Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].[CH3:19][O:20][C:21]1[C:22]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=[C:23]([CH2:29][CH2:30][NH2:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].O>ClCCl>[CH3:19][O:20][C:21]1[C:22]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=[C:23]([CH2:29][CH2:30][NH:31][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:1])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cccc(CCc2c(CCN)ccc(OC)c2OC)c1
Reactant: O=C(O)CCCCC(=O)NCCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CCc2c(CCNC(=O)CCCCC(=O)NCCc3ccccc3)ccc(OC)c2OC)c1
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A solution of 6-oxo-6-(2-phenylethylamino)hexanoic acid (1.2 g) and N,N'-carbonyldiimidazole (0.77 g) in dry dichloromethane (50 ml) was stirred at 20° for 2 hours and a solution of 3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneethanamine (1.5 g) in dry dichloromethane (10 ml) was added. The mixture was stirred at 20° for 16 hours. Water (50 ml) was added and the organic phase was separated and washed with 2N hydrochloric acid, aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo. The resulting solid was crystallised from isopropanol to yield 2.1 g of the sub-title compound as colourless prisms, mp 150°-151°.
Reaction SMILES: [CH2:1]([CH:5]([C:11](=[O:29])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[OH:27])[CH:13]=1)C(OCC)=O)[CH2:2][CH2:3][CH3:4].O[Li].O>C1COCC1.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11](=[O:29])[CH2:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:13]=2)=[O:28])=[C:21]([OH:27])[CH:22]=1
Reactant: CCCCC(C(=O)OCC)C(=O)c1cccc(NC(=O)c2ccc(Cl)cc2O)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(=O)c1cccc(NC(=O)c2ccc(Cl)cc2O)c1
Yield: 60.1 %

Procedure:
A solution of ethyl α-butyl-3-[(4-chloro-2-hydroxybenzoyl)amino]-β-oxobenzenepropanoate (32.0 mg, 77.0 μmol) and LiOH.H2O (11.0 mg, 0.26 mmol) in THF (3.0 mL) and water (1.5 mL) was heated to 55° for 48 h. The mixture was partitioned between water and EtOAc. The aqueous layer was acidified with aqueous 10% citric acid then extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by reversed phase HPLC (Whatman Partisil® ODS-3 C18 10μ, 22×500 mm; 0 to 80% MeCN+0.06% TFA/water+0.06% TFA) to give the title compound (16.0 mg, 60% yield) as a white solid: mp 134-136°; identical to the product of example 2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH2:10][C:11]2[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:16]=2)=[C:4]([OH:25])[CH:3]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([CH2:10][C:11]3[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[N:16]=3)[O:25][C:4]=2[CH:3]=1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(Br)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3ccc(Br)cc3o2)[nH]1
Yield: 23.2 %

Procedure:
The product is prepared according to the procedure described in Example 2, using 316 mg of N-(4-bromo-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide and 73 mg of 4-methylbenzenesulphonic acid hydrate, and replacing the toluene with xylene. After recrystallization from 30 ml of ethanol, 5 ml of methanol and 5 ml of dichloromethane and then purification of the formed precipitate by silica column chromatography, eluent: CH2Cl2/MeOH: 90/10, 70 mg of 2-[(6-bromo-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([F:10])=[CH:5][C:3]=1[NH:4][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: Nc1cc(F)c(I)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(F)c(I)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
To a solution of 2,5-difluoro-4-iodoaniline (5.3 g, 19.4 mmol, Can. J. Chem., 2000(78), 1081-1088) in DCM (50 ml) was added methanesulfonyl chloride (1.65 ml, 21.3 mmol) and pyridine (4.7 ml, 58.2 mmol) at 0° C. The mixture was stirred for 24 hours at room temperature. The mixture was partitioned between EtOAc and 2 M HCl aqueous solution. The organic layer was separated and washed with 2 M aqueous HCl solution and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with gradually from hexane/EtOAc (4:1) to hexane/EtOAc (3:1) to give the title compound (5.6 g, 87%) as purple solids.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[C:26]([NH:28][NH:29][C:30](=[O:36])[CH2:31][O:32][CH:33]([CH3:35])[CH3:34])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1>C(OCC)C>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[C:26]2[O:36][C:30]([CH2:31][O:32][CH:33]([CH3:35])[CH3:34])=[N:29][N:28]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)([CH3:6])([CH3:8])[CH3:7]
Reactant: CC(C)OCC(=O)NNC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)OCc1nnc(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)o1

Procedure:
Thionyl chloride was added to a solution of 4-tert-butyl-N-{4-chloro-2-[N′-(2-isopropoxy-acetyl)-hydrazinocarbonyl]-phenyl}-benzenesulfonamide (150 mg, 0.312 mmol) and pyridine (66 μL, 0.811 mmol) in diethyl ether (3 mL). The resultant solution was stirred for 18 h at room temperature followed by removal of the volatiles in vacuo. 2 mL toluene was subsequently added and the reaction was heated at reflux for 5 h. The resultant solution was concentrated at reduced pressure and the residue purified via flash column chromatography (0-50% ethyl acetate in hexane) to afford 4-tert-butyl-N-[4-chloro-2-(5-isopropoxymethyl-[1,3,4]oxadiazol-2-yl)-phenyl]-benzenesulfonamide as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[CH2:16])[N:8]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][S:2]([O:14][CH2:13][C:11]1[CH:10]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[CH2:16])[N:8]=[C:7]([Cl:6])[N:12]=1)(=[O:4])=[O:3]
Reactant: C=C(OCC)c1cc(CO)nc(Cl)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(OCC)c1cc(COS(C)(=O)=O)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.3 %

Procedure:
Methanesulfonyl chloride (0.369 mL, 4.73 mmol) was added to an ice-cold solution of (2-chloro-6-(1-ethoxyvinyl)pyrimidin-4-yl)methanol (846 mg, 3.94 mmol) in DCM (8 mL) containing N,N-diisopropylethylamine (1.0 mL, 5.91 mmol). The mixture was stirred at 0° C. for 10 min. DCM (30 mL) was added and the mixture was washed with water (5 mL). The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated to give the title compound (2-chloro-6-(1-ethoxyvinyl)pyrimidin-4-yl)methyl methanesulfonate (1249 mg, quant.).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([N:40]2[CH2:44][CH2:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[C:41]2=[O:52])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:32]=[CH:31][C:17]([CH2:18][N:19]([CH2:27][CH2:28][O:29][CH3:30])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([N:40]2[CH2:44][CH2:43][N:42]([C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[C:41]2=[O:52])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][NH:19][CH2:27][CH2:28][O:29][CH3:30])=[CH:31][CH:32]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccc(F)cc6)C5=O)cc4F)c3s2)cc1)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccc(F)cc6)C5=O)cc4F)c3s2)cc1
Yield: 135.6 %

Procedure:
A solution of 223 (60 mg, 0.082 mmol) and TFA (1 mL) in toluene (2 mL) was stirred 30 min at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether, the solid was collected and dried to give the title compound 220 (70 mg, 99.5%) as an off-white solid. 1HNMR (DMSO-d6) δ (ppm): 10.55 (s, 1H), 8.95 (s, broad, 2H), 8.52 (d, J=5.5 Hz, 1H), 8.13 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.84 (dd, J=2.5 and 13.1 Hz, 1H), 7.65-7.61 (m, 4H), 7.49 (t, J=8.8 Hz, 1H), 7.44 (dd, J=2.4 and 8.8 Hz, 1H), 7.30-7.25 (m, 2H), 6.65 (d, J=5.5 Hz, 1H), 4.21 (t, 1H), 3.93 (m, 4H), 3.57 (t, 2H), 3.30 (s, 3H), 3.11 (m, 2H). MS (m/z): 630.3 (M+H).
Reaction SMILES: [ClH:1].[S:2]1[C:6]23[CH:14]=[CH:13][CH:12]=[CH:11][C:7]2=[N:8][CH2:9][CH2:10][CH:5]3[CH:4]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH2:3]1.[CH2:23](N(CC)CC)C.CBr>C(Cl)(Cl)Cl>[ClH:1].[CH3:23][CH:3]1[S:2][C:6]23[CH:14]=[CH:13][CH:12]=[CH:11][C:7]2=[N:8][CH2:9][CH2:10][CH:5]3[CH:4]1[C:15]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)=[O:16]
Reactant: O=C(C1CSC23C=CC=CC2=NCCC13)N1CCOCC1
Reactant: CCN(CC)CC
Agent: CBr
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1SC23C=CC=CC2=NCCC3C1C(=O)N1CCOCC1
Yield: 82 %

Procedure:
In 5 ml of chloroform were dissolved 0.34 g of 4-(1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carbonyl)morpholine hydrochloride, 0.31 ml of triethylamine, and 0.11 g of methyl bromide, and the solution was refluxed for 30 minutes. Chloroform was distilled off under reduced pressure, 20 ml of an aqueous 5% sodium hydrogencarbonate solution and 50 ml of ethyl acetate were added to the residue, and the ethyl acetate layer was washed with a saturated sodium chloride solution and dried by sodium sulfate. Then, ethyl acetate was distilled under reduced pressure and the residue was purified by silica gel thin layer chromatography. Then, 1 ml of a mixture of 1N hydrochloric acid in ethyl acetate was added to the residue and crystals deposited were collected by filtration to provide 0.29 g (yield of 82%) of 4-(2 -methyl-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carbonyl)morpholine.hydrochloride.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:16][C:17]1[C:22]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][CH:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:8][CH:2]([CH3:1])/[CH:3]=[CH:4]/[C:5]([N:26]1[CH2:27][CH2:28][CH:23]([C:22]2[C:17]([CH3:16])=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:24][CH2:25]1)=[O:7]
Reactant: Cc1ncccc1C1CCNCC1
Reactant: CC(C)/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ncccc1C1CCN(C(=O)/C=C/C(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
(E)-4-Methylpent-2-enoic acid (26 mg, 0.23 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (20 μl, 0.23 mmol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 2-methyl-3-(4-piperidyl)pyridine hydrochloride (27 mg, 0.125 mmol) in DCM (2 ml). DIPEA (120 μl, 0.7 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 9.6 mg of a white solid (0.035 mmol, 15%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Br[CH2:20][CH2:21][O:22][CH3:23]>O1CCCC1>[CH3:23][O:22][CH2:21][CH2:20][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)C1CCCCC1
Reactant: COCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCC1(C(=O)OC)CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of lithium diisopropylamide (2.0 M, 20 mL) in tetrahydrofuran (20 mL) was added methyl cyclohexanecarboxylate (5.0 g) in tetrahydrofuran (30 mL). The mixture was stirred at −78° C. for 30 minutes and a solution of 1-bromo-2-methoxyethane (5.86 g) in tetrahydrofuran (10 mL) was added. The mixture was stirred overnight and the temperature was allowed to warm up to room temperature. The mixture was quenched with aqueous NH4Cl and extracted with ethyl acetate (200 mL) and washed with water (3×), brine and dried over Na2SO4. Filtration and evaporation of solvent gave crude product which was used in the next reaction without further purification.
Reaction SMILES: [H-].[Na+].C[CH:4]([CH2:8][CH3:9])[CH2:5][CH:6]=[O:7]>CCCCCC.C(COC)OC.COCC>[CH3:4][CH:9]([CH2:5][CH3:6])[CH2:8][CH:4]=[CH:5][C:6]([O:7][CH2:9][CH3:8])=[O:7]
Reactant: CCC(C)CC=O
Agent: CCOC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CCOC(=O)C=CCC(C)CC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 122 %

Procedure:
Sodium hydride (60% dispersion, 2.4 g, 65 mmol) was washed with hexane and suspended in dimethoxyethane 60 mL. While cooling in ice water bath triethyl phosphonoacetate was slowly added, calcd. 5 minutes. The reaction was stirred for 15 minutes at 0° C. and a solution of 3-methyl-1-pentanal 11 (6.5 g, 65 mmol) in methoxyethane 20 mL was added. After refluxing overnight, it was concentrated, water and hexane were added, the organic phase was separated, and the aqueous portion discarded. The solution was washed twice with brine and dried on magnesium sulfate. The solvent was evaporated to give 12 (6.75 g, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)C(OCC)=O.[CH3:13][Mg]Br.C([O:18][CH2:19][CH3:20])C>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:19]([OH:18])([CH3:20])[CH3:13])[CH:12]=1
Reactant: CCOCC
Reactant: C[Mg]Br
Reactant: CCOC(=O)c1cncc(Br)c1
Product: CC(C)(O)c1cncc(Br)c1

Procedure:
To a solution of ethyl 5-bromonicotinate (1.02 g, 4.4 mmol) in diethyl ether (15 ml) at −30° C. was added a 3M solution of methyl magnesium bromide (4 ml, 12 mmol) in ether. The resulting slurry was then refluxed for 2 hours then cooled and quenched with an excess of 0.5M aqueous monobasic sodium phosphate and partitioned between ether and water. The product from the organic phase was chromatographed on silica gel eluting with a 2:1:2 mixture of ether, pentane and ammonia-saturated methylene chloride to afford the 3-Bromo-5-(1-hydroxy-1-methylethyl)pyridine compound as a yellow oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][NH:28][CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:37](Br)[C:38]#[CH:39]>>[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][N:28]([CH2:39][C:38]#[CH:37])[CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: C#CCBr
Agent: Cl
Product: C#CCN1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)OC(C)(C)C)C1
Yield: 55.1 %

Procedure:
According to the procedure of Example 17, Step 3, 228.2 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate hydrochloride was reacted with 51 mg of propargyl bromide to provide 126 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-prop-2-yn-1-ylpyrrolidine -3-carboxylate in 55% yield. MS: 536.3(M+H)+
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[O:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH3:3])[CH3:2].[N+:23]([O-])([OH:25])=[O:24]>CC(O)=O>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N+:23]([O-:25])=[O:24])=[CH:6][C:5]=1[O:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)(=[O:15])=[O:14])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(OS(=O)(=O)c2ccc(C)cc2)cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
To a solution of toluene-4-sulfonic acid 2-isopropyl-4-methoxy-phenyl ester (19.00 g, 59 mmol) in 118 mL AcOH was added 236 ml fuming HNO3 over 20 min. After 16 h the solution was pouring into a rapidly stirring slurry of 2 l of ice/H2O. After 15 min the precipitate was filtered, washed with H2O and dried under vacuum (50° C.) to give toluene-4-sulfonic acid 2-isopropyl-4-methoxy-5-nitro-phenyl ester (21.27 g, 98%) and toluene-4-sulfonic acid 2-isopropyl-4-methoxy-3-nitro-phenyl ester and as a pale yellow solid (7:1 inseperable mixture).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(NC(C)C)(C)C.[C:38]1([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH:44]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Yield: 42.6 %

Procedure:
The target compound was prepared as a pale yellow oil in an amount 3.8 g at a yield of 42.6% in the same manner as in Example 1 except that 5.7 g (22 mmol) of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 23 ml of THF and 5.35 g (33 mmol) of CDI was dividedly added several times; 5.8 ml (44 mmol) of diisopropylamine and 10 ml of THF were added and 27.5 ml (44 mmol) of 1.63N BA solution was added dropwise; 6.6 ml (44 mmol) of ethyl phenylacetate instead of methyl phenylacetate was dissolved in 10 ml of THF; and 30 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 50 g of 4N hydrochloric acid was added, and 100 ml of ethyl acetate was further added. The analytical results on the target compound are given below.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([OH:9])=[C:7](CO)[CH:6]=[C:5]([CH3:12])[CH:4]=1.O=S(Cl)[Cl:15].[CH2:17]([Cl:19])Cl>>[Cl:15][CH2:2][C:3]1[C:8]([OH:9])=[C:7]([CH2:17][Cl:19])[CH:6]=[C:5]([CH3:12])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: ClCCl
Reactant: Cc1cc(CO)c(O)c(CO)c1
Product: Cc1cc(CCl)c(O)c(CCl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,6-Bis(hydroxymethyl)-p-cresol (0.6779 g, 4.03 mmol) was suspended in CH2Cl2 (10 ml), and to this suspension was added slowly SOCl2 (3 ml, 41.1 mmol) under cooling in an ice-bath, and the resulting mixture was stirred at room temperature for 18 hours. The color of the reaction solution turned yellow. After completion of the reaction, the solvent was removed by evaporation to give 2,6-bis(chloromethyl)-p-cresol.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[S:32]1[CH:36]=[C:35]([CH2:37][CH2:38][NH2:39])[N:34]=[CH:33]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][CH2:38][CH2:37][C:35]1[N:34]=[CH:33][S:32][CH:36]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCc1cscn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCc1cscn1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 41.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), 2-(thiazol-4-yl)ethanamine (8.92 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 40-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(2-(thiazol-4-yl)ethyl)acetamide (10.1 mg, 0.019 mmol, 40.2% yield): LCMS=542.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.82 (1 H, d, J=2.01 Hz), 8.13 (2 H, d, J=8.28 Hz), 7.49-7.72 (8 H, m), 7.08 (1 H, d, J=2.01 Hz), 5.08 (1 H, s), 3.53-3.69 (2 H, m), 3.03 (2 H, t, J=6.78 Hz); HPLC peak RT=2.6 min (Method E).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([CH:11]2[CH2:13][CH2:12]2)[CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([N:6]([S:22]([CH3:21])(=[O:24])=[O:23])[S:22]([CH3:21])(=[O:24])=[O:23])=[C:4]([CH:11]2[CH2:12][CH2:13]2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N)c(C2CC2)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(N(S(C)(=O)=O)S(C)(=O)=O)c(C2CC2)cc1Cl
Temperature: 5 °C
Yield: 80 %

Procedure:
A mixture of Example 18B (1.0 equivalent) and triethylamine (2.3 equivalents) in tetrahydrofuran (0.5 M final concentration based on product from Example 18B) was cooled to 5° C. and treated dropwise with methane sulfonyl chloride (2.3 equivalents) maintaining the temperature below 20° C. After the addition was completed, the reaction mixture was warmed up to ambient temperature for 20 minutes and partitioned with water and methylene chloride. The organic layer was washed with 5% aqueous NaCl solution, dried (Na2SO4), filtered and concentrated. The resulting solid was triturated with isopropyl acetate/heptane (2:1), and the solid was collected by filtration and dried to constant mass (80% yield).
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][Br:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][N:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13]>C(#N)C>[Br-:10].[CH3:11][N+:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])[CH2:9][CH2:8][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCOc1ccccc1
Reactant: CN(C)Cc1ccccc1
Solvent: CC#N
Product: C[N+](C)(CCOc1ccccc1)Cc1ccccc1
Product: [Br-]

Procedure:
A solution of 40.21 grams (0.20 mol) of 2-bromoethyl phenyl ether, 27.04 grams (0.20 mol) of N,N-dimethylbenzylamine and 135 milliters of acetonitrile was heated at reflux for 16.75 hrs. The reaction mixture was concentrated and then cooled. On standing, the residue crystallized. The solid was stirred in ether, collected and dried. The yield of product was 66.0 grams (98.13% of theory); mp=100°-110° C.