Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H](CC)C(OC[C@@H]1CC(=C(C)C)C1(C)C)=O.[C:18]([C@H:21]1[CH2:24][C@@H:23]([C:25]([OH:27])=[O:26])[C:22]1([CH3:29])[CH3:28])(=[O:20])[CH3:19].C[Mg]Cl>>[OH:20][C:18]([C@H:21]1[CH2:24][C@@H:23]([C:25]([OH:27])=[O:26])[C:22]1([CH3:29])[CH3:28])([CH3:1])[CH3:19]
Reactant: CC[C@H](C)C(=O)OC[C@@H]1CC(=C(C)C)C1(C)C
Reactant: CC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Agent: C[Mg]Cl
Product: CC(C)(O)[C@H]1C[C@@H](C(=O)O)C1(C)C

Procedure:
A method for making [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate (2), said method comprising (or consisting essentially of or consisting of) reacting (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid [(cis)-pinononic acid] with methyl magnesium chloride to form (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3) or reacting (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid [(cis)-pinononic acid] with methyl lithium, and then methyl magnesium chloride to form (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3); reacting (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3) with phosphorus oxychloride to form (1R,5S)-4,4,6,6-tetramethyl-3-oxabicyclo[3.1.1]heptan-2-one (4); reacting (1R,5S)-4,4,6,6-tetramethyl-3-oxabicyclo[3.1.1]heptan-2-one (4) with p-toluenesulfonic acid to form (R)-2,2-dimethyl-3-(1-methlethylidene)cyclobutanecarboxylic acid (5); reacting (R)-2,2-dimethyl-3-(1-methlethylidene)cyclobutanecarboxylic acid (5) with lithium aluminum hydride to form [(R)-(−)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methanol [(R)-maconelliol] (6), and reacting [(R)-(−)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methanol (6) with oxalyl chloride and (S)-2-methylbutanoic acid to form [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate [(R)-maconelliyl (S)-2-methylbutanoate] (2).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[O:8])=[CH:5][CH:4]=1
Reactant: C1=COCCC1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(OC1CCCCO1)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.6 %

Procedure:
In a mixed solvent of dichloromethane and tetrahydrofuran was dissolved 5 g of p-bromomethylbenzoic acid, and 10 g of dihydropyran and 585 mg of pyridinium p-toluenesulfonate were added to the solution and the mixture was stirred at room temperature for 6 hours. The thus-obtained solution was washed with a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of sodium chloride, dried on anhydrous magnesium sulfate and concentrated. The concentrate was recrystallized from a mixed solvent of n-hexane, ethyl acetate and chloroform to obtain 3.8 g of tetrahydropyranyl p-bromomethylbenzoate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]4[S:10][C:9]([NH:11][C:12](=[O:19])[C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: O=C(Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1)c1ccccc1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: O=C(Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)c1ccccc1

Procedure:
Crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzamide (49 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 8.2 mg of 165. MS (Q1) 457 (M)+
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].C[C:25]([N:27](C)C)=O>>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[O:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[C:25]#[N:27])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:7]=[CH:6]2
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Reactant: CC(=O)N(C)C
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C#N)cc21
Temperature: 150 °C
Yield: 95 %

Procedure:
6-Bromo-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole (31.2 g, 82 mmol) and Cu(I)CN (13.9 g, 156 mmol) were dissolved in DMA and degassed with nitrogen under vacuum. The reaction mixture was heated to 150° C. for 16 hours. The mixture was cooled to room temperature and diluted with ethyl acetate before washing twice with 7M NH4OH. The organics were washed with brine and degassed with nitrogen before being dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed eluting with 10% ethyl acetate in hexanes to afford 25.1 g of product (95% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]([CH3:15])[C:12]([NH2:14])=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([NH:19][NH2:20])=O>C(O)C.[Hg](Cl)Cl>[N:19]1[N:20]=[C:12]([C@@H:11]([NH:10][C:9](=[O:16])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:15])[NH:14][CH:17]=1
Reactant: NNC=O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(N)=S
Agent: Cl[Hg]Cl
Solvent: CCO
Product: C[C@H](NC(=O)OCc1ccccc1)c1nnc[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of benzyl[(1S)-2-amino-1-methyl-2-thioxoethyl]carbamate (13.4 g, 56.2 mmol) in ethanol (1.125 L) was added formic acid hydrazide (20.26 g, 337 mmol) and mercury(II) chloride (19.85 g, 73.1 mmol). After 1 h the reaction was filtered and concentrated. Saturated aqueous sodium carbonate and ethyl acetate were added. The organic layer was isolated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. A solution of the resulting residue in ethanol (1.125 L) was heated to 80° C. After 16 h, the reaction was concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol with 1% ammonium hydroxide) gave the title compound (8.7 g). MS 247.1 (M+1).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccccc1
Product: O=[N+]([O-])c1cc2c(NCCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>[O-]CC.[Na+]>[C:9]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: N#CCc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccc(F)cc1

Procedure:
By employing the procedures set forth in Examples 1 and 3, p-fluorophenylacetonitrile is reacted with diethyl oxalate in alcoholic sodium ethoxide to give ethyl 3-cyano-3-(p-fluorophenyl)-pyruvate. Reaction of the latter under similar conditions with p-fluorophenylacetonitrile results in 2,5-di-(p-fluorophenyl)-3,4-dioxoadiponitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[H-].[Na+].C1(=O)O[CH2:28][CH2:27][O:26]1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[N:12]([CH2:28][CH2:27][OH:26])[C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2
Reactant: O=C1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)N(CCO)C(=O)CN=C2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 150 mg (0.50 mmol) of 7,8-dimethoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one XXIIaa in 5 ml of DMF, add at 0° C. under an inert atmosphere 21 mg (0.52 mmol) of 60% NaH in oil. Stir at room temperature for 1 hour. Add at 0° C., 53 mg (0.60 mmol) of ethylene carbonate. Stir at room temperature overnight. Add 50 ml of H2O and extract three times with 50 ml of AcOEt; dry on MgSO4, evaporate the AcOEt and purify by silica chromatography (AcOEt 3/hexane 1, then AcOEt). Recrystallize in CHCl3/cHexane. Yield: 40%. M: 128–130° C. 1H-NMR (DMSO, 300 MHz): d 3.36–3.52 (m, 2H, HOCH2), 3.60 (s, 3H, OCH3), 3.70–3.86 (m, 5H, NCH2+OCH3), 4.11 (AB system, ? d=0.77, JAB=9.96, 2H, CH2), 4.77 (m, 1H, OH), 6.60 (s, 1H Ar), 7.39 (s, 1H Ar), 7.42–7.58 (m, 4H Ar). Mass: (M+H)+=341.16.
Reaction SMILES: CO[C:3](=[O:10])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][NH:5]1.C([O-])([O-])=O.[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[C:22]([Cl:24])[CH:23]=1>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[C:3](=[O:10])[C@@H:4]3[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]3[C:26]2=[O:27])[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1[C@@H]2C[C@H](O)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.1 %

Procedure:
To a solution of cis-4-hydroxy-L-proline methyl ester (0.53 g) (0.0036 mol) in 10 mL of DMF cooled at 0° C. was added K2CO3 (0.52 g) (1.1 eq.), then 3,5-dichlorophenyl isocyanate (0.75 g) (1.1 eq.). The reaction was stirred overnight at RT and the insoluble material removed by filtration. The solution was concentrated under vacuum and the residue dissolved in DCM. The organic layer was washed with water, dried over MgSO4, and evaporated under reduced pressure. The resulting residue was purified on a SiO2 column (eluent: DCM/acetone-95/5) to afford the titled compound as a white solid (0.25 g). NMR (CDCl3, 200 MHz): 7.35 (3H, s), 4.45 (1H, m), 4.30 (1H, dd), 4.0 (1H, d), 3.1 (1H, dd), 2.35-2.2 (2H, m), 1.95 (1H, bs, OH).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[CH2:5]([C@@H:7]1[O:9][CH2:8]1)[Cl:6]>C1COCC1.B(F)(F)F.CCOCC>[Cl:1][CH2:2][C@H:3]([OH:4])[CH2:8][O:9][CH2:7][CH2:5][Cl:6]
Reactant: ClC[C@H]1CO1
Reactant: OCCCl
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: O[C@@H](CCl)COCCCl
Temperature: 45 °C
Yield: 866.9 %

Procedure:
2-chloroethanol (34.8 g, 43.2 mmol) and boron trifluoride diethyl etherate (0.136 mL, 1.08 mmol) were dissolved in 20 mL of THF and cooled in an ice bath. (R)-(−)-epichlorohydrin (10.0 g, 10.8 mmol) in 10 mL of THF was added slowly through a syringe. After the addition, the ice bath was removed and the mixture was heated in a 45° C. oil bath for 90 min at which time the reaction was complete. The reaction was concentrated in vacuo to give an oily crude product (R)-1-chloro-3-(2-chloroethoxy)propan-2-ol (2I, 16.2 g, 86.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.56-3.71 (m, 6H) 3.85-3.92 (m, 3H).
Reaction SMILES: ClCCl.[CH3:4][C:5]([NH:15][CH:16]([CH3:20])[C:17](=O)[CH3:18])([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](Cl)=[O:30].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:6][C:5]([N:15]1[CH:16]([CH3:20])[C:17]([CH3:18])=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])[C:29]1=[O:30])([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:4]
Reactant: CC(=O)C(C)NC(C)(C)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Cc1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2ccc(Cl)c(Cl)c2)C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To 20 ml of dichloromethane were added 3.0 g of N-[1-methyl-1-(3,4-dichlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)amine and 3.5 g of pyridine, and 4.0 g of 2-fluorophenylacetyl chloride was then added dropwise thereto at 5° to 10° C. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with dichloromethane. After dried over anhydrous sodium sulfate, the solution was concentrated by an evaporator, and the resulting oil was dissolved in 20 ml of ethyl acetate. Next, 10 ml of a 28% methanol solution of sodium methylate was added thereto, and after stirring under reflux for 15 minutes, the temperature of the solution was returned to room temperature and water was then added, followed by extraction with ethyl acetate. Afterward, the solution was washed with a 12% hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate, and then dried over anhydrous sodium sulfate. Next, the solution was concentrated by an evaporator, and then subjected to silica gel chromatography to obtain 2.5 g of 1-[1-methyl-1-(3,4-dichlorophenyl)ethyl]-4,5-dimethyl-3-(2-fluorophenyl)-3-pyrroline-2-one.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Br[CH2:6][CH2:7][O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][N:10]=1.C(N(CC)CC)C>CO>[CH3:2][N:3]([CH3:4])[CH2:6][CH2:7][O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][N:10]=1
Reactant: BrCCOc1cc(-c2ccccc2)on1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)CCOc1cc(-c2ccccc2)on1
Yield: 62.9 %

Procedure:
After dimethylamine hydrochloride (815 mg) was dissolved in methanol (50 ml), 3-(2-bromoethoxy)-5-phenylisoxazole (268 mg) and triethylamine (2.8 ml) were added thereto, followed by reflux of the resulting mixture for 8 hours. After the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ether (20 ml), and the solution was washed with a diluted aqueous NaCl solution (20 ml), followed by drying of the organic layer over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound (146 mg, 63%) as colorless crystals.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:8])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[C:1]([NH:4][C:5](=[O:8])[CH2:6][S:7][C:16](=[O:17])[CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)CS
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC(=O)CSC(=O)Cc1ccccc1

Procedure:
One-half of the aqueous solution prepared in Step A. above was taken and ice was added while nitrogen was bubbled through the stirred solution. There was then added 4.65 g. (0.03 mole) of phenylacetyl chloride, and after that, with good stirring, there was added over 20 minutes a solution of 1.2 g. (0.03 mole) of sodium hydroxide in 30 ml. of water. Ice was added in intervals while the reaction mixture was stirred an additional hour. The water was then decanted from the solid product, after which it was triturated with cold water and decanted, then triturated with 0.5 ml. of acetic acid in 50 ml. of cold water and decanted. The solid was taken up in dichloromethane, dried, then evaporated to an oil. The oil was triturated with petroleum ether, after which it solidified, yielding 3.2 g. The product was recrystallized from dichloromethane/petroleum ether to yield 2.0 g. This material was chromatographed on a Waters high pressure liquid chromatography apparatus using silica gel and hexane: ethylacetate (2:1) as the eluent. A total of 800 mg. of product was obtained having an m.p. of 123°-124° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:4][C:5]([C:11]#[N:12])=[N:6][C:7]=1[NH:8][CH2:9][CH3:10].[CH:21]([N:24]=C=NC(C)C)(C)C.N1CCNCC1>C(#N)C>[NH2:24][C:21]1[N:8]([CH2:9][CH3:10])[C:7]2[C:2]([N:1]=1)=[C:3]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[N:4]=[C:5]([C:11]#[N:12])[N:6]=2
Reactant: CCNc1nc(C#N)nc(Nc2ccc(Cl)cc2)c1N
Reactant: CC(C)N=C=NC(C)C
Agent: C1CNCCN1
Solvent: CC#N
Product: CCn1c(N)nc2c(Nc3ccc(Cl)cc3)nc(C#N)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-amino-4-[(4-chlorophenyl)amino]-6-(ethylamino)pyrimidine-2-carbonitrile (0.41 g, prepared using the method of example 20) in acetonitrile (5 ml) was added to a stirred solution of FMOC-NCS (0.44 g) in acetonitrile (10 ml) at 0° C. After 1 h, diisopropylcarbodiimide (0.252 g) was added, the mixture heated under reflux for 4 h, cooled, piperazine (0.1 g) added and stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine, the organics dried (MgSO4) and evaporated under reduced pressure. The solid was purified by chromatography on silica eluting with 2-4% methanol in dichloromethane. Yield 0.12 g
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].Cl[C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:28]2)=[O:21])[CH2:17][CH2:18]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N1CCC(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 288 h
Yield: 88.4 %

Procedure:
A mixture of 2-[4-(2 tert-butylphenyl)piperazin-1-yl]-2-oxo-N-piperidin-4-ylacetamide dihydrochloride (Example 182-A, 0.35 g, 0.79 mmol), ethyl chloro(oxo)acetate (140 mg, 1.02 mmol) and triethylamine (439 3.15 mmol) in tetrahydrofuran (4 mL) was stirred at room temperature for 12 days. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 75:25 to 25:75) to give the title compound (0.33 g, 88%) as a white amorphous.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([CH2:38][NH2:39])[CH:35]=[C:34]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)[N:33]=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:39][CH2:38][C:36]3[CH:35]=[C:34]([C:40]4[CH:41]=[CH:42][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:44][CH:45]=4)[N:33]=[C:32]([O:31][CH3:30])[CH:37]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(CN)cc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2cc(OC)nc(-c3ccc(C(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
A solution of acid 18 (0.3 g, 0.97 mmol) in THF (15 mL) was added with DEPC (0.19 mL, 1.3 mol eq) and the mixture was stirred at room temperature several minutes. Then [2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27I (0.22 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water was added to the residue that is extracted with EtOAc (3×30 mL) and washed with brine (1×30 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (1/1 EtOAc/Petroleum ether) to afford a white solid (110 mg) after crystallization from ethyl ether. Yield=26%. 1HNMR (DMSO, 400 MHz) δ 1.21 (t, 5H, J=6.2), 1.41 (m, 2H), 3.54 (m, 2H), 3.94 (s, 3H), 4.18 (bs, 2H), 6.70 (s, 1H), 7.25 (d, 1H, J=2.1), 7.57 (d, 2H, J=2.3), 7.84 (d, 2H, J=8), 8.27 (m, 3H). [M+1] 574.66 (C24H23ClF3N3O4S2 requires 574.04).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:29]#[N:30])[CH:5]=[C:6]([CH:28]=1)[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=1[CH3:27])=[O:8].N1C=CC=CC=1.[C:37]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)#[N:38].C(=O)([O-])O.[Na+]>O1CCCC1>[C:29]([C:4]1[CH:5]=[C:6]([CH:28]=[C:2]([NH:1][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:39]([C:37]#[N:38])=[CH:40][CH:41]=2)[CH:3]=1)[C:7]([NH:9][C:10]1[C:11]([CH3:27])=[CH:12][C:13]([C:17]([F:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:14][C:15]=1[CH3:16])=[O:8])#[N:30]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(N)cc(C#N)c1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(C#N)cc(NC(=O)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a solution of 5-amino-3-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.199 mg, 0.46 mmol) (Example I9) in tetrahydrofuran (3 ml) were added successively pyridine (0.117 ml, 1.45 mmol) and 4-cyano-benzoyl chloride (80 mg, 0.48 mmol). The reaction mixture was stirred for 2 hours at ambient temperature. Aqueous sodium hydrogen carbonate (saturated) was added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to give Compound No. B1 of Table B (0.186 g, 71.9% yield). 1H-NMR (400 MHz, CHCl3): 8.45 (s, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.00 (m, 3H), 7.84 (m, 2H), 7.63 (s, 1H), 7.37 (s, 2H), 2.34 (s, 6H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)([O-:3])=[O:2].C1(N)CCCCC1>C(O)(C)C>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)c([N+](=O)[O-])c1
Solvent: CC(C)O
Solvent: NC1CCCCC1
Product: Cc1ccc(-c2ccc(C(O)CCC(=O)O)cc2)c([N+](=O)[O-])c1
Yield: 68 %

Procedure:
Prepared analogous to Example 25 from 4-(2'-nitro-4'-methyl-4-biphenylyl)-4-oxo-butyric acid. Yield: 68% of theory. Melting point of the cyclohexylamine salt: 156°-157° C. (from isopropanol).