Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.[F:26][C:27]([F:35])([F:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][NH:19][C:18]1[CH:21]=[CH:22][C:15]([N:31]2[CH2:32][CH2:33][CH:28]([C:27]([F:35])([F:34])[F:26])[CH2:29][CH2:30]2)=[CH:16][C:17]=1[N+:23]([O-:25])=[O:24]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CNc1ccc(N2CCC(C(F)(F)F)CC2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under argon sodium tert-butoxide (366 mg, 3.8 mmol) followed by palladium(II) acetate (22 mg, 0.1 mmol) and tri-tert-butylphosphine 10% in toluene (450 μL, 0.2 mmol) were added to a mixture of 4-bromo-2-nitro-N-methyl-aniline (440 mg, 1.9 mmol) and 4-(trifluoromethyl)piperidine (660 mg, 2.9 mmol) in toluene (7 mL). The reaction mixture was stirred at 100° C. overnight then allowed to cool and was concentrated. The crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[O:25][CH3:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.60 g) with 2-methoxybenzoyl chloride (1.0 g) and N,N-diisopropylethylamine (1.7 ml) in tetrahydrofuran (60 ml) was performed according to the method described in example 6.
Reaction SMILES: C1O[C:5]([OH:9])([CH2:7][OH:8])[CH2:4][O:3][C:2]1([OH:12])[CH2:10]O.[C:13](OC(=O)C)(=[O:15])[CH3:14].CO>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:13]([O:8][CH2:7][C:5]([CH2:4][O:3][C:2](=[O:12])[CH3:10])=[O:9])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1(O)COC(O)(CO)CO1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)OCC(=O)COC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of argon, 90 g of 1,3-dihydroxyacetone dimer and 250 mg of 4-(N,N-dimethylamino)pyridine were dissolved in 250 ml of pyridine. To the resulting solution, 225 ml of acetic anhydride was added droopowise at room temperature over 1 hour. After the resulting liquid was stirred at room temperature for 30 minutes, thereto was added 50 ml of methanol and the resulting liquid was further stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was subjected to a recrystallization from ether-petroleum ether to give 190 g of the desired compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:14][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+]=[N-].[ClH:17].[H][H]>[Pd].C(O)C>[ClH:17].[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:14][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(CN=[N+]=[N-])cc1O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(CN)cc1O
Yield: 71 %

Procedure:
Palladium on carbon (0.5 g 10% [w/w]) was added to a 1L hydrogenation flask under a nitrogen atmosphere. The crude ethyl 4-azidomethylsalicylate was dissolved in ethanol (200 mL) and transferred to the hydrogenation flask. Concentrated aqueous hydrochloric acid (2 mL) was then added, and the flask was affixed to the Parr hydrogenator. The reaction mixture was shaken under 35 psi of hydrogen for 4 hours at room temperature. The mixture was then filtered through Celite to remove the catalyst, and the filtrate was evaporated to dryness to afford an off-white solid. Finally, this solid was crystallized from EtOH to afford 3.1 g (71% yield) of ethyl 4-aminomethylsalicylate hydrochloride (m.p. 240°-241° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH:12]=[C:11]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=3)[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.C(O)C.[H][H]>[Pd].C1COCC1>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]2[CH:12]=[C:11]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=3)[CH:10]=[C:9]([O:8][C:7]3[CH:35]=[CH:36][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH:14]=2)=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Oc3ccc([N+](=O)[O-])cc3)cc(Oc3ccc([N+](=O)[O-])cc3)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Oc2cc(Oc3ccc(N)cc3)cc(Oc3ccc(N)cc3)c2)cc1
Yield: 100 %

Procedure:
To a 300-mL, 4-necked flask were added 2.46 g (5.03 mmol) of 1,3,5-tri(4-nitrophenoxy)benzene and 5% Pd/C (149 mg), and the inside was replaced with argon. Ethanol (50 mL) and THF (50 mL) were added thereto, and then the flask was equipped with a hydrogen balloon, and the mixture was stirred in a normal-pressure hydrogen atmosphere at room temperature for 3 days. The catalyst was separated by filtration and then the solvent was removed away in vacuo, whereby a desired product was obtained (Quantity: 2.01 g, 5.03 mmol, Yield: 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C([NH:24][C@@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(OC(C)(C)C)=O.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:2]2[NH:1][C:33](=[O:34])[C@@H:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=N[C@@H]1Cc1ccccc1
Reaction time: 120 h

Procedure:
The procedure of Example 1 was carried out using 2-amino-5-chlorobenzophenone (2.32 gm, 0.01 mol), Boc-D-Phenylalanine (2.65 gm, 0.01 mol), and DCC (10 ml of 1.0 M solution in CH2Cl2) in CH2Cl2 (10 ml). After filtration and evaporation, the crude solid was deprotected and cyclized by the procedure of Example 2. After stirring 5 days, the mixture was evaporated in vacuo, treated with H2O (50 ml), and extracted with EtoAc (2×100 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSO4, filtered and evaporated to dryness in vacuo. Chromatogaphy on silica gel eluted with 7.5% (v/v) Et2O in CH2Cl2 gave a white foam which was crystallized from Et2O. The solid was dried in vacuo at 65° C.: (m.p. 154°-7° C.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:21][OH:22])[NH2:20])[C:3]=1[S:23]([C:25]([F:28])([F:27])[F:26])=[O:24].N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36]>ClC(Cl)C>[C:35]([O:22][NH:21][C:19]([C:4]1[C:3]([S:23]([C:25]([F:27])([F:28])[F:26])=[O:24])=[C:2]([NH2:1])[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=1)=[NH:20])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: NC(=NO)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)ONC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinyl-3-pyrazolecarboxamide oxime (0.50 g, 1.06 mmol) was dissolved in 8 ml of dichloroethane, and then pyridine (0.10 ml, 1.2 mmol) was added and acetyl chloride (99 mg, 1.26 mmol) dissolved in 2 ml of dichloroethane was added dropwise at room temperature. After the completion of adding dropwise, the mixture was stirred at room temperature for 2 hours and the solvent was distilled off. To the resulting mixture, 50 ml of ethyl acetate was added, then 15 ml of water and 15 ml of an aqueous saturated sodium chloride solution was added. The ethyl acetate layer was taken and washed once with 30 ml of 0.5 N hydrochloric acid, then washed three times with 30 ml of an aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 0.54 g (1.06 mmol) of the title compound as a colorless amorphous. Yield 99%.
Reaction SMILES: [C:1]([N:4]1[CH:10]2[CH:8]([CH:9]2[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:6](=[O:28])[CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:44](OCC)(=[O:50])[C:45](OCC)=[O:46].Cl>CN(C=O)C>[CH2:13]([O:12][CH2:11][CH:9]1[CH:10]2[CH:8]1[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:6](=[O:28])[C:5]1[N:4]2[C:1](=[O:3])[CH:2]=[C:44]([OH:50])[C:45]=1[OH:46])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C2C(COCc3ccccc3)C21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1c2c(O)c(O)cc(=O)n2C2C(COCc3ccccc3)C2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 5-acetyl-2-(4-fluorobenzyl)-7-[(benzyloxy)-methyl]-2,5-diazabicyclo[4.1.0]heptane-3-one (700 mg, 1.83 mmol) in DMF (10 mL) under nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (1.0 M, 2.0 mL, 2.0 mmol) was added. After 30 min, diethyl oxalate (401 mg, 2.74 mmol) in DMF (2 mL) was added. After stirring for 1 h at room temperature, the resultant mixture was treated with additional lithium bis(trimethylsilyl)amide (1.0 M, 7.1 mL, 7.1 mmol), and stirred at room temperature overnight. The reaction mixture was treated with 1 N HCl, concentrated under vacuum. The residue was partitioned between brine and chloroform. The aqueous layer was extracted with chloroform twice. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[OH-].[K+].[C:12]1([CH:22]=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.O>CO>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC1N(C)C=C[NH+]1C
Reactant: O=Cc1cccc2ccccc12
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1C=C[NH+](C)C1C=Cc1cccc2ccccc12

Procedure:
A mixture of 6.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 1 g of potassium hydroxide and 6 ml of 1-naphthaldehyde in 25 ml of methanol is refluxed for 15 minutes during which time a precipitate is formed. The reaction mixture is cooled and 5 ml of water is added. The solid is filtered off, dried, and crystallized from absolute ethanol to yield 3.7 g of the title compound, melting point 251°-253° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][S:8][C:6]=2[N:7]=1.N[C:27]1N=C(N)C2C(C)=CSC=2N=1.C1C2CC3C(=CC=CC=3)NC=2C=CC=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][N:12]3[C:19]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:27][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=4)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)csc2n1
Reactant: Cc1csc2nc(N)nc(N)c12
Agent: c1ccc2c(c1)Cc1ccccc1N2
Product: Nc1nc(N)c2c(CN3c4ccccc4Cc4ccccc43)csc2n1

Procedure:
N-[(2,4-Diaminothieno[2,3-d]pyrimidin-5-yl)methyl]-9,10-dihydroacridine (Formula I: Ar=2,4-diaminothieno[2,3-d]pyrimidi-5-yl; W=CH2; X=N; Z=CH2; m=n=0) is prepared similarly to N-[(2,4-diaminothieno[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed in Example 11 above by using 2,4-diamino-5-methylthieno[2,3-d]pyrimidine (1.3 g, 7.4 mmol) in Step 1 and 9,10-dihydroacridine (134 mg, 0.8 mmol) in Step 3. The final product and its intermediates can b purified by chromatography.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:6][CH2:7][N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9]1)[CH2:4][OH:5].C1([O:26][C:27](=O)[NH:28][C:29]2[S:30][C:31]([CH2:34][CH3:35])=[N:32][N:33]=2)C=CC=CC=1.C(N(CC)CC)C>CS(C)=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH:10]2[CH2:11][N:8]([CH2:7][CH2:6][C@H:3]([NH:2][C:27]([NH:28][C:29]3[S:30][C:31]([CH2:34][CH3:35])=[N:32][N:33]=3)=[O:26])[CH2:4][OH:5])[CH2:9]2)=[CH:18][CH:17]=1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Reactant: CCc1nnc(NC(=O)Oc2ccccc2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)s1

Procedure:
A solution of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride (1.04 g, 2.82 mmol), (5-Ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester (0.70 g, 2.82 mmol) and triethylamine (1.6 ml, 11.28 mmol) in DMSO (70 ml) is stirred at ambient temperature for 18 hour, then partitioned between ethylacetate and saturated aqueous sodium bicarbonate solution. The organic phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by recrystallisation from hot ethylacetate to afford 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-urea. [M+H] 426.18.
Reaction SMILES: [OH:1][CH:2]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4][CH2:3]1.[B-](F)(F)(F)F.[CH3:18][CH2:19][O+](CC)CC>>[CH2:18]([O:6][C:5]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:2]([OH:1])[CH2:3][N:4]=1)[CH3:19]
Reactant: O=C1NCC(O)c2ccccc21
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Product: CCOC1=NCC(O)c2ccccc21

Procedure:
In a manner similar to that of Step A of Example 1, ethylation of 4-hydroxy-3,4-dihydroisocarbostyril (21.75 g.) with triethyloxonium fluoborate (0.147 + 0.073/3 mole) and two recrystallizations (the first recrystallization afforded a first crop of 8 g., of which 4.2 g. was recrystallized) of the resulting product from ethanol-ether afforded 1-ethoxy-4-hydroxy-3,4-dihydroisoquinoline (III: Q = C2H5, Y' = OH, Y = Z = Z' = H) fluoborate (3.9 g., m.p. 121°-123° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:27]=[C:28]3[C:32](=[C:33]([CH3:35])[CH:34]=2)[N:31]([CH3:36])[N:30]=[CH:29]3)=[O:25])[CH:19]=1>CN(C=O)C>[CH3:36][N:31]1[C:32]2[C:28](=[CH:27][C:26]([C:24]([C:20]3[N:21]=[CH:22][N:23]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:19]=3)=[O:25])=[CH:34][C:33]=2[CH3:35])[CH:29]=[N:30]1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2cnn(C)c12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2cnn(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
25 mg (0.12 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 35 mg (0.10 mmol) (6-chloro-pyrimidin-4-yl)-(1,7-dimethyl-1H-indazol-5-yl)-methanone and 25 μL (0.18 mmol) TEA were combined in 1 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and evaporated down to approx. 5 mL. This residue was neutralised with saturated sodium hydrogen carbonate solution, the precipitate formed was suction filtered and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([F:13])([F:14])[F:12])=[N:9][N:8]([CH:22]([CH3:24])[CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C(C)C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a suspension of 5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (13 g, 62.5 mmol) and cesium carbonate (61.1 g, 187.5 mmol) in DMF (70 mL) was added 2-iodo-propane (6.86 mL, 68.75 mmol) and the resulting mixture allowed to stir at room temperature for 16 hours. The crude reaction mixture was poured onto water (100 mL) and extracted with EtOAc (100 mL×3). The combined organics were washed with water (50 mL×2), brine (50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid in 65% yield, 10.2 g.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:6][CH:5]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[NH:20][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(C(N)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl
Product: COc1ccc(C(NC(=O)c2ccc(F)cc2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 88.3 %

Procedure:
In a similar manner to that described in Example (46c) α-(4-methoxyphenyl)-3-nitrobenzylamine hydrochloride (1.51 g) [prepared as described in Example 46(b) above] and 4-fluorobenzoyl chloride (813 mg) were reacted, to afford the title compound (1.72 g) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2)=[O:2].[CH2:17]([Mg]Br)[CH2:18][CH2:19][CH2:20][CH3:21]>CCOCC>[OH:2][CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)c1cccc2cc(C=O)ccc12
Reactant: CCCCC[Mg]Br
Solvent: CCOCC
Product: CCCCCC(O)c1ccc2c(C(=O)OC)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of methyl 6-formyl-1-naphthoate (36 mg, 0.17 mmol) in THE (1.7 mL) was cooled to 0° C. and treated with n-pentylmagnesium bromide (0.1 mL of a 2.0 M solution in Et2O, 0.2 mmol). The cooling bath was removed and after stirring at room temperature for 1 h the reaction was quenched with 1 N aqueous HCl, diluted with water (10 mL) and extracted with EtOAc (3×10 The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified on 12 g silica gel (100% hexanes→40% EtOAc/hexanes, gradient) to afford 34 mg (71%) of methyl 6-(1-hydroxyhexyl)-1-naphthoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1OC
Reaction time: 7 h
Yield: 88.5 %

Procedure:
To a solution of 1000 g (6.024 mol) of 3,4-dimethoxybenzaldehyde in 3 L pyridine, 1378.3 g (13.25 mol) of malonic acid and 100 mL of piperidine were added. The resulting mixture was stirred at 105° C. to 110° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and slowly quenched the reaction mixture into 10 L of 5% sodium hydroxide solution at 25° C. to 30° C. (pH: 9-10). The reaction mixture was washed with ethyl acetate (2×5 L) and the organic layer separated was washed with 2 L of 5% sodium hydroxide solution. The aqueous layers were combined and cooled to 15° C. to 20° C. The aqueous layer was acidified slowly with 2.5 L of 50% sulphuric acid below 20° C. (pH: 1-2). After an additional 30-45 min stirring at 15° C. to 20° C., the solid obtained was collected by filtration, washed with 10 L of water followed by 4 L of n-hexane. The partially dried compound was unloaded into trays and dried at 55° C. to 60° C. for 8-10 h to give 1110 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH2:25][NH2:26])[CH:20]=[N:19][CH:18]=1.CCOP(O)N(C(C)C)C(C)C>ClCCl.CN(C)C=O>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([NH:26][CH2:25][CH2:24][NH:23][C:21]1[CH:20]=[N:19][CH:18]=[C:17]([CH3:16])[N:22]=1)=[O:6]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: Cc1cncc(NCCN)n1
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cncc(NCCNC(=O)/C=C/C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (70 mg, 0.5 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (42 μl, 0.5 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-(6-methylpyrazin-2-yl)ethane-1,2-diamine (38 mg, 0.25 mmol) and EDIPA (175 μl, 1 mmol) in a mixture of anhydrous dichloromethane (2 ml) and anhydrous dimethylformamide (1 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 19.9 mg of a solid (0.07 mmol, 14.5% yield)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.CN(C)CCN(C)C.C([Li])CCC.[C:20]1(=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1.O>[CH3:1][N:2]1[C:6]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1cccn1
Reactant: O=C1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1C1(O)CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of 1-methylpyrazole (6.0 g, 73.1 mmol) and N,N,N′,N′-tetramethylethylenediamine (10.96 mL, 73.1 mmol) in THF (125 mL), butyl lithium (2.69 M solution in hexane; 31.8 mL, 85.5 mmol) was added at −78° C. The reaction solution was stirred at −78° C. for 30 minutes. Then, cyclohexanone (9.06 mL, 87.7 mmol) was added thereto, and the mixture was stirred at room temperature for 15 hours. To the reaction solution, water (500 mL) was added, followed by extraction with ethyl acetate (250 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=3:2), to yield the title compound (11.32 g, 86%) as a colorless oil.