Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](=[O:30])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)[C@@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C)C=O.O>[CH:20]1([O:1][C:2]2[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: BrC1CCCC1
Reactant: COC(=O)c1cnc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC)c(OC2CCCC2)c1
Temperature: 60 °C

Procedure:
A mixture of methyl 5-hydroxy-6-methoxynicotinoate (250 mg), anhydrous potassium carbonate (600 mg) and cyclopentyl bromide (0.26 mL) in dry dimethylformamide (5 mL) is stirred and heated at 60±5° C. for 24 hours. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The extracts are washed with water and dried (MgSO4). Concentration gave methyl 5-cyclopentyloxy-6-methoxynicotinoate (290 mg) as an oil.
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:9]([OH:11])=O)[CH2:5][C:6]([OH:8])=[O:7])=[O:2].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].Cl.[CH3:25][O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29]>C(O)(=O)C>[CH3:25][O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:29][C:9](=[O:11])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH:3][CH:1]=[O:2]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=CN[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC=O
Reaction time: 5 h

Procedure:
In 28.6 g of acetic acid, 16.1 g (0.1 mole) of N-formyl L-aspartic acid was suspended and 10.2 g (0.1 mole) of acetic anhydride was added. The mixture was warmed to 50°-55° C. and stirred for 5 hours at the same temperature. After finishing the reaction, the resulting mixture was cooled to 15°-20° C. and then 9.2 g (0.11 mole) of sodium acetate and 20.5 g (0.095 mole) of L-phenylalanine methyl ester hydrochloride were successively added at the same temperature. The reaction was carried out for 4 hours with stirring at the same temperature. The reaction mixture was then concentrated and 57.2 g of water was added and cooled to 10°-15° C. Precipitated crystals were filtered, washed and dried. Crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester thus obtained were 28.2 g. The crystals were analyzed by high performance liquid chromatography to give a ratio of α-isomer:β-isomer of 81.0:19.0. The crystals were purified with a conventional method to give high purity crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester. The yield was 20.8 g (68.0% yield on L-phenylalanine methyl ester hydrochloride).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(Br)cn1
Reaction time: 15 h
Yield: 58.5 %

Procedure:
In 100 ml of pyridine was dissolved 10.13 g of N-t-butoxycarbonylglycine and the solution was added with 5 g of 2-amino-5-bromopyridine, 13.85 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 7.06 g of 4-dimethylaminopyridine, individually at room temperature. Stirring was conducted for 15 hours at the same temperature. Water was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated under vacuum to give 5.58 g of 2-(N-t-butoxycarbonylglycinylamino)-5-bromopyridine. This compound was dissolved, along with 5.82 g of (S)-[N-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide, in 70 ml of dimethylformamide and added with 4.9 ml of triethyl amine and 2.97 g of dichlorobistriphenylphosphine palladium (II) at room temperature. Reaction was performed at 100° C. for 4 hours with stirring. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated under vacuum. Recrystallization of the concentrate provided 5.13 g of (S)-[N-3-(4-(2-(N-t-butoxycarbonylglycinylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl)methyl acetamide. This product was reacted with 1.65 ml of trimethylsilyl iodide in chloroform at room temperature for 30 min under a nitrogen atmosphere with stirring. Following the addition of chloroform, the organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo. The concentrate was purified through column chromatography to provide the title compound. 550 mg.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[NH:15][CH:14]=[CH:13][C:12]2=O>>[Br:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[Cl:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc[nH]c2c(Br)cccc12
Product: Clc1ccnc2c(Br)cccc12

Procedure:
A suspension of 2-bromoaniline (20.9 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (22.6 g) in 2-propanol (240 ml) was heated to reflux for 1 hour. The reaction solution was cooled to 0° C., and the deposit was then filtrated to obtain a pale yellow solid (35.0 g). A suspension of the obtained pale yellow solid (10.0 g) in Dowtherm (100 ml) was heated at 210° C. for 1 hour. After cooling, hexane (100 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-bromoquinolin-4(1H)-one (6.3 g). Phosphorus oxychloride (5.9 ml) was added to 8-bromoquinolin-4(1H)-one (9 g), and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 8-bromo-4-chloroquinoline (8.3 g) as a white solid.
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[O:9][C:7](=O)[CH2:6]2)[CH2:3][CH2:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C1(C)C(C)=CC=CC=1>O>[N:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:7](=[O:9])[CH2:6][C:4]3([CH2:3][CH2:2][CH2:1][CH2:5]3)[CH2:12][C:10]2=[O:11])=[CH:15][CH:16]=1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CC2(CCCC2)CC(=O)N1c1ccncc1

Procedure:
The starting material is prepared as follows: The mixture of 200 g of 3,3-tetramethyleneglutaric anhydride, 57 g of 4-aminopyridine and 1,500 ml of xylene is stirred and refluxed on a water separator for 3 days. After cooling slightly, the xylene solution is decanted from a small amount of oily material, and after cooling in an ice bath, the collected residue dissolved in 1,500 ml of boiling ethanol, the solution cooled to 5°, filtered and the residue dried, to yield the 8-(4-pyridyl)-8-azaspiro[4,5]decan-7,9-dione melting at 208°-211°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH:13][C@@H:14]([CH2:29][C:30]3[N:31]=[CH:32][S:33][CH:34]=3)[C:15]([N:17]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)=[O:16])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:38].O>CN(C=O)C>[CH2:25]([N:17]([CH2:18][C:19]1[N:20]=[C:21]([CH3:24])[S:22][CH:23]=1)[C:15](=[O:16])[C@@H:14]([N:13]([CH3:38])[S:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)(=[O:11])=[O:12])[CH2:29][C:30]1[N:31]=[CH:32][S:33][CH:34]=1)[CH:26]([CH3:27])[CH3:28]
Reactant: CI
Reactant: Cc1nc(CN(CC(C)C)C(=O)[C@H](Cc2cscn2)NS(=O)(=O)c2ccc3occc3c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CN(CC(C)C)C(=O)[C@H](Cc2cscn2)N(C)S(=O)(=O)c2ccc3occc3c2)cs1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of compound 58 (76 mg, 0.15 mmol) in DMF (1 ml) were added sodium hydride (12 mg, 0.30 mmol) and iodomethane (14 μl, 0.23 mmol). After 1 hr, water (7 ml) was added to quench the reaction. The aqueous phase was extracted with EtOAc (10 ml) and the organic layer was washed with brine (5 ml), dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified by preparative TLC (EtOAc) to provide compound 80 (49 mg, 61%) as an oil. [M+H]+ 533.0, HPLC purity: >99%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:7]=[CH:8][C:9]=1[Cl:10])(=[O:3])[CH3:2].[Br:24]Br>>[Br:24][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:7]=[CH:8][C:9]=1[Cl:10])=[O:3]
Reactant: BrBr
Reactant: COc1cc(OC)cc(C(=O)Nc2ccc(Cl)c(C(C)=O)c2)c1
Product: COc1cc(OC)cc(C(=O)Nc2ccc(Cl)c(C(=O)CBr)c2)c1

Procedure:
Procedure C was performed using N-(3-acetyl-4-chlorophenyl)-3,5-dimethoxybenzamide (0.1 g, 0.3 mmol) and Br2 (0.017 ml, 0.33 mmol to afford N-(3-(2-bromoacetyl)-4-chlorophenyl)-3,5-dimethoxybenzamide.
Reaction SMILES: [F:1][C:2]1[C:3]([F:32])=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=O)[NH:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>>[F:1][C:2]1[C:3]([F:32])=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=[S:42])[NH:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4cc(F)c(F)cc4o3)c(F)cc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4cc(F)c(F)cc4o3)c(F)cc2F)C1(F)F
Yield: 62 %

Procedure:
In a manner analogous to that described in Example 2b), the reaction of (R)-5-[5-(5,6-difluoro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (130 mg, 284 μmol) with Lawesson's reagent (126 mg, 312 μmol) yielded the title compound (83 mg, 62% yield as a white solid. MS (ISP): m/z=475.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])(=O)[CH3:2].[C:11](C1C=CC=CC=1S)(=O)C>C(OC(=O)C)C>[O:10]1[CH:11]=[CH:2][CH:1]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]12
Reactant: CC(=O)c1ccccc1O
Reactant: CC(=O)c1ccccc1S
Solvent: CCOC(C)=O
Product: C1=COC2C=CC=CC2=C1

Procedure:
Alternatively, such a 2-acetylphenol or 2-acetylthiophenol is condensed with ethylacetate and cyclized with dehydration to form a benzo[b]pyran which is then condensed with a Grignard reagent, e.g., ##STR10##
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.CN(CCN(C)C)C.[Li]CCCC.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C1COCC1>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]([C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=[C:2]([Cl:1])[N:10]=3)([OH:44])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C2(O)CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: -30 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
To a mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (2.5 g, 9.86 mmol) and TMEDA (2.1 mL, 14.8 mmol) in THF (80 mL) at −78° C. was added n-BuLi (6 mL, 2.5 M in hexanes, 14.8 mmol). The resulting mixture was allowed to warm to −30° C. for 30 min then cooled back to −78° C. before the addition of a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.9 g, 14.8 mmol) in THF (20 mL). The reaction mixture was slowly warmed to r.t. and stirred for 16 h then quenched with H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 10-75%) affording 4-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.2 g, 71%). LCMS (method H): RT 3.52 min [M+H]+ 453.3
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][O:19][CH:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.C(O)(=O)C>C(O)(C)C>[C:1]1([C:7](=[N:18][O:19][CH:20]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]2)[C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(ON)C1
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(ON=C(c2ccccc2)c2cc3ccncc3[nH]2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.2 %

Procedure:
To a mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (90 mg, 0.40 mmol) and tert-butyl 3-(aminooxy)pyrrolidine-1-carboxylate (Reference Example 9) (82 mg, 0.40 mmol) in isopropanol (6 mL) was added 4 Å molecular sieves. The pH of the solution was adjusted to pH 4-5 with glacial acetic acid. The reaction mixture was heated to reflux. After 3 days, the reaction mixture was cooled to ambient temperature. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. Purification by column chromatography (silica gel, 9.75:0.25 CH2Cl2/MeOH to 9.5:0.5 CH2Cl2/MeOH) followed by ion-exchange chromatography (SCX-2, 1:3 7 N NH4OH in MeOH/MeOH) gave tert-butyl 3-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]pyrrolidine-1-carboxylate (52.3 mg, 32%) as a mixture of isomers: mp 80-82° C.; 1H NMR (500 MHz, DMSO-d6) major isomer δ 1.37-1.39 (9H, m), 2.08-2.10 (2H, m), 3.13-3.17 (1H, m), 3.31-3.50 (3H, m), 4.92 (1H, br s), 6.23 (1H, s), 7.41-7.53 (6H, m), 8.08 (1H, d, J=5.4 Hz), 8.79 (1H, s), 11.85 (1H, s); ESI MS m/z 407 [C23H26N4O3+H]+; HPLC (Method A) 85.8% (AUC), tR=18.0 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:24]1[CH2:23][CH2:22][N:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])[CH2:26][CH2:25]1)=[O:5]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Product: O=C(c1cc([N+](=O)[O-])ccc1F)N1CCN(c2ccccc2F)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 2-Fluoro-5-nitro-benzoyl chloride and 1-(2-fluorophenyl)-piperazine (52%, orange solid, MS (m/e): 348.1 (M+H, 100%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:24]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(O)cc2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
A mixture of 4-{[4-(2-tert-Butylphenyl)piperazin-1-yl]carbonyl}phenol obtained in Example 20 (1.0 g), methyl bromoacetate (542 mg), potassium carbonate (1.38 g), and N,N-dimethylformamide (30 mL) was stirred at 50° C. for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (430 mg, 59%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17](I)=[C:12]2[CH:11]=[N:10]1.CC1(C)C(C)(C)[O:23][B:22](B2OC(C)(C)C(C)(C)O2)[O:21]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([B:22]([OH:23])[OH:21])=[C:12]2[CH:11]=[N:10]1
Reactant: Fc1cccc(F)c1-n1ncc2c(I)ccnc21
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1c(F)cccc1F
Temperature: 85 °C

Procedure:
To a 48 mL pressure bottle containing Intermediate 74A (1.19 g, 3.24 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.35 g, 13.86 mmol), potassium acetate (1.36 g, 13.86 mmol), and anhydrous DMSO (12.5 mL). The reaction mixture was purged with argon and treated with PdCl2(dppf).CH2Cl2 (56 mg, 0.077 mmol). The reaction mixture was heated to 85° C. for 1 h, then at 105° C. for 1 h to give conversion to the desired product. LC/MS (Condition B): ret. T=2.7 min, (M+H)+ 276.01.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:36])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:16][O:17][C:19]1[CH:20]=[C:21]2[NH:28][C@@H:27]([CH3:36])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1
Reactant: OCc1ccc(Oc2cccc(F)c2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cccc(F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-(3-fluorophenoxy)phenyl)methanol and (S)-tert-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][C:22](=[O:23])[O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Product: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)Oc1ccccc1

Procedure:
This compound was prepared according to the procedure of Example 35 using 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and phenyl chloroformate as the starting materials. LCMS for C17H10BrFN5O5 (M+H)+: m/z=461.9, 463.7.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1.C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:18])[CH:15]=[O:16])[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)CO)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(C(C)(C)C=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-amide (as prepared in the previous step, 1.00 g, 2.55 mmol) and NaHCO3 (1.07 g, 12.8 mmol) in 40 mL of DCM at 0° C. was added Dess-Martin periodinane (Adv. Syn. Chem., 2004, 346, 111-124, 2.16 g, 5.10 mmol). After stirring at 0° C. for 0.5 h, the reaction was warmed to RT and continued to stir for 2 h. The mixture was treated with 100 mL of EtOAc and washed with 10% aqueous Na2S2O3 (2×20 mL), aqueous saturated NaHCO3 (20 mL), H2O (20 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (0-3% MeOH/DCM) to afford the title compound (876 mg, 88%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C23H26N4O2, 391.2 (M+H). found 391.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:44]=[CH:43][C:22]([O:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[C:27]([NH2:29])=[O:28])=[CH:21][CH:20]=1)#[N:18].C(Cl)Cl>C(#N)C>[CH2:1]([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][N:12]([CH2:31][CH2:30][N:26]([CH2:25][CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:44][CH:43]=3)[C:27]([NH2:29])=[O:28])[CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCN(CCOc2ccc(C#N)cc2)C(N)=O)cc1
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1ccc(OCCN(CCN2CC3CN(Cc4ccccc4)CC(C2)O3)C(N)=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
3-Benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane (0.18 g, 0.82 mmol; see WO 01/28992) and toluene-4-sulfonic acid 2-{1-[2-(4-cyanophenoxy)ethyl]-ureido}ethyl ester (0.50 g, 1.24 mmol; see Preparation D above) were mixed in dry acetonitrile (15 mL) and stirred at 60° C. overnight. DCM (10 mL) was added, together with 0.5 g of PS—NCO (polymer-supported isocyanate). The mixture was stirred for 2 h, then filtered and evaporated. The crude product was put on a SCX-II (cation exchanger)-plug, which plug was then eluted with DCM:MeOH (NH3-saturated), 80:20. The product was further purified on a Horizon prep. column (40 g, A: DCM(1% MeOH), B: DCM/MeOH(NH3-sat.), 80:20. Gradient 0-30% B over 1080 mL). The product was then further purified by prep. HPLC and finally extracted with DCM/Na2CO3 (aq.) to give 193 mg (51.9%) of the title compound.