Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:12])([F:13])[F:14])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(Cl)ccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(Cl)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Add borane-THF complex (3.34 mL, 3.34 mmol) slowly to an ice-methanol cooled bath solution of 5-chloro-2-trifluoromethyl-benzoic acid (500 mg, 2.23 mmol) in THF (2 mL). Stir overnight at room temperature. Add water (1 mL) and solid potassium carbonate. Filter and concentrate to give an oil residue. Chromatograph on silica gel, eluting with 10:90 to 1:1 ethyl acetate:hexanes to give (5-chloro-2-trifluoromethylphenyl)-methanol as a white solid (347 mg, 75%). 1H NMR (400 MHz, MeOH-d4) δ 7.84 (s, 1H), 7.68 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=8.4 Hz), 4.81 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17]C)=O)[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]#[N:21]>>[CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15](=[O:17])[CH2:19][C:20]#[N:21])[N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC#N
Reactant: COC(=O)c1nccc(OCC2CCCCC2)n1
Product: N#CCC(=O)c1nccc(OCC2CCCCC2)n1

Procedure:
CH3CN addition to methyl 4-(cyclohexylmethoxy)pyrimidine-2-carboxylate following the method described in Example 6 gives 3-(4-(cyclohexylmethoxy)pyrimidin-2-yl)-3-oxopropanenitrile.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[S:10]1[C:14]2[CH:15]=[C:16]([S:19](Cl)(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1>>[Br:9][C:3]1[C:2]([NH:1][S:19]([C:16]2[CH:17]=[CH:18][C:13]3[N:12]=[CH:11][S:10][C:14]=3[CH:15]=2)(=[O:20])=[O:21])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Reactant: Cc1ccc(N)c(Br)n1
Product: Cc1ccc(NS(=O)(=O)c2ccc3ncsc3c2)c(Br)n1
Yield: 35 %

Procedure:
By working in a manner similar to that of Preparation VII, starting with 3-amino-2-bromo-6-methylpyridine and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a beige-colored paste (yield=35%).
Reaction SMILES: [NH3:1].C[O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1)=O>CO>[C:4]([C@@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1)(=[O:3])[NH2:1]
Reactant: N
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.5 %

Procedure:
Ammonia gas was passed into a solution of tert-butyl (1S,3R)-3-(methoxycarbonyl)cyclopentylcarbamate (2.0 g, 8.2 mmol) in MeOH (20 ml) at −78° C. in a steal bomb. The reaction mixture was slowly warmed to room temperature, heated to 80° C. and stirred further for 48 h. The reaction mixture was cooled to room temperature and concentrated to afford 1.6 g (85.5%) of tert-butyl (1S,3R)-3-carbamoylcyclopentylcarbamate as brownish solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.[OH-].[NH4+]>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: Clc1ncnc2nc[nH]c12
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ncnc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a warmed (60° C.) slurry of 6-chloropurine (20 g, 0.1294 mol) and R-toluenesulfonic acid monohydrate (0.35 g), dihydropyran (13.4 mL, 0.172 mol) was added with stirring over a period of 30 minutes. After an additional 30 minutes of heating, the mixture was allowed to cool to room temperature for 1 hour. Concentrated ammonium hydroxide (12 mL) was added and stirring was continued for 5 minutes. The solution was washed with water (4×70 mL) and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a syrup (about 29 g) which slowly crystallized upon standing. Extraction with boiling hexane gave the product as a solid, 24.36 g in two crops (784), mp 70°-71° C.
Reaction SMILES: Cl[C:2]1[C:7]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[C:7]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:6][CH:5]=[C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[N:3]=2)=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 78.7 %

Procedure:
A solution of tert-butyl (trans)-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (150 mg, 0.364 mmol), 4-chlorophenylboronic acid (67.3 mg, 0.432 mmol) and K2CO3 (149 mg, 1.09 mmol) in acetonitrile:water (4:1) was degassed for 20 min. Tetrakis triphenylphosphine palladium (4.2 mg, 0.00364 mmol) was added and the reaction mixture was heated at reflux for 16 h. After completion, the reaction mixture was poured into ice water (25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4 filtered and evaporated. The crude residue was purified by column chromatography (SiO2) using EtOAc:Pet ether (1:9) to afford tert-butyl (trans)-2-(2-(4-chlorophenyl)-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (140 mg, 79%) as white solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:6]1[CH3:21])#[N:2].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:22]1[C:1]([CH2:3][CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:6]2[CH3:21])=[N:2][N:24]=[N:23]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(Cc2cccnc2)c2ccccc2n1CCC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Cc2cccnc2)c2ccccc2n1CCc1nnn[nH]1
Temperature: 125 °C
Reaction time: 20 h
Yield: 21.6 %

Procedure:
A mixture of 1-(2-cyanoethyl)-2-methyl-3-(3-pyridylmethyl)indole (0.8 g), sodium azide (0.95 g), ammonium chloride (0.78 g) and dry dimethylformamide (12 ml) was heated with stirring at 125° C. for 20 hours and then evaporated. Water (25 ml) was added to the residue to dissolve inorganic material. The insoluble portion was crystallised from methanol/ethyl acetate to give 1-[2-(5-tetrazolyl)ethyl]-2-methyl-3-(3-pyridylmethyl)indole (0.20 g), m.p. 173°.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (from Aldrich, 690 mg, 3.7 mmol) and N,N-dimethylformamide (290 μL, 3.7 mmol) was stirred at room temperature for 10 minutes and then a solution of 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (869 mg, 2.49 mmol) in methylene chloride (14 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product was purified by silica gel chromatography, eluting with 0 to 100% EtOAc in hexanes.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH2:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:8]=1.Cl.[N:29]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:13][N:29]=[C:14]2[S:15]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: O=N[O-]
Reactant: Nc1ccc(OCCCCCl)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OCCCCCl)cc12
Temperature: 3 °C

Procedure:
A mixture of 4-(4-chloro-butoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (1.54 g, 3.8 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.34 g, 4.0 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.55 g, 3.75 mmoles).
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH:6]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])[CH3:7])([CH3:3])[CH3:2].Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH:6]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)/[C:11](=[N:23]\[NH:24][C:25]([NH2:27])=[O:26])/[C:9]1=[O:10])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(CN(C(C)C)C(C)C)N1C(=O)C(=O)c2ccccc21
Reactant: NNC(N)=O
Agent: Cl
Product: CC(CN(C(C)C)C(C)C)N1C(=O)/C(=N/NC(N)=O)c2ccccc21
Yield: 65.3 %

Procedure:
By using 1-(2-diisopropylamino-1-methylethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 10 was carried out and the reaction product was recrystallized from ethanol to obtain (E)-1-(2-diisopropylamino-1-methylethyl)isatin 3-semicarbazone having a melting point of 195°-197° C. (yield: 65.3%).
Reaction SMILES: CS(C)=O.CC(C)([O-])C.[K+].[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[N:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: Nc1cncnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Nc2cncnc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To 7 ml of dimethyl sulfoxide was added 0.69 g (6.15 mmol) of potassium tert-butoxide, and 468 mg (4.92 mmol) of 5-aminopyrimidine was added to the solution while cooling with water. After stirring at room temperature for 1 hour, 500 mg (2.46 mmol) of 2-bromo-5-nitropyridine was added thereto under cooling with water, followed by further stirring at room temperature for 30 minutes. The reaction solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, and the washing was adjusted to pH 8.5 with a 1 N sodium hydroxide aqueous solution and again extracted with ethyl acetate. The organic layer was combined with the above obtained organic layer, washed successively with water and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: chloroform-methanol). The resulting crude crystals were washed with ethyl ether to obtain 0.32 g (1.47 mmol) of 5-[N-(5-nitro-2-pyridyl)amino]pyrimidine.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>CN(C)C=O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:16][CH2:15][CH2:14][O:13][CH3:12])[N:10]=1
Reactant: COCCN
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Solvent: CN(C)C=O
Product: COCCNc1nc(Cl)ccc1C(N)=O
Temperature: 60 °C
Yield: 64 %

Procedure:
Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide (1). A sealed reaction vessel containing 2,6-dichloro-nicotinamide (1) (8.66 g, 45.3 mmol) and 2-methoxy-ethylamine (15.6 mL, 181 mmol) in anhydrous dimethylformamide (40 mL) was heated to 60° C. for 7 h. The reaction was then cooled to room temperature. Dimethylformamide was azeotropically removed by the addition and evaporation of toluene (6×700 mL) by rotary evaporation with water bath at 70° C. An orange oil was obtained (12.2 g). The oil was fractionated by dry-pack column chromatography as follows: the oil was diluted with CH2Cl2 (400 mL) followed by the addition of silica gel (100 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (200 g, 230-400 mesh) and eluted with 50% EtOAc/hexanes. Pure fractions were combined and concentrated to give the title compound as a white solid (5.37 g, 64% isolated yield). 1H NMR 400 MHz (d6-DMSO) δ 7.79 (d, J=7.8 Hz, 1H), 7.30 (s, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 4.04 (br t, J=4.7 Hz, 1H), 3.80 (td, J=5.5, 4.7 Hz, 2H), 3.63 (t, J=5.5 Hz, 2H), 2.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Product: COc1ccc(-c2ccc(OC)cc2[N+](=O)[O-])cc1
Yield: 90 %

Procedure:
4-Methoxyphenylboronic acid was reacted with 4-bromo-3-nitroanisole as described for 1a to furnish a yellow solid (90% yield): mp 122°-124° C.; [Lund, H. et al, Acta. Chem. Scand., 20, 1631-1644 (1966)]1H NMR (CDCl3) δ7.30 (m, 2H), 7.18 (d, 2H, J=9.0 Hz), 7.10 (d, 1H, J=8.4 Hz), 6.92 (d, 2H, J=9.0 Hz), 3.87 (s, 3H), 3.82 (s, 3H); 13C NMR (CDCl3): δ159.37, 158.80, 149.69, 132.76, 129.43, 129.19, 128.21, 118.60, 114.12, 108.90, 55.89, 55.28. Anal. Calcd for C14H13NO4 : C, 64.86; H, 5.05; N, 5.40. Found: C, 64.77; H, 4.96; N, 5.24.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10]C(=O)C(F)(F)F)=[C:4]([CH3:17])[CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH2:10])=[C:4]([CH3:17])[CH:3]=1
Reactant: COc1cc(NC(=O)C(F)(F)F)c(C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(N)c(C)cc1Cl
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a suspension of N-(4-chloro-5-methoxy-2-methylphenyl)-2,2,2-trifluoroacetamide (7.02 g) in ethanol (50 mL) was added 2 mol/L aqueous sodium hydroxide solution at room temperature, and the mixture was stirred at external temperature of 80° C. for 30 minutes. The reaction mixture was left to be cooled and concentrated under reduced pressure. To the residue was added water, and the mixture was stirred for 1 hour. The precipitate was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (4.15 g). 1H-NMR (CDCl3) δ ppm: 2.08 (3H, s), 3.40-3.82 (2H, br), 3.83 (3H, s), 6.29 (1H, s), 6.99-7.04 (1H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1(Br)[CH2:11][CH2:10][O:9][CH:8]1[O:12][CH3:13])=[O:6])[CH3:2].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[C:5]([CH:7]1[CH2:11][CH2:10][O:9][CH:8]1[O:12][CH3:13])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)C1(Br)CCOC1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(=O)C1CCOC1OC
Yield: 98.1 %

Procedure:
Ethyl-2-(3-bromo-2-methoxytetrahydrofuran-3-yl)-2-oxoacetate (8.5 g) was dissolved in Ethanol (85 ml). Triethyl amine (3.66 g) was added to the reaction mass. 5% Palladium on Carbon (0.85 g) was added and reaction was hydrogenated at 4-5 kg pressure of Hydrogen for 8 hrs. Reaction mass was filtered through hyflow and concentrated to residue. This residue was slurried in methyltert-butylether (42 ml) and filtered to remove triethylamine HBr salt. Filtrate was concentrated to get oily residue of Ethyl-2-(2-methoxytetrahydrofuran-3-yl)-2-oxoacetate (yield 6.0 g).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[Cl:13][C:14]1[C:15]([O:37][CH3:38])=[CH:16][C:17]([O:35][CH3:36])=[C:18]([CH2:20][CH2:21][C:22]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[O:27][C:26](=[O:28])[CH2:25][C:24](=[O:29])[CH2:23]2)[CH:19]=1>>[Cl:13][C:14]1[C:15]([O:37][CH3:38])=[CH:16][C:17]([O:35][CH3:36])=[C:18]([CH2:20][CH2:21][C:22]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[O:27][C:26](=[O:28])[C:25]([CH2:2][C:3]3[NH:4][C:5](=[O:12])[C:6]4[S:11][CH:10]=[CH:9][C:7]=4[N:8]=3)=[C:24]([OH:29])[CH2:23]2)[CH:19]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=c1[nH]c(CCl)nc2ccsc12
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ccsc4c(=O)[nH]3)C(=O)O2)cc1Cl
Yield: 20 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-(chloromethyl)thieno[3,2-d]-pyrimidine-4(3H)-one (Example B(56), Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 20%. 1H NMR (300 MHz, DMSO-d6) δ 1.24-1.67 (m, 8H), 1.90 (m, 1H), 2.04 (m, 1H), 2.32 (m, 1H), 2.40-2.54 (m, 3H, overlap with DMSO-d5), 2.71 (d, J=18 Hz, 1H), 3.52 (ABQ pattern, J=15 Hz, 2H, overlap with H2O), 3.69 (s, 3H), 3.80 (s, 3H), 6.65 (s, 1H), 6.71 (d, J=5.4 Hz, 1H), 7.05 (s, 1H), 7.96 (d, J=5.4 Hz, 1H), 10.88 (br s, 1H), 12.26 (br s, 1H). LC-MS (APCI) calcd for C27H29ClN2O6S: 544.14; found (M+H+) 544.9 m/z.
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]([F:51])([F:50])[C:6]1[CH:7]=[C:8]([C@H:16]2[O:20][C:19](=[O:21])[N:18]([CH2:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=3[C:33]3[CH:34]=[C:35]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]=[O:47])=[CH:42][C:41]=4[CH3:48])[CH:36]=[CH:37][C:38]=3[Cl:39])[C@H:17]2[CH3:49])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.[Cl-].[NH4+]>C1COCC1>[F:51][C:5]([F:4])([F:50])[C:6]1[CH:7]=[C:8]([C@H:16]2[O:20][C:19](=[O:21])[N:18]([CH2:22][C:23]3[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=[CH:25][C:24]=3[C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[C:35]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]([OH:47])[CH3:1])=[CH:42][C:41]=4[CH3:48])[CH:34]=3)[C@H:17]2[CH3:49])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: C[Mg+]
Reactant: Cc1cc(C=O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
MeMgBr (0.274 ml, 0.274 mmol, 1 M solution) was added to a solution of aldehyde from Example 50 (160 mg, 0.229 mmol) in THF (3 ml) at −78° C. The solution was stirred at −78° C. for 2 h. Saturated ammonium chloride solution was added. The mixture was extracted with EtOAc (3×10 ml). The combined EtOAc layers were washed with brine, and dried over sodium sulfate. The residue was purified by flash column on silica gel, eluting with EtOAc/hexane (30:70) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz): δ a mixture of 1:1 atopoisomers 7.89 (s, 1H), 7.72 (m, 4H), 7.58 (d, J=8.5 Hz, 1H), 7.48 (m, 1H), 7.38 (m, 1H), 7.32-7.20 (m, 4H), 5.62 (d, J=8.0 Hz, 1H), 5.00 (d, J=15.5 Hz, 0.5H), 4.93 (m, 1H), 4.82 (d, J=16.0 Hz, 0.5H), 4.10 (d, J=15.5 Hz, 0.5H), 4.01 (d, J=15.5 Hz, 0.5H), 3.88 (m, 0.5H), 3.87 (m, 0.5H), 2.34 (s, 1.5H), 2.33 (s, 1.5H), 1.55 (m, 3H), 0.61 (d, J=6.5 Hz, 1.5H), 0.58 (d, J=6.5 Hz, 1.5H). LC/MS: M+−18: 698.16.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([N:17]1[C:21]2[C:22](=[O:33])[N:23]([CH2:31][CH3:32])[C:24]3[N:25]([N:26]=[C:27]([CH2:29]Br)[N:28]=3)[C:20]=2[N:19]=[C:18]1[CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[CH2:10]([N:17]1[C:21]2[C:22](=[O:33])[N:23]([CH2:31][CH3:32])[C:24]3[N:25]([N:26]=[C:27]([CH2:29][O:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:28]=3)[C:20]=2[N:19]=[C:18]1[CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1ccccc1
Reactant: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CBr)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(COc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
66 mg of sodium hydride (66% in mineral oil) are added to a solution of 0.16 g of phenol in 15 ml of dimethylformamide. After 30 minutes' stirring at ambient temperature, 0.68 g of 6-benzyl-2-bromomethyl-7-cyclopentyl-4-ethyl-imidazo[4,5-e]-s-triazolo[1,5-a]pyrimidin-5-one are added. The mixture is stirred at elevated temperature (about 100° C.) until the reaction is complete (about 8 hours). For working up, some water is added and then the solvent is distilled off in vacuo. The residue remaining is taken up in 20 ml of dichloromethane and 20 ml of water. After acidification with aqueous 1N HCl solution, the organic phase is separated off, washed with water and dried over magnesium sulphate. The solvent is distilled off and the residue remaining is recrystallised from diethyl ether. 0.6 g of the title compound remain, pure enough to be used in the subsequent reactions.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:33](O)[CH3:34].O>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:18])[C:34]1[CH:33]=[CH:3][C:2]([C:21]2[C:20](=[O:23])[N:19]3[CH:24]=[CH:25][S:26][C:18]3=[N:17][C:16]=2/[CH:15]=[CH:14]/[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:6]=2[O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:1][CH:4]=1
Reactant: CCO
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(N(C)C)cc2)c1OCC1CC1

Procedure:
The title compound was prepared from Intermediate 2 (150 mg, 31 mmol), 4-N,N-dimethylaminophenylboronic acid (61 mg, 37 mmol), Pd[(C6H5)3P]4 (61 mg, 37 mmol) and sodium carbonate (206 mg, 1.91 mmol) in a mixture of toluene, ethanol and water according to the procedure outlined in Example 1 to afford a crude product which was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to give 110 mg of the product; 1H NMR (300 MHz, DMSO-d6) δ 0.26-0.28 (m, 1H), 0.50 (d, J=7.8 Hz, 2H), 1.06-1.08 (m, 1H), 6.77 (d, J=8.4 Hz, 2H), 6.88-6.90 (m, 1H), 6.97-7.04 (m, 3H), 7.14 (d, J=5.1 Hz, 2H), 7.95 (d, J=5.1 Hz, 1H), 8.10 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 474.19 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH3:13][NH2:14].O>O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([NH:14][CH3:13])=[O:5]
Reactant: CN
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: O
Product: CNC(=O)c1cc(Br)ccc1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of methyl 2-amino-5-bromobenzoate (Compound 106B, 65 g) and CH3NH2.H2O (1000 mL) was stirred at 80° C. overnight in a pressure tube. The mixture was diluted with H2O (1000 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were dried over MgSO4, concentrated to afford the title compound (55 g, yield: 87%) as a gray solid. 1H NMR (CDCl3, 400 MHz): δ=2.93 (d, J=5.2 Hz, 3H), 5.48 (s, br, 2H), 6.04 (s, br, 1H), 6.54 (d, J=8.4 Hz, 1H), 7.24 (dd, J=2.0, 8.4 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H).