Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)(C)C(N[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[C:14]([N:16](C(C)C)C(C)C)=O)=O.Cl.C[OH:31]>>[C:10]1(=[O:31])[C:11]2[C:6](=[N:16][CH:14]=[C:13]3[C:12]=2[CH:26]=[CH:25][CH:24]=[CH:23]3)[CH:7]=[N:8][CH2:9]1
Reactant: CC(C)N(C(=O)c1ccccc1-c1ccncc1NC(=O)C(C)(C)C)C(C)C
Reactant: CO
Agent: Cl
Product: O=C1CN=Cc2ncc3ccccc3c21
Reaction time: 24 h

Procedure:
All of 2-[3-(2,2-dimethyl-propionylamino)-pyridin-4-yl]-N,N-diisopropylbenzamide from the previous step was carried on and dissolved in methanol (20 mL). Concentrated HCl (1 mL) was added, followed by 24 h of refluxing. A white solid which precipitated out of solution was filtered and dissolved in H2O. After 15 minutes of stirring, the free base crashed out of solution. The solid was filtered and dried, providing 150 mg (33% for two steps) of the desired final product as a white solid. Mp=303-309° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.70 (s, 1H), 8.60 (d, 1H), 8.41 (t, 2H), 8.31 (d, 1H), 7.95 (t, 1H), 7.80 (t, 1H); C12H8N2O.(0.3H2O).(0.2ClH). Anal: Calcd for: C, 68.99; H, 4.25; N, 13.41. Found: C, 68.83; H, 3.99; N, 13.26.
Reaction SMILES: [NH2:1][C@@H:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl>[CH3:9][C:6]1[CH2:7][S:8][C@@H:3]2[C@H:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:14])[N:4]2[C:5]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A suspension of the polymer ester of (6R,7R)-7-amino-3-methylceph-3-em-4-carboxylic acid (5.00g, 5.0 m.mole, from example 18) in methylene chloride (100 ml) was stirred at room temperature (18°-21° ) under nitrogen for 30 minutes. After cooling to 0°, triethylamine (3.03g. 0.03 mole) was added, and stirring continued for 30 minutes. Thienylacetyl chloride (3.0 ml, 3.89g, 0.024 mole) was then added dropwise over a period of 10 minutes maintaining the temperature at 0°-5°. When addition was completed stirring was continued for 15 minutes at 0°-5° and for a further 5 hours at room temperature (18°-21° ). The reaction mixture was filtered and pulled as dry as possible. The product was washed with methylene chloride (3 × 100 ml) acetone (2 × 100 ml), water (4 × 100 ml), acetone (2 × 100 ml), and methylene chloride 3 × 100 ml): and dried to constant weight in vacuo at 40° to give a light brown coloured polymer ester of (6R,7R)-3-methyl-7-(2-thienyl) acetamidoceph-3-em-4-carboxylic acid (5.41g). The composition was confirmed by microanalytical data. ν max (Nujol) 3320w (NH), 1780s (β-lactam CO), 1722s (ester CO) abnd 1688s (amide CO) cm-1, τ [CDCl3 and CF3COOH (2:1)] 2.66 (triplet, J = 3.3 Hz: 2-thienyl proton), 2.97 (doublet, J = 3.3 Hz: 3-thienyl protons): 4.27 (double doublet, J 4.5, 9.0 Hz; 7-H), 4.88 (doublet J 4.5 Hz: 6-H), 5.99 (singlet: --CH2CO--), 6.41 and 6.77 (2 doublets, J 18 - 19 Hz: s-CH2), and 7.70 (singlet, --CH3).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[N:8]/[NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:11])=[CH:5][C:4]([Cl:18])=[C:3]([Cl:19])[CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C1OC=NN1>>[Cl:18][C:4]1[CH:5]=[C:6]([CH:7]2[N:8]([C:20](=[O:22])[CH3:21])[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[O:11]2)[CH:1]=[CH:2][C:3]=1[Cl:19]
Reactant: O=C(N/N=C/c1ccc(Cl)c(Cl)c1)c1ccncc1
Reactant: CC(=O)OC(C)=O
Agent: C1=NNCO1
Product: CC(=O)N1N=C(c2ccncc2)OC1c1ccc(Cl)c(Cl)c1
Yield: 36 %

Procedure:
The title compound was prepared from the isonicotinoylhydrazone of 3,4-dichlorobenzaldehyde and acetic anhydride, using the General Structural Outline for Oxadiazoline Synthesis in 36% yield, mp 101-104° C., IR ν 1667, 1628, 1598, 1552, 1410, 1365, 1334, 1314, 1266, 1212, 1169, 1130, 1094, 1072, 1032, 990, 926, 885, 857, 825, 745, 723, 702 cm−1.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([F:50])[C:37]([F:38])=[C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48]O)=[CH:41][CH:40]=3)[CH:35]=[CH:34][CH2:33]2)=[CH:28][CH:27]=1)(=[O:19])[CH:17]=[CH2:18].N1C(C)=CC=CC=1C.O>ClCCl>[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([F:50])[C:37]([F:38])=[C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[CH:41][CH:40]=3)[CH:35]=[CH:34][CH2:33]2)=[CH:28][CH:27]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=CC(=O)OCCCCOc1ccc(C2(F)CC=CC(c3ccc(CCCCO)cc3)=C2F)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: O
Product: C=CC(=O)OCCCCOc1ccc(C2(F)CC=CC(c3ccc(CCCCOS(=O)(=O)C(F)(F)F)cc3)=C2F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
3.10 g of trifluoromethanesulphonic anhydride dissolved in 10 ml of dichloromethane was added dropwise at 0° C. to a solution of 4.40 g of 4-[2',3'-difluoro-4"-(4-hydroxy-butyl)-1,2':4',1"-terphenyl-4-yloxy]-butyl acrylate and 1.18 g of lutidine in 100 ml of dichloromethane. The reaction mixture was stirred at 0° C. for 90 minutes and subsequently poured into 100 ml of water and extracted twice with 50 ml of dichloromethane. The combined organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) gave 4.20 g of 4-[2',3'-difluoro-4"-[4-(trifluoro-methanesulphonyloxy)-butyl]-1,2':4',1"-terphenyl-4-yloxy]-butyl acrylate.
Reaction SMILES: [Cl:1][C:2]1[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:3]=1[CH2:4][NH:5][C:6](=[O:42])[N:7]([C@H:9]([CH2:27][O:28][C:29](=[O:41])[NH:30][C:31]1[N:32]=[CH:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:10][CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)=[O:13])[CH3:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[C:31]([NH:30][C:29](=[O:41])[O:28][CH2:27][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]2[CH:43]=[CH:44][CH:45]=[C:46]([F:47])[C:2]=2[Cl:1])=[O:42])[CH2:10][CH2:11][C:12](=[O:13])[N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[N:32]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COC(=O)Nc1cc2ccccc2cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCNCC1)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a solution of (S)-tert-butyl 4-(4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(isoquinolin-3-ylcarbamoyloxy)pentanoyl)piperazine-1-carboxylate (22 g, 32.8 mmol) in DCM (200 mL) was added TFA (100 mL). The reaction mixture was stirred at RT for 3 h and concentrated. The residue was purified on silica gel column using a mixture of MeOH and DCM. The fractions were concentrated, dissolved in water (200 mL), neutralized to pH 8-9 with 1N NaOH, and extracted with EtOAc (300 mL×3). The organic layer was dried over Na2SO4, filtered, and concentrated to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-oxo-5-(piperazin-1-yl)pentyl isoquinolin-3-ylcarbamate (14 g, 75%). LRMS (M+H) m/z 571.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:32][C:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[C:36]([CH3:47])[NH:35][N:34]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:37]3[C:33]([CH3:32])=[N:34][NH:35][C:36]=3[CH3:47])[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1n[nH]c(C)c1-c1nn(C(C)c2oc3ccccc3c(=O)c2-c2cccc(F)c2)c2ncnc(N)c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 7.6 %

Procedure:
To a solution of Example 57c (0.350 g, 0.661 mmoles) in DMF (6 ml), ethanol (3 ml) and water (3 ml), 3,5-Dimethylpyrazole-4-boronic acid pinacol ester (0.191 g, 0.859 mmoles) and sodium carbonate (0.350 g, 3.30 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.150 g, 0.130 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.025 g, 7% yield). MP: 240-243° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 12.44 (s, 1H), 8.04 (dd, J=8.0, 1.6 Hz, 1H), 8.01 (s, 1H), 7.85 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.52 (dt, J=7.9, 0.7 Hz, 1H), 7.33 (br m, 1H), 7.12-6.95 (m, 3H), 5.97 (q, J=7.0 Hz, 1H), 2.09 (s, 6H), 1.86 (d, J=7.0 Hz, 3H). Mass: 495.84 (M+).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>C(OCC)(=O)C.C(OC)(C)(C)C>[C:6]1(=[O:7])[N:2]([O:1][C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=2)=[O:23])[C:3](=[O:8])[CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: Cc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
2.42 g (0.021 mol) of N-hydroxysuccinimide and 5.06 g (0.050 mol) of triethylamine were initially introduced into 5 ml of ethyl acetate and the suspension was stirred at room temperature. 2.72 g (0.020 mol) of solid 4-toluic acid were added to this suspension in the course of 5 min. and then a solution of 5.64 g (0.21 mol) of diphenyl chlorophosphate was added dropwise in the course of 20 min., the reaction mixture warming to about 35° C. The mixture was stirred at room temperature for 1 hour until the reaction was complete. The reaction mixture was then diluted with 100 ml of ethyl acetate and the organic phase was washed with 50 ml each of water, 2N hydrochloric acid and 10% strength aqueous sodium hydrogencarbonate solution and then evaporated. 4.65 g of crude product were isolated, which was then stirred at room temperature for 30 minutes with 20 ml of methyl tert-butyl ether. The white crystalline solid was filtered off and dried at 50° C. and 10 mbar. 4.28 g (94%) of 4-toluic acid succinimidyl ester were isolated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:5][N:6]([CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:7]([C:9]1[N:10]=[CH:11][N:12]([CH3:14])[CH:13]=1)=[O:8].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>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.O.C(O)C>[F:24][C:23]1[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:3][C:4]([CH2:5][N:6]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:7]([C:9]2[N:10]=[CH:11][N:12]([CH3:14])[CH:13]=2)=[O:8])=[CH:21][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: Cn1cnc(C(=O)N(Cc2ccc(F)c(Br)c2)C2CCOCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)N(Cc2ccc(F)c(-c3ccccc3)c2)C2CCOCC2)c1
Yield: 33.6 %

Procedure:
A mixture of N-(3-bromo-4-fluorobenzyl)-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-4-carboxamide (150 mg), phenylboronic acid (92 mg), tetrakis(triphenylphosphine)palladium (50 mg), potassium carbonate (110 mg), DMF (2 mL) and ethanol (1 mL) was subjected to reaction in a microwave reactor (150° C., 10 min). Water was added to the reaction mixture, followed by extraction with ethyl acetate and concentrating under reduced pressure. The resulting residue was purified by TLC (silica gel) (chloroform:methanol=10:1) to give the titled compound (50 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]=[C:39]([C:41]3[C:45]([CH2:46][CH2:47][CH3:48])=[C:44]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[O:43][N:42]=3)[O:38][N:37]=2)=[CH:32][CH:31]=1)[OH:29]>CS(C)=O>[OH:29][CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]=[C:39]([C:41]3[C:45]([CH2:46][CH2:47][CH3:48])=[C:44]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[O:43][N:42]=3)[O:38][N:37]=2)=[CH:32][CH:31]=1)[CH2:27][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1
Reactant: OC1CCCNC1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCCC(O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a mixture of piperidin-3-ol (20.04 mg, 0.198 mmol) in DMSO (2 mL) was added tetrabutylammonium hydroxide (0.198 mL, 0.198 mmol). After 5 minutes, 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Int-I-C (30 mg, 0.066 mmol) was added. The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 20 mL/min to yield 22 mg of 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-ol as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (2H, d, J=8.13 Hz), 7.83 (2H, dd, J=8.02, 1.65 Hz), 7.58-7.73 (5H, m), 5.17-5.28 (1H, m), 4.10 (1H, d, J=14.72 Hz), 3.06-3.91 (5H, m), 2.95-3.06 (2H, m), 2.59-2.95 (2H, m), 1.77-2.21 (2H, m), 1.64-1.76 (2H, m), 1.16-1.42 (1H, m), 0.98 (3H, t, J=7.36 Hz). MS (m+1)=475. HPLC Peak RT=3.32 minutes (Analytical Method A). Purity=98%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:11][CH:10]2C(OCC)=O)=[CH:5][C:4]=1[O:17][CH3:18])#[N:2].CC[O-].[Na+].O>C(O)C>[CH3:18][O:17][C:4]1[CH:5]=[C:6]([CH2:9][CH:10]=[O:11])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)C1OC1c1ccc(C#N)c(OC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(CC=O)ccc1C#N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl 3-(4-cyano-3-methoxyphenyl)oxirane-2-carboxylate (400 mg, 1.6 mmol) in 5 mL of dry ethanol was cooled to 0° C. Freshly prepared EtONa (2.1 mmol) in 4 mL of ethanol was added and stirred at 0° C. for 10 min. Then dropwise addition of 0.1 g of water, stirred at 0° C. for 2 hours, and the sodium salt of the epoxy compound was filtered. The sodium salt of the epoxy compound was then dissolved in 10 mL of water and added 10 mL of 1 N of HCl and 20 mL of toluene. The mixture was heated to reflux for 2 hours. The organic phase was separated, washed by saturated sodium chloride, dried over Na2SO4 and distilled off solvent to afford crude 2-methoxy-4-(2-oxoethyl)benzonitrile. MS m/z: 176 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[OH:11]O>C(O)(=O)C>[CH3:9][C:4]1[C:3](=[O:10])[C:2]([CH3:1])=[C:7]([CH3:8])[C:6](=[O:11])[CH:5]=1
Reactant: Cc1ccc(C)c(O)c1C
Reactant: OO
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Reaction time: 6 h
Yield: 94 %

Procedure:
500 mg of 2,3,6-trimethylphenol and 30 mg of the catalyst prepared in Example 6 were added to 5 ml of acetic acid, and 1 g of a 30% hydrogen peroxide aqueous solution was further added at room temperature. The mixture was stirred for 6 hours. After the completion of the reaction, the catalyst was removed by filtration, and the acetic acid solution was washed with an aqueous solution of NaHCO3 and extracted with ether. After drying over MgSO4, the solution was concentrated, and the residue was eluted through a silica gel column with dichloromethane, whereby 515 mg (94% yield) of trimethylbenzoquinone was obtained. The physical properties of the product (yellow needle-like crystals as crystallized from hexane, having a melting point of 28° C.) corresponded to the values identified in the literature [Org. Syn. 52, 83 (1972].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]=[CH2:14].C(N(CC)CC)C.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>ClCCl.CN(C)C1C=CN=CC=1>[Si:26]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]=[CH2:14])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCc1cc(C(=O)OC)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.168 g (26.9 mml) of the product of Step B in 50 mL of dichloromethane was added 4.40 mL (2.95 mmol) of triethylamine, 4.46 g (2.95 mmol) of tert-butyldimethylchlorosilane, 0.100 g of 4-dimethylaminopyridine, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then diluted with 50 mL dichloromethane, washed with 100 mL 1 N hydrochloric acid, dried (MgSO4), filtered and evaporated. The residual oil (7.993 g, 97%) was used in the next step without further purification.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:21]=[O:22])[N:11]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[CH:12]=1.CC(C)=[O:25].[OH-].[Na+]>O>[Br:7][C:8]1[CH:9]=[C:10]([C:21]([OH:25])=[O:22])[N:11]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[CH:12]=1
Reactant: CC(C)=O
Reactant: O=Cc1cc(Br)cn1-c1c(Cl)cccc1Cl
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cn1-c1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 2.0 g of potassium permanganate in 10 ml of water was added dropwise to a mixture of 0.85 g of 4-bromo-1-(2,6-dichlorophenyl)-1H-pyrrole-2-carbaldehyde and 18 ml of acetone while the mixture was maintained at 40° C. The resulting mixture was stirred at 40° C. for 2 hours. A precipitate was filtered off to obtain a filtrate. The filtrate was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution, and then extracted with chloroform two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.66 g of 4-bromo-1-(2,6-dichlorophenyl)-1H-pyrrole-2-carboxylic acid of the formula:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[S:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:18]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:25]2[CH2:26][CH2:27][S:28][CH:23]([C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)[CH2:24]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: c1cncc(C2CNCCS2)c1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCSC(c3cccnc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 2-pyridin-3-yl thiomorpholine hydrochloride (13 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (11.5 mg). Calcd for C20H19N3O2S: 365.1198, found 365.1200.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)C(C)C)(C)C.CN(C1C=CC=CN=1)C.[F:42][C:43]([F:49])([F:48])[S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:44]([C:43]([F:49])([F:48])[F:42])(=[O:46])=[O:45])[CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: Cc1nc(C2CCNCC2)sc1COc1ccc(C#N)c(Cl)c1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C2CCN(S(=O)(=O)C(F)(F)F)CC2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg 2-Chloro-4-(4-methyl-2-piperidin-4-yl-thiazol-5-ylmethoxy)-benzonitrile was dissolved in 20 ml dichloromethane. 0.25 ml N,N-Diisopropylethylamine and 50 mg dimethylaminopyridine were added. Then 0.26 ml trifluoromethanesulfonylchloride were added to the ice cooled reaction mixture. The cooling bath was removed and the reaction mixture stirred at room temperature overnight. The reaction mixture was washed with 10 ml saturated NaHCO3 solution and then dried over MgSO4. The solvent was removed in Vacuo. The resulting crude material was purified by reversed phase HPLC to obtain 350 mg 2-Chloro-4-[4-methyl-2-(1-trifluoromethanesulfonyl-piperidin-4-yl)-thiazol-5-ylmethoxy]-benzonitrile as amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[N:26]4)=[CH:21][CH:20]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Fc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: Brc1ccc2cccnc2c1
Product: Fc1ccc2c(c1)c1c(n2-c2ccc3cccnc3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg, 1.0 mmol; Example 161) and 7-bromoquinoline (312 mg, 1.5 mmol; Ark Pharm) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.95-2.22 (m, 4H) 2.96-3.03 (m, 1H) 3.09-3.29 (m, 4H) 4.32 (s, 2H) 6.86 (td, J=9, 2 Hz, 1H) 7.07-7.17 (m, 2H) 7.58-7.67 (m, 2H) 7.97 (d, J=2 Hz, 1H) 8.18 (d, J=9 Hz, 1H) 8.50 (d, J=8 Hz, 1H) 8.95 (dd, J=4, 2 Hz, 1H); MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:32])[C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[O:30][CH3:31])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:33].Cl.O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:32])[C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[O:30][CH3:31])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(C)cccc1OC)S(=O)(=O)c1ccc(Cl)c(C)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C)c1

Procedure:
4-Chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-methyl-benzenesulfonamide was hydrolyzed using 4 M HCl in dioxane (12 mL), and water (4 mL) at 100° C. to provide 4-chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-3-methyl-benzenesulfonamide. The product was purified by HPLC. MS m/z: 465.4 (M+H).