Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:16]([N:19]=[C:20]=[O:21])[CH:17]=[CH2:18].[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH2:16]([NH:19][C:20](=[O:21])[O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[O:14][CH3:15])=[CH:8][CH:9]=1)[CH:17]=[CH2:18]
Reactant: COC(CCOc1ccc(O)cc1)OC
Reactant: C=CCN=C=O
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CCNC(=O)Oc1ccc(OCCC(OC)OC)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(3,3-Dimethoxypropoxy)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. Allyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The dried solution is stirpped of solvent and unreacted isocyanate to yield the desired product O-[4-(3,3-dimethoxypropoxy)phenyl] N-allylcarbamate as the residue.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=3[F:28])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38](=[O:43])[CH2:39][C:40](O)=[O:41].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:27]=[CH:26][C:24]([NH:25][C:40](=[O:41])[CH2:39][C:38]([NH:37][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[O:30][CH3:29])=[O:43])=[CH:23][C:22]=3[F:28])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: CN(C)Cc1cccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc(CN(C)C)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
To a solution of the amine 150 (334 mg, 0.85 mmol), 3-(2-methoxyphenylamino)-3-oxopropanoic acid (27) (355 mg, 1.70 mmol), 1-hydroxybenzotriazole (275 mg, 2.04 mmol) in dimethylformamide (8.5 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (391 mg, 2.04 mmol) and the reaction mixture was stirred at room temperature until completion of the reaction. The dimethylformamide was evaporated and the residue was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated to afford title compound 146 as a white solid (180 mg, 36% yield). 1H NMR (DMSO-d6) δ (ppm): 10.59 (s, 1H), 9.64 (s, 1H), 8.52-8.50 (m, 1H), 8.08-8.06 (m, 2H), 7.88 (d, J=12.9 Hz, 1H), 7.78 (m, 2H), 7.51-7.38 (m, 4H), 7.07 (s, 2H), 6.92 (m, 1H), 6.65 (m, 1H), 3.86 (s, 3H), 3.65 (s, 2H), 3.48 (s, 2H), 2.18 (s, 6H). MS (m/z): 585.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C@@H:11]3[C@@H:6]([N:7]([C:15]([C:17]4[CH:25]=[CH:24][C:20]5[NH:21][CH:22]=[N:23][C:19]=5[CH:18]=4)=[O:16])[CH2:8][CH2:9][CH2:10]3)[CH2:5][C:4]=2[C:3]=1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:39](OCC)(OCC)[O:40]CC>CO>[NH:21]1[C:20]2[CH:24]=[CH:25][C:17]([C:15]([N:7]3[C@H:6]4[C@H:11]([C:12]5[CH:13]=[C:14]6[O:40][CH:39]=[N:1][C:2]6=[CH:3][C:4]=5[CH2:5]4)[CH2:10][CH2:9][CH2:8]3)=[O:16])=[CH:18][C:19]=2[N:23]=[CH:22]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc2c(c1O)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@H]2c3cc4ocnc4cc3C[C@H]21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of (cis-7-amino-8-hydroxy-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-(1H-benzoimidazol-5-yl)-methanone (100 mg), 4-toluenesulfonic acid hydrate (5 mg), triethyl orthoformate (40 μL), and methanol (1 mL) is stirred at 60° C. for 2 h. After cooling to room temperature, the mixture is concentrated and the residue is dissolved in ethyl acetate. The resulting solution is washed with 1 M NaOH solution, dried (Na2SO4), and concentrated to give the title compound. Yield: 50 mg (49% of theory); LC (method 1): tR=2.24 min; Mass spectrum (ESI+): m/z=359 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:4]1[C:5]([CH3:14])=[C:6]([C:10]([O:12]C)=[O:11])[CH:7]=[N:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([N:3]([CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[C:4]1[C:5]([CH3:14])=[C:6]([C:10]([OH:12])=[O:11])[CH:7]=[N:8][CH:9]=1)[CH3:2]
Reactant: CCN(c1cncc(C(=O)OC)c1C)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(c1cncc(C(=O)O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 77.4 %

Procedure:
To a stirred solution of methyl 5-[ethyl(oxan-4-yl)amino]-4-methylpyridine-3-carboxylate (415 mg, 1.49 mmol) in THF (7 ml) and MeOH (3 ml) was added 4M NaOH solution (932 μl, 3.73 mmol). The reaction was stirred at room temperature for 4.5 h after which the solution was neutralised via the addition of 1M HCl and the solvent was removed under reduced pressure, followed by the addition of saturated brine (10 ml). The aqueous phase was extracted with 1:1 IPA:CHCl3 (3×50 ml), the combined organics washed with brine (30 ml), dried using Na2SO4, filtered and evaporated to afford the title compound as an off-white solid (305 mg, 77%) which was suitable for use in the next stage without any further purification. LC-MS 99%, m/z=265.1, 1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.46 (s, 1H), 3.82 (d, J=11.6 Hz, 2H), 3.25 (t, J=10.9 Hz, 2H), 3.16-2.99 (m, 3H), 2.45 (s, 3H), 1.64 (d, J=11.0 Hz, 2H), 1.48 (dt, J=11.9, 5.7 Hz, 2H), 0.81 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](/[C:8](=[CH:35]\[C:36](\[CH3:51])=[CH:37]\[CH:38]([CH3:50])[CH2:39][CH:40]([CH3:49])[CH2:41][CH:42]([CH3:48])[CH2:43][CH:44]([CH3:47])[CH2:45][CH3:46])/[CH2:9][CH:10]([CH3:34])[C:11]([O:13]C1C(=O)OC(C(OC(C)(C)C)=O)C1C(OC(C)(C)C)=O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(#N)C.[OH-].[Na+]>O>[C:1]([O:5][C:6](/[C:8](=[CH:35]\[C:36](\[CH3:51])=[CH:37]\[CH:38]([CH3:50])[CH2:39][CH:40]([CH3:49])[CH2:41][CH:42]([CH3:48])[CH2:43][CH:44]([CH3:47])[CH2:45][CH3:46])/[CH2:9][CH:10]([CH3:34])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)OC1C(=O)OC(C(=O)OC(C)(C)C)C1C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 104.9 %

Procedure:
(Step 2) To di-tert-butyl 4-{(4Z,6E)-4-(tert-butoxycarbonyl)-2,6,8,10,12,14-hexamethylhexadec-4,6-dienoyloxy}-5-oxotetrahydrofuran-2,3-dicarboxylate (500 mg, 0.694 mmol) obtained in Step 1, acetonitrile (35 mL) and an aqueous sodium hydroxide solution (0.25 mol/L, 28 mL, 6.94 mmol) were added, and the resulting mixture was stirred at room temperature for 6.5 hours. To the reaction mixture, water was added, and then, Dowex 50 (registered trademark) (Muromachi Technos, 50WX8, 50-100 mesh, H+ form) was added thereto to neutralize the mixture, and the insoluble matter was removed by filtration. After the filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over sodium sulfate, and then, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=5/95 to 60/40), whereby Compound 8 (318 mg, quant.) was obtained.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[CH3:15][NH:16][C:17]1[C:30]2[C:29](=O)[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:32])[C:21]=2[C:20]([Br:33])=[CH:19][CH:18]=1>>[C:6]([C:5]1[C:4](=[O:14])[N:16]([CH3:15])[C:17]2[CH:18]=[CH:19][C:20]([Br:33])=[C:21]3[C:22](=[O:32])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:29]=1[C:30]=23)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: CCOC(=O)CC(=O)c1ccccc1
Product: Cn1c(=O)c(C(=O)c2ccccc2)c2c3c(c(Br)ccc31)C(=O)c1ccccc1-2

Procedure:
Benzoylacetic acid ethyl ester is reacted with 1-methylamino-4-bromoanthraquinone in a solvent to obtain 1-benzoyl-6-bromo-2,7-dihydro-3-methyl-2,7-dioxo-3H-dibenzo[f,ij]isoquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH2:5]Br.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH2:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:9]=[C:8]([CH3:10])[CH:7]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1cc(C)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)cc(CNc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of 3,5-dimethylbenzyl bromide (1.59 g, 7.986 mmol), 4-bromoaniline (1.374 g, 7.986 mmol), potassium carbonate (5.519 g, 39.93 mmol) and N,N-dimethylformamide (6.5 ml) was stirred at 80° for 2 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=15:1) to give the title compound (2.106 g, 57.2%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([O:13]CC)=[O:12])[N:7]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:5])[CH3:2].C(N)C1C=CC=CC=1>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([OH:13])=[O:12])[N:7]1[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](C(=O)OCC)N1Cc1ccccc1
Solvent: NCc1ccccc1
Product: CCOC(=O)[C@H]1CC[C@@H](C(=O)O)N1Cc1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Gazzetta Chimica Italiana, 1996, 126, 543-554 from (2R,5S)-1-benzyl-pyrrolidine-2,5-dicarboxylic acid diethyl ester prepared from benzylamine and diethyl meso-dibromoadipate according to the procedure described in J. Med. Chem. 2006, 49, 11, 3068-3076.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18](F)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1>CS(C)=O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:18]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: Fc1cccnc1-c1ccc(Cl)cc1
Reactant: OCC1CC1
Solvent: CS(C)=O
Product: Clc1ccc(-c2ncccc2OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a mixture of 16.20 g cyclopropanmethanol in 150 ml dry DMSO 11 g sodium hydride (55%) was added and the mixture was stirred at room temperature for 30 minutes. A solution containing 37.30 g 2-(4-chloro-phenyl)-3-fluoro-pyridine in 50 mL dry DMSO was added dropwise. The reaction mixture was then stirred at room temperature for 3 h. The resulting suspension was partitioned between water and methylene chloride, the phases were separated. The organic phase was washed with brine; then dried over MgSO4 and purified by chromatography on silica gel with a gradient of heptane to heptane:ethylacetate=2:1 to yield 34.95 g (74.90%) of the title compound as yellow oil, MS 260.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:31])[CH3:30])[CH:23]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH2:32][CH3:33])[N:9]=2)=[CH:4][CH:3]=1.[C:34]1([N:40]=[C:41]=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.CCN(CC)CC>[CH3:33][CH2:32][N:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])=[CH:7][CH:6]=2)[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:14]=2[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:30])[CH3:31])[CH:23]=2)[NH:19]3)=[CH:11]1
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(N)cc2)n1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a stirred solution of 4-[3-(4-aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (0.34 mmol) in tetrahydrofuran (5 mL) was added phenyl isocyanate (0.41 mmol) and two drops of Et3N. The reaction was stirred at room temperature for 1 h and concentrated to dryness under vacuum. The remaining solid was triturated with (1:1) diethyl ether:petroleum ether, filtered, and dried under vacuum. Purification by Gilson reverse phase HPLC gave the title compound as an off-white solid (44%). ESMS (M+H)+: 556.4
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[O:4][N:3]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc(-c2cc(O)no2)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Product: COc1ccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)cc1
Yield: 83.2 %

Procedure:
3-Hydroxy-5-(4-methoxyphenyl)isoxazole (0.22 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.32 g, 84%) as a colorless powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]=[CH:18][CH:17]=3)[CH:13]=2)[N:8]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[C:7]=1[CH2:38][C:39]([O:41]CC)=[O:40])=[O:5])C.[OH-].[Na+].O>CCO>[C:39]([CH2:38][C:7]1[N:8]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=2)[C:9]2[C:14]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:13][C:12]([O:15][C:16]1[C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=1)=[CH:11][CH:10]=2)([OH:41])=[O:40]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccnc4cc(Cl)ccc34)ccc2n1-c1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1c(C(=O)O)c2cc(Oc3ccnc4cc(Cl)ccc34)ccc2n1-c1ccc(OC(F)(F)F)cc1

Procedure:
A mixture of 5-(7-chloroquinolin-4-yloxy)-2-ethoxycarbonylmethyl-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (40 mg, 0.065 mmol, see step (a) above), NaOH (50 mg), water (1 mL) and EtOH (1 mL) was heated at reflux for 1 h. The EtOH was removed in vacuo and the mixture was acidified with HCl (aq, 1 M) to pH 4. The solid was filtered off to give the title compound. Yield 33 mg (91%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>N1C=CC=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][NH2:23])[C:7]=2[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: Clc1ccc(-c2ccnc(Cl)c2-c2ccncc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: NNc1nccc(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a stirring solution of 2-chloro-4-(4-chlorophenyl)-3,4′-bipyridine (1.3 g, 4.3 mmol) in pyridine (5 mL) at room temperature under argon was added hydrazine monohydrate (2.5 mL, 51.5 mmol). The reaction mixture was stirred at reflux under argon for 15 h. After cooling the reaction mixture to room temperature, most of the solvent was removed under reduced pressure. Water (25 mL) was added to the residue while stirring and a precipitate formed. The precipitate was collected by filtration and washed with water (15 mL×2). After drying under reduced pressure at elevated temperature, 1.0 g of the title compound was obtained as a yellow solid. HPLC/MS: retention time=1.68 min, [M+H]+=297.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[S:21][CH:20]=[CH:19][C:8]=2[N:9]=[C:10]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[N:11]=1.[OH-].[Li+]>C1COCC1.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[S:21][CH:20]=[CH:19][C:8]=2[N:9]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[N:11]=1
Reactant: CCOC(=O)CCc1nc(-c2ccco2)c2sccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1nc(-c2ccco2)c2sccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
A solution of ethyl 3-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-yl)propionate (0.07 g, 0.23 mmol) in THF (1.0 mL) and water (1.0 mL) was treated with lithium hydroxide (0.10 g, 2.32 mmol), stirred at room temperature for 16 h, concentrated in vacuo, dissolved in water, acidified to pH 2 by the addition of HCl (0.1 mL, 6.0-M), cooled in ice and filtered to give the title compound (0.052 g, 81%) as a white solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C)C=O.[CH:14]1([CH2:17][N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([C:33]2[CH:34]=[N:35][C:36]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[N:37][CH:38]=2)=[N:22][C:23]=3[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:16][CH2:15]1>C(OCC)(=O)C>[Cl:1][C:26]1[N:18]([CH2:17][CH:14]2[CH2:16][CH2:15]2)[C:19]2[C:24]([N:25]=1)=[C:23]([N:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)[N:22]=[C:21]([C:33]1[CH:38]=[N:37][C:36]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[N:35][CH:34]=1)[N:20]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)NCc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CC4)c3n2)cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reaction time: 4.5 h
Yield: 56.1 %

Procedure:
N-Chlorosuccinimide (0.92 g, 6.89 mmol) was added to an N,N-dimethylformamide solution (60 ml) of tert-butyl {5-[9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-yl}methylcarbamate (2.14 g, 4.59 mmol) at room temperature. The resulting mixture was stirred for 4.5 hours followed by the addition of N-chlorosuccinimide (0.12 g, 0.92 mmol) and the resulting mixture was further stirred for 2.5 hours. The reaction mixture was poured into ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=17:3 to 3:1) to give the title compound (1.29 g, 56%, two steps combined) as a colorless amorphous substance.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])=[CH:3]\[CH2:4][C:5]([OH:7])=[O:6].[CH3:19][O:20][C:21](=[O:30])[C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O.CO.C1CCC(N=C=NC2CCCCC2)CC1>CC(OC)(C)C.CN(C1C=CN=CC=1)C>[CH3:19][O:20][C:21]([C@H:22]([O:6][C:5](=[O:7])[CH2:4][CH:3]=[C:2]([CH3:1])[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30]
Reactant: COC(=O)[C@H](O)c1ccccc1
Reactant: CC1=C(CC/C(C)=C/CC(=O)O)C(C)(C)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)[C@H](OC(=O)CC=C(C)CCC1=C(C)CCCC1(C)C)c1ccccc1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
To a solution of 10.0 g (40 mmol) (E)-4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)-hex-3-enoic acid [H. S. Corey, J. R. D. Cormick, W. E. Swensen, J. Am. Chem. Soc. 1964, 86, 1884] in 100 ml MTBE were added at r.t. 6.64 g (40 mmol) (R)-(−)-mandelic acid methyl ester [α]D=−144.9 (c=1.04, MeOH) and 1.0 g DMAP. Then a solution of 8.24 g (40 mmol) DCC in 100 ml MTBE was added and the reaction mixture stirred for 3 h, filtered and the residue washed with MTBE. The combined organic phases were concentrated in vacuo and the residue (17.6 g) was purified by flash chromatography (250 g silicagel, hexane/MTBE 9:1) affording 12.2 g (88%) 4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)-hex-3-enoic acid (R)-methoxycarbonyl-phenyl-methyl ester (12) in form of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:20](=[O:32])[NH:19]2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[H-].[Na+].I[CH3:37]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:33])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:20](=[O:32])[N:19]2[CH3:37])=[CH:13][CH:14]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(C)c(C)c3)C(=O)N2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(C)c(C)c3)C(=O)N2C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
A solution of 2-(4-{2-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.128 g, 0.280 mmol) in DMF (4 mL) was treated with 60% oil suspension of NaH (0.028 g, 0.70 mmol) and stirred at room temperature under N2 for 15 minutes. The reaction was cooled to 0° C. and treated with iodomethane (0.16 g, 1.13 mmol) and then warmed to room temperature and stirred for 1 h. The reaction was quenched with 1 N HCl (3 mL) and worked up extractively with Et2O and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 5:1 hexanes:acetone to afford 0.098 g (74%) 2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. MS (ES+) Calc'd for C27H37N2O5 (M+1) 469. Found m/z 469 (100%). 1H NMR.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([OH:24])(=[S:23])[CH3:22]>C(Cl)(Cl)(Cl)Cl>[C:21]([S:23][CH:10]([CH2:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:24])[CH3:22]
Reactant: O=C(C=CC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Reactant: CC(O)=S
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)SC(CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A mixture of 2.57 g. of 1-(3-benzoylacryloyl)-L-proline, 1.42 ml. of thioacetic acid and 30 ml. of carbon tetrachloride is stirred for one hour and then concentrated in vacuo to an amber gum. This gum is dissolved in dichloromethane and the solvent removed in vacuo several times giving the desired product as an off-white glass.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].ClC1C=CC=C(C(OO)=[O:23])C=1>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH+:7]([O-:23])[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[NH+]([O-])c1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.1 %

Procedure:
tert-Butyl 2-pyridylcarbamate (7.4 g, 38 mmol) and 3-chloroperbenzoic acid (77%, 11.2 g, 50 mmol) were dissolved in ethyl acetate (100 ml), and the mixture was stirred at room temperature for 20 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:20, v/v) were collected and concentrated to give the titled compound (7.6 g, 95%).