Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2N=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:47][NH:48][C@H:49]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[CH2:50][NH:51][S:52]([CH3:55])(=[O:54])=[O:53].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C@@H:10]([C:11](=[O:12])[N:48]([C@H:49]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[CH2:50][NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH3:47])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH3:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1ccnc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 64.6 %

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionic acid (1.05 g, 3.2 mmol) was dissolved in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml). Hydroxy-7-azabenzotriazole (434 mg, 3.2 mmol) was added as a solid. The solution was cooled to 0° C. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (612 mg, 3.2 mmol) was added. The solution was stirred for 5 min at 0° C. A solution of N-((2R)-2-methylamino-3-phenylpropyl)methansulfonamide (703 mg, 2.9 mmol) in dichloromethane (2 ml) was added. Ethyldiisopropylamine (0.50 ml, 2.90 mmol) was added. The solution was stirred for 27 h, while it was warming up to room temperature. It was diluted with ethyl acetate (200 ml) and extracted with 1N hydrochloric acid (100 ml). The aqueous phase was extracted with ethyl acetate (50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (45 g), using ethyl acetate/heptane (2:1) as eluent, to give 1.037 g of N-((1R)-1-(N-((1R)-1-Benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH3:31])[CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=4)[NH:23][N:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:41][CH:42]([CH3:46])[C:43](Cl)=[O:44].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH3:31])[CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][C:43](=[O:44])[CH:42]([CH3:46])[CH3:41])[CH:28]=4)[NH:23][N:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(=O)Cl
Reactant: CC(Cc1n[nH]c2ccc(O)cc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1n[nH]c2ccc(OC(=O)C(C)C)cc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 3-(2-(9-fluorenylmethoxycarbonylamino)propyl)-1H-indazol-5-ol (0.17 g, 0.41 mmol) and diisopropylehtylamine (0.06 g, 0.50 mmol), in methylene chloride (10 mL) cooled at 0° C. is added 2-methylpropionyl chloride (0.05 g, 0.5 mmol) followed by 4-dimethylaminopyridine (0.05 g, 0.40 mmol). The reaction allowed to warm to room temperature and then is stirred at room temperature. The reaction mixture is added to dilute aqueous sodium bicarbonate and extracted with ether. The combined ether extracts are washed, dried (MgSO4) and concentrated. The residue is purified by chromatography.
Reaction SMILES: C1(N2C(=O)C3=CNC4C=C[C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=NC=4C3=N2)C=CC=CC=1.F[C:28]1[CH:37]=[CH:36][C:35]2[NH:34][CH:33]=[C:32]3[C:38](=[O:49])[N:39]([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[N:40]=[C:31]3[C:30]=2[N:29]=1.CN1CCNCC1.N1CCNCC1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([N:39]2[C:38](=[O:49])[C:32]3=[CH:33][NH:34][C:35]4[CH:36]=[CH:37][C:28]([N:22]5[CH2:23][CH2:24][N:19]([CH3:16])[CH2:20][CH2:21]5)=[N:29][C:30]=4[C:31]3=[N:40]2)=[CH:42][CH:43]=1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: COc1ccc(-n2nc3c4nc(F)ccc4[nH]cc-3c2=O)cc1
Agent: C1CNCCN1
Agent: CN1CCNCC1
Product: COc1ccc(-n2nc3c4nc(N5CCN(C)CC5)ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure described for 6a using 5c and 1-methylpiperazine instead of 5a and piperazine respectively. 1H-NMR (DMSO-d6) δ (ppm): 2.22 (3H, s), 2.56 (4H, m), 3.64 (4H, m), 6.98 (2H, d, J=9.07 Hz), 7.15 (1H, d, J=9.34 Hz), 7.78 (6H, d, J=9.34 Hz), 8.10 (2H, d, J=9.07 Hz), 8.45 (1H, s). m/z 391.4 (MH+).
Reaction SMILES: O.S.[Na].[N+:4]([C:7]1[CH:8]=[C:9]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)([O-])=O>CO>[NH2:4][C:7]1[CH:8]=[C:9]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: S
Agent: [Na]
Solvent: CO
Solvent: O
Product: Nc1cc([N+](=O)[O-])cc(S(N)(=O)=O)c1
Temperature: 25 °C

Procedure:
A suspension of sodium hydrogensulfide hydrate (3.88 g; 49 mmol) in Methanol (200 ml) was added to a solution of 3,5-dinitro-benzenesulfonamide (6 g; 24.27 mmol) in Methanol (500 ml). The reaction mixture was refluxed for 3 h then cooled to room temperature, filtered and concentrated in vacuo. The crude was washed with water, filtered and dried in vacuo. 3.2 g (15 mmol; 61% yield) of orange powder were obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:26]=[C:27]([CH2:31][C:32](O)=[O:33])[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:33])[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc2c1cnn2CCN1CCCC1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Product: O=C(Cc1cccc(Oc2ccccc2)c1)Nc1cccc2c1cnn2CCN1CCCC1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-ylamine and (3-phenoxy-phenyl)-acetic acid were processed as described in Example 3 to provide the title compound. MS (DCI/NH3) MS m/z 441 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.83 (m, 2 H), 2.01 (m, 2 H), 3.04 (m, 2 H), 3.52 (m, 2 H), 3.71 (q, J=5.72 Hz, 2 H), 3.79 (s, 2 H), 4.76 (t, J=6.24 Hz, 2 H), 6.90 (m, 1 H), 7.03 (m, 3 H), 7.15 (m, 2 H), 7.39 (m, 5 H), 7.66 (m, 1 H), 8.34 (s, 1 H), 9.67 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]([CH2:11][P:12]([OH:28])([CH:14]([NH:16][C:17]([O:19][CH:20]([O:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH3:21])=[O:18])[CH3:15])=[O:13])[C:8](O)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([O:38][C:39](=[O:43])[C@H:40]([CH3:42])[NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][C:39](=[O:43])[CH:40]([NH:41][C:8](=[O:9])[CH:7]([CH2:6][C:5]1[CH:29]=[CH:30][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:11][P:12]([OH:28])([CH:14]([NH:16][C:17]([O:19][CH:20]([O:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH3:21])=[O:18])[CH3:15])=[O:13])[CH3:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(OC(=O)NC(C)P(=O)(O)CC(Cc1ccc(Br)cc1)C(=O)O)OC(=O)C(C)C
Product: CC(OC(=O)NC(C)P(=O)(O)CC(Cc1ccc(Br)cc1)C(=O)NC(C)C(=O)OCc1ccccc1)OC(=O)C(C)C

Procedure:
Using 1 g of the compound from step 3 and 388 mg of alanine benzyl ester, the expected compound is obtained according to the protocol in step 4 of example 3. White solid.
Reaction SMILES: C1(C(C2C3C(=CC=CN=3)[NH:10][C:9]2=[O:17])=O)SC=CC=1.[C:18]1([C:23]([CH:25]2[C:33]3[C:28](=[CH:29][CH:30]=[N:31][CH:32]=3)[NH:27][C:26]2=[O:34])=[O:24])[S:22][CH:21]=[CH:20][CH:19]=1.C(=O)=NS(Cl)(=O)=O.ClS(NC=O)(=O)=O>CS(C)=O.CO.CCOCC.C(#N)C>[C:18]1([C:23]([CH:25]2[C:33]3[C:28](=[CH:29][CH:30]=[N:31][CH:32]=3)[N:27]([C:9]([NH2:10])=[O:17])[C:26]2=[O:34])=[O:24])[S:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1Nc2cccnc2C1C(=O)c1cccs1
Reactant: O=C1Nc2ccncc2C1C(=O)c1cccs1
Agent: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CO
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2cnccc21
Reaction time: 8 h

Procedure:
The title compound was prepared from 3-(2-thenoyl)-4-azaoxindole (Example 4C) according to the procedure of Example 2C, using 3-(2-thenoyl)-5-azaoxindole (500 mg, 2.0 mmol), N-chlorosulfonyl isocyanate (0.26, 3.0 mmol), and acetonitrile (15 mL). Reaction time: 2.25 hours. The crude N-chlorosulfonyl carboxamide was hydrolysed by stirring in DMSO (1.5 mL) for 1.5 hours in a flask open to the air. Ether was added to give a two phase mixture followed by methanol, which gave a homogenous solution. On standing for a brief period, a green precipitate formed which was removed by filtration. The filtrate was allowed to stand overnight, during which time the product crystallized from the solution. This was collected by filtration. Yield: 39 mg (7%). M.p. 250°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@@H:20]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)=O.CO.Cl.CO>C1COCC1>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[CH2:24][C@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:7]1[CH2:6][C:5]1[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C[C@H]2CCCN2C(=O)CCCCC(=O)N2CCC[C@@H]2Cc2ccc(OC)c(OC)c2)cc1OC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C[C@H]2CCCN2CCCCCCN2CCC[C@@H]2Cc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R,R)-1,6-bis[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]-1,6-dioxohexane (0.001 mol) in dry THF was added to a solution containing 0.5 mL (0.005 mol) 10M BH3 ·DMS, and the solution was heated under reflux in an argon atmosphere. Heating was maintained for 2 hours, after which time the mixture was cooled and 10 mL anhydrous methanol was added dropwise. After gas evolution had subsided, 10 mL of saturated HCl-MeOH was added dropwise and the mixture heated under reflux for 15 minutes. The mixture was cooled to room temperature and the solvent removed in vacuo, leaving an oily residue whose volume was further reduced by Kugelrohr distillation (100° C., 0.05 Torr). Finally, the residue was dissolved in isopropyl alcohol, and ether was added until the solution became cloudy. Crystallization occurred overnight, giving (R,R)-1,6-bis[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]hexane.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([CH2:12][OH:13])[C@@H:9]([OH:14])[C@H:8]([OH:15])[C@H:6]2[N:7]=1.C(N(CC)CC)C.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>CN(C1C=CN=CC=1)C.CN(C=O)C>[Si:28]([O:13][CH2:12][C@H:10]1[O:11][C@H:5]2[C@H:6]([N:7]=[C:3]([N:2]([CH3:16])[CH3:1])[S:4]2)[C@@H:8]([OH:15])[C@@H:9]1[OH:14])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 50 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a solution of (3aR,5R,6S,7R,7aR)-2-(dimethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (1 g, 4.03 mmol), DMAP (49.2 mg, 0.40 mmol) and triethylamine (611 mg, 6.05 mmol) in DMF (50 mL) was added tert-butylchlorodimethylsilane (665 mg, 4.43 mmol). After stirred overnight at 50° C., the resulting mixture was concentrated under vacuum to provide a residue, which was purified by silica gel column, eluted with 2-5% MeOH in dichloromethane to give compound 8 as a yellow solid (1.0 g, 65%). (ES, m/z): [M+H]+ 263.0; 1H NMR (300 MHz, CDCl3) δ 6.33-6.35 (d, J=6.3 Hz, 1H), 4.35-4.39 (t, J=5.7 Hz, 1H), 4.18-4.21 (t, J=4.5 Hz, 1H), 3.81-3.84 (m, 3H), 3.62-3.67 (m, 1H), 3.05 (s, 6H), 0.93 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([O:11]C)[O:9]C)[CH:3]=1.O[Li].O.[CH2:16]1[CH2:20]OC[CH2:17]1.CO>O>[NH:5]1[C:6]2[C:7](=[CH:2][CH:17]=[CH:16][CH:20]=2)[CH:3]=[C:4]1[C:8]([OH:9])=[O:11]
Reactant: COC(OC)c1cc(Cl)ccn1
Reactant: C1CCOC1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
To a solution of the above ether (770 mg, 2.1 mmol) in THF/MeOH (25 mL/10 mL) was added LiOH.H2O (218.1 mg, 2.50 eq) dissolved in 3 mL of water. The clear reaction solution was stirred at room temperature for 5 h, then concentrated in vacuo. The residual aqueous solution was diluted with water (15 mL), and extracted with ether. The organic layer was disgarded. The aqueous layer was acidified to pH 5 with 1.4 N HCl (˜2.5 mL). A large amount of white precipitates were extracted with 200 mL of EtOAc and washed with brine. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give the desired indole-2-carboxylic acid intermediate (644 mg, 90.5%) as a white foam.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([O:16][CH3:17])[CH:8]=1)[CH3:4].CN(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1COCC1>[CH3:23][S:24]([O:1][CH2:2][C@H:3]([NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([O:16][CH3:17])[CH:8]=1)[CH3:4])(=[O:26])=[O:25]
Reactant: COc1cc(C(=O)N[C@H](C)CO)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Agent: CN(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)N[C@H](C)COS(C)(=O)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of (R)—N-(1-hydroxypropan-2-yl)-3-methoxy-4-nitrobenzamide (1 equiv) in dry THF (0.2 M) was added trimethylamine (1.5 equiv) followed by addition of methanesulfonyl chloride (1.5 equiv). The reaction was stirred at room temperature overnight. The reaction mixture was washed with water (0.6 M) and brine (0.6 M) sequentially. The aqueous was extracted with ethyl acetate (0.23 M). The combined organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated. The crude material was purified by silica gel chromatography (20% ethyl acetate in petroleum ether) to afford the desired compound (62% yield). MS (ESI) m/z 253.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][C:6]1[N:5]=[C:4]([C:9]#[N:10])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccnc1C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)nc1C#N

Procedure:
A solution of 3-methoxy-pyridine-2-carbonitrile from Example 13b in CCl4 is treated with N-bromosuccinimide (1 equiv.) and catalytic 2,2-azobisisobutyronitrile and is heated at reflux for 18 h. The reaction mixture is evaporated, the residue is taken into ethyl acetate, washed with 5% Na2CO3 (aqueous), 5 % Na2S2O3 (aqueous), dried over MgSO4 and evaporated to give 6-bromo-3-methoxy-pyridine-2-carbonitrile.
Reaction SMILES: Cl.C([NH:5][CH2:6][CH2:7][N:8]([CH2:21][CH2:22][C:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2)[C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:10])(=O)C.[OH-].[Na+].C(Cl)(Cl)Cl>CO.O>[C:23]12([CH2:22][CH2:21][N:8]([CH2:7][CH2:6][NH2:5])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[O:10])[CH2:30][CH:29]3[CH2:28][CH:27]([CH2:26][CH:25]([CH2:31]3)[CH2:24]1)[CH2:32]2
Reactant: CC(=O)NCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: NCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Reaction time: 72 h
Yield: 21.7 %

Procedure:
Under ice-cooling, 6 N hydrochloric acid (15 ml) was added to a solution of 1-[2-(acetylamino)ethyl]-1-[2-(1-adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-103, 1.02 g, 2.39 mmol) in methanol (10 ml), and the mixture was heated at 90° C. with stirring for three days. The reaction mixture was neutralized with a 1 N aqueous sodium hydroxide solution (10 ml), and the whole was distributed between chloroform (50 ml) and water (10 ml). The organic layer was washed with a saturated aqueous sodium chloride solution (50 ml) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound (200 mg, 21.7%) as an oily matter.
Reaction SMILES: [CH:1]1([O:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.O>CS(C)=O.ClCCl.C(N(CC)CC)C>[CH:1]1([O:4][CH2:5][CH2:6][CH2:7][CH:8]=[O:9])[CH2:3][CH2:2]1
Reactant: OCCCCOC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=CCCCOC1CC1
Yield: 59.2 %

Procedure:
4-(cyclopropyloxy)butan-1-ol (400 mg) was dissolved in a mixture of DMSO (3.5 mL), dichloromethane (10 mL), and triethylamine (2.14 mL), and a solution of a sulfur trioxide pyridine complex (1.47 g) in DMSO (3.5 mL) added dropwise thereto under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour, and then poured into water (20 mL). The mixture was extracted with diethyl ether (200 mL), the organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20) to obtain 4-(cyclopropyloxy)butanal (233 mg).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O1CCCC1.[ClH:31]>O.C(O)C>[Cl:31][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH2:14][C:12]2[N:13]=[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:10][CH:11]=2)=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: ClCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
A mixture of 4-[2-[(E)-2-phenylethenyl]-4-oxazolyl methoxy]benzaldehyde (5.00 g), sodium borohydride (620 mg), tetrahydrofuran (50 ml) and ethanol (50 ml) was stirred for 16 hours at room temperature. The reaction mixture was poured into water and acidified with 2N hydrochloric acid. The resulting precipitate was collected by filtration and dried, which was suspended in chloroform (50 ml). To the suspension was added thionyl chloride (2.00 g). The mixture was stirred for one hour at room temperature. The reaction mixture was concentrated, to which was added ethyl acetate, followed by washing with saturated aqueous sodium hydrogencarbonate and water. The ethyl acetate layer was separated and dried (MgSO4). The solvent was distilled off to leave crystals, followed by recrystallization from chloroform-isopropyl ether to give 4-(4-chloromethylphenoxymethyl)-2-[(E)-2-phenylethenyl]oxazole (3.25 g, 61%) as colorless prisms, mp 116-117° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([OH:11])=O)[N:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([O-:26])=[O:25]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:36]2[CH2:37][CH2:38][N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N+:24]([O-:26])=[O:25])[CH2:34][CH2:35]2)=[O:11])[N:3]=1
Reactant: Cc1cc(C)n(CC(=O)O)n1
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3[N+](=O)[O-])CC2)n1
Reaction time: 1 h
Yield: 64 %

Procedure:
To (3,5-dimethyl-pyrazol-1-yl)-acetic acid (0.140 g, 0.908 mmol) in DMF is added carbonyl diimidazole (0.140 g, 0.863 mmol) in one portion. The mixture is stirred for 1 h. To this is added 1-(2-nitro-phenyl)-piperazine (0.197 g, 0.950 mmol). The mixture is stirred for 14 h and then diluted with 100 mL EtOAc. The reaction is quenched with 20 mL of saturated NH4Cl, washed with 2×20 mL of H2O and 1×20 mL of brine. The organic phase is dried (MgSO4), filtered and concentrated to give 2-(3,5-dimethyl-pyrazol-1-yl)-1-[4-(2-nitro-phenyl)-piperazin-1-yl]-ethanone in 64% yield.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH:11]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])[CH3:12]>C(Cl)(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:12][CH:11]([C:7]1[N:3]=[CH:4][NH:5][CH:6]=1)[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20]
Reactant: C[Si](C)(C)n1ccnc1
Reactant: Cc1cccc(C)c1C(C)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1C(C)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
To a mixture of N-(trimethylsilyl)imidazole (1.4 g) and titanium tetrachloride (1.6 ml) in dry chloroform (20 ml) a solution of 1-chloro-1-(2,6-dimethylphenyl)ethane (1.7 g) in dry chloroform (10 ml) was added. After stirring for 5 h at room temperature the product mixture was poured onto water, washed with ether and neutralized with sodium hydrogen carbonate. Filtration and extraction with methylene chloride gave 4-[(α-methyl)-2,6-dimethylbenzyl]imidazole, yield 33%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH2:8][CH2:9][CH2:10][CH:11]=[O:12])[CH:7]=1.[CH:15]([Mg]Br)=[CH:16][CH2:17][CH3:18].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[CH2:18][CH2:17][CH:16]=[CH2:15])[CH:7]=1
Reactant: CCC=C[Mg]Br
Reactant: COc1ccc(F)cc1CCCC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(O)CCCc1cc(F)ccc1OC
Yield: 63.7 %

Procedure:
To a solution of 4-(5′-fluoro-2′-methoxyphenyl)butyraldehyde (1.30 g, 6.6 mmol) in THF (15 mL) at 0° C. was added a solution 1-butenylmagnesium bromide (0.5 M in THF, 15 mL, 7.5 mmol) dropwise for 5 min. Then the reaction mixture was poured to a solution of saturated ammonium chloride (60 mL) in a separatory funnel. The organics were extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine (40 mL) and dried over sodium sulfate. The solvent then was removed in vacuo and crude product thus obtained was purified by a flash column chromatography (12.5% EtOAc in hexane, Rf=0.15) to give the product as a colorless oil (1.06 g, 61%).