Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CCC[CH2-].C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]([CH3:20])[C:17]([Cl:21])=[CH:16][N:15]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]=[O:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]([OH:36])[CH2:20][C:18]2[C:17]([Cl:21])=[CH:16][N:15]=[C:14]([Cl:13])[N:19]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1nc(Cl)ncc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)Cc2nc(Cl)ncc2Cl)CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
N-butyllithium (1.6 M in hexanes, 4.99 mL) is added drop wise to diisopropylamine (1.13 mL) in tetrahydrofuran (20 mL) at −50 to −60° C. under an argon atmosphere. The mixture is stirred for 30 min at this temperature, cooled to −70° C., and 2,5-dichloro-4-methyl-pyrimidine (1.00 g) is added. After 1 h a solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.37 g) in tetrahydrofuran (10 mL) is added and the resulting mixture is stirred for another hour. The reaction is quenched with acetic acid solution (1% in ethanol, 10 mL) and the mixture is diluted with ethyl acetate. The organic phase is separated, washed with water and aqueous NaHCO3 solution, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→30:70) to give the title compound. LC (method 7): tR=1.40 min; Mass spectrum (ESI+): m/z=376 [M+H]+.
Reaction SMILES: B(F)(F)F.CC[O:7][CH2:8][CH3:9].NC1[CH:12]=[C:13](C)[C:14]([Cl:17])=[N:15][CH:16]=1.N(OC(C)(C)C)=O.CCCCC>COCCOC>[Cl:17][C:14]1[C:13]([CH3:12])=[CH:9][C:8]([OH:7])=[CH:16][N:15]=1
Reactant: Cc1cc(N)cnc1Cl
Reactant: CCOCC
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: CCCCC
Solvent: COCCOC
Product: Cc1cc(O)cnc1Cl
Reaction time: 0.25 h

Procedure:
To a solution of boron trifluoride diethyl etherate (5.8 mL, 47.5 nmmol) in DME (18 mL) at -14° C. was added dropwise a solution of 5-amino-2-chloro-3-methylpyridine (4.5 g, 31.7 mmol) in DME (60 mL). The mixture was stirred for 15 minutes and then a solution of t-butyl nitrite (4.5 mL, 38 mmol) in DME (60 mL) was added dropwise. The mixture was stirred for 1 hour at 0° C., then pentane (100 mL) was added to give a solid. The solid was collected by filtration and dried to give the title compound (6.9 g): 1H NMR (MeOH-d4, 300 MHz) δ 2.58 (s, 3H), 8.86 (d, J=2.1 Hz, 1H), 9.41 (d, J=2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][O:43][C:44](=[O:58])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47](CN2C=CC(N)=N2)[CH:46]=1>C(Cl)Cl>[CH3:42][O:43][C:44](=[O:58])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)[CH:46]=1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: COC(=O)c1cccc(Cn2ccc(N)n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (250 mg, 0.76 mmol, prepared as in PCT WO 2004/052869 A1, Example 1) was dissolved in methylene chloride (3.8 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (380 μL, 0.76 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (180 μL, 1.52 mmol) was added. The reaction continued to stir at 0° C. for 20 min. The 3-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (176 mg, 0.76 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (40 mL), washed with water (2×10 mL), saturated aqueous brine solution (1×10 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (196 mg, 47%) as a white foam: ESI-LRMS m/e calcd for C27H30ClN3O5S [M+] 543.16, found 544.22 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.21 (m, 2H, CH2), 1.45-1.94 (m, 8H, 4×CH2), 2.15-2.34 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.52 (t, J=7.5 Hz, 1H, CH), 3.91 (s, 3H, CO2CH3), 5.19 (s, 2H, NCH2), 6.72 (d, J=2.2 Hz, 1H, Ar), 7.34 (m, 2H, Ar), 7.40 (d, Jo=7.7 Hz, 1H, Ar), 7.44 (dd, Jo=8.3, Jm=1.5 Hz. 1H, Ar), 7.58 (d, Jm=1.5 Hz, 1H, Ar), 7.84-7.91 (m, 2H, Ar and NH), 7.97 (d, Jo=7.7 Hz, 1H, Ar), 8.08 (d, Jo=8.3 Hz, 1H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH2:29][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[Cl:35])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccccc4Cl)cc3)c2cc1OC
Yield: 97.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-chlorophenyl)methanol (73 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (153 mg, yield 90%).
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])=[O:8])[N:4]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1.O1CCOCC1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])=[O:8])[N:4]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Yield: 25.5 %

Procedure:
0.13 g of 3-bromo-N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxamide was added to a 1,4-dioxane 6 ml solution comprising 0.14 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone, followed by reflux with heating for 18 hours. After the reaction liquid was stood to cool, it was poured to water, followed by extraction with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The filtrate was distilled under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 to 7/3) to obtain 33 mg of the desired product (melting point: 231 to 233° C.).
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:18]#[C:19][C:20](O)=[O:21])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.Cl.[CH3:35][N:36](C)CCCN=C=NCC>C(Cl)Cl>[CH3:35][NH:36][C:20](=[O:21])[C:19]#[C:18][C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:12][CH:13]=1)([OH:27])[C:23]([F:26])([F:25])[F:24]
Reactant: CC(C)CN(c1ccc(C(O)(C#CC(=O)O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)C#CC(O)(c1ccc(N(CC(C)C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.2 g of 4-[4-(benzenesulfonyl-isobutyl-amino)-phenyl]-5,5,5-trifluoro-4-hydroxy-pent-2-ynoic acid (see Example 69; 0.439 mmol) and 0.26 mL of methylamine (2M in THF) were combined in 3 mL of CH2Cl2 at rt. 0.1 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.527 mmol) was added. The resulting mixture was stirred at rt for 16 h. After addition of 80 mL of CH2Cl2 the resulting solution was washed with an aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and brine. The organic layers were dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica(EtOAc:hexanes, 1:1) to give the title compound. 1H NMR (400 MHz, CDCl3) δ 0.90 (m, 6H), 1.56 (m, 1H), 2.91 (d, J=5.0 Hz, 3H), 3.31 (m, 2H), 3.72 (br s, 1H), 6.26 (d, 5.0 Hz, 1H), 7.11 (d, J=8.7 Hz, 2H), 7.44–7.60 (m, 5H), 7.64 (d, J=8.7 Hz, 2H). Mass Spectrum (CI+) m/e=486 (M+18).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][S:8][C:9]([CH3:30])([CH3:29])[CH2:10][NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([CH3:28])([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH3:17])=[CH:5][CH:4]=1.[C:33]([O-])([O-])=O.[K+].[K+].Br[CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45]>CC#N>[C:44]([CH2:43][CH2:42][CH2:41][CH2:40][CH2:33][N:14]([CH2:15][C:16]([S:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)([CH3:28])[CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][C:9]([CH3:30])([S:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:32][CH:31]=1)[CH3:29])([O:46][CH2:47][CH3:48])=[O:45]
Reactant: COc1ccc(CSC(C)(C)CNCCNCC(C)(C)SCc2ccc(OC)cc2)cc1
Reactant: CCOC(=O)CCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCCN(CCNCC(C)(C)SCc1ccc(OC)cc1)CC(C)(C)SCc1ccc(OC)cc1
Yield: 32.8 %

Procedure:
To N,N'-bis-[2-(4-methoxybenzylthio)-2-methylpropyl]-ethylenediamine (4.13 g, 8.66 mmol) in CH3CN (50 mL) was added K2CO3 (1.21 g, 8.75 mmol, 101 mol %) followed by ethyl 5-bromovalerate (2.80 mL, 17.7 mmol, 204 mol %). The reaction was stirred at reflux overnight and was then concentrated to a paste in vacuo. The residue was partitioned between ethyl acetate (100 mL and 0.5M KOH (100 mL). The aqueous layer was extracted with ethyl acetate (1×50 mL) and the combined organic layers were washed with NaCl solution (50 mL), dried with Na2SO4 and concentrated to a yellow oil (~6 g). Purification by normal-phase preparative HPLC (100% CHCl3 to 5% methanol/chloroform over 25 min.) afforded pure title compound (1.759 g, 34% yield). FABMS analysis gave an (MH+) of 605 (compared with the value of 604.90 calculated for C33H52N2O4S2). Nuclear magnetic resonance characterization experiments yielded the following molecular signature:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH2:12]([N:15]1[C@H:20]([CH3:21])[CH2:19][N:18]([C@H:22]([C:37]2[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=2)[C:40](Cl)=[O:41])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][Si](C(C)(C)C)(C)C)[CH:24]=2)[C@@H:17]([CH3:46])[CH2:16]1)[CH:13]=[CH2:14]>>[CH2:12]([N:15]1[C@H:20]([CH3:21])[CH2:19][N:18]([C@H:22]([C:37]2[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=2)[C:40]([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:41])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[C@@H:17]([CH3:46])[CH2:16]1)[CH:13]=[CH2:14]
Reactant: c1ccc(NCC2CC2)cc1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(CC3CC3)c3ccccc3)c2)C[C@H]1C

Procedure:
N-(Cyclopropyl)methylaniline was coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(cyclopropyl)methyl-N-phenylbenzamide as an off-white powder. NMR (200 MHz, DMSO-d6): δ 0.09 (m, 2H); 0.39 (m, 2H); 0.92 (d, J=6.3 Hz, 3H); 0.96 (d, J=6.2 Hz, 3H); 1.28 (m, 1H); 1.69 (dd, J1 =7.4 Hz, J2 =11.5 Hz, 1H); 2.04 (dd, J1 =6.6 Hz, J2 =11.0 Hz, 1H); 2.30 (br d, J=12.1 Hz, 1H); 2.40-2.54 (m, 2H); 2.67 (br d, J=9.8 Hz, 1H); 2.85 (dd, J1 =7.4 Hz, J2 =13.7 Hz, 1H); 3.16 (dd, J1 =4.5 Hz, J2 =14.7 Hz, 1H); 3.72 (d, J=7.0 Hz, 2H); 4.77 (s, 1H); 5.12 (d, J=10.0 Hz, 1H); 5.18 (d, J=15.6 Hz, 1H); 5.70-5.85 (m, 1H); 6.44 (d, J=7.3 Hz, 1H); 6.57 (s, 1H); 6.65 (d, J=8.0 Hz, 1H); 7.02-7.33 (m, 10H); 9.33 (s, 1H). Mass spectrum (CI--CH4) m/e: 510 (M+1, 61%), 356 (42%), 153 (100%). [α]D20 =+8.9° (abs. ethanol, c=1.1). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.75 followed by precipitation with diethyl ether from dichloromethane to give the monohydrochloride salt as a hygroscopic off-white powder. Calc. for C33H39N3O2 HCl 1.25 H2O: C, 69.70; H, 7.53; N, 7.39; Cl, 6.23. Found: C, 69.82; H, 7.52; N, 7.36; Cl, 6.28.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(O)C.Cl.C(Cl)Cl.O=[Pt]=O>[C:34]([N:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[C:17]1[CH:16]=[C:11]([CH:10]=[C:9]([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH3:8])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: C=C(c1ccccc1)c1cc(C(=O)OC)cc(-c2ccccn2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1cc(C(C)C2CCCCC2)cc(C2CCCCN2C(C)=O)c1
Reaction time: 0.5 h

Procedure:
To an argon purged solution of methyl 3-(1-phenylvinyl)-5-(pyridin-2-yl)benzoate (73 mg, 0.23 mmol) in ethanol (5 mL) and HCl (conc. 1 mL) was added PtO2 (7 mg, 0.023 mmol). The mixture was hydrogenated under a hydrogen atmosphere (35 psi) for 6 h. The reaction mixture was purged with argon, filtered through a 0.2 μm filter, and concentrated. The resulting crude material was taken up with CH2Cl2 (5 mL) after which iPr2NEt (0.1 mL, 0.58 mmol) and acetyl chloride (18 μL, 0.25 mmol) were successively added. The mixture was stirred for 30 min, then diluted with CH2Cl2 (30 mL) and washed successively with 0.5 M HCl (1×10 mL), 9% sodium carbonate (1×10 mL), brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue containing the title compound was used without further purification. MS m/z=372 [M+1]+; Calc'd for C23H33NO3: 371.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1>>[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][CH:17]=1)[O:13][CH:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 84.8 %

Procedure:
The title compound (D35) (1.5 g) was prepared according to the experimental procedure described in Description 34 starting from 1-Boc-3-pyrrolidinol (1 g, 5.34 mmol) and 3-(Trifluoromethyl)phenol (0.640 ml, 5.34 mmol)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH:16]=[C:17](Br)[C:11]=2[N:10]([CH3:27])[C:9]1=[O:28])(=[O:3])[CH3:2].[CH3:29][Sn](C)(C)C>CN(C=O)C.CC(=O)OCC.O.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>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH:16]=[C:17]([CH3:29])[C:11]=2[N:10]([CH3:27])[C:9]1=[O:28])(=[O:3])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CC(=O)OCCCn1c(=O)c2c(c(Br)cn2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCCCn1c(=O)c2c(c(C)cn2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 3-(7-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (50 mg, 0.107 mmol) in DMF (2 mL) was added tetramethylstannane (38.2 mg, 0.214 mmol) and Pd(PPh3)2Cl2 (10 mg). The reaction was heated at 120° C. (MW) for 45 min, cooled to RT then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 3-(5-(4-chlorobenzyl)-1,7-dimethyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (40 mg, 92.8% yield) as an oil. LCMS: MH+ 404 and TR=1.630 min. Used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[CH3:27][C:28]([NH2:41])([CH3:40])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1.[BH4-].[Na+].O>C(O)C.ClCCl>[CH3:40][C:28]([NH:41][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:27])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=1
Reactant: CC(C)(N)Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(C)(Cc1cccc(C(F)(F)F)c1)NCC(O)c1cc(O)cc2c1OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 217 mg (1 mmol) 1,1-dimethyl-2-(3-trifluoromethyl-phenyl)-ethylamine are stirred for 3 hours in 5 mL ethanol at 65° C. The mixture is cooled to ambient temperature, 113 mg (3 mmol) of sodium borohydride are added and the mixture is stirred overnight. It is combined with 2 mL water, stirred for 30 minutes and then diluted with 10 mL dichloromethane. The solution is filtered through kieselguhr and washed with dichloromethane. The eluate is freed from solvent and the residue is dissolved in 5 mL ethanol and hydrogenated at 2.5 bar and ambient temperature with palladium on charcoal (10%) as catalyst. Then the catalyst is separated off and the crude product is purified by chromatography (reverse phase, acetonitrile/water gradient with 0.1% trifluoroacetic acid). Beige solid. Yield: 169 mg (31%, trifluoroacetate); mass spectroscopy: [M+H]+=425.
Reaction SMILES: [C:1]([NH2:4])([NH2:3])=[O:2].[OH:5][OH:6].C1(=O)[O:12][C:10](=O)[CH2:9]C1.C(NC1C=CC=CC=1)(=[O:16])C.OC1C=CC=C2C=1N=CC=C2.OO>>[C:1]([NH2:4])([NH2:3])=[O:2].[OH:5][OH:6].[OH:16][CH2:9][CH:10]([CH2:1][OH:2])[OH:12]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)Nc1ccccc1
Agent: NC(N)=O
Agent: OO
Agent: Oc1cccc2cccnc12
Product: OCC(O)CO

Procedure:
The stabilities of further test formulations prepared in the same manner as described above, containing 6.5% urea peroxide, and 0.5% added succinic anhydride (Example 9), 0.5% acetanilide (Control D) and 0.5% 8-hydroxyquinoline (Control E) were compared by storage for varying periods at 40° C. and measurement of the residual hydrogen peroxide contents as aforesaid. The following results were obtained:
Reaction SMILES: Cl[C:2]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[O:3].[CH3:54][NH:55][CH3:56]>C1(C)C=CC=CC=1>[CH3:54][N:55]([CH3:56])[C:2]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[O:3]
Reactant: CNC
Reactant: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)Cl
Solvent: Cc1ccccc1
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)N(C)C
Reaction time: 0.25 h

Procedure:
The solution of 0.290 g of benzyl 3-[4-chlorocarbonyl-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 69b) in 1.0 ml of toluene is slowly added dropwise to 2.4 ml of dimethylamine solution (5.6M in ethanol, precooled to 0° C.). After 15 minutes, the reaction solution is poured onto water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (1×30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.06 (2:1 EtOAc-heptane); Rt=5.67.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22](N)([CH3:25])[CH2:23][NH2:24].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:9])[C:18]3=[N:20][C:22]([CH3:25])([CH3:21])[CH2:23][N:24]3[C:10](=[O:17])[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]2=3)=[CH:6][CH:7]=1
Reactant: NC(=O)C1(c2ccc(Cl)cc2)OC(=O)c2ncccc21
Reactant: CC(C)(N)CN
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CN2C(=O)c3ncccc3C(O)(c3ccc(Cl)cc3)C2=N1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
A mixture of 3-(4-chlorobenzoyl)-2-pyridinecarboxylic acid (13 g), potassium cyanide (4.56 g), and acetic acid (30 mL) was heated at 120-125 C. in a sealed pressure bottle for 48 h. After cooling to ambient temperature, the mixture was poured into ice water. The precipitated solid was dissolved in ethyl acetate, washed with sodium bicarbonate saturated solution then with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was treated with ether. The formed solid was collected by filtration and dried to give 10.2 g of 5-(4-chlorophenyl)-7-oxo-5,7-dihydrofuro[3,4-b]pyridine-5-carboxamide. A mixture of 5-(4-chlorophenyl)-7-oxo-5,7-dihydrofuro[3,4-b]pyridine-5-carboxamide (5 g), 2-methyl-1,2-diamino propane (6.3 g), and toluene (80 mL) was heated at reflux for 18 h in a flask equipped with a water separator. The mixture was cooled to ambient temperature. The precipitated material was collected by filtration and dried to give the title compound (2.4 g), m.p. 257-260° C.