Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:10]=1[CH2:11][NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[N+:24]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)(=O)C.[Fe]>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:10]=1[CH2:11][NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[NH2:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)amino]3-nitrobenzoate (10 g) was dissolved in acetic acid (50 mL) (warming was required) and iron dust (6.92 g) was added followed by the addition of water (20 mL). There was an exothermic reaction (to 70° C.). The reaction mixture was stirred at ambient temperature for 16 hours, water (300 mL) was added and the mixture was extracted three times with ethyl acetate (100 mL each time). The combined extracts were washed consecutively with water (3×100 mL) and saturated aqueous sodium bicarbonate (2×100 mL) and dried (MgSO4). The residue obtained on removal of the solvent was filtered through silica, eluting initially with a mixture of dichloromethane and hexane (1/1 v/v) and then with dichloromethane, to give ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)amino]-3-aminobenzoate, yield 8.78 g, mp 135° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:14][CH2:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=O.O=C(C1SC=CC=1)C[NH:26][C:27]([C:29]1[S:30][C:31]2[C:37]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:36][CH:35]=[C:34]([O:44][CH3:45])[C:32]=2[N:33]=1)=O.FC(F)(F)C([O-])=O.[NH4+]>C(N(CC)CC)C>[CH3:45][O:44][C:34]1[C:32]2[N:33]=[C:29]([C:27]3[NH:14][CH:15]=[C:16]([C:18]4[S:19][CH:20]=[CH:21][CH:22]=4)[N:26]=3)[S:30][C:31]=2[C:37]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)=[CH:36][CH:35]=1
Reactant: NCC(=O)c1cccs1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3cccs3)nc12
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc(-c4cccs4)c[nH]3)nc12

Procedure:
In accordance with scheme 2,4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (for R1=morpholinyl, XII) and CDI (1,1′-carbonyl-diimidazole) was stirred at room temperature for about 1.5 hours. Then, for example, 2-amino-1-(2-thienyl)ethanone hydrochloride (for R3=thienyl) and triethylamine were added and stirring are continued over night at room temperature. Then a mixture of the obtained 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-2-thiophen-2-yl-ethyl)-amide (III) and ammonium triflouroacetate was melted at about 165° C. for 60 minutes to obtain 4-methoxy-7-morpholin-4-yl-2-(4-thiophen-2-yl-1H-imidazol-2-yl)-benzothiazole (Ia1 for R1=morpholinyl and R3=thienyl).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[CH2:27][O:28][CH2:29][CH:30]=[CH2:31])[CH:16]=[CH2:17]>>[CH2:15]([O:18][C:19]1[CH:26]=[CH:25][C:22](/[CH:23]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])=[CH:21][C:20]=1[CH2:27][O:28][CH2:29][CH:30]=[CH2:31])[CH:16]=[CH2:17]
Reactant: C=CCOCc1cc(C=O)ccc1OCC=C
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Product: C=CCOCc1cc(/C=C/C(=O)c2cc(C)cc([N+](=O)[O-])c2O)ccc1OCC=C
Yield: 44.8 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (500 mg, 2.56 mmol) and 4-(allyloxy)-3-[(allyloxy)methyl]benzaldehyde (760 mg, 3.27 mmol) were reacted according to the same procedure as Preparation 22 to give 470 mg (Yield 45%) of the title compound.
Reaction SMILES: O[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(O)ncnc3[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1

Procedure:
4-Chloro-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine is prepared, with the exclusion of moisture, by heating 4-hydroxy-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine to boiling point with an excess of POCl3. The suspension is concentrated to a residual volume of 20 ml by evaporation. The residue is introduced in portions into water, neutralized with solid NaHCO3, and 0.2 liter of ethyl acetate is added. Filtration and washing with hot THF yield the title compound, m.p. >280° C.; FAB-MS: (M+H)+ =275.
Reaction SMILES: [C:1]([C@H:4]1[C@H:9]2[O:10][C@H:6]([CH2:7][CH2:8]2)[C@H:5]1[NH:11]C(=O)OC(C)(C)C)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C@@H:5]1[C@@H:6]2[O:10][C@@H:9]([CH2:8][CH2:7]2)[C@@H:4]1[C:1]([NH2:2])=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1[C@@H](C(N)=O)[C@@H]2CC[C@H]1O2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)[C@@H]1[C@H](N)[C@H]2CC[C@@H]1O2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
tert-butyl(1R,2S,3R,4S)-3-carbamoyl-7-oxabicyclo[2.2.1]heptan-2-ylcarbamate (14) (40 mg, 0.156 mmol) was taken in DCM and cooled to 0° C. when TFA (10 eq) was added and the reaction mixture was then stirred at rt for 3-4 h when TLC confirmed completion of reaction. TFA was removed and afforded the product (40 mg, quantitative) as a yellow oil.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:10][CH2:9][C:7]([C:4]1[CH:5]=[CH:6][S:2][CH:3]=1)=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)c1ccsc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccccc1)c1ccsc1
Yield: 95.1 %

Procedure:
4 g of N-[(3-thienylcarbonyl)methyl]amine hydrochloride, 8 g of sodium bicarbonate and 3.6 g of benzoyl chloride are treated in the same manner as described in Preparation 1-(3). 5.25 g of N-benzoyl-N-[(3-thienylcarbonyl)methyl]amine are thereby obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Reactant: CS(N)(=O)=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(=O)C1(c2ccc(Br)cc2)CC1

Procedure:
1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid (5.0 g, 20.7 mmol) was dissolved in toluene (30 mL) then thionyl chloride (17.7 mL, 243 mmol) was carefully added. The reaction was heated to reflux for 4 hours then concentrated and azeotroped with toluene (2×30 mL). The intermediate acid chloride was dissolved in toluene (50 mL) then methanesulfonamide (11.41 g, 120 mmol) and triethylamine (15 mL, 0.108 mmol) were added. The reaction was refluxed for 3 hours then cooled and submitted to standard aqueous workup. The crude material was purified on silica gel to give the title compound.
Reaction SMILES: Br[CH2:2][C:3](CBr)=[O:4].[C:7]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH3:24])=[O:21])[CH:17]([CH3:19])[CH3:18])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:36][C:37]1[C:45]([F:46])=[C:44]([F:47])[C:43]([F:48])=[C:42]([F:49])[C:38]=1[C:39]([OH:41])=[O:40]>>[CH3:2][C:3]([O:40][C:39](=[O:41])[C:38]1[C:37]([F:36])=[C:45]([F:46])[C:44]([F:47])=[C:43]([F:48])[C:42]=1[F:49])=[O:4].[C:7]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH3:24])=[O:21])[CH:17]([CH3:18])[CH3:19])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CBr)CBr
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1F
Agent: CCCC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C)C(=O)O
Product: CC(=O)OC(=O)c1c(F)c(F)c(F)c(F)c1F

Procedure:
(Electrospray MS m/z 614 [MH+ ]) from of N-benzoyl-L-valyl-L-alanyl-L-norleucine bromomethyl ketone and 2,3,4,5,6-pentafluorobenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([Cl:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1

Procedure:
To a stirred solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.000 g, 4.00 mmol) in chloroform (15 mL) was added thionyl chloride (3.0 mL, 40.00 mmol). The reaction mixture was left stirring at reflux for 3 days and then concentrated in vacuo. The obtained crude solid, 4-chlorocarbonylpiperidine-1-carboxylic acid tert-butyl ester, was used without further purification.
Reaction SMILES: [O:1]1[C@H:3]2[C@@H:4]([OH:24])[CH:5]=[C:6]3[C@:20]([CH3:21])([C@@H:2]12)[C@@H:19]1[C@H:9]([C@H:10]2[C@:16]([CH3:22])([CH2:17][CH2:18]1)[C@@H:13]([CH2:14][CH3:15])[CH2:12][CH2:11]2)[C@H:8]([OH:23])[CH2:7]3.CCCCCC.C(OCC)C.C(Cl)Cl>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[O:1]1[C@H:3]2[C:4](=[O:24])[CH:5]=[C:6]3[C@:20]([CH3:21])([C@@H:2]12)[C@@H:19]1[C@H:9]([C@H:10]2[C@:16]([CH3:22])([CH2:17][CH2:18]1)[C@@H:13]([CH2:14][CH3:15])[CH2:12][CH2:11]2)[C@H:8]([OH:23])[CH2:7]3
Reactant: CC[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=C[C@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Thus, alcoholysis of compound (III) with a lower alcohol, such as methanol, ethanol, etc., in the presence of a basic compound, such as anhydrous potassium carbonate, anhydrous sodium carbonate, etc., at a temperature of about 0° to 30° C. yields an 1α,2α-epoxypregn-4-ene-3β,7α-diol derivative of general formula (IV). This 1α,2α-epoxypregn-4-ene- 3α,7α-diol derivative (IV) is oxidized with manganese dioxide in a solvent, such as hexane, diethyl ether, methylene chloride, chloroform, etc., at room temperature to give an 1α,2α-epoxy-7a-hydroxypregn-4-en-3-one derivative of general formula (V) and finally this 1α,2α-epoxy-7α-hydroxypregn-4-en-3-one derivative is subjected to dehydration reaction in t-butyl alcohol in the presence of potassium t-butoxide at room temperature to give the compound (I-2-2). The compound (I-2-2) thus obtained can be subjected to said 6α,7α-epoxidation to compound (I-2-3) and to the reduction to compound (I-6-1) which will be described hereinafter.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:11]=2)[CH:5]=1>C1COCC1>[OH:29][CH:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:21][N:12]1[N:11]=[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH3:3])[NH:8][N:7]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:20]
Reactant: Cc1cc(Nc2nn(CC(=O)c3ccccc3)c(=O)c3ccccc23)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nn(CC(O)c3ccccc3)c(=O)c3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.2 %

Procedure:
Sodium borohydride (6 mg, 0.15 mmol) was added in one portion to a stirred solution of 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(2-oxo-2-phenyl-ethyl)-2H-phthalazin-1-one (17 mg, 0.05 mmol) (Example E-9) in THF (1 ml). The reaction mixture was stirred at RT for two hours. After this time LC-MS indicated complete consumption of starting material, MeOH (0.5 ml) was added and the reaction mixture was concentrated under vacuum. The resulting residue was purified by flash column chromatography (elution: 97% DCM, 3% MeOH) to give the title compound (2.2 mg, 12% yield) as a white solid. MS (ESI+)=(M+H)+ 361.98.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1C=O.S(Cl)([Cl:14])(=O)=O>ClC1C=CC=CC=1Cl>[Cl:14][C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: O=S(=O)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cc1nn(C)c(Cl)c1Cl
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To 300 g of a 22.7% solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 1,2-dichlorobenzene are added dropwise at 80° C. 58 g of sulphuryl chloride within 120 minutes. After the metered addition has ended, the reaction solution is stirred for a further 3 hours. The reaction solution is cooled to 20° C. and the solution is analyzed by GC. 4,5-Dichloro-1,3-dimethyl-1H-pyrazole has formed quantitatively.
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([OH:9])[C:3]=1[CH3:10].FS([C:15]([F:20])([F:19])C(O)=O)(=O)=O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C>[F:19][CH:15]([F:20])[O:9][C:4]1[C:3]([CH3:10])=[C:2]([I:1])[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1cnc(O)c(C)c1I
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(OC(F)F)c(C)c1I
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
4-iodo-3,5-dimethylpyridin-2-ol (350 mg), 2-(fluorosulfonyl)difluoroacetic acid (0.17 mL), and sodium sulfate (39.9 mg) were added to acetonitrile (5.7 mL). The mixture was stirred at room temperature for 3.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to give the title compound (378.6 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][OH:44])=[CH:38][CH:37]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:44][CH2:43][CH2:42][C:39]3[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: OCCc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2ccc(Cl)cc2)cc1
Reaction time: 18 h
Yield: 27.9 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(4-chlorophenyl)ethanol (33.4 mg, 0.213 mmol) and Ph3P-resin (55.8 mg, 0.213 mmol) in THF (2 mL) was added DEAD (0.014 mL, 0.085 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(4-chlorophenethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (6.9 mg, 0.012 mmol, 27.9% yield). 1H NMR (500 MHz, DMSO-d6) δ7.21 (d, J=8.4 Hz, 1H), 7.07-6.93 (m, 3H), 5.83 (s, 1H), 4.34-4.19 (m, 2H), 3.34 (br. s., 1H), 3.28 (br. s., 1H), 3.06 (t, J=6.6 Hz, 2H), 2.79 (t, J=12.1 Hz, 1H), 2.43 (s, 3H), 2.18 (d, J=9.2 Hz, 1H), 2.05 (s, 3H), 1.98-1.93 (m, 1H), 1.91 (s, 3H), 1.49 (br. s., 1H), 1.29 (br. s., 1H), 1.18 (d, J=11.7 Hz, 1H), 1.12 (s, 9H), 1.02 (d, J=13.9 Hz, 1H), 0.85 (s, 3H), 0.60 (s, 3H). LCMS (M+H)=579.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:4][CH:3]=1.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>[OH-].[Na+]>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=3)=[CH:6][CH:7]=2)=[O:23])=[CH:25][CH:26]=1)([O-:17])=[O:16]
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc(-c2c[nH]c(=O)cn2)cc1)c1ccc([N+](=O)[O-])cc1
Yield: 49.1 %

Procedure:
A solution of 5-(4-aminophenyl)-2(1H)-pyrazinone (1.7 g) in sodium hydroxide was reacted with 4-nitrobenzoyl chloride (1.8 g) in a manner similar to that described in Example 9 to give 5-[4-(4-nitrobenzamido)phenyl]-2(1H)-pyrazinone (1.5 g, m.p. 298°-300° C.).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>O>[N:32]1([C:23]2[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=2[NH:21][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCC1)c1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
Isonicotinoyl chloride hydrochloride (705 mg, 3.96 mmol, commercially available product) and triethylamine (823 μl, 5.94 mmol) were sequentially added at 0° C. to a dichloromethane (10 ml) solution of 1-[2-amino-4-(trifluoromethyl)phenyl]pyrrolidine (516 mg, 2.24 mmol), obtained as described in Referential Example 3-2. The resulting mixture was warmed to room temperature and stirred for five hours. Water was added to the mixture, and the resulting mixture was extracted three times with dichloromethane. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25 g, hexane/ethyl acetate=1/2). Thus, N-[2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0617) (734 mg, 97.8%) was yielded as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: Clc1ncccn1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccn2)CC1

Procedure:
The title compound was prepared as described in EXAMPLE 13, except using benzyl 4-(aminomethyl)-1-piperidinecarboxylate (6.50 g, 26.19 mmol) and 2-chloropyrimidine (990 mg, 8.64 mmol) as starting materials without a solvent to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.ClC1C(Cl)=CC=CC=1C[NH:15][CH:16]1[CH2:18][CH2:17]1>>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:15][CH:16]1[CH2:18][CH2:17]1
Reactant: Clc1cccc(CNC2CC2)c1Cl
Reactant: Cc1cccc(C=O)c1C
Product: Cc1cccc(CNC2CC2)c1C

Procedure:
1B was synthesized from 2,3-dimethylbenzaldehyde (5.0 g, 37.3 mmol) using the procedure described for 1A. Yield: 6.0 g (92%) as light yellow oil. ESI-MS:m/z 176.3 (M+H)+, HPLC retention time: T=1.340 min (FAST-2).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.Cl.C([O-])(O)=O.[Na+]>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2([CH2:16][C:12]3[N:11]4[CH2:29][CH2:30][N:31]([CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])[C:32](=[O:33])[C:10]4=[C:9]([OH:8])[C:14](=[O:15])[N:13]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:23][CH:24]=1
Reactant: CC(N1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(N1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(O)c2C1=O)C(F)(F)F
Temperature: 70 °C
Yield: 52.7 %

Procedure:
To a stirred solution of 9-(benzyloxy)-6-((1-(4-chlorophenyl)cyclopentyl)methyl)-2-(1,1,1-trifluoropropan-2-yl)-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (44) (90.8 mg, 162 μmol, Eq: 1.00) in methanol (5 ml) was added HCl (conc) (240 mg, 0.2 ml, 6.58 mmol, Eq: 40.6) and the reaction mixture was heated at 70° C. for 18 hrs. The reaction mixture was neutralized with saturated aqueous NaHCO3 solution, extracted with dichloromethane, dried (MgSO4), concentrated, triturated with diethyl ether, filtered, and dried to obtain 6-((1-(4-chlorophenyl)cyclopentyl)methyl)-9-hydroxy-2-(1,1,1-trifluoropropan-2-yl)-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (45) (pink powder, 40.1 mg, 85.3 μmol, 52.6% yield).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH2:6]([O:8][C:9]([C:11]1[C:16]([O:17][CH2:18][CH3:19])=[C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:14]=[C:13]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[N:12]=1)=[O:10])[CH3:7]>C1(C)C=CC=CC=1>[CH2:6]([O:8][C:9]([C:11]1[C:16]([O:17][CH2:18][CH3:19])=[C:15]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:14]=[C:13]([C:26]2[CH:27]=[CH:28][C:29]([O:32][C:4](=[O:5])[NH:3][CH2:1][CH3:2])=[CH:30][CH:31]=2)[N:12]=1)=[O:10])[CH3:7]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1nc(-c2ccc(O)cc2)nc(N2CCOCC2)c1OCC
Solvent: Cc1ccccc1
Product: CCNC(=O)Oc1ccc(-c2nc(C(=O)OCC)c(OCC)c(N3CCOCC3)n2)cc1
Yield: 25.2 %

Procedure:
Ethyl isocyanate (0.013 ml, 1.5 eq.) was added to a stirred solution of 2-(4-hydroxy-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (40 mg, 1 eq.) in toluene (3 ml) and the mixture was reacted to reflux overnight. The reaction mixture was extracted with EA and washed with brine. The crude was purified by chromatography to give a product (12 mg, 25.2%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]([NH2:26])=[O:25])(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl[CH2:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1.[I-].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:24]([C@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[N:17]([CH2:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1)[S:14]([C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)(=[O:15])=[O:16])(=[O:25])[NH2:26]
Reactant: CCNC(=O)c1ccc(CCl)cc1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(CN([C@@H]2CCCC[C@@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
Cesium carbonate (1.4 mmol) was added to a solution of (1R,2S)-2-(4-Chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (0.62 mmol) in DMF (7 mL). 4-Chloromethyl-N-ethylbenzamide (0.76 mmol) was added to the mixture followed by potassium iodide (0.75 mmol). Reaction was stirred at room temperature overnight. Reaction mixture was diluted with ethyl acetate (20 mL) then was washed with water (2×15 mL). Organic layer was concentrated in vacuo. Residue was purified by preparatory HPLC (acetonitrile/water/trifluoroacetic acid). Proper fractions were combined. Acetonitrile was removed from the mixture in vacuo. Remaining aqueous was frozen and lyophilized to yield 4-[[(1R,2S)-(2-Carbamoyl-cyclohexyl)-(4-chlorobenzenesulfonyl)-amino]-methyl]-N-ethyl benzamide (120 mg) as a white solid in 40% yield.: 1H NMR (300 Mz, DMSO-d6) δ 8.40 (t, 1 H), 7.79 (d, 2 H, J=8.4), 7.70 (d, 2 H, J=8.4), 7.64 (d, 2 H, J=8.4 ), 7.32 (d, 2 H, J=8.1), 6.66 (s, 1 H), 4.68 (d, 1 H, J=17.2), 4.54 (d, 1 H, J=17.2), 3.85 (m, 1 H), 3.28 (m, 2 H), 2.78 (s, 1 H), 2.40 (m, 1 H), 1.78 (m, 1 H), 1.63 (m, 2 H), 1.42–1.17 (m, 3 H), 1.12 (t, 3 H), 0.92 (m, 1 H); MS m/e 500 (M+Na)+.