Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]2([S:11]([NH:14][C:15](=[O:17])[CH3:16])(=[O:13])=[O:12])[CH2:8][CH2:9][CH2:10]2)=[N:4][CH:3]=1
Reactant: NS(=O)(=O)C1(c2ncc(Br)s2)CCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)C1(c2ncc(Br)s2)CCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
1-(5-Bromo-1,3-thiazol-2-yl)cyclobutanesulfonamide (110 mg, 0.370 mmol, prepared according to Example 70, Steps 1-5) was taken up in pyridine (5 mL), and acetic anhydride (524 μL, 5.55 mmol) was added. The reaction was stirred at 70° C. overnight. The reaction was concentrated to dryness, diluted with water, acidified with 2 N HCl, and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to give N-{[1-(5-bromo-1,3-thiazol-2-yl)cyclobutyl]sulfonyl}acetamide (120 mg, 96%) as a beige solid. MS ESI: [M+H]+ m/z 338.9/340.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.CC(C)([O-])C.[K+].Cl[CH2:22]/[CH:23]=[CH:24]\[CH2:25]Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]([C:8]2([C:9]([O:11][CH3:12])=[O:10])[CH2:25][CH:24]=[CH:23][CH2:22]2)[CH:7]=1
Reactant: ClC/C=C\CCl
Reactant: COC(=O)Cc1cc(F)cc(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2cc(F)cc(OC)c2)CC=CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a stirred solution of methyl 5-fluoro-3-methoxyphenylacetate (708 mg, 3.6 mmol) in THF (10 ml) was added a 1.0 M solution of potassium t-butoxide in THF (4.0 ml, 4.0 mmol) at -30° C. over 0.25 hr. After stirring for 1 h at the same temperature, a solution of cis-1,4-dichlorobut-2-ene (526 mg, 4.0 mmol) in THF (2 ml) was added dropwise and the reaction mixture was warmed to room temperature over 2 hr period. The reaction mixture was cooled to -30° C., and 1.0 M solution of potassium t-butoxide in THF (4.0 ml, 4.0 mmol) was added and the mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried with MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 150 g; hexane/ethyl acetate (20/1)) afforded 495 mg (55%) of methyl 1-(5-fluoro-3-methoxyphenyl)cyclopent-3-ene-1-carboxylate as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1B(O)O>>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Product: Cc1cccc(C)c1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (50 mg, 0.153 mmol) and 2,6-dimethyl-phenylboronic acid (25 mg, 0.17 mmol) as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.92 (dd, 1H), 8.20 (d, 1H), 8.14 (m, 3H), 8.02, (d, 2H), 7.87 (d, 1H), 7.37 (dd, 1H), 7.34 (d, 2H), 7.21 (t, 1H), 7.14 (d, 2H), 2.05 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][NH:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:32][C:33]([F:37])([F:36])[CH2:34]I.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[CH:18][N:17]([CH2:34][C:33]([F:37])([F:36])[F:32])[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(-c3n[nH]cc3-c3ccncc3)cc2)cc1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Temperature: 60 °C

Procedure:
To a solution of 4-[3-(4-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyridine (0.42 g) in dimethyl formamide (7 ml) was added cesium carbonate (0.65 g) and 1,1,1-Trifluoro-2-iodo-ethane (0.29 ml). The reaction mixture was heated at 60° C. for 24 h, poured into water and extracted 3× with dichloromethane. Purification via biotage MPLC chromatography, eluting with 5% methanol/0.5% ammonium hydroxide/70% ethyl acetate/hexane provided the title compound. MS: (M+H m/z=410.0).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:34]3[C:29]([F:28])=[N:30][CH:31]=[CH:32][CH:33]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: OB(O)c1cccnc1F
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cccnc2F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 133 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1) and (2-fluoropyridin-3-yl)boronic acid to afford a white solid. HPLC (Condition 4) tR=5.22 min, UPLC-MS (Condition 3) tR=1.07 min, m/z=479.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.76 (m, 1H) 1.78-1.88 (m, 1H) 2.84-2.97 (m, 1H) 3.15 (m, J=4.70 Hz, 2H) 3.31-3.43 (m, 1H) 4.14-4.24 (m, 1H) 4.86 (br. s, 1H) 7.32 (d, J=8.99 Hz, 2H) 7.42-7.54 (m, 1H) 7.76-7.89 (m, 2H) 8.00 (d, J=2.35 Hz, 1H) 8.03-8.13 (m, 1H) 8.28 (d, J=4.69 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([CH:12]([CH3:14])[CH3:13])[C:10]#[N:11])=[CH:4][CH:3]=1.Cl.C[CH2:17][O:18]CC.C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([CH:12]([CH3:14])[CH3:13])[C:10](=[NH:11])[O:18][CH3:17])=[CH:6][CH:7]=1
Reactant: CC(C)C(C#N)Nc1ccc(Cl)cc1
Reactant: CCOCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=N)C(Nc1ccc(Cl)cc1)C(C)C
Temperature: 0 °C

Procedure:
A solution of 3.86 g (20 mmol) of 2-(4-chlorophenylamino)-3-methylbutyronitrile in 10 ml of methanol is saturated at reflux with hydrogen chloride gas. When all of the starting nitrile has been consumed, most of the methanol and excess hydrogen chloride is removed in vacuo. Ether is added to precipitate the hydrochloride of methyl 2-(4-chlorophenyl)-3-methylbutanimidate, which is isolated by filtration under nitrogen. The white solid is added with vigorous stirring to an ice-cold mixture of ether and aqueous sodium bicarbonate. The aqueous layer is discarded, and the ethereal layer is washed with cold water and dried over sodium sulfate. Filtration and concentration in vacuo gives methyl 2-(4-chlorophenylamino)-3-methylbutanimidate.
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH:42][C:43](=[O:49])[CH2:44][CH2:45][C:46](O)=[O:47])[CH:23]=[CH:24][C:25]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33].[O:50]([CH2:57][CH2:58][CH2:59][CH2:60][NH2:61])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl>CO>[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH:42][C:43](=[O:49])[CH2:44][CH2:45][C:46]([NH:61][CH2:60][CH2:59][CH2:58][CH2:57][O:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47])[CH:23]=[CH:24][C:25]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: NCCCCOc1ccccc1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)O)cc1Cl
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)NCCCCOc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (DMT-MM) (69 mg, 0.25 mmol) was added to a solution of N-(2-{[3-chloro-4-(2-methylbenzoyl)phenyl]amino}phenyl)-succinamic acid (100 mg, 0.23 mmol) (disclosed in WO 01/05746) and 4-phenoxybutylamine (30 mg, 0.25 mmol) in methanol (2.0 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into 1 N HCl (aq.) and was extracted with EtOAc (×2). The combined organic phases were washed with water, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using DCM/MeOH/NH3(aq.) 95:5:0.5 as the eluent to afford the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].C([Li])CCC.[P:15](Cl)([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1.CCCCCC>[CH2:1]([N:3]([CH2:8][CH3:9])[S:4]([CH2:7][P:15](=[O:16])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])(=[O:6])=[O:5])[CH3:2]
Reactant: CCN(CC)S(C)(=O)=O
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(CS(=O)(=O)N(CC)CC)OCC
Reaction time: 1.5 h

Procedure:
A solution of N,N diethyl methanesulfonamide (4.7 g) in tetrahydrofuran (50 ml) was stirred at 20° C and treated with butyllithium in hexane (2.6 N, 27.9 ml) and diethyl chlorophosphate (5.2 ml). The cooling bath was removed and the mixture was stirred for 1.5 hours and poured onto ice. The resulting mixture was saturated with sodium bicarbonate, extracted with methylene chloride and the organic phase was washed with water, dried with sodium sulfate and magnesium sulfate, filtered and concentrated in vacuo to give diethyl [[(diethylamino)sulfonyl]methyl]-phosphonate.
Reaction SMILES: [CH:1]([C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:36])[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)=O.[C:37]([NH:40][NH2:41])(=[O:39])[CH3:38].Cl>O1CCCC1.O>[C:37]([NH:40][N:41]=[CH:1][C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[N:7]2[C:25](=[O:36])[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)(=[O:39])[CH3:38]
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(=O)NN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NN=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 82.4 %

Procedure:
In a procedure similar to that described in Example I-3, diphenylmethyl 3-formyl-7-(2-thienylacetamido)-2-cephem-4-carboxylate (104 mg) and acetylhydrazine (30 mg) are left to react in a mixture of tetrahydrofuran (8 ml) and water (1.5 ml) in the presence of hydrochloric acid (2 equivalents) at room temperature overnight to give diphenylmethyl 3-(2-acetylhydrazono)methyl-7-(2-thienylacetamido)-2-cephem-4-carboxylate (95 mg). m.p. 168-178° C (decomposition). Yield: 83%. IR: λmaxNujol 3280, 1760, 1743, 1695, 1667, 1697, 1677, 1538cm-1. UV: λmaxEtOH 301nm(ε=31700). NMR: δCDCl 3 (60MHz) 1.82s3H, 3.82s2H, 5.07d(4Hz)1H, 5.40s1H, 5.50br1H, 6.63br1H, 6.83s1H. 6.88-7.58m15-16H. [α]D23 +416° (c= 0.501, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7]([CH3:18])([CH3:17])[C:4]=2[NH:5][N:6]=1.C(N(C(C)C)CC)(C)C.[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32][CH2:33]Cl>ClCCl>[NH2:1][C:2]1[C:3]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7]([CH3:18])([CH3:17])[C:4]=2[N:5]([CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[N:6]=1
Reactant: CC(C)(C)OC(=O)N1Cc2c(N)n[nH]c2C1(C)C
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2c(N)nn(COCC[Si](C)(C)C)c2C1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of tert-butyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (8.5 g, 33.9 mmol) and diisopropyl ethylamine (18 mL, 3.0 equiv) in dichloromethane (200 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (6.0 mL, 1.0 equiv) dropwise at 0° C. under nitrogen. The mixture was been stirred at 0° C. under nitrogen for two hours then warmed to room temperature and stirred over night. The reaction mixture was concentrated and purified by column chromatography to give the title compound J(i) as a white solid (2.27 g, 18%). 1H NMR (400 MHz, METHANOL-d4): δ ppm 0.81-0.97 (m, 2H) 1.45-1.59 (m, 9H) 1.72 (d, J=5.29 Hz, 13H) 3.53-3.67 (m, 2H) 4.26 (d, J=7.55 Hz, 2H) 5.17 (s, 2H). 2D-NOESY NMR showed proton at 5.17 ppm is correlated with proton at 1.72 ppm.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:36](OCC)[O:37]CC)=[C:5]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]([CH3:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:36]=[O:37])=[C:5]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]([CH3:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Yield: 91.7 %

Procedure:
To a solution of 2-(N-methyl-N-benzylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (7.25 g) in acetone (70 ml) was added 6N-hydrochloric acid (7 ml) and the resultant mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure. Water was added to the residue, where an oily substance appeared. The aqueous mixture was adjusted to an alkaline medium by addition of power of sodium bicarbonate, and then extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was distilled off under reduced pressure to give a reddish oil (5.8 g) of 2-(N-methyl-N-benzylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[OH-].[Na+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[O:16][CH3:17]>C(O)C.O>[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:1][C:2](=[O:3])[CH3:4])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: CC(C)=O
Reactant: COc1cc(C=O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C=CC(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.1 %

Procedure:
To a solution of acetone (15.30 g, 263.76 mmol) in a mixture of ethanol (35 mL) and water (15 mL) were added sodium hydroxide (2.90 g, 72.54 mmol) and 4-hydroxy-3-methoxybenzaldehyde (5.01 g, 32.97 mmol). The reaction mixture was stirred at room temperature for 15 h. The reaction was cooled to 0° C. and quenched with 2.0 N hydrochloric acid until the solution became slightly acidic. The solution was extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with water (50 mL) and saturated aqueous sodium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated at reduced pressure to afford 4-(4-hydroxy-3-methoxy-phenyl)but-3-ene-2-one (5.52 g, 87% yield) as a yellow solid: MS (EI) for C11H12O3: 193 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH2:4][CH:5]([CH3:7])[CH3:6].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[Br-].[Na+]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][O:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)CCOCCCCO
Reactant: BrCCCCBr
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCOCCCCOCCCCBr
Reaction time: 0.5 h

Procedure:
1.77 g (0.041 mol) of 55% sodium hydride dispersion in oil are carefully added over the course of 40 minutes, under nitrogen and while stirring, to 26.0 g (0.163 mol) of 4-isopentyloxy-butanol. The mixture is stirred at 60° for 30 minutes and 11.4 g (0.053 mol) of 1,4-dibromobutane are subsequently added dropwise and it is stirred at 60° for 20 hours. The resulting sodium bromide is suction filtered, washed with ether and the filtrate is evaporated. The residue is fractionally distilled in a high vacuum and apart from the excess 4-isopentyloxy butanol, 1-bromo-4-(4-isopentyloxy-butyloxy)-butane, having a B.P. of 121-123°/0.7 mm Hg, is obtained as a colourless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:27]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:28])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and isopropyl isocyanate; MS: m/e=379.4 (M+H+).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:13](=[O:25])[CH2:12]1)=O)C1C=CC=CC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH3:22][Si:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][O:18][CH2:17][N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:25]
Reactant: C[Si](C)(C)CCOCN1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1CCNCC1=O

Procedure:
3-Oxo-4-(2-trimethylsilanyl-ethoxymethyl)-piperazine-1-carboxylic acid benzyl ester (3.00 g, 8.22 mmol) was dissolved in THF (30 ml) and MeOH (30 ml), and vigorously stirred on 20% Pd(OH)2/C under a hydrogen atmosphere (1 atm) for 14 h. After N2 was purged, Pd(OH)2/C was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH=95/5 to 90/10) to obtain the intended compound as a colorless oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]=O)=[CH:26][CH:25]=1.N1CCCCC1>C(O)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])=[CH:26][CH:25]=1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: COc1ccc(CCC=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(CCC=C2SC(=O)N(CCCCSc3cccc4nccn34)C2=O)cc1

Procedure:
To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 657 mg (4.0 mmol) of 3-(4-methoxyphenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 3.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 1.08 g (76.8%, yellow oily substance) of the desired product.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Li].[O:13]1[C:17](C(Cl)=O)=[CH:16][CH:15]=[N:14]1.Cl>C1COCC1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][C:1]([C:17]1[O:13][N:14]=[CH:15][CH:16]=1)=[O:9])[CH3:7]
Reactant: O=C(Cl)c1ccno1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccno1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of diethyl malonate (2.6 ml, 2.74 g) in THF (40 ml) under an atmosphere of nitrogen at −60° C. was added nbutyl lithium (2.5 M, 18.9 ml) dropwise over 15 mins, keeping the temperature constant. The reaction became a cloudy white colour from the formation of the di-lithium salt then became yellowish. After 10 mins, the reaction was cooled to −78° C., when a solution of Isoxazole-5-carbonyl chloride (1 g) in THF (10 ml) was added dropwise over 15 mins. The reaction then warmed to −45° C. and stirred for 1 h, the solution had gone pale brown. The reaction was then poured into 1M HCl solution (50 ml) with stirring and extracted with CH2Cl2 (2×150 ml). The combined organic layers were washed with sat. NaCO3 soln (1×30 ml), dried over MgSO4, filtered and concentrated in vacuo to give the product as a pale oil which was used as such in the next step. Yield 1.1 g, 35.1%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C@@:20]([CH3:35])([C:24]([NH:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:21](O)=[O:22]>>[F:19][C@@:20]([CH3:35])([C:24]([NH:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:32])([F:30])[F:31])=[O:25])[C:21]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: C[C@@](F)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: CN1C(=O)[C@@H](NC(=O)[C@@](C)(F)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d), the condensation of (S)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and (2S)-2-fluoro-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid yielded the title compound as a white solid;
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[N:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC#N.O>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:2]1
Reactant: Oc1ccccc1-c1cc[nH]n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1ccccc1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(1H-pyrazol-3-yl)phenol (500 mg, 3.125 mmol), K2CO3 (517.5 mg, 3.75 mmol) and ethyl 2-bromoacetate (417.5 mg, 2.5 mmol) in MeCN (20 mL). The mixture was stirred at room temperature for 2 h, at which time TLC showed the completion of the reaction. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude product which was used in next step without further purification.