Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:37])[CH2:7][C@@H:8]([C:35]#[CH:36])[NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:34])/[CH:19]=[CH:20]/[CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:13]1)=[O:11])C.CCO>O.O1CCCC1>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][CH:21](/[CH:20]=[CH:19]/[C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10]([NH:9][C@H:8]([C:35]#[CH:36])[CH2:7][C:6]([OH:37])=[O:5])=[O:11])[CH2:13]2)=[O:34])[CH2:26][CH2:25]1)=[O:28])([CH3:31])([CH3:33])[CH3:32]
Reactant: C#C[C@H](CC(=O)OCC)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Reaction time: 3 h
Yield: 97.4 %

Procedure:
A solution of LiOH (79 mg) in H2O (10 ml) was added to a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine ethyl ester (1.34 g) in tetrahydrofuran (10 ml)-EtOH (10 ml) at 0° C. The reaction mixture was stirred for 3 hours at the same condition, and the solvent was evaporated in vacuo. The residue was resolved in ethyl acetate-water, and acidified with 10% aq. KHSO4. The whole was washed with water, brine, dried over MgSO4, and evaporated in vacuo to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine (1.23 g).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1.Cl>CN(C)C=O.O>[CH3:11][C:5]([CH3:12])([CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])[CH2:4][O:3][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1
Reactant: Clc1ccc2ncnn2n1
Reactant: CC(C)(CO)CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(COc1ccc2ncnn2n1)CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
In 15 ml of dimethylformamide was suspended 0.42 g of 60% sodium hydride in oil, followed by addition of 0.878 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide and the mixture was stirred under reduced pressure at room temperature for 30 minutes. Then, 0.773 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture was further stirred at room temperature for 1 hour. Following addition of 40 ml of iced water, the reaction mixture was adjusted to pH 6 with 1N-hydrochloric acid and the resulting crystals were collected by filtration and washed with 20 ml of water and 20 ml of ethyl ether. The washed crystals were recrystallized from hot ethanol to provide 1.16 g of the title compound. m.p. 181°-184° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:46]([C:47]([F:50])([F:49])[F:48])=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[CH:43]=[CH:44][CH:45]=[C:46]([C:47]([F:50])([F:49])[F:48])[C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1cccc(C(F)(F)F)c1F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(C(F)(F)F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-3-(trifluoromethyl)phenyl)boronic acid gave 268. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.38 (t, J=7.5 Hz, 1H), 7.90-7.75 (m, 2H), 7.62-7.50 (m, 3H), 5.05-4.71 (m, 2H), 4.22-4.06 (m, 1H), 4.05-3.92 (m, 1H), 3.75 (s, 3H), 3.34-3.21 (m, 1H), 2.18-2.10 (m, 1H), 1.88-1.72 (m, 4H), 1.69-1.60 (m, 1H). LCMS (ES+) m/z 517 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[C:25]([C:29]([OH:31])=O)[NH:26]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH3:32][NH:33][CH3:34].O1CCCC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[C:25]([C:29]([N:33]([CH3:34])[CH3:32])=[O:31])[NH:26]3)=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2ccc(CC3c4ccc(O)cc4CCN3c3ccc(F)cc3)cc2[nH]1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2ccc(CC3c4ccc(O)cc4CCN3c3ccc(F)cc3)cc2[nH]1
Yield: 48 %

Procedure:
The title compound was prepared as described in Example 34.B using 6-{[2-(4-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinolyl]methyl}indole-2-carboxylic acid (0.25 g, 0.6 mmol) and 2.0 M solution of dimethylamine in tetrahydrofuran (1.0 mL, 2.0 mmol) to provide the title compound (0.127 g, 48% yield): 1H NMR (CDCl3) 9.05 (br, 1H), 7.52 (d, 1H), 7.26-6.76 (m, 7H), 6.61 (d, 1H), 6.57 (d, 1H), 6.50 (dd, 1H), 4.80 (t, 1H), 3.58 (m, 1H), 3.47 (m and s, 4H), 3.27 (dd, 1H), 3.20 (s, 3H), 3.03 (dd, 1H), 2.89 (m, 1H), 2.67 (dt, 1H); ES-MS m/z 444 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[CH2:9][F:10])[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:11])[CH2:9][F:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CF)c1cccc(Br)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(CF)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(6-Bromopyridin-2-yl)-2-fluoroethanone (0.53 g, 2.43 mmol) was taken up in MeOH (12 mL) and cooled to 0° C. Sodium borohydride (0.092 g, 2.43 mmol) was added and the mixture stirred at 0° C. for 1 hour. Water was added and the reaction mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31](=[O:60])[C:32]([C:35]3[N:36]=[C:37]([NH:40][C:41]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[S:38][CH:39]=3)=[N:33][OH:34])[C:28](=[O:61])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].BrC[C:64]1[CH:74]=[CH:73][CH:72]=[C:66]2[C:67]([NH:69][C:70](=[O:71])[C:65]=12)=[O:68].[C:75](=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.CS(C)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31](=[O:60])[C:32]([C:35]3[N:36]=[C:37]([NH:40][C:41]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[S:38][CH:39]=3)=[N:33][O:34][CH2:75][N:69]3[C:70](=[O:71])[C:65]4=[CH:64][CH:74]=[CH:73][CH:72]=[C:66]4[C:67]3=[O:68])[C:28](=[O:61])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: O=C1NC(=O)c2c(CBr)cccc21
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCN3C(=O)c4ccccc4C3=O)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 0.085 g of the product of Step B, 0.12 g of bromomethyl phthalimide, 0.069 g of potassium carbonate and 0.4 ml of dimethylsulfoxide was vigorously stirred for 15 minutes at room temperature and 10 ml of 0.1 N hydrochloric acid were added thereto. The mixture was vacuum filtered and the product was washed with water and dried to obtain 0.124 g of raw product. The latter was dissolved in 1 ml of ethyl acetate and the solution was treated with activated carbon and the solvent was distilled off. The residue was efflorescenced with ether and the mixture was vacuum filtered to obtain 0.075 g of syn isomer of diphenylmethyl 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-phthalimidomethyloxyimino-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: FC1C=C(N2[C:13]3[CH2:14][CH2:15][O:16][CH2:17][C:12]=3[C:11]([C:18](N[C@@H](C(C)(C)C)C(NC)=O)=[O:19])=N2)C=CC=1F.[F:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[NH:38][NH2:39].[C:40]([O:44][C:45](=[O:52])[C@H:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[NH2:47])([CH3:43])([CH3:42])[CH3:41]>>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([F:30])=[C:32]([N:38]2[C:13]3[CH2:14][CH2:15][O:16][CH2:17][C:12]=3[C:11]([C:18]([NH:47][C@@H:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:52])=[O:19])=[N:39]2)[CH:33]=1
Reactant: CNC(=O)[C@@H](NC(=O)c1nn(-c2ccc(F)c(F)c2)c2c1COCC2)C(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: NNc1cc(Cl)ccc1F
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)c1nn(-c2cc(Cl)ccc2F)c2c1COCC2)C(C)(C)C

Procedure:
This intermediate was prepared according to the procedure escribed for the synthesis of Compound 114 by replacing 3,4-difluorophenylhydrazine with 2-fluoro-5-chlorophenylhydrazine in step 1, and replacing tert-leucine methyl amide with tert-leucine tert-butyl ester in step 3. LC-MS (+ESI) m/z=466.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:29])[NH:12][CH2:13][CH2:14][C:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:8][NH:7][CH2:6]1)=[O:4].[C:30]1([CH:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37](O)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1C=C2C(N(O)N=NC2=CC=1)=O.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[C:40]1([CH:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:37]([N:7]2[CH2:8][C@H:9]([C:11](=[O:29])[NH:12][CH2:13][CH2:14][C:15]3[N:19]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[CH:18]=[N:17][CH:16]=3)[CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]2)=[O:38])[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1CNC[C@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)C1
Agent: O=c1c2ccccc2nnn1O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)CN(C(=O)C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
cis-3-Methoxycarbonyl-5-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine (86.8 mg, 0.219 mmol) (EXAMPLE 2, Step A) diphenyl acetic acid (302 mg, 1.42 mmol), HOOBT (54.3 mg, 0.328 mmol), EDC (63 mg, 0.328 mmol), and Et3N (392 uL, 5.34 mmol) were dissolved in DMF (4 mL) and stirred at ambient temperature for 5 days. The solution was concentrated, the residue was taken up in EtOAc, washed with sat. NaHCO3 solution, water, and brine. The organics were dried (MgSO4), concentrated, and chromatographed (silica gel, 0.5-2% MeOH/CH2Cl2 with NH4 OH) to give the title compound. FAB MS=590 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:41]1[C:50]2[C:45](=[CH:46][C:47]([C:51]([O:53][CH3:54])=[O:52])=[CH:48][CH:49]=2)[CH2:44][CH2:43][NH:42]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]([N:42]2[CH2:43][CH2:44][C:45]3[C:50](=[CH:49][CH:48]=[C:47]([C:51]([O:53][CH3:54])=[O:52])[CH:46]=3)[CH2:41]2)=[O:16])([CH3:17])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: COC(=O)c1ccc2c(c1)CCNC2
Agent: CN(C)C(F)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CCN(C(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (0.830 g, 3.41 mmol) and triethylamine (0.792 mL, 5.68 mmol) in DMF (11.0 mL) was treated with TFFH (1.13 g, 4.26 mmol). The resulting mixture was stirred at rt for 30 min and then methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate hydrochloride (0.647 g, 2.84 mmol) and triethylamine (0.792 mL, 5.68 mmol) were added. The reaction mixture was stirred at rt for 2 days and then extracted with EtOAc three times. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated. Purification of the resulting residue by column chromatography (SiO2, 0-100% EtOAc in hexane) provided methyl 2-{[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (0.959 g, 82%). LC-MS: (FA) ES+ 439 (M+Na); 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J=10.1, 2.2 Hz, 2H), 7.19 (d, J=8.0 Hz, 1H), 4.79 (s, 2H), 3.95-3.77 (m, 5H), 3.67 (d, J=38.1 Hz, 2H), 3.21 (s, 2H), 2.92 (t, J=5.7 Hz, 2H), 2.24-2.10 (m, 2H), 1.61 (d, J=10.8 Hz, 1H), 1.44 (d, J=5.0 Hz, 10H), 1.33 (d, J=3.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[N:6][CH:7]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>CO.O1CCCC1>[Cl:1][C:2]1[C:3]([CH:14]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)(=[O:24])=[O:25])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of methyl 3-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]propionate (200 mg, 0.400 mmol) in a mixture of methanol (2 ml) and tetrahydrofuran (2 ml) was added a 1N aqueous sodium hydroxide solution (2 ml). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was made weakly acidic by the addition of 1N hydrochloric acid, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was recrystallized from hexane:ethyl acetate to give the title compound (161 mg, 0.331 mmol, 83%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](C=C[CH:30]=1)[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1)=[O:13])=O)([O-:3])=[O:2].[NH2:31]/[C:32](/[CH3:42])=[CH:33]\[C:34]([O:36][CH2:37][CH2:38][S:39][CH2:40][CH3:41])=[O:35].[CH2:43](O)[CH3:44]>>[CH3:43][C:44]1[NH:31][C:32]([CH3:42])=[C:33]([C:34]([O:36][CH2:37][CH2:38][S:39][CH2:40][CH3:41])=[O:35])[CH:9]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:30]=2)[C:11]=1[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=1)=[O:13]
Reactant: CC(=O)Nc1ccc(OCCOC(=O)CC(=O)C=Cc2cccc([N+](=O)[O-])c2)cc1
Reactant: CCSCCOC(=O)/C=C(/C)N
Reactant: CCO
Product: CCSCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(NC(C)=O)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: -5 °C
Yield: 60 %

Procedure:
15 g (0.04 moles) of 2-(4-acetylaminophenoxy)ethyl 2-(3-nitrobenzylidene)acetylacetate and 6.88 g (0.04 moles) of 2-ethylthioethyl 3-aminocrotonate were heated under reflux in 35 ml of ethanol for 8 hours. The solution was then cooled to -5° C. to obtain 2-(4-acetylaminophenoxy)ethyl 2,6-dimethyl-5-(2-ethylthioethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate as a yellow powder melting--after recrystallisation in ethanol--at 100°-104° C. The yield is 60% of the theoretical yield.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([OH:14])(=O)[CH2:9][C:10]([OH:12])=O.[CH3:15][NH:16][C:17]([NH2:19])=[O:18].CS(C)=O>C(O)(=O)C>[CH3:15][N:16]1[C:8](=[O:14])[CH2:9][C:10](=[O:12])[NH:19][C:17]1=[O:18]
Reactant: CNC(N)=O
Reactant: O=C(O)CC(=O)O
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN1C(=O)CC(=O)NC1=O
Temperature: 95 °C

Procedure:
Acetic anhydride (34 ml) was added to a solution of malonic acid (20 g) and methylurea (12.5 g) in acetic acid (46 ml). The mixture was heated to 95° C. for 3 hours then cooled to room temperature. The resulting solution was concentrated under reduced pressure and the residue as 20 mM stock solutions in dimethyl sulphoxide (DMSO, Sigma #D-5879) and serial dilutions were prepared from these solutions using DMSO, 2 μL of which were added to the wells. Activity at room temperature was measured by monitoring the increase in fluorescence using a TECAN Ultra platereader with 340 nm excitation and 465 nm emission filters. The compounds provided have measured IC50 of less then 400 μM
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=[O:4].C(N(CC)CC)C.Cl.[O:22]1[C:27]2([CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)[CH2:26][NH:25][CH2:24][CH2:23]1.O>C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[C:3]([OH:5])=[O:4].[F:10][C:7]([F:8])([F:9])[C:6]([N:25]1[CH2:26][C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[O:22][CH2:23][CH2:24]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Product: O=C(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of trifluoroacetic anhydride (9.6 mL) in DCM (10 mL) was added dropwise, over a period of 15 minutes, to a stirred solution of triethylamine (15.2 mL) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride [WuXi PharmaTech] (9.95 g) in DCM (100 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 30 minutes. More triethylamine (2.5 mL) was added, followed by more trifluoroacetic anhydride (1.6 mL) in DCM (10 mL), and stirring at 0° C. was continued for 1 hour. Water (100 mL) was added and the mixture was vigorously stirred for 10 minutes. The organic layer was separated, dried, and the solvent evaporated under reduced pressure. The residue was dissolved in DCM (100 mL) and the solution treated with trifluoroacetic acid (25 mL). This mixture was allowed to stand at 20° C. for 10 minutes and then diluted with toluene (40 mL). The solvents were removed under reduced pressure and the residue azeotroped with more toluene (×2) to yield the subtitled compound. Yield 14.0 g.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[CH:8][CH:7]=2)[CH2:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[ClH:19].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[CH:8][CH:7]=2)[CH2:28][CH2:27]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CC1(C)CC(=O)c2ccc(OCC3CO3)cc2O1
Solvent: CCO
Product: CC1(C)CC(=O)c2ccc(OCC(O)CN3CCN(c4ccccc4Cl)CC3)cc2O1
Product: Cl
Yield: 149.8 %

Procedure:
1,2-Epoxy-3-(2,2-dimethylchroman-4-on-7-yl)oxypropane (7.6 g) and N-(o-chlorophenyl)-piperazine (6.04 g) were heated under reflux in ethanol (150 ml) for 3 hours. The solution was evaporated to dryness in vacuo and treated with an excess of ethanolic hydrogen chloride and evaporated to dryness in vacuo. The residue was crystallised from ethanol/ether to give 1-(4-(o-chlorophenyl)-piperazino)-3-(2,2-dimethylchroman-4-on-7-yl)oxypropan-2-ol hydrochloride (11.07 g), m.p. 169°-173° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[C:5]2[OH:12].C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]([O:54][CH2:55][CH3:56])(=[O:53])C.[CH3:57][Si:58](C)([CH3:62])[CH2:59]CO>CN(C)C=O.[Pd](Cl)Cl.CO>[OH:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:51]([O:54][CH2:55][CH2:56][Si:58]([CH3:62])([CH3:59])[CH3:57])=[O:53])[CH:3]=2)[CH:8]=[N:7][CH:6]=1
Reactant: Oc1cncc2ccc(Br)cc12
Reactant: C[Si](C)(C)CCO
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[Si](C)(C)CCOC(=O)c1ccc2cncc(O)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
6-Bromo-4-hydroxyisoquinoline (15.7 g, 70.0 mmol) produced in Example 15 (15a) was dissolved in dimethylformamide (100 mL), to which 2-trimethylsilylethanol (100 mL), diisopropylethylamine (27.1 g, 210 mmol), 1,3-bis(diphenylphosphino)propane (8.67 g, 21.0 mmol), and palladium chloride (3.72 g, 21.0 mmol) were then added, followed by stirring at 60° C. for eight hours under a carbon monoxide atmosphere. The solvent was distilled off under reduced pressure. Water was added to the residue thus obtained, and the resulting mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography ((a mixed solvent of hexane:ethyl acetate-1:1):methanol, 100:0-70:30, V/V) to give the desired title compound (17.3 g, yield 85.4%).
Reaction SMILES: O[CH:2]([CH2:5][CH:6]=[CH2:7])[CH2:3][CH3:4].[CH3:8][CH2:9][O:10][C:11](/[C:13](/Cl)=[N:14]\[OH:15])=[O:12].C(N(CC)CC)C.C([O:26]CC)C>>[C:11]([C:13]1[CH2:4][CH:3]([CH2:2][CH2:5][CH:6]([OH:26])[CH3:7])[O:15][N:14]=1)([O:10][CH2:9][CH3:8])=[O:12]
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C=CCC(O)CC
Reactant: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NOC(CCC(C)O)C1
Temperature: 0 °C

Procedure:
To a solution of 6 g of 3-hydroxy-5-hexene in 150 ml of diethyl ether was added 18.1 g of ethyl chlorooximidoacetate. The solution was cooled to 0° C., and a solution of 21 ml of triethylamine in 210 ml of diethyl ether was added over 2.5 h. The amine hydrochloride salt was filtered and the residue was purified by silica gel column chromatography (5% to 10% EtOAc in CH2Cl2) to provide 5.5 g of desired product. 1H NMR (CDCl3): δ0.96 (t, 3H), 1.47 (t, 3H), 1.50-1.95 (m, 4H), 2.90 (m, 1H), 3.35 (m, 1H), 3.80 (m, 1H), 4.35 (q, 2H), 5.02 (m, 1H).