Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3](=[O:33])[CH2:4][C@@H:5]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:6]([NH:8][CH:9]([CH2:13][C:14]1[N:15](C(OC(C)(C)C)=O)[CH:16]=[N:17][CH:18]=1)[C:10]([NH2:12])=[O:11])=[O:7].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][C:2]([CH3:35])([CH3:34])[C:3](=[O:33])[CH2:4][C@@H:5]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][CH:9]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[C:10]([NH2:12])=[O:11])=[O:7]
Reactant: CC(C)(C)OC(=O)n1cncc1CC(NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)NC(Cc1c[nH]cn1)C(N)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
490 mg (0.565 mmol) of (S)-N-[(1S,2S,4S,5S or R)-1-(cyclohexylmethyl)-2,5-dihydroxy-6-[4-(2-hydroxyethyl)-1-piperazinyl]-4-isopropylhexyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]-3-t-butoxycarbonylimidazole-4-propionamide are dissolved in 5.5 ml of methanol, treated with 23 mg of potassium carbonate and stirred at room temperature for 5 hours. Thereafter, the reaction mixture is evaporated and the residue is chromatographed on 35 g of silica gel with a 110:10:1 mixture of methylene chloride, methanol and ammonia as the eluting agent, whereby there are obtained 347 mg of (S)-N-[(1S,2S,4S,5S or R)-1-(cyclohexylmethyl)-2,5-dihydroxy-6-[4-(2-hydroxyethyl)-1-piperazinyl]-4-isopropylhexyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide as a white foam, MS: 768 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].C(N(CC)CC)C.[F:27][C:28]([F:35])([F:34])[C:29](OCC)=[O:30]>CO>[F:27][C:28]([F:35])([F:34])[C:29]([NH:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17])=[O:30]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@](CO)(CNC(=O)C(F)(F)F)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
4′-C-Aminomethylthymidine (4) (1.5 mmol) was dissolved in methanol (10 mL) and triethylamine (1.5 mL) at ambient temperature. The solution was then treated with neat ethyl trifluoroacetate (1 mL) and the resulting solution stirred for 18 hours at ambient temperature with exclusion of moisture. The solvents and reagents were then removed under vacuum to give the crude product. Purification by flash column chromatography (9:1 dichloromethane:methanol) afforded the title compound (7) as a white foam (0.37 g, 66%). δH(300 MHz, CD3OD) 8.77(1H, t, br, N3—H), 7.73(1H, s, H-6), 6.24(1H, dd, H-1′), 4.56(1H, dd, H-3′), 3.6(3H, s, H-5′, obs d, 4′-C—CH2), 3.53(1H, d, 4′-C—CH2), 2.35(2H, m, H-2′), 1.81(3H, s, 5-CH3); δC(75.45 MHz, CD3OD), 166.24, 160.08–158.62(q, CF3CO), 152.21, 138.11, 123.01–111.51(q, CF3CO), 111.51, 88.93, 85.69, 72.79, 64.23, 41.70, 40.81, 12.40; ES +ve m/z 368 (M+H)+, 390(M+Na)+; ν cm−1 1684. For an alternative synthesis of this compound see Wang et al, Tetrahedron Letters 1996, 37, 6515–6518.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([NH2:17])[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-]=C=S.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:31]([C:33]3[CH:50]=[CH:49][C:36]4[N:37]=[C:38](NC5N(C(C)C)C=CN=5)[NH:39][C:35]=4[CH:34]=3)=[O:32])[CH:28]=2)[CH:23]=[N:22]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([NH:17][C:38]3[NH:39][C:35]4[CH:34]=[C:33]([C:31](=[O:32])[NH:30][C:27]5[CH:28]=[C:29]6[C:24]([CH:23]=[N:22][NH:21]6)=[CH:25][CH:26]=5)[CH:50]=[CH:49][C:36]=4[N:37]=3)[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)n1ccnc1Nc1nc2ccc(C(=O)Nc3ccc4cn[nH]c4c3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Agent: [N-]=C=S
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3nc4ccc(C(=O)Nc5ccc6cn[nH]c6c5)cc4[nH]3)sc2C1

Procedure:
The amine (0.5 mmol) from above was converted to corresponding isothiocyanate using general procedure A, which was then reacted with 3,4-diamino-N-(1H-indazol-6-yl)-benzamide (0.5 mmol; see Example 25) according to general procedure B to yield 2-[6-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester. MS: m/z 531 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([Br:18])=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]([Br:18])=[CH:16][C:12]([C:13]([Cl:23])=[O:14])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)c(Br)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(OCc2ccccc2)c(Br)cc1C(=O)Cl
Temperature: 25 °C

Procedure:
To a suspension of 4-(benzyloxy)-5-bromo-2-methylbenzoic acid (16.6 g, 51.7 mmol) in chloroform (80 mL) were added oxalyl chloride (5 mL, 56.9 mmol) and N,N-dimethylformamide (6 drops), and the mixture was stirred for an hour at room temperature. And then the reaction solution was concentrated to obtain 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride. Then to a chloroform suspension (60 mL) of N,O-dimethylhydroxylamine hydrochloride (5.55 g, 56.9 mmol) and triethylamine (15 mL, 103 mmol) cooled in ice was added dropwise a chloroform solution (60 mL) of 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride, and the mixture was stirred for an hour at room temperature. To the reaction solution cooled in ice were added water and chloroform to separate an organic layer. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide. To a tetrahydrofuran solution (150 mL) of the 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide was added at −10° C. lithium aluminum hydride (1.96 g, 51.7 mmol), and the mixture was stirred for an hour at the same temperature. To the reaction solution were added 1 M hydrochloric acid, and then ethyl acetate to separate an organic layer. The organic layer was washed with 1 M hydrochloric acid, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde. To a toluene solution (120 mL) of the 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde were added ethylene glycol (30 mL, 517 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.58 mmol), and heated to reflux for 1.5 hours with a Dean-Stark apparatus. To the reaction solution was added ethyl acetate to separate an organic layer. The organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1). In addition, the residue was further purified with NH type silica gel column chromatography (chloroform) to obtain the title compound (12.8 g, 71%, 3 steps) as a colorless powder.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([C:8]1[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=1)([CH3:7])([CH3:6])[CH3:5].NN>C(Cl)Cl>[CH3:1][N:2]([C:14]([NH:13][C:11]1[S:12][C:8]([C:4]([CH3:7])([CH3:6])[CH3:5])=[N:9][N:10]=1)=[O:15])[NH2:3]
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Reactant: CNN
Agent: NN
Solvent: ClCCl
Product: CN(N)C(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C

Procedure:
A solution of methylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-t-Butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-methyl-4-(5-t-butyl-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:20][CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[C:13](OC(C)(C)C)=[O:14])=[CH:7][CH:6]=1)C.FC(F)(F)C(O)=O.[CH2:34](Cl)[Cl:35]>>[CH:23]([O:22][CH2:21][CH2:20][N:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:26])=[CH:6][CH:7]=1)[C:13](=[O:14])[CH2:34][Cl:35])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1ccc(CN(CCOC(C)C)C(=O)OC(C)(C)C)cc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OCCN(Cc1ccc(C(=O)O)cc1)C(=O)CCl
Reaction time: 8 h

Procedure:
7.1 g of the crude 4-[N-(2-isopropoxyethyl)-N-tert-butoxycarbonylaminomethyl]benzoic acid ethyl ester are dissolved in 70 ml of methylene chloride, and 40 ml of trifluoroacetic acid are added. The clear solution is left to stand overnight at room temperature and then concentrated by evaporation. The residue is taken up in methylene chloride, washed with aqueous ammonia solution (pH>9) and concentrated by evaporation. The oily/crystalline residue is dissolved in 50 ml of ethanol, and 50 ml of 2N sodium hydroxide solution are added. After stirring for 2 hours at 60°-65°, the solution is concentrated by evaporation and the residue is adjusted to pH 1 with water and 2N hydrochloric acid. The solution immediately becomes extremely cloudy and after about 5 minutes a precipitate forms. The mixture is concentrated by evaporation and the residue is heated briefly with 100 ml of ethanol. The solution is dried with magnesium sulfate, filtered over Hyflo and concentrated by evaporation. The crude crystalline material is suspended in 80 ml of tetrahydrofuran, and 3.2 g of chloroacetyl chloride are added. The suspension is stirred at room temperature for 14 hours, then concentrated to dryness by evaporation. The residue is dissolved in methylene chloride, washed with diluted hydrochloric acid, dried and concentrated by evaporation. Sticky, sparingly soluble crystals are obtained corresponding to 4-[N-(2-isopropoxyethyl)-N-chloroacetylaminomethyl]-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4](I)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[Cl:1][C:2]1[C:3]([F:9])=[C:4]([C:31]#[C:30][CH2:29][OH:32])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCO
Reactant: Fc1c(Cl)cccc1I
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: OCC#Cc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-2-fluoroiodobenzene (5.00 g), copper(I) iodide (74.3 mg), triphenylphosphine (256 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (404 mg), propargyl alcohol (1.27 ml), diisopropylethylamine (13.6 ml) and tetrahydrofuran (90 ml) was stirred at room temperature for 8 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.15 g) as a brown oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:14]>C(Cl)Cl>[O:5]([CH2:6][CH:7]1[CH2:8][O:14]1)[CH2:1][CH:2]1[CH2:3][O:4]1
Reactant: C=CCOCC1CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C(OCC1CO1)C1CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 156.8 %

Procedure:
28.54 g of allyl glycidyl ether (0.15 mole) (Aldrich) is dissolved in 1000 ml of methylene chloride and cooled to 0° in an ice bath. In one single addition 51.75 g of m-chloroperoxybenzoic acid (1.05 equiv. @ 85% tech) (Aldrich) is added and the reaction stirred rapidly at 0° for 4 hours. The reaction is allowed to slowly warm to room temperature and stirred overnight. The precipitated m-chlorobenzoic acid is removed via filtration and washed with 50 ml of cold CH2Cl2. The CH2Cl2 solution is then washed with 2×200 ml of saturated potassium carbonate solution and dried over Na2SO4. The CH2Cl2 is removed in vacuo yielding 30.6 g (94%) of 2,2'-(oxybismethylene)bisoxirane as a colorless liquid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[N:13]=2)=[CH:10][CH:11]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:18][C:17]1[C:12]([C:9]2[S:8][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][OH:2])=[CH:11][CH:10]=2)=[N:13][C:14]([NH:19][CH:20]2[CH2:21][C:22]([CH3:28])([CH3:29])[NH:23][C:24]([CH3:27])([CH3:26])[CH2:25]2)=[N:15][CH:16]=1
Reactant: COC(=O)CCCc1ccc(-c2nc(NC3CC(C)(C)NC(C)(C)C3)ncc2C)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cnc(NC2CC(C)(C)NC(C)(C)C2)nc1-c1ccc(CCCCO)s1
Reaction time: 0.5 h

Procedure:
The ester from Step B (37 mg, 0.09 mmol) was dissolved in 1 ml of THF and LAH (1M in THF, 0.22 ml, 0.22 mmol) was added. After 30 minutes, the mixture was quenched with water and extracted with ether. The organic layers were washed with brine, dried over sodium sulfate and evaporated. The crude product was purified by preparative HPLC. Yield: 15 mg (43%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][CH:16]2[O:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][CH:26]=1>>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][CH:16]([OH:18])[CH2:17][NH:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:29][CH:30]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CCCCOCCOCc1ccc(OCC2CO2)cc1
Product: CCCCOCCOCc1ccc(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3)cc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-n-butyloxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-3-(2H)-pyridazinone.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[Li]CCCC.[CH3:24][N:25]1[N:29]=[N:28][C:27]([C:30]2[CH:41]=[C:40]([CH3:42])[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH:38]=[O:39])=[C:32]([CH3:43])[CH:31]=2)=[N:26]1.Cl>C1COCC1.O>[CH3:24][N:25]1[N:29]=[N:28][C:27]([C:30]2[CH:41]=[C:40]([CH3:42])[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH:38]([C:11]3[NH:10][C:18]4[C:13]([CH:12]=3)=[CH:14][CH:15]=[CH:16][N:17]=4)[OH:39])=[C:32]([CH3:43])[CH:31]=2)=[N:26]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(O)c1cc2cccnc2[nH]1
Temperature: -50 °C
Reaction time: 1 h
Yield: 25.5 %

Procedure:
To a cold solution of 1-phenylsulfonyl-7-azaindole (1.29 g, 5 mmol) in 250 ml of THF was added at -30° C. n-BuLi (2.5M in hexane, 4 ml, 10 mmol). The mixture was stirred at -30°-40° C. for 1 h and then cooled to -50° C. To the above mixture was added dropwise at -50° C. a solution of 4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]butyraldehyde (1.37 g, 5 mmol) in 25 ml of THF, and the mixture was stirred at -40°-50° C. for 1 h and then allowed to warm to -5° C. for 2 h. Water was added to the mixture, and the resulting reaction mixture was acidified with 1N HCl solution, and then re-basified with an aqueous sodium bicarbonate solution, extracted with methylene chloride, and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/5-1/0; then methylene chloride/acetone 2/1-1/1) followed by recrystallization from methylene chloride/methanol to afford 501 mg (25%) of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-1-hydroxy-butyl]-7-azaindole, as a white crystalline solid, m.p.166°-169° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][C@@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[S:15][CH:14]=[N:13][CH:12]=2)=[O:9])[C@@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=1
Reactant: Cc1ccc(-c2cncs2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-c2cncs2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(thiazol-5-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 475 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[CH:12]([CH2:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(N(CC)CC)C>ClCCl>[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCCCCN1CCCC2CC=CC=C21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCCCCCN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 233.4 g (1 mole) of N-hydroxyhexyltetrahydroquinoline and 153.1 g (1.5 moles) of acetic anhydride in dichloromethane are added 151.8 g (1.5 moles) of triethylamine and 8.5 g (1 mole %) of 4-N,N-dimethylaminopyridine, and the reaction is stirred at room temperature for 3 hours. The product solution is washed with cold 2N HCl followed by saturated sodium bicarbonate, and the organic layer is filtered through cotton and evaporated.
Reaction SMILES: CSC(=NC)[N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10](Cl)=[CH:9]C=1)[CH3:5].C[NH:17]C(N(C)CC1C=CN=CC=1)=S>[N+](C)([O-])=O>[CH3:5][NH:4][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:17]=1
Reactant: CN=C(SC)N(C)Cc1ccc(Cl)cc1
Reactant: CNC(=S)N(C)Cc1ccncc1
Solvent: C[N+](=O)[O-]
Product: CNCc1ccccn1

Procedure:
To 4.98 g (0.0205 mole) of S-methyl-N-(4-chlorobenzyl)-N-methyl-N'-methylisothiourea prepared in (1) was added 25 ml of nitromethane and the mixture was refluxed for 6.5 hours. The nitromethane was distilled off and the residue was subjected to silica gel (240 g) column chromatography using MeOH--CHCl3 (1:10) as an eluent to give 5.23 g of an orange-colored oil. To this oil were added small amounts of EtOH and ether and the mixture was cooled in a dry ice-acetone bath and triturated to give crystals. After addition of ether, the crystals were collected by filtration, washed with ether and dried. The procedure gave 3.69 g of the title compound as pale yellow cyrstals.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:16])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.COC(C)(C)C>[CH2:14]([O:13][C:11]([C:10]1[C:9]([CH3:16])=[N:8][N:7]2[C:2]([O:1][CH2:21][CH2:20][CH:19]([CH3:23])[CH3:18])=[CH:3][C:4]([CH3:17])=[CH:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Reactant: CC(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nn2c(OCCC(C)C)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 180 mg (0.768 mmol) of 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester from Example 8A in 7 ml of dry tetrahydrofuran was admixed with 0.167 ml (1.537 mmol) of 3-methylbutan-1-ol (CAS 123-51-3), 423.2 mg (1.614 mmol) of triphenylphosphine and 0.32 ml (1.614 mmol) of diethyl azodicarboxylate. The resulting mixture was stirred at room temperature for 1 h. Some of the solvent was drawn off under reduced pressure and the residue was admixed with 5 ml of tert-butyl methyl ether. The resulting precipitate was filtered off and the mother liquor was partitioned between dichloromethane (15 ml) and water (10 ml). The organic phase was removed and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 225 mg (69% of theory, 72% pure) of the target compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]=[C:4]1[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH3:2].[CH3:16][O:17][CH:18]([O:22][CH3:23])N(C)C>CO>[CH3:16][O:17][CH:18]([O:22][CH3:23])[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][C:4]2[N:3]([CH2:1][CH3:2])[CH2:7][CH2:6][N:5]=2)[CH2:15][CH2:14]1
Reactant: COC(OC)N(C)C
Reactant: CCN1CCN=C1CCC1CCNCC1
Solvent: CO
Product: CCN1CCN=C1CCC1CCN(C(OC)OC)CC1

Procedure:
A solution of 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]piperidine (0.66 g, 0.0031 M) in methanol (6 ml) and dimethylformamide dimethylacetal (6 ml) was heated at 90° C. for 6 hrs. Removal of the excess of dimethylformamide dimethylacetal gave 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-1-piperidine carboxaldehyde dimethylacetal. The solution of the piperidine carboxaldehyde dimethylacetal in chloroform (5 ml) was then added to a mixture of 6-aminopenicillanic acid (0.6 g, 0.0028 M) and diisopropylethylamine (0.5 ml) in chloroform (6 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr and room temperature for 3 hrs. The solvent was removed and water (10 ml) was added. After being washed with ethylacetate, the aqueous solution, acidified from about pH 3 to about 3.5 was purified on Sephadex LH B 20 columns to give [2S-(2-alpha,5alpha, 6beta)]-6-[[[4-[2-(1-ethyl-4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.46 g, 35% yield).
Reaction SMILES: ClC1N=C2C(=CC=1)C=C1N2[C@H](C)CNC1=O.C(OC([C:22]1[N:31]([C@H:32]([CH3:42])[CH2:33][NH:34][C:35](OC(C)(C)C)=[O:36])[C:25]2=[N:26][C:27]([Br:30])=[CH:28][CH:29]=[C:24]2[CH:23]=1)=O)C>>[Br:30][C:27]1[N:26]=[C:25]2[C:24](=[CH:29][CH:28]=1)[CH:23]=[C:22]1[N:31]2[C@H:32]([CH3:42])[CH2:33][NH:34][C:35]1=[O:36]
Reactant: CCOC(=O)c1cc2ccc(Br)nc2n1[C@H](C)CNC(=O)OC(C)(C)C
Agent: C[C@@H]1CNC(=O)c2cc3ccc(Cl)nc3n21
Product: C[C@@H]1CNC(=O)c2cc3ccc(Br)nc3n21

Procedure:
This compound was prepared in analogy to Example 1, intermediate b) from (R)-6-bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester.