Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:25][C:26]1[N:31]=[C:30]([NH:32]C(=O)C(F)(F)F)[CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(N)=O>CO.C(NCC)C.CN(C)C=O>[NH2:32][C:30]1[N:31]=[C:26]([CH2:25][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[C:11]([C:9]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=3)=[O:10])=[CH:12]2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Nc1cccc(CBr)n1)C(F)(F)F
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1C
Agent: NC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCNCC
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(N)n3)c3ccccc3c2=O)nc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 127 mg (0.46 mmol) of 3-(5,6-dimethyl-pyridine-2-carbonyl)-1H-quinolin-4-one, 22 mg (0.55 mmol) of 60% sodium hydride, 155 mg (0.55 mmol) of N-(6-bromomethyl-pyridin-2-yl)-2,2,2-trifluoro-acetamide and 1 mL of N,N-dimethylformamide. The 130 mg of trifluoroacetamide product were heated to 60° C. in a mixture of 1 mL of methanol and 4 mL of diethylamine for 3 h, then overnight at 45° C. The product was filtered off and washed with a small amount of DCM. Yield: 36 mg of a white solid: LC-MSD, m/z for C23H20N4O2 [M+H]+=385.2; HPLC retention time: 0.8 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[CH3:17][O+:18](C)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>ClCCl.O>[C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:17][OH:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc[n+]([O-])cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccnc(CO)c1
Yield: 73 %

Procedure:
4-t-Butyl-pyridine N-oxide (11.0 g, 72.9 mmole) is dissolved in 200 ml dichloromethane in a 500 ml one neck round bottom flask under nitrogen. The solution is treated with trimethyloxonium tetrafluoroborate (10.8 g, 72.9 mmole), is stirred 1h at room temperature, and the volatiles are removed in vacuo. The solid residue is dissolved in 200 ml methanol in a 500 ml one neck round bottom flask. The solution is heated to reflux, is treated with ammonium persulfate (3.3 g, 14.5 mmole) in 15 ml water, and the reaction mixture is vigorously refluxed for 30 min. The reaction is treated with a second lot of ammonium persulfate (1.65 g, 7.2 mmole) in 7 ml water and is refluxed for an additional 1 h. The reaction is cooled and the bulk of the methanol is removed in vacuo. The residue is diluted with 300 ml conc ammonium hydroxide and the mixture is extracted with 4×100 ml dichloromethane. The combined organics are dried over potassium carbonate and are concentrated in vacuo to a yellow oil. The crude material is chromatographed over 400 g silica gel (230-400 mesh), eluting with 40% acetone/hexane, while collecting 50 ml fractions. Fractions 26-52 are combined and concentrated to afford 8.79 g (73%) of 4-t-Butyl-2-hydroxymethyl-pyridine as a yellow oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH2:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21].[OH-].[Na+]>ClCCl>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH:16][C:23]([N:22]([CH2:26][CH3:27])[CH2:20][CH3:21])=[O:24])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:18][CH3:19]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCCN(CCC)C1CCc2cccc(CN)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCN(CCC)C1CCc2cccc(CNC(=O)N(CC)CC)c2C1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
1.6 g (6 mmol) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were dissolved in 16 ml of dichloromethane under nitrogen. 0.81 g (6 mmol) of diethylcarbamoyl chloride was then added dropwise at a maximum of +25° C. The batch was then stirred for 26 h at room temperature. The batch was then stirred into 160 ml of ice water. The mixture was adjusted to pH 9 using 1 N sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulphate. The solvent was subsequently removed by distillation. The residue was purified by column chromatography. Diisopropyl ether/isopropanol/triethylamine, 80:19.5:0.5, was used as eluent. The final product could be crystallized from petroleum ether 30-50 and was dried at +40° C. in vacuo.
Reaction SMILES: Cl[C:2]1[C:3]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][S:10][C:4]=2[N:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(N(CC)CC)C.CC(O)C>O>[Cl:9][CH2:8][C:6]1[N:7]=[C:2]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:3]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][S:10][C:4]=2[N:5]=1
Reactant: ClCc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reactant: NCc1ccccn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O
Product: ClCc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 27.4 %

Procedure:
A reaction mixture of 4-chloro-2-chloromethyl-5-phenylthieno[2,3-d]pyrimidine (0.50 g, 1.69 mmol), 2-aminomethylpyridine (0.17 ml, 1.69 mmol), triethylamine (0.26 ml, 1.86 mmol) and propan-2-ol (15 ml) was stirred at ambient temperature for 4 days. The solution was then poured into water (150 ml) and extracted with ethyl acetate (3×75 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (1:4) gave (2-chloromethyl-5-phenylthieno[2,3-d]pyrimidin-4-yl)pyridin-2-ylmethylamine as a yellow solid (0.17 g), m.p. 97°-99° C.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][CH:23]=[N:22][CH:21]=3)[CH:15]=2)[CH3:13])[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.[OH-].[Na+]>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][CH:23]=[N:22][CH:21]=3)[CH:15]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cnc[nH]2)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(-c2cnc[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of 3-hexyl-6-[3-(1H-imidazol-5-yl)phenyl]-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 75, 21 mg, 62.3 μmol) in tetrahydrofuran (1.5 ml) at room temperature was added lithium aluminium hydride (1.0 M in tetrahydrofuran, 0.12 ml, 0.12 mmol) over 2 min. The reaction mixture was stirred at room temperature for 30 min and then heated under reflux for 2 h before cooling to room temperature. Aqueous sodium hydroxide solution (1 M, a few drops) and excess ethyl acetate were added followed by solid sodium hydrogen carbonate. The reaction mixture was stirred rapidly for 1 h before filtering. The mother liquor was concentrated in vacuo and the crude residue was chromatographed on silica gel eluting with ethyl acetate and then ethyl acetate:methanol (80:20) to give the product as a colourless semi-solid (15 mg, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH2:58][CH2:59][CH3:60])=[N:56][C:52]=2[CH:51]=1.BrCl>O1CCCC1.ClCCl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:61][C@H:57]([C:55]1[NH:54][C:53]2[CH:62]=[CH:63][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][CH2:59][CH3:60])=[O:7]
Reactant: CCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClBr
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCO
Product: CCC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)butylamine in tetrahydrofuran. Yield: quantitative; Rf value: 0.57 (silica gel: dichloromethane/ethanol=9:1); C23H22BrClN4O2 (501.814); mass spectrum: (M+H)+=501/503/505 (bromo-chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Br:14])=[O:23]
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Reactant: O=C=Nc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Br)c1
Reaction time: 4 h
Yield: 72.6 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-bromophenyl isocyanate (0.30 ml, 2.40 mmol) in THF (2 ml) was added Et3N (33 ml, 0.24 mmol) at room temperature. After 4 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-bromophenyl)ureido]phenylacetate (770 mg, 73%) as a pale brown powder. 1H-NMR (CDCl3) δ3.55 (s, 2H), 3.70 (s, 3H), 6.97 (dd, J=7.3, 1.5 Hz, 1H), 7.22 (dd, J=8.5, 2.2 Hz, 1H), 7.29-7.33 (m, 2H), 7.48 (d, J=1.0, 2.2 Hz, 1H), 7.54 (dd, J=8.0, 1.2 Hz, 1H), 8.01 (m, 2H); MS (ESI) m/z 443 (M++1), 445 (M++3), 447 (M++5).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14](N)=[CH:13][CH:12]=3)=[O:5])[CH3:2].N([O-])=O.[Na+].[I-:24].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>Cl.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([I:24])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)cc12
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(I)cc12
Temperature: 100 °C
Yield: 30 %

Procedure:
1.3 mmoles of 6-amino-β-carbolin-3-carboxylic acid ethyl ester are diazotized at 0° C. in 4 ml of semi-concentrated hydrochloric acid with 1.3 mmoles of sodium nitrite in 2 ml of water. 1.35 mmoles of potassium iodide in 2 ml of water are added to this mixture. The mixture is then slowly heated to 100° C. until the nitrogen evolution has ceased. The mixture is then diluted with 100 ml of water, approximately 20 mg of sodium thiosulphate are added and the mixture is filtered with suction. The residue is extracted by boiling with methylene chloride/acetone, filtered, and the filtrate is concentrated by evaporation. The residue is chromatographed on silica gel with chloroform/ethanol (9:1). 6-Iodo-β-carbolin-3-carboxylic acid ethyl ester of melting point 286°-287° C. (decomposition) is thereupon obtained in 30% yield.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([C@@H:7]([NH:17]C(=O)OCC2C=CC=CC=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][CH3:16])=[O:14])=[N:4][CH:3]=1.Br>C(Cl)Cl.CC(O)=O.CO>[NH2:17][C@H:7]([C:5]1[NH:6][C:2]([I:1])=[CH:3][N:4]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(I)[nH]1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)CCCCC[C@H](N)c1ncc(I)[nH]1
Reaction time: 1 h

Procedure:
A solution of D6 in DCM (0.2 M) was treated with an excess of HBr solution in AcOH at 0° C. and the reaction mixture was stirred at this temperature for 1 h. Then solvents were removed under reduced pressure and excess reagents were removed by repeated addition of toluene and evaporation of the solvent. The residue obtained was dissolved in MeOH, passed through a SCX resin cartridge and the cartridge washed with MeOH. Then, the cartridge was treated with a 7N solution of NH3 in MeOH and the organic solution was concentrated under reduced pressure to give the title compound as a white powder. MS (ES+) C11H19IN4O: 351 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:10](=[O:11])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][NH2:20]>C(#N)C>[CH3:19][NH:20][C:10]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([NH:9][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:18])=[O:11]
Reactant: CN
Reactant: O=C1N(c2ccccc2)C(=O)N1c1ccccc1
Solvent: CC#N
Product: CNC(=O)N(C(=O)Nc1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
In 30 ml of acetonitrile, 6.0 g (0.025 mol) of 1,3-diphenyl-1,3-diazetidine-2,4-dione was added. Then 3.9 ml (0.05 mol) of aqueous solution (40%) of methylamine was added dropwise thereinto with stirring. The reaction was continued at 50° C. for 0.5 hours, then the solvent was removed by distillation under a reduced pressure. The residue thus obtained was recrystallized from ethanol to obtain 5.1 g (yield 76%) of 1-methyl-3,5-diphenylbiuret having a melting point of 145°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=2)[NH:13][CH:12]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=2)[NH:13][CH:12]=1
Reactant: OC(c1ccc(Cl)cc1Cl)c1c[nH]c2ncc(Oc3ccccc3)cc12
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Cc2c[nH]c3ncc(Oc4ccccc4)cc23)c(Cl)c1

Procedure:
To (2,4-dichloro-phenyl)-(5-phenoxy-1H-pyrrolo[9,3-b]pyridin-3-yl)-methanol (33, 30 mg, 0.078 mmol) in acetonitrile (8 mL), triethylsilane (1 mL, 7 mmol) and trifluoroacetic acid (0.5 mL, 7 mmol) were added. The reaction solution was heated to reflux for 4 hours. Then, the reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water, and brine, dried over anhydrous magnesium sulfate, filtrated and concentrated. The crude material was suspended in acetonitrile (1˜2 mL). The precipitated material was collected with vacuum filtration to provide the compound (P-0037, 13 mg, 45%). MS (ESI) [M+H+]+=369.1 and 371.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14](=[O:35])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[O:26])=[CH:19][CH:18]=2)[CH:11]=[CH:12][CH:13]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][NH:27][C:25](/[CH:24]=[CH:23]/[C:20]1[CH:21]=[CH:22][C:17](/[CH:16]=[CH:15]/[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[O:35])=[CH:18][CH:19]=1)=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(/C=C/c1ccc(/C=C/C(=O)c2cccc(CO)c2)cc1)NOC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCc1cccc(C(=O)/C=C/c2ccc(/C=C/C(=O)NOC3CCCCO3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
Methanesulfonyl chloride (0.41 ml, 5.3 mmol) was added to a stirred solution of (E)-3-{4-[(E)-3-(3-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (1.08 g, 2.68 mmol) and TEA (1.47 ml, 10.6 mmol) in DCM (18 ml) and DMF (12 ml). The mixture was stirred at room temperature for 30 min and then brought to basic conditions with 5% NaHCO3. The resulting slurry was extracted with Et2O and the organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: petroleum ether/AcOEt 1:1) to give 600 mg of a mixture of the title compound and (E)-3-{4-[(E)-3-(3-chloromethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as the main product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30](O)=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[Cl:29])[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:40][CH2:41][CH2:42][NH:43][CH:44]([CH3:46])[CH3:45])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CCCCCC.O.C(OCC)(=O)C>[Si:33]([O:40][CH2:41][CH2:42][N:43]([CH:44]([CH3:46])[CH3:45])[C:30]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[Cl:29])[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:31])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: O=C(O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
To a stirred white suspension of 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (205) (500 mg, 1.05 mmol) in pyridine (5.5 mL) was added [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) (344 mg, 1.58 mmol), cooled to −10° C., POCl3 (0.3 mL, 3.17 mmol) was added at the same temperature. The mixture was stirred at 0° C. for 2 h. Silica thin layer chromatography was performed (50% ethyl acetate in hexane, Rf=0.8). After completion of the reaction, ice cooled-water (30 mL) was added to the reaction mixture at 0° C., a saturated solution of NaHCO3 (pH˜8) was added, the mixture was extracted with ethyl acetate (4×50 mL), the organic part was dried and concentrated, the crude product was purified by a CombiFlash column (eluted at 30%-50% ethyl acetate in hexane) to get 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (206) (250 mg, 35.18%) as a yellow sticky mass.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][C@H:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8]1)=[O:28]
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2C(=O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 1G and 3-chlorobenzoyl chloride by procedures analogous to those described in Example 160. HPLC; 100% at 6.3 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min, UV detection at 220 nm). MS (ES): m/z 452 [M+1]+. Chiral HPLC 100% e.e.; retention time=50.4 min; Conditions: AD (4.6×250 mm); Eluted with 25% isopropanol in hexane for 70 min at 1 mL/min.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:5].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>O1CCCC1>[N:14]1[CH:15]=[CH:16][C:11]([S:10][CH2:9][CH2:8][CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:1][C:21]2=[O:22])=[CH:12][CH:13]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1C(=O)NCCCSc1ccncc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c(=O)n1CCCSc1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
Under nitrogen atmosphere, to a solution of 718 mg (2.5 mmol) of 4-[3-(2-aminobenzoylamino)propylthio]pyridine in 15 ml of tetrahydrofuran, 811 mg (5.0 mmol) of 1,1'-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off and the residue was dissolved in chloroform. The solution was washed with water and dried. The solvent was distilled off and the residue was recrystallized from ethanol/chloroform/ether to give 514 mg of the desired product (65.7% yield, white crystals).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[C:13](=O)([O-:15])[O-:14].[Na+].[Na+]>O1CCOCC1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].[Pd].O.C(=[Mo](=C=O)(=C=O)(=C=O)(=C=O)=C=O)=O>[CH2:11]([C:9]1[CH:10]=[C:2]([C:13]([OH:15])=[O:14])[CH:3]=[C:4]2[C:8]=1[NH:7][N:6]=[CH:5]2)[CH3:12]
Reactant: CCc1cc(Br)cc2cn[nH]c12
Reactant: O=C([O-])[O-]
Agent: O=C=[Mo](=C=O)(=C=O)(=C=O)(=C=O)=C=O
Agent: [Pd]
Agent: [CH2-]c1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCc1cc(C(=O)O)cc2cn[nH]c12
Yield: 73.6 %

Procedure:
To a solution of 5-bromo-7-ethyl-1H-indazole (225 mg, 1.00 mmol) in dioxane (1.5 mL), hexacarbonylmolybdenum (132 mg, 0.50 mmol), Herrmann's catalyst (trans-Bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium) (46.9 mg, 0.05 mmol) and a solution of sodium carbonate (318 mg, 3.00 mmol) in water (2 mL). The suspension was sealed and irradiated in a microwave at 165° C. for 15 minutes (high absorption setting). The vial was vented, filtered through diatomaceous earth, washed with EtOAc and concentrated to provide the title compound (140 mg, 74%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH2:14][CH2:15][F:16])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[Cr](O)(O)(=O)=[O:18]>CC(C)=O.Cl>[F:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH2:14][CH2:15][F:16])=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]([OH:18])=[O:8]
Reactant: O=[Cr](=O)(O)O
Reactant: O=Cc1cccc(OCCF)c1OCCF
Agent: Cl
Solvent: CC(C)=O
Product: O=C(O)c1cccc(OCCF)c1OCCF
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3.0 grams (0.013 mole) of 2,3-di(2-fluoroethoxy)benzaldehyde in 10 ml of acetone was added 4.9 ml of a 2.6 M solution of aqueous chromic acid in acetone (Jones' reagent). The mixture was stirred at room temperature for 30 minutes, and the solvent was removed by evaporation under reduced pressure leaving a residue. This residue was dissolved in 30 ml of 1 N hydrochloric acid, and the acidic solution was extracted with five 30 ml portions of diethyl ether. The combined organic phase was extracted with three 35 ml portions of an aqueous, 10% sodium hydroxide solution. The basic extracts were combined and acidified. The acidic solution was extracted with five 30 ml portions of diethyl ether. The extracts were combined and washed with two 25 ml portion of an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a solid residue. This solid was recrystallized from toluene to yield 1.4 gram of 2,3-di(2-fluoroethoxy)benzoic acid, mp 104°-105° C.