Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([CH3:20])([S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:6])C.O.[OH-].[Li+]>C1COCC1.O.O>[CH3:20][C:5]([S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:6])[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
To a solution of 15.3 g (47 mmol) of 2-methyl-2-(4-trifluoromethyl-benzenesulfonyl)-propionic acid ethyl ester in THF/water (4/1, 160 mL) were added 3.95 g (94 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The reaction was further diluted with water (60 mL) and then washed with DCM (2×40 mL). The basic aqueous layer was cooled in an ice bath and then acidified with 1N aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with DCM (3×60 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 11.6 g of 2-methyl-2-(4-trifluoromethyl-benzenesulfonyl)-propionic acid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[C:22]([F:31])[C:21]=1[F:32])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([OH:38])(C)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:28])[F:29])=[C:22]([F:31])[C:21]=1[F:32])[CH2:16][CH:17]=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(C(F)(F)F)c(F)c1F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=CC[C@@H](Cc1c(Cl)cc(C(F)(F)F)c(F)c1F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 816.6 %

Procedure:
Treat a solution of (R)-4-Benzyl-3-[(S)-2-(6-chloro-2,3-difluoro-4-trifluoromethyl-benzyl)-pent-4-enoyl]-oxazolidin-2-one (Preparation 45) (0.72 g, 1.5 mmol) in THF (9 mL) and water (3 mL) with 2.5% OsO4 in tBuOH (1.5 g, 0.15 mmol). Then, add sodium periodate (0.96 g, 4.5 mmol) to the solution and stir the reaction for 4 hr at room temperature. Quench the reaction with water and extract with EtOAc. Wash the organic with 1N sodium thiosulfate and brine. Separate the organic, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 0.60 g (82%) of desired product. MS (m/e): 490 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[OH:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][N:26]=[CH:27]2)=[CH:22][CH:21]=1.[H-].[Na+]>CN(C=O)C>[CH:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][C:5]3[N:4]=[N:3][C:2]([O:19][C:20]4[CH:29]=[C:28]5[C:23]([CH:24]=[CH:25][N:26]=[CH:27]5)=[CH:22][CH:21]=4)=[C:7]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[CH:6]=3)[CH:29]=2)[CH:24]=[CH:25][N:26]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2Cl)cc1
Reactant: Oc1ccc2ccncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4ccncc4c3)nnc2Oc2ccc3ccncc3c2)cc1

Procedure:
The title compound was prepared analogous to the procedure used to prepare Example 48, using 3,6-dichloro-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 45(d)), (443 mg, 1.5 mmol), 7-hydroxyisoquinoline (444 mg, 3.1 mmol, Lancaster) and NaH (151 mg, 3.8 mmol, 60% suspension in mineral oil, Aldrich) in DMF (10 mL). Purification by flash silica gel chromatography with 2M NH3 in MeOH/CH2Cl2 (0:1→1:24) as eluant gave the title compound as a tan amorphous solid. Mp: 82–86° C. MS (ESI, pos ion.) m/z: 511 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].Cl.N>C(OCC)(=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Nc1ccccn1
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNc1ccccn1
Temperature: 95 °C
Reaction time: 50 h

Procedure:
A mixture of 2-aminopyridine (200 g) and ethyl acrylate (468 g) was heated to 90-100° C. and then stirred for 50 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-35° C. Ethyl acetate was added to the reaction mixture and treating the reaction mixture with hydrochloric acid, followed by ammonia. Both the organic and aqueous layers were separated, the organic layer was washed with sodium chloride solution and then distilled off the solvent completely from the organic layer to get title compound as a residue. Yield: 295 grams.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:23])([CH3:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:5][CH:4]=1)=[O:2].[Mn]([O-])(=O)(=O)=[O:31].[K+].O>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]([OH:31])=[O:2])=[CH:8][CH:7]=2)=[C:10]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=1)([CH3:23])[CH3:22])[CH3:21]
Reactant: CCOC(=O)CC(C)(C)c1ccc(-c2ccc(C=O)cc2)c(OCCCOC)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CC(C)(C)c1ccc(-c2ccc(C(=O)O)cc2)c(OCCCOC)c1
Reaction time: 18 h
Yield: 96 %

Procedure:
Ethyl 3-[4′-formyl-2-(3-methoxypropoxy)biphenyl-4-yl]-3-methylbutanoate (1.0 g, 2.5 mmol) was dissolved in acetone (40 mL) and a solution of potassium permanganate (1.4 g, 8.8 mmol) and water (20 mL) was added at room temperature. The mixture was stirred for 18 hrs and then filtered. Dichloromethane was added and the mixture was then acidified at 0° C. with HCl 1N. The aqueous layer was extracted three times with dichloromethane and the combined organic layers were washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 1.0 g, (96%) of the desired product as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14]C([O-])=O.N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[CH:14][C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1ccc(OC)cc1OC
Reaction time: 0.33 h

Procedure:
83 g of 2,4-dimethoxybenzaldehyde and 66 g of monoethyl malonate are dissolved in 100 ml of dry pyridine and, after addition of 1 ml of piperidine and 40 g of molecular sieves, refluxed until evolution of CO2 has ceased. The reaction mixture is cooled and then poured onto crushed ice, and the pH is adjusted to 1-2 with concentrated hydrochloric acid, while stirring. Stirring is continued for 20 minutes, and the product which has separated out is filtered off with suction, washed with 1 N hydrochloric acid and water and dried in a desiccator. Yield: 100.2 g, melting point 58° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:9][CH:3]1[CH2:4][CH2:5]2
Reactant: CS(=O)(=O)Cl
Reactant: CN1C2CCC1CC(O)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2CCC1CC(OS(C)(=O)=O)C2
Temperature: 2.799999952316284 °C
Reaction time: 0.25 h

Procedure:
Tropine (500 g, 3.54 mol) and triethylamine (590 mL, 430 g, 4.25 mol) were mixed in dichloromethane (10 L) and cooled to <−5° C. under a stream of nitrogen. A solution of methane sulphonyl chloride (329 mL, 487 g, 4.25 mol) in dichloromethane (2 L) was added over 4.33 h between −10.4 and −4.9° C. The mixture was stirred for 15 min, the cooling bath removed, and potassium carbonate solution (2.5 L, GB98596-043)) and deionised water (1.25 L) were added. The additions took 4 min and caused an exotherm raising the temperature to 2.8° C. The mixture was warmed to 15 to 20° C., filtered and the phases allowed to separate. The aqueous phase was extracted further with dichloromethane (2.5 L). The combined organic phases were heated to distil off dichloromethane at atmospheric pressure; 10 L were collected over 1.75 h reaching a base temp. of 42.8° C. and vapour temperature of 42° C. Hexane (7.5 L) was added and after allowing the mixture to cool (overnight) the mixture was filtered and the filtrate returned to a clean flask. The solution was reheated to distil at atmospheric pressure; 7.5 L were collected up to base and vapour temperatures of 60.5 and 62° C. respectively. The mixture was cooled to 0 to 5° C., stirred for 1 h, the product filtered off and washed with hexane (1.5 L). The product was dried under vacuum in a dessicator. Crystallisation from ethyl acetate/hexane or dichloromethane/hexane gave crystalline title compound which was then used in Step 3.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].[CH3:26][O:27][C:28](=[O:31])[CH2:29]Br>CN(C)C=O>[CH3:26][O:27][C:28](=[O:31])[CH2:29][N:22]1[C:23]([CH3:25])=[CH:24][C:20]([C:17]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([C:4](=[O:5])[NH:6][CH2:7][C:8]3([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:16]=2)=[N:21]1
Reactant: COC(=O)CBr
Reactant: Cc1cc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)n[nH]1
Solvent: CN(C)C=O
Product: COC(=O)Cn1nc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A mixture of 2-chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-methyl-1H-pyrazol-3-yl)-benzamide (1.08 g, 3 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,2,3-diazaphosphorine on polystyrene (2.0 g, 4.6 mmol) and bromo-acetic acid methyl ester (0.69 g, 4.5 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The mixture was filtered and washed with dichloromethane. The filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate to afford the title compound (1.05 g). (3-{4-Chloro-3-[(1-hydroxy-cycloheptylmethyl)-carbamoyl]-phenyl}-5-methyl-pyrazol-1-yl)-acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:27]([CH3:29])[CH3:28])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([NH:16][CH:17]([CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:18]([CH3:20])[CH3:19])=[O:15])=[O:8])=[O:4].[Mn]([O-])(=O)(=O)=O.[K+]>CO>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:27]([CH3:29])[CH3:28])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([NH:16][CH:17]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:18]([CH3:20])[CH3:19])=[O:15])=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NC(C(C)C)C(O)C(F)(F)F)C(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NC(C(=O)C(F)(F)F)C(C)C)C(C)C
Temperature: 10 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Using a similar oxidation procedure to that described in Example 2, but using (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoro-1-hydroxyethyl)propyl]-pyrrolidine-2-carboxamide and adding the potassium permanganate solution at 5-10° C. and then stirring at 10° C. for one hour prior to treatment with methanol, there was obtained (after vork-up by extration into tert-butyl methyl ether, followed by washing with brine and concentration in vacuo) (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoroacetyl)propyl]-pyrrolidine-2-carboxamide as a gum (in 75% yield); SSS:SSR ratio of 53:47; hydrate:ketone 1:1; 1H NMR similar to that of the product of Example 1. [Using a similar procedure, but adding the potassium permanganate solution at ambient temperature instead of 5-10° C., the product was obtained in a ratio of SSS:SSR of 47:53.]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.Cl.[CH3:13][O:14][NH2:15].C([O-])([O-])=O.[K+].[K+]>COCCOC>[CH3:13][O:14]/[N:15]=[CH:7]/[C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[C:4]([F:11])[C:5]=1[F:10]
Reactant: CON
Reactant: O=Cc1cc(Br)cc(F)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CO/N=C/c1cc(Br)cc(F)c1F
Temperature: 40 °C
Yield: 100 %

Procedure:
A mixture of 5-bromo-2,3-difluorobenzaldehyde (17.38 g, 78.6 mmol), O-methylhydroxylamine hydrochloride (7.23 g, 86.46 mmol), and K2CO3 (13 g, 94.32 mmol) in DME (80 mL) was heated at 40° C. for 14 h. Work-up: the reaction mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (0-2% EtOAc in petroleum ether), to give (E)-5-bromo-2,3-difluorobenzaldehyde O-methyl oxime (19.65 g). 1H NMR (CDCl3, 300 MHz): δ 8.20 (s, 1H), 7.76-7.73 (m, 1H), 7.35-7.29 (m, 1H), 4.01 (s, 3H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](Cl)(=[O:14])[CH2:12][CH3:13].O.O.CN(C=O)C>CN(C=O)C>[C:11]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])(=[O:14])[CH2:12][CH3:13]
Reactant: CCC(=O)Cl
Reactant: Nc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.2 %

Procedure:
To a room temperature solution of 50.22 g anthranilic acid (I) (370 mmol, 1.00 equiv) dissolved in 200 mL dry DMF was added 35.0 mL propionyl chloride (400 mmol, 1.10 equiv) dropwise by addition funnel over 1.5 h. The addition rate was slow enough to maintain internal temperature of the reaction below 38° C. Upon completed addition of the acid chloride, the heterogeneous reaction mixture was stirred for 2.5 h at ambient temperature and then poured into 1600 mL water. The resulting water/DMF mixture, with white precipitate, was stirred vigorously at ambient temperature for one h, after which time the solid was collected by vacuum filtration, rinsing the solid with cold water (2×100 mL). The product was dried in vacuo over phosphorous pentoxide overnight affording 48.04 g of a white solid. m.p. 120.1° C. 1H NMR (CDCl3) δ 1.30 (t, 3H, J=7.4 Hz), 2.52 (q, 2H, J=7.4 Hz), 7.12 (t, 1H, J=7.2 Hz), 7.60 (t, 1H, J=7.1 Hz), 8.13 (d, 1H, J=6.3 Hz), 8.76 (d, 1H, J=7.8 Hz) ppm. MS (ESI−) 192.1 [M−H]−.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.[Li]C(C)(C)C.[Sn:11](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15].[NH4+].[Cl-]>C1COCC1>[CH2:20]([Sn:11]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]1[O:1][CH2:2][CH2:3][CH:4]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C1=COCC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 108.6 %

Procedure:
A solution of 2,3-dihydrofuran (10.7 mL, 141 mmol) in anhyd THF (80 mL) was cooled to −60° C. A solution of t-BuLi (1.7 M in pentane, 100 mL, 170 mmol) was added dropwise. The yellow solution was stirred at −60° C. for 10 min then at 0° C. for 50 min. The reaction mixture was cooled down to −60° C. and Bu3SnCl (52.7 mL, 185 mmol) was added dropwise to give a colorless solution that was stirred at 0° C. for 90 min. Sat. aq NH4Cl was added dropwise and the reaction mixture was extracted with Et2O. The aqueous phase was further extracted with Et2O and the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was distilled under 24 mbar vacuum at 150° C. and the residue was distilled again under 22 mbar vacuum at 154° C. to yield the title compound (55 g, 100%) as a light yellow liquid.
Reaction SMILES: C(C1N=C(OCC)C(C2N(C(Cl)=O)[C@@](C3C=CC(Cl)=CC=3)(C)[C@@](C3C=CC(Cl)=CC=3)(C)N=2)=C[N:6]=1)(C)(C)C.[C:38]([C:42]1[N:47]=[CH:46][C:45]([C:48]2[N:49]([C:69]([N:71]3[CH2:76][CH2:75][CH:74]([CH2:77][S:78]([CH3:81])(=[O:80])=[O:79])[CH2:73][CH2:72]3)=[O:70])[C@@:50]([C:62]3[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=3)([CH3:61])[C@@:51]([C:54]3[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=3)([CH3:53])[N:52]=2)=[C:44]([O:82][CH2:83][CH3:84])C=1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([C:42]1[N:6]=[C:44]([O:82][CH2:83][CH3:84])[C:45]([C:48]2[N:49]([C:69]([N:71]3[CH2:72][CH2:73][CH:74]([CH2:77][S:78]([CH3:81])(=[O:80])=[O:79])[CH2:75][CH2:76]3)=[O:70])[C@@:50]([C:62]3[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=3)([CH3:61])[C@@:51]([C:54]3[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=3)([CH3:53])[N:52]=2)=[CH:46][N:47]=1)([CH3:40])([CH3:41])[CH3:39]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CS(C)(=O)=O)CC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was reacted with 4-methanesulfonylmethyl-piperidine (example 52) to give the title compound. HR-MS (ES, m/z) calculated for C35H44Cl2N5O4S [(M+H)+] 700.2486, observed 700.2485.
Reaction SMILES: C[Sn](C)(C)[C:3]1[C:8]([F:9])=[CH:7][C:6]([N:10]2[CH2:14][CH:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])=[CH:5][C:4]=1[F:21].[O:24]1[CH2:29][CH2:28][O:27][CH2:26]C1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:26][O:27][C:28]1[C:29](=[O:24])[CH:5]=[CH:4][C:3]([C:3]2[C:8]([F:9])=[CH:7][C:6]([N:10]3[CH2:14][CH:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]3=[O:20])=[CH:5][C:4]=2[F:21])=[CH:8][CH:7]=1
Reactant: C1COCCO1
Reactant: CC(=O)NCC1CN(c2cc(F)c([Sn](C)(C)C)c(F)c2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccc(-c2c(F)cc(N3CC(CNC(C)=O)OC3=O)cc2F)ccc1=O
Temperature: 110 °C
Yield: 9 %

Procedure:
The (±)-N-[[3-[4-(trimethylstannyl)-3,5-difluorophenyl ]-2-oxo-5oxazolidinyl]methyl]acetamide (80 mg, 0.185 mmol) was dissolved in 1,4-dioxane (5 mL) and then treated with the 5-bromo-2-methoxytropolone (49.5 mg, .230 mmol). After degassing the solution 3 times with N2, the bis(triphenylphosphine)palladium(II) chloride (28 mg, .040 mmol) was added. The solution was degassed (3x) again, after which the reaction was heated to reflux (110° C.) for 5 h. At this point, the reaction was incomplete; more catalyst (28 mg, 0.040 mmol) was added and, after degassing (3×), the solution was again heated to reflux for 5 h. At this time, the reaction was still incomplete; the above process was repeated a third time with more fresh catalyst (28 mg). Finally, the solvent was removed in vacuo and the residual oil was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with aqueous KF (75 mL) and brine (50 mL). After drying over anhydrous Na2SO4, the organic layer was filtered and concentrated under reduced pressure to yield a foamy solid. This solid was purified first by preparative TLC (5% MeOH/CHCl3), and then by radial chromatography (eluting with a gradient of 0-5% MeOH in 10% CH3CN/CHCl3) to give 7 mg (9%) of the title compound as a solid with a HRMS (M+) calculated for C20H18F2N2O5 404.1184, found 404.1183.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([OH:13])=[CH:6][C:5]=1[CH3:14].[CH3:15]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH3:15])=[CH:6][C:5]=1[CH3:14]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a suspension of sodium hydride (1.2 mmol) in DMF (6 mL), 4-chloro 3-methyl 6-nitrophenol (1.0 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 15 minute then methyliodide was added at 0° C. and the mixture was stirred for 4 hours at room temperature. Water (60 mL) was added and the mixture extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 5-8% EtOAc in hexane to give the title compound (87%) as a solid.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[F:31].C(=O)([O-])[O-].[Cs+].[Cs+]>>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:3]1[C:4]2=[N:9][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:7][C:6](=[O:16])[N:5]2[CH2:17][C@@:2]1([CH3:1])[C:18]([F:21])([F:19])[F:20]
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: Fc1cccc(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1Cc1cccc(F)c1F

Procedure:
The product is prepared according to the procedure described in stage k of Example 1, using 100 mg of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (Example 1j) and 82 mg of 1-(bromomethyl)-2,3-difluorobenzene, replacing the sodium hydride with 214 mg of caesium carbonate. After purification by preparative HPLC/MS (method C), 90 mg of (2S)-1-(2,3-difluorobenzyl)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one are obtained in the form of a white semi-solid, the characteristics of which are the following:
Reaction SMILES: Cl.[Cl:2]C1C=CC(C2C3C4CCNCCC=4NC=3C=CC=2)=CC=1.C([N:31]1[CH2:44][CH2:43][C:42]2[C:41]3[C:40]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=4)=[CH:39][CH:38]=[CH:37][C:36]=3[NH:35][C:34]=2[CH2:33][CH2:32]1)(=O)C1C=CC=CC=1>>[ClH:2].[ClH:51].[Cl:51][C:47]1[CH:46]=[C:45]([C:40]2[C:41]3[C:42]4[CH2:43][CH2:44][NH:31][CH2:32][CH2:33][C:34]=4[NH:35][C:36]=3[CH:37]=[CH:38][CH:39]=2)[CH:50]=[CH:49][CH:48]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4cccc(Cl)c4)c3c2CC1
Reactant: Clc1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)cc1
Agent: Cl
Product: Clc1cccc(-c2cccc3[nH]c4c(c23)CCNCC4)c1

Procedure:
Following the procedure for the preparation of 10-(4-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride, making non-critical variations, starting with 3-benzoyl-10-(3-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, the title compound was obtained. 1H NMR (DMSO-d6) δ 3.05, 3.21, 3.31, 4.51, 6.85, 7.1-7.5, 11.3.
Reaction SMILES: C([C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[C:13]=1[O:26][CH3:27])([CH2:9][CH2:10][CH3:11])[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+]>C(O)C.O>[CH3:27][O:26][C:13]1[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[CH:15][CH:16]=[CH:17][C:12]=1[CH:3]([CH2:9][CH2:10][CH3:11])[C:4]([OH:6])=[O:5]
Reactant: CCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC(C(=O)O)c1cccc(Oc2ccccc2C)c1OC
Yield: 94 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]valerate (4.6 g) and potassium hydroxide (3.5 g) in ethanol (50 ml) and water (25 ml) was treated in a similar manner to that of Example 14-(7) to give oily 2-[2-methoxy-3-(o-tolyloxy)phenyl]valeric acid (3.7 g).