Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccncc1
Reactant: N#CCc1ccc(F)cc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: N#CC(C(=O)c1ccncc1)c1ccc(F)cc1

Procedure:
Sodium (2.48 g) was dissolved in dry ethanol (37 ml) under nitrogen atmosphere. To the solution was added 4-fluorophenylacetonitrile (11.65 g) and ethyl isonicotinate (16.41 ml) and the solution was refluxed for 3 hours. The reaction mixture was cooled and poured into water. The ethanol of the mixture was removed under reduced pressure. The resulting aqueous solution was washed with ether and neutralized with diluted hydrochloric acid. The separated solid was collected, washed with water and dried to give 2-(4-fluorophenyl)-3-oxo-3-(pyridin-4-yl)propanenitrile (16.43 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[S:8][CH:6]1[OH:7])(=[O:3])[CH3:2].[CH2:25]([C:27]1[CH:41]=[CH:40][C:30]([CH2:31][C:32]2[C:38](O)=[CH:37][CH:36]=[CH:35][C:33]=2[OH:34])=[CH:29][CH:28]=1)[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[S:8][C@H:6]1[O:7][C:38]1[CH:37]=[CH:36][CH:35]=[C:33]([OH:34])[C:32]=1[CH2:31][C:30]1[CH:29]=[CH:28][C:27]([CH2:25][CH3:26])=[CH:41][CH:40]=1)(=[O:3])[CH3:2]
Reactant: CCc1ccc(Cc2c(O)cccc2O)cc1
Reactant: CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2c(O)cccc2O[C@@H]2S[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16.6 %

Procedure:
2,3,4,6-Tetra-O-acetyl-5-thio-D-glucopyranose (1.29 g, 3.54 mmol), 2-(4-ethylbenzyl)resorcinol (2.42 g, 10.6 mmol), triphenylphosphine (1.86 g, 7.09 mmol) and toluene (13 mL) were mixed, and to the resulting mixture, diisopropyl azodicarboxylate (40% in toluene, 3.58 g) was then slowly added dropwise in ice. After stirring at room temperature for 24 hours, the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=65:35-50:50) to give a crude product of 3-hydroxy-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside (338 mg). To a mixture of this crude product (338 mg) and pyridine (2 mL), acetic anhydride (0.5 mL) was added at room temperature. After stirring at room temperature for 20 hours, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate =2:1) to give the titled compound (134 mg, 6%) as a light-yellow gum.
Reaction SMILES: [N:1]1([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=O)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH2:36])[NH:34][N:35]=2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1.C[Al](C)C>C1(C)C=CC=CC=1>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:36][C:33]3[NH:34][N:35]=[C:31]([CH2:30][CH2:29][C:23]4[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:21]([O:20][CH3:19])[CH:22]=4)[CH:32]=3)=[O:14])=[CH:17][CH:18]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCNCC4)cc3)[nH]n2)cc(OC)c1
Yield: 2.7 %

Procedure:
4-(1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared following the procedure as outlined for Example 99, starting from ethyl 4-(1,4-diazepan-1-yl)benzoate (0.497 g, 2 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.495 g, 2.00 mmol) and 2M trimethylaluminium (2.50 mL, 5.0 mmol) in toluene (10 ml). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% 2.5 M ammonia MeOH in DCM. Fractions containing the product were evaporated to dryness and further purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.024 g, 2.67%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:27]COC)([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[CH2:31][CH2:32][CH3:33])[CH2:7][CH2:6]1)=[O:4].CC(O[C:38]1[CH:39]=[C:40]([C:44]2([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]2=[O:50])[CH:41]=[CH:42][CH:43]=1)C>>[F:22][C:19]([F:21])([F:20])[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][N:5]([C:3](=[O:4])[CH2:2][N:46]3[C:45](=[O:50])[C:44]([C:40]4[CH:39]=[CH:38][C:43]([O:27][CH:18]([CH3:19])[CH3:15])=[CH:42][CH:41]=4)([CH3:51])[NH:48][C:47]3=[O:49])[CH2:6][CH2:7]2)=[C:13]([CH2:31][CH2:32][CH3:33])[CH:14]=1)([OH:27])[C:23]([F:26])([F:25])[F:24]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CBr)CC1
Reactant: CC(C)Oc1cccc(C2(C)NC(=O)NC2=O)c1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cc3)C2=O)CC1

Procedure:
2-Bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-1,4-diazepan-1-yl)ethanone and 5-(3-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].C(OC(=O)C)(=O)C.[N+:19]([O-])([OH:21])=[O:20].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[N+:19]([C:7]1[NH:6][C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])=[CH:9][CH:8]=1)([O-:21])=[O:20]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(c1ccc([N+](=O)[O-])[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
21.3 g (0.1 mol) of 2-trichloroacetylpyrrole and 100 ml of acetic anhydride were introduced into a round-bottomed flask. At 0° C., a solution of 4.2 ml of fuming nitric acid, 8 ml of acetic acid and 8 ml of acetic anhydride was added dropwise and the temperature was permitted to increase to room temperature. The reaction medium was poured into ice, the pH adjusted to 8 with sodium bicarbonate, extracted with dichloromethane, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (60-40). There were recovered 5.5 g (21%) of 5-nitro-2-trichloroacetylpyrrole in the form of a dark green oil and 11.2 g of 4-nitro-2-trichloroacetylpyrrole of melting point 160°-163° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:30])(=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])=[CH:25][CH:24]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(C)nc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and purified by HPLC. 1H NMR (CDCl3) δ 9.66 (br s, 1H, NH), 8.34 (d, 1H, J=2.2 Hz), 7.75 (d, 1H, J=8.8 Hz), 7.72 (d, 1H, J=8.0 Hz, J=2.2 Hz), 7.56 (d, 2H, J=8.4 Hz), 7.51 (dd, 1H, J =8.8 Hz, J=2.2 Hz), 7.32 (d 1H, J=2.2 Hz), 7.26 (d, 1H, J=7 Hz), 7.09 (d, 2H, J=8.4 Hz), 3.65 (s, 3H), 2.97(t, 2H, J=7.6 Hz), 2.66 (s, 3H), 2.51 (t, 2H, J=7.6 Hz). MS: m/z 473 (M+1).
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:35]=[CH:34][CH:33]=[CH:32][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:21]=2)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:37]([C:40]1[CH:48]=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[C:42]([OH:49])[CH:41]=1)(=[O:39])=[O:38]>>[C:1]([C:9]1[O:10][C:11]2[CH:35]=[CH:34][CH:33]=[CH:32][C:12]=2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][S:37]([C:40]3[CH:48]=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[C:42]([OH:49])[CH:41]=3)(=[O:39])=[O:38])=[C:22]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:21]=2)=[CH:18][CH:19]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1oc2ccccc2c1-c1ccc(-c2ccc(O)c(C3CCCC3)c2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(C(=O)c5ccccc5)oc5ccccc45)cc3)cc2C2CCCC2)cc1O

Procedure:
The title compound was prepared from 4′-(2-benzoyl-benzofuran-3-yl)-3-cyclopentyl-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a yellow solid, mp 105-108° C.; MS m/e 694 (M-H)+;
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH:11]=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[O-:13]Cl=O.[Na+]>O.CS(C)=O>[Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=Cc1csc2c(Cl)ncnc12
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1csc2c(Cl)ncnc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
NaH2PO4.2H2O (170 mg, 1.07 mmol) was dissolved in water (0.6 mL) and 4-chlorothieno[3,2-d]pyrimidine-7-carbaldehyde (100 mg, 0.47 mmol) dissolved in DMSO (4.8 mL) was added thereto at 10° C. The reaction mixture was cooled to 0° C. and NaClO2 (170 mg, 1.88 mmol) dissolved in water (0.6 mL) was added thereto at 0° C. The reaction mixture was heated to room temperature, stirred for 2 hours, and water (10 mL) was added thereto. The reaction mixture was stirred for 2 hours and then filtered. The filtrate was concentrated to obtain the title compound as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C@@H:4]2[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1>CS(C)=O>[F:32][C:31]([F:34])([F:33])[C:27]1[N:26]=[C:25]([NH:1][C@@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:9][C@@H:4]3[CH2:3]2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](N)C[C@H]2C1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](Nc3cccc(C(F)(F)F)n3)C[C@H]2C1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To (7S,8aS)-tert-butyl 7-aminohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (310 mg, 1.29 mmol) and sodium carbonate (0.26 g, 2.5 mmol) in dimethyl sulfoxide (1 mL) was added 2-chloro-6-(trifluoromethyl)pyridine (0.35 g, 1.93 mmol). The mixture was stirred at 100° C. for 3 days and then concentrated. The residue was purified by chromatography on silica gel (100% ethyl acetate) to provide the title compound. MS (ESI) m/z 387 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl-].[Li+]>CS(C)=O.O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:3]([OH:17])=[O:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)CC(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Yield: 23.3 %

Procedure:
Cyanoester 2 (0.76 g, 3.91 mmol), water (0.14 mL, 7.82 mmol) and lithium chloride (0.66 g, 15.6 mmol) were heated to 150° C. in DMSO (40 mmL) for 22 hours. The mixture was allowed to cool, diluted with water (150 mL), and extracted with ether (3×50 mL). The combined ether fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane-ethyl acetate, 95:5) to give the cyanide 3 (0.21 g, 44%) as a 60:40 mixture of diastereoisomers; Rf(heptane-ethyl acetate, 9:1) 0.44; νmax(film)/cm−1 2238 (CN); Major diastereoisomer: δH (400 MHz; CDCl3) 2.97 (1H, m), 2.87 (2H, m), 2.32–2.18 (2H, m), 2.10–1.96 (3H, m), 1.92–1.78 (2H, m), 1.48–1.38 (1H, m); Minor diastereoisomer: δH (400 MHz; CDCl3) 3.13 (1H, m), 2.87 (2H, m), 2.32–2.18 (2H, m), 2.10–1.96 (3H, m), 1.92–1.78 (2H, m), 1.48–1.38 (1H, m).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].[CH3:18][O: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:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:29]3[CH2:28][CH2:27][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][CH3:18])[CH2:31][CH2:30]3)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc2ccc(OCC3CO3)cc2o1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CC(O)COc2ccc3cc(C(N)=O)oc3c2)CC1

Procedure:
The procedures of Example 8a were repeated except that 1.2 g (0.005 mole) of 2-carbamoyl-6-(2,3-epoxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine were employed to give the desired compound.
Reaction SMILES: C(OC1[O:42][C@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[C@@H:16]([O:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][CH2:21][CH:22]=[CH2:23])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[CH2:48]([Cl:50])Cl>[Zn+2].[Br-].[Br-]>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][CH2:21][CH:22]=[CH2:23])[C@@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:42][C@@H:48]1[Cl:50])(=[O:10])[CH3:9]
Reactant: C=CCO[C@H]1[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)C(OC(C)=O)O[C@@H]2COC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: ClCCl
Agent: [Br-]
Agent: [Zn+2]
Product: C=CCO[C@H]1[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](Cl)O[C@@H]2COC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 1 h
Yield: 11.7 %

Procedure:
To a solution of 2 (3.5 g, 5.17 mmol) in CH2Cl2 (10 mL) Cl2CHOCH3 (0.56 mL, 6.2 mmol) and ZnBr2 (100mg) were added under an Ar atmosphere. The mixture was stirred for 1 h, then concentrated and the residue was chromatographed on silica gel with pentane-EtOAc (6:4) to give 3 (396 mg, 85%), [α]D+93.4° (c 1.2, CHCl3); 1H NMR (CDCl3) δ 6.22 (s, 1H, J1,2=3.9 Hz, H-1), 5.80 (m, 1H, Hc), 5.56 (t, 1H, J3,4 and J2,3≈9.7 Hz, H-3), 5.31 (dd, 1H, J4′,3′=3.5 Hz, J4′,5′=0.8 Hz, H-4′), 5.20 (1H, Hb), 5.12 (1H, Ha), 4.93 (dd, 1H, H-2),4.86(dd, 1H, J2′,3′=10.2 Hz, H-3′), 4.58 (dd, 1H, J6a,6b=12.1 Hz, J5,6a=0.7 Hz, H-6a), 4.34 (d, 1H, J1′,2′=7.7 Hz, H-1), 4.29 (dd, 1H, J5,6b =4.2 Hz, H-6B),4.25-4.01 (m, 5H, Hd, He, H-5, H-6′a, H-6′b), 3.85-3.78 (m, 2H, H-4, H-5′), 3.42 (dd, 1H, H-2′). Calc'd for C27H37Cl16 (653.025) C, 49.66; H, 5.71, Cl, 5.43. Found C, 49.68, H, 5.68, Cl, 5.73.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH:14]([C:19]([OH:21])=[O:20])[CH2:15][CH2:16][S:17][CH3:18]>[Ni].[Pd]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][CH:14]([C:19]([OH:21])=[O:20])[CH2:15][CH2:16][S:17][CH3:18]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CSCCC(N)C(=O)O
Agent: [Ni]
Agent: [Pd]
Product: CSCCC(NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The product was made from D-glucose and DL-methionine using Raney nickel or palladium/activated carbon (10%) as a catalyst. The compound had a melting point of 245° C. (decomposition) and an RF -value of 0.71 (determined as indicated in Example K).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH3:11][NH2:12]>C1COCC1>[CH3:11][NH:12][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
In a 3 necked round bottom flask (250 ml), put under nitrogen atmosphere, a solution of 3-(bromomethyl)benzonitrile (5 g; 25.5 mmol; 1 eq.) in anhydrous THF (20 ml) was added dropwise into methylamine (63.76 ml; 2 M; 127.52 mmol; 5 eq.) (2M solution in THF) over 1 hour. The reaction mixture was stirred at RT for 2 hours. Some bis-benzylation was observed (7%). The reaction mixture was filtered to remove the salt. The filtrate was evaporated under reduced pressure. The residue was taken up with DCM and evaporated again to give the title compound as a yellow oil (3.78 g, quantitative yield). It was used in the next step without any further purification. LC/MS (Method B) 146.8 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH2:30][CH3:31])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39]([N:8]2[CH2:17][CH2:16][C:15]3[C@:10]([CH2:28][O:29][CH2:30][CH3:31])([CH2:11][C:12]4[CH:20]=[N:19][N:18]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=5)[C:13]=4[CH:14]=3)[CH2:9]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 1c using (R)-4a-ethoxymethyl-1-(4-fluorophenyl)-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and 6-chloropyridine-3-sulfonyl chloride. LCMS (Method B): 503 (M+H)+, Retention time 4.1 minutes.
Reaction SMILES: [CH3:1][CH:2]([C:4](Br)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3].[Cl-].[Li+].O>CN(C=O)C>[CH3:1][C:2](=[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3]
Reactant: CCCCC(=O)C(Br)(c1ccccc1)C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(=O)C(=C(C)C)c1ccccc1
Temperature: 130 °C
Yield: 46 %

Procedure:
The crude 2-methyl-3-bromo-3-phenyloctan-4-one (intermediate IIb-1) was dissolved in magnetically stirred anhydrous DMF (35 ml) under a nitrogen atmosphere. Lithium chloride (3.2 gram, 0.075 mol) was added and the resulting mixture was heated at 130° C. for 90 minutes. The resulting mixture was allowed to attain room temperature and was subsequently poured into water and extracted with diethyl ether. The organic layer was separated and washed with water (4 portions). The organic layer was dried over Na2SO4, filtered and concentrated. The obtained residue was purified using Sepacore equipment: (petroleum ether/diethyl ether=98/2 (v/v)) to give 2-methyl-3-phenyloct-2-en-4-one (Intermediate III-1) (1.96 gram, 46% yield) as a pale yellow oil; 1H-NMR (400 MHz, CDCl3) δ 0.81 (d, J=7, 3H), 1.13-1.24 (m, 2H), 1.43-1.52 (m, 2H), 1.66 (s, 3H), 2.00 (s, 3H), 2.25 (t, J=7, 2H), 7.15 (br d, J=8, 2H), 7.20-7.39 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.O>C(O)=O.C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Agent: C=O
Solvent: O=CO
Solvent: O
Product: CN1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
The tert-butyl 4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate (2.0 g, 4.76 mmol, Eq: 1.00) was dissolved in the solvent mixture of formic acid (40.0 ml) and formaldehyde, 37% (80.0 ml). The reaction mixture was stirred at 70° C. overnight until reaction was complete as determined by LCMS analysis, then cooled to ambient temperature. Water was added and the resultant aqueous mixture was washed with CH2Cl2 and the CH2Cl2 layer was discarded. The pH of the aqueous layer was adjusted to pH=12 carefully with solid K2CO3, which resulted in precipitation of a solid. The solid was collected by filtration, washed with water and dried in vacuum oven at 50° C. over 72 h to afford 1.4 g of the desired product. (M+H)+=334 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.84 (dd, J=8.31, 3.02 Hz, 4 H) 1.99-2.19 (m, 2 H) 2.35 (s, 3 H) 2.42-2.68 (m, 1 H) 3.02 (d, J=12.09 Hz, 2 H) 3.81 (s, 3 H) 6.86 (d, J=8.31 Hz, 1 H) 7.52 (dd, J=8.50, 2.46 Hz, 1 H) 8.16-8.33 (m, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:20]O>S(Cl)(Cl)=O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:20])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CO
Reactant: N#Cc1ccc(Oc2ccc(CC(=O)O)cc2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 22.25 g of [p-(p-cyanophenoxy)phenyl]acetic acid in 55 ml of thionyl chloride is refluxed for one hour. The solvent is removed under vacuum, benzene is added (three times) and the solvent removed under vacuum. The residue is dissolved in 135 ml of methanol and stirred at room temperature for 1 hour. The solvent is removed under vacuum to give a gum. The gum is dissolved in 50 ml of warm methanol and the solution is chilled and filtered to give the product, mp 58°-60° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:16]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2cccnc2nc1-c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4cccnc4nc3-c3ccccn3)c2cc1OC
Temperature: 140 °C
Reaction time: 48 h
Yield: 12.1 %

Procedure:
2-Pyridin-2-yl-[1,8]naphthyridin-3-ol (9 mg), 4-chloro-6,7-dimethoxyquinoline (27 mg), and 4-dimethylaminopyridine (16 mg) were suspended in o-dichlorobenzene (1.5 ml), and the mixture was stirred at 140° C. for 48 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (2 mg, yield 12%).