Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].N1C=CC=CC=1.[CH:43](F)=[O:44]>O1CCCC1>[CH:43]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[O:44]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: O=CF
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
Diphenylmethyl 3-hydroxymethyl-7β-(2'-thienylacetamido)-ceph-3-em-4-carboxylate (3 g., 5.8 mmole.) and pyridine (6.5 ml., 82 mmole.) were dissolved in dry tetrahydrofuran (100 ml.), and cooled to -60°. A solution of formyl fluoride (~80 mmole.) in dry tetrahydrofuran (100 ml.), and cooled to -60°. A solution of formyl fluoride ( 80 mmole.) in dry tetrahydrofuran was added dropwise and the mixture maintained at -40° for 1 hour. On reaching room temperature, the mixture was filtered, concentrated, and partitioned between ethyl acetate and 2N-hydrochloric acid. On washing with more acid the ethyl acetate solution precipitated some product (1.77 g.); the remaining ethyl acetate was dried and evaporated to give more product (1.32 g.). A sample of the product was recrystallised from ethyl acetate, m.p. 189°, νmax (CHBr3), 1792 (β-lactam), 1730 and 1232 (COOR), 1690 and 1518 cm-1 (CONH). N.M.R. spectrum (dimethylsulphoxide) CHO at 179τ. (Found: C, 61.7; H, 4.4; N, 4.8. C28H24H2O6S2 requires C, 61.3; H, 4.4; N, 5.1%) NF = 0.7 (Kieselgel G plate, benzene:ethyl acetate = 2:1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14].[C:16](=O)([O-])[O-].[K+].[K+].CN(C=O)C.CI>CCOC(C)=O>[CH3:16][O:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CN1Cc2c(O)ccc([N+](=O)[O-])c2C1=O
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c2c1CN(C)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 4-Hydroxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 205C, 50.0 mg, 0.240 mmol), potassium carbonate (49.8 mg, 0.360 mmol) in DMF (2 mL, 20 mmol) was treated with methyl iodide (22.4 μL, 0.360 mmol) and allowed to stir at room temperature overnight. The reaction was poured into EtOAc and washed with water and brine and the crude material was purified using an ISCO Combiflash unit (MeOH in DCM: 0-1%) to obtain the title product as a solid. (27 mg, 50% yield). 1H NMR (400 MHz, CD3OD) δ=3.17 (s, 3H), 4.02 (s, 3H), 4.44 (s, 2H), 7.27 (d, J=8.8 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H). MS (ES+): m/z 223.19 (100) [MH+]; HPLC: tR=0.76 min (UPLC, analytical).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(C(Cl)=O)=O.[C:19]1([NH2:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Into a 1-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-nitrobenzoic acid (167 g, 999.29 mmol, 1.00 equiv) in dichloromethane (400 mL) and ClCOCOCl (317.5 g, 2.50 equiv). This was followed by the addition of N,N-dimethylformamide (1 mL) dropwise with stirring. The resulting solution was stirred for 4 h at room temperature. The mixture was concentrated under vacuum. To the residue was added a solution of PhNH2 (93 g, 1.00 equiv) in dichloromethane (400 mL), triethylamine (415 mL, 3.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was washed with 2×500 mL of HCl (10%) and 1×500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was diluted with 500 mL of petroleum ether/ethyl acetate=5:1. The solids were collected by filtration. This resulted in 205 g (85%) of 4-nitro-N-phenylbenzamide as light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.12-7.17 (m, 1H), 7.32-7.41 (m, 2H), 7.78-7.81 (m, 2H), 8.16-8.21 (m, 2H), 8.36-8.42 (m, 2H), 10.58 (s, 1H); MS (ESI) m/z 243 ([M+H]+).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[N:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH3+:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)=[O:5].[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[C:22]([NH:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14](/[N:13]=[N:12]/[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:11][CH:10]=2)=[CH:19][CH:18]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)c1ccc(N=Nc2ccc(C[NH3+])cc2)cc1
Reactant: CCCC(=O)Cl
Agent: [Cl-]
Solvent: c1ccncc1
Product: CCCC(=O)NCc1ccc(/N=N/c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Into the solution of the amine 4 (915 mg, 3.0 mmol) in pyridine (15 mL) was added dropwise butyryl chloride (477 mg, 4.5 mmol), and the reaction was stirred overnight at room temperature. The solvent was evaporated, the residue dissolved in chloroform, washed with hydrochloric acid (1.0 M), water and brine, and dried with magnesium sulfate. Silica gel chromatography with chloroform as eluent gave pure 10 (916 mg, 90%) as orange crystals. 1H NMR (360 MHz, CDCl3): δ 8.19 (d, J=8.4 Hz, 2H), 7.96-7.91 (m, 4H), 7.44 (d, J=8.0 Hz, 2H), 5.86 (br s, 1H), 4.55 (d, J=6.0 Hz), 3.97 (s, 3H), 2.56 (t, J=7.6 Hz, 2H), 1.73 (q, J=7.6 Hz, 2H), 0.99 (t, J=7.6 Hz, 3H). 13C NMR (100.61 MHz, CDCl3): δ 172.55, 166.14, 154.70, 151.49, 141.99, 131.44, 130.22, 128.06, 123.11, 122.26, 51.95, 42.77, 38.29, 18.78, 13.42. HRMS (m/z): [M+H]+ calcd. for C19H21N3O3 340.1656. found 340.1669.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.C[O:16][C:17](=O)[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=2)[NH:22][CH:21]=1)=O.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:18]1[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(OC)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.544 g, 2.89 mmol) and (5-methoxy-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.648 g, 2.81 mmol) in DMF (40 mL) under N2 was added a 1.0 M solution of potassium-tert-butoxide in THF (9.8 mL, 9.8 mmol) dropwise over 5 minutes. The mixture was stirred 8 h at room temperature and then heated at 65–70° C. for 15 h. The mixture was cooled to room temperature, quenched with 1N HCl (excess) and poured into EtOAc. The organic layer was separated, washed with water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated to ˜30 mL. Upon standing 4 h, a bright red solid precipitated which was isolated by filtration and dried under vacuum at 80–100° C. overnight affording the title compound (0.421 g, 41%). 1H NMR (400 MHz, DMSO-d6) 11.81 (br s, 1H), 11.80 (s, 1H), 8.06 (d, J=3.1 Hz, 1H), 7.58, dd, J=7.5, 1 Hz, 1H), 7.31 (d, J=3 Hz, 1H), 7.22 (d, J=9 Hz, 1H), 6.93 (dd, J=7.5 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 6.53 (dd, J=9, 2.5 Hz, 1H), 6.50 (d, J=3 Hz, 1H), 5.80 (d, J=2.5 Hz, 1H), 3.80 (s, 3H), 2.70 (s, 3H). MS (electrospray, m/z) 372.1 (M++1), 370 (M−−1). HRMS 372.1345 (M++1, calcd for C22H18N3O3 372.1348). Anal. Calcd for C22H17N3O3: C, 71.15; H, 4.61; 11.31. Found: C, 71.05; H, 4.59; N, 11.17.
Reaction SMILES: [CH:1]([CH:4]1[NH:8][CH2:7][CH2:6]O1)([CH3:3])[CH3:2].[BH4-].[Na+].C[CH2:12][OH:13]>>[CH2:4]([NH:8][CH2:7][CH2:6][CH2:12][OH:13])[CH:1]([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)C1NCCO1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)CNCCCO
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 2-isopropyltetrahydro-1,3-oxazole (4.94 g, 38.2 mmol) in abs. EtOH (100 mL) at 0° C. was added NaBH4 (2.17 g (57.4 mmol, 1.5 equiv.) in small portions over 15 min. and the resulting mixture was stirred at room temp.overnight. The resulting mixture was concentrated under reduced pressure, then treated with EtOAc (150 mL) and water (100 mL) (CAUTION; gas evolution), and stirred at room temp for 30 min. The resulting organic layer was washed with a saturated NaCl solution. The combined aqueous layers were back-extracted with EtOAc (150 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford N-isobutyl-3-hydroxypropylamine as a colorless oil (5.04 g, 100%): 1H NMR (CDCl3) δ0.84 (d, J=6.6 Hz, 6H), 1.60-1.71 (m, 3H), 2.36 (d, J=6.6 Hz, 2H), 2.80 (dd, J=5.9, 5.9 Hz, 2H), 3.10-3.30 (br s, 2H), 3.74 (dd,, J=5.5, 5.5 Hz, 2H); 13C NMR (CDCl3) δ20.5, 28.1, 30.6, 50.0, 57.8, 64.1.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:10]=1[CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:37]([CH2:44][C:45](=O)[CH3:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)(=O)C>O1CCCC1>[CH3:7][O:8][C:9]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:10]=1[CH:11]=[C:45]([CH3:46])[CH2:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: COc1ccc(OC)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C=C(C)CCc2ccccc2)c1

Procedure:
A solution of n-butyl lithium (29 ml. of 2.2 M) is added dropwise to 2,5-dimethoxybenzyl triphenylphosphonium bromide (31.5 g.) in tetrahydrofuran (200 ml.) with stirring and the resulting deep red solution is stirred for one-half hour. Benzyl acetone (9.4 g.) is added dropwise and the reaction mixture stirred for 12 hours. It is then adjusted to pH 7 by addition of acetic acid and concentrated under reduced pressure. The residue is extracted with methylene chloride and the extract evaporated to give crude 1-(2,5-dimethoxyphenyl)-2-methyl-4-phenyl-1-butene as an oil. It is purified by chromatography on silica gel and elution with benzene.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.[C:26]([O:30][C:31](=[O:34])[CH2:32]Br)([CH3:29])([CH3:28])[CH3:27].CCN(CC)CC>CC#N>[C:26]([O:30][C:31](=[O:34])[CH2:32][N:6]1[CH2:7][C@@H:2]2[CH2:8][C@H:5]1[CH2:4][N:3]2[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:24][CH:25]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Reaction time: 18 h

Procedure:
To a stirred solution of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (257 mg, 0.63 mmol) and bromoacetic acid tert-butyl ester (110 μL, 0.75 mmol) in CH3CN (4.0 mL) at rt was added Et3N (270 μL, 1.9 mmol). After 18 h at rt, the suspension was partitioned between CH2Cl2 (200 mL) and satd. aq. NaHCO3 (80 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (5% CH3OH in CH2Cl2) afforded the title compound as a viscous, colorless oil (218 mg, 77%). MS (ESI): mass calcd. for C25H29N3O3S, 451.19; m/z found, 452.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.75 (d, J=7.7 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.39 (m, 1H), 7.34-7.25 (m, 3H), 3.75 (m, 2H), 3.43 (br s, 1H), 3.33 (m, 3H), 2.88 (m, 2H), 2.82 (br d, J=10.0 Hz, 1H), 2.70 (dd, J=10.0, 2.2 Hz, 1H), 1.78 (s, 2H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([C@H:12]1[CH2:16][O:15]C(C)(C)[O:13]1)[CH2:6][CH2:5]2.O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([C@H:12]([OH:13])[CH2:16][OH:15])[CH2:6][CH2:5]2
Reactant: CC1(C)OC[C@H]([C@@H]2CCc3cc(F)ccc3O2)O1
Solvent: CC(=O)O
Solvent: O
Product: OC[C@@H](O)[C@@H]1CCc2cc(F)ccc2O1
Temperature: 65 °C
Yield: 42.8 %

Procedure:
(S)-6-fluoro-3,4-dihydro-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromene (1.10 g, 4.4 mmol) was dissolved in acetic acid (9 ml) and demi water (3 ml). The reaction mixture was stirred vigorously and heated to 65° C. After 2.5 h at 60° C. the reaction mixture was cooled to 25° C. The solution was then concentrated in vacuo to obtain a vetrous oil. Chromatographic separation on silica of the crude, using a mixture of heptane:ethyl acetate 1:1 as eluent, furnished 0.40 g of (R)-1-((S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethane-1,2-diol as a white solid (43% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH:28]1([Mg]Br)[CH2:30][CH2:29]1>C1COCC1>[CH:28]1([C:19]([C:9]2[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:27])[CH:8]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[OH:20])[CH2:30][CH2:29]1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(c3ccccn3)C3CC3)cc(-c3c(C)noc3C)cc2[nH]1
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (40 mg, 0.11 mmol) was dissolved in dry THF (1.1 mL) and cyclopropylmagnesium bromide (0.5 M in diethylether, 1.1 mL, 0.55 mmol) was added dropwise at rt and the reaction was allowed to stir for 10 minutes. The reaction was quenched with water, concentrated, and purified by reverse-phase HPLC to give cyclopropyl(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanol intermediate which was taken up in 1.0 mL EtOH and 0.7 mL 4.0M HCl/dioxane and heated for 2 hours at 65° C. Reaction was then concentrated down and purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=O)[CH3:13])(=O)[CH3:2].C([O-])(=O)C.[NH4+:19]>C(O)(=O)C>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:11]=[C:12]([CH3:13])[N:19]=[C:1]2[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)cc1C(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1nc(C)c2cc(Br)ccc2n1
Temperature: 100 °C
Yield: 23.4 %

Procedure:
415 mg N-(2-acetyl-4-bromophenyl)acetamide and 0.624 g of ammonium acetate was dissolved in 5 mL of glacial acetic acid and heated for 2 days at 100° C. The solvent was removed and the residue suspended in water and extracted with DCM. The organic phase was concentrated and purified via FCC (25 g SiO2, DCM:MeOH 100:0→70:30) to yield 90 mg of 6-bromo-2,4-dimethylquinazoline as oil. Analysis: HPLC-MS: Rt=1.26 min (method V003—003), M+H=237/239.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:3][CH:2]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:4]2[CH:5]=[CH:6][C:1]([CH3:12])=[CH:2][CH:3]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C2CCCN2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(C2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound, white solid, m.p. 124° C. and MS: m/e=315 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-p-tolyl-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C1C=C[C:36]2N(O)N=[N:39][C:37]=2[CH:38]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.C1(N)CC1>CN(C=O)C>[CH:37]1([NH:39][C:6]([CH:4]2[CH2:5][C:2]([F:1])([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH2:19][C:18]([C:24]5[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=5)([C:20]([F:21])([F:22])[F:23])[O:17][N:16]=4)=[CH:13][CH:14]=3)[CH2:3]2)=[O:8])[CH2:38][CH2:36]1
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 7, 0.1 g, 0.195 mmol) in DMF (3 mL) was added HOBt (0.026 g, 0.195 mmol), DIPEA (0.051 g, 0.391 mmol) followed by addition of EDCl.HCl (0.056 g, 0.293 mmol) and cyclopropyl amine (0.011 g, 0.195 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (20 mL) and extracted with EtOAc (5×20 mL). Combined organic layer was washed with saturated water (100 mL), brine (100 mL), dried over sodium sulphate and evaporated in vacuo to get a yellow semisolid (0.108 g, crude). Crude was purified by column chromatography on silica gel (100-200 mesh). Compound was eluted using 0.5% methanol in DCM to afford off white solid (0.020 g, 19%, CR963-125249-74-1). 1H-NMR (400 MHz, CDCl3) δ: 0.49-0.51 (m, 2H), 0.76-0.81 (m, 2H), 2.52-2.58 (m, 1H), 2.67-2.76 (m, 3H), 2.93-3.06 (m, 2H), 3.68 (d, 1H, J=17.04 Hz), 4.08 (d, 1H, J=17.16 Hz), 5.55 (bs, 1H), 7.51 (d, 2H, J=8.08 Hz), 7.63 (s, 2H), 7.68 (d, 2H, J=8.20 Hz); LC-MS (m/z): [M−H] 546.80.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[C:9]([CH3:25])([O:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:10].CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:10][C:9]([C@@H:5]1[C:6](=[O:8])[NH:7][C@@H:4]1[CH2:3][C:2]([OH:28])=[O:1])([O:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])[CH3:25]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC(=O)O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (3R,4R)-4-(2-hydroxyethyl)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-azetidin-2-one (10 mg) in acetone (0.6 ml) was added 2N Jones reagent (50 μl) at 0° C. and the mixture was stirred at 0° C. for 20 minutes. Isopropyl alcohol (100 μl) was added to the mixture at 0° C. and the mixture was evaporated in vacuo. The residue was dissolved in chloroform (10 ml) and the solution was washed with brine. The aqueous layer was separated and extracted with chloroform (5 ml). The conbined organic layers were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (0.5 g) eluting with a mixture of methylene chloride and methanol (20:1 to 5:1) to give pure {(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl}acetic acid (3 mg) and impure material (5 mg).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=O)=[O:20]>ClCCl>[C:1]([O:9][C:18]1[C:19](=[O:20])[C:21]2[C:22](=[CH:27][CH:28]=[C:29]([F:31])[CH:30]=2)[N:23]([CH3:26])[CH:24]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN(C=O)c1ccc(F)cc1C(=O)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(OC(=O)c2ccccc2)c(=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of benzoic acid (6.7 g) and triethylamine (9.9 ml) in dichloromethane (80 ml) was added to the solution of 2'-(2-chloroacetyl)-4'-fluoro-N-methylformanilide at 0°. The mixture was stirred at ambient temperature for 24 hours and then heated under reflux for 2 hours. The mixture was washed with water (2×50 ml) and dried over magnesium sulphate. The solvent was removed by distillation and the residue added to potassium carbonate (1.76 g) and dry dimethylformamide (30 ml). The mixture was heated under nitrogen at 60° for 6 hours. Further potassium carbonate (1.0 g) was added and the heating continued for 6 hours. The solvent was removed under reduced pressure at 60° C., the residue triturated with water (30 ml), and the solid collected by filtration to give the novel compound 6-fluoro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl benzoate, m.p. ]88°-190°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:9]1([C:2]2[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH2:11][CH2:10]1
Reactant: Nc1ccc(Br)cn1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(C2CC2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a mixture of 5-bromopyridin-2-amine (5.0 g) in a mixed solvent of toluene (100 mL) and water (5 mL) were added cyclopropylboronic acid (4.59 g), tricyclohexyl phosphine (1.62 g), palladium(II) acetate (0.649 g) and tripotassium phosphate (21.5 g) at room temperature. The mixture was stirred overnight at 80° C. under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, and the insoluble substance was removed by filtration. To the filtrate was added ethyl acetate, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.33 g).
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24]4[N:25]=[C:26]([CH3:29])[S:27][CH:28]=4)[CH2:20][CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>C1COCC1>[CH3:29][C:26]1[S:27][CH:28]=[C:24]([CH:21]2[CH2:22][CH2:23][CH:18]([NH2:17])[CH2:19][CH2:20]2)[N:25]=1
Reactant: Cc1nc(C2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)cs1
Solvent: C1CCOC1
Solvent: CCNCC
Product: Cc1nc(C2CCC(N)CC2)cs1

Procedure:
1.10 g (2 mmol) of 9H-fluoren-9-ylmethyl[4-(2-methylthiazol-4-yl)cyclohexyl]carbamate (cis compound) and 15 mL of diethylamine are stirred in 30 mL of THF for 16 hours at ambient temperature. Then the reaction mixture is concentrated by evaporation and the residue is combined with THF and concentrated again by evaporation. The residue is purified by chromatography. Yield: 0.13 g (36%).