Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@@H]1CO
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])C[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
Reflux a mixture of (2R,4R)-4-amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (198 g, 0.92 mol), 5-bromo-fluoronitrobenzene (224 g, 0.98 mol), triethylamine (273 mL, 1.96 mol) in ethyl acetate (2 L) for 16 h under nitrogen with vigorous stirring. Cool to room temperature and wash with brine. Back-extract the brine layer with ethyl acetate (1 L), combine the organic layers, dry over sodium sulfate, filter and concentrate. Dissolve the resulting solid in warm ethyl acetate (2 L), concentrate to approximately 500 mL and allow crystals to start forming Treat the solution slowly with hexanes (2 L) and allow the mixture to stand at room temperature for 2 h. Collect the yellow solid by filtration, wash with hexanes and dry at 40° C./20 mm Hg to obtain 227 g of desired product. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (2:3:5 ethyl acetate/dichloromethane/heptane gradually increasing to 2:3 ethyl acetate/heptane) to obtain an additional 54 g of desired product. Overall yield: 281 g (70%). [α]D20−81 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.40 (s, 9H), 1.90 (m, 1H), 2.48 (br s, 1H), 3.14 (m, 1H), 3.45 (m, 1H), 3.63 (m, 1H), 3.81 (m, 2H), 4.29 (m, 1H), 5.12 (m, 1H), 7.08 (d, 1H), 7.65 (dd, 1H), 8.15 (d, 1H), 8.57 (br d, 1H, NH).
Reaction SMILES: CC(C)(C[N:6]1[C:10]2[N:11]=[C:12]([NH:15]C3C=CC(N4CCNCC4)=CN=3)[N:13]=[CH:14][C:9]=2[C:8]2[CH:28]=[CH:29]N=[CH:31][C:7]1=2)CO.[CH3:33][O:34][C:35]1[C:40](B(O)O)=[CH:39][CH:38]=[C:37]([O:44][CH3:45])[N:36]=1.C1(P(C2CCCCC2)C2C(OC)=CC=CC=2OC)CCCCC1>C(O)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:7]1([NH:6][C:10]2[C:9]([C:40]3[C:35]([O:34][CH3:33])=[N:36][C:37]([O:44][CH3:45])=[CH:38][CH:39]=3)=[CH:14][N:13]=[C:12]([NH2:15])[N:11]=2)[CH2:8][CH2:28][CH2:29][CH2:31]1
Reactant: COc1ccc(B(O)O)c(OC)n1
Reactant: CC(C)(CO)Cn1c2cnccc2c2cnc(Nc3ccc(N4CCNCC4)cn3)nc21
Agent: [Pd]
Agent: COc1cccc(OC)c1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Product: COc1ccc(-c2cnc(N)nc2NC2CCCC2)c(OC)n1
Temperature: 100 °C
Yield: 52.6 %

Procedure:
Compound 2 (2.00 g, 7.78 mmol), 2,6-dimethoxypyridin-3-ylboronic acid (2.13 g, 11.7 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.214 g, 0.233 mmol), and dicyclohexyl(2,6-dimethoxyphenyl)phosphine (0.156 g, 0.467 mmol), were dissolved in n-butanol (2.5 mL). The reaction was purged with argon and heated at 100° C. for 19 hours. The resulting solution was added to 80 mL water and extracted with ethyl acetate (2×150 mL). The combined organics were dried (MgSO4) and evaporated to give an orange oil. Silica gel chromatography (gradient elution dichloromethane+2.5% TEA/0-5% methanol) afforded compound 267 as an off-white solid (1.29 g, 53%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17]Cl>>[CH2:1]([NH:8][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCOCCOCCCl
Reactant: NCc1ccccc1
Product: c1ccc(CNCCOCCOCCNCc2ccccc2)cc1

Procedure:
J. Gatto, et al. in "4,13-Diaza-18-Crown-6 (1,4,10,13-Tetraoxa-7,16-diazacyclooctadecane)," Organic Synthesis, Vol. 68, 1989, pp. 227-233, teach the preparation of the title compound by a three-step procedure that might be considered the standard preparation for these materials. First, benzylamine is reacted with 1,2-bis(2-chloroethoxy)ethane to produce 1,10-dibenzyl-4,7-dioxa-1,10-diazadecane. The product of the first step is then reacted in the presence of 1,2-bis(2-iodoethoxy)ethane, anhydrous sodium carbonate and sodium iodide in acetonitrile to give N,N'-dibenzyl-4,13-diaza-18-crown-6 in the second step. The phenyl groups of the second step product are then removed in a third, hydrogenation step over a palladium catalyst on a carbon support.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].ClS(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11])[C:14](=[O:16])[CH2:13][CH2:12]2
Reactant: O=C(O)CCc1ccc(C(F)(F)F)c(Cl)c1
Agent: O=S(=O)(O)Cl
Product: O=C1CCc2cc(Cl)c(C(F)(F)F)cc21
Yield: 70 %

Procedure:
3-(3-Chloro-4-(trifluoromethyl)phenyl)propanoic acid (I-85c: 1.0 g, 3.96 mmol) was reacted with chlorosulfonic acid (12.6 mL) for 5 hours at 0° C. Purification by column chromatography on silica gel (10% ethyl acetate in hexane) afforded 650 mg of the product 69.8% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:16])([CH3:15])[C:9]([NH:11][CH2:12][CH2:13][OH:14])=O>C(OCC)C>[F:7][C:8]([F:16])([CH3:15])[CH2:9][NH:11][CH2:12][CH2:13][OH:14]
Reactant: CC(F)(F)C(=O)NCCO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(F)(F)CNCCO
Reaction time: 1.5 h

Procedure:
To a stirred solution of lithium aluminum hydride (5.5 g, 146 mmol) in diethyl ether (85 ml) was added a solution of 2,2-difluoro-N-(2-hydroxy-ethyl)-propionamide (11.2 g, 73 mmol) in diethyl ether (55 ml) dropwise at such a rate to maintain a gentle reflux. After an additional 1.5 hours, the reaction was quenched with sodium sulfate decahydrate, diluted with ethyl acetate and allowed to stir for 18 hours. The mixture was filtered with the aid of diatomaceous earth, washing with ethyl acetate. The filtrate was concentrated in vacuo and fractionally distilled (11 torr, collecting fractions distilling at 75–88° C.) to afford the title compound (I-3c) as a colorless oil, 4.5 g.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)(O)/[C:9](=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])/[CH:8]([CH3:25])[CH2:7][C:5]=2[N:6]=1>C1COCC1>[Br:1][C:2]1[S:3][C:4]2[C:10]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)=[C:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:25])=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)/C=C1\C(C)Cc2nc(Br)sc2C1(O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
Polyphosphoric acid (PPA) (140 g) and THF (210 mL) were heated to 75° C. in a 1 L recovery flask. (E)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-7-hydroxy-5-methyl-4,5-dihydrobenzo[d]thiazol-6(7H)-ylidene)acetate (31.0 g, 70.0 mmol) was added via addition funnel in THF (70 mL) over 2 min. The funnel was rinsed with THF (20 mL). The reaction mixture was heated at 80° C. for 2.5 h. After cooling to rt, the mixture was poured onto a 1 M K2HPO4 (1.5 L) solution followed by EtOAc (700 mL). The layers were separated, and the organic layer was washed with brine (500 mL). The organic layer was dried, filtered, and concentrated in vacuo to give desired product that was used without further purification. 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.45 (d, 2H, J=8 Hz), 7.29 (d, 2H, J=8 Hz), 4.13 (q, 2H, J=7 Hz), 3.57 (s, 2H), 2.45 (s, 3H), 1.23 (t, 3H, J=7 Hz).
Reaction SMILES: Cl.[CH3:2][NH:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][Cl:6].[C:10](Cl)(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[CH3:2][N:3]([C:10](=[O:12])[CH3:11])[C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][Cl:6]
Reactant: CC(=O)Cl
Reactant: CN[C@@H](CCl)C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)N(C)[C@@H](CCl)C(=O)O
Yield: 91 %

Procedure:
181 g of methyl 3-chloroalanine hydrochloride were heated under reflux with 163.9 g of acetyl chloride in 1.5 l of anhydrous toluene for about 5 hours until a clear solution was obtained. This was evaporated to dryness and the residue was crystallized from ethyl acetate/petroleum ether. 170 g of product of m.p. 104° C. were obtained.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14](=[O:24])[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:16])=[CH:6]1)([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>C(#N)C>[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14](=[O:24])[C:15]([NH:17][CH:18]2[CH2:19][CH2:20][N:21]([CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:22][CH2:23]2)=[O:16])=[CH:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)n1cc(C(=O)C(=O)NC2CCNCC2)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)n1cc(C(=O)C(=O)NC2CCN(CCNC(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 65 °C
Reaction time: 72 h

Procedure:
The title compound was prepared according to general procedure C described in Scheme 2. 2-(1-Isopropyl-1H-indol-3-yl)-2-oxo-N-(piperidin-4-yl)acetamide hydrochloride (200 mg, 0.64 mmol) was treated with acetonitrile (3 mL), K2CO3 (265 mg, 1.91 mmol), and tert-butyl 2-bromoethylcarbamate (266 mg, 1.28 mmol). The reaction mixture was stirred at 65° C. for 72 h and was then concentrated under reduced pressure. The crude material was purified by silica chromatography (Biotage, 0-5% MeOH/DCM, 30 min.) to provide the title compound as a brown oil. The material was further purified using reverse phase HPLC to provide the desired product as a pink solid TFA salt (132 mg, 45%).
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>CO>[CH3:1][NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: CN(CCC1CCN(c2ccncc2)CC1)Cc1ccccc1
Solvent: CO
Product: CNCCC1CCN(c2ccncc2)CC1
Reaction time: 2 h
Yield: 30 %

Procedure:
N-Benzyl-N-methyl-2-(1-(pyridin-4-yl)piperidin-4-yl)ethanamine (1.4 g, 3.63 mmol, 1 eq) was dissolved in MeOH (20 ml) and degassed for 30 min with nitrogen. 20% Pd—(OH)2 (200 mg) was added and hydrogenation was carried out for 2 h at RT under balloon pressure (H2). After monitoring by thin-layer chromatography, the reaction mixture was filtered off over Celite and washed with MeOH (3×25 ml), and the filtrate was concentrated under reduced pressure. Yield: 30% (240 mg, 1.09 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH2:4][C:5](=[O:40])[CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:25]C2CCCCO2)[C:18]([CH3:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:32]C2CCCCO2)[CH2:12][C:11]1=[O:39].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:41])[CH2:4][C:5](=[O:40])[CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:25])[C:18]([CH3:23])([CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([OH:32])[CH2:12][C:11]1=[O:39]
Reactant: CCCCC(C)(C)[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCC(=O)CC(=O)OC)OC1CCCCO1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCC(=O)CC(=O)OC
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 42.3 %

Procedure:
A mixture of 42 mg of the tetrahydropyran-2-yloxy compound (prepared as described in Example 2), 0.4 ml of 65% v/v aqueous acetic acid, and 4 drops of tetrahydrofuran was stirred for 5 minutes at 80° C. The reaction solution was diluted with ethyl acetate, washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to obtain 12.6 mg of the title compound having the following physical characteristics:
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[O:24][CH2:23][CH2:22][O:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH:25]3[CH2:30][CH2:29][N:28]([CH:2]([CH3:12])[C:3]([C:5]4[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=4)=[O:4])[CH2:27][CH2:26]3)[O:24][CH2:23][CH2:22][O:21]2)=[CH:16][CH:15]=1
Reactant: Fc1ccc(C2(C3CCNCC3)OCCO2)cc1
Reactant: CC(Br)C(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C(=O)c1ccc(F)cc1)N1CCC(C2(c3ccc(F)cc3)OCCO2)CC1

Procedure:
The reaction is performed under the conditions of Example 4a, starting with 9.24 g (0.04 mole) of 2-bromo-1-(4-fluorophenyl)-1-propanone, 10.05 g (0.04 mole) of 2-(4-fluorophenyl)-2-(4-piperidyl)1,3-dioxolane and 5.56 g of potassium carbonate in 150 ml of acetonitrile.
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O>>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:39]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][C:28]([O:30][CH3:31])=[C:27]([O:32][CH3:33])[CH:26]=3)[N:20]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: COc1cccc(C=O)c1
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3cc(OC)c(OC)cc3c(=O)[nH]2)c1
Yield: 31.4 %

Procedure:
According to the preparation of 42, 11 (1.0 g, 5.1 mmol) and 3-methoxybenzaldehyde (34) (0.7 g, 5.1 mmol) were used to afford 53 (0.5 g, 30.8%) as pale yellow prism crystals.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:4][C:3]=2[O:2]1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:48]2[CH:55]=[CH:54][C:51]([CH2:52][Cl:53])=[CH:50][CH:49]=2)[CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:68].Cl>>[ClH:53].[ClH:68].[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=5)[CH:19]=4)[CH2:13][CH2:12]3)[CH2:52][C:51]3[CH:54]=[CH:55][C:48]([C:40]4[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:38]([O:37][CH3:36])[CH:39]=4)=[CH:49][CH:50]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2ccc(CCl)cc2)cc(OC)c1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(-c2ccc(CN(c3ccc4c(c3)OCO4)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)cc2)cc(OC)c1OC

Procedure:
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([O:34]C)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Li+].Cl.[Na+].[Cl-]>ClCCl.CO.O.O1CCOCC1>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([OH:34])=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of methyl 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoate (2.47 g, 4.54 mmol), 2N lithium hydroxide (9.1 ml), p-dioxane (45 ml) and water (27 ml) was stirred at room temperature for 2 h. Water (200 ml) was added and acidified with conc HCl to pH 3 at 0° C. Aqueous NaCl (50 ml) was added and further stirred at 0° C. for 1H. The precipitate was filtered, washed with water, and dried, to give a beige solid, 1.88 g, 78% yield; mp 230° C. (from dichloromethane-MeOH). NMR spectrum was consistent with structure. Calcd. For C29H26N2O6S.H2O:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20](S(C)(=O)=O)[N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:1][C:2]2[CH:11]=[CH:10][C:5]3[C:6]([CH3:9])=[N:7][O:8][C:4]=3[C:3]=2[C:12]([O:14][CH3:15])=[O:13])[N:19]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)c1c(O)ccc2c(C)noc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2c(C)noc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
A mixture comprising 1.3 g of methyl 6-hydroxy-3-methyl-benzisoxazol-7-carboxylate, 1.4 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1 g of potassium carbonate in 20 ml of N,N-dimethylformamide, was heated and stirred at 70° C. for two hours. The mixture was returned to room temperature, poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure, and the obtained crystals were thoroughly washed with isopropyl ether to obtain 1.6 g (yield: 73%) of the desired compound.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15]=1Cl)=[O:5])C.Cl.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][NH2:26]>C1(C)C(C)=CC=CC=1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[C:4](=[O:5])[C:6]2=[N:7][NH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:15]2=[N:26]1
Reactant: NNc1ccccc1F
Reactant: CCOC(=O)c1nnc2c(c1Cl)CCCC2
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=c1c2n[nH]c3c(c-2nn1-c1ccccc1F)CCCC3
Yield: 42.3 %

Procedure:
4-Chloro-5,6,7,8-tetrahydrocinnoline-3-carboxylic acid ethyl ester (0.5 g), 2-fluorophenylhydrazine hydrochloride (0.34 g) and H{umlaut over (u)}nig's base (0.73 ml) in xylene were heated under reflux for 3 h. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography using a gradient elution: CH2Cl2 (500 ml), CH2Cl2/(MeOH/NH3 10:1) 99:1 (500 ml), CH2Cl2/(MeOH/NH3 10:1) 98:2 (500 ml), CH2Cl2/(MeOH/NH3 10:1) 97:3 (500 ml), CH2Cl2/(MeOH/NH3 10:1) 96:4 (500 ml), CH2Cl2(MeOH/NH3 10:1) 95:5 (500 ml). The appropriate fractions were combined and evaporated under reduced pressure to give a solid (250 mg, 42%). δH (360 MHz; DMSO) 1.83 (4H, m, CH2), 2.61 (2H, t, J=5.3 Hz, CH2), 2.75 (2H, t, J=5.3 Hz, CH2), 7.30-7.57 (4H, m, ArH), m/z (ESP+) 285 (MH+). C15H13FN4O requires C, 63.37; H, 4.61; N, 19.71; found C, 63.18; H, 4.70; N, 19.35%.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[CH2:18](O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][C:4]([CH3:7])([CH2:5][CH3:6])[C:3](=[O:9])[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])=[O:1]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: OCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)OCCc1ccccc1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A mixture of (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carboxylic acid (570 mg; 2.36 mmol), phenethyl alcohol (432 mg; 3.54 mmol), dicyclohexylcarbodiimide (780 mg; 3.78 mmol), 4-dimethylaminopyridine (98 mg; 0.79 mmol) and camphorsulphonic acid (183 mg; 0.79 mmol) in methylene chloride (30 mL) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo, and the crude material was purified on a flash column (25% ethyl acetate in hexane) to obtain 600 mg of the product as a colorless oil. 1H NMR (CDCl3; 300 MHz) δ0.87 (t, 3H); 1.21 (s, 3H); 1.25 (s, 3H); 1.64–1.94 (m, 6H); 2.17 (m, 1H); 2.97 (m, 2H); 3.49 (m, 2H); 4.36 (m, 2H); 4.51 (m, 1H); 7.22–7.33 (m, 5H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[OH:38][C@@H:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[NH2:44].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:38][C@@H:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[NH:44][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[CH:5][N:4]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: Cn1c(=O)cc[nH]c1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1c(N[C@@H]2CCC[C@H]2O)nccc1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 76.5 %

Procedure:
3-Methyluracil (12.6 mg, 0.1 mmol) was dissolved in 0.5 mL of DMF, and then BOP (71 mg, 0.16 mmol) was added. The mixture was stirred at room temperature for two minutes, then (1R,2R)-(−)-2-hydroxycyclopentylamine hydrochloride salt (22 mg, 0.16 mmol) was added, followed by DBU (51 uL, 3.4 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was purified by a semi-preparative HPLC to give pure product (16 mg, yield 76%). MS (ESI) m/z 210.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=2)[CH2:4][O:3]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])/[C:23](=[N:25]/O)/[NH2:24]>N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[C:22]([C:23]2[N:25]=[C:13]([C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:7][CH:5]4[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[O:6]4)=[CH:10][CH:11]=3)[O:14][N:24]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC1(C)OCC(COc2ccc(C(=O)Cl)cc2)O1
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(OCC4COC(C)(C)O4)cc3)n2)cc1Cl
Temperature: 200 °C
Yield: 56.7 %

Procedure:
In a 25 mL microwave tube 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoyl chloride (0.483 g, 1.784 mmol) and (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.272 g, 1.189 mmol) in pyridine (15 mL) were combined to give an orange solution. The vessel was capped and the reaction heated at 200° C. for 20 min under microwave irradiation (Biotage Optimizer, 300 W). The mixture was cooled, the solvent was removed to afford a yellow solid, which was partitioned between water (100 mL) and EtOAc (50 mL), extracted by EtOAc (2×30 mL), the combined EtOAC layer was washed by water (2×30 mL), and concentrated to afford a yellow solid, which was purified via silica gel chromatography (40 g, 30% EtOAc:Heptane) to afford 3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1,2,4-oxadiazole (0.3 g, 0.674 mmol, 56.7% yield) as white solid. LC/MS (30—95 NH4OAc 4m GC8.olp) Rt=3.22 min.; MS m/z: 445.31 (M+H)+. 1H NMR (400 MHz, Solvent d-DMSOδ ppm 8.17-8.09 (m, 2H), 8.05 (d, J=2.13 Hz, 1H), 7.99 (dd, J=8.64, 2.15 Hz, 1H), 7.38 (d, J=9.01 Hz, 1H), 7.26-7.19 (m, 2H), 4.88-4.77 (m, 1H), 4.45 (s, 1H), 4.23-4.07 (m, 3H), 3.79 (dd, J=8.42, 6.29 Hz, 1H), 1.35 (m, 12H).