Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[CH3:22][C:23]1([CH3:42])[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[N:33]=1>C(#N)C>[CH3:22][C:23]1([CH3:42])[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[S:30][C:31]([F:21])=[C:32]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[N:33]=1
Reactant: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2)c(F)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
The Selectfluor® reagent (2.042 g, 5.76 mmol) in 250 mL of acetonitrile was added under nitrogen dropwise to a solution of 4-[2-(4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl]benzonitrile (1.566 g, 5.23 mmol), prepared in Example 6, in 250 mL of acetonitrile at room temperature. After the addition, the reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure to remove the acetonitrile. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed once with water, and the solvent removed under reduced pressure. Purification of the residue on a Horizon™ Flash Collector (the Biotage FLASH 25+™ cartridge) using a linear gradient of methylene chloride in hexane as the eluent gave the title compound (566.7 mg, 34%) as a white solid, mp 177-178° C.; MS (ESI) m/z 318 [M+H]+. Anal. Calcd for C15H12FN3O2S: C, 56.77; H, 3.81; N, 13.24. Found: C, 56.53; H, 3.91; N, 13.12.
Reaction SMILES: Cl.[OH:2][C:3]([CH3:23])([CH3:22])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[S:13][C:12]([NH:14][C:15](=[O:21])[C@@H:16]([NH2:20])[CH2:17][CH2:18][CH3:19])=[N:11][CH:10]=1)[CH3:8].[CH3:24][CH2:25][C:26](=O)[CH2:27][CH3:28].C([O-])(=O)C.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].C([BH3-])#N.[Na+]>C(O)(=O)C.ClC(Cl)C>[OH:2][C:3]([CH3:22])([CH3:23])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[S:13][C:12]([NH:14][C:15](=[O:21])[C@@H:16]([NH:20][CH:26]([CH2:27][CH3:28])[CH2:25][CH3:24])[CH2:17][CH2:18][CH3:19])=[N:11][CH:10]=1)[CH3:8]
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(C)CCCC(C)(C)O)s1
Reactant: CCC(=O)CC
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCC[C@H](NC(CC)CC)C(=O)Nc1ncc(C(C)CCCC(C)(C)O)s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(S)-amino-pentanoic acid [5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide HCl salt (200 mg, 0.55 mmol) and 3-pentanone (237 mg, 2.76 mmol), 5 drops of acetic acid, sodium acetate (100 mg), sodium sulfate (100 mg) and sodium cyanoborohydride (222 mg, 2.75 mmol) in dichloroethane (15 mL) was stirred at 40° C. overnight. The mixture was quenched with water, and extracted with methylene chloride. The organic layer was concentrated to dryness. The residue was purified by Shimadzu HPLC to give 2-(S)-(1-ethyl-propylamino)-pentanoic acid [5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide as a colorless oil, LC-MS, RT=1.6 min, M+1=398.6.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30]>C1CCCCC1.C(OCC)(=O)C>[CH3:33][O:32][C:28](=[O:31])/[CH:29]=[CH:30]/[C:2]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1
Reactant: C=CC(=O)OC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COC(=O)/C=C/c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C#N)cc2)CC1

Procedure:
Prepared in analogy to example 139 from 4-[4-(2-Iodo-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile (Example AG) and methyl acrylate. Chromatography (SiO2; cyclohexane/ethyl acetate 3:7) yields the title compound as a slightly yellow solid (M+H+: 454.3)
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[CH3:1][C:2]([CH3:13])([CH3:12])[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([C-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)=[O:9].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]
Reactant: CC(C)(C)C(=O)CCCCC(=O)Cl
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)CCCCC(=O)[c-]1cccc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
7,7-Dimethyl-6-oxooctanoylchloride (assumed to be 0.1 mole from the above preparation) in methylene chloride (200 ml) and ferrocene (18.6g; 0.1 mole) were stirred at -20°C and aluminium chloride (13.4g; 0.1 mole) was added over 1 hr. After stirring for a further 2 hrs at -20°C, the reaction had almost gone to completion. Water was added and the organic layer separated. The aqueous layer was extracted with methylene chloride and the combined organic layers were washed with saturated sodium bicarbonate and water, and dried (sodium sulphate) to yield a brown oil which crystallised on addition of petroleum ether and was recrystallised from petroleum ether: cyclohexane (750 ml of 1:1) to yield 7,7-dimethyl-6-oxo-octanoylferrocene as an orange-brown solid. mp 90°-2° (65.3%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([O-])([O-])=[O:12].[K+].[K+].C(OC)=O>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][CH:11]=[O:12])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: COC=O
Product: O=CNNc1ccc(Br)cc1
Reaction time: 12 h

Procedure:
10 g of 4-bromophenylhydrazine hydrochloride are dissolved in 30 ml of water; 6.2 g of K2CO3 and 36 ml of methyl formate are added and then the mixture is heated at reflux for 1 hour and then at AT for 12 hours. The precipitate formed is filtered off and then washed with an isopropanol/PE mixture (50/50; v/v). This gives 10.5 g of the expected compound.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]1[CH:19]([C:20]([O:22]CC)=[O:21])C(O)(C)CC[CH:15]1[C:27]([O:29]CC)=[O:28].[OH-].[Na+].C(O)C>O1CCOCC1.O>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)C1CCC(C)(O)C(C(=O)OCC)C1c1ccc2oc3c(c2c1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: O=C(O)CC(CC(=O)O)c1ccc2oc3c(c2c1)CCCC3

Procedure:
A solution of 44.2 g (0.1 mol) of diethyl 2-(6,7,8,9-tetrahydro-2-dibenzofuranyl)-4-hydroxy-4-methyl-1,3-cyclohexanedicarboxylate in 250 ml of dioxan is added dropwise to a solution of 120 g (3 mols) of sodium hydroxide in 125 ml of water with 250 ml of ethanol at 90° in the course of 30 minutes. The reaction mixture is heated to 90° for 30 minutes and then concentrated to about 1/3rd of its volume by distilling off the solvents. After diluting the mixture with 750 ml of water, 350 ml of concentrated hydrochloric acid are added, with ice-water cooling. The crude acid which has precipitated is filtered off, washed thoroughly with water and dried. 3-(6,7,8,9-Tetrahydro-2-dibenzofuranyl)-glutaric acid is thus obtained as light yellow-brown crystals of melting point 165°-170°. A sample crystallised from ethanol/water melts at 169°-174°.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[H-].[Na+].[C:9](#[N:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)Cl>C1COCC1.O>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[C:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5]
Reactant: N#Cc1ccccc1
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CSC(=C(N)c1ccccc1)S(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
4.38 Grams of methyl methylthiomethyl sulfoxide was dissolved in 45 ml of THF, and to the solution 900 mg of sodium hydride was added under cooling with ice, and the system was stirred for an hour at room temperature. Upon addition of 4 ml of benzonitrile and subsequent stirring for 42.5 hours at room temperature, the entire system was solidified, to which 100 ml of methylene chloride and 3 ml of water were added, followed by 30 minutes' stirring and then drying with Glauber's salt. The light yellow solid obtained by the subsequent concentration under reduced pressure was washed with 100 ml of carbon tetrachloride, and 5.158 g of 1-methylsulfinyl-1-methylthio-2-amino-2-phenylethylene was obtained as a light yellow solid. The washing was concentrated under reduced pressure, and subjected to a column chromatography (silica gel, ethyl acetate, and methanol) to allow the recovery of 1.106 g of a light yellow, oily substance. Upon NMR analysis, the oily substance was confirmed to be composed of 972 mg of methyl methylthiomethyl sulfoxide and 134 mg of 1-methylsulfinyl-1-methylthio-2-amino-2-phenylethylene. The latter's isolation yield was 66%, and the conversion yield was 84.8%.
Reaction SMILES: OC([C@@H](NC(OC(C)(C)C)=O)CCCC)C(O)=O.C(=O)([O-])O.[Na+].C(Br)C1C=CC=CC=1.[OH:32][CH:33]([C@@H:44]([NH:49]C(OC(C)(C)C)=O)[CH2:45][CH2:46][CH2:47][CH3:48])[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].C(OCC)(=O)C.Cl>C(OCC)(=O)C.CN(C)C=O>[NH2:49][C@@H:44]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:33]([OH:32])[C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)OCc1ccccc1
Agent: BrCc1ccccc1
Agent: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC[C@H](N)C(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 13.1 g (50 mmol) of (2RS,3S)-2-hydroxy-3-[N-(2-methyl-2-propyloxycarbonyl)amino]heptanoic acid synthesized in accordance with the method described in Reference Example 11 and 100 ml of suspension of dimethylfomiamide of 6.3 g (75 mmol) of sodium hydrogen carbonate, 20 ml of dimethylformamide solution of 9.4 g (55 mmol) of benzyl bromide was added and stirred at the room temperature for 18 hours. The reaction solution was added with ethyl acetate and washed with water twice and washed with saturated brine once. The resultant organic extracted layer was dried over anhyrous sodium sulfate and then the solvent was distilled away under reduced pressure, whereby the crude product of phenylmethyl (2RS,3S)-2-hydroxy-3-[N-(2-methyl-2-propyloxycarbonyl) amino]heptanoate was obtained. To the obtained phenylmethyl (2RS,3S)-2-hydroxy-3-[N-(2-methyl-2-propyloxycarbonyl)amino]heptanoate, 100 ml of 4N hydrogen chloride-ethyl acetate were added and was left alone at room temperature for one hour and thereafter the reaction solution was concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether twice and the water layer was made basic with addition of sodium carbonate and was extracted with ethyl acetate three times. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate and, the solvent was distilled away from the reaction mixture under reduced pressure, whereby 9.3 g of phenylmethyl (2RS,3S)-3-amino-2-hydroxyheptanoate was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([C:10]4[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=4)=[N:7][C:6]=3[CH:17]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(-c2nc3cc(Br)ccc3o2)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc3oc(-c4ccc(C)cc4)nc3c2)cc1
Temperature: 150 °C
Yield: 38.1 %

Procedure:
To a solution of 5-bromo-2-p-tolylbenzo[d]oxazole (146.1 mg, 0.50 mmol) in dioxane (1.5 mL) was added water (0.5 mL), 4-methoxyphenylboronic acid (114 mg, 0.75 mmol), potassium carbonate (138 mg, 1.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (3 mg). The resulting suspension was heated in the microwave at 150° C. for 15 min. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 1:99 v/v to afford 60 mg (38%) of the title compound (LCMS RT=9.18 min, MH+ 316.1)
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)[O:3]1.I([O-])(=O)(=O)=O.[Na+].C([O-])(=O)C.[NH4+].O>CC(C)=O>[CH3:24][C:21]([O:20][C:18]([N:15]1[CH2:14][CH2:13][C:12]2[CH:25]=[CH:26][C:9]([B:4]([OH:5])[OH:3])=[CH:10][C:11]=2[CH2:17][CH2:16]1)=[O:19])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(B(O)O)cc2CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
1,1-Dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (E264, Step 1) (1.60 g, 4.29 mmol) was dissolved in acetone (25 ml), treated with sodium periodate (2.75 g, 12.9 mmol), ammonium acetate (0.73 g, 9.44 mmol) and water (25 ml) and the resulting mixture was stirred for 18 hours at room temperature. The acetone was removed by evaporation in vacuo and the remaining water layer was extracted with ethyl acetate and dichloromethane. The organic layers were combined, dried under magnesium sulfate and evaporated in vacuo to give the title compound (1.06 g); MS (ES+) m/e 192 [(M+H)—CO2tBu]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH2:2][C@@H:3]([NH:5][C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12])[CH3:4])(=[O:23])=[O:22]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 36 h
Yield: 59.2 %

Procedure:
(S)-tert-Butyl 1-hydroxypropan-2-ylcarbamate (10.25 g, 58.5 mmol) was dissolved DCM (20 ml). Triethylamine (12.23 ml, 87.7 mmol) was added and the solution was cooled to 0° C. under nitrogen. Methanesulfonylchloride (5.0 ml, 64.3 mmol) was diluted with DCM (5 ml) and added drop wise to the reaction mixture keeping the temperature under 10° C. After addition, the reaction mixture was allowed to warm up to RT and stirring was continued for 36 h. Next, the reaction mixture was diluted with DCM (150 ml) and washed several times with NaHCO3-solution and water, the organic layer dried with Na2SO4, filtered and evaporated affording 8.78 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.06 (d, 3H), 1.38 (s, 9H), 3.16 (s, 3H), 3.75 (m, 1H), 4.04 (m, 2H), 6.93 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F-].[Cs+].C(=O)([O-])[O-].[K+].[K+].[C:29]([O:32][CH2:33][CH3:34])(=O)C>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=2)=[CH:3][C:2]=1[O:1][CH2:34][CH:33]1[CH2:29][O:32]1
Reactant: CCOC(C)=O
Reactant: COC(=O)Cc1cccc(-c2ccc(OC)c(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(-c2ccc(OC)c(OCC3CO3)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
205 mg of Methyl (3′-hydroxy-4′-methoxybiphenyl-3-yl)acetate was dissolved in 3 ml of N,N-dimethylformamide, then 205 mg of glycidyl nocylate, 35 mg of cesium fluoride and 130 mg of potassium carbonate were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, to give 79 mg of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH2:16])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:6]=1.[CH3:17][O:18][CH:19]([O:30][CH3:31])[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22](F)[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C.O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([NH:1][C:22]2[CH:21]=[C:20]([CH:19]([O:30][CH3:31])[O:18][CH3:17])[CH:25]=[CH:24][C:23]=2[N+:26]([O-:28])=[O:27])[S:3][C:4]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1sc(N)nc1-c1ccccc1Cl
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3ccccc3Cl)c(C(N)=O)s2)c1
Yield: 89.1 %

Procedure:
A mixture of 0.15 g (0.60 mmole) of 2-amino-4-(2-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.20), 0.15 g (0.72 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitrobenzene, 0.99 g (3.0 mmole) of cesium carbonate and 10 mL of dimethylformamide was heated at 70 degrees for one day. The reaction mixture was diluted with ethyl acetate and water. The precipitate was collected by filtration, washed with water and dried under vacuum to give 0.24 g of 4-(2-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.20a).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[C:21](OC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[CH:21]=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](C=O)N(Cc2ccccc2)C1
Reaction time: 0.17 h

Procedure:
To a solution of (2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-2-methoxycarbonylpyrrolidine (20 g) in toluene (100 ml) was added dropwise diisobutyl aluminum hydride (1.02M solution in toluene) (112 ml) with stirring at a temperature kept below -60° C. and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added dropwise ethanol (20.1 ml) with stirring at a temperature kept below -60° C. After stirring for 30 minutes at the same temperature, 5N aqueous sodium hydroxide solution was carefully added. This solution was stirred without further cooling until the temperature reached 20° C. (ca. 1.5 hours). The reaction mixture was allowed to stand for 10 minutes. The organic layer was separated, washed with water (100 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give a solution of (2R,4S)-1-benzyl-2-formyl-4-(t-butyldimethylsilyloxy)pyrrolidine (ca. 40 ml) in toluene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][C:3]=1[N+:21]([O-])=O>C1COCC1.CCO.[Pd]>[NH2:21][C:3]1[CH:4]=[C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c(N)c2)CC1
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of compound 14 (2.1 g, 6.58 mmol) in a mixture of THF (15 mL) and EtOH (30 mL) was added Pd—C (0.21 g, 10% wet basis), and the mixture was subjected to hydrogenation in a Parr apparatus at 10 psi for 3 hours. After filtering over the pad of celite, the solution was concentrated and loaded over a silica column, eluting with ethyl acetate:hexanes (50:50), and then changing to (90:10) to get compound 18. Yield 96%, light brown gum. IR KBr, cm−1) 3429, 3330 (NH2), 3036 (Ar—H), 2983 (Alph-H), 1691 (CO), 1628, 1520, 1415 (C═C), 1229 (C—N), 1160 (CO); 1H NMR (500 MHz, CDCl3) δ 1.46 (s, 91-1, OC(CH3)3), 2.40 (br. s, 2H, CH2), 3.43 (m, 2H, CH2), 4.02 (br. s, 2H, CH2), 4.38 (br. s, 4H, 2NH2), 5.93 (br. s, 1H, CH), 7.06 (dd, J=2.6, 8.2 Hz, 1H, H-6), 730 (d, J=2.5 Hz, 1H, H-2), 7.46 (d, J=8.2 Hz, 1H, H-5). 13C NMR (125.7 MHz, CDCl3) δ 26.89 (CH2), 28.33 (OC(CH3)3), 29.39 (CH2), 42.84 (CH2), 79.99 (OC(CH3)3), 118.77 (CH), 119.19 (C-5), 120.37 (C-2), 129.19 (C-1), 130.65 (C-3), 131.16 (C-6), 141.82 (C4), 154.63 (CO). Anal. Calcd for C16H23N3O2. C, 66.41; H, 8.01; N, 14.52%. Found: C, 66.33; H, 8.07; N, 14.43%.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:17]=2[OH:18])[C:12](O)=[O:13])[CH:6]=[CH:7][CH:8]=1.[CH2:31]([O:38][C:39]1[CH:53]=[CH:52][C:42]([CH2:43][O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][NH2:51])=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C.Cl>O=S(Cl)Cl.C(Cl)Cl>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:43][O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][NH:51][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:17]([OH:18])=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=3)[CH:10]=2)=[CH:52][CH:53]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NCCCCCCOCc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(NCCCCCCOCc1ccc(OCc2ccccc2)cc1)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
A stirring solution of 3,5-bis-(m-trifluoromethylphenyl)-4-hydroxybenzoic acid (0.800 g, 1.87 mmol) in SOCl2 (10 mL) was heated at reflux for 1.5 h, then cooled and concentrated in vacuo. The acid chloride was dried in vacuo overnight. The acid chloride was dissolved in CH2Cl2 (10 mL) and added to a solution of 6-(4-benzyloxy-benzyloxy)hexylamine (0.765 g, 2.44 mmol) and triethylamine (0.92 mL, 6.54 mmol) in CH2Cl2 (10 mL) at 0° C. After stirring for 4 h at 0° C., 1.0 N HCl was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), and concentrated to give 1.15 g (85%) of the amide as an oil: 1H NMR (DMSO-d6) δ 9.30 (s, 1H), 8.44 (t, 1H), 7.94–7.70 (m, 10H), 7.41 (m, 4H), 7.20 (d, 2H), 6.95 (d, 2H), 5.08 (s, 2H), 4.35 (s, 2H), 3.42–3.20 (m, 4H), 1.50 (m, 4H), 1.32 (m, 4H).