Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>ClCCl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:27][CH:24]([CH3:26])[CH3:25])[N:7]=3)=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:18][CH:19]=1
Reactant: CC(C)N
Reactant: Fc1ccc(-c2nn3c(c2-c2ccnc(Cl)n2)CCCC3)cc1
Solvent: ClCCl
Product: CC(C)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CCCC3)n1
Temperature: 34 °C
Reaction time: 18 h

Procedure:
A mixture of 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (i.e. the product of Step B) (200 mg, 0.54 mmol) and isopropylamine (5.0 mL) was stirred at 34° C. for 18 h. The reaction mixture was diluted with dichloromethane (50 mL) and treated with silica gel (20.0 g). The silica gel suspension was concentrated under reduced pressure to leave a mixture of silica gel and crude product, which was purified by silica gel chromatography using a gradient of ethyl acetate/hexanes (1:9 to 1:0) as eluant to give 115 mg of the title product, a compound of the present invention, as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:18]([O:22][C:23](=[O:37])[CH2:24][NH:25][C:26]([C:28]1[S:29][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:31][CH:32]=1)=[O:27])([CH3:21])([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C>[C:18]([O:22][C:23](=[O:37])[CH2:24][NH:25][C:26]([C:28]1[S:29][C:30]([C:33]([NH:35][N:36]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:10][CH:11]=2)[CH3:17])=[O:34])=[CH:31][CH:32]=1)=[O:27])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)NCC(=O)OC(C)(C)C)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 80.9 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (49 mg, 0.17 mmol) in isopropanol (2.0 mL) was heated with tert-butyl{[5-(hydrazinocarbonyl)thiophene-2-carbonyl]amino}acetate (44 mg, 0.15 mmol) prepared in Reference Synthetic Example 8 and 3 mg of p-toluenesulfonic acid monohydrate at 100° C. for 8 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, methanol and chloroform and dried to give 69 mg of the desired product (yield 83%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12]1([CH3:15])[CH2:14][CH2:13]1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28](O)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:2]([CH3:1])[C:3]([C:12]4([CH3:15])[CH2:13][CH2:14]4)=[CH:4]5)=[O:29])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: Cn1c(C2(C)CC2)cc2cc(N)ccc21
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(C2(C)CC2)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21
Temperature: 80 °C
Reaction time: 6 h

Procedure:
1-Methyl-2-(1-methylcyclopropyl)-1H-indol-5-amine (20.0 mg, 0.100 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (42.1 μL, 0.300 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 6 h at 80° C. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(1-methyl-2-(1-methylcyclopropyl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 388.2, found 389.2 (M+1)+. Retention time of 3.05 minutes.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([CH2:18][CH2:19]O)=[C:16]([CH3:21])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:28])CC)C.O>ClCCl>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([CH2:18][CH2:19][F:28])=[C:16]([CH3:21])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1CCO
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1CCF
Reaction time: 4 h

Procedure:
2.0 g (6.5 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-6-methyl-5-(2-hydroxyethyl)pyrimidine (Example 33) were dissolved in 30 ml of dichloromethane, and 1.16 g (7.2 mmol) of diethylaminosulfur trifluoride (DAST) were added at -50° C. The mixture was allowed to rise to room temperature, and was subsequently stirred for 4 hours. It was poured into water, the dichloromethane phase was extracted by stirring with sodium hydrogen carbonate solution and the organic extracts were dried and concentrated. Chromatography on silica gel gave 1.55 g (77.6% of theory) of product as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[C:17](I)[CH:16]=3)=[O:11])=[CH:4][CH:3]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[C:17]([C:26]#[C:25][CH2:24][OH:27])[CH:16]=3)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(I)ccc2c1O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(C#CCO)ccc2c1O
Reaction time: 8 h

Procedure:
To a mixture of the title compound of Example 39 (0.439 g), copper iodide (0.010 g) and dichlorobis(triphenylphosphine)palladium (II) (0.035 g) in 15 mL diethylamine is added propargyl alcohol (0.058 mL). The reaction is allowed to stir overnight. The solvents are evaporated and the residue is chromatographed on silica, eluting with 3% MeOH/CH2Cl2 to yield 0.271 g of the desired product as a tan solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27].C(NC(C)C)(C)C>C1COCC1.[Cu]I.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>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]#[C:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCCCOc1ccc(-c2ccc(C#CC(C)(C)O)cc2)cc1

Procedure:
A stirred mixture of compound 68 (15.00 g, 0.039 mol), 2-methylbut-3-yn-2-ol (7.15 g, 0.085 mol), copper(I) iodide (0.34 g, 1.80 mmol), tetrakis(triphenylphosphine)palladium(0) (2.89 g, 2.50 mmol) and diisopropylamine (150 ml) was heated under reflux in a dry nitrogen atmosphere for 24 h. The resultant mass was dissolved in THF and filtered over hyflo filter aid to remove inorganic materials. Volatile materials were removed in vacuo and the brown solid was recrystallised from ethanol to give a white, fluffy solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl:16][C:17]1[CH:18]=[C:19]([S:27](Cl)(=[O:29])=[O:28])[CH:20]=[CH:21][C:22]=1[S:23](=[O:26])(=[O:25])[NH2:24]>CC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([S:27]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][CH3:8])[CH2:11][CH2:12]2)(=[O:28])=[O:29])[CH:20]=[CH:21][C:22]=1[S:23]([NH2:24])(=[O:25])=[O:26]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: COC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC1CCN(S(=O)(=O)c2ccc(S(N)(=O)=O)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Triethylamine (4.2 ml) and 4-methoxypiperidine (3.15 g) were added to a solution of 3-chloro-4-sulphamoyl-benzene sulphonyl chloride (8.7 g) in acetone (100 ml). The mixture was stirred at room temperature for 1 hour and then poured into 50 ml of N-hydrochloric acid. The resulting product was removed by filtration, washed with water and recrystallized from isopropanol to give the desired compound (8.4 g), m.p. 165°-167°C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:17][CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:11][CH2:12]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2ccccc2)CC1
Reaction time: 1 h
Yield: 165.7 %

Procedure:
NaH (60% oil dispersion, 53 mg, 1.3 mmol) was added in portions to a solution of 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine (240 mg, 1.1 mmol) and benzyl bromide (0.40 mL, 0.58 g, 0.33 mmol) in DMF (2.0 mL). After 1 h, additional NaH (60% oil disperison, 15 mg, 0.38 mmol) was added. After a total of 2.25 h, the mixture was quenched with water and extracted with EtOAc. The organic layer was washed with saturated aq. NaCl, dried (Na2SO4), and evaporated. Purification by flash column chromatogaraphy on silica gel, eluting with 5-10% EtOAc in hexane gave 167 mg of 4-(benzyloxymethyl)-1-(tert-butoxycarbonyl)piperidine. A portion (160 mg, 0.55 mmol) of this intermediate was dissolved in CH3OH (2.0 mL) and a solution of HCl (2 N in ether, 2.0 mL, 4 mmol) was added. The mixture was stirred overnight at RT and evaported to give the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:9])([F:8])[S:4](Cl)(=[O:6])=[O:5].C(=O)([O-])O.[Na+].[OH:15][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].O>C(#N)C>[F:8][C:3]([F:9])([S:4]([O:15][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])(=[O:6])=[O:5])[CH2:2][OH:1]
Reactant: O=C1CCC(=O)N1O
Reactant: O=S(=O)(Cl)C(F)(F)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CCC(=O)N1OS(=O)(=O)C(F)(F)CO
Temperature: 0 °C
Yield: 57.9 %

Procedure:
In 100 mL of acetonitrile, 25.5 g of a liquid of 2-hydroxy-1,1-difluoroethanesulfonyl chloride (purity: 98%, equivalent to 0.138 mol) was dissolved by stirring. The resulting solution was cooled to 0° C., admixed with 14.0 g (0.166 mol) of sodium hydrogencarbonate and 17.5 g (0.152 mol) of N-hydroxysuccinimide, and then, reacted at 0° C. for 24 hours. To the thus-obtained reaction solution, 125 mL of water was added. The reaction solution was subsequently extracted twice with 100 mL of ethyl acetate. The resulting organic layer was washed twice with 100 mL of water. The organic layer was further subjected to concentration and purified by distillation. With this, 20.7 g of the target compound was obtained as a colorless oily substance (yield: 52%, purity: 90%, pure content: 18.7 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:34][CH:35]([CH3:38])[CH:36]=O.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:34][CH:35]([CH3:38])[CH3:36])[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)C=O
Agent: [BH4-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(CC(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml).). 2-Methylpropionaldehyde (0.104 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 19 mg; HRMS (FAB+, NBA) (M+H)+ 409.2858, C26H37N2O2 requires 409.2855; LC-MS: (M+H)+ 409.2, tr 5.97 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:33]([OH:35])=[O:34])[C:10]([S:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:38](=O)([O-])O.[K+]>CN(C)C=O>[CH3:38][O:34][C:33](=[O:35])[C@@H:9]([C:10]([S:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH3:12])[CH3:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 97.2 %

Procedure:
To the solution of N-t-butoxycarbonyl-S-trityl-D-penicillamine (A-2) (6.0 g) in dimethylformamide (40 ml), were added methyl iodide (1.5 ml) and potassium hydrogencarbonate (2.4 g), and the mixture was stirred for 14 hours. To the reaction mixture was added ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated saline, and dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, to give N-t-butoxycarbonyl-S-trityl-D-penicillamine methyl ester (6.0 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(N(CC)CC)C.[O:25]([C:32]1[N:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:38]([C:35]1[CH:36]=[N:37][C:32]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:33][CH:34]=1)(=[O:39])=[O:40])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)nc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of (R)-benzyl 3-amino-4-(dimethylamino)butanoate (32 mg, 0.086 mmol), triethylamine (50 μL, 0.36 mmol) and DMAP (1 mg, 0.008 mmol) in anhydrous CH2Cl2 (1 mL) was added 6-phenoxypyridine-3-sulfonyl chloride is reacted with R-aminocarnitine benzyl ester (67 mg, 0.25 mmol). The solution was stirred overnight at room temperature. The solvents were removed in vacuo and the residue was purified by preparatory HPLC. The residue was dissolved into CH2Cl2 (50 mL) and washed with 0.1 N NaOH (5 mL), dried over MgSO4 and concentrated to give the title compound as a white solid (18 mg, 37%). MS ESI 470.2 [M+H]+, calcd for [C24H27N3O5S+H]+ 470.17.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)[CH2:16][C:17]([C:19]([OH:21])=[O:20])=[O:18].Cl>O.C1(C)C=CC=CC=1>[CH2:9]([C:10]([OH:14])([C:11]([OH:13])=[O:12])[CH2:16][C:17](=[O:18])[C:19]([OH:21])=[O:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CC(=O)C(=O)O
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C(=O)CC(O)(Cc1ccccc1)C(=O)O
Yield: 37 %

Procedure:
After 16.23 g of potassium hydroxide (having a purity of 85% by weight) was dissolved in 48 ml of water, 5.0 g (30.5 mmol) of phenylpyruvic acid and 12.1 g (91.4 mmol) of oxalacetic acid were added to the resulting solution, for reaction at ambient temperature for 72 hours (about pH 13 at the start of the reaction). Using conc. hydrochloric acid, the reaction solution was adjusted to pH 2.2, and extracted in ethyl acetate. The organic layer was rinsed in aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated to obtain the residue. The residue was recrystallized in ethyl acetate and toluene, to obtain 2.8 g (11.3 mmol) of 4-benzyl-4-hydroxy-2-ketoglutaric acid in crystal form.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](Cl)[N:18]=3)[S:14][C:13]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>O1CCOCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)[N:18]=3)[S:14][C:13]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Reactant: CN1CCN(CCCN)CC1
Solvent: C1COCCO1
Product: CN1CCN(CCCNc2nccc(-c3cc4ccc(CNC(=O)OC(C)(C)C)cc4s3)n2)CC1
Yield: 70.2 %

Procedure:
A mixture of [2-(2-chloropyrimidin-4-yl)-benzo[b]thiophen-6-ylmethyl]-carbamic acid tert-butyl ester (1.47 g, 3.90 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (1.36 g, 8.60 mmol) in dioxane (38 mL) is refluxed for 3 hours. The solvent is removed and the residue is subjected to chromatography on silica gel, eluting with 2.0 M NH3/MeOH in CHCl3 0-10%, to obtain the title compound (1.36 g, 70% yield). ES+(m/z) 497 [M+H].
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].Br[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[Cl:17][C:15]1[CH:16]=[C:11]([CH:12]=[C:13]([Cl:18])[CH:14]=1)[CH2:10][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: Clc1cc(Cl)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 60 °C
Yield: 91 %

Procedure:
To a solution of 2-nitroimidazole and 1-bromomethyl-3,5-dichloro-benzene in anhydrous DMSO was added Na2CO3. The reaction mixture was heated to 60° C. for 6 h. The reaction mixture was then diluted with EtOAc and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH to afford 1-(3,5-dichloro-benzyl)-2-nitro-1H-imidazole (0.66 g, 91%).
Reaction SMILES: O[C:2]1[C:7]([C:8]2[CH:13]=CC=C[CH:9]=2)=[N:6][C:5]([Br:14])=[CH:4][N:3]=1.OC1C(C(C)C)=NC([Br:25])=CN=1>>[Br:25][C:2]1[C:7]([CH:8]([CH3:13])[CH3:9])=[N:6][C:5]([Br:14])=[CH:4][N:3]=1
Reactant: Oc1ncc(Br)nc1-c1ccccc1
Reactant: CC(C)c1nc(Br)cnc1O
Product: CC(C)c1nc(Br)cnc1Br

Procedure:
This compound is prepared by replacing the 2-hydroxy-3-phenyl-5-bromopyrazine used in Step A of Preparation 87 by an equivalent quantity of 2-hydroxy-3-isopropyl-5-bromopyrazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)Br.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[S:24].CO>C(O)C>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]1[S:24][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:25]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccccc2F)cc1
Reactant: NC(=S)c1ccccc1Cl
Solvent: CCO
Solvent: CO
Product: CSc1ccc(-c2sc(-c3ccccc3Cl)nc2-c2ccccc2F)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A solution of 1-(2-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone from Step 3 (1.39 g, 4.1 mmol) and 2-chlorothiobenzamide (0.71 g, 4.1 mmol) in 10 mL of ethanol was heated to reflux for 4.4 hours. The solution was cooled to room temperature and poured into 25 mL of methanol, chilled with an ice bath whereupon crystals of pure product formed which were isolated by filtration and air dried to afford the thiazole (1.34 g, 79%): mp 117°-119° C. 1H NMR (CDCl3) 300 MHz 8.37 (m, 1H), 7.62 (m, 2H), 7.49 (d, J=7.7Hz,1H), 7.32 (m, 7H), 7.22 (d, J=8.5Hz, 2H), 2.51 (s, 3H). Mass spectrum M+ +H=412.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:15][CH3:16])C.O.[NH2:19][NH2:20]>C(O)C>[CH2:15]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:7]=1[NH:6][CH2:5][C:4]([NH:19][NH2:20])=[O:3])[CH3:16]
Reactant: NN
Reactant: CCOC(=O)CNc1c(CC)cccc1CC
Solvent: CCO
Solvent: O
Product: CCc1cccc(CC)c1NCC(=O)NN

Procedure:
58.7 g (0.25 mol) of 2,6-diethyl-anilino-acetic acid ethyl ester and 25 g of hydrazine hydrate were left to stand in 200 ml of ethanol for 24 hours. Thereafter, the mixture was concentrated by distilling off the solvent and the residue was extracted by stirring with water. After drying, 50.5 g (91% of theory) of colorless crystals of 2,6-diethyl-anilino-acetic acid hydrazide of melting point 71° to 73° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][CH3:13])[C:5]#[N:6].Cl.[Cl:15][CH2:16][C:17](=N)OCC>C(O)C>[ClH:15].[CH2:11]([N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[C:17]1[CH2:16][Cl:15])[CH2:12][CH3:13]
Reactant: CCCNc1ccc(C#N)cc1N
Reactant: CCOC(=N)CCl
Agent: Cl
Solvent: CCO
Product: CCCn1c(CCl)nc2cc(C#N)ccc21

Procedure:
A solution of 3-amino-4-n-propylaminobenzonitrile (7.38 g, 42.1 mmol) and ethyl chloroacetimidate hydrochloride (9.92 g, 63.2 mmol) in ethanol (100 mL) is heated at reflux for 17 h, then cooled and concentrated to give 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole hydrochloride. Prior to use in the next step, this material is converted to free base by adding aqueous bicarbonate and extracting with dichloromethane, drying (Na2SO4), and concentrating. ii) Alternatively, chloroacetylchloride rather than ethyl chloroacetimidate can by used: To a solution of 3-amino-4-n-propylaminobenzonitrile (5.15 g, 29.4 mmol) and triethylamine (4.51 mL) in ethyl acetate (52 mL) at room temperature, chloroacetyl chloride (2.57 mL) is added slowly. After stirring the reaction mixture for 30 minutes at room temperature, acetic acid (5 mL) is added and the reaction mixture heated to reflux. After heating for 20 h, the reaction mixture is cooled to room temperature and diluted with water (50 mL). The organic solution is washed twice with 1.0 M sodium hydroxide (2×50 mL), then washed with an aqueous solution of 0.25 M KH2PO4 (50 mL), followed by brine (50 mL). The organic layer is dried (sodium sulfate), concentrated in vacuo, and the solid recrystallized by heating in ethyl acetate (20 mL), adding hexane (40 mL) and cooling to room temperature with stirring to afford 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole as brown crystals. 1H NMR (CDCl3): δ 8.08 (d, J=0.8 Hz, 1H), 7.57 (dd, J=1.65, 8.52 Hz, 1H), 7.45 (d, J=8.24 Hz, 1H), 7.26 (s, 1H), 4.84 (s, 2H), 4.24 (t, J=7.6 Hz, 2H), 1.94 (pentet, J=7.4. 7.6 Hz, 2H), 1.03 (t, J=7.4 Hz, 3H). (B) Preparation of 1-Propyl-2-{([2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole