CC=CC=1.CO>[O-:13][P:12]([O:15][P:16]([O-:19])([O-:18])=[O:17])(=[O:11])[O-:14].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)CCCC
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: CCCC[NH+](CCCC)CCCC

Procedure:
Tetrasodium diphosphate decahydrate (2.23 g, 5 mmol) was dissolved in water (50 mL), the solution was applied to a column of Dowex 50WX8 (100 mL) in the pyridinium form, and the column was washed with 300 mL water-methanol (1:1). The eluate was directly dropped into a cooled (ice water) and stirred solution of tri-n-butylamine (2.38 mL, 10 mmol) in methanol. The solution was evaporated to dryness and re-evaporated twice with methanol and finally with anhydrous DMF (30 mL) on an oil pump.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])C1C=CC=CC=1C(O[Si](C)(C)C)C#N.Cl.[OH:20][CH:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1C(F)(F)F)[C:22](=[NH:26])[O:23][CH2:24][CH3:25]>>[OH:20][CH:21]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([C:2]([F:18])([F:17])[F:1])[CH:32]=1)[C:22](=[NH:26])[O:23][CH2:24][CH3:25]
Reactant: C[Si](C)(C)OC(C#N)c1ccccc1C(F)(F)F
Reactant: CCOC(=N)C(O)c1ccccc1C(F)(F)F
Agent: Cl
Product: CCOC(=N)C(O)c1cccc(C(F)(F)F)c1

Procedure:
By the procedures of Examples 2 and 11 (Method A) 2-(2-trifluoromethylphenyl)-2-trimethylsiloxyethanenitrile (15.5 g.) in 500 ml. of saturated ethanolic hydrogen chloride was converted to ethyl 1-hydroxy-1-(3-trifluoromethylphenyl)methanecarboximidate [9.6 g., 70%; m/e 247; ir (KBr) 1661, 1389, 1333, 1305, 1163, 1117 cm-1 ].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]([N:12]=[C:13]=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([NH:12][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Piperidin-4-ol (1 g) was dissolved in dichloromethane, and tert-butyl isocyanate was added thereto. Then, triethylamine was added thereto at room temperature, and the reaction mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, crystallized in the presence of ether 50 mL, and filtered to obtain the title compound (1.8 g) as a white solid.
Reaction SMILES: O[CH:2]([CH:8]([CH3:10])[CH3:9])[CH:3]([C:5]([OH:7])=[O:6])[NH2:4].ON[C@H](C(O)=O)CC(C)C>>[NH2:4][C@H:3]([C:5]([OH:7])=[O:6])[CH2:2][CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C(O)C(N)C(=O)O
Agent: CC(C)C[C@H](NO)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
A mutant strain which was resistant to 5 g/L of L-valine was selected from E. coli K-12 and obtained the strain No. 101 (Valr), which did not produce L-leucine. From the strain No. 101, a mutant strain which was resistant to 1.3 g/L of azaleucine. The obtained strain, No. 51 (Varr, ALr), produced about 0.05-0.1 g/L of L-leucine. Then, a strain having a resistance to 2 g/L of 3-hydroxy-D,L-leucine (hereinafter referred to as hydroxyleucine) was selected from the strain No. 51 and obtained the strain No.4 (Varr, ALr, Hleur). The symbol, "Hleur " represents the strain which was conferred hydroxyleucine resistance. The strain No. 4 produced more leucine (about 0.4-0.6 g/L).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[C:33]([CH3:39])[C:27]=1[CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:32][C:29]2([CH2:28][C:27]3[C:33]([CH3:39])=[C:34]([CH3:38])[CH:35]=[C:36]([CH3:37])[C:26]=3[CH3:25])[CH2:31][CH2:30]2)=[CH:11][CH:10]=1
Reactant: Cc1cc(C)c(C)c(CC2(N)CC2)c1C
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: Cc1cc(C)c(C)c(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)c1C

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 203 mg (1 mmol) 1-(2,3,5,6-tetramethyl-benzyl)-cyclopropylamine. Yield: 93 mg (18%, trifluoroacetate); mass spectroscopy: [M+H]+=411.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][C:11](=[O:13])[O:16][C:14]1=[O:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1 g (4.29 mmol) of N-(tert-butoxycarbonyl)-DL-aspartic acid and 0.98 g (5.15 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) in 100 mL of DCM, was stirred at room temperature overnight. The solution was extracted three times with 5% aq. NaHSO4, the organic extracts were dried over anh. sodium sulfate and the solvent evaporated under vacuum. In this way 750 mg of the title compound were recovered. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.38 (s, 9 H) 2.78-2.90 (m, 1 H) 3.15-3.28 (m, 1 H) 4.54-4.65 (m, 1 H) 7.73 (d, J=7.91 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[C:14]#[N:15].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=2[C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 92.3 %

Procedure:
To a solution of 3.95 g (0.0307 moles) of 4-chlorophenol dissolved in 150 ml of DMSO was added 1.23 g (0.0307 moles) of NaOH. The slurry was heated at 60° C. for 15 minutes and 5.04 g (0.0276 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture was heated at 75° C. for 3 hrs. The reaction mixture was cooled and poured into water. The product was collected by filtration, washed well with water and dried, to produce 7.0 g of the product (92% yield). Recrystallization from ethanol afforded purified 2-(4-chlorophenoxy)-5-nitrobenzonitrile, mp 163°-164° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2F)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(CNS(C)(=O)=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
To 4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (207) (1.45 g, 4.48 mmol) in MeCl2 (10 mL) was added methanesulfonyl chloride (0.51 g, 4.48 mmol) and pyridine. The reaction was allowed to stir at room temperature for 18 h. The reaction mixture was then diluted with EtOAc (50 mL) and washed with H2O (50 mL) and brine (50 mL). The organic phase was concentrated to dryness yielding 1.43 g (80%) product.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH2:11]([O:18][C:19](=[O:36])[C:20]([CH3:35])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH:24]=1)[CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(=O)CC>[C:6]([C@H:4]([C@@H:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[CH2:11]([O:18][C:19](=[O:36])[C:20]([CH3:21])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C@H:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH:24]=1)[CH3:35])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(Oc1cccc(C2CCCNC2)c1)C(=O)OCc1ccccc1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCC(C)=O
Product: CC(C)(Oc1cccc([C@H]2CCCNC2)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
D-(−)-tartaric acid (3.80 g, 25.3 mmol) was suspended in 105 mL of 2-butanone containing 2.5% water, then the suspension was warmed to reflux to give a clear solution. (R)-enriched 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester (9.10 g, 25.7 mmol) was dissolved in 15 mL of of 2-butanone containing 2.5% water and was then added to the refluxing solution of D-(−)-tartaric acid. The reaction solution stirred at reflux for 15 minutes, then cooled slowly to room temperature and stirred for 16 hr. The resulting white precipitate was collected by filtration and rinsed with 2-butanone followed by drying in vacuo to give (R)-2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester-(D)-tartrate salt (9.64 g, 89%, 93% e.e.) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[C:4]([NH2:8])=[N:3][CH:2]=1.[CH:9](O)=O>C(OC(OCC)OCC)C>[N:1]1[CH:6]=[C:5]2[C:4]([NH:8][CH:9]=[N:7]2)=[N:3][CH:2]=1
Reactant: Nc1cncnc1N
Reactant: O=CO
Solvent: CCOC(OCC)OCC
Product: c1ncc2nc[nH]c2n1
Yield: 100 %

Procedure:
A solution of pyrimidine-4,5-diamine (718 mg, 6.53 mmol) and HCOOH (0.36 mL) in triethoxymethane (19 mL) was stirred at 90° C. for 3.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 40:1 DCM/MeOH to give 9H-purine as a brown solid (784 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 13.40 (br s, 1H), 9.12 (s, 1H), 8.92 (s, 1H), 8.60 (s, 1H). LCMS (ESI) m/z 121 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:18]([CH3:20])[CH3:19])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O:25]C(NC(C1CCOC1)C(O)=O)=O)(C)(C)C>>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][C:10](=[O:17])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:18]1[CH2:19][CH2:21][O:25][CH2:20]1)[CH3:16]
Reactant: CCOC(=O)CC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C1CCOC1
Product: CCOC(=O)CC(=O)C(NC(=O)OC(C)(C)C)C1CCOC1

Procedure:
Procedure same as that for ethyl(S)-4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate, using 2-((tert-butoxycarbonyl)amino)-2-(tetrahydrofuran-3-yl)acetic acid as a starting material. 1H NMR (CD3OD, 400 MHz): δ 4.25-4.13 (m, 3H), 4.00-3.45 (m, 4H), 2.75-2.65 (m, 1H), 2.12-1.98 (m, 1H), 1.77-1.62 (m, 1H), 1.49 (s 9H), 1.30 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][OH:9])[CH:2]=1.[CH2:10]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[CH:11]=[CH2:12]>C(Cl)(Cl)Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:12][CH:11]([CH2:10][N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])[O:9][N:8]=2)[CH:2]=1
Reactant: ON=Cc1cccnc1
Reactant: C=CCN1CCCC1=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1CCCN1CC1CC(c2cccnc2)=NO1
Yield: 57.7 %

Procedure:
The desired compound was prepared by the method of Example 8 from 500 mg (4.09 mmol) of 3-pyridine aldoxime and 1.02 g (2 equivalents) of 1-allyl pyrrolidin-2-one prepared in Example 6, and purified by separation with silica gel column chromatography using ethyl acetate and then chloroform/methanol (30:1) as eluent to obtain 578.4 mg (58% yield) of 1-(3-pyridin-3-yl-4,5-dihydro-isoxazol-5-yl-methyl)-pyrrolidin-2-one.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:9]5[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CCC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 96.4 %

Procedure:
tert-Butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (147 mg, 0.386 mmol) and 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (93 mg, 0.43 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (193 mg, 96%) as a yellow oil: ESI MS m/z 519 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.CN1CCCC1=O.[OH-].[K+].[CH2:35]([SH:43])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl>C1(C)C(C)=CC=CC=1>[CH2:35]([S:43][C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1C
Product: CCCCCCCCSc1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc2c1
Temperature: 172.5 °C
Reaction time: 4.5 h

Procedure:
To a 500-mL, round-bottomed flask are charged 30 g (0.083 mol) of 5-chloro-2-(2-hydroxy-3,5-di-tert-butylphenyl)-2H-benzotriazole, 65 g (0.65 mol) of N-methyl-pyrrolidinone, 13.5 g (0.21 mol) of potassium hydroxide pellets and 25 g (0.16 mol) of n-octyl mercaptan are added. The mixture is agitated and the resultant slurry is heated to 170-175° C. and held at that temperature for 4.5 hours. The reaction mixture is then cooled to 120° C. at which time 150 g of xylene and 90 g of 10% aqueous hydrochloric acid are added. The brine layer is split off and the xylene phase at 90° C. is washed three times with water. Xylene is partially distilled under vacuum and then 80 g of methanol are added. The temperature of the reaction mixture is reduced to ambient temperature to induce crystallization. The yellow slurry formed is further cooled to 0-5° C. and filtered. The wetcake is washed with 100 g of cold methanol and dried to constant weight. The title compound is obtained as yellow needles in a yield of 37.7 g (97%). The structure of the product is verified by 1HNMR and mass spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:13][N:12]([C:14](=O)[CH2:15][CH3:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.[H-].[H-].[H-].[H-].[Li+].[Al+3].O1CCCC1>C(O)C>[CH2:14]([N:12]1[CH2:11][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:13]1)[CH2:15][CH3:16]
Reactant: CCC(=O)N1CC(c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl[Sn]Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCN1CC(c2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(3-(4-Nitrophenyl)azetidin-1-yl)propan-1-one (3.16 g, 13.49 mmol) was dissolved in ethanol (200 ml) and SnCl2.2H2O (15.20 g, 67.45 mmol) was added. The resulting mixture was refluxed for 8 h and then the solvent was removed under vacuum. The raw material was dissolved in ethyl acetate and washed successively with 2N aqueous NaOH (×2) and water. The organic layer was dried (Na2SO4), filtered through a pad of celite and evaporated. The crude 1-[3-(4-amino-phenyl)-azetidin-1-yl]-propan-1-one was then dissolved in tetrahydrofuran (THF) (200 ml) and 1M LiAlH4 in tetrahydrofuran (19.5 ml, 19.5 mmol) was added dropwise at 0° C. After stirring at room temperature for 2 h, the reaction mixture was carefully quenched with THF/H2O 9:1 (20 ml) at 0° C., then filtered through a pad of celite and the solvents were removed under reduced pressure. The crude 4-(1-propyl-azetidin-3-yl)-phenylamine was used without any further purification for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C[O-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29]>CN(C)C=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 14.0 g of 4-nitrophenol in 250 ml of dimethylformamide is treated with 6.0 g of sodium methoxide. After 15 minutes, 28.2 g of 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione is added, and the mixture then stirred at room temperature for 16 hours. The reaction mixture is diluted with 1500 ml of cold water, the precipitated solid collected, washed with water, and dried. Recrystallization from ethanol gives the desired compound, m.p. 112°-114° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][Zn]C.C(OCC)(=O)C.O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:16])[N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Zn]C
Reactant: Clc1cc(Cc2ccccc2)nc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cc2ccccc2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
4-Benzyl-2,6-dichloro-pyrimidine (2.5 g, 10.5 mmol) was dissolved in tetrahydrofuran (40 mL) under an atmosphere of nitrogen and subsequently treated with dimethylzinc (2M in toluene, 5.76 mL) and tetrakis(triphenylphosphine)palladium(0) (245 mg). After stirring for 18 h at ambient temperature, ethyl acetate and water were added, the phases separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. Column chromatography on silica gel using heptane/ethyl acetate 9:1 v/v) as eluent afforded the title compound (1.89 g, 83%) as colorless oil.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>C(Cl)(Cl)Cl>[Br:1][CH2:14][C:13]([C:7]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=1)=[O:15]
Reactant: BrBr
Reactant: COc1ccc(C(C)=O)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)CBr)cc1OC
Reaction time: 1.5 h
Yield: 47.6 %

Procedure:
A solution of bromine (30.6 g, 1.2 eg) in chloroform (150 ml) was added dropwise to a solution of 1-(3,4-dimethoxyphenyl)-1-ethanone (28.8 g) in chloroform (50 ml) over a period of 3-5 hr. The mixture was stirred for 1.5 hr. A stream of nitrogen was passed to remove the hydrobromic acid gas. The mixture was diluted with chloroform, washed with water, aqueous sodium bicarbonate and water, dried and evaporated. The crude product (48.3 g) was passed through a silica gel column (1.5 kg) using ethyl acetate-hexane (1:4) and the eluates were evaporated to give 2-bromo-1-(3,4-dimethoxyphenyl)-1-ethanone (19.7 g), mp 87°-90° C.