Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11](Cl)=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](OP(=O)=O)(C)C>>[C:2]1([C:1]2[O:8][C:11]3[C:10]([N:9]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccnc1Cl)c1ccccc1
Agent: C[Si](C)(C)OP(=O)=O
Product: c1ccc(-c2nc3cccnc3o2)cc1

Procedure:
1.9 g (8 mmol) of 3-benzoylamino-2-chloropyridine, prepared in stage A, are added to the PPSE solution and then brought to reflux for 15 hours. The 1,2-dichlorobenzene is then evaporated off under vacuum. The residue is treated with a water/ice mixture. The pH of the solution is adjusted to 7-8 with 5% sodium bicarbonate solution. The precipitated product is filtered off and then recrystallized in cyclohexane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16])#[N:2].C[N+]1([O-])CC[O:23]CC1.OS([O-])=O.[Na+].[OH2:32].CC(C)=O>C(O)(C)(C)C.O.[Os](=O)(=O)(=O)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:14])[C:11]([OH:23])([CH3:13])[CH2:12][OH:32])=[CH:5][C:4]=1[C:15]([F:17])([F:16])[F:18])#[N:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: CC(O)(CO)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 50 ml flask, equipped with a magnetic stirrer, 0.50 g of the compound (7) in 1.8 ml of tert-butyl alcohol was added to a mixture of 0.301 g of N-methylmorpholine-N-oxide (=NMO) (monohydrate) and 16 mg of osmium tetroxide in 15 ml of a water/acetone mixture (5:2). The reaction mixture was stirred at room temperature overnight. The conversion was ˜60%. Another 0.30 g of NMO (monohydrate) and 16 mg of osmium tetroxide were added and the reaction was followed with HPLC. Stirring was continued for 3.5 hours. The reaction was worked-up by addition of a slurry of 1.0 g NaHSO3 and 1.0 g of Celite in 40 ml of water. The Celite was removed by filtration, and the filtrate was neutralised to pH 7.0 with 1N aqueous H2SO4, and the acetone was removed at reduced pressure. The remaining solution was set to pH 2.0 with 1N aqueous H2SO4 and was extracted with 3×35 ml of ethyl acetate. The combined organic layers were washed with 35 ml of brine, dried (Na2SO4) and concentrated at reduced pressure. The crude product was purified by column chromatography (Merck 60 SiO2, eluens ethyl acetate) to give the purified (5C) as a slightly coloured oil, which solidified (off-white solid) after a few days. Isolated yield: 0.400 gram (70.5%). 1H-NMR confirmed the structure.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH:10]=1.C(O)(=O)C>C(O)C.O.[Fe]>[F:28][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2ccccc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccccc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Yield: 80.5 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-nitrophenyl)isonicotinamide (350 mg, 0.87 mmol, 1.00 equiv) in ethanol/H2O (1/1) (30 mL), iron (489 mg, 8.73 mmol, 10.00 equiv), and acetic acid (0.1 mL). The resulting solution was heated to reflux for 0.5 h. The solids were filtered out. The resulting solution was extracted with of ethyl acetate and the organic layers combined and dried over magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The product was obtained as 260 mg (80%) of a yellow solid.
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=O)[CH2:5][C:4]1([CH3:13])[CH3:12].[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>[Pt].CO>[CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([NH:18][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:5][C:4]1([CH3:13])[CH3:12]
Reactant: CCCCN
Reactant: CON1C(C)(C)CC(=O)CC1(C)C
Agent: [Pt]
Solvent: CO
Product: CCCCNC1CC(C)(C)N(OC)C(C)(C)C1
Yield: 80.2 %

Procedure:
A mixture of 10.1 g (54.5 mmol) of 1-methoxy-2,2,6,6-tetramethylpiperidin-4-one, 27.9 g (382 mmol) of n-butyl amine, 100 ml of methanol, and 1.0 g of 5% platinum on carbon is hydrogenated (50 psi, 25° C.) for 5 hours. The catalyst is removed by filtration. Evaporation of the filtrate gives an oil which is purified by fractional distillation to afford 10.6 g (80% yield) of the title compound, a colorless oil, b.p. 93°-100° C. (0.25 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(F)n1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1cccc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=308.2 (M+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-fluoro-6-methylpyridine.
Reaction SMILES: [OH:1][C@:2]1([C@@H:17]2[CH2:21][S:20][C:19](=[O:22])[N:18]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:7][C@H:6]([OH:8])[CH2:5][C@@H:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:3]1.O[C@:33]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@@H](O)C[C@@H](CCCC=C)O1>>[OH:8][C@@H:6]1[CH2:5][C@@H:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:3][C@:2]([C@@H:17]2[CH2:21][S:20][C:19](=[O:22])[N:18]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([O:1][CH3:33])[CH2:7]1
Reactant: C=CCCC[C@@H]1C[C@H](O)C[C@](O)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(O)C[C@H](O)C[C@@H](CCc3ccccc3)O2)cc1
Product: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H](O)C[C@@H](CCc3ccccc3)O2)cc1

Procedure:
Application of the method shown in Example 13, with the modification that (R)-4-((2R,4R,6R)-2,4-dihydroxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one is substituted for (R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:7])[CH2:6][CH2:5][CH2:4]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][C:3]1([NH:7][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:6][CH2:5][CH2:4]1
Reactant: CC1(N)CCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1(NS(C)(=O)=O)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
To a stirred solution of 1-methyl-cyclobutylamine hydrochloride (0.100 g, 0.8 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.095 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The mixture was diluted with ethyl acetate and washed with 2 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown oil (0.090 g, 67%). 1H NMR (300 MHz, CDCl3) δ 4.49 (br s, 1H), 3.03 (s, 3H), 2.40-2.25 (m, 2H), 2.12-2.00 (m, 2H), 1.95-1.75 (m, 2H), 1.58 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:14]2[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Br:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][C:24](Br)=[CH:25][CH:26]=2)[CH:21]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(COC)OC>[Br:19][C:20]1[CH:21]=[C:22]2[C:27]([CH:26]=[CH:25][C:24]([C:12]3[CH:11]=[CH:10][C:9]4[C:8]5[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:2]([CH3:1])([CH3:18])[C:14]=4[CH:13]=3)=[CH:23]2)=[CH:28][CH:29]=1
Reactant: CC1(C)c2ccccc2-c2ccc(B(O)O)cc21
Reactant: Brc1ccc2ccc(Br)cc2c1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CC1(C)c2ccccc2-c2ccc(-c3ccc4ccc(Br)cc4c3)cc21
Temperature: 85 °C
Reaction time: 9 h
Yield: 48 %

Procedure:
In argon atmosphere, a mixture of 16.65 g (69.9 mmol) of 9,9-dimethyl-9H-fluorene-2-ylboronic acid, 20.00 g (69.9 mmol) of 2,7-dibromonaphthalene, 4.04 g (3.50 mmol) of tetrakis(triphenylphosphine)palladium (0), 200 ml of toluene, 200 ml of dimethoxyethane, and 106 g of a 2 M sodium carbonate aqueous solution was stirred at 85° C. for 9 h and left standing overnight. The reaction mixture was added with water and stirred at room temperature for one hour. After filtration, the filtrate was extracted with toluene. The organic phase was washed with water and then with a saturated saline solution and dried over sodium sulfate, and then the toluene was removed by distillation under reduced pressure. The obtained brown oily substance was purified by silica gel chromatography to obtain 13.4 g (yield: 48%) of 2-(7-bromonaphthalene-2-yl)-9,9-dimethyl-9H-fluorene.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([O:18]C)=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-]>CO.O>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
Methyl(2S,4S)-1-Boc-4-azidopyrrolidine-2-carboxylate (10 g, 37 mmol) obtained in Step D of Preparation 1 was dissolved in MeOH (100 mL) and water (100 mL). LiOH (2.5 g, 111 mmol) was added thereto. The reaction solution was stirred for 3 hours at room temperature, concentrated in vacuo and acidify with 1N HCl. The solution was extracted with EtOAc. The extracted organic solution was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (9.5 g, 95%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]1([CH:18]=[CH:19][CH:20]([OH:23])[C:21]#[CH:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:12]1(/[CH:18]=[CH:19]/[C:20](=[O:23])/[CH:21]=[CH:22]/[C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#CC(O)C=Cc1ccccc1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccc1)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
4-iodobenzotrifluoride (150 μL, 1 mmol), phenylpent-1-en-4-yn-3-ol (190 mg, 1.2 mmol), bis(triphenylphosphine)palladium(II) dichloride (14 mg, 0.02 mmol), copper iodide (3 mg, 0.03 mmol) and triphenylphosphine (52 mg, 0.2 mmol) were introduced in a 10 mL microwave vial flushed with argon. This was diluted with anhydrous triethylamine (700 μL, 4 mmol) in anhydrous degased 1,4-dioxane (1.3 mL). The solution was heated under microwave irradiation at 120° C. for 45 min. The reaction mixture was poured into a mix of 1M aqueous solution of hydrochloric acid (10 mL) and saturated aqueous ammonium chloride solution (10 mL), and this was extracted with dichloromethane (3×15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to give crude product which was purified by flash chromatography (SiO2, DCM/Hexanes 3:7). The resulting yellow solid was recrystallized (EtOH/Hexanes 1:3) to give pure final compound TG008A86 as a pale yellow powder (155 mg, 51%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12](=[O:14])[CH3:13])=[CH:4][N:3]=1.[CH3:15][S-:16].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH:9]([NH:8][C:6]1[C:5]([C:12](=[O:14])[CH3:13])=[CH:4][N:3]=[C:2]([S:16][CH3:15])[N:7]=1)([CH3:11])[CH3:10]
Reactant: CC(=O)c1cnc(Cl)nc1NC(C)C
Reactant: C[S-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1ncc(C(C)=O)c(NC(C)C)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
1-(2-chloro-4-isopropylamino-pyrimidin-5-yl)-ethanone (11.1 g, 0.052 mol) and sodium thiomethoxide (5.75 g, 0.078 mol) are taken up in 100 mL dioxane and stirred for 16 h at 20° C. The solvent is eliminated in vacuo, the residue is taken up in ethyl acetate and extracted 2× with water. The organic phase is dried, the solvent is eliminated in vacuo and 1-(4-isopropylamino-2-methylsulphanyl-pyrimidin-5-yl)-ethanone (HPLC-MS: tRet.=1.82 min, MS(M+H)+=226; method FECB3) is obtained.
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O.C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccccc1OCC(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccccc1OCC(F)F
Yield: 90 %

Procedure:
The 1-(2,2-difluoro-ethoxy)-2-nitro-benzene (2.16 mmol) was dissolved in a 1:1-mixture of ethanol and ethyl acetate in order to obtain a final concentration of 0.05M. Hydrogenation was performed at 60° C., 1 bar of hydrogen and with palladium on charcoal (10%) as the catalyst. After evaporation of the solvent the title compound was obtained in 90% yield and could be used in the next step without further purification; (calculated) C8H9F2NO [173.16]; (found) [M+H]+=174.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:28]([O:30][CH3:31])=[O:29])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21](=[O:23])[CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:28]([O:30][CH3:31])=[O:29])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([OH:23])[CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Cc1ccccc1-3
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(O)Cc1ccccc1-3
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Sodium borohydride (50 mg, 1.3 mmol) was added to a solution of methyl 13-cyclohexyl-6,7-dihydro-6-oxo -5H-indolo[2,1-a][2]benzazepine-10-carboxylate (29 mg, 0.074 mmol) in methanol (4 mL) and tetrahydrofuran (2 mL) at rt. The evolution of H2 was instantaneous and stirring was continued for 30 min at rt. The mixture was concentrated on a rotary evaporator and and the residue purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (27.5 mg, 96%). ESI-MS m/z 390 (MH+); 1H NMR (500 MHz, CHLOROFORM-D) □ 1.18–1.31 (m, 1 H) 1.32–1.53 (m, 2 H) 1.60–1.70 (m, 1 H) 1.71–1.84 (m, 2 H) 1.86–2.18 (m, 4 H) 2.38–3.12 (m, 3 H) 3.36–3.83 (m, 1 H) 3.94 (m, 3 H) 4.39–4.68 (m, 2 H) 7.32–7.48 (m, 4 H) 7.76 (t, J=8.39 Hz, 1 H) 7.88 (t, J=8.09 Hz, 1 H) 8.14 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:27][CH3:28])[C:22](OCC)=[O:23])[C:11](=[O:29])[C@@H:10]([CH2:30][C:31]([OH:33])=[O:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+].CO>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:27][CH3:28])[CH2:22][OH:23])[C:11](=[O:29])[C@@H:10]([CH2:30][C:31]([OH:33])=[O:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](CC)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: CC[C@@H](CO)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 300 mg (0.61 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3) in 12 mL of Et2O was added lithium tetrahydroborate (39.8 mg, 1.83 mmol) at 0° C. After being stirred for 20 min, methanol (37.0 μl, 914 μmol) was added at 0° C. and the resulting solution was stirred at 25° C. for 2 h. The reaction was quenched (10% citric acid), extracted (2×EtOAc) and washed (1×sat. aq. NaCl solution). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 35 to 75% acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) provided the title compound as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16](=[O:25])[CH:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:14][O:15][C:16](=[O:25])[CH:17]([NH:24][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C(N)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1ccccn1
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To (S)-2-tert-Butoxycarbonylamino-propionic acid (1.54 g, 8.12 mmol), Amino-pyridin-2-yl-acetic acid methyl ester (1.35 g, 8.12 mmol) and HATU (3.1 g, 8.12 mmol) was added the DMF (20 mL) and Et3N (2.26 ml, 16.20 mmol) and the solution was stirred for 2 h. The mixture was concentrated to remove most of the DMF was removed. The resulting oil was dissolved in EtOAc, washed with water, 0.1 N HCl aq., 1 N NaHCO3 aq., followed by Brine. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo to provide ((S)-2-tert-Butoxycarbonylamino-propionylamino)-pyridin-2-yl-acetic acid methyl ester (2.7 g, 98%) as a yellow oil, m/z 338.61 [M+1]+
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:9](S(C(F)(F)F)(=O)=O)[S:10]([C:13]([F:16])([F:15])[F:14])(=O)=[O:11]>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([O:8][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cccnc1Br
Solvent: c1ccncc1
Product: O=S(=O)(Oc1cccnc1Br)C(F)(F)F
Temperature: 23 °C
Reaction time: 1.25 h
Yield: 94 %

Procedure:
To a solution of 2-bromo-3-hydroxypyridine[CAS 6602–32–0, commercially available] (25.0 g, 144 mmol) in anhydrous pyridine (145 mL) at −10° C. (ice/NaCl) was drop wise added Tf2O (24.2 mL, 147 mmol) keeping the temperature below −5° C. (30 min). The cooling bath was removed and mixture was allowed to reach 23° C., stirred at 23° C. for 75 min, poured into sat. NaHCO3-sol., extracted with DCM, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by vacuum distillation: bp 65° C. (0.82 mbar) (42 g colorless oil, with some solid); triturated with hexane, filtered the undesired solid off, washed with hexane, collected the mother liquor, evaporated the solvent to give the title compound as a colorless liquid (41.52 g, 94%). MS (TOF ESP) 306 [(M+H)+], 307.85 [(M+2+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][CH2:31]CS([O-])(=O)=O)[CH2:13][C:12](=[O:14])[N:11]([C:15](=[O:28])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:38]1([C:44]2([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][CH2:31][N:47]3[CH2:46][CH2:45][C:44]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48]3)[CH2:13][C:12](=[O:14])[N:11]([C:15](=[O:28])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CC(CCCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CC(CCCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the method of example 3.3 using 3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-5-oxo-pyrrolidin-3-yl]-propyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C@@H:14]([CH3:15])[CH2:13][O:12][C@H:11]([CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[NH2:8].[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH:32]=O)=[N:28][NH:29]2)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([C:32]3[NH:8][C:7]4[CH:6]=[CH:5][C:4]([N:9]5[C@@H:14]([CH3:15])[CH2:13][O:12][C@H:11]([CH2:16][N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[CH2:10]5)=[CH:3][C:2]=4[N:1]=3)=[N:28][NH:29]2)=[CH:25][CH:24]=1
Reactant: CCN(CC)C[C@@H]1CN(c2ccc(N)c(N)c2)[C@@H](C)CO1
Reactant: O=Cc1n[nH]c2cc(F)ccc12
Product: CCN(CC)C[C@@H]1CN(c2ccc3[nH]c(-c4n[nH]c5cc(F)ccc45)nc3c2)[C@@H](C)CO1

Procedure:
The title compund is synthesized according to the general procedure described in Example 4 with {[(2R,5S)-4-(3,4-diaminophenyl)-5-methylmorpholin-2-yl]methyl}diethylamine and 6-fluoro-1H-indazole-3-carbaldehyde.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7](O)[C:6]([NH2:10])=[C:5](O)[N:4]=1.P(Cl)(Cl)([Cl:14])=O>[Cl-].C([N+](CC)(CC)CC)C>[NH2:2][C:3]1[N:8]=[C:7]([Cl:1])[C:6]([NH2:10])=[C:5]([Cl:14])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)c(N)c(O)n1
Reactant: Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Product: Nc1nc(Cl)c(N)c(Cl)n1
Yield: 50 %

Procedure:
Dry 2,5-Diamino-4,6-dihydroxypyrimidine hydrochloride (1.8 g), tetraethyl ammonium chloride (9.8 g) (dry) and phosphorus oxychloride (5.5 ml) were heated at 105° for 20 hours. The reaction mixture was processed as in Example 1 on a smaller scale to give 0.9 g (50% yield) 2,5-diamino-4,6-dichloropyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C#N)[CH:15]=3)[N:10]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][O:26][CH2:27][CH2:28][C:29]([OH:31])=O.Cl.[CH3:33][N:34](C)CCCN=C=NCC>ClCCl>[C:33]([CH:22]1[CH2:21][O:20][CH:19]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:29](=[O:31])[CH2:28][CH2:27][O:26][CH3:25])[CH:7]=[CH:6][CH:5]=3)=[N:9]2)[CH2:24][CH2:23]1)#[N:34]
Reactant: COCCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: Cl
Solvent: ClCCl
Product: COCCC(=O)Nc1cccc(-c2nn(C3CCC(C#N)CO3)c3ccccc23)c1

Procedure:
The title compound was prepared as described in example 222B using 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.300 g, 0.94 mmol) in dichloromethane (10 mL), 3-methoxypropionic acid (0.097 mL, 1.034 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.216 g, 1.13 mmol). The product was used without chromatographic purification (0.437 g, quantitative yield): ES-MS (m/z) 405 [M+H]+.