Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C@H:9]([CH:10]=O)[C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]1=[O:20].[C:27]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:29])[NH2:28]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C@@H:9](/[CH:10]=[CH:30]/[C:27](=[O:29])[NH2:28])[C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:7]1=[O:20]
Reactant: NC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2C=O)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2/C=C/C(N)=O)c(OC)c1
Reaction time: 1 h
Yield: 80.7 %

Procedure:
4.0 g (11 mmol) of t-butyl(3S,4S)-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidinecarbamate are dissolved in 300 ml of methylene chloride and the solution obtained is treated dropwise with a solution of 3.9 g (12 mmol) of carbamoylmethylene-triphenylphosphorane in 100 ml of methylene chloride. After 1 hour, the mixture is filtered and the crystals obtained are washed with methylene chloride. There are obtained 3.6 g (81%) of t-butyl(3R,4S)-1-(2,4-dimethoxybenzyl)-4-[(E)-2-carbamoylvinyl]-2-oxo-3-azetidinecarbamate of melting point 270° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[C-:13]([N+:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH2:23][CH3:24])[CH:17]=2)[C:12]([NH:25][C:26](=[O:54])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:53])[CH2:35][O:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])=[CH:39][C:38]=3[C:48]([CH2:51][CH3:52])([CH3:50])[CH3:49])[CH:28]=2)=[N:11]1.[H][H]>C(O)C.[Ni]>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH:18]([CH2:23][CH3:24])[CH2:17]2)[C:12]([NH:25][C:26](=[O:54])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:53])[CH2:35][O:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])=[CH:39][C:38]=3[C:48]([CH2:51][CH3:52])([CH3:50])[CH3:49])[CH:28]=2)=[N:11]1
Reactant: CCc1c[n+](-[c-]2c(NC(=O)c3cccc(NC(=O)COc4ccc(C(C)(C)CC)cc4C(C)(C)CC)c3)nn(-c3c(Cl)cc(Cl)cc3Cl)c2=O)ccc1C
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCC1CN(C2C(=O)N(c3c(Cl)cc(Cl)cc3Cl)N=C2NC(=O)c2cccc(NC(=O)COc3ccc(C(C)(C)CC)cc3C(C)(C)CC)c2)CCC1C

Procedure:
7.9 grams of 1-(2,4,6-trichlorophenyl)-3-[3-{(2,4 -di-tert-amylphenoxy)acetamido}benzamido]-4-(3-ethyl-4-methyl-1-pyridinio)-5-oxo-2-pyrazolin-4-ide (Compound 1-3; m.p.; 162° - 165° C.) was dissolved in 500 ml of ethanol, and about 10 g of Raney nickel catalyst was added thereto. Then, reaction was conducted in an autoclave at 80° C. for 20 hours with an initial hydrogen pressure of 60 atmospheres. After the reaction, the catalyst was removed, followed by distilling off the solvent. Upon crystallizing the resulting residue from acetonitrile-ethyl acetate (10:1 by volume) 4.2 g of Compound 2-3 having a melting point of 145° - 155° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[NH:4][N:3]=1.[B-](F)(F)(F)[F:11].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(O)(=O)C.[B-](F)(F)(F)F.[B-](F)(F)(F)F.C[N+]12CC[N+](F)(CC1)CC2>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[C:6]([F:11])=[C:5]([C:7]([OH:9])=[O:8])[NH:4][N:3]=1
Reactant: O=C(O)c1cc(Cl)n[nH]1
Reactant: F[B-](F)(F)F
Agent: C[N+]12CC[N+](F)(CC1)CC2
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)c1[nH]nc(Cl)c1F

Procedure:
3-chloro-1H-pyrazole-5-carboxylic acid (200 mg, 1.37 mmol) was suspended in acetonitrile (3 mL) followed by the addition Selectfluor 11(550 mg, 1.55 mmol) and acetic acid (500 g, 8.33 mmol). The mixture was submitted to microwave irradiation, maintaining the temperature at 100 C for 2 h. An additional 550 mg of Selectfluor II was added and the reaction returned to the microwave where the temperature was maintained at 100 C for 1 h. The reaction mixture was diluted with 3 mL of EtOAc then washed with water (5 mL) three times. The solvent was stripped in vacuo and 3-chloro-4-fluoro-1H-pyrazole-5-carboxylic acid was isolated by semi prep HPLC (ACN/water+0.05% TFA).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:33]([F:36])([F:35])[F:34])[CH2:13][CH2:12][N:11]([C:14]3[CH:28]=[CH:27][C:17]([CH2:18][NH:19]C(=O)OC(C)(C)C)=[C:16]([C:29]([F:32])([F:31])[F:30])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:33]([F:36])([F:35])[F:34])[CH2:13][CH2:12][N:11]([C:14]3[CH:28]=[CH:27][C:17]([CH2:18][NH2:19])=[C:16]([C:29]([F:30])([F:31])[F:32])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A mixture comprising t-butyl {4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-pyrrolidin-1-yl]-2-(trifluoromethyl)benzyl}carbamate (6.0 g), concentrated hydrochloric acid (20 mL) and ethanol (100 mL) was stirred at 50° C. for three hours. After cooling the mixture to room temperature, the reaction solution was diluted by adding water (150 mL) and ethyl acetate (150 mL). By adding sodium carbonate in small portions, the solution was neutralized. After the extraction using ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure to obtain the title compound (5.2 g).
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([O-:26])=[O:25].[C:31](O)(=O)[CH3:32].[Na]>CCCCCC.C(OCC)(=O)C>[CH2:31]([O:25][C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[NH:21][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1)=[O:26])[CH3:32]
Reactant: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Reactant: CC(=O)O
Reactant: Nc1ccccc1C(=O)[O-]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1ccccc1N[C@H]1CC[C@H]2CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]2C1
Yield: 41.8 %

Procedure:
Following the procedure from Example 3A, and using ethyl 6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (537 mg, 1.9 mmol), 2-aminobenzoate (165 mg, 1.0 mmol), glacial acetic acid (0.36 mL, 6.0 mmol), and sodium triacethoxyborohydride (590 mg, 2.8 mmol), flash chromatography (silica gel, hexane-ethyl acetate 3:1) afforded 181 mg (42% yield) of the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][CH:22]=2)=[CH:12][CH:11]=1)(=O)=O.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[C:36]([O:38][CH2:39][CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:25]1(/[CH:24]=[CH:23]/[C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][CH:14]=3)[N:19]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl methanesulfonate (430 mg), ethyl 2-imidazolecarboxylate (155 mg), potassium carbonate (305 mg) and N,N-dimethylformamide (10 ml) was stirred for two hours at temperatures ranging from 80 to 90° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. The crystalline product obtained from the fraction eluted with ethyl acetate-hexane (2:1, v/v) was recrystallized from ethyl acetate-hexane to give ethyl 1-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]-2-imidazolecarboxylate (280 mg, 60%) as colorless prisms, mp 96-97° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:15].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N+:3]=1[O-:15]
Reactant: Cc1ccc(F)c(Br)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(F)c(Br)[n+]1[O-]
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To an ice-cold solution of 2-bromo-3-fluoro-6-picoline (1.00 g) in chloroform (25 mL) was added 3-chloroperoxybenzoic acid (1.77 g), and the mixture was stirred while warming to room temperature for 22 hr. After cooling in ice again, additional 3-chloroperoxybenzoic acid (590 mg) was added and the mixture was stirred while warming to room temperature for 21 hr. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the resulting mixture was then stirred. Thereafter, saturated aqueous sodium hydrogen carbonate solution and water were added thereto, followed by extraction with chloroform. The organic phase was washed with brine, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=98:2-0:100) to afford 2-bromo-3-fluoro-6-methylpyridine 1-oxide (604 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[CH:16][CH:15]=3)[N:11]=[C:10]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)[CH:9]=2)=[CH:4][CH:3]=1.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:2]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[CH:16][CH:15]=3)[N:11]=[C:10]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)CCNC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)CCNC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of the intermediate from example 79 step F (50 mg, 0.079 mmol) in toluene (1 mL) was added phenyl boronic acid (10 mg, 0.079 mmol), Na2CO3 solution (2.0M, 79 uL) and tetrakis triphenyl phosphine palladium (0) (5 mg, 0.003 mmol). The resulting mixture was placed in the CEM microwave instrument for 10 min at a temperature of 100° C. and power 150 W. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 3:10 ethyl acetate-hexanes to give the desired product, a colorless oil. To a solution of this material in DCM (2 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and lyophilized from acetonitrile-water to give the title compound. 1H NMR (DMSO, 500 MHz): δ 8.5 (t, J=5.5 Hz, 1H), 7.91 (d, J=1.9 Hz, 2H), 7.81 (d, J=8.2 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.74 (d, J=7.3 Hz, 2H), 7.58 (m, 3H), 7.51 (t, J=7.6 Hz, 2H), 7.42 (t, J=7.6 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=8.2 Hz, 2H), 5.56 (s, 2H), 3.45 (q, J=7.1 Hz, 2H), 2.47 (t, J=7.1 Hz, 2H). LC-MS: 2.73 min; (M+H)=570.1.
Reaction SMILES: Cl[C:2]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:4][N:3]=1.[C:25]([CH:27]1[CH2:29][CH2:28]1)#[CH:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:2]([CH2:26][CH2:25][CH:27]3[CH2:29][CH2:28]3)=[N:3][CH:4]=[C:5]([CH:16]=2)[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:19][CH:20]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: C#CC1CC1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(CCC2CC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Examples 1d tole, using 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide and ethynylcyclopropane as starting materials; yield 189 mg, 46% over two steps; m/z (ISP+): 399.2, 401.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>[Pt].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:12](=[O:14])[CH3:13])=[C:6]([OH:8])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CC(=O)OC(C)=O
Agent: [Pt]
Solvent: CO
Product: CC(=O)Nc1ccc(F)cc1O
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (5 g, 31.8 mmol), acetic anhydride (4.86 g, 47.7 mmol) and platinum on carbon (5%, 200 mg) in methanol was hydrogenated at 35 psi for 3 hours. The catalyst was filtered off and the residue was purified by silica gel flash chromatography to give the subtitled compound (4.7 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[C:15](OCC)(=[O:17])C>>[C:12]([C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:15]=[O:17])=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11])#[N:13]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCOC(C)=O
Agent: Cl
Product: N#Cc1ccc(N=C=O)cc1C(F)(F)F

Procedure:
5-Amino-2-cyanobenzotrifluoride (0.07 g, 0.36 mmol) was dissolved in ethyl acetate (2 mL) and dry hydrogen chloride in ethyl acetate (3.5 M, 5.5 mL) was added. After 15 min the solution was concentrated to dryness and co-evaporated three times from toluene (3×5 mL). The residue was added toluene (2.5 mL) and flushed with nitrogen for about 10 min. before diphosgene (0.43 mL) was added. Then the mixture was gently refluxed for 1 hour under a nitrogen atmosphere. The mixture was cooled and concentrated to dryness in vacuo and then co-evaporated twice from toluene to remove excessive diphosgene to afford 4-cyano-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27][CH2:28][N:29]=[C:30]=[O:31].[H-].[Na+].O>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:25]=[CH:24][C:22]([N:23]3[CH2:27][CH2:28][NH:29][C:30]3=[O:31])=[CH:21][CH:20]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NCCCl
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N3CCNC3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A mixture of 4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}aniline (1.1 g, 3.26 mmol) and 2-chloroethyl isocyanate (0.369 g, 3.5 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for overnight. Sodium hydride was added to the reaction mixture and the mixture was stirred at room temperature for 3 h. Water was added to the reaction solution, and the resulting solid was collected and washed with water, diethyl ether, dried over anhydrous magnesium sulfate, and dried under reduced pressure to give the title compound as a solid (1.2 g, 91%).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][C@@H:6]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:8][C:7]1=[O:16])(C)C.[H][H]>CO>[CH:10]1([C@@H:9]2[NH:8][C:7](=[O:16])[C@@H:6]2[OH:5])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(C)[Si](O[C@H]1C(=O)N[C@H]1c1ccccc1)(C(C)C)C(C)C
Reactant: [H][H]
Solvent: CO
Product: O=C1N[C@@H](C2CCCCC2)[C@H]1O
Temperature: 90 °C
Reaction time: 120 h
Yield: 85 %

Procedure:
A suspension of 500 mg (3.06 mmol) of 4-phenyl-3-hydroxy-2-azetidinone 1a and 15 mg of Rh-C in 10 mL of methanol was heated at 90° C. under 800 psi in an autoclave. After 5 days, the hydrogen pressure was released and the catalyst filtrated on celite. Evaporation of the solvent afforded a solid which was recrystallized in ethyl acetate to give 440 mg (85%) of 3e as a white solid: White solid; mp 140-140.5° C.; [α]D20 +65.1° (c 0.66, CH3OH); 1H NMR (250 MHz, MeOH-d4) δ 0.75-1.10 (m, 2H), 1.12-1.35 (m, 3H), 1.40-2.00 (m, 6H), 3.28 (dd, J=9.7, 4.6 Hz, 1H), 4.81 (d, J=4.6 Hz, 1H); 1H NMR (250 MHz, DMSO-d6) δ 0.75-1.00 (m, 2H), 1.10-1.35 (m, 3H), 1.37-1.55 (m, 1H), 1.58-1.85 (m, 5H), 3.10 (dd, J=9.6, 4.7 Hz, 1H), 4.67 (in, 1H), 5.87 (d, J=7.8 Hz, 1H), 8.21 (bs, 1H); 13C NMR (63 MHz, DMSO-d6) δ 25.08, 25.36, 26.07, 28.83, 29.17, 37.51, 59.04, 76.41, 170.21; IR (KBr) 3312, 3219, 2928, 1726 cm−1. Anal. Calcd for C9H15NO2: C, 63.88, H, 8.93, N, 8.28. Found: C, 63.70, H, 9.00, N, 8.06.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[O:25][CH:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH:22]3[NH2:35])=[N:16][CH:17]=1)([O-:11])=[O:10].N1C=CC=CC=1>CN(C=O)C>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[O:25][CH:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH:22]3[NH:35][C:1](=[O:3])[CH3:2])=[N:16][CH:17]=1)([O-:11])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CC(c2ccccc2)Oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)NC1CC(c2ccccc2)Oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc21
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Acetic anhydride (60 μl) was added into a cooled solution of 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ylamine hydrochloride (100 mg) and pyridine (41 μl) in dry DMF. Resulting mixture was stirred for a further 20 hours at 0° C. Reaction was quenched with ice water and neutralised. Resulting mixture was extracted with dichloromethane, dried with Na2SO4 and evaporated. Mixture of diastereomers of N-[6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-yl]-acetamide was recrystallised from dichloromethane. (M)+=405 (24%), 301 (14%), 259 (100%), 242 (55%), 224 (96%).
Reaction SMILES: [K].[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[Cl:10][CH2:11][CH2:12][CH2:13]Cl>CN(C)C=O>[Cl:10][CH:11]=[CH:12][CH2:13][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9]
Reactant: ClCCCCl
Reactant: O=c1ncc(Cl)c[nH]1
Agent: [K]
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1CC=CCl
Temperature: 60 °C
Yield: 60 %

Procedure:
A mixture of the potassium salt of 5-chloropyrimid-2-one (0.01 mol) and 1.3-dichloropropane (0.02 mol) in dimethylformamide (50 ml) was heated at 60° C. for 8 h. The reaction mixture was then evaporated (1 mm Hg) and the residue dissolved in chloroform (80 ml). This solution was washed with 1 N NaOH (2 ml) and water before drying and evaporation; yield 60%, m.p. 102°-104° C. (benzene/ligroin). (Found: C, 41.83; H, 3.02. Calc. for C7H6ClN2O: C, 41.01; H, 2.95).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:25])[C@@H:13]2C(=O)[CH2:17][CH2:16][CH2:15][C@H:14]2[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CO[CH:28]([O:31][CH3:32])[O:29][CH3:30].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:25])[C@@H:13]2[C:28]([O:29][CH3:30])([O:31][CH3:32])[CH2:17][CH2:16][CH2:15][C@H:14]2[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@@H]1C(=O)CCC[C@H]1N1CCCC1
Reactant: COC(OC)OC
Agent: Cl
Solvent: CO
Product: COC1(OC)CCC[C@@H](N2CCCC2)[C@@H]1N(C)C(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
To a solution of trans-(±)-3,4-dichloro-N-methyl-N-[6-oxo-2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide, prepared as described in Part B hereinabove, in 50 ml of dry methanol there is added 5 ml of trimethylorthoformate and 0.5 ml of 4M methanolic hydrogen chloride. The resulting mixture is refluxed for about 16 hours, cooled, and the solvent is removed in vacuo. The residual oil is crystallized from a hot methanol solution thereof, diluted with diethyl ether until the mixture becomes cloudy to obtain the titled trans-(±)-3,4-dichloro-N-methyl-N-[6,6-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide, which is converted to a hydrochloride salt.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH:16]([CH3:18])[CH3:17])[NH2:12].[CH3:19][CH:20]([CH2:24][CH2:25][CH3:26])[C:21](Cl)=[O:22]>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:12][C:21](=[O:22])[CH:20]([CH3:19])[CH2:24][CH2:25][CH3:26])[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(N)cc1Cl
Reactant: CCCC(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCC(C)C(=O)Nc1ccc(C(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0 %

Procedure:
To 36 ml of toluene were added 1.0 g (5.9/1000 mole) of 3-chloro-4-isopropylaniline and 0.7 g of pyridine, and 0.9 g (5.9/1000 mole) of 2-methylvaleryl chloride was added. The mixture was stirred at room temperature for 20 minutes. The crystals that precipitated were separated by filtration. Water (70 ml) was added to the filtrate, and the mixture was extracted with toluene. The toluene solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The resulting dried solution was concentrated by an evaporator. Recrystallization of the resulting crude crystals from methanol gave 1.2 g of N-(3-chloro-4-isopropylphenyl)-2-methylvaleramide in a yield of 76.0 % based on 3-chloro-4-isopropylaniline.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C@@H:33]3[CH2:37][CH2:36][C@H:35]([NH:38]C(=O)OC(C)(C)C)[CH2:34]3)[N:14]3[C:19]4[CH:20]=[CH:21][N:22]([S:23]([C:26]5[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=5)(=[O:25])=[O:24])[C:18]=4[N:17]=[CH:16][C:15]=23)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].O1CCOCC1.[ClH:52]>CCOCC>[NH2:38][C@H:35]1[CH2:36][CH2:37][C@@H:33]([C:13]2[N:14]3[C:19]4[CH:20]=[CH:21][N:22]([S:23]([C:26]5[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=5)(=[O:24])=[O:25])[C:18]=4[N:17]=[CH:16][C:15]3=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:10][CH:9]=3)[N:12]=2)[CH2:34]1.[ClH:52]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)nc([C@@H]4CC[C@H](NC(=O)OC(C)(C)C)C4)n23)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)nc([C@@H]4CC[C@H](N)C4)n23)cc1
Temperature: 60 °C

Procedure:
To a flask was added tert-butyl (1S,3R)-3-(3-(4-(2-hydroxypropan-2-yl)phenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentylcarbamate (0.48 g, 0.76 mmol; prepared using J.1 from Example #2, Step B with (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid [PepTech], L.1 with mercury(II) trifluoroacetate, AB and D with Preparation #H.1), 1,4-dioxane (7.6 mL) and HCl (4.0 M in 1,4-dioxane, 1.9 mL, 7.6 mmol). The reaction mixture was heated to about 60° C. for about 30 min. The mixture was cooled to rt and diluted with Et2O (20 mL). The solid was collected by filtration, washed with Et2O (10 mL) and dried under reduced pressure at about 60° C. overnight to give 2-(4-(1-((1R,3S)-3-aminocyclopentyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol, hydrochloric acid (0.39 g, 91% yield): LC/MS (Table 2, Method a) Rt=3.06 min; MS m/z 574 (M+H)+.