Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCC(F)(F)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(F)CCN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(3,3-difluoropyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (193 mg, 0.74 mmol) and TFA (1 mL) in DCM (2 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording 1-Azetidin-3-yl-3,3-difluoropyrrolidine as a white solid (122 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 3.63 (m, 4H), 3.48 (m, 1H), 2.87 (t, J=13.1 Hz, 2H), 2.70 (t, J=7.0 Hz, 2H) and 2.29 (m, 2H)
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:3]=1[CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[Li]CCCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:2]([B:27]([OH:32])[OH:28])=[C:3]([CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])[CH:16]=1
Reactant: COc1ccc(Br)c(CO[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(CO[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
[(2-bromo-5-methoxybenzyl)oxy](triisopropyl)silane (1 eq) was dissolved in anhydrous THF (0.43M solution) and the solution was cooled to −78° C. A solution of n-BuLi (1.6M in hexanes, 1.05 eq) was added and the resulting mixture was stirred for 1 h at −78° C. Then triisopropyl borate (50% in THF, 1.3 eq) was added dropwise and the mixture was allowed to warm to RT overnight. 1N HCl was added and the resulting mixture was stirred at RT for 30 min. THF was removed in vacuo and replaced with Et2O. The organic phase was washed with water and with brine, then dried over Na2SO4 and evaporated in vacuo. The product was obtained as a colourless oil (64% yield, 65% pure) which was used without further purification in the next reaction.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O1CCOCC1>CCOC(C)=O>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16]
Reactant: Cc1cccc2c1CCC(=O)N2CCCCl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccc2c1ccc(=O)n2CCCCl
Yield: 66.1 %

Procedure:
A microwave vial was charged with 1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one (0.081 g, 0.34 mmol), DDQ (0.116 g, 0.51 mmol), dioxane (2 mL) and sealed. After microwave irradiation, 175° C., 10 min, the reaction was diluted with EtOAc (50 mL), washed with sat aqueous NaHCO3 (2×15 mL) and the organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and the residue was purified with prep RP-HPLC to yield the crude title compound (0.053 g), which was used without further purification. HPLC-MS (ammonium acetate) [M+H]+=236.2.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[NH:4].[C:18](OC(=O)C)(=O)[CH3:19].O>N1C=CC=CC=1>[CH3:18][C:19]1[O:1][N:2]=[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
To a solution of tert-butyl 4-(N-hydroxycarbamimidoyl)piperazine-1-carboxylate (771 mg, 3.16 mmol) in pyridine (8 mL) was added acetic anhydride (320 L, 3.42 mmol) and the reaction was heated to 80° C. for 3 h. The mixture was cooled to room temperature, poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure to yield 774 mg of a yellow solid. After purification by flash chromatography (silica, gradient of 0.5 to 3% methanol in dichloromethane) 509 mg of an off-white solid were obtained (1.897 mmol, 60%). MS (ESI) m/z=291.1 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([O:26]C)=[O:25])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[OH-].[Li+]>O1CCCC1.O>[NH2:1][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(-c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)cnc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2ccc(-c3cnc(N)c(C(=O)O)n3)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Methyl 3-amino-6-[4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl]pyrazine-2-carboxylate was dissolved in anhydrous tetrahydrofuran (10 mL). Lithium hydroxide (0.113 g, 4.72 mmol) in water (19 mL) was added at room temperature and the resulting mixture was stirred at 50° C. for 3 h. The tetrahydrofuran was evaporated and the pH of the water phase was adjusted to 6 with HCl (aq). The precipitated product was filtered and washed with water and dried to give 0.763 g (86% yield) of the title compound as a pale yellow solid: 1HNMR (TFA) δ 8.83 (s, 2H), 8.23 (m, 2H), 7.97 (m, 2H), 4.09 (m, 2H), 3.76 (m, 2H), 2.25 (m, 2H), 3.04 (m, 5H); 13CNMR (TFA) δ 165.81, 147.39, 139.5, 139.2, 135.7, 132.1, 131.1, 128.5, 127.3, 53.9, 43.5, 43.2; MS (ESP) m/z 378 (M++1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]CC(O)=O)=[CH:5][C:4]=1C.[C:16](Cl)(=[O:20])[C:17](Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[CH3:10][C:9]1[CH:17]=[C:16]2[C:4]([C:3](=[O:2])[CH2:8][CH2:7][O:20]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(CCCC(=O)O)cc1C
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)OCCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A stirred solution of 5.0 grams (0.028 mole) of 3-(3-methylphenoxy)propanoic acid (i) and 5.3 grams (0.042 mole) of oxalyl chloride in 100 mL of methylene chloride was cooled to −5° C. and a few drops of DMF was added. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about two hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue: which was 3-(3-methylphenoxy)propanoic acid chloride. The acid chloride was stored under a nitrogen atmosphere for about 18 hours, and then it was dissolved in 50 mL of methylene chloride. The stirred solution was cooled to −4° C. and 4.1 grams (0.031 mole) of aluminum chloride was added portionwise while maintaining the reaction mixture temperature at 5° C. or less. Upon completion of addition, the reaction mixture was maintained at 5° C. for about three hours. After this time, the reaction mixture was poured into ice and extracted with three 100 mL portions of methylene chloride. The combined extracts were washed with two 50 mL portions of water and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of ethyl acetate and hexane as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 3.5 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]Br>CO>[Br:32][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CO
Product: NS(=O)(=O)c1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
90.3 g of the product of Example 4 are dissolved in 900 ml of methanol, 0.9 g of benzoyl peroxide are then added and 24 ml of bromine are added dropwise. The mixture is stirred under ultra-violet irradiation for 24 h, at ambient temperature, then concentrated. The residue is taken up in water, filtered off, washed with isopropanol and pentane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)=O.C([SiH](CC)CC)C.B(F)(F)F>ClCCl.C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][CH:16]=1
Reactant: CCc1ccc(C(=O)c2cc(I)ccc2Br)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Product: CCc1ccc(Cc2cc(I)ccc2Br)cc1
Temperature: 47.5 °C
Reaction time: 4 h

Procedure:
A solution of (2-bromo-5-iodo-phenyl)-(4-ethyl-phenyl)-methanone (32 g) and triethylsilane (50 mL) in dichloromethane (30 mL) and acetonitrile (100 mL) is cooled in an ice-bath. Then, boron trifluoride diethyletherate (20 mL) is added dropwise over 5 min. The cooling bath is removed and the solution is heated to 45-50° C. and stirred at this temperature for 4 h. After cooling to ambient temperature, 4 M aqueous KOH solution is added and the resulting mixture is extracted with ethyl acetate. The combined organic phases are washed with 2 M potassium hydroxide solution and brine and then dried (sodium sulphate). After the solvent is evaporated, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:0->9:1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([CH:17]=[O:18])=[CH:15][CH:16]=2)=[CH:8][CH:7]=1>CO.ClCCl>[CH3:3][O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([CH2:17][OH:18])=[CH:15][CH:16]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(C=O)s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(CO)s2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
Sodium borohydride (155 mg, 4.1 mmol) is added to a solution of 4-(5-formylthiophen-2-yl)benzoic acid methyl ester (1.01 g, 4.1 mmol) in methanol/dichloromethane (16 ml/4 ml) and the resulting solution is stirred for 90 minutes at room temperature. The reaction is quenched by the addition of saturated aqueous ammonium chloride solution (100 ml) and extracted with dichloromethane (100 ml). The organic layer is washed with brine, dried over magnesium sulphate, filtered and concentrated in vacuo to give 4-(5-hydroxymethyl-thiophen-2-yl)benzoic acid methyl ester (800 mg)
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[K+].[CH3:14][C:15]([CH:17]=O)=O.O>C(O)C>[CH3:17][C:15]1[CH:14]=[N:11][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:10]=1
Reactant: CC(=O)C=O
Reactant: Nc1cccc([N+](=O)[O-])c1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cnc2c([N+](=O)[O-])cccc2n1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 3-nitro-1,2-phenylenediamine (2.67 g) and a 2N KOH (8.7 mL) in ethanol (250 mL) was added a 40% aqueous solution of pyruvic aldehyde (17.72 g) at 60° C. The mixture was heated under reflux for 10 minutes, and thereto was added water (150 mL). The mixture was cooled to room temperature, and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with cold water, and dried under reduced pressure to give 2-methyl-5-nitroquinoxaline (2.21 g, 67%) as pale brown solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]I.C(=O)([O-])[O-].[K+].[K+].[CH2:13]1[C:16]2([CH2:20][C:19]([C:21]3[CH:26]=[N:25][C:24]4[NH:27][N:28]=[CH:29][C:23]=4[C:22]=3[NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:18][O:17]2)[CH2:15][CH2:14]1>CN(C)C=O.O>[CH2:15]1[C:16]2([CH2:20][C:19]([C:21]3[CH:26]=[N:25][C:24]4[N:27]([CH2:3][C:2]([F:6])([F:5])[F:1])[N:28]=[CH:29][C:23]=4[C:22]=3[NH:30][CH:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[N:18][O:17]2)[CH2:13][CH2:14]1
Reactant: c1nc2[nH]ncc2c(NC2CCOCC2)c1C1=NOC2(CCC2)C1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1ncc2c(NC3CCOCC3)c(C3=NOC4(CCC4)C3)cnc21
Temperature: 80 °C

Procedure:
1,1,1-Trifluoro-2-iodoethane (0.07 gm, 0.33 mmol) and potassium carbonate (0.125 gm, 0.9 mmol) were added to the solution of 5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.1 gm, 0.3 mmol) (example 29) in dimethylformamide and the reaction mixture was heated at 80° C. for about 3 hours. It was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>ClCCCl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:19]([C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)=[O:20])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a cold (0° C.) mixture of anisole (17.7 mL, 0.162 mol, 1.0 eq.) and aluminium trichloride (26.9 g, 0.202 mol, 1.25 eq.) in 1,2-dichloroethane (140 mL) was slowly added 3-nitrobenzoylchloride (30 g, 0.162 mol). The cooling bath was removed, and the reaction mixture was stirred 2 h at 20° C. The reaction mixture was poured into ice water. Concentrated hydrochloric acid (5 mL) was added. The aqueous layer was extracted with dichloromethane (2 times). The combined organic layers were dried over sodium sulfate, filtered and the volatiles were removed in vacuo. Purification by flash chromatography afforded the title compound (35.1 g, 84%) as an orange solid, m.p.: 88-89° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:17]([O:16][C:14](=[O:15])[C:13]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)([CH3:20])[CH3:19])[CH3:18]
Reactant: Oc1ccc2ccncc2c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc2ccncc2c1
Temperature: 95 °C
Yield: 53.3 %

Procedure:
7-Hydroxyisoquinoline (500 mg, 3.4 mmol), ethyl 2-bromoisobutyrate (3 g, 15 mmol) and potassium carbonate (2.1 g, 15 mmol) were mixed in 7 ml of anhydrous DMF. The reaction was heated to 95° C. under N2 for 18 hrs. The reaction was concentrated under reduced pressure and purified by flash column chromatography (33% EtOAc/Hexanes) to yield 470 mg (53%) of the title product of this preparation as a yellow oil.
Reaction SMILES: [CH2:1]([CH:3]([N:17]1[C:21](=[O:22])[C:20]2=[C:23]([N+:27]([O-])=O)[CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])[CH3:2].[N-:31]=[N+:32]=[N-].[Na+]>CS(C)=O>[CH2:1]([CH:3]([N:17]1[C:21](=[O:22])[C:20]2=[C:23]([N:27]=[N+:31]=[N-:32])[CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])[CH3:2]
Reactant: CCC(CCCCCCCCC(C)(C)CO)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CCCCCCCCC(C)(C)CO)N1C(=O)c2cccc(N=[N+]=[N-])c2C1=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
A mixture of 20.9 g (0.05 mol) of N-(1-ethyl-10,10-dimethyl-11-hydroxyundecyl)-3-nitrophthalimide and 3.55 g (0.055 mol) of sodium azide in 100 ml of dimethylsulphoxide is stirred for 24 hours at 80° C. The solution is evaporated in vacuo and the residue is diluted with 300 ml of water. The resulting emulsion is extracted with twice 100 ml of diethyl ether. The ether extracts are first dried with anhydrous sodium sulphate, and then evaporated. 14.7 g (71% of theory) of N-(1-ethyl-10,10-dimethyl-11-hydroxyundecyl)-3-azidophthalimide are obtained in the form of a viscous oil which cannot be distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([O:16]C)=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([OH:16])=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:19])[F:20]
Reactant: COc1cnc(-c2ccc(Cl)c(C(F)(F)F)c2)n(C)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(-c2ccc(Cl)c(C(F)(F)F)c2)ncc(O)c1=O
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 625 mg (1.96 mmol) 2-[4-chloro-3-(trifluoromethyl)phenyl]-5-methoxy-3-methylpyrimidin-4(3H)-one in 25 ml CH2Cl2 was added 5.88 ml (5.88 mmol) of a 1 M solution of BBr3 in CH2Cl2. The reaction mixture was stirred for 1 h, then quenched with 25 ml MeOH, and concentrated in vacuo. Purification by HPLC gave 418 mg (70% yield) of 2-[4-chloro-3-(trifluoromethyl)phenyl]-5-hydroxy-3-methylpyrimidin-4(3H)-one. 1H NMR δ (ppm)(CDC3): 7.86 (1 H, d, J=1.95 Hz), 7.73 (1 H, s), 7.67-7.61 (2 H, m), 3.54 (3 H, s). HRMS (ESI positive) calc (M+H)+=305.0299. Found 305.0300.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]2[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][C:25]([C:23]4[CH:24]=[C:19]([N:16]5[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]5)[N:20]=[C:21]([NH2:35])[N:22]=4)=[CH:26][CH:27]=3)[CH2:32]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)c3ccc(Cl)cc3)CC4)nc(N)n2)CC1
Reaction time: 0.5 h

Procedure:
4-Chlorobenzoic acid chloride (4.4 μL, 0.034 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (16 μL, 0.12 mmol) in tetrahydrofuran (0.3 mL). After 30 min, the mixture was purified by RP-LCMS (pH=10) to afford the desired products. Analytic LCMS (M+H)+: m/z=463.3/465.3
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][C:35]([OH:37])=[O:36]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH2:34][C:35]([OH:37])=[O:36])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)CC1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 60.8 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.29 g, 0.61 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.11 g, 0.61 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a light yellow solid (0.2 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([CH2:18][NH:19][O:20][CH3:21])=[CH:16][C:15]=1[CH3:24]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:19]([CH2:18][C:17]2[CH:22]=[CH:23][C:14]([F:13])=[C:15]([CH3:24])[CH:16]=2)[O:20][CH3:21])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(F)c(C)c1
Product: CON(Cc1ccc(F)c(C)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 95 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-fluoro-3-methyl-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (95% yield): mp 107-108° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 2.26 (3H, broad s, CH3), 3.69 (3H, s, OCH3), 4.75 (2H, s, NCH2), 6.39 (1H, s, CH), 6.95 (1H, m, aromatic), 7.13-7.19 (2H, m, aromatics). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.24; H, 5.47; N 4.29.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)=[C:12]=[S:13]>>[OH:4][CH2:3][C@H:2]([NH:1][C:12]([NH:11][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:27][CH:26]=3)[N:21]=2)=[CH:18][CH:19]=1)=[S:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OC[C@H](NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccccc1

Procedure:
The title compound was prepared with (R)-2-amino-2-phenylethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole (Lambert, W.; et al., WO 2011017513) and isolated as an off-white solid (0.285 g, 69%): mp 98-101° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.37 (s, 1H), 8.40 (d, J=7.9 Hz, 1H), 8.07-8.01 (m, 4H), 7.73 (d, J=7.7 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.38-7.24 (m, 5H), 5.42 (s, 1H), 5.12 (s, 1H), 3.73 (s, 2H); ESIMS m/z 500 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Br>CC(O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][CH:23]=[C:13]([NH:12][C:5]2[C:6]3[N:7]([N:8]=[CH:9][N:10]=3)[C:2]([Br:1])=[CH:3][N:4]=2)[CH:14]=1)[CH3:20]
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: CCOC(=O)c1cccc(N)c1
Agent: Br
Solvent: CC(C)O
Product: CCOC(=O)c1cccc(Nc2ncc(Br)n3ncnc23)c1
Temperature: 85 °C
Yield: 98 %

Procedure:
5,8-Dibromo-[1,2,4]triazolo[1,5-a]pyrazine (1.39 g, 5.00 mmol) and ethyl 3-aminobenzoate (0.93 g, 5.60 mmol) are stirred in iPrOH (10 mL) and HBr (48% aq., 1.14 mL, 10 mmol) is added. The mixture is heated at 85° C. for 4 h and then cooled to rt and quenched with NaHCO3 (sat. aq., 25 mL). The resulting suspension is cooled to 0° C. and the white solid is collected by suction filtration and washed with water (10 mL). The crude product is taken up in EtOH and the solvent evaporated to afford the title compound as an off-white solid (1.79 g, 4.9 mmol) which is used without further purification.