Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH:13]C(OCC2C=CC=CC=2)=O)[CH:5]=1.O>[Pd].CO>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH2:13])[CH:5]=1
Reactant: CCOc1cc(NC(=O)OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCOc1cc(N)cc(C(=O)OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture of 3-benzyloxycarbonylamino-5-ethoxy-benzoic acid methyl ester (D47) (15 g, 45.5 mmol, 1 equiv), 10% palladium on charcoal (50% wet, 1.5 g, 5% w/w) and NH4COOH (15 g, 455 mmol, 10 equiv) H2O (50 ml) and MeOH (200 ml) was stirred at 50° C. for 2 h. The mixture was cooled to room temperature and the catalyst was filtered off through a pad of celite. Most of the MeOH was removed in vacuo and the residue was partitioned between saturated aqueous NaHCO3 solution and AcOEt. The aqueous phase was re-extracted with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give 3-amino-5-ethoxy-benzoic acid methyl ester (D49) (8.8 g, 99%) as a pale green solid which was used in the next step without further purification. [M+H]+=196.1, RT=2.49 min
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1.O>O1CCCC1>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1
Reactant: CC(C)=CCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
To a solution of 3-methyl-2-buten-1-ol (780 mg, 9 mmol) and sodiumhydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 0.3 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[Cl:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.Br[CH:14]([CH2:22][CH2:23]Br)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl>CC1CCCO1.BrC(CCBr)C(OC(C)(C)C)=O.C[Si](C)(C)[O-].[K+]>[Cl:7][C:8]1[CH:9]=[N:10][N:11]([C:14]2([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:23][CH2:22]2)[CH:12]=1
Reactant: Clc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)C(Br)CCBr
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)C1(n2cc(Cl)cn2)CC1
Reaction time: 0.08 h
Yield: 126.7 %

Procedure:
Into a flask was added potassium trimethylsilanolate (20.85 g, 146.31 mmol), 4-chloro-1H-pyrazole (15 g, 146.31 mmol) and 2-methyltetrahydrofuran (400 mL). The mixture was stirred for 5 min followed by the addition of tert-butyl 2,4-dibromobutyrate (27.84 mL, 146.31 mmol) over a period of 20 to 30 seconds. The reaction mixture was stirred for 60 min. Potassium trimethylsilanolate (20.85 g, 146.31 mmol) in 2-methyltetrahydrofuran (80 mL) was added over a period of 5 min. The reaction mixture was stirred for 1 h before adding tert-butyl 2,4-dibromobutyrate (1 mL, 5.3 mmol). After 30 min, an additional portion of tert-butyl 2,4-dibromobutyrate (2 mL, 10.5 mmol) was added. The mixture was stirred for 40 min before adding tert-butyl 2,4-dibromobutyrate (1 mL, 5.3 mmol) and potassium trimethylsilanolate (2 g, 14 mmol). The reaction mixture was stirred for 18 h. Hydrochloric acid (146.31 mL, 146.31 mmol) was added and the mixture was stirred for 5 min. The layers were separated, and the organics were washed with water (200 mL) and concentrated under reduced pressure. Toluene (100 mL) was added and the mixture was concentrated to dryness to afford tert-butyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarboxylate (45 g). 1H NMR (400 MHz, CDCl3): δ 1.40 (s, 9H), 1.57 (q, 2H), 1.75 (q, 2H), 7.44 (s, 1H), 7.51 (s, 1H); MS (EI+) (M+) 242; GCMS retention time: 2.37 minutes (Method O).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][N:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@H:4]2[CH2:3]1.CC(C)([O-])C.[K+].Br[C:27]1[CH:32]=[N:31][C:30]([CH:33]2[CH2:35][CH2:34]2)=[CH:29][N:28]=1.CO>O1CCCC1>[CH:33]1([C:30]2[N:31]=[CH:32][C:27]([O:1][C@H:2]3[CH2:19][N:5]4[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C@H:4]4[CH2:3]3)=[N:28][CH:29]=2)[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@H](O)C[C@@H]2C1
Reactant: Brc1cnc(C2CC2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Reaction time: 0.08 h
Yield: 58.1 %

Procedure:
tert-Butyl (8R,9aR)-8-hydroxy-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (60 mg, 0.222 mmol, 1.0 equivalent, Example 46, Part D) was dissolved in tetrahydrofuran (1.0 mL). Potassium tert-butoxide (0.311 mL, 0.311 mmol, 1 M in tetrahydrofuran, 1.4 equivalents) was added at room temperature, and the resulting yellow solution was stirred for five minutes. Then 2-bromo-5-cyclopropylpyrazine (57.4 mg, 0.289 mmol, 1.3 equivalents) was added as a solution in tetrahydrofuran (0.5 mL), and the reaction mixture was stirred for 16 hours at the same temperature. The reaction mixture was quenched with 1 drop of saturated sodium bicarbonate, the solvent was removed in vacuo, and the crude material was loaded onto a 12 g silica column with 5% methanol/dichloromethane and eluted with 100:0 to 95:5 dichloromethane:methanol over 20 minutes to give the titled compound (50 mg, 0.129 mmol, 58.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (s, 1H), 7.94 (d, J=1.1 Hz, 1H), 5.38 (br s, 1H), 4.23 (br s, 2H), 3.95 (t, J=7.2 Hz, 1H), 3.90-3.73 (m, 2H), 3.00 (br s, 2H), 2.71-2.45 (m, 3H), 2.18-1.86 (m, 2H), 1.47 (s, 9H), 1.05-0.85 (m, 4H); MS (ESI+) m/z 333.0 (M-tBu+H)+.
Reaction SMILES: Cl[P:2]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[O:3][CH2:4][CH3:5].[NH2:17][CH:18]1[CH2:24][CH2:23][S:22][CH2:21][N:20]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:19]1=[O:31]>C(Cl)Cl>[CH2:4]([O:3][P:2]([NH:17][CH:18]1[CH2:24][CH2:23][S:22][CH2:21][N:20]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:19]1=[O:31])([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:5]
Reactant: CCOC(=O)CN1CSCCC(N)C1=O
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CN1CSCCC(NP(=O)(CCCCc2ccccc2)OCC)C1=O

Procedure:
A mixture of crude chloro(4-phenylbutyl)phosphinic acid, ethyl ester, dry methylene chloride and 5-amino-tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester are reacted as set forth in Example 1(f). Work up of the reaction mixture according to Example 1(f) yields 5-[[ethoxy(4-phenylbutyl)phosphinyl]amino]tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][NH2:11])=[CH:4][C:3]=1[CH3:12].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][NH:11][C:20](=[O:22])[CH3:21])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(CCN)cc(C)c1Br
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1cc(C)c(Br)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 2-(4-bromo-3,5-dimethylphenyl)ethanamine (100 mg) and triethylamine (68 μL) in dichloromethane (3 mL) is added acetyl chloride (31 μL). The mixture is stirred for 2 hours at 0° C. Then the mixture is partitioned between dichloromethane and water. The organic phase is separated and dried (MgSO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 25 mg; LC (method 7): tR=0.98 min; Mass spectrum (ESI+): m/z=270 [M+H]+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC#N>[O:4]=[C:5]1[CH2:6][CH2:7][CH:8]([CH:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:12][CH3:13])[CH2:9][CH2:10]1
Reactant: CCC(NS(C)(=O)=O)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: CCC(NS(C)(=O)=O)C1CCC(=O)CC1

Procedure:
A solution of N-(1-1,4-dioxaspiro[4.5]decan-8-ylpropyl)methanesulfonamide (as prepared in the previous step, 38 mg, 0.14 mmol, 1.00 equiv) in CH3CN (5 mL) and HCl (2M, 1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 10 mL of aq. sodium bicarbonate (1M). The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:11]([Mg]Br)([CH3:13])[CH3:12]>>[Br:8][C:6]1[CH:7]=[C:2]([CH:11]([CH3:13])[CH3:12])[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: CC(C)[Mg]Br
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: CC(C)c1cc(Br)cn(C)c1=O

Procedure:
Examples 512-514 as described in Table 23 were prepared in three steps. Using conditions similar to those described by Malhotra, et. al. in Organic Letters 2013, Vol. 15, No. 14, pp. 3698-3701 (supporting information, compounds 4c and 3a), 3,5-dibromo-1-methylpyridin-2-one was alkylated at the 3-position using isopropylmagnesium bromide to give 5-bromo-1-methyl-3-propan-2-ylpyridin-2-one which was then reacted with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane using conditions similar to those described in Example 248, step 2 to give the pinacol ester, 1-methyl-3-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one. This pinacol ester was then substituted for the pinacol ester of the example shown under Synthetic Method in Table 23 and reacted in the same way as the example to obtain the title compounds.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[BH4-].[Na+]>CO>[Cl:3][C:4]1[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][CH2:1][NH2:2]
Reactant: CCCOc1c(Cl)cccc1C=O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1c(Cl)cccc1CCN
Reaction time: 72 h
Yield: 96 %

Procedure:
A solution of methylamine (8.5 mL of a 2.0 M solution in MeOH, 17 mmol) was added to 3-chloro-2-propoxybenzaldehyde (0.425 g, 2.14 mmol) and the mixture was stirred for 72 h. The solution was concentrated under reduced pressure. The resulting clear oil was dissolved in EtOH (8.5 mL) and treated with NaBH4 (0.080 g, 2.1 mmol). After stirring for 18 h, the reaction mixture was concentrated under reduced pressure and then dissolved in 1 N NaOH (10 mL). The mixture was extracted with Et2O (3×50 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (0.441 g, 96%) as a light yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.37-7.31 (m, 2H), 7.08 (t, J=7.7 Hz, 1H), 3.85 (t, J=6.4 Hz, 2H), 3.67 (s, 2H), 2.26 (s, 3H), 2.04 (br s, 1H), 1.82-1.70 (m, 2H), 1.02 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:23]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1>>[C:23]1([O:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:18]([CH3:20])[CH3:19])[N:12]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: COC1=CCCCCCC1
Product: CC(C)c1nc(COC2=CCCCCCC2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 25 %

Procedure:
The compound 14 (33.1 mg, 0.1 mmol) was converted to the enolether with 1-methoxycyclooctene (140 mg, 1 mmol) in the same manner as the example 16 to give the compound 18 (11.0 mg, 22%) as oil. Rf 0.50 (Al2O3 60, Type E, toluene).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:13]=[C:14]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])[CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)(=[O:26])=[O:25])[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[S:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[S:24]([N:21]1[CH2:22][CH2:23][N:18]([C:17]2[CH:16]=[CH:15][C:14]([C:32]([OH:41])([C:37]([F:39])([F:40])[F:38])[C:33]([F:34])([F:35])[F:36])=[CH:13][C:12]=2[C:11]#[C:10][CH2:9][NH:8][S:52]([CH3:51])(=[O:54])=[O:53])[CH2:19][CH2:20]1)(=[O:26])=[O:25]
Reactant: NCC#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCC#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
To a solution of 2-(3-(3-amino-1-propyn-1-yl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol trifluoroacetate (102 mg, 0.17 mmol, Example 159) in CH2Cl2 (4 mL) was added diisopropylethylamine (89 μL, 0.51 mmol) and methanesulfonyl chloride (14 μL, 0.19 mmol). The reaction mixture was stirred at room temperature for 20 min and then partitioned between CH2Cl2 (5 mL) and saturated aqueous sodium bicarbonate (5 mL). The layers were separated, the organic material was separated, washed with saturated aqueous sodium bicarbonate (5 mL), dried (Na2SO4), filtered, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (12 g of silica gel, 10% to 50% EtOAc in hexanes) to provide N-(3-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-propyn-1-yl)methanesulfonamide (57 mg) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (br s, 1H), 8.09 (br s, 1H), 7.48-7.78 (m, 4H), 7.32 (br s, 1H), 7.11 (d, J=7.63 Hz, 1H), 4.07 (br s, 2H), 3.41-3.32 (m., 4H), 3.21-3.05 (m, 4H), 2.93 (s, 3H); m/z (ESI, +ve ion) 606.0 (M+H)+. GK-GKRP IC50 (Binding)=0.783 μM. GK-GKRP EC50 (LC MS/MS-2)=0.412 μM.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](F)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH2:28]([O:30][C:31]([C@H:33]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][C@@H:40]([OH:51])[C:41]2[CH:46]=[CH:45][C:44](/[C:47](=[N:49]/O)/[NH2:48])=[CH:43][CH:42]=2)[CH2:34]1)=[O:32])[CH3:29].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(#N)C>[OH:51][C@@H:40]([C:41]1[CH:46]=[CH:45][C:44]([C:47]2[N:49]=[C:16]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]=3[C:12]([F:15])([F:14])[F:13])[O:17][N:48]=2)=[CH:43][CH:42]=1)[CH2:39][N:35]1[CH2:36][CH2:37][CH2:38][C@H:33]([C:31]([O:30][CH2:28][CH3:29])=[O:32])[CH2:34]1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: CCOC(=O)[C@H]1CCCN(C[C@@H](O)c2ccc(/C(N)=N/O)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)[C@H]1CCCN(C[C@@H](O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 2 h

Procedure:
3-Phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride, Int-I-G (214 mg, 0.78 mmol) was dissolved in acetonitrile (5.00 mL). DIEA (0.272 mL, 1.555 mmol) and (S)-ethyl-1-((S)-2-hydroxy-2-(4-((Z)-N′-hydroxycarbamimidoyl) phenyl)ethyl)-piperidine-3-carboxylate (261 mg, 0.778 mmol) were added. The reaction mixture was stirred for 2 hours, then 1M TBAF in THF (0.778 mL, 0.778 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and purified by HPLC in three batches. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were partitioned between EtOAc and saturated NaHCO3 with back extracting aqueous layer once. The organic layer was dried with MgSO4, filtered, and concentrated to give 155mg of (S)-ethyl 1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.04 (2H, d, J=8.13 Hz), 7.55-7.60 (2H, m), 7.41-7.54 (5H, m), 4.81 (1H, ddd, J=8.35, 4.06, 3.84 Hz), 3.96-4.10 (2H, m), 2.82-3.08 (1H, m), 2.67-2.82 (1H, m, 2.36-2.61 (3H, m), 2.08-2.33 (2H, m), 1.73-1.87 (1H, m, J=8.54, 8.54, 4.45, 4.17 Hz), 1.32-1.70 (3H, m), 1.09-1.19 (3H, m). MS (m+1)=557. HPLC Peak RT=3.36 minutes. Purity=99%.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)[CH:6]=1>C(O)C>[NH:2]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)[CH:6]=1)[NH2:3]
Reactant: NN
Reactant: OC1CN(c2cc(Cl)ncn2)C1
Solvent: O
Solvent: CCO
Product: NNc1cc(N2CC(O)C2)ncn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
At RT, 27.2 ml (27.9 g, 279.1 mmol) of hydrazine hydrate are added dropwise with stirring to a solution of 10.4 g (55.8 mmol) of 1-(6-chloropyrimidin-4-yl)azetidin-3-ol in 100 ml of ethanol. The reaction solution is stirred at 80° C. for 16 h. For work-up, the mixture is concentrated under reduced pressure, and the precipitate is filtered off and washed twice with in each case 10 ml of ethanol. Yield: 2.0 g (19% of theory)
Reaction SMILES: Cl.[NH2:2][C:3]1[C:14]2[C:6](=[N:7][C:8]3[CH2:9][NH:10][CH2:11][C:12]=3[C:13]=2[C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[S:5][C:4]=1[C:20]([NH2:22])=[O:21].[Cl:23][CH2:24][CH2:25][CH2:26]Br.C(N(CC)CC)C>CN(C=O)C>[NH2:2][C:3]1[C:14]2[C:6](=[N:7][C:8]3[CH2:9][N:10]([CH2:26][CH2:25][CH2:24][Cl:23])[CH2:11][C:12]=3[C:13]=2[C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[S:5][C:4]=1[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CNC3
Reactant: ClCCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CN(CCCCl)C3
Temperature: 60 °C

Procedure:
A mixture of 3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide hydrochloride (0.7 g, 2 mmol), 1-chloro-3-bromopropane (4 mmol), and triethylamine (2 ml) in 10 ml of anhydrous DMF was heated at 60° C. for 24 hours. The solvent was removed in vacuo, and the residue was purified by silica gel column (chloroform/methanol, 40:1) to give pure compound as a yellow solid. 1H-NMR (300 MHz, DMSO-d6): δ 7.88 (d, J=5.1 Hz, 1H), 7.29 (d, J=3.6 Hz, 1H), 7.27 (dd, J=3.6, 5.1 Hz, 1H), 7.22 (brs, 2H), 5.98 (brs, 2H), 4.00 (s, 2H), 3.77 (s, 2H), 3.67 (t, J=6.3 Hz, 2H), 2.78 (t, J=6.3 Hz, 2H), 1.90 (m, 2H). ES MS m/z 393, 395 (M+H)+.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[CH3:12][C:13]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: Cc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: Cc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, yellow gum, MS: m/e=341.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methyl-4-trifluoromethyl-benzoic acid (CAS 23984-82-9).
Reaction SMILES: S([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]1[CH:24]=[N:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:27][CH:28]=1)=[O:22])(C)(=O)=O.[N+:36]([O-])([O-:38])=[O:37]>C1(C)C=CC=CC=1>[O:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]1[CH:24]=[N:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:27][CH:28]=1)=[O:22])[N+:36]([O-:38])=[O:37]
Reactant: O=[N+]([O-])[O-]
Reactant: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCCCOS(C)(=O)=O)cn2)CC1
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCCCO[N+](=O)[O-])cn2)CC1

Procedure:
To a solution of N-(14-mesyloxytetradecyl)-6-(4-methyl-1-piperazinyl)pyridine-3-carboxamide in toluene was added Amberlyst A-26 (a nitrate form) and the mixture was heated under reflux for 3 hours. The ion-exchange resin was filtered off and the filtrate was distilled off. The residue thus obtained was chromatographed over a silica gel column to afford 0.85 g of the title compound.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13]12([C:23](Cl)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>O.C1COCC1.CCCCCC>[O:24]=[C:23]([C:13]12[CH2:22][CH:17]3[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]3)[CH2:20]1)[CH2:14]2)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C12CC3CC(CC(C3)C1)C2)OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a tetrahydrofuran (200 ml) solution of dimethyl methylphosphonate (20.2 g) was added a 1.6 M hexane solution of n-butyl lithium (100 ml) at -60° C. under nitrogen. To this mixture was added a THF solution of 1-adamantyl carboxylic acid chloride (30 g) and it was stirred at the same temperature for 5 hrs and at room temperature for 12 hrs. The mixture was diluted with water and extracted with diethyl ether. The extract was dried and concentrated in vacuo. After the residue was distilled off the volatile impurity (~200° C./0.6 mmHg), there was obtained dimethyl 2-oxo-2-(1-adamantyl)-ethylphosphonate as an oil.
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].[ClH:6].[CH3:7][C:8]1[C:9](=[O:24])[C:10]2[C:15]([C:16](=[O:23])[C:17]=1[CH2:18][CH2:19][C:20](=O)[CH3:21])=[CH:14][CH:13]=[CH:12][CH:11]=2.CC1C(=O)C2C(C(=O)C=1)=CC=CC=2.O=C(C)CCC(O)=O.O1SSO1.[NH4+]>[N+]([O-])([O-])=O.[Ag+]>[ClH:6].[CH3:7][C:8]1[C:9](=[O:24])[C:10]2[C:15]([C:16](=[O:23])[C:17]=1[CH2:18][CH2:19][C:20](=[N:5][NH:4][C:1](=[NH:3])[NH2:2])[CH3:21])=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CC(=O)CCC1=C(C)C(=O)c2ccccc2C1=O
Reactant: N=C(N)NN
Agent: [Ag+]
Agent: CC(=O)CCC(=O)O
Agent: CC1=CC(=O)c2ccccc2C1=O
Product: CC(CCC1=C(C)C(=O)c2ccccc2C1=O)=NNC(=N)N

Procedure:
2-Methyl-3-(2-amidinohydrazono)butyl-1,4-naphthoquinone hydrochloride, mp 108°-110° C. is prepared in a manner similar to that of Example 1 by reaction of aminoguanidine hydrochloride with 2-methyl-3-(3-oxobutyl)-1,4-naphthoquinone. This naphthoquinone is prepared by reaction of 2-methyl-1,4-naphthoquinone, 4-oxopentanoic acid, silver nitrate and ammonium peroxydisulfide in a manner similar to that described above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=1.[CH3:17][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]([OH:15])([CH3:17])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=1
Reactant: O=C(Cn1ccnc1)c1cc(Cl)ccc1O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(Cn1ccnc1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 24.5 %

Procedure:
A suspension of 1-(5-chloro-2-hydroxyphenyl)-2-(1H-1-imidazolyl)-1-ethanone [compound (5-1)] (2.37 g, 10 mmol) in tetrahydrofuran (200 mL) was added to a solution of methylmagnesium bromide in tetrahydrofuran (1 mol/L, 100 mL, 0.1 mol) under cooling with ice, and the mixture was stirred for 17 hours at room temperature. The solvent was removed, a solution of saturated ammonium chloride was added to the resultant mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure. Subsequently, the residue was purified through silica gel column chromatography and dried under reduced pressure, to thereby yield 4-chloro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol as colorless crystals (620 mg, yield: 24.5%).