Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:8][CH2:7]1>CO>[CH3:1][O:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)CCCC1CCNCC1
Solvent: CO
Product: COC(=O)CCCC1CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.6 %

Procedure:
Trimethylsilyl chloride (9.2 ml, 72.46 mmol) was added to a solution of 4-piperidin-4-yl-butyric acid (1) (5.00 g, 24.15 mmol) dissolved in anhydrous methanol (100 mL). The resulting solution was stirred at room temperature for 48 hours, and concentrated under vacuum to complete dryness to give 2 (4.50 g, 97%) as a white solid, which was used directly in the next step without further purification: 1H NMR (300 MHz, CD3OD) δ 1.20-1.46 (m, 4H), 1.52-1.74 (m, 3H), 1.96 (d, 2H), 2.35 (t, 2H), 2.96 (t, 2H), 3.36 (t, 2H), 3.68 (s, 3H); ESI MS m/z 186 [C10H19NO2+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[C:5]([NH2:14])=[C:6]([N+:11]([O-])=O)[C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2]>[Pd].O1CCCC1>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[C:5]=1[NH2:14])[CH3:16]
Reactant: CCN(CC)c1ccc(F)c([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(F)c(N)c1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under hydrogen gas atmosphere, a mixture of N1,N1-diethyl-4-fluoro-3-nitrobenzene-1,2-diamine (380 mg, 1.67 mmol), 10% palladium on carbon (50% wet, 80 mg) and tetrahydrofuran (8 mL) was stirred at room temperature for 20 hr. The reaction mixture was filtered and concentrated in vacuo to give N1,N1-diethyl-4-fluorobenzene-1,2,3-triamine as a brown oil, which was used for the next step without further purification. To a solution of above crude compound in tetrahydrofuran (16 mL) was added 2,4-dichlorophenyl isothiocyanate (320 mg, 1.57 mmol) at room temperature. The resultant mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture to give a solid, which was washed with disopropyl ether to afford the title compound as a colorless solid (306 mg, 0.762 mmol, 49%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br-:20].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:20][C:17]1[CH:18]=[C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=2)[CH:14]=[CH:15][C:16]=1[OH:19]
Reactant: Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.3 %

Procedure:
To a solution prepared by dissolving the resulting 2.88 g of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenol in 300 ml of chloroform, 4.80 g of tetra-n-butyl ammonium tribromide was slowly added with stirring under room temperature. After 12 hours, the reaction solution was concentrated, and the residue was extracted twice with 100 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 2.53 g of 2-bromo-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenol (yield, 69%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:60]1[S:61][CH:62]=[CH:63][N:64]=1>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:61]1[CH:62]=[CH:63][N:64]=[C:60]1[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Brc1nccs1
Reactant: Clc1ccn2ccnc2c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: c1csc(-c2ccn3ccnc3c2)n1
Yield: 30.3 %

Procedure:
In a 500 mL round bottom flask, stir a suspension of 7-chloro-imidazo[1,2-a]pyridine (7.5 g, 49.2 mmol) in 250 mL 1,4-dioxane with bis(pinacolato)diboron (13.74 g, 54.1 mmol, 1.1 eq), potassium acetate (7.24 g, 73.8 mmol, 1.5 eq) and tricyclohexylphosphine (1.66 g. 5.9 mmol, 0.12 eq). Deoxygenate the resulting slurry with two cycles of evacuation and bubbling nitrogen through the slurry for 10 minutes each. Fit the flask with a reflux condenser and add tris(dibenzylidineacetone)dipalladium (0) (2.25 g, 2.45 mmol, 0.05 eq) and stir the mixture under nitrogen at 80° C. overnight. Filter the hot mixture over a ˜1 cm pad of celite, wash with 50 mL 1,4-dioxane, then concentrate the combined filtrate and wash to give a brown pasty solid. Suspend a portion of the solid (32.8 mmol) in 80 mL of dioxane, combine with 41.25 mL of 2 M aqueous sodium carbonate (82.5 mmol, 2.5 eq) and 2-bromothiazole (4.38 mL, 8.07 g, 49.2 mmol, 1.5 eq), then deoxygenate twice via evacuation and bubbling nitrogen through the suspension. Add tetrakis (triphenylphosphine) palladium (1.89 g, 1.64 mmol, 0.05 eq), fit the flask with a reflux condenser and stir the mixture under nitrogen at 100° C. overnight. Filter the dark brown-black hot mixture through a 1 cm pad of Celite®, wash with 50 mL dioxane, then apply the combined filtrate and wash equally to three 25 g SCX Mega Bond-Elut™ SCX cartridges (Varian) each pre-washed with 200 mL 1:1 CH2Cl2:MeOH. After loading with vacuum assist, wash each cartridge with 300 mL 1:1 CH2Cl2:MeOH, then elute with 160 mL 1:1 CH2Cl2:2 M NH3-MeOH. Concentrate the combined eluates in vacuo and purify through a 330 g silica gel cartridge using a 0 to 5% methanol gradient in dichloromethane. Concentrate the pooled clean fractions and dry to yield 3 g (45%) of 7-thiazol-2-yl-imidazo[1,2-a]pyridine as a tan solid. MS (ES) mm/z 202, (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:21]=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=[C:24]([F:27])[C:25]=1F.Cl>CS(C)=O>[Cl:19][C:20]1[CH:21]=[C:22]([C:28]([F:29])([F:30])[F:31])[CH:23]=[C:24]([F:27])[C:25]=1[O:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1
Reactant: CCOC(=O)n1nc(O)cc1C
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 40 °C
Yield: 72.9 %

Procedure:
To a DMSO (15 mL) solution of ethyl 3-hydroxy-5-methylpyrazole-1-carboxylate (1.36 g, 8.0 mmol) and potassium carbonate (1.1 g, 8.0 mmol) was added 3-chloro-4,5-difluorobenzotrifluoride (1.77 g, 8.0 mmol) and the mixture was stirred under heating at 40° C. for 8 hours. After completion of the reaction, the reaction mixture was poured into 2 mol/L hydrochloric acid (30 mL) and extracted with ethyl acetate. The organic layers combined were washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The thus-obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:7˜1:5) to give a white solid of ethyl 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxylate (2.14 g, yield: 72.9%). Melting point: 127˜129° C., 1H-NMR (CDCl3, TMS, ppm): δ1.40 (t, J=7.1 Hz, 3H), 2.53 (d, J=0.8 Hz, 3H), 4.41 (q, J=7.1 Hz, 2H), 5.81 (d, J=0.8 Hz, 1H), 7.38 (dd, J=2.1 Hz, JHF=9.5 Hz, 1H), 7.50˜7.60 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]#[C:4][C:5]#[C:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][NH2:11].C=O.[C:21]([BH3-])#N.[Na+]>C(O)C>[CH3:21][NH:11][CH2:10][CH2:9][N:8]([CH2:7][C:6]#[C:5][C:4]#[C:3][C:2]([CH3:17])([CH3:18])[CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCN(CC#CC#CC(C)(C)C)CCN
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CCO
Product: CCCCCN(CC#CC#CC(C)(C)C)CCNC
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
In 1 ml of ethanol was dissolved 30 mg of N-(6,6-dimethyl-2,4-heptadiynyl)-N-pentylethylenediamine. Then 20 μl of 35% formalin and 8.3 mg of sodium cyanoborohydride were added to the solution. The mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was fractionated, washed with saturated sodium bicarbonate aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was then removed under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 10 g, methylene chloride/methanol=50/1) to give 10 mg (yield: 32%) of the title compound as colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC#N>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CNCC2
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 7-cyano-1,2,3,4-tetrahydroisoquinoline (ABCR, 2 g; 12.64 mmol) and K2CO3 (3.49 g, 25.28 mmol) in CH3CN (40 mL), was added tert-butyl bromoacetate (1.96 mL; 13.27 mmol) and the reaction mixture was stirred at RT for 4 hours. Solvents were removed under vacuum and solid residue was extracted with EtOAc from a saturated aqueous solution of NaHCO3, dried over MgSO4 and evaporated under vacuum to give the title compound a as colorless oil (3.32 g; 96%). 1H NMR (DMSO-d6) δ 7.55 (m, 2H), 7.30 (m, 1H), 3.72 (s, 2H), 3.31 (s, 2H), 2.86-2.79 (m, 4H), 1.49 (s, 9H). LC/MS (Method B): 217.1 (M+1-1)+.
Reaction SMILES: [OH:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[C:9](Cl)(=[O:13])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:10][C:9]([O:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1)=[O:13])[CH3:12]
Reactant: O=C1C=CC(O)OC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)OC1C=CC(=O)CO1
Temperature: 0 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
12 g of 6-hydroxy-2H-pyran-3(6H)-one was dissolved in 100 ml of methylene chloride, and the solution was cooled to 0° C. Then, 11.4 g of ethyl chlorocarbonate was added, and a solution comprising 10.6 g of triethylamine and 20 ml of methylene chloride was dropwise added thereto. The mixture was stirred for 3 hours, and the reaction mixture was poured into ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure, and the residue was subjected to distillation under reduced pressure to obtain 12.3 g (yield: 63%) of the above-identified compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]1[CH:13]([C:14]([O:16]CC)=[O:15])[CH:7]12.[OH-].[Na+]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]1[CH:13]([C:14]([OH:16])=[O:15])[CH:7]12
Reactant: CCOC(=O)C1C2CCc3c(F)ccc(F)c3C21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1C2CCc3c(F)ccc(F)c3C21

Procedure:
4,7-Difluoro-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylic acid was synthesized analogously to Example 43e from ethyl 4,7-difluoro-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate (0.45 g, 1.8 mmol) by stepwise hydrolysis first with excess of NaOH at r.t. and then with the excess of NaOH at heating (60° C., 1.5 h) to give 80 mg of product as white crystals (cis/trans ratio 78:22 according to HPLC).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([OH:10])=O.C1N=C[N:13](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([NH2:13])=[O:10]
Reactant: Cc1nc(C(=O)O)c(Br)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(C(N)=O)c(Br)s1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-methyl-thiazole-4-carboxylic acid (14.4 g, 64.8 mmol) was dissolved in 100 ml DMF and CDI (11.6 g, 71.3 mmol) was added. The solution was stirred for 2 hrs at 60° C., cooled and NH4OH (150 ml, 973 mmol) was added. The reaction mixture was stirred over night at room temperature and extracted two times with ethyl acetate and water. The organic extracts were washed four times with water, dried with sodium sulfate, filtered and evaporated. The crude product (11.3 g, 79%) [MS: m/e=222.8 (M+H+)] was used without any further purification for the next step.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CS(C)=O.C(#N)C>[CH2:16]([C:12]1([CH2:12][CH2:13][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCBr
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CS(C)=O
Product: CCCCCCCC1(CCCCCCC)c2ccccc2-c2ccccc21
Reaction time: 0.08 h

Procedure:
0.2 mol of fluorene is dissolved in 300 ml of DMSO at 80° C. 0.01 mol of phase transfer catalyst (aliquot) is added to the solution which is stirred for a further 5 minutes. For the alkylation, 0.5 mol of 50% sodium hydroxide solution and 0.5 mol of heptyl bromide are required. The addition is effected in three stages, and commences with the addition of one third of the amount of sodium hydroxide solution used. The solution changes color to deep red and slowly becomes yellow by addition of heptyl bromide. When the solution has become yellow, the second third of sodium hydroxide solution is added, etc. The end of the reaction is checked by means of TLC on RP18 in acetonitrile.
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:4][CH2:5][C:6]([O:8]CC)=[O:7].CC(C)=O.[C:19]1(C)[CH:24]=[CH:23]C=[CH:21][CH:20]=1>>[C:6]1(=[O:7])[O:8][C:13]([CH3:14])([CH:19]([CH2:24][CH3:23])[CH2:20][CH3:21])[O:12][C:3](=[O:11])[CH2:4][CH2:5]1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(CC)C1(C)OC(=O)CCC(=O)O1
Temperature: 40 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
Sodium hydride in an amount of 2 moles was suspended in 1.0 liter of toluene and heated at 40° C. To this, a mixed solution of 1 mole of diethyl succinate and 1.2 moles of acetone was added dropwise in 3 hours with stirring. The reaction was carried out for further 3 hours. Then, the reaction solution was poured into 1 kg of ice. The water layer was separated, made acidic by pouring 700 ml of 5M HCl thereinto, and extracted with 1.0 liter of 1,2-dichloroethane. The resulting organic layer was dried over anhydrous sodium sulfate, and concentrated. To the resulting residue, 1.0 liter of ethanol and 30 ml of concentrated sulfuric acid were added. The reaction was carried out under reflux for 4 hours. After the reaction, the solvent was removed from the reaction solution by distillation. The objected substance was extracted with dichloromethane and purified by distillation under reduced pressure to give diethylisopropylidene succinate in yield of 51%.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:25][C:26]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+].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].C(COC)OC>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:36]5[CH:35]=[N:34][N:33]([C:26]([CH3:25])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1

Procedure:
9-Bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 (500 mg, 0.001 mol) and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate (594 mg, 0.0015 mol) were reacted under palladium catalyzed Suzuki coupling conditions with Pd(dppf)Cl2 and Cs2CO3 water and dimethoxyethane to give ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate together with the corresponding acid. LC/MS (ESI+): m/z 490 (M+H)
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH:24]=[O:25])[CH2:4][CH3:5])[CH3:2].[Li].[CH3:27][Li]>C1COCC1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])[C:8]=1[CH:24]([OH:25])[CH3:27])[CH2:4][CH3:5])[CH3:2]
Reactant: [Li]C
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C=O
Agent: [Li]
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(C)O

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-carbaldehyde with methyllithium lithium in THF at −78° C. The desired product was isolated after silica gel column chromatography to give 60.1% of colorless oil. 1H NMR(CDCl3) d 6.87(s,2H), 6.06(s,1H), 5.7(q,1H), 3.3(m,1H), 2.29(s,3H), 2.12(s,6H), 2.069s,3H), 1.4–1.7(m,4H), 1.59(d,3H), 0.8–1.0(m,6H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([OH:35])=O)[N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:63]([O:70][C:71](=[O:77])[C@@H:72]1[CH2:76][CH2:75][CH2:74][NH:73]1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>CN(C=O)C.C(Cl)CCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:73]3[CH2:74][CH2:75][CH2:76][C@H:72]3[C:71]([O:70][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[O:77])=[O:35])[N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C

Procedure:
To a solution of 9.5 g 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 80 ml DMF were added 2.5 g HOBt, 5.7 ml DIPEA and 3.9 g L-proline benzyl ester hydrochloride at 0° C. At this temperature were added 3.1 g EDC portionwise and the suspension allowed to warm to RT over a period of 12 h. The solvent was evaporated, the residue dissolved in ethyl acetate and subsequently extracted with aqueous LiCl (4 w/w), 0.1 M HCl and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: Cl[C:2]1[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:6]([CH:15]=1)[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8].[NH:23]1[CH2:25][CH2:24]1>CCOC(C)=O>[N:23]1([C:2]2[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:6]([CH:15]=2)[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8])[CH2:25][CH2:24]1
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)cc1C(=O)NCC(O)CO
Reactant: C1CN1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(N2CC2)cc1C(=O)NCC(O)CO
Yield: 76 %

Procedure:
A solution of the above benzamide (0.84 g, 2.38 mmol) and aziridine (0 74 mL, 14 3 mmol) in EtOAc (20 mL) was stirred at room temperature for 16 h. The reaction mixture was worked up and the residue was chromatographed on silica gel, eluting with EtOAc/MeOH (4:1) to give 10 (0.65 g, 76%), mp (EtOAc) 120-123° C. 1H NMR [(CD3)2SO] δ8.71 (t, J=5.8 Hz, 1H, NH), 8.45 (s, 1H, H-3), 744 (s, 1H, H-6), 477 (d, J=5 0 Hz, 1H, CHOH), 4.54 (t, J=5 8 Hz, 1H, CH2OH), 3.70-361 (m, 1H, CHOH), 3.45-3.36 (m, 3H, CH2OH, CONHCHH), 3 41 (s, 3H, CH3), 3.17-3.07 (m, 1H, CONHCHH), 2.47 (s, 4H, aziridine-H). Anal. Calcd for C13H17N3O7S.0.5H2O: C, 42.39,H, 4.93; N, 11.41. Found C, 41.98; H, 5.11, N, 10.97%.
Reaction SMILES: BrBr.[ClH:3].[CH3:4][C:5]1[N:12]2[C:8](=[N:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=32)[S:7][C:6]=1[C:17](=[O:19])[CH3:18]>C(O)(=O)C>[ClH:3].[ClH:3].[CH2:11]([N:12]([CH2:5][CH3:4])[CH2:18][C:17]([C:6]1[S:7][C:8]2=[N:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]2[C:5]=1[CH3:4])=[O:19])[CH3:10]
Reactant: CC(=O)c1sc2nc3ccccc3n2c1C
Agent: BrBr
Agent: Cl
Solvent: CC(=O)O
Product: CCN(CC)CC(=O)c1sc2nc3ccccc3n2c1C
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Bromine (1 ml) and concentrated hydrochloric acid (2 ml) were added to an acetic acid (200 ml) solution of 1-(3-methylthiazolo[3,2-a]benzoimidazol-2-yl)ethanone (Can. J. Chem., 45 (23), 2903-2912 (1967)) (2.3 g), and the mixture was stirred at 90° C. for 30 minutes. The reaction solution was cooled to room temperature, and the thus formed precipitate was collected by filtration and washed with EtOAc. Under ice-cooling, a 1.2 g portion of this was added to an acetonitrile (30 ml) solution of diethylamine (3 ml), and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was mixed with water, extracted with EtOAc, washed with water and saturated brine and dried with anhydrous Na2SO4, and the solvent was evaporated under a reduced pressure. The resulting residue was purified by a column chromatography (eluent; Hex:EtOAc=2:1˜1:1) and further converted into hydrochloride in the usual way to obtain the title compound (355 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][C:15](OCC)=[O:16]>CN(C)C=O.O>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([N:1]2[CH2:12][CH2:13][CH2:14][C:15]2=[O:16])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCCBr
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Yield: 66.8 %

Procedure:
A solution of 4-aminobenzoic acid (Aldrich, 3.0 g, 21.9 mmol) and ethyl 4-bromobutyrate (Aldrich, 6.4 g, 32.8 mmol) in 20 mL of dimethylformamide was stirred at reflux for 24 h. The solvent was removed under vacuum to give a crude solid which was suspended in 15 mL of water, collected by filtration and dried. The solid was suspended in a small amount of ether (5 mL), filtered and dried to give 3.0 g (66%) of the title compound as a white solid, mp 244-246° C. (ether/ethanol), lit.mp 244-245° C. [Hopff et al. Ger. 859, 007, Sep. 22, 1952; Chem. Abstr. 52 11124h (1958)].