Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:23]([NH:24]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22](=[O:44])[N:13]3[C:14]=2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:1]1([CH2:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:23]([NH2:24])[C:22](=[O:44])[N:13]3[C:14]=2[C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1=C(CCc2ccccc2)CS[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C1=C(CCc2ccccc2)CS[C@@H]2C(N)C(=O)N12
Reaction time: 1 h

Procedure:
The cephem (XX111) (77 mg) was dissolved in acetone (1 ml) and cooled to 0°C. p-Toluene sulphonic acid monohydrate (24 mg) was added and the mixture was stood at 0°C for 1 hour. The mixture was then allowed to attain room temperature and was stood at room temperature for 6 hours. The mixture was evaporated. The residue was suspended in ethyl acetate (20 ml) and shaken with saturated sodium bicarbonate solution (5 ml). The organic layer was separated and washed with brine. The dried (MgSO4) organic layer was evaporated to give t-butyl 3-β-phenylethyl-7-amino-3-cephem-4-carboxylate (XXV) contaminated with triphenylmethanol as a solid (61 mg). ##SPC6##
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:1]([NH:5][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CNS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.14 g of isobutylamine (56.6 mmol) and 2.86 g of triethylamine (28.3 mmol) in 40 mL of CH2Cl2 was slowly added 5.0 g of benzenesulfonyl chloride (28.3 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 min and then at rt for 1 hr. 150 mL of CH2Cl2 were added, and the organic layer was washed with saturated aqueous solution of NH4Cl and brine (30×2 mL), dried over MgSO4, filtered, and the filtrate was concentrated to give the title compound. 1H NMR (CDCl3) δ 0.87 (d, J=6.6 Hz, 6H), 1.71 (tsept, J=6.7, 6.5 Hz, 1H), 2.76 (dd, J=6.5, 6.7 Hz, 2H), 4.61 (t, J=6.5 Hz, 1H), 7.49–7.88 (m, 5H). Mass Spectrum (CI+) m/e=214 (M+1).
Reaction SMILES: FC1C=C2C(=CC=1)N(C[C:12]1[O:13]C(C(F)(F)F)=CC=1)C(=O)C2C1C(O)=CC2OCOC=2C=1.[Br:32][C:33]1[CH:34]=[CH:35][C:36]([OH:49])=[C:37]([CH:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][C:40]2=[O:48])[CH:38]=1>>[Br:32][C:33]1[CH:34]=[CH:35][C:36]([OH:49])=[C:37]([C:39]2([CH2:12][OH:13])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][C:40]2=[O:48])[CH:38]=1
Reactant: O=C1C(c2cc3c(cc2O)OCO3)c2cc(F)ccc2N1Cc1ccc(C(F)(F)F)o1
Reactant: O=C1Nc2ccccc2C1c1cc(Br)ccc1O
Product: O=C1Nc2ccccc2C1(CO)c1cc(Br)ccc1O

Procedure:
Following the procedure as described in PREPARATION 35D, and making non-critical variations to replace 5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one with 3-(5-bromo-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 334.2 (M+1), 336.2 (M+1).
Reaction SMILES: C(=O)([O-])O.[K+].F[C:7]1[CH:8]=[C:9]([O:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].O.[CH2:24]([OH:26])[CH3:25]>>[CH2:24]([O:26][C:7]1[CH:8]=[C:9]([O:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH3:25]
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])c(F)c2)n[nH]1
Reactant: CCO
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CCOc1cc(Oc2cc(C)[nH]n2)ccc1[N+](=O)[O-]
Yield: 42.3 %

Procedure:
Potassium hydrogencarbonate (0.15 g, 1.5 mmol) was added to a solution of 3-(3-fluoro-4-nitrophenyloxy)-5-methylpyrazole (0.36 g, 1.5 mmol) in ethanol (5 ml), and the mixture was refluxed under heating for 10 hours. After completion of the reaction, the reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove magnesium sulfate, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a yellow solid of 3-(3-ethoxy-4-nitrophenyloxy)-5-methylpyrazole (0.17 g, yield: 42.3%). mp: 123-124° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.47 (t, J=7.0 Hz, 3H), 2.33 (d, J=0.5 Hz, 3H), 4.13 (q, J=7.0 Hz, 2H), 5.73 (d, J=0.5 Hz, 1H), 6.68 (dd, J=2.5 and 9.1 Hz, 1H), 6.81 (d, J=2.5 Hz, 1H), 7.91 (d, J=9.1 Hz, 1H), 9.53 (br s, 1H).
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([CH3:14])([CH3:13])[C:8]1[S:12][CH:11]=[N:10][CH:9]=1.[CH:15](N1CCOCC1)=[O:16].Cl>C1COCC1>[CH3:6][Si:7]([CH3:14])([CH3:13])[C:8]1[S:12][C:11]([CH:15]=[O:16])=[N:10][CH:9]=1
Reactant: C[Si](C)(C)c1cncs1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cnc(C=O)s1
Temperature: 25 °C

Procedure:
n-Butyllithium (1.50M in hexane, 39 mmol, 22 ml) was added dropwise at -78° C. to a solution of 5-(trimethylsilyl)thiazole (A. Dondoni et al, J. Org. Chem, 1988, 53, 1748) (5.2 g, 33 mmol) in THF (40 ml). After 30 min. a solution of N-formylmorpholine (4.57 g) in THF (40 ml) was added dropwise over 15 min. The resulting red solution was stirred a further 30 mi. and then allowed to warm to room temperature , dilute d with 4N hydrochloric acid and extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulphate and evaporated to leave a brown oil (5.5 g). M+ 185; 360 MHz 1H n.m.r (CDCl3) 9.89 (1H, s), 7.95 (1H, s), 0.24 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[CH2:13][C:14]([OH:16])=O)[CH2:8][CH2:7]1)=[O:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:43]1([N:49]2[CH:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:17])[CH2:13][C:14]([NH:54][C:52]2[CH:51]=[N:50][N:49]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:53]=2)=[O:16])[CH2:10][CH2:11]1)=[O:5]
Reactant: Nc1cnn(-c2ccccc2)c1
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1cnn(-c2ccccc2)c1
Reaction time: 0.03 h
Yield: 36 %

Procedure:
DMAP (68 mg, 0.56 mmol) was added to 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid (100 mg, 0.28 mmol) in DMF (2 mL) followed by EDCI (64 mg, 0.33 mmol) and HOBT (45 mg, 0.33 mmol). After 2 minutes, 1-phenyl-1H-pyrazol-4-ylamine (54 mg, 0.33 mmol) was added and stirring was continued at room temperature overnight. Cold water was then added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 50 mg (35.97% yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(1-phenyl-1H-pyrazol-4-yl)-propionamide. LC/MS [M+H]+: 596.09, 87.79%. 1H NMR (300 MHz, DMSO-d6): δ 10.4 (d, 1H), 8.5 (d, 1H), 7.84-7.64 (m, 4H), 7.54-7.2 (m, 5H), 4.0-3.8 (m, 7H), 3.2-3.1 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:32]([C:29]2[CH:30]=[CH:31][C:26]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:27][CH:28]=2)=[O:33])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)c1ccc(-c2ccccc2)cc1
Yield: 75.1 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (112 mg) with 4-biphenyl carbonyl chloride (95 mg) provided 128 mg (83%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([O:38][CH3:39])[C:32]([CH3:41])([CH3:40])[CH2:31]2)[N:3]=1.[NH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46]>>[CH3:39][O:38][N:33]1[C:32]([CH3:41])([CH3:40])[CH2:31][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]3[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]3)[N:7]=[C:2]([NH:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])[N:3]=2)[CH2:35][C:34]1([CH3:37])[CH3:36]
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Reactant: NCCC(=O)O
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)nc(NCCC(=O)O)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and β-alanine according to the procedure of Example 15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[S:14][C:15]=1[CH3:16].O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[S:14][C:15]=1[CH3:16])[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CO)ccc1OCc1nc(N2CCCCC2)sc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(N2CCCCC2)sc1C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
To a mixture of {3-methoxy-4-[(5-methyl-2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol (0.36 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.21 g), tributylphosphine (0.30 g) and tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.38 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(5-methyl-2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as crystals (0.23 g, yield 44%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 180-181° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:9].[C:18]([CH2:21][N:22]1[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24])(O)=[O:19].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH3:9])[C:18](=[O:19])[CH2:21][N:22]1[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24]
Reactant: COC(=O)CNCCN(C)C(=O)OC(C)(C)C
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CN(CCN(C)C(=O)OC(C)(C)C)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
To a suspension of N-[(N-Boc)(N-methyl)-2-aminoethyl]-glycine methyl ester (0.9 g, 0.0037 mol) and DHBT-OH (0.65 g, 0.004 mol) in CH2Cl2 10 ml was added N-1-carboxymethylthymine (0.74 g, 0.04 mol) dissolved in DMF (6 ml). The solution was cooled in an ice bath and DCC (0.905, 0.049 mol) was added. The reaction mixture was stirred for 1 hour and the ice bath was removed. The reaction mixture was left for 16 hours at room temperature. The reaction mixture was filtered and washed twice with 1N KHSO4 (15 ml) and three times with NaHCO3 (15 ml), brine (10 ml) and water (10 ml) and dried with Na2SO4. The product was purified by column chromatography on silica gel with CH2Cl2/MeOH 95:5 eluent. The yield of the title compound was 55%.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1.C1(C=O)CC1>CN(C=O)C.O>[CH:17]1([CH:21]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:19][CH2:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: C1CCOC1
Agent: O=CC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=CC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 13.0 ml (64.85 mmol) of ethyl diethylphosphonoacetate were added dropwise to a suspension of 2.59 g (64.85 mmol) of sodium hydride (60% in mineral oil) in 110 ml of abs. THF. After 30 min, the mixture was warmed to RT and, after cooling again to 0° C., 5.3 ml (71.34 mmol) of cyclopropanecarboxaldehyde were added dropwise. After the end of the addition, the reaction mixture was warmed to RT and diluted with 35 ml of DMF. The mixture was stirred at RT overnight and then added to water. The mixture was extracted three times with ethyl acetate. The combined organic phases were concentrated under reduced pressure and the crude product was purified by filtration through silica gel (mobile phase cyclohexane/ethyl acetate 10:1→6:1). This gave 8.53 g of the target product (93.8% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:11]2[CH2:12][CH:13]([CH2:15][O:16][CH3:17])[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](OC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C2CC(CO)(C)OC=2C=1)=O)(C)(C)C.CI>>[C:1]([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:15][O:16][CH3:17])([CH3:31])[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(C)(CO)C2
Reactant: COCC1Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Solvent: CI
Product: COCC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 201a, from 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227d) and methyl iodide. 1H NMR (400 MHz, CDCl3) δ 7.88-7.93 (m, J=9.47, 2.78, 2.40 Hz, 2 H) 7.28 (s, 1 H) 7.21 (d, J=1.26 Hz, 1 H) 7.04-7.10 (m, 2 H) 3.41-3.50 (m, 2 H) 3.40 (s, 3 H) 3.10 (d, J=16.67 Hz, 1 H) 3.07 (s, 3 H) 2.75 (d, J=16.67 Hz, 1 H) 1.56 (s, 9 H) 1.46 (s, 3 H); LCMS for C23H28O7S m/z 449.00 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][O:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C:8]1[N:7]([CH2:17][CH2:18][O:19][CH3:20])[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:9]=1)[CH3:15]
Reactant: COCCBr
Reactant: CCOC(=O)Cc1nc(C(C)(C)C)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1nc(C(C)(C)C)nn1CCOC
Temperature: 55 °C
Reaction time: 6 h
Yield: 66.1 %

Procedure:
Ethyl (3-tert-Butyl-1H-1,2,4-triazol-5-yl)acetate (Preparation 116, 27.4 g, 0.13 mol) and 1-bromo-2-methoxyethane (13.7 mL, 0.143 mol) was dissolved in DMF (400 mL). K2CO3 (90.0 g, 0.65 mol) was added and the reaction mixture was stirred for 6 hours at 50-60° C. The reaction was cooled to room temperature, diluted with water (400 mL), and extracted with Et2O (3×100 mL). The combined organic extracts were washed with brine (3×200 mL), dried with Na2SO4, and evaporated to afford a mixture of alkylated triazole residues. The mixture was separated using HPLC (Luna 10 u 018(2), 100 A, 21.2×250 mm, H2O/acetonitrile 30-40%) to afford ethyl[3-tert-Butyl-1-(2-methoxyethyl)-1H-1,2,4-triazol-5-yl]acetate (23.14 g, 66%).
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([SH:7])[CH3:6].Cl[C:9]1[C:10]([C:15](=[O:18])[CH2:16][CH3:17])=[N:11][CH:12]=[CH:13][N:14]=1.O>C(O)C>[CH2:5]([S:7][C:9]1[C:10]([C:15](=[O:18])[CH2:16][CH3:17])=[N:11][CH:12]=[CH:13][N:14]=1)[CH3:6]
Reactant: CCC(=O)c1nccnc1Cl
Reactant: CCS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCSc1nccnc1C(=O)CC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
A mixture of sodium ethoxide (100 mg, 1.47 mmoles) and ethanethiol (110 mg, 1.77 mmoles) in 7 ml of absolute ethanol is stirred under nitrogen at room temperature for 10 minutes. 1-(3-Chloro-2-pyrazinyl)-1-propanone (250 mg, 1.47 moles) in 5 ml absolute ethanol is added to the above mixture, and the reaction mixture is stirred for 4 hours at which time thin layer chromatography indicates that all of the starting materials have reacted. The mixture is poured into water (100 ml) and extracted with methylene chloride (3×10 ml), and the extracts are combined and washed with water (1×50 ml) and saturated NaCl solution (1×50 ml). After drying (MgSO4), the solvent is removed under reduced pressure to give an 87% yield of 1-(3-ethylthio-2-pyrazinyl)-1-propanone (m.p. 45°-48° C.).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].[NH:22]([C:29](=[O:33])[C:30](O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[NH:22]([C:29](=[O:33])[C:30]([N:16]1[CH2:17][CH2:18][C@H:13]([NH:12][C:10]([C:5]2[NH:6][C:7]([CH2:8][CH3:9])=[C:3]([Cl:2])[N:4]=2)=[O:11])[C@H:14]([O:19][CH2:20][CH3:21])[CH2:15]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: O=C(O)C(=O)Nc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(C(=O)C(=O)Nc2ccccc2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 48.3 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol) and anilino(oxo)acetic acid (49 mg, 0.30 mmol) were suspended in DMF (3 mL). The suspension was subjected to the same operation as in Example (138a) to obtain 64.3 mg of the title compound as a colorless solid (48%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:23][CH2:22][CH2:21][O:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[N:8][N:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCOC1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCOC1
Yield: 70 %

Procedure:
A solution of 4-methoxy-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (254 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (207 mg), tetrakis(triphenylphosphine)palladium(0) (77.0 mg) and 2M aqueous sodium carbonate solution (1.0 mL) in DME (15 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (181 mg).
Reaction SMILES: [CH:1]([Mg]Br)=[CH:2][CH3:3].[Cl:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([I:16])=[CH:9][N:8]=1>O1CCCC1>[Cl:6][C:7]1[N:8]=[CH:9][C:10]([I:16])=[C:11]2[C:2]([CH3:3])=[CH:1][NH:13][C:12]=12
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Reactant: CC=C[Mg]Br
Solvent: C1CCOC1
Product: Cc1c[nH]c2c(Cl)ncc(I)c12
Reaction time: 0.75 h

Procedure:
To a solution of 1-propenylmagnesium bromide (0.5M solution in tetrahydrofuran, 264 ml) at 0° C. under nitrogen was added a solution of 2-chloro-5-iodo-3-nitro-pyridine (11 g) in dry tetrahydrofuran (225 ml), dropwise over 45 minutes. After 10 minutes at 0° C. the reaction was quenched with saturated ammonium chloride (300 ml). The mixture was then extracted with ethyl acetate (300 ml) which was dried over magnesium sulphate, filtered and evaporated to give a red oily solid. The residue was triturated with diethyl ether and refrigerated over night. The solid was then filtered onto a sinter, sucked dry then dried at 60° C. under vacuum to afford the title compound (3.27 g). The filtrate was evaporated, dissolved in the minimum of diethyl ether and seeded with the above, refrigerated overnight, filtered and dried under vacuum at 60° C. to afford a further crop (345 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([Cl:10])[N:4]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].[H-].[Na+]>C1COCC1>[Cl:10][C:5]1[N:4]=[C:3]([S:2][CH3:1])[N:8]=[C:7]([CH:12]([C:11]#[N:15])[C:13]#[N:14])[CH:6]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(C(C#N)C#N)n1
Temperature: 60 °C
Yield: 76.5 %

Procedure:
2-Methylthio-4,6-dichloropyrimidine (1b) (10 g, 51.27 mmoles) was suspended in 150 mL of dry THF along with malononitrile (3.72 g, 56.14 mmoles) and trans-dichloro-bis(triphenylphosphine)palladium (II) (2.0 g, 2.85 mmoles). The reaction mixture was purged with a stream of nitrogen gas for five minutes with rapid stirring before the cautious portion wise addition of sodium hydride (60% oil dispersion, 6.15 g, 154 mmoles). Note that the reaction is exothermic and THF starts to reflux upon addition of NaH. Nitrogen purging was continued throughout the addition. Upon completion of the sodium hydride addition, the nitrogen purge was ceased and the reaction mixture was placed into a pre-heated oil bath at ˜70° C. The reaction mixture was heated under a blanket of nitrogen for 2 hours or until complete (color changes from a yellow to orange brown). The reaction was cooled and cautiously quenched with 30 mL of aq. 1N HCl solution and when gas formation ceased the majority of the solvent was removed under reduced pressure. The concentrated mixture was diluted with aq. 0.25 N HCl solution with stirring and the orange brown precipitate was collected via suction filtration, washed with water and vacuum-dried. The crude cake was transferred to a round bottomed flask containing acetonitrile (250 mL) and stirred vigorously for one hour. The precipitate was isolated via suction filtration, washed with acetonitrile and cautiously washed with DCM. The cake was then re-suspended in acetonitrile, warmed to ˜60° C., allowed to cool while stirring, and re-isolated via suction filtration and vacuum-dried. 8.81 g of a pale yellow solid was obtained (77% yield).