Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)[C:3]=1[CH:22]=[O:23].[CH3:24][N:25]1[C:30](=[O:31])[C:29]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][N:42]([CH:45]4[CH2:48][O:47][CH2:46]4)[CH2:41][C@H:40]3[CH3:49])=[CH:35][N:34]=2)=[CH:28][C:27](C2C(C=O)=C(N3C=CN4C5CCCCC=5C=C4C3=O)N=CC=2)=[CH:26]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:24][N:25]1[C:30](=[O:31])[C:29]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][N:42]([CH:45]4[CH2:46][O:47][CH2:48]4)[CH2:41][C@H:40]3[CH3:49])=[CH:35][N:34]=2)=[CH:28][C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[S:18][C:17]5[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=5[C:11]=4[CH:10]=[N:9]3)[C:3]=2[CH:22]=[O:23])=[CH:26]1
Reactant: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ccn5c6c(cc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridine-3-carbaldehyde 124a (84 mg, 0.24 mmol), (R)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 151g (173 mg, 0.36 mmol), PdCl2(dppf) (20 mg, 0.024 mmol), K3PO4 (100 mg, 0.48 mmol), sodium acetate (40 mg, 0.48 mmol), acetonitrile (20 mL), and water (2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 154a as a red solid (112 mg, 70%). MS-ESI: [M+H]+ 665
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][O:4][C:5](=[O:33])[C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21](=O)[CH2:22][S:23](=[O:29])(=[O:28])[NH:24][CH:25]([CH3:27])[CH3:26])=[C:9]([CH3:31])[NH:8][C:7]=1[CH3:32].[BH4-].[Na+].C(Cl)Cl.C(OCC)(=O)C>C(O)(C)C>[F:34][C:2]([F:1])([F:35])[CH2:3][O:4][C:5](=[O:33])[C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10](/[CH:21]=[CH:22]/[S:23](=[O:28])(=[O:29])[NH:24][CH:25]([CH3:27])[CH3:26])=[C:9]([CH3:31])[NH:8][C:7]=1[CH3:32]
Reactant: CC1=C(C(=O)CS(=O)(=O)NC(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC(F)(F)F)=C(C)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1=C(/C=C/S(=O)(=O)NC(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC(F)(F)F)=C(C)N1
Yield: 82.7 %

Procedure:
Analogously to Example 18, a solution of 1.56 g of 1,4-dihydro-5-[(isopropylsulfamoyl)acetyl]-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid 2,2,2-trifluoroethyl ester in 15 ml of isopropanol was treated with 0.12 g (3 mmol) of sodium borohydride. After chromatography with methylene chloride/ethyl acetate (4:1) as the elution agent there were obtained 1.25 g of 1,4-dihydro-5-[(E)-2-(isopropylsulfamoyl)vinyl]-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid 2,2,2-trifluoroethyl ester in the form of yellow crystals, m.p. 180°-182°. Recrystallization from isopropanol did not increase the melting point.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:3][CH2:4][CH:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCNC(CCO)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (7.28 g, 28.2 mmol) was dissolved in THF (100 mL) at 0° C. then added LAH (21.14 mL, 21.14 mmol). The reaction was monitored by TLC. After 30 mins, the reaction was first quenched with 0.8 mL water, then added 1.6 mL 2N NaOH followed by 4 mL water. The above slurry was diluted with ethyl acetate and MgSO4 was added. The mixture was stirred at RT for ½ h, then filtered and concentrated to yield the title compound: LC-MS (IE, m/z): 231 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:2]1.C([BH3-])#N.[Na+]>C(O)(=O)C.[OH-].[Na+].ClCCl>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH2:2]1)[CH3:15]
Reactant: CCOC(=O)Cc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CC1CNc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Ethyl indole-3-acetate (4 g, 19 mmol, 98%) was taken up in acetic acid (40 cm3) and sodium cyanoborohydride (4 g, 63 mmol) was added. The reaction was stirred at room temperature for 2 h, then diluted with aqueous sodium hydroxide until basic. The aqueous mixture was extracted with ethyl acetate and the organic layer was separated, dried and concentrated to dryness under reduced pressure. The solid obtained was taken up in dichloromethane and chromatographed on silica eluting with dichloro-methane with increasing volumes of methanol. The product containing fractions were combined and concentrated to yield ethyl-2,3-dihydro-indole-3-acetate as a solid (3 g, 15 mmol, 78%).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[CH:32]1([C:35]([N:29]2[CH2:28][CH2:27][N:26]([C:24]([C:6]3[N:5]([CH:2]([CH3:3])[CH3:4])[C:13]4[C:8]([CH:7]=3)=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=4)=[O:25])[CH2:31][CH2:30]2)=[O:36])[CH2:34][CH2:33]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(C(=O)C4CC4)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and cyclopropanoyl chloride. Light-yellow solid. MS (m/z): 481.5 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:13]2[NH:12][C:11]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:10]=3[C:9]=2[CH:8]=[CH:7][CH:6]=1.[O:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH3:3][O:4][C:5]1[C:13]2[N:12]([CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[OH:19])[C:11]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:10]=3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2c3c([nH]c12)CCN(C)C3
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c3c(n(CC(O)c4ccncc4)c12)CCN(C)C3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.6 %

Procedure:
Sodium hydride (60%) (555 mg, 13.88 mmol) was added portionwise to a solution of 6-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 4.629 mmol) in DMF (10 mL) and stirred at RT for 15 min, the suspension was allowed to cool at 0° C. 4-(Oxiran-2-yl)pyridine (896 mg, 7.407 mmol) was added dropwise and reaction mixture was stirred at RT for 48 h. The reaction mixture was poured in to ice-cooled water and extracted with EtOAc (3×50 mL), and the organic layer was washed with water (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo, afforded crude was purified by reverse phase HPLC to afford 2-(6-methoxy-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol (165 mg) as the formate salt. 1H NMR (CDCl3, freebase) δ (ppm): 8.60 (d, 2H), 7.31 (d, 2H), 7.02 (m, 2H), 6.66 (d, 1H), 5.08 (dd, 1H), 4.66 (dd, 1H), 4.12 (dd, 1H), 3.99 (s, 3H), 3.60 (d, 1H), 3.56 (d, 1H), 2.9 (m, 1H), 2.81 (m, 1H), 2.72 (m, 1H), 2.64 (m, 1H), 2.55 (s, 3H). Separation by chiral HPLC provided enantiomers 44a and 44b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:23]=[C:24](\[CH3:30])/[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([CH3:22])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C2CCCCO2)=[CH:11][N:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:23]=[C:24](\[CH3:30])/[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([CH3:22])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][N:10]=1
Reactant: CCOC(=O)/C(C)=C/c1cc(C)c(Oc2ccc(OC3CCCCO3)cn2)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)/C(C)=C/c1cc(C)c(Oc2ccc(O)cn2)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of ethyl (E)-3-(3-chloro-5-methyl-4-{[5-(tetrahydro-2H-pyran-2-yloxy)pyridin-2-yl]oxy}phenyl)-2-methylprop-2-enoate (2.58 g) in EtOH (40 mL) was added p-toluenesulfonic acid (1.14 g) at room temperature, then the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=10/1 to 2/1) to afford ethyl (E)-3-{3-chloro-4-[(5-hydroxypyridin-2-yl)oxy]-5-methylphenyl}-2-methylprop-2-enoate as a colorless amorphous (1.98 g).
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH3:11][SiH:12]([CH3:14])Cl.Cl>BrCCBr.O1CCCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([SiH:12]([CH3:14])[CH3:11])=[CH:6][CH:5]=1
Reactant: COc1ccc(Br)cc1
Reactant: C[SiH](C)Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1ccc([SiH](C)C)cc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
In a flask under a nitrogen atmosphere were placed 2.54 g (0.104 mole) of magnesium metal and approximately 25 mL of dry tetrahydrofuran. To this mixture was added a few drops of 1,2-dibromoethane. This was followed by the slow addition of a solution of 19.54 g (0.104 mole) of 4-methoxybromobenzene in 30 mL of tetrahydrofuran. After completion of addition, this reaction mixture was heated at reflux for one hour and was then cooled to room temperature. Slowly 9.89 g (0.105 mole) of dimethylchlorosilane was added to the reaction mixture which was then heated at reflux for one hour. To this was added 50 mL of 1 N hydrochloric acid, and the organic and aqueous phases were separated. The aqueous phase was extracted three times with 50 mL of diethyl ether, and these washes were combined with the organic phase. The combined extracts were then washed with 200 mL of a saturated, aqueous solution of sodium chloride and were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, leaving a residue. Distillation of this residue yielded 14.4 g of (4-methoxyphenyl)dimethylsilane as a clear, yellow liquid, b.p. 80-90° C. at 9 mm of Hg. The proton nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([OH:28])([C:9](=[O:27])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[OH:28][C:4]([C:9](=[O:27])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:29])=[O:2]
Reactant: COC(=O)C(O)(CC(C)C)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Yield: 93.6 %

Procedure:
A mixture of 430 mg (1.09 mmol) (R/S)-2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid methyl ester in 6 ml tetrahydrofuran and of 50.1 mg (1.19 mmol) lithiumhydroxide monohydrate in 3 ml water was stirred overnight at room temperature. The solvent was evaporated and the residue extracted at pH 1 with ethylacetate to yield 390 mg (94%) (R/S)-2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid, MS (m/e): 381.0 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS([Cl:47])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26][Cl:47])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(CO)cn4c3-c3ccccc3)cc2)CCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(CCl)cn4c3-c3ccccc3)cc2)CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of {1-[4-(6-hydroxymethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg) in DCM (1.9 mL), was treated with triethylamine (0.062 mL), cooled to 0° C. (ice bath), treated with methanesulfonyl chloride (0.028 mL, 0.358 mmol) and stirred for 2 hours at rt. The reaction mixture was partitioned between DCM and saturated aqueous sodium hydrogen-carbonate solution and the organic phase washed with brine, dried and concentrated in vacuo to give the crude title compound.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH2:7][CH:6]([C:9](=O)[CH2:10][CH:11](OC)[O:12]C)[CH:5]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[N+:2]=[N-:3].[NH2:24]O.Cl>N1C=CC=CC=1>[N:1]([CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][O:12][N:24]=2)[CH:5]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[N+:2]=[N-:3]
Reactant: NO
Reactant: COC(CC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1)OC
Agent: Cl
Solvent: c1ccncc1
Product: [N-]=[N+]=NC1CCC(c2ccon2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
A solution of 130 mg (0.40 mmol) of 3-(SR)-azido-2-(SR)-(4-fluorophenyl)-1-(SR)-(3,3-dimethoxy-1-oxo-propyl)cyclopentane (from Example 97, Step C) in 3 mL of pyridine was treated with 150 mg (2.2 mmol) of hydroxylamine×HCl and stirred at rt for 3 h. The reaction mixture was partitioned between 50 mL of ether and 25 mL of 2.0N HCl and the layers were separated. The organic layer was washed with 25 mL of sat'd NaHCO3, 25 mL of sat'd NaCl, dried over MgSO4 and concentrated in vacuo. A mixture of the crude ketoxime and 200 mg of Amberlyst 15 H+ resin in 4 mL of acetone was heated at reflux for 2 h. The mixture was cooled, the resin filtered and the filtrate concentrated in vacuo. Flash chromatography on 7 g of silica gel using 10:1 v/v hexanes/ether as the eluant afforded 79 mg (72%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]([CH3:27])([CH3:26])[CH2:10]2)[N:5]=[C:4]([O:28][CH:29]2[CH2:34][C:33]([CH3:36])([CH3:35])[N:32]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:31]([CH3:47])([CH3:46])[CH2:30]2)[N:3]=1.[CH2:48]([CH2:50][NH2:51])[OH:49]>>[OH:49][CH2:48][CH2:50][NH:51][C:2]1[N:3]=[C:4]([O:28][CH:29]2[CH2:30][C:31]([CH3:46])([CH3:47])[N:32]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:33]([CH3:35])([CH3:36])[CH2:34]2)[N:5]=[C:6]([O:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]([CH3:26])([CH3:27])[CH2:10]2)[N:7]=1
Reactant: NCCO
Reactant: CCCCCCCCON1C(C)(C)CC(Oc2nc(Cl)nc(OC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(Oc2nc(NCCO)nc(OC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,3,5-triazine with ethanolamine.
Reaction SMILES: [CH3:1][O:2][C:3](C1C=CC=C2C=1NC=C2)=[O:4].[C:14]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](OC(F)(F)F)[CH:24]=2)[N:19]([CH2:31][C:32]([OH:34])=[O:33])[CH:18]=1)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[N:19]([CH2:31][C:32]([OH:34])=[O:33])[CH:18]=[C:17]2[C:14](=[O:16])[CH3:15])=[O:4]
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: COC(=O)c1cccc2c(C(C)=O)cn(CC(=O)O)c12

Procedure:
was prepared from 1H-indole-7-carboxylic acid methyl ester in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. MS: 276 [M+H]+; tR (HPLC conditions k): 2.89 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:16]([O:17][CH3:18])=[CH:15][C:13]([NH2:14])=[C:12]([Cl:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>ClCCl>[C:4]([Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([Cl:19])[C:13]([N:14]=[C:21]=[O:23])=[CH:15][C:16]=1[O:17][CH3:18])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1cc(N)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N=C=O)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 263.5 %

Procedure:
A solution of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-5-methoxyaniline (intermediate 39; 300 mg, 1 mmol) in 4 ml of dichloromethane was cooled externally with an ice bath while dropping a solution of triphosgene (108 mg; 0.36 mmol) in 5 ml of dichloromethane. Triethylamine (0.28 ml; 2.01 mmol) was added slowly and the system stirred at room temperature for 3 hr. Half of the solvent is then evaporated in vacuo and 25 ml of pentane added. The white precipitate of ureas was filtered and the filtrate evaporated to dryness giving 311 mg of the title compound that were used without further purification in the next step.
Reaction SMILES: [CH2:1]([N:4]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3]>C(O)(=O)C.O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:4]2[CH2:1][CH:2]3[C:6]([C:7]([O:9][CH3:10])=[O:8])([CH2:3]3)[C:5]2=[O:11])=[CH:13][CH:14]=1
Reactant: C=CCN(C(=O)CC(=O)OC)c1ccc(F)cc1
Agent: [Cu+2]
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C12CC1CN(c1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 12.1 %

Procedure:
A solution of methyl 3-(allyl(4-fluorophenyl)amino)-3-oxopropanoate (10 g, 39.7 mmol) in acetic acid (50 mL) was added into a suspension of manganese (III) acetate dihydrate (21 g, 79.7 mmol) and copper (II) acetate monohydrate (7.9 g, 39.7 mmol) in acetic acid (200 mL). The reaction was allowed to stir for 3 days at room temperature. The reaction was quenched with 10% aqueous sodium bisulfite solution (100 mL). The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (50% EtOAc in hexane) to afford the product (1.2 g, 12% yield) as a brown power. LRMS (APCI pos) m/e 250.1 (M+1). 1H NMR: (CDCl3, 400 MHz) δ 7.49-7.54 (m, 2H), 7.02-7.07 (m, 2H), 4.02-4.07 (m, 1H), 3.83 (s, 3H), 3.70 (d, 1H), 2.45-2.53 (m, 1H), 2.02-2.09 (m, 1H), 1.29-1.33 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[C:11]1(C)[CH:16]=[CH:15][C:14](S(O)(=O)=O)=[CH:13][CH:12]=1.O>C1(C)C=CC=CC=1>[CH3:14][C:13]1[N:1]([C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=2)[C:16]([CH3:15])=[CH:11][CH:12]=1
Reactant: Cc1cc(N)nc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(-n2c(C)ccc2C)nc(C)c1Br

Procedure:
To a stirred solution containing 2.76 g (13.75 mmol) of 2-amino-5-bromo-4,6-dimethylpyridine (13) in 25 mL of toluene were added 2.02 mL (17.18 mmol) of 2,5-hexadienone followed by 130 mg (0.68 mmol) of p-toluene sulfonic acid. The reaction mixture was stirred at reflux overnight under argon atmosphere. The reaction mixture was poured into 150 mL of water and then extracted with a portion of 200 mL of ethyl acetate. The organic solution was washed with a portion of 150 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 5:1 gave the expected product as an orange oil: yield 2.37 g (62%). 1H-NMR (CDCl3) δ 6.93 (s, 1H), 5.88 (s, 2H), 2.70 (s, 3H), 2.47 (s, 3H), 2.12 (s, 6H); 13C-NMR (CDCl3) δ 157.35, 149.32, 128.42, 122.49, 121.22, 25.58, 23.41, 13.10.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.[CH2:21]([O:28][C:29](=[O:44])[C@@H:30]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:31][CH2:32][C:33](O)=[O:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[C:40]([O:39][C:37]([NH:36][C@@H:30]([CH2:31][CH2:32][C:33](=[O:34])[S:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:19])[F:20])=[CH:17][CH:16]=1)[C:29]([O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:44])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Reactant: FC(F)(F)c1ccc(S)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)Sc1ccc(C(F)(F)F)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
N,N′-Diisopropylcarbodiimide (0.510 ml, 3.26 mmol), N,N-dimethylaminopyridine (45.2 mg, 0.370 mmol), 4-(trifluoromethyl)benzenethiol (0.211 ml, 1.55 mmol) were added to a solution of (S)-5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid (Compound 5a-2) (500 mg, 1.48 mmol) in dichloromethane (5 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was then purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→20/80) to afford (S)-benzyl 2-((tert-butoxycarbonyl)amino)-5-oxo-5-((4-(trifluoromethyl)phenyl)thio)pentanoate (Compound 5f-2) (373 mg, 51%).
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]([C:27]3[C:28]([O:33][C:34]4[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=4[Cl:41])=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:26])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)C>[Cl:41][C:35]1[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:34]=1[O:33][C:28]1[C:27]([C:25]([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([S:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:42])=[O:2])=[CH:7][CH:8]=3)(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[O:26])=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)N2CCN(C(=O)c3cccnc3Oc3cc(Cl)ccc3Cl)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccc(S(=O)(=O)N2CCN(C(=O)c3cccnc3Oc3cc(Cl)ccc3Cl)c3ccccc32)cc1
Temperature: 25 °C
Yield: 12.7 %

Procedure:
To a suspension of 3-(4-{4-[2-(2,5-dichloro-phenoxy)-pyridine-3-carbonyl]-3,4-dihydro-2H-quinoxaline-1-sulfonyl}-phenyl)-propionic acid methyl ester (36 mg, 0.058 mmol, 1.0 equiv) in ethanol (1 mL) was added a 1 M solution of sodium hydroxide (120 μL, 0.12 mmol, 2.0 equiv; [CAS RN 1310-73-2]) and the reaction mixture stirred at rt over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 4.5 mg (13%) of the title compound as a light yellow powder. MS (ISP): 612.1 [M+H]+.