Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)(=O)C>[N:9]1([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: Nc1cnc(Br)cn1
Solvent: CCOC(C)=O
Product: Nc1cnc(N2CCCC2)cn1
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A mixture of 5-bromopyrazin-2-amine (1.2 g, 6.9 mmol) and pyrrolidine (4 mL, 48 mmol) was microwaved at 180° C., 200 W for 2 h. The reaction was diluted into 125 mL ethyl acetate and extracted with water (3×50 mL) and brine (50 mL). It was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (0 to 3% methanol/methylene chloride) to afford 5-(pyrrolidin-1-yl)pyrazin-2-amine (495 mg, 3. mmol, 43.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (1 H, d, J=1.51 Hz), 7.36 (1 H, d, J=1.76 Hz), 5.21 (2H, s), 3.24-3.29 (4 H, m), 1.90 (4 H, ddd, J=6.48, 3.53, 3.34 Hz). MS (LC/MS) R.T.=0.52; [M+H]+=165.29.
Reaction SMILES: [OH:1][C:2]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:17].[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:1][C:2]2[C:15]3[C:6](=[C:7]([O:16][C:30](=[O:31])[C:29]4[CH:28]=[CH:27][C:26]([O:25][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:34][CH:33]=4)[C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:5]=[CH:4][C:3]=2[O:17][C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:34][CH:33]=2)=[O:31])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: O=C1c2ccccc2Cc2c1ccc(O)c2O
Product: O=C(Oc1ccc2c(OC(=O)c3ccc(OCc4ccccc4)cc3)c3ccccc3cc2c1OC(=O)c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Yield: 18.7 %

Procedure:
Using 1,2-dihydroxy-10-anthrone (2.26 g) and 4-benzyloxybenzoyl chloride (8 g) obtained in Synthesis Example 1, (2), the reaction was carried out in the same manner as described in Synthesis Example 1, (3). The crude solid (3.5 g) was chromatographed on silica gel (Wakogel C-200, a trade name, mfd. by Wako Pure Chemical Industries, Ltd.) with n-hexane/methylene chloride [4/1→2/1→1/1 (v/v)] as eluent to give 1.6 g of 1,2,10-tris(4-benzyloxybenzoyloxy)anthracene as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N+:9]([O-])[CH:8]=[CH:7]2.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:16])[NH:9][CH:8]=[CH:7]2
Reactant: [O-][n+]1ccc2cccc(Br)c2c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: O=c1[nH]ccc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of (a) (630 mg, 2.8 mmol) in DMF (10 ml) was treated with trifluoroacetic acid anhydride (4 ml). The clear solution was stirred at room temperature overnight then evaporated. The residue was treated with dilute aqueous sodium carbonate solution and extracted several times with 5% methanol/dichloromethane. The combined organic extracts were washed with brine, dried and evaporated. The crude product was chromatographed on silica eluting with 0-10% methanol in dichloromethane affording a white solid (180 mg, 29%).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[CH3:15][N:16]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:17]([N:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]1[CH2:32][O:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:18]>CO>[ClH:1].[ClH:1].[CH3:15][N:16]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH:20]1[CH2:32][O:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:18]
Reactant: CN(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1COc1cccnc1)c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: CN(C(=O)N1CCNCC1COc1cccnc1)c1ccccc1
Reaction time: 12 h
Yield: 81 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(N-methyl-N-phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (28.1 mg, 0.052 mmol) in MeOH (1 mL). After 12 h, the reaction mixture was concentrated under reduced pressure, yielding 16.9 mg (81%) of the desired product as a yellow solid. LC-MS: RT=3.83 min, [M+H]+=327.1.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:4][CH:1]2[CH2:3][CH2:2]2)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CC1
Yield: 47 %

Procedure:
Cyclopropylamine (1.8 ml) and N,N-diisopropylethylamine (6.6 ml) were dissolved into 75 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (5.0 g) in dichloromethane (15 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 40 min. Purification was conducted by a column chromatography to obtain a bright-yellow solid (2.6 g) in a yield of 47%. 1H NMR (400 MHz, CDCl3): δ 8.84 (s, 1H), 7.35 (s, 1H), 3.84 (m, 1H), 1.36 (m, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:9]1[O:10][CH2:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH:13]=[C:8]1[CH:7]=[C:6]2[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([O:48]O)=[CH:44][CH:43]=2)=[CH:38][CH:37]=1.[F:50][C:51]([F:67])([C:57]([F:66])([F:65])[C:58]([F:64])([F:63])[C:59]([F:62])([F:61])[F:60])[CH2:52][CH2:53][C:54](O)=[O:55].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:9]1[O:10][CH2:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH:13]=[C:8]1[CH:7]=[C:6]2[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([O:48][C:54](=[O:55])[CH2:53][CH2:52][C:51]([F:50])([F:67])[C:57]([F:65])([F:66])[C:58]([F:63])([F:64])[C:59]([F:60])([F:62])[F:61])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1
Reactant: O=C(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: COc1cc2c(cc1OC)C1OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C1C=C2c1ccc(-c2ccc(OO)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C1OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C1C=C2c1ccc(-c2ccc(OC(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
A solution of 8,9-dimethoxy-6-[4′-hydroxyoxybiphen-4-yl]-3-phenyl-3-(4-pyrrolidinophenyl)-3H-naphtho[1,2-b]pyran (0.95 g, 1.5 mmol) and 4,4,5,5,6,6,7,7,7-nonafluoroheptanoic acid (0.53 g, 1.8 mmol) in DCM (20 mL) containing 4-dimethylaminopyridine (0.02 g) and N,N′-dicyclohexylcarbodiimide (0.33 g, 1.6 mmol) under N2 was stirred at room temperature for 1 h. The resulting mixture was filtered through a short plug of silica using EtOAc (5% in DCM) as eluent. The solvent was removed under reduced pressure and the residue chromatographed on silica using EtOAc (0-25% gradient in toluene) as eluent. The solvent was removed under reduced pressure and the residue washed with toluene/hexanes to give the title compound (0.69 g, 51%) as a pale violet powder, mp 218-219° C. The liquors provided a further 0.16 g (12%) after evaporation and washing with acetone.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].C([O-])(=O)C.[Na+].Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)(=O)C>[OH:20][C:13]1[CH:12]=[CH:1][CH:2]=[C:3]([CH3:4])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C/C=C/C=O
Reactant: CCOC(=O)CC(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)cccc1O
Temperature: 25 °C
Yield: 65 %

Procedure:
A stirred mixture of crotonaldehyde (21.0 g, 0.30 mol) and anhydrous sodium acetate (25.0 g, 0.30 mol) in glacial acetic acid is heated to reflux temperature under N2, treated dropwise with ethyl chloroacetoacetate (41.1 g, 95%, 0.25 mol) over a 2.25 hr. period, heated at reflux temperature for 16 hr., cooled to room temperature and concentrated in vacuo to give a residue. The residue is partitioned between ethyl acetate and water. The organic phase is diluted with hexanes, washed sequentially with water and aqueous NaHCO3 and concentrated in vacuo to give the title product as an oil, 41.0 g, 71.4% purity (65% yield), characterized by NMR analysis.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([S:38]([C:35]5[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:37][CH:36]=5)(=[O:40])=[O:39])[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CCNC[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
(8S,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (35 mg, 0.108 mmol, 1.0 equivalent, prepared as described in Example 46, Part H) was suspended in dichloromethane (1.0 mL) in a 4-mL scintillation vial. Triethylamine (32.7 mg, 0.323 mmol, 3.0 equivalents) was added followed by the addition of 4-(trifluoromethyl)benzene-1-sulfonyl chloride (34.3 mg, 0.140 mmol, 1.3 equivalents). The resulting solution was allowed to stir for 30 minutes at room temperature. The reaction solution was loaded directly onto a 4 g silica gel column and eluted with 0:100 to 50:50 ethyl acetate:heptanes (flow rate=18 mL/minute) over 20 minutes to give the title compound as a white solid (30 mg, 56%). 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (d, J=1.3 Hz, 1H), 7.91 (dd, J=9.0, 4.9 Hz, 3H), 7.82 (d, J=8.4 Hz, 2H), 5.43 (t, J=3.9 Hz, 1H), 4.25 (dd, J=16.5, 9.6 Hz, 1H), 4.16-3.95 (m, 3H), 3.57 (dd, J=13.7, 4.0 Hz, 1H), 2.96-2.83 (m, 1H), 2.82-2.64 (m, 2H), 2.65-2.52 (m, 1H), 2.47 (dd, J=13.4, 9.3 Hz, 1H), 2.04-1.84 (m, 2H), 1.08-0.77 (m, 4H); MS (ESI+) m/z 497.0 (M+H)+; [a]D23.8=−0.15 (c=0.13, CH3OH).
Reaction SMILES: CO[CH:3](OC)[CH2:4]Br.Cl.C(=O)(O)[O-].[Na+].[CH2:14]([O:21][C:22]1[N:27]=[C:26]([NH2:28])[CH:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.O1CCOCC1.C(OCC)(=O)C>[CH2:14]([O:21][C:22]1[N:27]2[CH:3]=[CH:4][N:28]=[C:26]2[CH:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cc(-c2ccccc2)cc(OCc2ccccc2)n1
Reactant: COC(CBr)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(COc2cc(-c3ccccc3)cc3nccn23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of bromoacetaldehyde dimethyl acetal (0.16 mL, 1.38 mmol) in water (2 mL) was added hydrochloric acid (0.046 mL, 0.276 mmol). After stirring at room temperature for 2 hours, the reaction was heated to 80° C. for 40 mins to give a clear solution. The reaction was cooled down to room temperature, and sodium bicarbonate (147 mg, 1.75 mmol) was added, followed by a solution of 6-(benzyloxy)-4-phenylpyridin-2-amine (254 mg, 0.919 mmol) in 1,4-dioxane (2 mL). The reaction was stirred overnight at ambient temperature, then diluted with ethyl acetate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to give 5-(benzyloxy)-7-phenylimidazo[1,2-a]pyridine. LRMS (ESI) calculated for C20H17N2O [M+H]+, 301.1; found 301.0.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:9]2[O:10][CH2:11][C@@H:12]([O:13]C(C3C=CC=CC=3)=O)[C@H:8]2[O:7][C@H:4]1[O:5][CH3:6].[OH-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][C@@H:3]1[C@H:9]2[O:10][CH2:11][C@@H:12]([OH:13])[C@H:8]2[O:7][C@H:4]1[O:5][CH3:6]
Reactant: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OC(=O)c2ccccc2)[C@H]1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2O)[C@H]1OC
Yield: 85 %

Procedure:
A solution of methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-D-glucofuranoside (820 mg, 3.1 mmol) and 50% sodium hydroxide (248 mg, 3.1 mmol) in methanol (10 mL) was stirred at room temperature for 30 minutes. The material was adsorbed on silica gel (5 g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) to give methyl 3,6-anhydro-2-O-methyl-β-D-glucofuranoside as a colorless oil, 420 mg, 85% yield. 1H NMR (400 MHz; CDCl3): 5.04 (s, 1H), 5.84-5.81 (tr, 1H), 4.44-4.42 (tr, 1H), 4.25-4.19 (m, 1H), 3.85-3.75 (m, 1H), 3.49 (s, 3H), 3.43 (s, 3H), 2.75-2.72 (d, 1H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCOCC1.O>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH:27]=[C:28]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc([N+](=O)[O-])cnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
A mixture of 2-bromo-3-methyl-5-nitropyridine (10.0 g), cesium carbonate (42 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane complex (1.88 g), and N-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (15 g) in 1,4-dioxane (150 ml) and water (50 ml) was stirred at 110° C. for 2.5 hours. To the reaction solution was added water, extracted with chloroform, the organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained solid was washed with a mixed solution of n-hexane and ethyl acetate to give 4-(3-methyl-5-nitropyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (13.25 g) as a red solid.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7][C:6]=1/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH3:4].[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:20][C:19](=[O:21])/[CH:18]=[CH:17]/[C:6]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCc1c(/C=C/C(=O)O)ccc2ccc(OC)cc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)ccc2ccc(OC)cc12
Yield: 83.1 %

Procedure:
As in Example 113, (E)-3-(1-butyl-7-methoxy-2-naphthalenyl)-2-propenoic acid (1.35 g) was reacted with 4-nitrophenol (0.73 g) in dichloromethane (25 mL) in the presence of 1,3-dicyclohexylcarbodiimide (0.99 g) to give 1.6 g of (E)-3-(1-butyl-7-methoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester. Crystallization of a portion from diethyl ether furnished the analytical sample, mp 114°-115° C. Anal. Calcd for C24H23NO5 : C, 71.10; H, 5.72; N, 3.45 Found: C, 70.85; H, 5.56; N, 3.24
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23]Br)[CH:7]=1)[CH3:2].[CH3:26][C:27]([SH:30])([CH3:29])[CH3:28]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][S:30][C:27]([CH3:29])([CH3:28])[CH3:26])[CH:7]=1)[CH3:2]
Reactant: CC(C)(C)S
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CSC(C)(C)C)c1

Procedure:
As described for Example 21, [3-(2-bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and 2-methyl-2-propanethiol were reacted to provide [3-(2-tert-butylsulfanylmethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-tert-butylsulfanylmethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester. The amine was treated with trimethylacetyl chloride to provide {3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-chloro-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided the acid.
Reaction SMILES: [C:1]([N:11]([CH3:36])[C@H:12]([C:16]([N:18]([CH3:35])[C@H:19]([C:32](O)=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C[N:38]1CCOCC1>C1COCC1.ClC(OCC)=O>[C:1]([N:11]([CH3:36])[C@H:12]([C:16]([N:18]([CH3:35])[C@H:19]([C:32]([NH2:38])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:29])([CH3:31])[CH3:30])[CH:22]=1)=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 1.96 g of Z-N-Me-Val-N-Me-Tyr(3-tBu)-OMe in 1,4-dioxane (40 ml), 2 N NaOH (5 ml) was added at room temperature and the mixture was stirred for 2 hours. The reaction mixture was adjusted to pH 3 with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and the organic layer was dried with sodium sulfate. The solvent was distilled off under reduced pressure to give Z-N-Me-Val-N-Me-Tyr(3-tBu)-OH. To a solution of this Z-N-Me-Val-N-Me-Tyr(3-tBu)-OH in THF (20 ml), ethyl chloroformate (0.40 ml) and NMM (0.46 ml) were added under cooling with ice and the mixture was stirred for 15 minutes. Subsequently, ammonia gas was bubbled into the reaction mixture for 5 minutes. The solvent was distilled off under reduced pressure and the precipitating salt was filtered off and washed with ethyl acetate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent; n-hexane:ethyl acetate=2:3) to give Z-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 1.17 g (61%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[N+:30]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)([O-:32])=[O:31]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:35][C:34]3[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=3[N+:30]([O-:32])=[O:31])=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccccc2[N+](=O)[O-])c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccccc2[N+](=O)[O-])c1

Procedure:
The reaction of hydroxylamine 55 (0.80 g, 2 mmol) with 2-nitrobenzaldehyde (59) (0.302 g, 2 mmol) afforded, after workup, a yellow oil. The crude product was purified by flash chromatography with 1:1 ethyl acetate/hexane as the eluant to obtain 0.80 g (1.49 mmol. 75%) of 70 as a yellow oil. The oil crystallized from ether-petroleum ether to yield yellow crystalline solid: mp 114°-116° C.; IR (CH2Cl2) 3440, 2980, 1700, 1625, 1575, 1528, 1470, 1345, 1300, 1215, 1105, 905, 852, 775 cm-1 ; 1H NMR (CDCl3) δ 1.10 (d, J=6.2 Hz, 3H), 1.23 (d, J=6.2 Hz, 3H), 2.29 (s, 6H), 3.31 (s, 3H), 3.56 (t, J=4.8 Hz, 2H), 4.19 (m, 2H), 4.93 (septet, J=6.2 Hz, 1H), 5.07 (s, 1H), 6.54 (s, 1H), 7.30-9.25 (m, 9H); 13C NMR (CDCl3) δ 19.98, 20.02, 22.47, 22.72, 40.34, 51.67, 67.85, 103.69, 104.37, 120.22, 121.84, 125.25, 125.61, 128.97, 129.17, 130.11, 131.01, 131.08, 134.11, 145.29, 145.82, 148.17, 149.75, 150.35, 167.43, 168.46; mass spectrum, m/e (relative intensity) 522 (0.2), 518 (10.8), 386 (13.3), 326 (22.5), 296 (100), 254 (53.4), 196 (44.7), 121 (18.9). Anal. Calcd for C28H31N3O8 : C, 62.57; H, 5.77. Found C, 62.72; H, 5.80.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[CH:6][CH:5]=1)([O-])=O.CO>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[CH:6][CH:5]=1
Reactant: O=C1CCCN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N2CCCC2=O)cc1
Reaction time: 12 h
Yield: 92.4 %

Procedure:
A mixture of 1-(4-nitrophenyl)pyrrolidin-2-one (1.00 g, 4.85 mmol), 10% palladium on carbon (100 mg), methanol (20 ml) and tetrahydrofuran (20 ml) was stirred under hydrogen atmosphere for 12 hours, insoluble substances were removed by filtration, and the filtrate was concentrated to give 790 mg (92.5%) of the desired product as an oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].O[C@H]1CC[C@@H](NC2C(C#N)=CN=C(S(C)=O)N=2)CC1(C)C.[NH2:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([S:53]([NH2:56])(=[O:55])=[O:54])=[C:49]([Cl:57])[CH:48]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:57][C:49]1[CH:48]=[C:47]([CH2:46][CH2:45][NH:44][C:11]2[N:10]=[C:9]([NH:8][CH:5]3[CH2:6][CH2:7][CH:2]([OH:1])[C:3]([CH3:21])([CH3:22])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)[CH:52]=[CH:51][C:50]=1[S:53]([NH2:56])(=[O:55])=[O:54]
Reactant: NCCc1ccc(S(N)(=O)=O)c(Cl)c1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Agent: CS(=O)c1ncc(C#N)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)CC(Nc2nc(NCCc3ccc(S(N)(=O)=O)c(Cl)c3)ncc2C#N)CCC1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, 0.28 mmol) and 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile, 4-(2-amino-ethyl)-2-chloro-benzenesulfonamide (90 mg, 0.38 mmol) and DIEA (72 mg, 0.56 mmol) in THF (4 mL) was stirred at 100° C. in a microwave reactor for 1 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by standard methods to afford the title compound (28.6 mg, 0.060 mmol, 26% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 7.93 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 4.26-4.12 (m, 1H), 3.66-3.46 (m, 2H), 3.31-3.25 (m, 1H), 2.87 (t, J=6.8 Hz, 2H), 1.86-1.35 (m, 6H), 0.90 (s, 3H), 0.88 (s, 3H). MS (ESI) m/z 479.1 [M+H]+.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)[C:3](=O)[CH3:4].[C:15]([NH:18][C:19]([NH2:21])=[S:20])(=[O:17])[CH3:16]>C(O)C>[CH3:4][C:3]1[N:21]=[C:19]([NH:18][C:15](=[O:17])[CH3:16])[S:20][C:2]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: CC(=O)NC(N)=S
Reactant: CC(=O)C(Br)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CC(=O)Nc1nc(C)c(-c2cccc([N+](=O)[O-])c2)s1
Temperature: 70 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture of 1-bromo-1-(3-nitro-phenyl)-propan-2-one (Example 49a) (0.5 g, 1.94 mmol) and N-acetylthiourea (0.23 g, 1.94 mmol) in ethanol (10 ml) is stirred at 70° C. for 2 hours. After cooling the reaction to room temperature, the precipitated product is removed by filtration and dried under vacuum to give the titled compound (0.28 g).