Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:8]([C@@H:9]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:10][C@@H:11]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:21])[CH:17]=[CH:18][CH:19]=O)[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].O1C[CH2:39][CH2:38][CH2:37]1>>[C:1]([O:5][C@@H:6]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:8]([C@@H:9]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])[CH2:10][C@@H:11]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[C:38]([CH3:39])[CH3:37])[CH2:7]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H](C=CC=O)[C@H]1CC[C@H]2[C@@H]3C[C@H](OC(C)(C)C)[C@@H]4C[C@H](OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1CCOC1
Product: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](OC(C)(C)C)[C@@H]4C[C@H](OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h

Procedure:
A solution of 3α,6α-bis(t-butyloxy)-5β-cholen-24-al (prepared as described in my U.S. patent application Ser. No. 236,160) was dissolved in 5 ml of tetrahydrofuran and added dropwise to the ylid solution (described in Example I). The mixture was stirred for 2 hours and then the solution was refluxed for 2 hours. After evaporation of the solvent, the residue was dissolved in a 90% methanol-10% water mixture, extracted with petroleum ether and the petroleum ether extract evaporated. The residue was identified by NMR and IR data as the 3α,6α-bis(t-butyloxy)-5β-cholest-24-ene.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].ON1C2C=CC=CC=2N=N1.Cl.[CH3:39][O:40][C:41](=[O:44])[CH2:42][NH2:43].C(N1CCOCC1)C>CN(C)C=O>[CH3:39][O:40][C:41](=[O:44])[CH2:42][NH:43][C:25](=[O:27])[CH2:24][NH:23][C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dicyclohexylcarbodiimide (47.46 g, 0.23 mole) is added to a cooled (0° C), stirred solution of t-butoxycarbonyl-glycine (35.6 g, 0.2 mole) and 1-hydroxybenzotriazole (27.03 g, 0.2 mole) in dimethylformamide (400 ml). The mixture is stirred for 1 hour at 0° C and 1 hour at room temperature. A solution of glycine methyl ester hydrochloride (26.4 g, 0.21 mole) and N-ethylmorpholine (52.5 ml, pH 8) in dimethylformamide (1000 ml) is added to above mixture and the mixture is stirred overnight at room temperature. The mixture is filtered and the filtrate is evaporated. The residue is dissolved in ethyl acetate and the solution is washed with 10% citric acid (3×200 ml), saturated sodium bicarbonate (3×270 ml) and brine (2×135 ml), dried over anhydrous magnesium sulfate and evaporated to give t-butoxycarbonylglycyl-glycine methyl ester. To a cooled (0° C) solution of the latter compound (28.6 g, 0.12 mole) in methanol ( 200 ml) is added dropwise IN sodium hydroxide (120 ml). The mixture is stirred for 2 hours at room temperature, cooled to 0° C and acidified with 50% citric acid to pH 4. The solution is evaporated to about one-half volume and the mixture is extracted with ethyl acetate. The organic extract is washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue is crystallized from ethyl acetate to give t-butoxycarbonyl-glycyl-glycine, mp 134°-136° C.
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:20])[O:8][CH2:7][C@@H:6]2[CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][N:5]2[CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:1][CH2:2][C:3]1([CH3:20])[O:8][CH2:7][C@@H:6]2[CH2:9][NH:10][CH2:11][CH2:12][N:5]2[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN2CC(C)(CI)OC[C@@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CI)CN2CCNC[C@H]2CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
(9aS)-tert-butyl 3-(iodomethyl)-3-methylhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (108 mg, 0.273 mmol) was taken up in DCM (3 mL) and TFA (0.42 mL, 5.45 mmol) was added. The reaction was stirred at rt for 1 h. The solvent was removed in vacuo and the material was taken up in MeOH. The solution was loaded onto an SCX column (5 g, benzenesulfonic acid sorbent) and rinsed with MeOH, then 7N NH3/MeOH solution to release the product. The solvent was removed in vacuo give (9aS)-3-(iodomethyl)-3-methyloctahydropyrazino[2,1-c][1,4]oxazine (79 mg) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][OH:10].C[O-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:10][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: Clc1ncccc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncccc1Br
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
Under an argon atmosphere, to a solution of 3-bromo-2-chloropyridine (4.76 g) in DMF (30 mL) was added 28% sodium methoxide methanol solution (5.73 g) at room temperature, and the mixture was stirred at 80° C. for 30 min. Water was added at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (4.43 g) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@@H:10]([NH:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1)[CH2:11][CH2:12][CH3:13].O>C(Cl)(Cl)Cl>[Br:1][C:20]1[N:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:22]2[C:18]([N:19]=1)=[C:17]([NH2:30])[N:16]=[C:15]([NH:14][C@H:10]([CH3:9])[CH2:11][CH2:12][CH3:13])[N:23]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC[C@@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC[C@@H](C)Nc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Yield: 29.6 %

Procedure:
N-Bromosuccinimide (2.08 g, 11.69 mmol) was added portionwise to a stirred solution of N2-[(1R)-1-methylbutyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (2.27 g, 7.46 mmol) in chloroform (30 ml) at 0° C. under at atmosphere of nitrogen. The reaction mixture was allowed to stir for 1.5 hours when chloroform (20 ml) and water (50 ml) were added. After mixing the layers were separated using a hydrophobic frit, the aqueous layer was washed with an additional portion of chloroform and the combined organic extracts were evaporated. The residue was dissolved in dichloromethane and purified on a 110 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate in cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white foam (0.846 g).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[N+](C1C2C(=O)C3C(=C([N+]([O-])=O)C=CC=3)C(=O)C=2C=CC=1)([O-])=O.[N+](C1C2C(=O)C3C(=CC=CC=3[N+]([O-])=O)C(=O)C=2C=CC=1)([O-])=O.C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[N+]([O-])(O)=O.[OH-].[Na+].[H][H].O=O>S(=O)(=O)(O)O.[C].[Pd]>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Agent: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Solvent: O=[N+]([O-])O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 30 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
A 500 ml. electromagnetically stirred autoclave was charged with 5.0 g (0.0178 mole of 1-nitroanthraquinone) of 1-nitroanthraquinone (having a purity of 90% and containing 5% of 1,5-dinitroanthraquinone, 3% of 1,8-dinitroanthraquinone and 2% of 1,6- and 1,7-dinitroanthraquinones) prepared by nitrating anthraquinone with nitric acid in sulfuric acid and roughly purifying the product, 100 g of a 4% aqueous solution of sodium hydroxide (0.1 mole as sodium hydroxide) and 0.15 g of 5% palladium-carbon. The inside of the autoclave was purged with hydrogen, and the 1-nitroanthraquinone was hydrogenated with stirring at 30°C. In about 4 hours, the reaction stopped with the absorption of 0.083 mole of hydrogen. The hydrogen in the autoclave was replaced by nitrogen, and 0.00126 mole, calculated as oxygen, of air was caused to be absorbed by the reaction mixture at 30°C. over the course of 2 hours. The resulting precipitate was separated by filtration together with the catalyst. The filtrate was oxidized with air. The crystals precipitated were filtered, washed with water, and dried to afford 3.81 g of 1-aminoanthraquinone. As a result of a thin-layer chromatographic analysis, this product was found to be free from 1,5- and 1,8-diaminoanthraquinones and contain only traces of other diaminoanthraquinones. The purity of the product was more than 99% when determined by infrared absorption spectroscopy. The yield of the product was 95% on a purity basis.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(O/[CH:12]=[C:13](/[C:19](=O)[C:20]([F:23])([F:22])[F:21])\[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.[Cl-].[Na+].O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]1[C:19]([C:20]([F:21])([F:22])[F:23])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[N:2]1
Reactant: NNc1ccccn1
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccccn2)c1C(F)(F)F
Temperature: -33.5 °C
Reaction time: 0.67 h
Yield: 81.3 %

Procedure:
A solution of 2-hydrazinopyridine (5 g, 45.8 mmol) in THF (200 mL) under nitrogen was cooled in a dry ice/isopropanol bath to −34° C. A solution of (Z)-ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (11 g, 45.8 mmol) in THF (73 mL) was added in a slow stream over 25 minutes, with nitrogen flush. During the addition, the internal reaction temperature averaged −34° C., and never exceeded −31° C. After completion of the addition, stirring at −33.5° C. was continued for ˜40 min. Additional (Z)-ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (0.89 mL, 0.10 eq) was added and stirring at −30° C. was continued for 11 min. EtOAc (270 mL) was added along with sat. aq. NaHCO3 solution (250 mL) and brine (20 mL). The layers were separated and the organic layer was washed with sat. aq. NaHCO3 solution, brine, then dried (Na2SO4) and concentrated under vacuum to yield an orange viscous oil. Flash chromatography on silica gel yielded ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (10.62 g) as a yellow solid. The compound had an HPLC retention time=2.5 min.−Column: YMC COMBISCREEN® ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=286.1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]1[CH2:36][C@@:34]2([CH3:35])[C@@H:30]([CH2:31][CH2:32][C@@H:33]2[OH:37])[C@@:29]2([CH:38]=[CH2:39])[C@H:20]1[C:21]1[CH:22]=[CH:23][C:24]([OH:40])=[CH:25][C:26]=1[CH2:27][CH2:28]2>>[N:1]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]2[CH2:36][C@@:34]3([CH3:35])[C@@H:30]([CH2:31][CH2:32][C@@H:33]3[OH:37])[C@@:29]3([CH:38]=[CH2:39])[C@H:20]2[C:21]2[CH:22]=[CH:23][C:24]([OH:40])=[CH:25][C:26]=2[CH2:27][CH2:28]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCCl)C[C@@]1(C)[C@H]2CC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCN1CCCC1)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with pyrrolidine (10 equivalents) with the addition of sodium carbonate analogously to instructions 17.2, 32 mg of mixture 30b yields 33 mg of amine 33b as a colorless foam (GC-MS: m/z theor.: 451, pract.: 451).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][NH:6][C:7]1[C:15]2[O:14][CH:13]([CH2:16][CH3:17])[CH2:12][C:11]=2[C:10]([CH3:18])=[CH:9][CH:8]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=O)C=1.COC(NNC1C2OC(C)CC=2C(C)=CC=1)=O>>[CH3:1][O:2][C:3]([N:5]=[N:6][C:7]1[C:15]2[O:14][CH:13]([CH2:16][CH3:17])[CH2:12][C:11]=2[C:10]([CH3:18])=[CH:9][CH:8]=1)=[O:4]
Reactant: CCC1Cc2c(C)ccc(NNC(=O)OC)c2O1
Agent: COC(=O)NNc1ccc(C)c2c1OC(C)C2
Agent: O=C(OO)c1cccc(Cl)c1
Product: CCC1Cc2c(C)ccc(N=NC(=O)OC)c2O1

Procedure:
6 was prepared, as a red syrup by treating 6B with MCPBA, according to the procedure described in Example 1 for preparing 1 from 1F.
Reaction SMILES: [OH:1][CH:2]([CH:29]1[CH2:33][O:32]C(C)(C)[O:30]1)[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14](=[O:28])(=[O:27])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[C:23]([F:26])([F:25])[F:24])[CH:9]=1)(=[O:7])=[O:6].O>CO>[OH:1][CH:2]([CH:29]([OH:30])[CH2:33][OH:32])[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14](=[O:28])(=[O:27])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[C:23]([F:25])([F:26])[F:24])[CH:9]=1)(=[O:6])=[O:7]
Reactant: CC1(C)OCC(C(O)CNS(=O)(=O)c2cccc(S(=O)(=O)Nc3ccc(F)cc3C(F)(F)F)c2)O1
Solvent: CO
Solvent: O
Product: O=S(=O)(NCC(O)C(O)CO)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Reaction time: 1 h

Procedure:
2.78 g (5 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-benzenesulfonic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in 10 ml of methanol, 10 ml of water and a catalytic amount of cation exchanger Amberlyst 15 are added and boiled for 1 hour. The ion exchanger is filtered off and the filtrate is evaporated to dryness. 2.12 g (4.12 mmol)=82.3% of the theoretical yield of the product is obtained as an amorphous solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([F:12])=[CH:7][C:6]=2[C:5]2[C:13]([CH2:24][C:25](O)=[O:26])=[N:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:17])[C:4]1=2)[CH3:2].[C:28](N1C=CN=C1)([N:30]1C=CN=[CH:31]1)=O.CNC>O1CCCC1>[CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([F:12])=[CH:7][C:6]=2[C:5]2[C:13]([CH2:24][C:25]([N:30]([CH3:31])[CH3:28])=[O:26])=[N:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:17])[C:4]1=2)[CH3:2]
Reactant: CCn1c2ccc(F)cc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CCn1c2ccc(F)cc2c2c(CC(=O)N(C)C)nn(-c3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.6 %

Procedure:
A suspension of 1 g (2.73 mmol) of 5-ethyl-8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid and of 0.7 g (4.3 mmol) of 1,1′-carbonylbis-1H-imidazole in 200 ml of tetrahydrofuran is stirred for 3 h at 50° C. The reaction mixture is cooled to 25° C., an excess of liquefied dimethylamine is added and the reaction mixture is stirred for 12 h at room temperature. It is concentrated under reduced pressure, 100 ml of dichloromethane and 100 ml of water are added and the organic phase is separated, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The resulting oil crystallizes from ether. After filtering and recrystallizing from ethyl acetate, 0.75 g (1.9 mmol) of white crystals is isolated.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:34]([C:37]1[CH:44]=[C:43]([Br:45])[CH:42]=[C:41]([CH:46]([CH3:48])[CH3:47])[C:38]=1[CH:39]=O)([CH3:36])[CH3:35]>C1COCC1>[CH:34]([C:37]1[CH:44]=[C:43]([Br:45])[CH:42]=[C:41]([CH:46]([CH3:48])[CH3:47])[C:38]=1[CH:39]=[CH:2][O:3][CH3:4])([CH3:36])[CH3:35]
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1C=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=Cc1c(C(C)C)cc(Br)cc1C(C)C
Temperature: 0 °C
Yield: 78.8 %

Procedure:
Methoxymethyl triphenylphosphonium chloride (18.68 g, 54.5 mmol) was suspended in 200 mL of THF at −78° C. Lithium hexamethyldisilazide (1.0 M in THF, 50 mL) was added dropwise. The resulting mixture was warmed up to 0° C. with stirring. After cooling the solution to −78° C., 2,6-diisopropyl-4-bromobenzaldehyde (11.5 g, 42.7 mmol) in 20 mL of THF was added dropwise. The mixture was slowly warmed up to room temperature and continually stirred overnight. After regular work up, the crude product was distilled at 165° C. under vacuum to afford 2,6-diisopropyl-4-bromo-β-methoxystyrene (10 g). This product was dissolved in 20 mL of dioxane and 100 mL of 18% HCl solution and refluxed at 100° C. for 6 h. After regular work up, the crude product was distilled at 160° C. under vacuum to afford 2,6-diisopropyl-4-bromophenylacetaldehyde (7.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=O.[C:15]([O:19][C:20](=[O:24])[CH2:21][CH2:22][NH2:23])([CH3:18])([CH3:17])[CH3:16].[BH4-].[Na+]>S([O-])([O-])(=O)=O.[Mg+2].ClCCl>[C:15]([O:19][C:20](=[O:24])[CH2:21][CH2:22][NH:23][CH2:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc2ccccc2c1C=O
Reactant: CC(C)(C)OC(=O)CCN
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc2ccccc2c1CNCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.4 %

Procedure:
To a solution of 0.559 g (3 mmol) 2-methoxynaphthaldehyde and 0.436 g (3 mmol) 3-aminopropionic acid tert-butyl ester in 6 ml of dichloromethane magnesium sulphate was added and the mixture was shaken for 18 h at room temperature. Magnesium sulphate was separated from the reaction mixture and washed two times with dichloromethane. After evaporating the combined organic layers the residue was re-dissolved in methanol. To the stirred and cooled (0° C.) solution 227 mg (6 mmol) sodium borohydride was added in small portions. Stirring was continued for 1 h at 0° C. Methanol was evaporated, water (50 ml) was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petrolether/ether=1:1) to yield 297 mg (31%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]1[S:12](=[O:14])(=[O:13])[O:11][CH2:10][CH2:9]1>C(#N)C>[C:2]1([NH2+:1][CH2:10][CH2:9][CH2:8][S:12]([O-:14])(=[O:13])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: Nc1ccccc1
Solvent: CC#N
Product: O=S(=O)([O-])CCC[NH2+]c1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of aniline (7 mmol) and propane sultone (10 mmol) was heated in 10 mL of acetonitrile at 12.0-130° C. for 9 h in a pressure tube under argon atmosphere. The product was allowed to cool to room temperature and the solid of 3-phenylammonio-1-propanesulfonate was filtered and air-dried. Yield: 95%.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[CH2:12][CH2:13][CH:14]=1.Cl>C1COCC1>[CH3:25][O:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[CH2:15][N:11]1[CH2:12][CH2:13][CH:14]=[C:9]([CH2:8][CH2:7][C:6]([OH:27])=[O:5])[C:10]1=[O:26]
Reactant: COC(=O)CCC1=CCCN(Cc2ccc(OC)cc2OC)C1=O
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CCC=C(CCC(=O)O)C2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
11 mg of LiOH.H2O solution (0.26 mmol) was added to 0.75 ml of THF solution containing 58 mg of 3-[1-(2,4-dimethoxy benzyl)-2-oxo-1,2,5,6-tetrahydro pyridine-3-yl]-propionic acid methyl ester (d) (0.17 mmol) in a dropwise manner at 0° C. After the reaction mixture was stirred for 2 hrs at 0° C. and for 1 hr at room temperature, 5% HCl was added to the mixture to pH 2. Then 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 methanol/chloroform (1:10) solvent mixture as an eluant to give 44 mg of the title compound (f1) (yield: 80%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:31]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH:32]([F:34])[F:33])=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:31]([NH:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:32]([F:34])[F:33])=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2)C(F)F)cc1
Yield: 99.7 %

Procedure:
TFA (2.50 mL) was added to a stirred solution of N-(5-chloro-2-{2,2-difluoro-1[(4-methoxyphenyl)amino]ethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamide (0.256 g, 0.49 mmol) in CH2Cl2 (5.0 mL). After 1 h the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and saturated aqueous Na2CO3. The organic layer was dried (Na2SO4) and evaporated in vacuo to give the N-(5-Chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-L-prolinamide (0.207 g) as a gum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C@@H:19]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Sc2ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)c1
Temperature: 63 °C

Procedure:
To a solution of N-[[4-[(3-methylphenyl)thio]phenyl]sulfonyl]-D-valine, 1,1-dimethylethyl ester, from Example 1c (3.96 g, 9.08 mmol) in 30 mL DMF was added 4-(2-chloroethyl)-morpholine hydrochloride (5.07 g, 27.2 mmol) and K2CO3 (3.76 g, 27.2 mmol). The solution was heated to 63° C. for 24 hours. Additional K2CO3 (1.25 g, 9.08 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride (1.69 g, 9.08 mmol) was added and the mixture heated for an additional 24 hours at 63° C. The mixture was then partitioned between ethyl acetate and H2O, and the organic was washed with sat'd NaCl (3×30 mL) and dried over MgSO4. After concentration in vacuo, the residue was purified by flash chromatography (20:80 hexane/EtOAc) to afford N-[[4-[(3-methylphenyl)thio]phenyl]sulfonyl)-N-[2-(4-morpholinyl)ethyl]-D-valine, 1,1-dimethylethyl ester, as a white solid (5.21 g): MS MH+ calc'd for C28H41N2O5S2 : 549, found: 549. HRMS calc'd for C28H41N2O5S2 : 548.2379; found: 548.2384.