Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH2:26][CH3:27])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][C:10](OCC)=[O:11])=[C:4]([CH3:28])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH2:26][CH3:27])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:10][OH:11])=[C:4]([CH3:28])[CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1C)c1c[nH]c2c(CSCC)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCSCc1cccc2c(C(CCO)c3ccc(Cl)cc3C)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.23 g (5.49 mmol) of the compound from Example 41A in 20 ml of tetrahydrofuran was added dropwise to 5.7 ml (5.7 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 50 ml of tetrahydrofuran at RT under argon. The mixture was stirred at RT for 15 min and then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 458 mg (76% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:42]=[CH:41][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=4)=[CH:20][C:19]=3[N:32]([CH3:40])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.Cl.O1CCOCC1>>[OH:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]3[N:17]=[C:15]([CH2:14][O:13][C:12]4[CH:41]=[CH:42][C:9]([CH2:8][CH:4]5[S:3][C:2](=[O:1])[NH:6][C:5]5=[O:7])=[CH:10][CH:11]=4)[N:32]([CH3:40])[C:19]=3[CH:20]=2)=[CH:30][CH:29]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(O)cc3)cc21
Yield: 21.8 %

Procedure:
Using 1.49 g of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-hydroxyphenoxy)phenyl}-N-methylcarbamate and 10 ml of a 4N hydrochloric acid/dioxane solution, reaction and purification were carried out in a similar manner to that described in Example (2-2a), whereby 0.26 g of the title compound were obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]2[NH:10][C:9]([CH2:11][CH2:12][CH2:13][CH3:14])=[N:8][C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.CO>C1COCC1.[Cl-].[Na+].O>[CH2:11]([C:9]1[NH:10][C:4]2[C:5]([N:8]=1)=[N:6][CH:7]=[CH:2][C:3]=2[CH3:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1nc2ncc(Br)c(C)c2[nH]1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCc1nc2nccc(C)c2[nH]1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
To a cooled (-78° C.) stirred solution of 6-bromo-2-butyl-7-methylimidazo[4,5-b]pyridine (98 mg, 0.366 mmol) in THF (4 mL) was added tert-butyllithium (0.86 mL of a 1.7M solution in pentans, 1.46 mmol). After 15 minutes, MeOH (0.5 mL and brine were added the mixture was warmed to room temperature and extracted with EtOAc (4×10 mL). Drying (K2CO3), concentration, and purification (SiO2, 100% EtOAc) gave 60 mg (87%) of the title compound as an oil: 1H NMR (300 MHz, CDCl3) δ 8.18 (d, 1H, J=5 Hz), 7.08 (d, 1H, J=5 Hz), 3.05 (t, 2H, J=7.6 Hz), 2.72 (s, 3H), 2.03-1.89 (m, 2H), 1.62-1.43 (m, 2H), 0.96 (t, 3H, J=7.8 Hz).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH:17][C:18]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])=[CH:7][C:8]2[O:12][C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[C:9]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].CC1OCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.OC(C(O)C([O-])=O)C([O-])=O.[Na+].[K+]>CC(OC)(C)C>[C:1]([C:5]1[CH:16]=[C:9]([C:10]([CH3:15])([CH3:14])[CH2:11][OH:13])[C:8]([OH:12])=[CH:7][C:6]=1[NH:17][C:18]([C:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc2c(cc1NC(=O)c1c[nH]c3ccccc3c1=O)OC(=O)C2(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC1CCCO1
Product: CC(C)(C)c1cc(C(C)(C)CO)c(O)cc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 3-neck 50 mL round bottom flask was equipped with magnetic stirrer, nitrogen bubbler and thermocouple. Compound 21 (514 mg, 1.27 mmol) and 2-MeTHF (4 mL) are charged to the flask. The reaction mixture was stirred at room temperature. Lithium aluminum hydride (204 mg, 6.6 mmol) was added as solid until 100% conversion is achieved, which was monitored using HPLC. Potassium sodium 2,3-dihydroxybutanedioate tetrahydrate salt (50 mL of a 400 g/L solution) and MTBE (50 mL) were added to the reaction mixture. The resulting solution was stirred for 15 minutes and then let sit for 15 min. The organic layer was separated and the pH of the aqueous layer was adjusted to a pH of about 6-7 by adding Tartaric acid. The aqueous layer was extracted with MTBE. The organic layer was concentrated and dried under high vacuum to provide the title compound as an off-white powder. The 1H-NMR spectrum was consistent with that reported above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[OH:29])=[CH:12][CH:11]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[O:29][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc(F)c(F)c3)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccc(F)c(F)c4)cc3)cc21

Procedure:
Analogously to Method D, 0.540 g of tert-butyl 4-{4-[3-(3,4-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.353 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.26 (1:1 EtOAc-heptane); Rt=5.98.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Cl:11][C:12]1[CH:13]=[C:14]2[CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:25](O)=[O:26])=[O:22])[NH:18][C:15]2=[CH:16][N:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C@H:24]([NH:23][C:21]([C:19]2[NH:18][C:15]3=[CH:16][N:17]=[C:12]([Cl:11])[CH:13]=[C:14]3[CH:20]=2)=[O:22])[C:25](=[O:26])[N:6]2[CH2:7][CH2:8][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:4][CH2:5]2)=[CH:34][CH:33]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: FC(F)(F)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(C(F)(F)F)CC1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 4-trifluoromethyl piperidine (17 mg, 0.11 mmol) was added a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228, 40 mg, 0.11 mmol) in DMF (400 μL) followed by a solution of HATU (50 mg, 0.13 mmol) in DMF (400 μL) and finally a solution of DIPEA (23 μL, 0.13 mmol) in DMF (200 μL). The resulting mixture was stirred at rt for 96 h then solvent was removed in vacuo. The crude material was purified by crystallisation from THF/petroleum ether to give the title compound as a yellow powder. (ES+)=497.23 [M+H]+; RT=3.50 min.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16]SC2SC3C=CC(OC)=CC=3N=2)[N:14]([CH:29]([C:40]([CH3:42])=[CH2:41])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:13]1=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44]1([S:50](C#N)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:50]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)(=[O:51])=[O:52])[N:14]([CH:29]([C:40]([CH3:42])=[CH2:41])[C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C:13]1=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2cc(OC)ccc2s1
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 93 %

Procedure:
A 250 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(5-methoxybenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 79 mg of benzenesulfonyl cyanide were dissolved in 2.5 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 5 was followed, producing benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3butenoate in a yield of 93%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below shows the NMR spectrum data thereof.
Reaction SMILES: CS([Cl:5])(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH:18]=[CH:19][CH2:20]O)[S:16][CH:17]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:5][CH2:20][CH:19]=[CH:18][C:15]1[S:16][CH:17]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[N:14]=1
Reactant: OCC=Cc1nc(-c2ccc(F)cc2)cs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(-c2csc(C=CCCl)n2)cc1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
258 μl (3.3 mmol) of methanesulfonyl chloride were slowly added to 265 mg (1.12 mmol) of 3-(4-(4-fluorophenyl)thiazol-2-yl)prop-2-en-1-ol and 456 mg (4.5 mmol) of triethylamine in 10 ml of dichloromethane at room temperature and the mixture was stirred for 3 h. After standing at room temperature over the weekend, the mixture was extracted with a sodium hydrogencarbonate solution. Evaporation of the organic phase yielded 280 mg of the title compound.
Reaction SMILES: [BH4-].[Na+].[C:3]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:3]([N:11]1[CH2:12][CH2:13][CH:14]([CH:17]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=2)[OH:28])[CH2:15][CH2:16]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1ccc(C(=O)C2CCN(C(=O)c3ccccc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(C(O)C2CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (1.13 g, 30 mmol) was added to a stirred suspension of 1-benzoyl-4-(4-acetamidobenzoyl)piperidine (10.0 g, 29 mmol) in ethanol (300 ml), cooled in a water bath. The mixture was stirred at room temperature for 1 hour then additional sodium borohydride (1.13 g, 30 mmol) was added and stirring was continued for 2 hours. The solvent was evaporated under reduced pressure and water (200 ml), HCl--H2O (6M, 15 ml) and methanol (15 ml) were added. The mixture was extracted with dichloromethane (4×200 ml) and the combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure to give an off-white solid which was crystallized from ethanol to give the piperidine as white crystals. (5.77 g, 57%)
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:8])[CH2:6][SH:7])[CH2:3][CH2:2]1.C[O-].[Na+].Cl[C:13]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([Cl:23])=[C:17]([CH3:24])[C:14]=1[C:15]#[N:16].O>CO>[CH:1]1([NH:4][C:5]([C:6]2[S:7][C:13]3=[N:20][C:19]([O:21][CH3:22])=[C:18]([Cl:23])[C:17]([CH3:24])=[C:14]3[C:15]=2[NH2:16])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(CS)NC1CC1
Reactant: COc1nc(Cl)c(C#N)c(C)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-cyclopropyl-2-mercapto-acetamide (6.65 g, 50.68 mmol) in MeOH (100 ml), is added sodium methoxide solution (25% wt. in MeOH)(11.59 ml, 50.68 mmol). The resulting solution is stirred at room temperature for 10 minutes, and then treated with 2,5-dichloro-6-methoxy-4-methyl-nicotinonitrile (10.0 g, 46.07 mmol). The reaction vessel is sealed and heated at 100° C. for 2 hours. The reaction mixture is cooled to room temperature and poured over 500 ml of cold water. A thick white precipitate is formed. The mixture is stirred at 0° C. for 10 minutes, then the solid is collected by filtration. The fluffy white solid (title compound) is placed in the vacuum oven at 60° C. to dry overnight (7.74 g, 54%). Mass (m/z): 312.0 (M++1).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[O:8][CH:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH3:10]>C(OC(=O)C)C>[CH3:5][C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[O:8][CH:9]([C:11]1[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=1)[CH3:10]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccccc1OC(C)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: Cc1ccccc1OC(C)c1nnc(N=C=O)s1
Reaction time: 8 h

Procedure:
A 500 milliliter, 3-neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotometer was charged with 50 milliliters of ethylacetate which was saturated with phosgene at 20° C. (approximately 0.5 mole of phosgene) and cooled in an ice bath. An additional 50 milliliters of ethylacetate was added and then 6.8 grams of 5-[1-(2-methylphenoxy)ethyl]-2-amino-1,3,4-thiadiazole, (prepared above); a cloudy solution formed, the solution was stirred overnight, and then filtered to remove a small amount of insoluble sediment. The clear solution was topped on a roto-vac at 70° C. to form 8.1 grams of a viscous yellow residue of 5-[1-(2-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:5]=[C:6]([CH:8]=O)[CH:7]=1.[NH2:23][C:24]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:25]=1[C:26]([NH2:28])=[O:27].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+].FC(F)(F)C(O)=O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:28][C:26](=[O:27])[C:25]3[C:24](=[CH:32][C:31]([O:33][CH3:34])=[CH:30][C:29]=3[O:35][CH3:36])[N:23]=2)[CH:5]=[C:4]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc(C=O)c2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(Cl)cc(N4CCNCC4)c3)nc2c1
Temperature: 110 °C
Yield: 29.3 %

Procedure:
A solution of tert-butyl 4-(3-chloro-5-formylphenyl)piperazine-1-carboxylate (3, 0.300 g, 0.918 mmol) and 2-amino-4,6-dimethoxybenzamide (4, 0.120 g, 0.612 mmol) in DMA (4 mL) was treated with p-TsOH (0.424 g, 1.46 mmol) and NaHSO3 (0.290 g, 1.84 mmol) and then heated at 110° C. for 16 h. The reaction mixture was cooled to room temperature, trifluoroacetic acid (5 mL) was added and the mixture was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. The product fractions were concentrated and the residue was dissolved in acetonitrile and water. The mixture was basified with concentrated NH4OH and the precipitate filtered, washed with water, and dried under vacuum to afford the title compound (0.072 g, 29%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 7.60-7.70 (m, 2H), 7.08-7.12 (m, 1H), 6.78 (d, J=2.3 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.24 (t, J=5.2 Hz, 4H), 3.28 (t, J=5.2 Hz, 4H); ESI MS m/z 401 [M+H]+.
Reaction SMILES: [NH2:1][C@:2]1([C@H:10]([CH3:12])[OH:11])[O:7][C:5](=[O:6])[C:4]([OH:8])=[C:3]1[O-:9].[NH2:13][C@H:14]([C:20](Cl)=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>N1C=CC=CC=1>[NH2:13][C@H:14]([C:20]([OH:21])=[O:6])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].[NH2:1][C@:2]1([C@H:10]([CH3:12])[OH:11])[O:7][C:5](=[O:6])[C:4]([OH:8])=[C:3]1[O-:9]
Reactant: NCCCC[C@H](N)C(=O)Cl
Agent: C[C@H](O)[C@@]1(N)OC(=O)C(O)=C1[O-]
Solvent: c1ccncc1
Product: NCCCC[C@H](N)C(=O)O

Procedure:
6-Deoxyamino ascorbate (5 mmoles) is reacted with lysyl chloride (7 mmoles) in dry pyridine and the reaction product is worked up according to Cousine et al. It is crystallized from ethanol.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:38])[CH2:27][N:28]4[C:32]([CH3:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[N:29]4)[CH2:22][CH2:21]3)[S:18][CH:19]=2)[CH2:11]1)(=O)[CH3:2].[NH2:39][OH:40].O>C(O)C>[OH:40][N:39]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:38])[CH2:27][N:28]4[C:32]([CH3:33])=[CH:31][C:30]([C:34]([F:36])([F:37])[F:35])=[N:29]4)[CH2:24][CH2:25]3)[S:18][CH:19]=2)[CH2:11]1)[CH3:2]
Reactant: CC(=O)c1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)(F)F)cc4C)CC3)n2)=NO1
Reactant: NO
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)(F)F)cc4C)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-{4-[5-(2-acetylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (150 mg) in ethanol (5 ml) was added dropwise hydroxylamine (50% in water, 4 eq.) at room temperature. After stirring at room temperature overnight, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave 1-[4-(4-{5-[2-(N-hydroxyethanimidoyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (33 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[C:19](Cl)=[O:20])([CH3:15])([CH3:14])[CH3:13]>COCCOC>[C:7]([C:6]1[CH:10]=[C:2]([NH:1][C:19](=[O:20])[C:18]2[CH:22]=[C:23]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:24]([OH:25])=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:17]=2)[CH:3]=[CH:4][C:5]=1[Cl:11])([OH:9])=[O:8]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.7 %

Procedure:
A suspension of 6.90 g (0.04 mole) of 5-amino-2-chlorobenzoic acid in 100 ml of 1,2-dimethoxyethane was mixed with a solution of 5.08 g (0.02 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the mixture was stirred at 25° C. for about 72 hours. The reaction mixture was heated gently for 30 minutes and then allowed to cool before being filtered to remove the hydrochloride salt of the excess starting amine. The filtrate was concentrated under vacuum and then diluted with water. The resulting precipitate was collected, and was then recrystallized twice from a mixture of ethanol and water to give 2.8 g of off-white solid N0(3-carboxy-4-chlorophenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 265°-267° C. Analysis: Calculated for C22H26NO4Cl: %C, 65.4; %H, 6.5; %N, 3.4; Found: %C, 65.8; %H, 6.6; %N , 3.5.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([CH:18]=O)=[CH:13][C:12]=3[CH:20]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([CH2:18][N:29]4[CH2:30][CH2:31][CH:26]([NH:25][C:23](=[O:24])[C:22]([F:21])([F:32])[F:33])[CH2:27][CH2:28]4)=[CH:13][C:12]=3[CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)C(F)(F)F
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C=O)CCO3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3c(c2)C=C(CN2CCC(NC(=O)C(F)(F)F)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carbaldehyde (2.0 g) and 4-trifluoroacetamidopiperidine (1.56 g) dissolved in 1,2-dichloroethane (50 ml) was added under ice cooling sodium triacetoxyborohydride (1.8 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. Thereto were added triethylamine (1.1 ml) and sodium triacetoxyborohydride (0.8 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was neutralized with a 1 N aqueous solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and then was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals (3.0 g). A portion of the crystals was recrystallized from ethyl acetate/hexane to obtain 1-(7-(4-methylphenyl)-2,3-dihydro-1-benzooxepin-4-ylmethy)-4-trifluoroacetamidopiperidine as light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.I[CH3:19]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:19]
Reactant: O=C(Cc1cccnc1)c1ccc(F)cc1F
Reactant: CI
Product: CC(C(=O)c1ccc(F)cc1F)c1cccnc1
Yield: 73.6 %

Procedure:
Methylation of the product of part (i) (5.0 g) with iodomethane (7.60 g) according to the method of Example 11(ii) gave the title compound as an oil (3.90 g) which was used directly in the next stage.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17]C(C)(O)C)=[CH:12][CH:11]=1.[H-].[Na+].C(OC(C)C)(C)C.Cl>C1(C)C=CC=CC=1.O>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:12]=1)#[CH:17]
Reactant: COCCCCCCOc1ccc(C#CC(C)(C)O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: C#Cc1ccc(OCCCCCCOC)cc1
Yield: 99.6 %

Procedure:
Under a nitrogen atmosphere, to a solution of 4-[4-(6-methoxyhexyloxy)phenyl]-2-methyl-3-butyn-2-ol (3.0 g) in toluene (18 ml) was added sodium hydride (abt. 60% in oil suspension), and the mixture was refluxed for 2 hours. After cooling, to the reaction mixture was added isopropyl ether (100 ml) and water (100 ml), and neutralized by 1N-hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude red oil. The crude red oil was purified by silica gel chromatography (10:1 hexane-ethyl acetate) to give 1-ethynyl-4-(6-methoxyhexyloxy)benzene (2.39 g) as an orange powder.