Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[Cl:23])[CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.Cl>O1CCCC1.O.C(Cl)Cl.[NH4+].[OH-].C(OCC)(=O)C>[ClH:22].[Cl:23][C:17]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=1[C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]2[C:7]=1[O:6][C@@H:5]([CH2:4][NH2:1])[CH:14]=[CH:13]2
Reactant: [N-]=[N+]=NC[C@H]1CCc2cc(F)cc(-c3cc(Cl)ccc3Cl)c2O1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC[C@H]1C=Cc2cc(F)cc(-c3cc(Cl)ccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-2-azidomethyl-8-(2,5-dichloro-phenyl)-6-fluoro-chroman (240 mg, 0.68 mmol) in tetrahydrofuran (10 mL) and water (0.5 mL) was added triphenylphosphine (0.27 g, 10.2 mmol) and the reaction mixture stirred at room temperature for 24 hours. The solvent was removed under vacuum to form a colorless oil. Chromatography with 0–5% methanol in methylene chloride plus 1% NH4OH afforded {[(R-8-(2.5-dichlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl}amine as a colorless oil. The oil was dissolved in ethyl acetate and made into its hydrochloride salt (121 mg, 45%) using excess ethereal hydrochloric acid to give a white solid, mp 217–219° C.; MS (ES) m/z 324.0 ([M+H]+); [α]D25=+191.22° (c=5.1 mg/0.7 mL MeOH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:14][O:13][CH2:12]3)[N:7]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:6]=2[CH:22]=1.[I:23]C1C=CC2N=C(C(Cl)(Cl)Cl)N(C3C=CN=C(N)N=3)C=2C=1>COCCO>[I:23][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:7]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:6]=2[CH:22]=1
Reactant: Nc1nccc(-n2c(OC3COC3)nc3ccc(Br)cc32)n1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(I)cc32)n1
Solvent: COCCO
Product: COCCOc1nc2ccc(I)cc2n1-c1ccnc(N)n1

Procedure:
The title compound was prepared by the procedure described for the synthesis of 4-[6-bromo-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine by reacting 4-[6-iodo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine with 2-methoxyethanol: LC-MS: m/z=+412 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH:9]=[C:10](Br)Br)[C:3]=1[CH2:13][CH3:14].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[Cl:1][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([C:5]([F:8])=[CH:6][CH:7]=1)[CH2:9][C:10]1[NH:17][CH2:16][CH2:15][N:18]=1
Reactant: NCCN
Reactant: CCc1c(Cl)ccc(F)c1C=C(Br)Br
Product: CCc1c(Cl)ccc(F)c1CC1=NCCN1

Procedure:
2-(3-Chloro-2-ethyl-6-fluoro-benzyl)-4,5-dihydro-1H-imidazole was prepared from 1-chloro-3-(2,2-dibromo-vinyl)-2-ethyl-4-fluoro-benzene and ethylenediamine in analogy to Example 1e): yellow crystals; MS (ISP): 243.3 ([M+H]+, 30%), 241.2 ([M+H]+, 100%).
Reaction SMILES: [CH:1]1[N:5]=[C:4]2[C:6]([N:8]=[CH:9][NH:10][N:3]2[CH:2]=1)=O.O=P(Cl)(Cl)[Cl:13]>>[CH:1]1[N:5]=[C:4]2[C:6]([Cl:13])=[N:8][CH:9]=[N:10][N:3]2[CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc[nH]n2ccnc12
Product: Clc1ncnn2ccnc12
Yield: 66 %

Procedure:
Imidazo[1,2-f][1,2,4]triazin-4-ol (400 mg, 2.94 mmol, 1.0 eq) was dissolved in POCl3 (10 mL, 109.2 mmol, 37.1 eq) and the resulting mixture was stirred at reflux for 2 h. The mixture was concentrated in vacuo to remove POCl3. The residue was poured into ice water (30 mL) and neutralized with saturated aqueous NaHCO3 solution to adjust the pH to 6-7 while keeping the temperature below 5° C. The mixture was extracted with ethyl acetate (30 mL×4). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (16% ethyl acetate in petro ether) to afford 4-chloroimidazo[1,2-f][1,2,4]triazine (300 mg, 66.0% yield).
Reaction SMILES: C(N=C([N:12]1[CH2:17][CH2:16][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)OC1C=CC=CC=1)#N.[NH3:44]>CO>[C:29]([N:34]=[C:35]([N:12]1[CH2:13][CH2:14][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)[NH2:36])#[N:44]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=NC#N)Oc2ccccc2)CC1
Reactant: N
Solvent: CO
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(N)=NC#N)CC1
Yield: 91 %

Procedure:
Phenyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate (100 mg, 0.175 mmol) and a solution of ammonia in methanol (2 mL, 1.4 M) was stirred at ambient temperature for 20 hours. After evaporation of the excess ammonia and the solvent, the residue was subject to flash chromatography (Mega Bond Elut Si, MeOH/EtOAc, 10% to 40%) to afford N′-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidamide as amorphous solid (79 mg, 91%). 1H NMR (CDCl3, 300 MHz): δ 7.68-7.65 (m, 1H), 7.42-7.34 (m, 2H), 7.30-7.24 (m, 4H), 7.20-7.18 (m, 2H), 6.11 (s, 2H), 4.65 (t, J=8.5 Hz, 1H), 3.82-3.78 (m, 2H), 3.27-3.20 (m, 4H), 2.53 (s, 3H), 2.45-2.25 (m, 4H), 1.96-1.84 (m, 10H), 1.64 (d, J=7.5 Hz, 2H). HRMS m/z (M+H)+ calcd: 496.3189, obsd: 496.3181.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:26])=O>C1C=CC=CC=1.CN(C)C=O>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([Cl:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A slurry of 0.4 g of triphenylacetic acid in 10 ml of benzene was stirred at 25° C. and treated with 0.2 g of oxalyl chloride and 1 drop of dimethylformamide. Effervesence occurred over a period of about 30 minutes, after which time a solution was obtained. This solution was left to stand at room temperature for 1.5 hours and was then evaporated to give triphenylacetyl chloride in the form of an oil. The acid chloride was cooled to about -10° C. by means of an ice/salt bath and 10 ml of dry pyridine and 0.36 g of 5'-amino-2',5'-dideoxy-5-ethyluridine were added. The mixture was shaken for about 15 minutes, whereby the acid chloride dissolved and the temperature rose to 0° C. The solution was then stirred at 0° C. for 4 hours and then evaporated. The residue was re-evaporated three times with toluene, there being obtained a gum which was triturated with 20 ml of water to give 0.66 g of a solid of melting point 110°-140° C. Recrystallization from 12 ml of ethanol removed residual triphenylacetic acid and the residue was chromatographed on a column of silica gel using methylene chloride/methanol (9:1) for the elution. Recrystallization from a mixture of 5 ml of toluene, 10 ml of cyclohexane and 0.1 ml of ethyl acetate gave 0.25 g of 2',5'-dideoxy-5-ethyl-5'-(triphenylacetamido)uridine of melting point about 110°-120° C. (decomposition).
Reaction SMILES: O=[C:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH:4]3[C:12]([OH:14])=[O:13])[CH2:8]2.[NH3:15]>C(O)C.[Pt]=O>[NH2:15][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH:4]3[C:12]([OH:14])=[O:13])[CH2:8]2
Reactant: N
Reactant: O=C1C2CC3CC(C2)C(C(=O)O)C1C3
Agent: O=[Pt]
Solvent: CCO
Product: NC1C2CC3CC(C2)C(C(=O)O)C1C3

Procedure:
4.7 Grams of 4-oxo-2-adamantanecarboxylic acid [preparation is described in G. Snatzke, et. al., CHEM. BER. 100:1710-1724(1967)] is hydrogenated in 75 ml of ethanol over 0.47 g of platinum oxide in the presence of ammonia gas under 60 psi of pressure at room temperature. The solvent is removed under reduced pressure and 15 ml of water is added and removed under reduced pressure. Another 15 ml of water is added and removed under reduced pressure then the residue is dried at 100° C. in a vacuum oven for 1 hour to give 4-amino-2-adamantanecarboxylic acid which is represented by the following formula ##STR63## Substitution of an equivalent quantity of 4-amino-2-adamantanecarboxylic acid for the 3-amino-1-adamantanecarboxylic acid of Example 1 and substantial repetition of the procedures detailed in Examples 1 through 9 provides methyl L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-4-amino-2-adamantanecarboxylate hydrochloride which is represented by the following formula ##STR64##
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:44])[CH:17]([O:42][CH3:43])[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([O:40][CH3:41])[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[C:30]([O:32]CC1C=CC=CC=1)=[O:31])=[O:24])=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:30]([C@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:23](=[O:24])[CH:22]([O:40][CH3:41])[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]([O:42][CH3:43])[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:44])([OH:32])=[O:31]
Reactant: COC(CCCCC(OC)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(CCCCC(OC)C(=O)N1CCC[C@@H]1C(=O)O)C(=O)N1CCC[C@@H]1C(=O)O
Yield: 84.8 %

Procedure:
182 mg (0.3 mmol) (R)-1-[8-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2,7-dimethoxy-8-oxo-octanoyl]-pyrrolidine-2-carboxylic acid benzyl ester in 10 ml methanol were hydrogenated in the presence of 30 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded 109 mg (84%) (R)-1-[8-[(R)-2-carboxy-pyrrolidin-1-yl]-2,7-dimethoxy-8-oxo-octanoyl]-pyrrolidine-2-carboxylic acid as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>C[O-].[Na+].[Cu]>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: Oc1ccccc1
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(Oc2ccccc2)c1C(=O)O
Temperature: 25 °C
Yield: 66.4 %

Procedure:
2-Chloro-6-methyl-benzoic acid (30 mmol, 5.22 g) and phenol (40 mmol, 3.8 g) were dissolved in a solution of NaOMe (30 wt %) in MeOH (ca. 66 mmol, 12 mL). To the solution was added copper bronze (3 mmol, 193 mg) before it was concentrated in vacuo. Then, 1,2-dichlorobenzene (24 mL) was added and the mixture was refluxed under nitrogen for 2 h with stirring. After cooling to ambient temperature water (200 mL) and Et2O (150 mL) were added and the mixture was stirred vigorously for 30 min before the organic phase was separated and discarded. The aqueous phase was washed with Et2O (150 mL) before it was acidified by addition of 5 N hydrochloric acid. The resulting mixture was extracted with ethyl acetate (1×100 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was recrystallized from hexanes/toluene to give the title compound as a tan solid (4.55 g); MS-(−)-ion: M−1=226.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[NH2:43][C:44]1[CH:49]=[CH:48][C:47](Br)=[CH:46][N:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:43][C:44]1[N:45]=[CH:46][C:47]([C:31]2[CH:32]=[CH:33][C:28]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:16](=[O:17])[C:15]4[N:14]=[CH:13][N:12]([C:18]5[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=5)[C:11]=4[N:10]=3)=[CH:29][CH:30]=2)=[CH:48][CH:49]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(ncn4-c4cccc(S(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 1-(4-chloro-phenyl)-9-(3-methanesulfonyl-phenyl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,9-dihydro-purin-6-one (prepared as described in example 38, 0.300 g, 0.497 mmol) in N,N-dimethylformamide (20 mL) is degassed with argon for 0.5 h. Then 2-amino-5-bromopyridine (0.129 g, 0.746 mmol), cesium carbonate (0.324 g, 0.995 mmol), Pd(dppf)2Cl2 (0.036 g, 0.049 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 6 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford 2-[4-(6-amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-9-(3-methanesulfonyl-phenyl)-1,9-dihydro-purin-6-one. 1H NMR (DMSO-d6, 400 MHz) δ 8.77 (br, 1H), 8.45 (m, 1H), 8.30 (m, 1H), 8.23-8.27 (m, 2H), 8.13 (br, 1H), 8.04 (d, 1H), 7.90 (t, 1H), 7.55 (m, 2H), 7.41-7.53 (m, 5H), 7.01 (d, 1H), 3.30 (s, 3H); LC-MS calculated for C29H21ClN6O3S (M+H+) 569.1, found 569.2.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[CH2:20][C@@H:19]([C:21]3[CH:32]=[CH:31][C:24]4[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=4[CH:22]=3)[O:18][C:17]2=[O:33])=[CH:10][CH:9]=1)(=O)C.O([Si](C)(C)C)[K].P([O-])([O-])([O-])=O.O>C1COCC1>[CH3:29][C:26]1([CH3:30])[O:25][C:24]2[CH:31]=[CH:32][C:21]([C@H:19]3[O:18][C:17](=[O:33])[N:16]([CH2:15][CH2:14][C:11]4[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][OH:4])=[CH:13][CH:12]=4)[CH2:20]3)=[CH:22][C:23]=2[CH2:28][O:27]1
Reactant: CC(=O)OCCOc1ccc(CCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)cc1
Agent: C[Si](C)(C)O[K]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCO)cc4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethyl acetate (3.7 g) in THF (100 mL) was treated with KOSiMe3 (1.39 g) and stirred at room temperature for 3 h. The solution was then poured into phosphate buffer (pH 6.5) and water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo to give the title compound (3.31 g). LCMS RT=2.91 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[Cl:28])[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:29].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[Cl:28])[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[N:11][C:10]1=[O:29]
Reactant: COc1cc(-c2ccc(F)cc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1cc(-c2ccc(F)cc2Cl)c2cnc(=O)n(-c3c(Cl)cccc3Cl)c2c1
Temperature: 25 °C

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-5-(2-chlorofluorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinazolinone (112 mg, 0.248 mmol) (INTERMEDIATE 30) in 1,4-dioxane (5 mL) at 65° C. under an argon atmosphere was added a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (115 mg, 0.51 mmol) in 1,4-dioxane (2.5 mL). After 2 h the solution was cooled to RT and partitioned between NaHCO3 and EtOAc. The phases were separated and the organic phase washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using 3 to 5% acetone in DCM as the eluent to give 1-(2,6-dichlorophenyl)-5-(2-chloro-4-fluorophenyl)-7-(methoxy)-2(1H)-quinazolinone. 1H NMR(CDCl3, 500 MHz): δ 3.70 (s, 3H), 5.94 (d, 1H, J=2.1 Hz), 6.74 (d, 1H, J=2.1 Hz), 7.18 (app dt, 1H, J=8.1, 2.5 Hz), 7.35 (m, 1H), 7.42 (m, 1H), 7.47 (t, 1H, J=8.2 Hz), 7.56-7.60 (m, 2H). MS(ES) 449 (M+H); LC 1: 3.40 min.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:15])=[C:10](B(O)O)[CH:11]=1)[CH3:2].FC(F)(F)S(O[C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:31])[CH2:29][CH3:30])=[CH:24][C:23]=1[CH2:32][CH2:33][CH3:34])(=O)=O.[Cl-].[Li+].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:15])=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:31])[CH2:29][CH3:30])=[CH:24][C:23]=2[CH2:32][CH2:33][CH3:34])[CH:11]=1)[CH3:2]
Reactant: CCCc1cc(C(=O)CC)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CCOCOc1ccc(C)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCCc1cc(C(=O)CC)ccc1-c1cc(OCOCC)ccc1C

Procedure:
1.56 g (7.4 mmol) of 5-ethoxymethoxy-2-methylphenylboronic acid, 2 g (6.2 mmol) of 4-propionyl-2-propylphenyl 1,1,1-trifluoromethanesulfonate, 517 mg (12 mmol) of lithium chloride and 7.4 ml of 2M potassium carbonate solution are dissolved in 50 ml of 1,2-dimethoxyethane in a round-bottomed flask and under a stream of nitrogen. The mixture is refluxed for 10 hours. It is then poured into water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. A brown oil is obtained, which is used without further purification for the rest of the synthesis.
Reaction SMILES: [C:1]([C:3]1[CH2:9][CH:8]2[N:10]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH:5]([CH2:6][CH2:7]2)[CH:4]=1)#[N:2].CO.[BH4-].[Na+].P([O-])(O)(O)=O.[K+]>N1C=CC=CC=1>[C:1]([CH:3]1[CH2:4][CH:5]2[N:10]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH:8]([CH2:7][CH2:6]2)[CH2:9]1)#[N:2]
Reactant: N#CC1=CC2CCC(C1)N2CC(F)(F)F
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CO
Product: N#CC1CC2CCC(C1)N2CC(F)(F)F
Temperature: 80 °C
Yield: 100.8 %

Procedure:
An oven-dried 10 ml round bottom flask was fitted with a reflux condenser and magnetic stirrer and the apparatus filled with a nitrogen atmosphere. 3-Cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]oct-2-ene (0.216 g, 1 mmol) was charged to the flask followed by methanol (0.5 ml) and pyridine (1.5 ml) to give a solution. Sodium borohydride (0.046 g, 1.2 mmol) was added in a single portion and the mixture was heated to 80° C. The reaction was held at this temperature overnight, refluxed for 3 hours and then cooled to ambient. Saturated aqueous potassium dihydrogen phosphate (10 ml) was added to the reaction mass and the aqueous solution (pH7) was then extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine (10 ml), dried (Na2SO4) and concentrated in vacuo to give 3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane (0.22 g, 74% yield) as a mixture of epimers (12:1 equatorial:axial).
Reaction SMILES: [C:1]1([CH:7]([C:24]([O-:26])=[O:25])[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:29])=O>ClCCCl>[Cl:29][C:9]1([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:24](=[O:25])[O:26]1
Reactant: O=C(CC(C(=O)[O-])c1ccccc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C1OC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1c1ccccc1

Procedure:
In 4 ml of 1,2-dichloroethane was dissolved 100 mg of the Compound 62 obtained in Example 62. To the solution was added 0.1 ml of thionyl chloride, and the mixture was heated for 4 hours under reflux. The solvent was evaporated off, then the residue was chromatographed on Florisil, followed by elution with hexane-ethyl acetate (2:1) to give 63 mg of the subject Compound (63) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:16][S:17][CH2:18]Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]2[CH2:12][CH2:13]2)=[CH:4][C:5](=[O:8])[N:6]([CH2:16][S:17][CH3:18])[CH:7]=1
Reactant: Oc1cc(OCC2CC2)c(Br)cn1
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCn1cc(Br)c(OCC2CC2)cc1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a solution of the title compound from Step 2 (330 mg, 1.35 mmol) in DMF (5 mL) was added NaH (40 mg, 2 mmol, 60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 30 minutes. Then, chloromethyl methyl sulfide (131 mg, 1.35 mmol) was added. The mixture was warmed to room temperature and stirred for 5 hours. The mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EA (10 mL×3). The combined organic layers were washed with saturated brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE: EA=3:1) to afford the title compound (205 mg, 50%) as yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), 5.86 (s, 1H), 4.96 (s, 1H), 3.84 (d, J=6.8 Hz, 2H), 2.17 (s, 3H), 1.32-1.25 (m, 1H), 0.70-0.67 (m, 2H), 0.41-0.39 (m, 2H).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=1[Cl:17])([CH2:3][CH3:4])[CH3:2].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][NH:16][C:12]1[CH:11]=[C:10]([Cl:17])[C:9]([O:8][C:7]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:6]=2)=[C:14]([Cl:15])[CH:13]=1)[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: CCC(C)c1cc(Oc2c(Cl)cc(N)cc2Cl)ccc1OC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Temperature: 120 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
To 4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine (71.8 g, 0.21 mol) was added ethyl bromoacetate (35.26 g, 0.21 mol) and diisopropylethyl amine (27.92 g, 0.21 mol) in DMF (718 mL) were stirred at 120° C. for 18 h. The reaction mixture was poured in to ice-water. The product was taken up in ethyl acetate, washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography over flash silica gel (Hexane:Ethylacetate 90:10) to afford the pure product [4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamino]-acetic acid ethyl ester. (48.0 g, 54% yield)
Reaction SMILES: C([C:3](CC)(C([O-])=O)[C:4]([O-])=[O:5])C.[Na].[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])=[C:17]([O:28][CH3:29])[N:16]=1.[OH-].[K+]>C(O)C>[OH:5][C:4]1[CH2:3][CH:23]([C:18]2[C:19]([O:21][CH3:22])=[N:20][C:15]([O:14][CH3:13])=[N:16][C:17]=2[O:28][CH3:29])[CH2:24][C:25](=[O:27])[CH:26]=1
Reactant: COc1nc(OC)c(C=CC(C)=O)c(OC)n1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: COc1nc(OC)c(C2CC(=O)C=C(O)C2)c(OC)n1
Temperature: 90 °C
Yield: 69.1 %

Procedure:
Diethylmalonate (4.5 g) was added to a solution of sodium metal (0.65 g) in absolute ethanol (30 ml) and the mixture was heated under reflux with stirring. 1-(2,4,6-Trimethoxy-5-pyrimidylbut-1-en-3-one (6.4 g) was added and the mixture was then boiled under reflux for 2 hours. An aqueous solution of potassium hydroxide (3.5 g in 80 ml of water) was added and the mixture was heated under reflux for a further 5 hours. The solution was cooled and extracted with chloroform (50 ml) and then the aqueous layer was heated to 90° C. and carefully acidified (pH 4.5) with dilute aqueous hydrochloric acid. The resultant precipitate was removed by filtration to give 3-hydroxy-5-(2,4,6-trimethoxy-5-pyrimidyl)cyclohex-2-en-1-one (5.2 g) as a pale yellow crystalline solid, mp 215° C. (dec). Extraction of the filtrate with ethylacetate gave a further 0.7 g of product.