Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:21]([CH2:22][CH:23]=[CH2:24])=[C:20]([O:25][CH2:26][O:27][CH3:28])[CH:19]=[C:18]([O:29][CH2:30][O:31][CH3:32])[C:3]=1[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]([O:25][CH2:26][O:27][CH3:28])[CH:19]=[C:18]([O:29][CH2:30][O:31][CH3:32])[C:3]=1[C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: C=CCc1c(OCOC)cc(OCOC)c(C(=O)C=Cc2ccc(OCOC)cc2)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(OCOC)cc(OCOC)c(C(=O)CCc2ccc(OCOC)cc2)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Then an ethyl acetate solution of 21.1 g of 2'-hydroxy-4,4',6'-tris(methoxymethoxy)-3'-(2-propenyl)chalcone was added to a suspension of 8.0 g of 5% palladium/carbon in 50 ml of ethyl acetate, in which a hydrogen gas had been sufficiently absorbed, and the mixture was stirred at room temperature in a hydrogen atmosphere for 3 hours. After the reaction, the reaction mixture was filtered and the solvent was removed from the filtrate by distillation to obtain quantitatively 21.2 g of 1-[2-hydroxy-4,6-bis(methoxymethoxy)-3-n-propylphenyl]-3-(4-methoxymethoxyphenyl)-1-propanone in the form of a colorless oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14]1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH:13]1(/[CH:16]=[C:17](\[O:19][CH2:20][CH3:21])/[O:18][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]1
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)CC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCO/C(=C\C1CC1)O[Si](C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium in hexanes (1.6M, 26 ml) was added with stirring to a solution of diisopropylamine (6.2 ml) in tetrahydrofuran (8 ml) at below -25° C. under nitrogen. After 30 min, the mixture was cooled to -75° C. and ethyl cyclopropylacetate (4.5 g) added dropwise keeping the temperature below -65° C. The mixture was then maintained below -75° C. for 3 h before chlorotrimethylsilane (3.8 ml) was added below -65° C. The reaction was allowed to warm to ambient temperature and then evaporated to dryness. The residue was slurried with hexane and filtered. The filtrate was evaporated to an orange oil which was distilled in vacuo to give the title compound (4.0 g) as a clear mobile liquid, b.p 80-82° C., 3×10-2 bar.
Reaction SMILES: Cl[CH:2]([C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:11]=1)[CH:3]([CH3:9])[CH2:4][O:5][CH2:6][CH2:7][OH:8].C1CCN2C(=NCCC2)CC1.O>CS(C)=O>[OH:8][CH2:7][CH2:6][O:5][CH2:4][C:3]([CH3:9])=[CH:2][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:11]=1
Reactant: CC(COCCO)C(Cl)c1ccc(Cc2cccnc2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=Cc1ccc(Cc2cccnc2)cc1)COCCO
Yield: 62 %

Procedure:
In 29.1 ml of dimethylsulfoxide was dissolved 5.82 g of 3-[p-[1-chloro-3-(2-hydroxyethyl)oxy-2-methylpropyl]benzyl]pyridine, and 5.44 ml of DBU was added to the resulting solution, after which the resulting mixture was subjected to reaction at a temperature of 100° to 110° C. for 2 hours. The reaction mixture was poured into 200 ml of water, and the resulting mixture was subjected to extraction with two 50-ml portions of ethyl acetate. The extracts were combined, washed with 20 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform] to obtain 3.20 g (yield 62.0%) of colorless, oily 3-[p-[3-(2-hydroxyethyl)oxy-2-methyl-1-propenyl]benzyl]pyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[N:11]=[C:10]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(C)=O.O.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]>[CH3:27][S:28]([C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:21])[F:20])[N:11]=[C:10]([C:23]([OH:26])([CH3:24])[CH3:25])[CH:9]=3)=[CH:6][CH:7]=2)[CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(O)c1cc(-c2ccc(Br)cc2)n(-c2ccccc2C(F)(F)F)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(C)(O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)n(-c2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a solution of 2-(5-(4-bromophenyl)-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol (115 mg, 0.27 mmol) and 3-(methylsulfonyl)phenylboronic acid (66 mg, 033 mmol) in 1,2-dimethoxyethane (1.5 mL) was added K2CO3 (110 mg, 0.80 mmol) and H2O (1.5 mL). The resulting biphasic suspension was stirred at ambient temperature and sparged with nitrogen for 10 minutes. The reaction was then treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (11) dichloromethane adduct (15 mg, 18 μmol) and heated to 80° C. in an oil bath. The reaction was heated at 80° C. for three hours and then allowed to cool to ambient temperature overnight. The cooled reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude product as a dark oil. The crude product was purified by flash-column chromatography eluting with a gradient from 10% to 100% EtOAc/hexane to afford 2-(5-(3′-(methylsulfonyl)biphenyl-4-yl)-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol (122 mg, 90% yield) as an off-white powder. MS(ES): 501 [M+H]+.
Reaction SMILES: C[C:2]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)([O:6][CH3:7])[C:3]([OH:5])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:35][NH:36][O:37][CH3:38]>ClCCl.C([O-])(O)=O.[Na+]>[N:14]1([C:11]2[CH:10]=[CH:9][C:8]([CH:2]([O:6][CH3:7])[C:3]([N:36]([O:37][CH3:38])[CH3:35])=[O:5])=[CH:13][CH:12]=2)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: COC(C)(C(=O)O)c1ccc(-n2cccn2)cc1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(C(=O)N(C)OC)c1ccc(-n2cccn2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 75.5 %

Procedure:
To a solution of methyl 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetic acid (0.18 g, 0.77 mmol) in dry dichloromethane (5 mL) under argon was added N-methylmorpholine (0.18 mL, 1.7 mmol). The reaction mixture was cooled to 0° C., isobutylchloroformate was added, (0.11 mL, 0.85 mmol) and the mixture was stirred for 40 minutes. N,O-dimethylhydroxylamine hydrochloride (0.098 g, 1 mmol) was then added in one portion and slowly allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-80% EtOAc-hexanes) provided 2-(4-(1H-pyrazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide (0.16 g, 76% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1>>[CH:9]1([CH2:12][O:13][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11][CH2:10]1
Reactant: Brc1ccc(Br)nc1
Reactant: OCC1CC1
Product: Brc1ccc(OCC2CC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and cyclopropylmethanol by the method of Example 10(b).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.[OH-].[Na+].[ClH:32]>C(Cl)Cl.C(Cl)Cl.CCOCC.CCOCC>[ClH:32].[ClH:32].[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)cc2F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(CN2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6.2 g (19.85 mmol) of the title A compound, t-butyl 4-(2,4-difluorobenzyl)piperazine-1-carboxylate in 50 mL of DCM at 0° C. is added 15 mL of trifluoroacetic acid. The reaction mixture is warmed to RT and stirred for 1 h, and 10 mL of 1N aqueous sodium hydroxide (NaOH) are added. The mixture is extracted with 2×100 mL of DCM and the organic layer is washed with water, dried over anhydrous MgSO4 and evaporated to dryness in vacuo. The residue is dissolved in a mixture of DCM-Et2O and two equivalents of HCl in Et2O are added, the precipitate solid is collected by filtration and washed with acetone to afford 4-(2,4-difluorobenzyl)piperazine dihydrochloride as a white solid: m.p=237° C. LC/MS (M+1=213.1). 1H NMR (DMSO-d6, 400 MHz) δ 3.44 (m, 8H), 4.39 (s, 2H), 7.25 (dt, 1H, J=8.4 Hz and 1.6 Hz), 7.43 (dt, 1H, J=9.2 Hz and 2.0 Hz), 7.84 (dd, 1H, J=15.2 Hz and 8.4 Hz), 9.84 (br s, NH). Anal. calculated for (C11H14F2N2, 2HCl+0.25H2O) C, 45.61; H, 5.74; Cl, 24.48; F, 13.12; N, 9.67; O, 1.38. Found C, 45.56; H, 5.90; N, 9.68.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][N:63]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:62][CH2:61]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Clc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.038 g, 0.00013 mol) in DMF (2 mL) was added DIPEA (0.0872 g, 0.00067 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0325 g, 0.00017 mol) at ambient temperature. After 2 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.0334 g, 0.00013 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.0382 g (65%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 438.16 (M+1)+, 98.29%, 1H NMR (DMSO-d6): δ 13.8 (s, 1H), 8.1 (s, 1H), 7.78 (d, 2H), 7.44 (m, 2H), 7.38 (m, 1H), 7.26 (d, 2H), 7.1 (m, 2H), 6.84 (d, 1H), 6.6 (t, 1H), 4.9 (d, 1H), 4.3 (d, 1H), 4.2 (d, 2H), 3.8 (d, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 1.9 (t, 2H), 1.3 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH2:14]([O:21][CH2:22][C:23]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COCc1ccccc1)N1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzylpiperazine is reacted with 2-benzyloxyacetyl chloride in dichloromethane in the presence of triethylamine to give 2-benzyloxy-1-(4-benzyl-piperazin-1-yl)-ethanone which is then hydrogenated over a palladium on carbon catalyst in a methanol/hydrochloric acid mixture to remove the benzyl group and give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C[Al](C)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]3[C:36](=O)[O:35][CH2:34][CH2:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[H-].[Na+]>C(Cl)Cl.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]3[C:36](=[O:35])[N:16]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]5[CH2:12][CH2:13][CH2:14][CH2:15]5)=[C:2]([Cl:1])[CH:3]=4)[CH2:34][CH2:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(OCCN2CCCC2)c(Cl)c1
Reactant: O=C1OCCc2nc(-c3ccc(Cl)cc3)sc21
Agent: CS(=O)(=O)Cl
Agent: C[Al](C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc(OCCN2CCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.7 %

Procedure:
Dissolve 3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.20 g, 0.83 mmol) in CH2Cl2 (10.0 mL) and treat with trimethylaluminum (2.0M in hexanes, 0.6 mL, 1.20 mmol). Stir at room temperature for 15 min and add 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (0.22 g, 0.83 mmol) neat and stir the reaction at room temperature for 2 h. Carefully quench the mixture with saturated Rochelles salt solution and stir at room temperature for 1 h. Dilute with water and extract with CH2Cl2 (2×). Combine the organic portions and dry, filter and concentrate. Dissolve the residue in CH2Cl2, and treat with triethylamine (0.50 mL, 3.56 mmol) followed by methanesulfonyl chloride (0.05 mL, 0.65 mmol). Stir for 1 h at room temperature, dilute with water and extract with CH2Cl2 (2×). Combine the organic portions and dry, filter, and concentrate. Dissolve the residue in THF and treat with NaH (0.03 g, 0.75 mmol) and stir at room temperature for 18 h. Dilute the reaction with water and extract with CH2Cl2 (2×). Combine the organic portions, dry, filter, and concentrate. Purify the crude material by flash chromatography, using a gradient of 0% to 10% 2N NH3/MeOH in CH2Cl2, to give the title compound (80 mg, 37%). MS (ES+) 488.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 2H, J=8.3 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.39 (d, 1H, J=2.2 Hz), 7.22 (dd, 1H, J=8.8, 2.6 Hz), 6.97 (d, 1H, J=9.2 Hz), 4.22 (t, 2H, J=5.9 Hz), 4.07 (t, 2H, J=7.0 Hz), 3.28 (t, 2H, J=7.0 Hz), 3.01 (t, 2H, J=5.9 Hz), 2.73 (m 4H), 1.84 (m 4H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][OH:21])[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3[N:15]=[N:16][N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2].OCCNC(=O)OC(C)(C)C.Br[CH2:34][C:35]#[C:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(Br)C#C>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:34][C:35]#[C:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3[N:15]=[N:16][N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCO
Reactant: BrCC#Cc1ccccc1
Agent: C#CCBr
Agent: CC(C)(C)OC(=O)NCCO
Product: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCOCC#Cc1ccccc1

Procedure:
The general method described in Part A of Example 81 was followed, using 2-(8-ethoxymethyl-5,6-dimethyl-7H-imidazo [4,5-c]tetrazolo [1,5-a]pyridin-7-yl)ethanol (4.51 g, 15.5 mmol) in lieu of tert-butyl 2-hydroxyethylcarbamate and 3-bromo-1-phenylpropyne, prepared as described in Part A of Example 7, in lieu of propargyl bromide. The crude product was triturated with diethyl ether, isolated by filtration, and dried under reduced pressure to provide 5.93 g of 8-ethoxymethyl-5,6-dimethyl-7-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:37])[C:15]3[CH:20]=[CH:19][C:18]([O:21]CC4C=CC=CC=4)=[C:17]([O:29]CC4C=CC=CC=4)[CH:16]=3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[N:3]=1>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:37])[C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:29])[CH:16]=3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[N:3]=1
Reactant: COc1ccc(Cc2cc(C3CCN(C(=O)c4ccc(OCc5ccccc5)c(OCc5ccccc5)c4)CC3)nc(N)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Cc2cc(C3CCN(C(=O)c4ccc(O)c(O)c4)CC3)nc(N)n2)cc1
Yield: 74.3 %

Procedure:
2-Amino-4-[1-(3,4-dibenzyloxybenzoyl)-4-piperidinyl]-6-(4-methoxyphenylmethyl)pyrimidine (293 mg, 0.48 mmol) was dissolved in a mixture of methanol (3 ml) and ethyl acetate (3 ml), and hydrogenated under 1 atm in the presence of 10% palladium on carbon (80 mg) for about 3 hours. The catalyst was filtered off and washed with methanol. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (chloroform:methanol=97:3) to give the titled compound (155 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[CH3:10]C1C2C(=CC=CC=2)NC=1>>[CH3:10][N:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: Cc1c[nH]c2ccccc12
Product: Cn1ccc2cccnc21
Yield: 58 %

Procedure:
According to the procedure of Preparation 40 (a), except substituting 7-azaindole (2.28 g, 1.83 mmole) for the 3-methylindole, the title compound (1.4 g, 58%) was prepared as a yellow oil: MS (ES) m/e 133 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[NH2:40])[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].CO>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[NH2:40])[N:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3Sc3ccccc3N)ncc2[N+](=O)[O-])CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ccccc1Sc1ccccc1CNc1ncc([N+](=O)[O-])c(NC[C@H]2CC[C@H](N)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the above [4-({2-[2-(2-amino-phenylsulfanyl)-benzylamino]-5-nitro-pyrimidin-4-ylamino}-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (35 mg, 0.06 mmol) in CH2Cl2 (10 mL) was added TFA (1.2 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then treated with saturated NaHCO3. During the work-up, some MeOH was added to solubilize the product in the organic phase. The organic phase was then dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 10:1:0.1 CH2Cl2:MeOH:NH4OH as an eluent to afford 20 mg 70%) of the title compound as an off-white solid, m/z 477.9 (M−1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]([OH:39])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[Sn]>>[C:10]([O:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][O:5][C:10](=[O:39])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=[O:39])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: OCC(CO)(CO)CO
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Sn]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCC(CO)(CO)COC(=O)CCCCCCCCCCCCCCCCCCCCCCCCCCC
Temperature: 100 °C

Procedure:
28.1 g pentaerythritol (0.207 mole), 165 g montanic acid (0.413 mole) and 0.4 g tin powder were heated as in Example 1 to 200° C. with application of a gentle vacuum. The vacuum was increased to 20 mbar over a period of 2 h. The product had an acid value of approximately 1. A yellow, brown-tinged hard wax having a dropping point of 79° C. was obtained after cooling to 100° C., bleaching and filtering.
Reaction SMILES: [OH-].[Na+:2].CO.C([O:7][C:8](=[O:19])[CH2:9][C@@H:10]([CH2:15][N+:16]([O-:18])=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])C>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Na+:2].[CH3:13][CH:12]([CH3:14])[CH2:11][C@H:10]([CH2:15][N+:16]([O-:18])=[O:17])[CH2:9][C:8]([O-:19])=[O:7]
Reactant: CCOC(=O)C[C@H](CC(C)C)C[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@@H](CC(=O)[O-])C[N+](=O)[O-]

Procedure:
In a beaker 100 mg of EstC (lyophilized) were dissolved/suspended in 10 mL of potassium phosphate buffer (1 mM, pH 7.2). The pH drops to pH ˜6.8 and was adjusted to pH=7.4 with aqueous NaOH (0.1 M). Then 250 μL of methanol and 200 mg of 5-methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl) were added and the pH was kept at 7.4 by continuous addition of aqueous NaOH (0.1M). After 45% conversion (corresponding to 4.0 mL of 0.1M NaOH consumption) the reaction was stopped by addition of 10 mL of ethyl acetate. The layers were separated and the aqueous layer was extracted once more with 10 mL of ethyl acetate. Then the aqueous layer was concentrated to give the title compound with an ee of 98%.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:44])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([C:22]2[NH:26][C:25](=[S:27])[O:24][N:23]=2)[CH:19]=[C:18]([O:28][CH2:29][C:30]([N:32]2[CH2:36][CH2:35][CH2:34][C@@H:33]2[C:37]([O:39]C(C)(C)C)=[O:38])=[O:31])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:44])[CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([C:22]2[N:26]=[C:25]([S:27][C:20]([CH3:22])([CH3:21])[CH3:19])[O:24][N:23]=2)[CH:21]=1)[O:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([OH:39])=[O:38])=[O:31])([OH:5])=[O:7]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc(-c2noc(=S)[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Sc1nc(-c2cc(OCC(=O)N3CCC[C@@H]3C(=O)O)cc(OCC(=O)N3CCC[C@@H]3C(=O)O)c2)no1
Reaction time: 8 h
Yield: 111 %

Procedure:
A solution of 315 mg (0.5 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl -pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl) -phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 160 mg (57%) of the title compound as a white powder. MS m/e (%): 599 (M+Na+, 54), 594 (M+NH4+, 71), 577 (M+H+, 100), 521 (37).