Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:9]2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCC(c2c[nH]c3ccccc23)CC1
Product: CN1CCC(c2cn(C(=O)c3ccc(F)cc3)c3ccccc23)CC1

Procedure:
(27.2 mg, 81%); from 3-(1-methyl-4-piperidinyl)-1H-indole (Example 5d, 21.5 mg, 0.10 mmol) and 4-fluorobenzoyl chloride (23.8 mg, 0.15 mmol), HRMS-FAB+ for C21H21N2OF, calculated MH+ : 337.17163; found: 337.17162.
Reaction SMILES: [NH2:1][CH:2]([PH:4](=[O:6])[OH:5])[CH3:3].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>>[C:12]1([CH2:11][O:10][C:8]([NH:1][CH:2]([PH:4](=[O:5])[OH:6])[CH3:3])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(N)[PH](=O)O
Reactant: O=C(Cl)OCc1ccccc1
Product: CC(NC(=O)OCc1ccccc1)[PH](=O)O

Procedure:
The process is performed according to the operating conditions described in 1.4., starting with 1.7 g (15.6 mmol) of (1-aminoethyl)phosphinic acid and 3.12 g (18.29 mmol) of benzyl chloroformate. 2.8 g of product are recovered (yeld=73.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19]CC(C4C=CC(OC)=CC=4)=O)=[CH:15][C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)COc2ccc3oc(C(=O)c4ccc(OC)cc4)c(C)c3c2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(Cc2oc3ccc(O)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
A mixture of 2-(p-methoxybenzoyl)-3-methyl-5-(p-methoxyphenacyloxy)-benzofuran (5.35 gm, 12.4 mmoles) and zinc dust (5.3 gm) in acetic acid (200 mL) was stirred at room temperature overnight. The solids were filtered off and washed with some ethylacetate. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel using 20% ethylacetate in hexane as eluent to yield 0.85 gm (26%) of 2-(p-methoxybenzyl)3-methyl5-hydroxybenzofuran, mp. 128°-131° C.
Reaction SMILES: [CH3:1][C:2]1[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[O:8][C:9]([CH3:12])=[N:10][N:11]=1)=[O:5].[C:25]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[CH3:25][N:6]([C:7]1[O:8][C:9]([CH3:12])=[N:10][N:11]=1)[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])[C:2]=1[CH3:1]
Reactant: Cc1nnc(NC(=O)c2ccc(C(F)(F)F)c(S(C)(=O)=O)c2C)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: Cc1nnc(N(C)C(=O)c2ccc(C(F)(F)F)c(S(C)(=O)=O)c2C)o1

Procedure:
180 mg (0.495 mmol) of 2-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide are dissolved in 6 ml of DMF (abs.), and 68 mg (0.495 mmol) of K2CO3 and 0.047 ml (0.495 mmol) of dimethyl sulfate are added. The reaction mixture is boiled under reflux for 15 hours. Then the mixture is filtered, and the filtrate is concentrated and purified by column chromatography (silica gel; heptane/ethyl acetate).
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH:7]=[CH:8][C:9]([Cl:15])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C=CC1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C=CC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-cyclohexyl-acrylic acid (5.0 g, 32.5 mmol) and oxalyl chloride (3.4 ml, 34.0 mmol) in anhydrous DCM (50 ml) was treated with one drop of dimethylformamide. The resulting solution was stirred at room temperature for 18 h, concentrated and used directly in the next step.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:13])OC(=O)[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[NH2:11][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=1[C:8]([NH:17][CH:14]([CH3:16])[CH3:15])=[O:13]
Reactant: CC(C)N
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Product: CC(C)NC(=O)c1c(N)cccc1F

Procedure:
2-Amino-6-fluoro-N-(1-methylethyl)benzamide was prepared from 5-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione and isopropyl amine following a procedure substantially as described for the preparation of Intermediate 25. MS: (M+H)+=197.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH:9]=1.Cl>>[CH3:1][O:2][C:3]1[CH2:4][CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC1=CC=CCC=C1
Agent: Cl
Product: COC1=CC=CC=CC1

Procedure:
subsequently isomerizing said 3-methoxycycloheptatriene by acid catalyzed rearrangement with methanolic hydrogen chloride followed by neutralization to give a crude 1-methoxycycloheptatriene product and
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=O.C(NC(C)C)(C)C.C([Li])CCC.ClP(=O)(OCC)[O:31][CH2:32][CH3:33]>CCCCCC.C(N=CC)(C)(C)C.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)=[CH:33][CH:32]=[O:31])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(c1cccc(F)c1)c1cccc(F)c1
Reactant: CCOP(=O)(Cl)OCC
Agent: CC=NC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=CC=C(c1cccc(F)c1)c1cccc(F)c1

Procedure:
The compound was prepared according to the procedure described in Example 84. The following reagents were used: 3,3'-difluorobenzophenone (19.8 g), diisopropylamine (32.2 mL), 1.55M n-butyl lithium in hexane (148 mL), acetaldehyde N-tertbutylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofurane (200 mL). The usual work up gave 23 g of material which was crystallized from hexane to give 17.4 g of 3,3-bis(3-fluorophenyl)-2-propenal, mp 51°-53° C. A small portion was recrystallized from the same solvent to provide the analytical sample, mp 52°-54° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[O:33][CH:34]=[CH:35][CH:36]=1)CCC>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Product: c1ccc(COc2ccc(Nc3ncnc4cnc(-c5ccco5)cc34)cc2)cc1

Procedure:
Prepared according to Procedure B from 4-(4-benzyloxyanilino)-6-chloropyrido[3,4-d]pyrimidine and 2-(tri-n-butylstannyl)furan (Aldrich); δH [2H6]-DMSO 9.08 (1H,s), 8.70 (1H,s), 8.55 (1H,s), 7.90 (1H,d), 7.69 (2H, d), 7.40 (5H,m), 7.10 (1H,d), 7.03 (2H,d), 6.69 (1H,m), 5.10 (2H,s); m/z (M+1)+395.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N([O-])=O.[Na+].[I-:16].[K+].S(=O)(O)[O-].[Na+]>Cl.O.S(=O)(=O)(O)O>[F:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([I:16])[CH:10]=1
Reactant: [I-]
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(F)cc1I
Temperature: 100 °C

Procedure:
To a 0° C. mixture of 2-amino-4-fluorobenzoic acid (1.18 g, 7.6 mmol) in 12N hydrochloric acid (2.3 mL) and water (13.7 mL) was added dropwise a solution of sodium nitrite (543 mg, 7.9 mmol) in water (1.2 mL). This resulting diazonium salt solution was stirred 10 min at 0° C. A solution of potassium iodide (1.9 g) in sulfuric acid (450 35 μL) and water (3.2 mL) was added dropwise to the 0° C. solution. The reaction mixture was heated to 100° C. for 2 h then cooled to room temperature. 10% sodium bisulfite solution was added and stirred. The precipitate was filtered, washed with water, air dried and recrystallized from toluene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH3:9][C:10]1([CH3:13])[CH2:12][O:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:9][C:10]([OH:11])([CH3:13])[CH3:12])[C:4](=[O:8])[CH:3]=1
Reactant: CC1(C)CO1
Reactant: O=c1cc(Br)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(Br)cc1=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-1H-pyridin-2-one (0.25 g), 2,2-dimethyl-oxirane (0.26 mL), and potassium carbonate (0.40 g) in dimethylformamide (2.5 mL) was stirred under microwave irradiation at 120° C. for 30 min. After cooling to ambient temperature, the mixture was concentrated and purified by HPLC on reversed phase (acetonitrile/water) to afford the title compound. Yield: 0.34 g (96% of theory); Mass spectrum (ESI+): m/z=246/248 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:6][C:7]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=1[CH:9]=[CH2:1]
Reactant: [Li]CCCC
Reactant: O=Cc1cc(F)ccc1Br
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(F)ccc1Br
Temperature: 0 °C

Procedure:
21.12 g Methyltriphenylphosphonium bromide were suspended in 150 ml tetrahydrofuran and cooled in an ice bath. 21.68 ml n-butyl lithium (2.5 M in n-heptane) were added dropwise and the reaction mixture stirred at 0° C. for thirty minutes. Then 10.0 g commercially available 2-bromo-5-fluorobenzaldehyde were added slowly so that the reaction temperature did not exceed +5° C. After completion of the addition the cooling bath was removed and the reaction mixture stirred at room temperature for one hour. The reaction mixture was diluted by addition of 300 ml ethyl acetate and washed three times with portions of 120 ml brine. The organic phase was dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with the eluent heptane=>n-heptane:ethyl acetate=9:1 to obtain 7.9 g 1-Bromo-4-fluoro-2-vinyl-benzene as an oil.
Reaction SMILES: [CH2:1]([CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]1=[O:12])[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[C:14](=O)([O-])O.[Na+]>CO>[CH2:1]([C:6]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]=1[O:12][CH3:14])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C([O-])O
Reactant: CCCCCC1C(=O)CCC1=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCC1=C(OC)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 32.5 g (0.19 mol) of 2-n-pentyl-1,3-cyclopentanedione was added 650 ml of methanol containing 1 wt % of hydrogen chloride (prepared by preliminarily blowing hydrogen chloride therein), followed by heating under reflux for 5 hours and cooling to 25° C. Then, thereto was gradually added 15.4 g of sodium hydrogencarbonate followed by stirring for 30 minutes at 25° C. Methanol was distilled off in vacuo and then 200 mL of water and 200 mL of isobutanol were added. The resulting mixture was stirred for 10 minutes at 25° C. and then allowed to stand to separate the organic phase. Isobutanol in the organic phase was distilled off, yielding 2-pentyl-3-methoxy-2-cyclopentenone (a compound in which R20 represents an n-pentyl group, and R21 represents a methyl group in the above formula (14)). Gas chromatographic analysis showed that the yield of 2-pentyl-3-methoxy-2-cyclopentenone relative to 2-n-pentyl-1,3-cyclopentanedione was 80%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([CH3:28])[C:20]=1[CH2:21]Br.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][CH2:21][C:20]2[C:19]([CH3:18])=[CH:26][C:25]([F:27])=[CH:24][C:23]=2[CH3:28])[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=1
Reactant: Cc1cc(F)cc(C)c1CBr
Reactant: CCOC(=O)c1c(C)nc2c(N)cc(Br)cn12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C)nc2c(NCc3c(C)cc(F)cc3C)cc(Br)cn12
Yield: 59.1 %

Procedure:
A mixture of 8-amino-6-bromo-3-carboethoxy-2-methylimidazo[1,2-a]pyridine (2.06 g, 6.91 mmol), 2,6-dimethyl-4-fluorobenzylbromide (1.05 g, 4.48 mmol), sodium iodide (0.45 g), sodium carbonate (2.2 g) and acetone (40 ml) was refluxed for 22 h. The reaction mixture was filtered. The filtered material was washed with CH2Cl2. The methylene chloride solution was washed with water, dried and evaporated in vacuo. The residue was suspended in ethanol/ether and filtered to give 1.15 g (56%) of the title compound.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11]([NH:20][CH2:21][CH2:22][OH:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(CO)[CH2:26][OH:27].CCOC(C)=O.O>CN1C(=O)CCC1>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:12]=[C:11]([NH:20][CH:21]([CH2:26][OH:27])[CH2:22][OH:23])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(CO)CO
Reactant: CS(=O)(=O)Nc1cc(NCCO)nc(SCc2ccccc2)n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)Nc1cc(NC(CO)CO)nc(SCc2ccccc2)n1
Temperature: 100 °C

Procedure:
To a solution of the subtitle product of Example 19 step (0.20 g) in NMP (0.5 ml) was added 2-aminopropane-1,3-diol (1.0 g) and the reaction was heated at 100° C. for 2 days. To the reaction was added EtOAc (50 ml) and H2O (50 ml). The organic layer was separated and washed with H2O (2×20 ml) and brine (20 ml). The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a solid. This was purified by column chromatography (1:1 EtOAc/iso-hexane then EtOAc) to give the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:10]=[C:11]([CH3:12])[C:3]=12.[H-].[Na+].FC(F)(F)S(O[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[N:9]([Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:10]=[C:11]([CH3:12])[C:3]=12
Reactant: Cc1c[nH]c2c(Cl)ncc(Br)c12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cn([Si](C)(C)C(C)(C)C)c2c(Cl)ncc(Br)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-7-chloro-3-methyl-1H-pyrrolo[2,3-c]pyridine (1.07 g) in dry tetrahydrofuran (50 ml) at 0° C. under an atmosphere of nitrogen was added portionwise sodium hydride (60% dispersed in mineral oil, 384 mg). After addition, the solution was stirred at room temperature for 30 minutes. The solution was then recooled to 0° C. and a solution of tert-butyldimethylsilyl trifluoromethanesulphonate (2 ml) in dry tetrahydrofuran (10 ml) was added dropwise. The solution was stored at 5° C. overnight. The solution was partitioned between ethyl acetate and water and washed with water twice. The organic layer was dried (MgSO4) and evaporated to give a brown oil (2 g). The residue was used in the next step (d) without further purification.
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=C[C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]([OH:18])(=[O:17])[CH3:16].O.S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6]>[N+:8]([C:6]1[CH:7]=[CH:2][C:3]([C:11]([F:12])([F:13])[F:14])=[C:16]([CH:5]=1)[C:15]([OH:18])=[O:17])([O-:10])=[O:9]
Reactant: CC(=O)O
Reactant: Cc1cc([N+](=O)[O-])ccc1C(F)(F)F
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1C(F)(F)F

Procedure:
5-Nitro-2-trifluoromethyl-benzoic acid is prepared from the known 2-methyl-4-nitro-1-trifluoromethyl-benzene by oxidation with chromium trioxide in an acetic acid/water/sulfuric acid mixture following a procedure described by Aeberli et al. [P. Aeberli, P. Eden, J. H. Gogerty, W. J. Houlihan, C. Penberthy, J. Med. Chem. 18, 177 (1975)]: colourless solid, MS (ISN): 233.9 M−H−.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:29]=[N:30][N:31]([CH2:33][C@H:34]5[O:39][CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]5)[CH:32]=4)[N:22]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>O1CCOCC1>[NH:36]1[CH2:37][CH2:38][O:39][CH:34]([CH2:33][N:31]2[CH:32]=[C:28]([NH:27][C:23]3[N:24]=[CH:25][N:26]=[C:21]([N:18]4[CH2:17][CH2:16][N:15]([C:12]5[N:11]=[CH:10][C:9]([C@H:1]([C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)[OH:8])=[CH:14][N:13]=5)[CH2:20][CH2:19]4)[N:22]=3)[CH:29]=[N:30]2)[CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C(=O)c6ccccc6)cn5)CC4)n3)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O[C@@H](c1ccccc1)c1cnc(N2CCN(c3ncnc(Nc4cnn(CC5CNCCO5)c4)n3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of (S)-tert-butyl 2-((4-(4-(4-(5-benzoylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (80 mg, 0.127 mmol, crude) in dioxane (4 mL) was added 4 M HCl-dioxane (4 mL), and the reaction was stirred at room temperature overnight. LCMS showed the reaction was completed. The solvent was removed, and the residue was purified by Prep-HPLC to provide the title compound (S)-(2-(4-(4-(1-(morpholin-2-ylmethyl)-1H-pyrazol-4-ylamino)-1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanol (Compound 189) (24.0 mg, 18%) as a yellowish solid.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]1[CH2:18][CH2:17][N:16]([C:19]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)(=O)=O)([O-])=O.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.Br[C:40]1[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=1>CN(C)C=O.C(OCC)(=O)C>[F:47][C:46]([F:49])([F:48])[C:43]1[CH:44]=[CH:45][C:40]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3([C:22]([O:24][CH3:25])=[O:23])[CH2:20][CH2:21]3)[CH2:17][CH2:18]2)=[N:41][CH:42]=1
Reactant: COC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CC2)CC1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 1-[4-(2-nitrobenzenesulfonyl)-piperazin-1-yl]-cyclopropanecarboxylate (0.60 g, 1.63 mmol) from Example 16C in anhydrous dimethylformamide (5 mL) was treated with potassium carbonate (0.67 g, 4.88 mmol) and thiophenol (0.21 g, 1.95 mmol) and stirred one hour at room temperature. This reaction mixture was then treated with 2-bromo-5-trifluoromethylpyridine (0.44 g, 1.95 mmol) and heated overnight at 80° C. Reaction diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with 9:1 hexane:ethyl acetate to afford the title compound. MS (ESI) m/z 330 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]CC([O-])=O)=[CH:3][CH:2]=1.[BrH:12]>>[BrH:12].[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][Br:12])=[CH:3][CH:2]=1
Reactant: O=C([O-])CCc1ccncc1
Agent: Br
Product: BrCc1ccncc1
Temperature: 124 °C

Procedure:
4-Picolylacetate (300 g., 87% pure) was combined with 3.0 l. of 48% hydrobromic acid. A spontaneous exotherm occurred, the temperature rising from 26° to 42° C. The mixture was heated to reflux and refluxed for about 1 hour (pot temperature 124° C.). The reaction mixture was then concentrated in vacuo to yield a gummy solid which was dissolved in 1500 ml. of absolute alcohol. Crude hydrobromide salt (379 g.) crystallized on chilling and was recovered by filtration. Purified 4-picolylbromide hydrobromide (33.1 g., m.p. 187.5°-189° C.) was obtained by recrystallization of 50 g. of crude from absolute alcohol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:21])[N:7]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C(O[K])(C)(C)C>CS(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:21][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[N:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1cccc2nc(-c3cccs3)c(-c3cccs3)nc12
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Nc2cccc3nc(-c4cccs4)c(-c4cccs4)nc23)cc1
Reaction time: 14 h

Procedure:
While agitating 3.1 g (9.9 mmol) of 2,3-di(2-thienyl)-5-aminoquinoxaline, 1.4 g (9.9 mmol) of 4-fluoronitrobenzene and 15 g of dimethylsulfoxide, 3.3 g (29.6 mmol) of t-butoxy potassium was gently added. After completion of the addition, the reaction container was purged with nitrogen, followed by agitation at room temperature for 14 hours. After completion of the reaction, 100 ml of water was added while cooling, and the resulting compound was filtered and dried, followed by purification with a silica gel column.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:30][C:31]1[C:32]([F:39])=[CH:33][C:34]([I:38])=[C:35]([OH:37])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:30][C:31]1[C:32]([F:39])=[CH:33][C:34]([I:38])=[C:35]([CH:36]=1)[O:37][C:8]1[CH:7]=[CH:6][C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Oc1cc(Cl)c(F)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3cc(Cl)c(F)cc3I)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyI)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68, 335 mg, 0.77 mmol) in dimethylsulfoxide (10 ml), was added 5-chloro-4-fluoro-2-iodophenol (Preparation 734, 200 mg, 0.73 mmol) and potassium carbonate (229 mg, 1.47 mmol). The flask was purged with nitrogen (3×). The resulting suspension was allowed to stir at room temperature for 18 hours. The reaction was poured into a 1M aqueous solution of sodium hydroxide, and extracted with dichloromethane (3×). The combined organic phase was then dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to leave the desired product as an off white solid (504 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[C:7]([O:12][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 177.3 %

Procedure:
A mixture of (3,5-dihydroxy-phenyl)-acetic acid methyl ester (from Aldrich, 70 g, 0.385 mole), benzylbromide (137 mL, 1.16 mole), potassium carbonate (160 g, 1.16 mole) and DMF (1.5 L) under N2 was mechanically stirred at room temperature overnight. The resulting reaction mixture was poured into a mixture of 1.5 L of ice-water with stirring. The precipitate was obtained by filtration and washed with heptane successively to remove benzyl bromide to give the title compounds (123.7 g) as a brown solid which was air dried for the next reaction.