Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][S:2]([F:55])([F:54])([F:53])([F:52])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]4[N:29]=[N:30][N:31](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:32]=4)=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1.C(O)=O.O>O1CCCC1>[F:55][S:2]([F:1])([F:52])([F:53])([F:54])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]4[N:29]=[N:30][NH:31][CH:32]=4)=[CH:22][CH:23]=3)[N:15]=2)=[CH:7][CH:8]=1
Reactant: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nn4)cc3)co2)cc1
Solvent: C1CCOC1
Solvent: O=CO
Solvent: O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCc4c[nH]nn4)cc3)co2)cc1
Temperature: 60 °C
Reaction time: 21 h

Procedure:
A mixture of 98 mg 4-[4-(4-{2-[(E)-2-(-4-pentafluorosulfanyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1-trityl-1H-[1,2,3]triazole, 100 μl formic acid, 10 μl water and 1.0 ml tetrahydrofuran was stirred at 60° C. for 21 h. After removal of solvents in vacuo 4-[4-(4-{2-[(E)-2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole was obtained by HPLC-MS-purification.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=2)[O:8]1.Cl[C:20]1[S:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:28][O:27][C:25]([C:22]1[S:21][C:20]([O:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:18])[CH2:16][CH2:15]3)=[N:24][CH:23]=1)=[O:26]
Reactant: COC(=O)c1cnc(Cl)s1
Reactant: Cc1ccccc1C1CCc2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(Oc2ccc3c(c2)CCC(c2ccccc2C)O3)s1
Temperature: 50 °C
Reaction time: 10 h
Yield: 97.6 %

Procedure:
A suspension of 2-o-Tolyl-chroman-6-ol (2.5 g, 10.4 mmol), methyl 2-chloro-thiazole-5-carboxylate (1.9 g, 10.6 mmol, 1.02 eq) and potassium carbonate (1.9 g, 1.3 eq) in dimethylformamide (30 ml) was stirred at 50° C. for 10 h. The suspension was cooled to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with water, dried with sodium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel; ethyl acetate/heptane gradient). The product was obtained as a pale yellow solid (3.87 g, 98%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:10][Si:11]([CH3:30])([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[O:12][Si:13]([CH3:23])([CH3:22])[CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH:19]1[CH2:21][O:20]1>C(O)C>[OH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([CH2:21][CH:19]([OH:20])[CH2:18][O:17][CH2:16][CH2:15][CH2:14][Si:13]([CH3:22])([CH3:23])[O:12][Si:11]([CH3:30])([CH3:10])[CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC1CO1
Reactant: OCCN1CCNCC1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC(O)CN1CCN(CCO)CC1
Temperature: 70 °C

Procedure:
2-piperazin-1-yl ethanol (0.74 g) and 20 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 1,1,3,3-Tetramethyl-3-(3-oxiranylmethoxy-propyl)-1-(2-trimethylsilanyl-ethyl)-disiloxane (2.0 g) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. The reaction progress was monitored by NMR spectroscopy. Upon reaction completion, ethanol was removed under vacuum, and the mixture was vacuum distilled to remove impurities.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15]Cl.[OH-].[Na+].O>CO>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: C1=Cc2ccccc2C1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)CCCC1=CCc2ccccc21
Reaction time: 4 h

Procedure:
A mixture of 232 g. (2.0 moles) of indene and the free base prepared from 264 g. (1.6 moles) of 3-dimethylaminopropylchloride-hydrochloride is added in portions over 1 hour to a rapidly stirred mixture of 300 g. (7.5 moles) of sodium hydroxide, 300 g. of water and 300 ml. of 40% Triton B in methanol. The initial temperature is 50° and the rate of addition controlled to keep the temperature between 55°-60°. The green mixture is stirred at 60° for 4 hours, cooled, diluted with 1500 ml. of water and extracted with ether. The ether extract is in turn extracted with a solution of 180 ml. of conc. hydrochloric acid in 600 ml. of water and the aqueous phase separated, basified with 100 g. of sodium hydroxide and extracted with ether. Solvent removal gives 182 g. of brown oil which is distilled to give 102 g. of oil, b.p. 88°-93 ° at 0.05 mm. Redistillation gives 19.6 g; b.p. 87.5°-89.5° at 0.05 mm. and 71.1 g., b.p. 89.5°-90° at 0.05 mm.
Reaction SMILES: [Cl:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32](OC)=[O:33])[CH:27]=2)[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:9](=[O:11])[NH2:10])=[C:4]([NH:22][C:23]([OH:25])=[O:24])[CH2:3]1.[CH3:36][NH2:37]>>[Cl:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32](=[O:33])[NH:37][CH3:36])[CH:27]=2)[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:21])[F:20])[C:9](=[O:11])[NH2:10])=[C:4]([NH:22][C:23]([OH:25])=[O:24])[CH2:3]1
Reactant: COC(=O)c1cccc(C2(Cl)C=CC(N(C(N)=O)c3ccccc3C(F)(F)F)=C(NC(=O)O)C2)c1
Reactant: CN
Product: CNC(=O)c1cccc(C2(Cl)C=CC(N(C(N)=O)c3ccccc3C(F)(F)F)=C(NC(=O)O)C2)c1
Reaction time: 8 h

Procedure:
To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL, 1.7 mmol) and the resulting mixture was stirred at room temp. overnight, then concentrated under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC (100% EtOAc) Rf 0.35.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]([CH2:14][CH:15]1[C:30](=[O:31])[C:19]2[C:20]3[CH2:21][CH2:22][C:23](=[O:29])[NH:24][C:25]=3[CH:26]=[C:27]([CH3:28])[C:18]=2[CH2:17][CH2:16]1)CCCC)[C:3]1C=CC=[CH:5][CH:4]=1>C(O)C.[Pd]>[OH2:29].[OH2:29].[ClH:1].[CH2:2]([NH:9][CH2:14][CH:15]1[C:30](=[O:31])[C:19]2[C:20]3[CH2:21][CH2:22][C:23](=[O:29])[NH:24][C:25]=3[CH:26]=[C:27]([CH3:28])[C:18]=2[CH2:17][CH2:16]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN(Cc1ccccc1)CC1CCc2c(C)cc3c(c2C1=O)CCC(=O)N3
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCCNCC1CCc2c(C)cc3c(c2C1=O)CCC(=O)N3
Product: O
Reaction time: 3 h
Yield: 136.8 %

Procedure:
9(N-Benzyl-N-butylaminomethyl)-6-methyl-1,2,3,4,7,8,9,10-octahydro-benzo[f]quinoline-3,10-dione hydrochloride (10 g) is dissolved in 300 ml of ethanol whereupon 2 g of 10% palladium-on-carbon is added, and the whole is kept under an atmosphere of hydrogen for 3 hours. The product partially crystallized out is dissolved well by adding methanol, and the catalyst is filtered off. The solvent is distilled off under reduced pressure, and the remaining crystals are recrystallized from ethanol to give 4.0 g of 9-butylaminomethyl-6-methyl-1,2,3,4,7,8,9,10-octahydro-benzo[f]quinoline-3,10-dione hydrochloride dihydrate as colorless needles, melting at 194°-196° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]2[S:17][C:18](=[CH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:31]=4[C:38]([F:41])([F:40])[F:39])=[C:25]([O:42][CH3:43])[CH:24]=3)[C:19](=[O:21])[N:20]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:43][O:42][C:25]1[CH:24]=[C:23]([CH:22]=[C:18]2[S:17][C:16]([NH:15][CH2:14][CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[N:20][C:19]2=[O:21])[CH:28]=[CH:27][C:26]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:31]=1[C:38]([F:40])([F:39])[F:41]
Reactant: COc1cc(C=C2SC(NCC3CN(C(=O)OC(C)(C)C)CCO3)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C=C2SC(NCC3CNCCO3)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
LC/MS (m/z) [M+1]+618.8 (calculated for C29H29F3N4O6S, 618.63). 2-({5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-methyl)-morpholine-4-carboxylic acid tert-butyl ester (0.1 g, 0.16 mmol) was dissolved in dry dichloromethane (6 mL). To the reaction mixture was then added at 0° C. trifluoroacetic acid (2 mL). The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 30 minutes. The reaction mixture was then partitioned with saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (6% ammonia 2.0 M methanol/dichloromethane) to yield the compound as a solid (0.052 g, 63%).
Reaction SMILES: Cl.C([O:6][C:7]([N:9]1[CH2:14][CH:13]([CH3:15])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:11](=[O:24])[CH2:10]1)=O)(C)(C)C.[CH:25](N(CC)C(C)C)(C)C.C(OC(=O)C)(=O)C>C(OCC)(=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:7]([N:9]1[CH2:14][CH:13]([CH3:15])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:11](=[O:24])[CH2:10]1)(=[O:6])[CH3:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C(C)C1
Reaction time: 1 h

Procedure:
A steady stream of anhydrous HCl gas was bubbled through a cold (0° C.) solution of 4-[(tert-butoxy)carbonyl]-1-(4-fluorobenzyl)-6-methylpiperazin-2-one (0.62 g, 1.9 mmol) in ethyl acetate (20 mL) for 5 minutes. The resultant mixture was capped and stirred at the same temperature for 1 h. The product mixture was concentrated under vacuum. The residue was treated with a mixture of N,N-diisopropylethylamine (1.00 mL, 5.8 mmol), DMAP (5 mg), and acetic anhydride (0.22 mL, 2.3 mmol) in methylene chloride (10 mL). The resultant mixture was concentrated and the residue was subjected to column chromatography on silica gel eluting with a mixture of 10% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the title piperazinone.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13]3[C:19]4[C:20]([NH:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)=[C:27]([Cl:39])[CH:26]=5)=[N:21][CH:22]=[N:23][C:18]=4[S:17][C:14]=32)=[N:9]1)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C>CC#N>[CH2:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]3[S:17][C:14]4[C:15]5[C:10]([CH2:11][CH2:12][C:13]=4[C:19]=23)=[N:9][N:8]([CH2:7][CH2:6][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH:16]=5)=[CH:26][C:27]=1[Cl:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4ccccc4)c(Cl)c3)c12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Nc2ncnc3sc4c(c23)CCc2nn(CCN3CCOCC3)cc2-4)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
To CH3CN (4 mL) were sequentially added 2-(6-{[4-(benzyloxy)-3-chlorophenyl]amino}-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl)ethyl methanesulfonate (85 mg, 0.15 mmol), morpholine (0.04 mL, 0.44 mmol), and diisopropylethylamine (0.05 mL, 0.29 mmol). The mixture was stirred at 70° C. for 16 h after which time the mixture was removed from heating, and allowed to cool to rt. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and purified by prep HPLC. The combined fractions were treated with saturated Na2CO3 and dried to afford free base product (35 mg, 42%) as a white solid. 1H-NMR (DMSO-d6) δ 8.42 (s, 1H), 8.25 (s, 1H), 7.93 (s, 1H), 7.72 (d, 1H), 7.33-7.49 (m, 6H), 7.18 (d, 1H), 5.19 (s, 2H), 4.18 (t, 2H), 3.55 (m, 4H), 3.39 (t, 2H), 2.89 (t, 2H), 2.71 (t, 2H), 2.42 (m, 4H); LCMS RT=1.98 min, [M+H]+=573.4.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:28]=[C:29]1[O:33][C:31](=[O:32])[CH2:30]1>C1(C)C=CC=CC=1>[O:33]=[C:29]([CH3:28])[CH2:30][C:31]([O:20][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:32]
Reactant: C=C1CC(=O)O1
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OC(COCc1ccccc1)COCc1ccccc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
1.00 g (3.67 mmol) 1,3-dibenzyloxy-2-propanol is dissolved in 10 ml toluene, 3.72 mg (0.04 mmol) triethylamine are added, and the mixture is stirred at 90° C. 401 mg (4.77 mmol) diketene are added, and stirring is continued for 1 h. The mixture is cooled to room temperature, diluted with ice-water and extracted with toluene. The organic layer is dried over magnesium sulfate and evaporated to dryness. The crude product is purified by column chromatography on silica gel (eluent: cyclohexane/ethylacetate 2:1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][O:18][CH2:19][CH2:20]Br.Cl>CN(C)C=O.O.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:20][CH2:19][O:18][CH3:17])[CH:5]=[O:6]
Reactant: COCCBr
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(C=O)cc1O
Temperature: 0 °C
Reaction time: 120 h
Yield: 23.1 %

Procedure:
Commercially available 3,4-dihydroxybenzaldehyde (39.3 g, 285 mmol) and sodium carbonate (45.2 g, 427 mmol) were dissolved in N,N-dimethylformamide (400 mL), then commercially available 2-bromoethyl methyl ether (26.7 mL, 285 mmol) was added under nitrogen atmosphere at room temperature, and the mixture was stirred for 5 days. The mixture was cooled to 0° C. and then 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The aqueous layer was extracted with ethyl acetate, then the combined organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate, and then filtered. The solvent was evaporated, dichloromethane was added, the precipitate was separated by filtration, and then the resultant filtrate was purified with silica gel column chromatography (n-heptane:ethyl acetate=17:3-1:1). The target fraction was concentrated under vacuum to obtain the title compound (12.9 g, 23%).
Reaction SMILES: O.O.[C:3]([O-:6])(=[O:5])[CH3:4].[Li+].[C:8]([O:11][C:12](=[O:14])[CH3:13])(=[O:10])[CH3:9].[CH2:15]=[CH:16][CH:17]=[CH2:18].O=O>C([O-])(=O)C.[Ag+].C(O)(=O)C>[C:3]([O:6][CH2:15][CH:16]([O:11][C:8](=[O:10])[CH3:9])[CH:17]=[CH2:18])(=[O:5])[CH3:4].[C:3]([O:6][CH2:15][CH:16]=[CH:17][CH2:18][O:11][C:12](=[O:14])[CH3:13])(=[O:5])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Reactant: C=CC=C
Agent: [Ag+]
Agent: O=O
Agent: [Li+]
Solvent: CC(=O)O
Solvent: O
Product: C=CC(COC(C)=O)OC(C)=O
Product: CC(=O)OCC=CCOC(C)=O
Temperature: 140 °C
Reaction time: 1 h

Procedure:
Another run was conducted according to the instant invention employing the same apparatus as that used in Example I. In this run, the reactor was charged with 7.6 grams (75 mmols) of lithium acetate dihydrate, 6.7 grams (40 mmols) of silver acetate, 50 ml of acetic acid, 25 ml of acetic anhydride, and 11.5 grams (213 mmols) of butadiene charged from the vapor phase. The reactor was placed in an oil bath, pressured to 30 psig with oxygen and heated to 140° C. About one hour was required to bring the temperature of the oil bath up to the desired reaction temperature. During the reaction period of 6.8 hours, the reactor was intermittently pressured with oxygen to 120 psig. At the end of the reaction period, the reactor was vented and there was collected 0.5 grams of unreacted butadiene in a cold trap. The reaction mixture was filtered to recover 4.3 grams of white solid. The filtrate was transferred to a distilling flask and the acetic acid removed by distillation at 75 mm mercury pressure. The distillation residue was taken up in ether, filtered through diatomaceous earth, washed with water, washed with a sodium carbonate solution and then dried over magnesium sulfate and filtered. The ether was removed on a rotary evaporator. The residue remaining weighed 18.2 grams and was analyzed by gas-liquid phase chromatography (GLC). The analysis showed that there was obtained 11.15 grams (64.8 mmols) of 1,2-diacetoxy-3-butene and 3.42 grams (19.9 mmols) of 1,4-diacetoxy-2-butene for a yield of diacetoxybutenes of 40 percent based on the butadiene charged.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.C([Li])CCC.[CH3:37][C@H:38]1[C@@H:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:41][C:40](=[O:49])[NH:39]1.C(OC(=O)C(C)(C)C)(=O)C(C)(C)C>C1COCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([N:39]2[C@@H:38]([CH3:37])[C@@H:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:41][C:40]2=[O:49])=[O:17])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1C(=O)Cc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution containing 4-phenoxyphenylacetic acid (10.0 g, 43.8 mmol) in THF (62.6 mL) at -78° C. was added pivaloyl chloride (5.49 g, 45.6 mmol) followed by triethylamine (4.61 g, 45.6 mmol). The mixture was stirred at -78° C. for 15 minutes, at 0° C. for 1 hour, then recooled to -78° C. In a separate flask, 2.5M n-butyllithium (20 mL, 50 mmol) was added to a solution of (4S,5R)-(-)-4-methyl-5-phenyl-2-oxazolidinone (8.86 g, 50 mmol) in THF (100 mL) at -78° C., stirred for 15 minutes, then transferred to the flask containing pivalic anhydride via cannula. The mixture was stirred 15 minutes at -78° C. then at room temperature for 18 hours. The solvent was removed, and the residue was partitioned between diethyl ether (500 mL) and 1N HCl (500 mL). The organic layer was dried (MgSO4), filtered and concentrated to provide a light yellow solid. The solid was chromatographed with 10% ethyl acetate in hexane to yield 10.9 g (64%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Br:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[Br:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:17]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CN1CCc2c(N)cccc2C1
Product: CN1CCc2c(cccc2NC(=O)c2ccccc2Br)C1

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2-bromobenzoyl chloride according to the procedure of Example 19 to yield 5-(2-bromobenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 206.5°-208.5° C. after purification from ethanol.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][N:37]([CH2:40][C:41]([NH:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=4)=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: NCc1ccccn1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCc2ccccn2)CC1

Procedure:
In a manner analogous to the method described in example 99, {4-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid was coupled with 2-(Aminomethyl)pyridine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H48Cl2N7O3 [(M+H)+] 756.319, observed 756.3194.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:23][C:24]([NH2:26])=[O:25].CN(C)[CH:29]=[O:30]>>[CH:29]([NH:23][C:24]1[O:25][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[N:26]=1)=[O:30]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)CBr)cc2)CC1
Reactant: NC(N)=O
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3coc(NC=O)n3)cc2)CC1
Temperature: 92.5 °C

Procedure:
A mixture of the product from Example 48A (100 mg, 0.27 mmol) and urea (33 mg, 0.54 mmol) in N,N-dimethylformamide (5 mL) was heated at 90-95° C. under N2 for 2 hours. The mixture was concentrated, and purified on a RP-HPLC to provide the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (m, 2H), 1.19 (t, J=7.05 Hz, 3H), 1.48 (m, 2H), 1.69-1.85 (m, 5H), 2.22 (d, J=6.75 Hz, 2H), 2.47 (m, 1H), 4.07 (q, J=7.05 Hz, 3H), 4.14 (m, 1H), 7.28 (d, J=8.29 Hz, 2H), 7.63 (d, J=8.29 Hz, 2H), 8.29 (s, 1H), 8.95 (br s, 1H), 11.50 (br s, 1H); MS (ESI) m/z 356.9 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]1([CH2:16][CH2:17][CH2:18][Br:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:6]([C:13]1[CH:14]=[CH:15][C:10]([CH2:16][CH2:17][CH2:18][Br:19])=[CH:11][CH:12]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: BrCCCc1ccccc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(CCCBr)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.7 %

Procedure:
Concentrated sulfuric acid (18.3 g) was gradually added dropwise to 13.94 g of concentrated nitric acid and the mixture was vigorously shaken for 10 minutes. To the mixed solution, 10 g of 3-phenylpropyl bromide was gradually added dropwise at -20° C. and the mixture was stirred at -20° C. for 1 hour. The reaction mixture was poured into 500 ml of ice water and extracted with ether. The extract was washed and dried, and the solvent was distilled away. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to give 4.5 g of 3-(4-nitrophenyl)propyl bromide as a colorless, oily substance.