Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.CC[N:27](C(C)C)[CH:28]([CH3:30])[CH3:29].[CH3:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36]>>[C:19]([OH:21])(=[O:36])[CH3:20].[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:16]2[N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:27][CH:28]5[CH2:30][CH2:39][N:37]([C:35](=[O:36])[CH3:34])[CH2:38][CH2:29]5)[S:3][C:4]=4[CH:10]=3)[CH:13]=[N:14][C:15]=2[CH:20]=1
Reactant: CC(=O)N(C)C
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Reactant: CCN(C(C)C)C(C)C
Product: CC(=O)O
Product: COc1cc2ncn(Cc3ccc4nc(NC5CCN(C(C)=O)CC5)sc4c3)c2cc1OC
Temperature: 120 °C
Yield: 7 %

Procedure:
A stirred mixture of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (80 mg, 0.198 mmol) from Example 2,1-(4-aminopiperidin-1-yl)ethanone (56 mg, 0.396 mmol) and DIEA (77 mg, 0.594 mmol) in anhydrous DMA (1 mL) was heated at 120° C. for 15 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford 1-(4-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)piperidin-1-yl)ethanone acetate (7 mg, 7%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.65 (s, 1H), 7.30-7.37 (m, 1H), 7.14-7.25 (m, 3H), 5.41 (s, 2H), 4.18 (m, 1H), 3.94 (m, 1H), 3.75-3.77 (m, 7H), 3.11-3.24 (m, 2H), 2.78-2.85 (m, 1H), 1.95-2.05 (m, 4H), 1.89 (s, 3H), 1.19-1.48 (m, 2H). LCMS (ESI) m/z 466 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[S-2:16].[CH3:17][Na]>CN(C=O)C>[CH3:17][S:16][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1F
Reactant: C[Na]
Reactant: [S-2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccccc1C=O
Temperature: 55 °C
Yield: 84.9 %

Procedure:
2-fluoro-benzaldehyde (2.00 g, 16.1 mmol), potassium carbonate (2.45 g, 17.7 mmol) and methyl sodium sulfide (17.1 mmol) were dissolved in 10.0 mL DMF in a 50 mL round-bottomed flask under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 55° C. for 24 hr. After cooling, the mixture was added to 50 mL of saturated potassium carbonate solution and extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using 1:1 dichloromethane/n-hexane as eluent to give a yellow oil (2.08 g, 85%). 1H NMR (200 MHz, CDCl3): δ 2.49 (s, 3H), 7.24-7.58 (m, 3H), 7.80 (dd, J1=7.6, J2=1.4, 1H), 10.25 (s, 1H) ppm.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].[CH3:10][S:11][C:12]1[N:17]=[C:16](Cl)[C:15]([N+:19]([O-:21])=[O:20])=[C:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH:24]=2)[N:13]=1>O1CCCC1>[CH3:10][S:11][C:12]1[N:17]=[C:16]([O:5][CH2:4][C:3]([O:7][CH2:8][CH3:9])=[O:6])[C:15]([N+:19]([O-:21])=[O:20])=[C:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([N:31]([CH3:32])[CH3:33])=[O:30])[CH:24]=2)[N:13]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1nc(SC)nc(Oc2cccc(C(=O)N(C)C)c2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To sodium hydride (0.63 g, 15.72 mmol) in 30 mL tetrahydrofuran at 0° C. was added ethyl glycolate (1.15 mL, 12.09 mmol) over 10 minutes. The resulting alkoxide was then added to 2-methylthio-4-chloro-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine, a compound of formula (C), (4.46 g., 12.09 mmol), dropwise at 0° C. over 5 minutes. After 1 hours, the reaction mixture was warmed to ambient temperature and stirred for an additional 2 hours. The volatiles were evaporated to yield 2.55 g (48% yield) of 2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine, a compound of formula (Q), as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH2:14])(=[O:13])[CH2:9][C:10]([CH3:12])=O.[CH2:15]([CH2:22][C:23](=O)[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>>[CH3:12][C:10]1[C:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:23]([CH3:24])[NH:14][C:8](=[O:13])[CH:9]=1
Reactant: CC(=O)CC(N)=O
Reactant: CC(=O)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1cc(=O)[nH]c(C)c1Cc1ccccc1
Temperature: 125 °C
Yield: 53.7 %

Procedure:
To a mixture of PPA (10 g) and acetoacetamide triethylamine (2.02 g, 20 mmol) was added benzylacetone (5.92 g, 5.98 mL, 40 mmol). The resulting mixture was heated at 125° C. for 3 hours. The brown mixture was poured onto crushed ice and neutralized with solid NaHCO3. The mixture was filtered to give a yellow solid, which was purified by flash column (silica, 10% MeOH/DCM) to give the pyridinone (2.29 g, 53.8%) as a yellow solid. 1H NMR (CDCl3) δ 2.07 (s, 3H), 2.37 (s, 3H), 3.81 (s, 2H), 6.38 (s, 1H), 7.00-7.40 (m, 5H); MS (CI) m/z 214.1 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=O.[CH:20]1([NH:23][C:24]2[S:25][CH2:26][C:27](=[O:29])[N:28]=2)[CH2:22][CH2:21]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:20]1([NH:23][C:24]2[S:25]/[C:26](=[CH:1]\[C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]4[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])/[C:27](=[O:29])[N:28]=2)[CH2:22][CH2:21]1
Reactant: O=C1CSC(NC2CC2)=N1
Reactant: CC(C)COc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)COc1c(C#N)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-isobutoxy-quinoline-3-carbonitrile (example 66b), 2-cyclopropylamino-thiazol-4-one (example 37c), sodium acetate and acetic acid to give 6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-isobutoxy-quinoline-3-carbonitrile. LC-MS m/e 393 (MH+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[S:17][N:16]=[C:15]([CH3:18])[C:14]=1[CH2:19][S:20][C:21]1[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][N:22]=1.[OH2:28]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[S:17][N:16]=[C:15]([CH3:18])[C:14]=1[CH2:19][S:20]([C:21]1[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][N:22]=1)(=[O:9])=[O:28]
Reactant: Cc1nsc(Cl)c1CSC1=NOC(C)(C)C1
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1nsc(Cl)c1CS(=O)(=O)C1=NOC(C)(C)C1
Reaction time: 1 h
Yield: 47 %

Procedure:
2.96 g of m-chloroperbenzoic acid (purity: 70%, 12.00 mmoles) was added, with ice-cooling, to a solution of 1.38 g (5.00 mmoles) of [(5-chloro-3-methyl-isothiazol-4-yl)-methylthio]-5,5-dimethyl-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The reside was purified by silica gel column chromatography to obtain 0.65 g (yield: 47.0%) of [(5-chloro-3-methyl-isothiazol-4-yl)-methylsulfonyl]-5,5-dimethyl-2-isoxazoline as a light yellow powder (melting point: 113 to 114° C.)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][C:13]([O:15]CC)=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.C(NB)(C)(C)C.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:8]2[OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1Cc2ccc(Br)cc2C1=O
Agent: BNC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC1Cc2ccc(Br)cc2C1O
Temperature: 42.5 °C
Reaction time: 0.5 h

Procedure:
The product from Example 52A in THF was treated with tert-butylaminoborane (1.18 g, 13.5 mmol) and heated at 40-45° C. for 2.5 hours. The mixture was treated with sodium hydroxide solution (1.8 g in water, 40 mL) and heating was continued for 30 minutes. The mixture was allowed to cool to room temperature and the aqueous layer was separated. The organic layer was diluted with isopropyl acetate (40 mL) and water (40 mL) and combined with the aqueous layer. The solution was cooled to 0° C. and the pH was adjusted to 2 by addition of concentrated hydrochloric acid. The mixture was filtered and the filter cake dried at room temperature. The solid was slurried in dichloromethane (6 mL), refiltered, and redried to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:14]1([CH2:13][N:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]2=[O:9])[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: COc1cc[nH]c(=O)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccn(CC2CC2)c(=O)c1C#N
Temperature: 110 °C
Yield: 94.5 %

Procedure:
To a solution of 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (12.2 g, 81.48 mmol) in acetonitrile (250 ml) were added bromomethyl-cyclopropane (11 g, 81.48 mmol) and potassium carbonate (22.48 g, 162.9 mmol) and the mixture was heated at 110° C. for 24 hours. The mixture was cooled to room temperature and the solid was filtered off The filtrate was evaporated till dryness and the resulting crude residue was then triturated with diethylether to yield pure intermediate 2 (15.72 g, 94%) as a white solid.
Reaction SMILES: [ClH:1].O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[ClH:1].[CH2:4]1[C:5]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][C:6]=2[CH2:7][CH2:8][NH:3]1
Reactant: O=C1CCNCC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: c1ccc2c3c([nH]c2c1)CCNC3
Yield: 87.6 %

Procedure:
4-Piperidone monohydrate hydrochloride (10 g, 65.1 mmol) and phenylhydrazine hydrochloride (9.4 g, 65.1 mmol) are suspended in ethanol (200 ml) and stirred at reflux overnight. The resulting solid is filtered off and washed with diethyl ether to afford pure sub-title compound (11.9 g) in 88% yield. tR (LC-2) 0.89; ESI-MS (positive ion): m/z 173.34 [M+H]+ (calcd 172.23 for C11H12N2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]Br)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O.CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:26]=[N+:27]=[N-:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN=[N+]=[N-])c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.867 g, 2.08 mmol) in DMSO (9 mL) was added sodium azide (0.175 g, 2.49 mmol), and the reaction was stirred at 60° C. for 4 hours. The mixture was cooled to room temperature and diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with H2O, then brine, and dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][CH2:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:20].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[N:9]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=4[CH3:16])=[CH:30][CH:29]=3)=[O:27])[CH2:10][CH2:11][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2n1-c1ccccc1NCC2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3nnc(C)n3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5 mmol of 5,6-dihydro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then washed with water, aqueous NaHCO3 and brine. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel with ethyl acetate-hexane as solvent to give the desired product.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(O[CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH3:14])(=O)C>[OH-].[Na+].O.CC(C)=O>[C:1]([S:3][CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH3:14])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: CC(=O)OC1NC(=O)C1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)SC1NC(=O)C1C

Procedure:
A solution of 1.5 ml of thioacetic acid in 20.5 ml of 1N sodium hydroxide solution is added dropwise at room temperature, under nitrogen, to a solution of 2 g of 4-acetoxy-3-methyl-azetidin-2-one (produced according to K. Clauss et. al., Lieb. Ann. Chem., 1974, 539; racemic mixture of cis- and trans-isomer in a ratio of 3:1, Mp. 53°-65°) in 5.16 ml of water and 1.25 ml of acetone, and the mixture is stirred at the same temperature for 3 hours. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over 150 g of silica gel with toluene/ethyl acetate (9:1) and yields the almost pure trans-isomer of the title compound with the following physico-chemical properties:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([S:15]([CH3:18])(=[O:17])=[O:16])([CH3:14])[C:11]([OH:13])=O)=[C:4]([F:19])[CH:3]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][NH2:27].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:14])([S:15]([CH3:18])(=[O:17])=[O:16])[C:11]([NH:27][O:26][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)=[O:13])=[C:4]([F:19])[CH:3]=1
Reactant: NOC1CCCCO1
Reactant: CC(CCc1ccc(Br)cc1F)(C(=O)O)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CCc1ccc(Br)cc1F)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
4-(4-Bromo-2-fluoro-phenyl)-2-methanesulfonyl-2-methyl-butyric acid (1.96 g, 5.55 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.910 g, 7.77 mmol), 1-hydroxy benzotriazole monohydrate (1.53 g, 9.99 mmol), triethylamine (1.39 mL, 9.99 mmol) and 1, (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.49 g, 7.77 mmol) were combined followed by the addition 60 mL of dichloromethane. The reaction was allowed to stir at room temperature overnight, was then diluted with 20 mL of dichloromethane and 60 mL of water. The aqueous layer was re-extracted with DCM (2×40 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated onto silica gel. Silica chromatography (40% ethyl acetate 60% heptane to 40% ethyl acetate 60% heptane to 80% ethyl acetate 20% heptane for 60 minutes) afforded the title compound as a white foam 2.0 g, (79.9%). LC-MS m/z 452.1 (M−1)
Reaction SMILES: Cl[CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[N:14]1([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.O>CN(C=O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[N:14]1[CH2:19][CH2:18][N:17]([CH2:2][C:3]2[NH:4][C:5]3[C:10]([C:11](=[O:13])[N:12]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:16][CH2:15]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=c1[nH]c(CCl)nc2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1nc(CN2CCN(c3ncccn3)CC2)[nH]c2ccccc12
Temperature: 25 °C
Yield: 74.5 %

Procedure:
300 mg of 2-(chloromethyl)quinazolin-4(3H)-one and 300 mg 2-(piperazin-1-yl)pyrimidine were dissolved in 5 ml of DMF at room temperature. After a few seconds, 0.5 ml of triethylamine was added, and the reaction mixture was stirred at ambient temperature, while being monitored by TLC. Once the reaction was completed (overnight), additional 0.2 ml of triethylamine was added, followed by 3 ml of water, and the mixture was cooled to 0° C. The solid precipitate was thereafter collected by vacuum filtration, washed with cold water and dried for 2 hours at 50° C., to give 370 mg (75% yield) of the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=O)[N:10](C)[C:11]([NH:20][C:21]([CH3:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:43])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:22][C:21]([NH:20][C:11]1[N:10]=[C:9]([Cl:43])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:12]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:29]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(NC(C)(C)c2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Nc1nc(Cl)c(-c2ccc(F)cc2)c(-c2ccncc2)n1)c1ccccc1
Temperature: 100 °C

Procedure:
5-(4-fluorophenyl)-3-methyl-2-((1-methyl-1-phenylethyl)amino)-6-(4-pyridyl)-(3H)-pyrimidin-4-one (1.24 g, 2.99 mmol), benzyltriethylammonium chloride (2.04 g, 8.97 mmol), and diisopropylethylamine (1.16 g, 1.6 mL 8.97 mmol) were combined in phosphorous oxychloride (ca. 20 mL) and the resulting solution was heated at 100° C. for 16 h. The reaction was cooled to RT, the phosphorous oxychloride was evaporated in vacuo and the residue was partitioned between sat. aq. NaHCO3 and CHCl3. The organic layer was dried over Na2SO4 and then concentrated. The residue was purified by flash chromatography (20% EtOAc:CHCl3) to provide the product as a white solid; MS m/z (M+H)+ 419; C24H20ClFN4 requir. 418.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]([OH:24])[C:22]#[CH:23])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([C:21](=[O:24])[C:22]#[CH:23])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C#CC(O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C#CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
To a cold (0° C.) solution of 1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (5.00 g, 15.0 mmol) in chloroform (400 mL) was added manganese dioxide (130 g, 1.50 mol). The reaction mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to provide 1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]-2-propyn-1-one (3.44 g, 69%) as a clear oil. Rf 0.39 (4:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.61 (d, 1H), 7.72–7.69 (m, 3H), 7.17 (m, 2H), 3.06 (s, 1H); MS m/z 333 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2([NH:13][C:14]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)=[O:15])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.F[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[C:33]([F:36])([F:35])[F:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CC(C)=O>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([O:1][C:2]2[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]3([NH:13][C:14]([C:16]4[CH:21]=[N:20][CH:19]=[N:18][CH:17]=4)=[O:15])[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)=[C:26]([C:33]([F:34])([F:35])[F:36])[CH:27]=1)#[N:30]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(NC1(C(=O)NCc2ccc(O)cc2)CC1)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: N#Cc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cncnc4)CC3)cc2)c(C(F)(F)F)c1
Yield: 82 %

Procedure:
A solution of 100 mg (0.32 mmol) of pyrimidin-5-carboxylic acid[1-(4-hydroxy-benzylcarbamoyl)-cyclopropyl]-amide, 60.5 mg (0.32 mmol) of 4-fluoro-3-trifluoromethyl-benzonitrile and 110 mg (0.8 mmol) of potassium carbonate in 5 mL DMF was stirred for two hours at 110° C. After cooling the mixture was diluted with approx. 3 mL acetone, filtered and evaporated down. The crude product thus obtained was purified by column chromatography (reversed phase).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[C:7]([C@H:9]([NH2:11])[CH3:10])[CH:8]=1.C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([F:13])([F:14])[F:15])=[C:7]([C@H:9]([NH:11][C:45]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:46])[CH3:10])[CH:8]=1
Reactant: C[C@@H](N)c1cc(F)ccc1C(F)(F)F
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3cc(F)ccc3C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(5-fluoro-2-(trifluoromethyl)phenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 589 [M+H]+.
Reaction SMILES: BrC1C=CC(N2CCN(S(CC(C(C)C)C(O)=O)(=O)=O)CC2)=CC=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:33][CH:32]=2)[CH:26]=1.[CH3:43][O:44][C:45]([C:47]1([CH2:53][S:54](Cl)(=[O:56])=[O:55])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)=[O:46]>>[CH3:43][O:44][C:45]([C:47]1([CH2:53][S:54]([N:40]2[CH2:41][CH2:42][N:37]([C:34]3[CH:33]=[CH:32][C:31]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[CH:36][CH:35]=3)[CH2:38][CH2:39]2)(=[O:56])=[O:55])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)=[O:46]
Reactant: c1cncc(-c2ccc(N3CCNCC3)cc2)c1
Reactant: COC(=O)C1(CS(=O)(=O)Cl)CCOCC1
Agent: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)O
Product: COC(=O)C1(CS(=O)(=O)N2CCN(c3ccc(-c4cccnc4)cc3)CC2)CCOCC1
Yield: 55 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-bromophenyl)piperazine-1-sulfonylmethyl]-3-methyl-butyric acid tert-buryl ester, from 1-(4-pyridin-3-yl-phenyl)piperazine (0.18 g) and 4-chlorosulfonylmethyl tetrahydropyran-4-carboxylic acid methyl ester (0.23 g), to yield the title compound as a white solid (0.19 g, 55%).