Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]([C@@H:9]3[O:14][C@H:13]([CH3:15])[C@@H:11]([OH:12])[C@H:10]3[F:16])[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].CO>N1C=CC=CC=1>[Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]([C@@H:9]3[O:14][C@H:13]([CH3:15])[C@@:11]([C:20](=[O:22])[CH3:21])([OH:12])[C@H:10]3[F:16])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H]1O[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@H](F)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)[C@@]1(O)[C@@H](C)O[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H]1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5,6-Dichloro-1-(2,5-dideoxy-2-fluoro-beta-D-ribofuranosyl)-1H-benzimidazole (0.45 g, 1.5 mmoles) was dissolved in pyridine (Aldrich, Sure Seal, 20 mL) and boiled to remove water. The solution was chilled to 0° C. in an ice bath. Acetic anhydride (Aldrich, 260 μL, 2.9 mmoles, 2 eq.) was added and the reaction was allowed to warm to room temperature while stirring overnight. Methanol (3 mL) was added and the solvents removed in vacuo. Residual pyridine was removed by coevaporation with toluene (3×). The residue was partitioned between water and ethyl acetate. The ethyl acetate solution was dried with MgSO4, filtered, and the solvent removed in vacuo. The product was used without further purification. The yield was 0.45 g, 88%. MS (FAB+): m/z, 347; 1H NMR (DMSO-d6) δ8.61 (s,1H, H-2), 8.08 (s,1H, Ar—H), 8.00 (s,1H, Ar—H), 6.38 (d, 1H, H-1′, J=18 Hz), 5.70 (d, 1H, H-2′, J=53 Hz), 5.1 (m, 1H), 4.2 (m, 1H), 2.1 (s, 3H, acetyl), 1.38 (d, 3H, H-5′, J=6 Hz).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])[C:6]([CH3:22])=[CH:5][C:4]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)#[CH:2].[N:33]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)=[N+:34]=[N-:35].[Na].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O>CN(C=O)C.O.[Cu]I>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:33]2[CH:2]=[C:1]([C:3]3[N:8]=[C:7]([C:9]([N:11]4[CH2:16][CH2:15][CH:14]([N:17]5[CH2:21][CH2:20][CH2:19][CH2:18]5)[CH2:13][CH2:12]4)=[O:10])[C:6]([CH3:22])=[CH:5][C:4]=3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=3)[N:35]=[N:34]2)=[CH:42][CH:41]=1
Reactant: C#Cc1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Agent: [Cu]I
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cc(-c3nc(C(=O)N4CCC(N5CCCC5)CC4)c(C)cc3-c3cccc(C(F)(F)F)c3)nn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A solution of 0.30 g (0.68 mmol) of [6-ethynyl-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 24) and 0.116 g (0.71 mmol) of 1-azidomethyl-4-methoxy-benzene in 3.0 ml of DMF was treated with 0.013 g (0.066 mmol) of (+)-sodium-L-ascorbate and 0.129 g (0.68 mmol) of copper(I) iodide in 1.0 ml of H2O and the reaction was stirred at RT for 2 hours. Then, the solvents were removed by evaporation in high vacuum, the residue was diluted with H2O/NH4OH (25%) and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 95:5) to give 0.363 g (88%) of the title compound as light brown oil. MS: 605.4 (MH).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:16]([OH:17])[C:15]4[S:18][CH2:19][CH2:20][S:21][C:14]=4[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:25]([N:28]1[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1)(=[O:27])[CH3:26]>CN(C)C=O.O.C(Cl)(Cl)Cl>[C:25]([N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:17][CH:16]2[N:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[C:13](=[O:22])[C:14]3[S:21][CH2:20][CH2:19][S:18][C:15]2=3)=[O:35])[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCN(C(=O)Cl)CC1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc2ccc(Cl)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)N1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Temperature: 2 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
6-(7-Chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (2.5 g.) is added, at 0° C., to a suspension of sodium hydride (0.20 g.) in anhydrous dimethylformamide (10 cc.). The reaction mixture is stirred for 1 hour at 2° C., and then a solution of 1-acetyl-4-chlorocarbonylpiperazine (2.85 g.) in anhydrous dimethylformamide (20 cc.) is added. After 18 hours at 2° C., the reaction mixture is diluted with distilled water (100 cc.). The precipitate formed is filtered off, washed with distilled water (10 cc.) and dried in air. The product obtained (3.5 g.) is dissolved in chloroform (50 cc.), and the solution is filtered through silica gel (50.0 g.) contained in a column of diameter 4.1 cm. Elution is carried out using a mixture of chloroform and methanol (98-2 by volume; 400 cc.), and the eluate is discarded. Elution is continued using a similar mixture (400 cc). This eluate is evaporated to dryness under reduced pressure (20 mm.Hg). The chromatographed product is purified by recrystallisation from a mixture of dimethylformamide and ethanol (50-50 by volume; 20 cc.). 5-(4-Acetylpiperazin-1-yl)carbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (1.40 g.), which melts at 271° C., is obtained.
Reaction SMILES: [Si:1]([O:8][C:9]([CH:11]1[C:16]([CH3:18])([CH3:17])[S:15][CH2:14][CH2:13][NH:12]1)=[O:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19][N:20]1CCOCC1.N1[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]3[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][C:35]=3[CH:36]=2)=[CH:28][CH:27]=1.O>ClCCl>[Si:1]([O:8][C:9]([CH:11]1[C:16]([CH3:18])([CH3:17])[S:15][CH2:14][CH2:13][N:12]1[S:41]([C:38]1[CH:39]=[CH:40][C:34]2[O:33][C:32]([C:29]3[CH:30]=[CH:31][C:19]([NH2:20])=[CH:27][CH:28]=3)=[CH:36][C:35]=2[CH:37]=1)(=[O:43])=[O:42])=[O:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: O=S(=O)(Cl)c1ccc2oc(-c3ccncc3)cc2c1
Reactant: CC1(C)SCCNC1C(=O)O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CC1(C)SCCN(S(=O)(=O)c2ccc3oc(-c4ccc(N)cc4)cc3c2)C1C(=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
58.7 mmol of 2,2-dimethyl-3-thiomorpholinecarboxylic acid tert-butyl(dimethyl)silyl ester are dissolved in 500 ml of anhydrous dichloromethane. At −20° C., there are added 16 ml of N-methylmorpholine, followed by 57.5 mmol of 2-(4-pyridyl)-1-benzofuran-5-sulphonyl chloride described in Preparation C. The whole is stirred for 48 hours at room temperature and then poured into 300 ml of water. After decanting, washing with water, drying and evaporation, the expected product is obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2>C(O)(=O)C>[NH2:1][CH:2]1[CH2:10][CH2:9][CH:8]2[CH:4]([CH2:5][CH2:6][NH:7]2)[CH2:3]1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Product: NC1CCC2NCCC2C1

Procedure:
A 1.0 g sample of 5-aminoindole was hydrogenated at 4 atm H2 in 50 mL of acetic acid over 2 g of Pt2O at room temperature for 90 hours. The solution was filtered, and the solvent was removed
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:31]=[CH:30][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=O)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl.[CH2:41]([O:43][NH2:44])[CH3:42]>C(O)C>[ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6](/[C:7](=[N:44]\[O:43][CH2:41][CH3:42])/[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)=[CH:30][CH:31]=3)[CH2:11][CH2:10]2)=[CH:32][CH:33]=1
Reactant: O=C(O)c1ccc(Oc2ccc(CN3CCC(C(=O)c4ccc(Br)cc4)CC3)cc2)cc1
Reactant: CCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCO/N=C(\c1ccc(Br)cc1)C1CCN(Cc2ccc(Oc3ccc(C(=O)O)cc3)cc2)CC1

Procedure:
To a solution of the compound prepared in Example 5(15) (912 mg) in ethanol (10 mL) were added pyridine (5 mL) and O-ethylhydroxyamine hydrochloride (340 mg) and the solution was refluxed for 3 hours. After finishing the reaction, the reaction solution was concentrated. Water and 2N hydrochloric acid were added thereto and the solution was extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:methanol=25:1) and 4N hydrogen chloride/ethyl acetate solution was added to the obtained residue, which was concentrated to give the compound of the present invention (E-form: 409 mg, Z-form: 500 mg) having the following physical data.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][C:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][C:30]1[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]4[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=34)[S:5]2(=[O:17])=[O:16])[CH2:34][CH:35]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Reactant: Fc1ccc2[nH]cc(CC3=CCNCC3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CC=C(Cc2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 11.6 %

Procedure:
The procedure is as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2 g), 4-[(5-fluoro-3-indolyl)methyl]-1,2,3,6-tetrahydropyridine hydrochloride (2 g) and sodium bicarbonate (1.3 g) in a mixture of dimethylformamide (70 cc) and tetrahydrofuran (45 cc). The mixture is heated to boiling for 20 hours and then cooled to a temperature in the region of 20° C. After purification by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with dichloromethane and then ethyl acetate as eluents, 2-{2-[4-((5-fluoro-3-indolyl)methyl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (0.4 g) is obtained in the form of a yellow oil, which is converted to an acid oxalate, m.p. 128° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[NH2:17][CH2:18][CH2:19][OH:20]>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:17][CH2:18][CH2:19][OH:20])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: NCCO
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)OC(CNCCO)OC2

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), 2-aminoethanol (0.5 ml, 24.9 mmol) and EtOH (1.0 ml). 1H-NMR (400 MHz, MeOH): δ 7.51 (1H, dd, J1 8.0 Hz, J2 1.6 Hz), δ 7.41 (1H, d, J 1.2 Hz), δ 7.32 (1H, d, J 8.0 Hz), δ 5.27 (1H, t, J 4.8 Hz), δ 5.09 (2H, dd, J1 50.0 Hz, J2 15.6 Hz), δ 3.68 (2H, t, J 5.6 Hz), δ 3.11 (3H, s), δ 3.02 (2H, t, J 4.0 Hz), δ 2.82 (2H, t, J 5.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[F:21][CH:22]([F:43])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]23[NH:42][CH2:41][CH2:40][N:31]2[C:32](=[O:39])[C:33]2[N:34]([CH:36]=[CH:37][CH:38]=2)[CH2:35]3)=[CH:26][CH:25]=1>C(Cl)Cl.N1C=CC=CC=1>[F:43][CH:22]([F:21])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]23[N:42]([C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][CH:5]=4)=[O:9])[CH2:41][CH2:40][N:31]2[C:32](=[O:39])[C:33]2[N:34]([CH:36]=[CH:37][CH:38]=2)[CH2:35]3)=[CH:26][CH:25]=1
Reactant: O=C1c2cccn2CC2(c3ccc(OC(F)F)cc3)NCCN12
Reactant: Cc1nocc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1ccc(OC(F)F)cc1
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To generate the acid chloride, 3-methyl-1,2-oxazole-4-carboxylic acid (95.53 mg, 0.75 mmol) was dissolved in CH2Cl2 (10 mL). Oxalyl chloride (0.22 mL, 2.63 mmol) and a drop of DMF were added at 0° C. The ice bath was removed and the mixture stirred for 1 h before the solvent and the unreacting oxalyl chloride was removed with a stream of nitrogen. The residue was further dried in vacuo. 10a-[4-(difluoromethoxy)phenyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (60 mg, 0.19 mmol) was dissolved in pyridine (4 ml) and the solution added to the previously generated acid chloride in pyridine (1 mL) at 0° C. The ice bath was removed after 15 min and the mixture stirred at room temperature for 18 h. LCMS analysis showed only a trace amount of product. Further 4 equivalent of acid chloride were prepared as described above and added to the reaction mixture. The resultant mixture was then heated at 50° C. until completion (28 h, monitored by LCMS). The resultant suspension was then concentrated in vacuo and the residue partitioned between CH2Cl2 (20 mL) and a saturated aqueous solution of NaHCO3 (10 mL). The organic layers were washed with further a saturated aqueous solution of NaHCO3 (10 mL) and brine (5 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow residue. This residue was purified by flash column chromatography (Biotage SP4, 12 g cartridge, 70-100% EtOAc gradient in n-hexanes) to give 10a-[4-(difluoromethoxy)phenyl]-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one compound (I) as a white solid (42 mg, yield 52%).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:8]([F:23])=[C:9]([CH:12]=[C:13](O[Si](C(C)(C)C)(C)C)[CH:14]=1)[CH:10]=[O:11])(C)(C)C.[F-].[K+].[CH3:28]I.CN([CH:33]=[O:34])C>O>[F:23][C:8]1[C:7]([O:6][CH3:28])=[CH:14][C:13]([O:34][CH3:33])=[CH:12][C:9]=1[CH:10]=[O:11]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CI
Agent: [F-]
Agent: [K+]
Solvent: O
Product: COc1cc(C=O)c(F)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of the 3,5-bis-(tert-butyl-dimethyl-silanyloxy)-2-fluoro-benzaldehyde (3.0 g, 7.8 mmol) obtained in Example 251.1, potassium fluoride (1.81 g, 31.2 mmol), methyl iodide (1.17 ml, 18.7 mmol) and DMF (25 ml) was stirred for 2 h. at room temperature. Water (25 ml) was added and the mixture was extracted with diethyl ether. The organic phase was washed with water, dried, filtered and concentrated. The residue was purified by chromatography (SiO2, cyclohexane/EtOAc 18:1=>1:1). There was obtained 0.87 g (60%) of 2-fluoro-3,5-dimethoxy-benzaldehyde as a colorless solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:15][CH2:14][CH2:13][O:6]1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: ClCCCC1(c2ccccc2)OCCO1
Yield: 61.2 %

Procedure:
Add 4-chlorobutyrophenone (50 g, 274 mmol), ethylene glycol (28 g, 452 mmol) and p-toluenesulfonic acid (1.04 g, 5.48 mmol) to benzene (600 mL) and heat at reflux for 16 h under a water trap. Cool the reaction to RT and wash with 1 N NaOH (500 mL) and brine (750 mL). Dry (sodium sulfate) and concentrate to give a solid. Recrystallize the solid from hot hexanes to give the title compound as a white powder (38 g, 61%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[OH:32])([CH3:22])[CH3:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[OH:32][C:24]1[C:25]([CH:29]([CH3:30])[CH3:31])=[CH:26][C:27]([C:9]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=2)=[O:11])=[CH:28][C:23]=1[CH:20]([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)c2ccc(S(C)(=O)=O)cc2)cc(C(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.8 %

Procedure:
To a solution of 4-methylsulfonylbenzoic acid (4.08 g, 24 mmol) and oxalyl chloride (3.9 mL, 44 mmol) in DCM (70 mL), three drops of DMF was added at 0° C. The reaction mixture was stirred at room temperature for 3 hours and concentrated on a rotavapor. The residue was dissolved in 20 mL of DCM and was added into a suspension of 2,6-diisopropylphenol (2.12 g, 11.9 mmol) and aluminum chloride (1.6 g, 12 mmol in 50 mL of DCM. After stirring for 14 hour, the reaction mixture was poured into 100 mL of ice-water and extracted with diisopropyl ether (2×100 mL). The organic layer was washed with 1 N HCl, saturated aqueous NaHCO3, and brine, and was dried over anhydrous MgSO4. After filtration, the solution was condensed on a rotary evaporator. The crude product was suspended in 100 mL of methanol and 30 mL of water. The resultant suspension was treated with an excess amount of solid NaOH for 16 h at room temperature and acidified by 1 N HCl to pH of 4. The reaction mixture was extracted with ethyl acetate (2×100 mL). After washing with saturated aqueous NaHCO3 and brine, the organic layer was dried over anhydrous Na2SO4 and filtered. The solution was concentrated and the residue was purified by flash silica gel chromatography to afford the desired product as a yellow solid (550 mg, Yield 13%). 1H NMR (500 MHz, CDCl3, δ): 1.27 (s, 6H), 1.29 (s, 6H), 3.12 (s, 3H), 3.18 (hept, J=6.9 Hz, 2H), 5.40 (br s, 1H), 7.57 (s, 2H), 7.90 (dd, J=6.6, 1.7 Hz, 2H), 8.06 (dd, J=6.5, 1.7 Hz, 2H); Anal. Calcd for (C19H21FO2+H)+: 361. Found: 361.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].CN(C=O)C.Cl.CN(C)CCCN=C=NCC>CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCCC(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 100 mL round bottomed flask containing 4-(tert-butoxycarbonylamino)butanoic acid (1 g, 4.92 mmol) was treated with N-hydroxysuccinimide (0.680 g, 5.90 mmol), treated with DMF (8 ml), cooled to 0° C., treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.226 g, 6.40 mmol), stirred at ambient temperature for 2 hours, diluted with Et2O (100 mL), washed with H2O (2×25 mL), dried (MgSO4), filtered and concentrated to provide the title compound. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.90-2.00 (m, 2H), 2.66 (t, J=7.54 Hz, 2H), 2.84 (s, 4H), 3.15-3.28 (m, 2H), 4.73 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(F)cc2)N1

Procedure:
The same method as employed in the preparation of intermediate 1 and 2 but starting from racemic tryptophan methyl ester and 4-fluorobenzaldehyde gave the cis isomer as white crystals m.p.: 92° C. and the trans isomer as pale yellow crystals m.p.: 183° C.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C1(P([N:24]=[N+:25]=[N-:26])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.O>[CH2:1]([N:24]=[N+:25]=[N-:26])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccnc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cccnc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
To a suspension of nicotinic acid (1.23 g, 10.0 mmol) in DMF (15 mL) was added diphenylphosphoryl azide (2.60 mL, 12.0 mmol) followed by triethylamine (1.67 mL, 12.0 mmol). The mixture was stirred at room temperature for 2.5 h and diluted with water (50 mL). The mixture was extracted three times with EtOAc and the combined organic extracts were washed three times with water, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc 7:3) provided I-3a as a white solid (1.13 g).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[C:4]1([CH3:14])[CH:9]=CC(S(O)(=O)=O)=CC=1.[CH:15](=[O:18])[CH2:16]C.[OH-].[Na+]>O.C1CCCCC1>[CH2:1]([O:3][CH:9]([O:18][CH2:15][CH3:16])[CH2:4][CH3:14])[CH3:2]
Reactant: CCC=O
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCCCC1
Product: CCOC(CC)OCC
Reaction time: 0.08 h

Procedure:
To 553.2 g of ethanol, 900 g of cyclohexane, and 5.7 g of p-toluenesulfonic acid placed in a 4 liter three-necked flask fitted with a stirrer, dropping funnel, reflux condenser, and internal thermometer, 348.6 g of propionaldehyde are added with stirring in the course of 5 minutes. Owing to the acetal formation, which starts spontaneously, the internal temperature rises to about 40° C. The mixture is allowed to react at 40° C. for 30 minutes, a pH of 7.0 is then established in the reaction mixture, which is composed of a lower water phase and an upper organic phase, by addition of sodium hydroxide solution (20% aqueous solution) and the water phase is separated. To remove the low-boiling components, the organic phase is subjected to initial distillation at 1013 mbar and a bottom temperature up to 121° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH:25]=O)=[N:3]1.C(O)(=O)[CH2:28][C:29]([OH:31])=[O:30].N1CCCCC1>N1C=CC=CC=1>[OH2:11].[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=2)=[N:5][C:4]([CH:25]=[CH:28][C:29]([OH:31])=[O:30])=[N:3]1
Reactant: O=C(O)CC(=O)O
Reactant: Cn1nc(C=O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cn1nc(C=CC(=O)O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Product: O
Yield: 192.6 %

Procedure:
A solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-carboxaldehyde (0.8 g), malonic acid (0.23 g), piperidine (0.05 ml) and pyridine (5 ml) was heated at 90° for 4 h. The resulting solution was azeotroped with toluene to give a brown foam (0.9 g) which was partitioned between aqueous sodium hydroxide and diethyl ether. The aqueous layer was acidified (pH 5.5) to precipitate the title compound (0.4 g) as a white solid, m.p. 95°-100° [decomp].