Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][NH2:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>ClCCl.[Cl-].[Na+].O>[C:29]([NH:14][CH2:13][CH2:12][S:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:2]([NH2:1])[N:10]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: NCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
To 6-amino-9-benzyl-2-(2-aminoethyl)thiopurine (50 mg, 0.17 mmol) suspended in 2 ml of dichloromethane was added triethylamine (30 ml, 0.2 mmol) and then acetic acid anhydride (20 ml, 0.2 mmol) under ice cooling. After 1 hour the mixture warmed to room temperature. Thereto was added saturated brine. The mixture was extracted with chloroform and the organic layer was dried on magnesium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (34 mg, yield 66%).
Reaction SMILES: [S:1]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([O:11][C:12](=[O:14])[CH3:13])[CH3:10])(=[O:3])=[O:2].C([O-])(=O)C.S(C1C=CC(C)=CC=1)(OCCCCC(O)C)(=O)=O.COC(C1C=CC=CC=1)(C(F)(F)F)C([O-])=O>>[S:1]([C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[CH:20][CH:21]=1)([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][C:12](=[O:14])[CH3:13])=[CH2:10])(=[O:2])=[O:3]
Reactant: CC(=O)OC(C)CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: CC(=O)[O-]
Agent: COC(C(=O)[O-])(c1ccccc1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)OCCCCC(C)O)cc1
Product: C=C(CCCCOS(=O)(=O)c1ccc(C)cc1)OC(C)=O

Procedure:
1H NMR analysis indicated 5-acetoxyhexyl tosylate as the sole product, and hydrolysis of the acetate, conversion of the resulting 5-hydroxyhexyl tosylate to the α-methoxy-α-trifluoromethylphenylacetate (using the corresponding optically pure acid chloride), 1H NMR analysis and comparison to the racemate indicated 78% ee for 5-acetoxyhexyl tosylate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20](OC)=[O:21].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].NCC([O-])=O.[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: NCC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 110 °C
Yield: 86.1 %

Procedure:
A pressure flask was charged with 3e (30.92 g), glycine (22.52 g), methanol (155 mL), sodium methoxide solution (64.81 g) and sealed (as an alternative, sodium glycinate was used in place of glycine and sodium methoxide). The reaction was heated to about 110° C. until reaction was complete. The mixture was cooled, filtered, washed with methanol, dried under vacuum, dissolved in water and washed with ethyl acetate. The ethyl acetate was removed and to the resulting aqueous layer an acetic acid (18.0 g) solution was added. The suspension was stirred at room temperature, filtered, and the solid washed with water (3×30 mL), cold acetone (5-10° C., 2×20 mL), and dried under vacuum to obtain 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamido)acetic acid (Yield: 86.1%, HPLC: 99.8%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C@H:15]1[C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17][N:16]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:5])=[O:4])[CH3:2].[H][H]>CO.C1COCC1.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[C:7]([C@H:15]2[C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17][N:16]2[C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH:8]=1
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc([N+](=O)[O-])ccc1S(=O)(=O)CC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)CC
Yield: 102.2 %

Procedure:
To 35E (2.2 g) in methanol (50 mL) and THF (30 mL) was added 10% Pd/C (700 mg). The mixture was hydrogenated with a hydrogen balloon for 6.0 h. The Pd/C was removed by filtration and the filtrate was concentrated to afford 35G (2.1 g, 95% yield). 1H NMR (500 MHz, DMSO-d6, 100° C.) δ ppm 1.13 (t, J=7.42 Hz, 3H) 1.16-1.23 (t, J=7.42 Hz, 3H) 1.31 (s, 9H) 1.93-2.01 (m, 1H) 2.17 (m, 1 H) 2.78 (br s, 1H) 3.14 (br s, 2H) 3.38-3.47 (m, 1H) 3.66 (t, J=8.52 Hz, 1H) 4.10 (q, J=7.42 Hz, 2H) 5.60 (s, 1H) 5.83 (br s, 1H) 6.51-6.58 (m, 2H) 7.49 (d, J=9.34 Hz, 1H); LC-MS 427 (M+H).
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:23][CH3:24])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=2)[N:14]=1)C1C=CC=CC=1.[OH-].[Na+]>Cl>[CH2:23]([N:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=2)[N:14]=[C:10]1[CH2:9][OH:8])[CH3:24]
Reactant: CCn1cc(-c2ccc(F)c(C)c2)nc1COCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1cc(-c2ccc(F)c(C)c2)nc1CO
Yield: 96.9 %

Procedure:
4 g 2-benzyloxymethyl-1-ethyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazole was stirred 24 h at 85° C. in 40 mL concentrated aqueous hydrochloride acid. The mixture was dropped in a cooled 10% aqueous sodium hydroxide solution. The precipitate was filtered, washed with water and dried at 50° C. to yield 2.8 g of the desired product. Rt: 0.60 min (method J), (M+H)+: 235
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20]([C:24]([OH:26])=O)=[CH:19][CH:18]=[CH:17]4)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH2:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH2:42])=[O:34])=[CH:31][CH:30]=1>>[NH2:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[NH:35][C:33]([C:32]1[CH:43]=[CH:44][C:29]([CH2:28][NH:27][C:24]([C:20]2[C:21]3[C:16](=[CH:15][C:14]([O:13][C:7]4[C:6]5[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)[N:10]=[CH:9][CH:8]=4)=[CH:23][CH:22]=3)[CH:17]=[CH:18][CH:19]=2)=[O:26])=[CH:30][CH:31]=1)=[O:34]
Reactant: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: COc1ccc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc2c1
Product: COc1ccc2c(Oc3ccc4c(C(=O)NCc5ccc(C(=O)Nc6ccccc6N)cc5)cccc4c3)ccnc2c1
Yield: 84.9 %

Procedure:
The title compound (48.3 mg, 85% yield) was prepared as a brown solid from 6-(7-methoxyquinolin-4-yloxy)-1-naphthoic acid (34.5 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-aminophenyl)benzamide (28.9 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 3.95 (s, 3H, —OCH3), 4.64 (d, J=5.6 Hz, 2H, —CH2), 4.87 (s, 2H, benzene-NH2), 6.58-6.62 (m, 2H, Ar—H), 6.78 (dd, J=1.2 and 7.8 Hz, 1H, Ar—H), 6.97 (td, J=1.4 and 8.1 Hz, 1H, Ar—H), 7.18 (d, J=7.0 Hz, 1H, Ar—H), 7.31 (dd, J=2.5 and 9.2 Hz, 1H, Ar—H), 7.44 (d, J=2.4 Hz, 1H, Ar—H), 7.53-7.56 (m, 3H, Ar—H), 7.62 (t, J=8.0 Hz, 1H, Ar—H), 7.72 (d, J=6.1 Hz, 1H, Ar—H), 7.86 (d, J=2.5 Hz, 1H, Ar—H), 7.98-8.06 (m, 3H, Ar—H), 8.24 (d, J=9.1 Hz, 1H, Ar—H), 8.39 (d, J=9.2 Hz, 1H, Ar—H), 8.64 (d, J=5.2 Hz, 1H, Ar—H), 9.21 (t, J=6.0 Hz, 1H, —CONH), 9.61 (s, 1H, benzene-NH). LC-MS (m/z) 569 (M+1).
Reaction SMILES: Br[C:2]1[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[Cl:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])O.[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:18][C:19]1[C:24]([C:2]2[NH:6][CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1c[nH]c(-c2cccnc2Cl)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 32.9 %

Procedure:
5-Bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (2.67 g), (2-chloropyridin-3-yl)boronic acid (2.00 g), sodium hydrogen carbonate (2.15 g) and tetrakis(triphenylphosphine)palladium (738 mg) were added to a deaerated mixture of 1,2-dimethoxyethane (40 mL) and water (10 mL), and the mixture was stirred under a nitrogen atmosphere at 80° C. for 5 hr. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1). The obtained pale-yellow oil was dissolved in methanol (15 mL) and tetrahydrofuran (15 mL), 8 mol/L aqueous sodium hydroxide solution (15 mL) was added dropwise at room temperature and the mixture was stirred for 30 min. The reaction mixture was diluted with saturated brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue and insoluble crystals were collected by filtration to give the title compound as brown crystals (yield 578 mg, 33%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[S:3]([O:6][CH2:7][CH2:8][F:9])(=[O:5])=[O:4].[CH2:12]([O:15][C:16]([N:18]1[C@H:22]([CH2:23][C:24]2[S:28][C:27]3=[CH:29][N:30]=[C:31]([CH3:32])[N:26]3[CH:25]=2)[CH2:21][C@H:20]([S:33][C:34]2[C@H:35]([CH3:51])[C@@H:36]3[C@@H:46]([C@H:47]([OH:49])[CH3:48])[C:45](=[O:50])[N:37]3[C:38]=2[C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH2:19]1)=[O:17])[CH:13]=[CH2:14]>>[F:1][C:2]([F:11])([F:10])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:12]([O:15][C:16]([N:18]1[C@H:22]([CH2:23][C:24]2[S:28][C:27]3=[CH:29][N:30]([CH2:7][CH2:8][F:9])[C:31]([CH3:32])=[N+:26]3[CH:25]=2)[CH2:21][C@H:20]([S:33][C:34]2[C@H:35]([CH3:51])[C@@H:36]3[C@@H:46]([C@H:47]([OH:49])[CH3:48])[C:45](=[O:50])[N:37]3[C:38]=2[C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH2:19]1)=[O:17])[CH:13]=[CH2:14]
Reactant: O=S(=O)(OCCF)C(F)(F)F
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4c(C)ncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4c(C)n(CCF)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 89.2 %

Procedure:
2-Fluoroethyl trifluoromethanesulfonate (40.6 mg) is added to 30.6 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate described in Example 31-a), and the mixture is stirred in an argon atmosphere at room temperature for 3.5 hr. The solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 36.4 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-(2-fluoroethyl)-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate trifluoromethanesulfonate as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[C:6]([F:9])[N:7]=[CH:8][C:3]=2[CH2:2][N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cc(-c2ccc(Cl)cc2)c(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)cc2-c2ccc(Cl)cc2)CC1

Procedure:
A mixture of EXAMPLE 307B (1.24 g), tert-butyl piperazine-1-carboxylate (0.768 g), and potassium carbonate (0.570) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel using 10% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CCCCO)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of benzyl 5-hydroxypentanoate (2.01 g, 9.65 mmol) in anhydrous dichloromethane (30 mL) under nitrogen at −15° C. was added triethylamine (2.7 mL, 19.3 mmol) followed by a solution of methanesulfonyl chloride (1.5 mL, 19.3 mmol) dropwise over 20 minutes. The reaction was stirred at room temperature overnight and then diluted to 75 mL using dichloromethane. The organic layer was washed three times with saturated NaHCO3 and the combined aqueous layers backextracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered, and concentrated. The resulting dark orange oil was purified by column chromatography (column 5″L×1″W; eluted with a gradient of 100% hexanes→10%→20%→25% diethyl ether in hexanes) to afford the product as a pale yellow oil (1.39 g, 50%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[Cl:20][C:21]1[C:22]([C:37]([F:40])([F:39])[F:38])=[CH:23][C:24]2[NH:28][C:27](=[O:29])[N:26]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:25]=2[CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)[CH2:49][C:50](=[O:52])[CH3:51]>O>[CH3:49][CH:50]([O-:52])[CH3:51].[Cl:20][C:21]1[C:22]([C:37]([F:40])([F:39])[F:38])=[CH:23][C:24]2[NH:28][C:27](=[O:29])[N:26]([CH:30]3[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][CH2:4][CH:5]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:6]4[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=4)[CH2:34][CH2:35]3)[C:25]=2[CH:36]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)c(Cl)cc2n1C1CCNCC1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: CC(=O)CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)[O-]
Product: O=c1[nH]c2cc(C(F)(F)F)c(Cl)cc2n1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 3.5 parts of 1-chloro-4,4-bis(4-fluorophenyl)-butane, 2.5 parts of 6-chloro-1,3-dihydro-1-(4-piperidinyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one, 2.65 parts of sodium carbonate and 100 parts of 4-methyl- 2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled to room temperature and water is added. The organic layer is separated, dried, filtered and evaporated. The solid residue is purified by column-chromatography over silicagel, using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 6-chloro-1-{1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one 2-propanolate; mp. 200° C.
Reaction SMILES: I[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])=[N:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH3:22][N:23]([CH3:33])[C:24]1[CH:29]=[C:28]([C:2]2[C:10]3[S:9][C:8]([NH:11][C:12]([C:14]4[S:15][C:16]([CH3:19])=[CH:17][CH:18]=4)=[O:13])=[N:7][C:6]=3[C:5]([O:20][CH3:21])=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(I)c2sc(NC(=O)c3ccc(C)s3)nc12
Reactant: CN(C)c1cccc(B(O)O)c1
Product: COc1ccc(-c2cccc(N(C)C)c2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 71 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid [7-(3-dimethylamino-phenyl)-4-methoxy-benzothiazol-2-yl]-amide is synthesized from 5-methyl-thiophene-2-carboxylic acid (7-iodo-4-methoxy-benzothiazol-2-yl)-amide (100 mg, 0.23 mmol) and 3-dimethylaminophenylboronic acid (58 mg, 0.35 mmol) using the general procedure A as a light yellow solid in 71% yield. MS: m/e=424 (M+H+).
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[CH2:22]([O:29][C@@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:32][C@H:31]1[O:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][OH:78])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)Cl.S(=O)(=O)(O)O>C(O)C>[CH2:22]([O:29][C@@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:34]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:32][C@H:31]1[O:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH:77]=[O:78])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCCCCCCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: ClCCl
Product: O=CCCCCCCCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
PDC oxidation of 16-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyloxy)-n-hexadecanol. Under an atmosphere of nitrogen, pyridinium dichromate (320 mg, 0.851 mmol) was added to a dry methylene chloride solution (6 mL) of 16-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyloxy)-n-hexadecanol (455 mg, 0.583 mmol). The resulting brown slurry was stirred at room temperature under nitrogen. TLC analysis (visualization by UV and char with 10% sulfuric acid in ethanol) of the reaction mixture indicated complete consumption of the starting material and the formation of a new compound after 17 h. The reaction mixture was treated with ether (10 mL), filtered through silica gel and Celite with an ether wash (25 mL) and concentrated to an off-white oil. Chromatographic purification (silica gel, 10% ethyl acetate in hexanes) afforded 345 mg (0.443 mmol, 76%) of 16-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyloxy)-n-hexadecanal as a clear oil. Rf =0.72 (silica gel, 30% ethyl acetate in hexanes); 1H NMR (CDCl3, 300 MHz) δ: 9.75 (t, J=1.5 Hz, 1H), 7.30 (m, 20H), 4.95 (d, J=11.7 Hz, 2H), 4.75 (m, 2H), 4.63 (d, J=11.7 Hz, 1H), 4.43 (d, J=4.5 Hz, 2H), 4.36 (d, J=7.8 Hz, 1H), 3.65 (m, 2H), 3.82 (dt, J=8.7, 1.5 Hz, 1H), 3.56 (m, 6H), 2.40 (dt, J=7.5, 1.5 Hz, 2H), 1.60 (m, 4H), 1.26 (m, 24 H); MS (FAB+): 801.3 (M+Na, 14), 785.3 ((M+Li)+, 29), 253.1 (10), 181.1 (100), 160.0 (16), 136.0 (21), 123.0 (12).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH2:11]1[O:22][CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[O:13][CH2:12]1>>[O:13]1[CH2:12][CH2:11][O:22][CH:14]1[C:15]1[CH:16]=[C:17]([NH:21][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(C2OCCO2)c1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cn1

Procedure:
The title compound is prepared according to the reaction sequence described above for L-7 starting from 5-chloropyridine-2-carboxylic acid and 3-aminobenzaldehyde ethylene acetal to yield 5-chloro-pyridine-2-carboxylic acid (3-[1,3]dioxolan-2-yl-phenyl)-amide; LC-MS A: tR=0.84 min; [M+H]+=305.13 which is treated with m-chloro-perbenzoic acid to deliver 5-chloro-1-oxy-pyridine-2-carboxylic acid (3-[1,3]dioxolan-2-yl-phenyl)-amide; LC-MS A: tR=0.77 min; [M+H]+=321.02, then deprotected with HCl 10% to yield 5-chloro-1-oxy-pyridine-2-carboxylic acid (3-formyl-phenyl)-amide LC-MS A: tR=0.72 min; [M+H]+=277.01.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24]O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:7][O:6][C:4](=[O:5])[C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[CH:9][C:8]=1[O:12][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14]
Reactant: COC(=O)c1c(O)cccc1O
Reactant: CC(C)(C)OC(=O)NCCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2,6-dihydroxybenzoate (1.0 g, 5.95 mmol) and 4-(Boc-amino)-1-butanol (1.1 mL, 5.95 mmol) in 60 mL THF is added PPh3 (1.7 g, 6.5 mmol) and DEAD (2.97 mL, 6.5 mmol) and the mixture is stirred at RT overnight. The solvent is removed under reduced pressure and the residue is purified by flash chromatography eluting with hexanes/EtOAc (5:1 to 2:1) to give the title compound as a colorless liquid: 1H NMR (CDCl3) δ 11.42 (s, 1H), 7.29 (t, J=8.34 Hz, 1H), 6.57 (d, J=8.34 Hz, 1H), 6.37 (d, J=8.34 Hz, 1H), 4.63 (s, 1H), 3.99 (t, J=6.06 Hz, 2H), 3.93 (s, 3H), 3.22-3.17 (m, 2H), 1.88-1.81 (m, 2H), 1.74-1.67 (m, 2H), 1.43 (s, 9H); (M−1)−=338.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC[O-].[Na+].[C:14]1(=[O:19])[O:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][CH2:16][CH2:15][C:14]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: O=C1CCCO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(OCCCC(=O)O)cc1
Temperature: 155 °C
Reaction time: 0.08 h

Procedure:
4-Methoxyphenol was added to a solution of NaOC2H5 made by dissolving 2.3 g of Na in 50 ml ethanol. After 5 minutes, gamma-butyrolactone was added and the mixture heated at reflux overnight. Ethanol was distilled off and the residue heated at 155° C. overnight, then cooled, diluted with water and acidified to pH 3 with dilute hydrochloric acid. The product was collected by filtration, 19.5 g, m.p. 103-104° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH2:17][CH2:16]2.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][CH2:17][CH2:16]3)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc(Cl)nc1Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2,4-dichloro-5-nitropyrimidine (5.0 g, 25.8 mmol) in dioxane (35 mL) was added a solution of 5-aminoindane (3.43 g, 25.8 mmol) in dioxane (9 mL) and diisopropylethyl amine (4.5 mL, 25.8 mmol). The mixture was stirred at 25° C. for 1 hr and then concentrated to a residue to provide crude (2-chloro-5-nitro-pyrimidin-4-yl)-indan-5-yl-amine, (1).