Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:7](=[O:19])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:9][CH:10]=1.C(Cl)Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(NC(C)C)(C)C>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:7](=[O:19])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:16][CH:17]=2)[CH2:9][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CCC1=CCN(Cc2ccc(N)cc2)C1=O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COC(=O)CCC1=CCN(Cc2ccc(NC(=O)c3ccccc3)cc2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
10 mg of 3-[1-(4-amino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (h) prepared by above Step 1 was dissolved in methylene chloride solution (0.04 mmol) at room temperature. And then 8.5 μl of benzoyl chloride (0.07 mmol) and 19.1 μl of diisopropylamine (0.11 mmol) were added thereto and the mixture was stirred for 2 hrs at 0° C. The reaction was quenched with methanol and the mixture was extracted three times with 10 ml of ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with ethyl acetate and hexane (1:2) as an eluant to give 12 mg of 3-[1-(4-benzoylamino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (i) (yield: 87%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:54]([O:58][C:59]([NH:61][C@H:62]([C:64]([NH:66][C@H:67]([C:69](O)=[O:70])[CH3:68])=[O:65])[CH3:63])=[O:60])([CH3:57])([CH3:56])[CH3:55]>ClCCl>[C:54]([O:58][C:59]([NH:61][C@H:62]([C:64]([NH:66][C@H:67]([C:69]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:70])[CH3:68])=[O:65])[CH3:63])=[O:60])([CH3:57])([CH3:56])[CH3:55]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 55 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-oleamide and N-tert-butyloxycarbonyl-L-alanyl-L-alanine. Yield 55%. [α]D =+10.3° (c=0.85, dichloromethane).
Reaction SMILES: CO.C([O:5][C:6]([C:8]1[S:12][CH:11]=[N:10][C:9]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH:19]([C:36]2[C:37]([F:48])=[C:38]3[C:43](=[C:44]([O:46][CH3:47])[CH:45]=2)[O:42][CH2:41][CH2:40][CH2:39]3)[NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[O:29][N:28]=3)=[CH:23][CH:22]=2)=[N:14]1)=[O:7])C.[OH-].[Na+].C(O)(=[O:53])C>[Fe].O>[F:33][C:32]([F:35])([F:34])[C:30]([OH:53])=[O:29].[C:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][CH:19]([C:36]2[C:37]([F:48])=[C:38]3[C:43](=[C:44]([O:46][CH3:47])[CH:45]=2)[O:42][CH2:41][CH2:40][CH2:39]3)[C:15]2[NH:16][C:17](=[O:18])[N:13]([C:9]3[N:10]=[CH:11][S:12][C:8]=3[C:6]([OH:7])=[O:5])[N:14]=2)=[CH:22][CH:23]=1)(=[NH:28])[NH2:31]
Reactant: CCOC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)CCCO3)[nH]c1=O
Reactant: CC(=O)O
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncsc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCC2
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2 ml of a methanol solution containing 74 mg of 4-(3-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiazole-5-carboxylic acid ethyl ester, 0.5 ml of a 5 N sodium hydroxide aqueous solution was added. The resulting mixture was stirred at room temperature for 18 hours, and then 2 ml of acetic acid, 1.5 ml of water, and 74 mg of iron powder were added thereto. The mixture was stirred at 60° C. for 15 hours under a nitrogen atmosphere. The reaction mixture was filtered and purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (34 mg).
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]([F:23])([F:22])[C:8](=[O:21])[C:9](=[N:19][OH:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]>C1(C)C=CC=CC=1>[OH:21][C:8]1([C:7]([F:22])([F:23])[F:6])[C:17]2[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][C:9]1=[N:19][OH:20]
Reactant: Cc1ccccc1CCC(=NO)C(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1cccc2c1CCC(=NO)C2(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
Cold concentrated H2SO4 (12 ml, 98% w/v H2SO4 in water) was added to a stirred suspension of 1,1,1-trifluoro-5-(2-methylphenyl)-2,3-pentanedione 3-oxime (11.9 g, 45.9 mmol) in toluene (16 mL) at 0° C. The reaction mixture and allowed to warm to room temperature (25° C.) and then stirred for 30 min. Ice was added to the reaction mixture. The resulting mixture was extracted with diethyl ether (2x). The ether extract was washed successively with water and a saturated aqueous solution of NaHCO3, dried (MgSO4) and concentrated under reduced pressure to give the title compound (10.4 g, 87% yield). This product was used for the reaction described in the following example. A small sample was triturated with hexane to give-off white crystals; mp 154°-156° C.; nmr (CDCl3) δ 2.3 (s, 3H), 2.9 (m, 4H), 7.2 (m, 2H), 7.6 (m, 1H); ir (CHCl3) 3570, 3480, 1170 cm-1 ; uvλmax (MeOH) 273 nm (ε570), 266 (590).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Cl>CN(C)C=O>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:15]2[CH:14]=[C:13]([C:12]3[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=3)[O:17][N:16]=2)=[CH:20][CH:21]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: COc1cccc(CCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of this solid and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 3-methoxybenzyl chloride (17.0 mg, 0.11 mmol), which was stirred for 12 hours at 60° C. This reaction mixture was cooled to room temperature, and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (34.4 mg, 81%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:21]=[N:22][N:23]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:24]=3[CH:25]=[CH:26][CH:27]=2)=[O:18])=[CH:11][N:10]=1)(=[O:8])=[O:7].[BH4-].[Li+]>C1COCC1>[OH:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[N:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:21]=[N:22][N:23]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[C:24]=3[CH:25]=[CH:26][CH:27]=2)=[O:18])=[CH:13][CH:14]=1)(=[O:8])=[O:7]
Reactant: COC(=O)CCS(=O)(=O)c1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCc1ccc(S(=O)(=O)CCCO)nc1)c1cccc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 3-[5-({[1-(4-fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridine-2-sulfonyl]-propionic acid methyl ester (33 mg, 0.066 mmol) in THF (5 mL) was treated with lithium borohydride (8.7 mg, 0.40 mmol) at room temperature and the mixture was warmed at reflux. After 1 hour, the reaction was cooled to room temperature, quenched with water (50 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in CH2Cl2 to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:41])(C)C>CC(CC)=O>[ClH:41].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: COc1cccc(C(=O)N2CCC3(CC2)N[C@@H](Cc2ccccc2)C(=O)N3Cc2ccccc2)c1
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(3-methoxybenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one (404 mg, 0.9 mmol) was dissolved in ethyl methyl ketone (3.2 mL), and water (9 μL) and TMSCl (120 μL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(3-methoxybenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 358 mg (82%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([F:12])([F:11])[O:8][C:7]([F:14])([F:13])[C:6]=2[CH:15]=1>CO.CC#N.CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][O:8][C:9]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([F:12])([F:11])[O:8][C:7]([F:14])([F:13])[C:6]=2[CH:15]=1)=[O:10]
Reactant: FC1(F)Oc2ccc(Br)cc2C(F)(F)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)C(F)(F)OC(F)(F)O2
Temperature: 75 °C
Reaction time: 8 h
Yield: 169.8 %

Procedure:
A suspension of 6-bromo-2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxine (4.75 g, 16.6 mmol) and Pd(PPh3)4 (950 mg, 8.23 mmol) in MeOH (20 mL), MeCN (30 mL) and Et3N (10 mL) was stirred under carbon monoxide atmosphere (55 psi) at 75° C. (oil bath temperature) overnight. The cooled reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column (Petroleum Ether) to give 2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxine-6-carboxylic acid methyl ester (3.75 g, 85%). 1H NMR (CDCl3, 300 MHz) δ 8.34 (s, 1H), 8.26 (dd, J=2.1, 8.7 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:9][N:10]([CH3:32])[CH:11]1[C:25]2=[CH:26][CH:22]([O:23][C:24]2=[O:27])[CH:21]2[CH:17]([O:18][C:19](=[O:29])[CH:20]2[CH3:28])[CH2:16][C:15]2([CH3:30])[CH:13]([O:14]2)[CH:12]1[OH:31].N1C=CN=C1.O>CN(C=O)C>[O:31]([CH:12]1[CH:11]([N:10]([CH3:9])[CH3:32])[C:25]2=[CH:26][CH:22]([O:23][C:24]2=[O:27])[CH:21]2[CH:17]([O:18][C:19](=[O:29])[CH:20]2[CH3:28])[CH2:16][C:15]2([CH3:30])[CH:13]1[O:14]2)[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1C(=O)OC2CC3(C)OC3C(O)C(N(C)C)C3=CC(OC3=O)C21
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1C(=O)OC2CC3(C)OC3C(O[Si](C)(C)C(C)(C)C)C(N(C)C)C3=CC(OC3=O)C21
Reaction time: 20 h
Yield: 55.4 %

Procedure:
Terbutyldimethylsilyl chloride (80 μmol, 12 mg) is added to a solution of the compound of Example 5 (80 μmol; 27 mg) and imidazole (160 μmol; 11 mg) in DMF (0.5 ml). The solution obtained is stirred for 20 hours then the reaction mass is poured into water. The aqueous phase is extracted twice with ethyl acetate, the organic phase is washed with water then with a solution of sodium chloride. The organic phase is dried over magnesium sulphate, filtered then evaporated. The residue is eluted on silica with a mixture of isopropyl acetate and dichloromethane (20/80). 20 mg of product is obtained in the form of a white powder.
Reaction SMILES: O=C([C@@:6]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O:18][C:19](=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])C([O-])=O.[C:42]([OH:45])(=[O:44])C>[Zn]>[CH2:35]([C@H:34]([CH:6]([O:18][C:19](=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:42]([OH:45])=[O:44])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCCCC(=O)O[C@](CCCCCCCCCCC)(CCc1ccccc1)C(=O)C(=O)[O-]
Agent: [Zn]
Product: CCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCC)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 115 °C
Yield: 86 %

Procedure:
Zinc dust (24.42 g, 373.3 mmol) was added to a solution of 46 (16.28 g, 28.42 mmol) in acetic acid (150 mL). The mixture was then heated to reflux (115° C.) for 3 h. The mixture was then concentrated in vacuo, and the residual pyridine removed by dissolving the residue in toluene (100 mL) and concentrating in vacuo. The resulting residue was by silica gel chromatography, eluting with a gradient of 0% through 30% ethyl acetate/hexanes to provide (R)-benzyl 3-(tetradecanoyloxy)tetradecanoic acid (47, 11.14 g, 86% yield) as a colorless oil. 1H NMR (CDCl3) δ 5.29-5.18 (m, 1H), 2.62-2.55 (m, 2H), 2.34-2.25 (m, 2H), 1.65-1.58 (m, 3H), 1.28-1.20 (m, 40H), 0.85 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH:15]([OH:16])[CH2:14][N:13]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:12]1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:32][C:33]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])[CH3:34].CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH:15]([O:16][Si:36]([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37])[CH2:14][N:13]([C:17](=[O:25])[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2ccc(Cl)cc2)CC1O
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Reaction time: 48 h
Yield: 40 %

Procedure:
To a solution of {2-[1-(4-chloro-benzoyl)-4-hydroxy-pyrrolidin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester (750 mg, 1.95 mmol) in DMF (0.25 mL) at 0° C., was added imidazole (663 mg, 9.15 mmol) and TBDMSCl (309 mg, 2.05 mmol). The reaction mixture was stirred for 2 days. EtOAc (5 mL) was added. The organic phase was washed with Sat. NH4Cl, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:MeOH: 10:1) to give the desired product (389 mg, 40% yield) as a colorless oil. MS: (ESI), M/Z, 498 (M+1). Retention time: 2.21 min (FA-polar).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30]OS(C)(=O)=O)[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:36]([F:39])([F:38])[F:37])[CH:10]=2)=[O:5])[CH3:2].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30][N:44]3[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]3)[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:36]([F:37])([F:39])[F:38])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(COS(C)(=O)=O)cc1=O
Solvent: ClCCl
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(CN2CCN(C)CC2)cc1=O
Temperature: 45 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(7-trifluoromethyl-quinolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 18 (123 mg, 0.215 mmol) was dissolved in dichloromethane (5 mL). 1-Methyl-piperazine (60 μL, 0.54 mmol) was added via syringe. The mixture was stirred at 45° C. for 2 h. After cooling to room temperature CH2Cl2 (75 ml) was added and the mixture was washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=9:1. 4-[5-(6-(4-Methyl-piperazin-1-ylmethyl)-4-oxo-4H-pyran-3-yloxy)-pentyloxy]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester EHT 8791 was obtained (38 mg, 31% yield) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:19]([O-])=[O:20])([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:19]([C:12]([CH3:18])([CH3:11])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[O-:20]
Reactant: CC(=O)OCC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1ccc(F)cc1F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)OCC(C)(C)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (428.2 mg, 3.01 mmol), 2-methyl-2-nitro-1-acetoxypropane (467.8 mg, 2.90 mmol) and zinc (321.7 mg, 4.92 mmol) in ethanol (5 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.57 ml, 9.9 mmol) was added dropwise to the mixture and was warmed to room temperature and stirred for 16 hours. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (380.8 mg; 48%).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:15])[CH3:14])[CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:24])C=1>>[O:24]1[CH2:4][CH:3]1[CH:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:15])[CH3:14])[CH3:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(C)Oc1ccccc1NC(C)=O
Product: CC(=O)Nc1ccccc1OC(C)C1CO1

Procedure:
The compound was prepared from N-{2-[(1-Methyl-2-propenyl)oxy]phenyl}acetamide (549 mg, 2.67 mmol) and m-chloroperbenzoic acid (80%, 923 mg, 4.28 mmol) analogously to that described in Example 8 (ii). Purification wag done on silica gel with petroleum ether/ethyl acetate 10/15 as eluent. This gave separation of the two diastereomeric pairs.
Reaction SMILES: C(S[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.[Cl:18]N1C(C)(C)C(=O)N(Cl)C1=O.[S:29](S([O-])=O)([O-:32])(=O)=[O:30].[Na+].[Na+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl.O.C(O)(=O)C>[N+:15]([C:14]1[C:9]([S:29]([Cl:18])(=[O:32])=[O:30])=[N:10][CH:11]=[CH:12][CH:13]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cccnc1SCc1ccccc1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccnc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-Benzylsulfanyl-3-nitro-pyridine (6 g, 24.39 mmol) was dissolved in dichloromethane (84 mL). Acetic acid (12 mL) and water (24 mL) were added. The mixture was chilled to 0° C. With vigorous stirring, 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (14.4 g, 73.17 mmol) was added portionwise as a suspension in dichloromethane (48 mL). The mixture was allowed to slowly warm to 25° C. and continued to stir for 16 h. The mixture was poured into 5% aqueous sodium metabisulfite solution (100 mL) and shaken well. Dichloromethane (200 mL) and 20% aqueous dibasic potassium phosphate solution (100 mL) were added and the mixture was shaken well. The layers were separated. The crude desired product, 3-nitro-pyridine-2-sulfonyl chloride, dissolved in the organic layer was used directly in the next step without further isolation or characterization.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[CH2:9]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>N1C=CC=CC=1>[CH2:9]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCc1nnc(N)s1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CC)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
2-Amino-5-ethyl-1,3,4-thiadiazole (169 mg, 1.3 mmol) was suspended in pyridine (0.5 mL). p-Dodecylbenzenesulfonyl chloride (300 mg, 0.87 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred at this temperature for 1 h. The reaction mixture was then added to aqueous 10% HCl (5 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and volatiles evaporated to yield a solid mass. Chromatography on silica gel (70-230 mesh) eluted with 2% MeOH in CH2Cl2 gave the product (225 mg, 0.51 mmol, 59%). Recrystallization from hexanes:ethyl acetate (3:7) gave an analytical sample, mp 93-94° C.; 1H NMR (500 MHz, CDCl3) δ 0.88 (3, t, J=6.5 Hz), 1.20-1.36 (18, m), 1.33 (3, t, J=7.5 Hz), 1.54-1.63 (2, m), 2.63 (2, t, J=7.5 Hz), 2.84 (2, q, J=7.5 Hz), 7.25 (2, d, J=8.5 Hz), 7.83 (2, d, J=8.5 Hz), 12.30 (1, br s); 13C NMR (125 MHz, CDCl3) δ 12.6, 14.1, 22.7, 24.4, 29.2, 29.3, 29.4, 29.5, 29.6, 31.1, 31.9, 35.9, 126.5, 128.8, 138.4, 148.2, 160.1 168.2; MS (ESI+, m/z) Calcd for C22H36N3O2S2 438.2249. found 438.30 (M+H)+; HRMS (ESI+, m/z) Calcd for C22H36N3O2S2 438.2249. found 438.2247 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([Cl:12])=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:13]([O:15][C:16](=[O:23])[CH:17]=[C:18]([NH2:22])[O:19][CH2:20][CH3:21])[CH3:14]>C(O)(C)C>[CH2:13]([O:15][C:16]([C:17]1[CH:7]([C:6]2[C:9]([Cl:12])=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:17]([C:16]([O:15][CH2:13][CH3:14])=[O:23])[C:18]([O:19][CH2:20][CH3:21])=[N:22][C:18]=1[NH2:22])=[O:23])[CH3:14]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1Cl
Yield: 65 %

Procedure:
Upon heating a solution of 9.3 g of 3-nitro-6-chlorobenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of isopropanol for 6 hours, 2-amino-4-(3-nitro-6-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 136°-37° C (isopropanol) is obtained. Yield: 65% of theory.