Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=4[N:17]=3)[CH3:15])=[O:12])=[CH:10][C:2]=2[Cl:1])=[O:5])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC(=O)N1CCNCC1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C(=O)c2ccc(C(=O)NC(C)c3nc4cc(Cl)ccc4[nH]3)cc2Cl)CC1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4-acetylpiperazine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.99 minutes; C23H23Cl2N5O3 (488.37); mass spectrum: (M−H)−=487/489/491 (chlorine isotope).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cn1c(-c2ccccc2)cc2ccccc21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(-c2ccccc2)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
At 0° C., aluminum (III) chloride (2.5 g, 19 mmol) was added per portion to a solution of 1-methyl-2-phenyl-1H-indole (1 g, 4.8 mmol) and ethyl chlorooxoacetate (900 μL, 8.05 mmol) in dichloromethane (10 mL). The mixture was stirred for 2 hours at 0° C. and then hydrolyzed with a saturated solution of sodium bicarbonate. After removing the aqueous layer, organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired keto-ester (8a) (630 mg, 2.05 mmol, 43%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:18]=2)[N:10]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=1>>[F:15][C:14]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([O:36][CH2:35][C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)=[CH:7][C:2]=2[F:1])=[N:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:18]=2)=[N:12][CH:13]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1ccc(F)cc1
Product: CS(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(OCc4ccc(F)cc4)cc3F)n2)c1

Procedure:
Example 17 was prepared under similar conditions as described in the preparation of Example 16 using 4-(2,4-difluorophenyl)-5-fluoro-N-{3-[(methylsulfonyl)methyl]phenyl}pyrimidin-2-amine (Intermediate 16.2) and (4-fluorophenyl)methanol (ABCR GmbH & CO. KG). The batch was purified by preparative HPLC.
Reaction SMILES: ClCC([NH:5][CH:6]1[C:17](=[O:18])[N:8]2[C:9]([C:14]([OH:16])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)=O.C[Si](C)(C)Cl.N.C(N(CCCCCCCCCCCCCCCC)C1C=CC=CC=1)C.P(Cl)(Cl)(Cl)(Cl)Cl>CO.C(Cl)Cl>[NH2:5][CH:6]1[C:17](=[O:18])[N:8]2[C:9]([C:14]([OH:16])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)CCl)[C@H]2SC1
Agent: CCCCCCCCCCCCCCCCN(CC)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
8.7 g of 7-chloroacetylamino-3-methyl-3-cephem-4-carboxylic acid are suspended in a 100 ml of methylene dichloride and 7.4 ml of trimethylchlorosilane are added. Dry ammonia gas is then introduced until the temperature which has arisen begins to sink. After refluxing for a short time and cooling to -14°, 15.8 ml of N-ethyl-N-hexadecylaniline are added. 8 g of phosphorus pentachloride are then added in 3 portions so that the temperature does not rise above -10°. The reaction mixture is stirred for a further 30 minutes at -12° to -10° and then poured into 150 ml of methanol, pre-cooled to -14°. The mixture is then mixed with 150 ml of ice water. After strong stirring for a short time, the phases are separated. The aqueous phase is washed with methylene dichloride and the pH is adjusted to 3.8 with ammonia solution. The colourless precipitate is filtered off, washed each time with 30 ml of water and acetone and dried in vacuo at 50°. The title compound (5.85 g; 91%) results as a colourless powder in pure form. The N-ethyl-N-hexadecylaniline base can be regenerated in the same manner as described in Example 1 for N-methyl-N-dodecylaniline.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[N:4]1[CH2:13][C:14]([O:16]C)=[O:15]>C(O)(=O)C>[O:2]=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[N:4]1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CN1C(=O)CCc2cnccc21
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)CCc2cnccc21
Temperature: 60 °C

Procedure:
Aqueous 1N HCl (2 mL) was added to a solution of methyl 2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetate (1.24 g, 5.67 mmol) in acetic acid (5 mL) and the resulting mixture was heated to 60° C. for 4 h. The solution was concentrated under vacuum to give 2-(2-Oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetic acid. Retention time (min)=0.275, method [1], MS (ESI) 207.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:33])[O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([O:23][CH:22]([F:33])[F:21])=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(difluoromethoxy)picolinic acid [J. D. Scott et al. WO2011044181 (2011)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=463.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]=[CH:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:8]=[N:7][N:6]=1.[CH3:21][C@H:22]1[O:27][C@@H:26](C)[CH2:25]NC1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C.ClCCl.CO.Cl.C(OCC)C>[CH3:25][C@H:26]1[O:27][C@@H:22]([CH3:21])[CH2:1][N:2]([CH2:3][CH2:4][C:5]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[N:8]=[N:7][N:6]=2)[CH2:20]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CN(C)C=Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: C[C@@H]1CN(CCc2nnnn2-c2ccc(C(F)(F)F)cc2)C[C@H](C)O1
Temperature: 65 °C
Reaction time: 4 h
Yield: 9.6 %

Procedure:
To a solution of dimethyl(2-{1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}ethenyl)amine (may be prepared as described in Intermediate 4) (100 mg, 0.353 mmol) in ethanol (2 mL) was added (cis)-2,6-dimethylmorpholine (122 mg, 1.059 mmol, Alfa Aesar, Ward Hill, USA) and acetic acid (0.061 mL, 1.059 mmol). The reaction mixture was heated to 65° C. and stirred for 4 hours. The reaction mixture was cooled and the solvent removed under vacuum. The residue was dissolved in ethanol (2 mL) before the addition of further (cis)-2,6-dimethylmorpholine (122 mg, 1.059 mmol) and acetic acid (0.061 mL, 1.059 mmol). The reaction mixture was heated to 65° C. and stirred for 3 hours. The reaction mixture was cooled and the solvent removed under vacuum. The solid residue was partitioned between DCM (3 mL) and saturated aqueous NaHCO3 (2 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum. The residue was dissolved in dry dichloromethane (DCM) (2 mL) before the addition of sodium triacetoxyborohydride (224 mg, 1.06 mmol). The reaction mixture was shaken at room temperature for 18 hours. The reaction mixture was partitioned between DCM (3 mL) and saturated aqueous NaHCO3 (2 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum. The residue was purified by MDAP. Fractions containing the desired product were combined and the solvent removed. The residue was dissolved in methanol and passed through a 1 g SAX cartridge, eluting once with methanol. The methanol fractions were combined and the solvent removed to yield a yellow gum. The gum was dissolved in a minimum of methanol and 1N HCl in diethyl ether (2 mL) added. The solvent was removed under a stream of argon to yield a sticky orange gum. The product was partitioned between saturated aqueous NaHCO3 (1 mL) and DCM (1 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum. The product was further purified by silica chromatography (Biotage SP4 eluting a gradient from 50-100% EtOAc over 15 column volumes) to yield the title compound as a solid (12 mg).
Reaction SMILES: N1(C2N=C3C=CC=CC=C3N=2)CCNCC1.[N:17]1[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26][C:20]2=[N:19][C:18]=1[N:27]1[CH2:32][CH2:31][N:30]([C:33](=[NH:35])[NH2:34])[CH2:29][CH:28]1CC.N1C2=CC=CC=CC2=NC=1N1CCN(C(=N)N)CC1C.BrC1C=CC2C(=CC=1)N=C(N1CCN(C(=N)N)CC1)N=2.C(C1C=CC2C(=CC=1)N=C(N1CCN(C(=N)N)CC1)N=2)CC.C(OC1C=CC2C(=CC=1)N=C(N1CCN(C(=N)N)CC1)N=2)C.FC(F)(F)C1C=CC2C(=CC=1)N=C(N1CCN(C(=N)N)CC1)N=2>>[N:17]1[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26][C:20]2=[N:19][C:18]=1[N:27]1[CH2:28][CH2:29][N:30]([C:33](=[NH:34])[NH2:35])[CH2:31][CH2:32]1
Reactant: CCC1CN(C(=N)N)CCN1c1nc2cccccc-2n1
Agent: CC1CN(C(=N)N)CCN1c1nc2cccccc-2n1
Agent: CCCc1ccc2nc(N3CCN(C(=N)N)CC3)nc-2cc1
Agent: CCOc1ccc2nc(N3CCN(C(=N)N)CC3)nc-2cc1
Product: N=C(N)N1CCN(c2nc3cccccc-3n2)CC1

Procedure:
In the same manner but replacing 2-(1-piperazinyl)cycloheptimidazole with an equivalent amount of another compound of formula I described in Example 2, the following compounds of formula I are obtained, respectively: 4-(2-cycloheptimidazolyl)-3-ethyl-1-piperazinecarboximidamide, 4-(2-cycloheptimidazolyl)-3-methyl-1-piperazinecarboximidamide, 4-(6-bromo-2-cycloheptimidazolyl)-1-piperazinecarboximidamide, 4-(6-propyl-2-cycloheptimidazolyl)-1-piperazinecarboximidamide, 4-(6-ethoxy-2-cycloheptimidazolyl)-1-piperazinecarboximidamide, and 4-(6-trifluoromethyl-2-cycloheptimidazolyl)-1-piperazinecarboximidamide.
Reaction SMILES: C1(S)C=CC=CC=1.C[O:9][C:10]1[CH:15]=[C:14]([C:16]2[N:17]=[CH:18][N:19]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=2)[CH:13]=[CH:12][C:11]=1[C:29]1[N:34]=[N:33][C:32]([N:35]([CH3:46])[CH:36]2[CH2:41][C:40]([CH3:43])([CH3:42])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]2)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:46][N:35]([CH:36]1[CH2:37][C:38]([CH3:45])([CH3:44])[NH:39][C:40]([CH3:43])([CH3:42])[CH2:41]1)[C:32]1[N:33]=[N:34][C:29]([C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:17]=[CH:18][N:19]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:28])[CH3:26])[CH:20]=3)=[CH:15][C:10]=2[OH:9])=[CH:30][CH:31]=1
Reactant: COc1cc(-c2cn(COCC[Si](C)(C)C)cn2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(c1ccc(-c2ccc(-c3cn(COCC[Si](C)(C)C)cn3)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1

Procedure:
Following GENERAL METHOD 3-1 for methoxy deprotection using thiophenol, 6-(2-methoxy-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (50 mg, 0.09 mmol) was treated with thiophenol (0.01 mL, 0.11 mmol) and K2CO3 (12 mg, 0.09 mmol) in NMP (2 mL) for 30 minutes at 190° C. to afford 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenol and an impurity (50 mg, MS: 537.6 [M+H+]).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@H:16]([C:24]([NH2:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:17]([C@@H:16]1[NH:15][C:11]2([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[NH:26][C:24]1=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)[C@H](Cc1ccccc1)N2

Procedure:
N-tert-Butyloxycarbonylpiperidone (6.0 g, 29.8 mmol) was added to a solution of (S)-phenylalaninamide (4.9 g, 29.8 mmol) in dry EtOH (20 ml) and the mixture was heated for 2.5 h under reflux. The solvent was distilled off and the tert-butyl 3-(S)-benzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (10.8 g) was used without further workup.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (27, 2.45 g, 8.77 mmol) in 68 mL of tetrahydrofuran, sodium hydride (0.4208 g, 10.52 mmol) is added and the reaction is stirred at room temperature for 30 minutes. 4-Methyl-benzenesulfonyl chloride (28, 1.838 g, 9.643 mmol) is added and the reaction stirred at room temperature overnight. Water is added and the reaction is extracted with ethyl acetate, resulting in some precipitate that is removed by filtration. The aqueous layer is separated and extracted with ethyl acetate. The organic layers are combined, washed with water, then brine and dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue is suspended in ethyl acetate, sonicated for 30 minutes, and the solid collected by filtration to provide the desired compound (29, 3.325 g). MS (ESI) [M+H+]+=433.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.Cl>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:10][C:11]([OH:13])=[O:12])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)C=Cc1cc(Br)cs1
Temperature: 100 °C
Reaction time: 14 h
Yield: 115.5 %

Procedure:
The mixture of 4-bromo-thiophene-2-carbaldehyde (10 g, 0.052 mol), malonic acid (6.5 g, 0.063 mol) and piperidine (0.5 ml) in pyridine (40 ml) was stirred for 14 hours at 100° C., which was cooled down to room temperature and poured into water, and resultant mixture was acidified with concentrated HCl. The generated precipitate was collected by filtration, which was suspended with EtOH (50 ml) and water (100 ml). The precipitate was collected by filtration and dried under the reduced pressure to give 3-(4-bromo-thiophen-2-yl)-acrylic acid (14 g). 1H NMR (400 MHz, DMSO-d6) ppm 7.79 (s, 1H), 7.67 (d, J=15.9 Hz, 1H), 7.56 (s, 1H), 6.26 (d, J=15.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)(=O)C>[C:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:6][CH:7]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Yield: 97.3 %

Procedure:
A mixture of 11.6 g (50 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid, 200 ml glacial acetic acid, and 10.5 ml (110 mmol) of acetic anhydride is heated at reflux for 4 hrs. The mixture is cooled, filtered, and the solid washed with ether and dried under vacuum at 50° to give 13.3 g of 2-[4-(acetylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid; mp>310°.
Reaction SMILES: [CH:1]1([C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)([OH:12])[CH2:5][CH2:6][N:7](C)[C:8](=O)C)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>CS(C)=O>[CH:1]1([C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)([OH:12])[CH2:5][CH2:6][NH:7][CH3:8])[CH2:2][CH2:3]1
Reactant: CC(=O)N(C)CCC(O)(c1cccc(C(F)(F)F)c1)C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNCCC(O)(c1cccc(C(F)(F)F)c1)C1CC1
Temperature: 0 °C

Procedure:
A mixture of 5 g. (0.016 mole) of 1-cyclopropyl-3-(N-methylacetamido)-1-(3-trifluoromethylphenyl)-1-propanol, 2.9 g. (0.024 mole) of potassium tertiary butoxide and 25 ml. of dimethyl sulfoxide was warmed on a steam bath for 45 minutes. The mixture was cooled, poured into ice water and extracted with benzene. The benzene extract was dried over magnesium sulfate and concentrated to an oil which was distilled at 108°C./0.15 mm. The yield was 2.6 g. (59%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH3:20])[C:9]=2/[CH:21]=[CH:22]/[CH:23]([OH:32])[CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH3:20])[C:9]=2[CH:21]=[CH:22][CH:23]([OH:32])[CH2:24][CH:25]([OH:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(O)CC(O)C=Cc1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 79.9 %

Procedure:
A solution of (E)-7-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoic acid, methyl ester (235 mg, 0.54 mmol) in THF (8 ml) was treated with triethylborane (1.0M in THF, 1.13 ml, 1.13 mmol). Twenty milliliters of air was bubbled through the solution and the mixture was stirred at room temperature for 25 minutes. The solution was cooled to -78° C. and treated with NaBH4 (20.7 mg, 0.55 mmol) followed by dropwise addition of dry methanol (1.25 ml). After stirring at -78° C. for 1.5 hours, the mixture was quenched with 30% H2O2 (3.5 ml) in H2O (8 ml). The mixture was kept at -78° C. for 15 minutes, then warmed to room temperature and stirred for 30 minutes. The solution was poured into 50% saturated NaHCO3 and extracted with Et2O (3×). The combined Et2O extracts were washed with H2O, saturated NaHCO3 and brine, then dried (Na2SO4), filtered and stripped. Purification of the resulting oil (Flash, Merck SiO2, 70% EtOAc/30% hexane) gave (3R*, 5S*, 6E)-7-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid, methyl ester (188 mg, 80%) as a colorless oily foam.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([C:14]#[N:15])[C:11]=2[C:12]#[N:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]Br.C>C(Cl)(Cl)Cl>[Br:16][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]#[N:13])[C:10]=1[C:14]#[N:15]
Reactant: BrBr
Reactant: N#Cc1c[nH]c(-c2ccccc2)c1C#N
Agent: C
Solvent: ClC(Cl)Cl
Product: N#Cc1c(Br)[nH]c(-c2ccccc2)c1C#N
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen purge, 2-phenyl-pyrrole-3,4-dicarbonitrile (1.4 g; 0.0075 mol) is added to CHCl3 (35 mL), much of the solid dissolving. A solution of bromine (0.4 mL; 0.008 mol) in CHCl3 (5 mL) is added dropwise over 20 minutes. Initially the color is discharged rapidly, but as a new, gummy solid begins to precipitate, the color remains. After stirring 30 minutes at ambient, the mixture is brought to reflux, resulting in a much more discreet solid. After refluxing 90 minutes, the reaction mixture is cooled and an aliquot is removed and analyzed (HPLC), showing ca. 60% starting material still remaining. In a single portion fresh bromine (0.2 mL; 0.004 mol) is added, and refluxing continued another 45 minutes whereupon an aliquot shows 10% starting material remaining. Another fresh portion of bromine (0.2 mL; 0.004 mol) is added to the refluxing suspension and refluxing is continued another 30 minutes. The suspension is cooled and stirred 18 hours at room temperature. Solvent is removed under reduced pressure to yield a greenish solid which is extracted with hot CHCl3, leaving behind a dark residue. The extract is treated with DARCO and filtered hot. The clear yellow filtrate quickly began to deposit a white precipitate. After cooling to -10° C., the white solid is collected by filtration.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Br:30])=[CH:6][N:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(Br)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
To a solution of 0.91 g (6-bromo-pyridin-3-yl)-methanol in 10 mL of dichloromethane was added 1.88 g of triphenyl phosphine and 2.38 g of carbon tetrabromide. This mixture was stirred at room temperature for 3 hours. It was then concentrated on silica gel, eluted with heptane/ethyl acetate to provide 0.91 g of 2-bromo-5-bromomethyl-pyridine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:28]=1[C:29](Cl)=[O:30]>>[Cl:26][C:27]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:28]=1[C:29]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:30]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc([N+](=O)[O-])ccc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-chloro-5-nitrobenzoyl chloride as starting compounds. The crude product is purified by column chromatography (silica gel and DCM/EA=1:1) and by crystallization from EA and diethyl ether to yield 2-{1-[(2-chloro-5-nitrophenyl)carbonyl]piperidin-4-yl}-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one as the product.