Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:27]1(B(O)O)[CH2:29][CH2:28]1.F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:27]1([C:2]2[C:3]([O:16][CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]3)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCCC2CCC(F)(F)CC2)cc1F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCCC2CCC(F)(F)CC2)cc1F
Temperature: 100 °C
Reaction time: 24 h
Yield: 25.5 %

Procedure:
To a solution of tert-butyl 5-chloro-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoate (0.681 g, 1.70 mmol) in toluene-water (v/v 20:1, 10.5 mL) was added cyclopropylboronic acid (0.227 g, 2.60 mmol), tricyclohexylphosphine tetrafluoroborate (0.064 g, 0.17 mmol) and potassium phosphate tribasic (1.658 g, 7.80 mmol). The mixture was sparged with nitrogen gas for 10 minutes and sonicated for an additional 5 minutes. Palladium (II) acetate (0.019 g, 0.082 mmol) was added and the reaction mixture heated at 100° C. under nitrogen for 16 hours. The mixture was then cooled to ambient temperature then charged with additional cyclopropylboronic acid (0.227 g, 2.60 mmol), tricyclohexylphosphine tetrafluoroborate (0.070 g, 0.19 mmol) and palladium(II) acetate (0.021 g, 0.094 mmol). The mixture was heated to 100° C. and stirred for an additional 24 hours. The solution was then cooled to ambient temperature and filtered through diatomaceous earth with ethyl acetate. The solution was concentrated in vacuo and purified by column chromatography (0% to 20% ethyl acetate in hexanes) to afford the title compound (0.173 g, 25%): 1H NMR (300 MHz, CDCl3) δ 7.38 (d, J=8.4 Hz, 1H), 6.51 (d, J=12.7 Hz, 1H), 4.04 (t, J=6.2 Hz, 2H), 2.15-2.07 (m, 2H), 2.02-1.95 (m, 1H), 1.88-1.61 (m, 7H), 1.57 (s, 9H), 1.43-1.31 (m, 2H), 0.92-0.86 (m, 2H), 0.66-0.61 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]3[N:17]=[CH:18][CH:19]=[C:20]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:15]3=N[C:13]=2[CH:27]2[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[NH:29]1[CH2:28][CH:27]([C:13]2[CH:38]=[C:15]3[C:20]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:19][CH:18]=[N:17][N:16]3[C:12]=2[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[CH2:30]1
Reactant: CCOC(=O)c1ccc(-c2c(C3CN(C(=O)OC(C)(C)C)C3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(-c2c(C3CNC3)cc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 19e (170 mg, 0.335 mmol) in DCM (2 mL), TFA (2 mL) was added. The resulting mixture was stirred at rt for 1 h and concentrated. The resulting residue was dried in vacuo for 4 h and suspended in ether. The mixture was concentrated and the resulting residue was dried in vacuo overnight to obtain ethyl 4-(6-(azetidin-3-yl)-4-morpholinopyrrolo[1,2-b]pyridazin-7-yl)benzoate trifluoro acetic acid salt (19g), which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:12])=[CH:4][CH:3]=1.[NH2:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>CCOC(C)=O>[NH2:25][C:26]1[N:31]=[C:30]([O:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]=3[NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:15][CH:16]=2)[CH:29]=[CH:28][N:27]=1
Reactant: O=C(Nc1ccc(O)cc1)c1ccccc1Nc1ccc(F)cc1
Reactant: Nc1nccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1nccc(Oc2ccc(NC(=O)c3ccccc3Nc3ccc(F)cc3)cc2)n1
Temperature: 150 °C

Procedure:
A mixture of 2-(4-fluorophenylamino)-N-(4-hydroxyphenyl)benzamide (157 mg, 486 μmol), 2-amino-4-chloropyrimidine (60 mg, 463 μmol), and cesium carbonate (302 mg, 926 μmol) in DMSO (2316 μl, 463 μmol) was placed in a microwave pressure vial, the vial was sealed, and the vial (reaction mixture) was heated in a Biotage Microwave to 150° C. for 12 minutes. LCMS analysis indicated that the reaction was complete. Reaction was diluted with EtOAc and washed with sat NaHCO3 (aq). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a brown color oil. The oil was taken up in minimal amount of DMSO and purified by Gilson HPLC {10-80% (0.1% TFA in CH3CN) in H2O over 20 min} to afford pure N-(4-(2-aminopyrimidin-4-yloxy)phenyl)-2-(4-fluorophenylamino)benzamide. MS Calcd for C23H18FN5O2=415. Found: [M+H]+=416.
Reaction SMILES: [Br:1][C:2]([Br:9])([Br:8])[CH2:3][CH2:4][C:5]([Cl:7])=[O:6].S(Cl)([Cl:12])=O.ClN1C(=O)CCC1=O>>[Cl:12][CH:4]([CH2:3][C:2]([Br:9])([Br:8])[Br:1])[C:5]([Cl:7])=[O:6]
Reactant: O=C(Cl)CCC(Br)(Br)Br
Reactant: O=S(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Product: O=C(Cl)C(Cl)CC(Br)(Br)Br
Temperature: 60 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a solution of 343,2 g (1 mole) 4,4,4-tribromobutyric acid chloride in 600 g of thionylchloride 266,0 g (2 mole) of N-chlorosuccinimide is added portion wise at 60° C. while the reaction mixture is irradiated with a mercury high-pressure lamp. After addition of the N-chlorosuccinimide the reaction mixture is stirred for 5 hours at 60° C. while irradiation is continued. Then the thionyl chloride is evaporated and the residue is distilled in vacuo. 309.7 (82% of theory) of 2-chloro-4,4,4-tribromobutyric acid chloride, b.p. 59°-63° C./0,05 torr is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][N:22]=1>C(O)C>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][N:22]=[C:21]2[NH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=3)[S:8][C:4]=2[CH:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc2nc(NC(=O)c3cccnc3)sc2c1
Solvent: CCO
Product: COc1cc2ncnc(Nc3ccc4nc(NC(=O)c5cccnc5)sc4c3)c2cc1OC

Procedure:
N-[6-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-2-yl]nicotinamide was prepared by heating a mixture of N-(6-aminobenzothiazol-2-yl)nicotinamide (IM 4, 30 mg, 0.111 mmol) and 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 25 mg, 0.111 mmol) in ethanol (3 mL) to 80° C. for 2 h. The resulting precipitate was separated by filtration, washed with ethanol and dried (yellow solid, 44 mg, 96 μmol, 87%), LC/ESI-MS: m/z=459 [M+H]+; m/z=457 [M+H]−; Rt=2.60 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([O:13]CC)=[O:12])[N:9]=1)(=[O:3])[CH3:2]>C(O)C>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([OH:13])=[O:12])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1csc(NC(C)=O)n1
Solvent: CCO
Product: CC(=O)Nc1nc(CC(=O)O)cs1

Procedure:
Ethyl 2-(2-acetylaminothiazol-4-yl)acetate was reacted in a mixture of ethanol-1M sodium hydroxide aqueous solution (1:1) at room temperature, and then the reaction mixture was worked up and purified in a usual manner to obtain 2-(2-acetylaminothiazol-4-yl)acetic acid as a colorless solid. MS: 201.
Reaction SMILES: [CH3:1][C:2]1([C:5]2[O:6][C:7](=[O:10])[NH:8][N:9]=2)[CH2:4][CH2:3]1.[C:11]1([Sn:17](Cl)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([C:5]2[O:6][C:7](=[O:10])[N:8]([Sn:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:9]=2)[CH2:4][CH2:3]1
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(c2n[nH]c(=O)o2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2nn([Sn](c3ccccc3)(c3ccccc3)c3ccccc3)c(=O)o2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 5 g (0.035 mole) 2-(1'-methylcyclopropyl)-5-oxo-1,3,4-oxadiazoline and 13.5 g (0.035 mole) triphenyl tin chloride in methylene chloride (about 100 ml), 3.5 g (0.035 mole) triethylamine in methylene chloride (about 50 ml) was added dropwise. The reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was refluxed (at about 40° C.) for about 3 hours, cooled and then allowed to stir at ambient temperature for about one hour. The reaction mixture was washed with water and then extracted with methylene chloride. The methylene chloride extract was dried and then stripped. The residue was washed with hexane to precipitate the above-identified product, melting point 165°-167° C.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][O:13][CH:14]=2)[CH:5]=1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li]>>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][O:13][CH:14]=2)[CH:5]=1)=[O:15])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1cccc(-c2cocn2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cocn2)c1

Procedure:
3-Oxazol-4-yl-benzoic acid methyl ester (0.85 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-(3-oxazol-4-yl-phenyl)-3-oxo-propionic acid tert-butyl ester (1.46 g) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][O:11][CH2:12][C:13]([NH:15][C:16]([C:18]2[C:23](Cl)=[N:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[NH:14])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].O.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][O:11][CH2:12][C:13]2[NH:15][C:16](=[O:17])[C:18]3[C:23](=[N:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N=C(COCCc1ccc(F)c(Cl)c1)NC(=O)c1nccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(COCCc2ccc(F)c(Cl)c2)nc2nccnc12
Temperature: 100 °C
Yield: 45.1 %

Procedure:
A mixture of crude 3-chloro-pyrazine-2-carboxylic acid{2-[2-(3-chloro-4-fluoro-phenyl)-ethoxy]-1-imino-ethyl}-amide (300 mg) and K2CO3 (223 mg, 1.616 mmol) in DMF (3 ml) was heated to 100° C. for 2 h. Then water was added and the pH was adjusted to 5 by addition of 0.1 N HCl. The brown precipitate that formed was filtered off, washed with water and dried. The resulting solid was triturated with Et2O. The remaining solid was filtered off, washed with a small amount of Et2O and dried to give the title compound as a light brown solid (122 mg, 45%). MS: m/e=335.2 [M+H+].
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[C:30]1([C@@H:36]2[CH2:38][C@H:37]2[C:39]([OH:41])=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([C@@H:36]2[CH2:38][C@H:37]2[C:39]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:41])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Product: CN(C(=O)[C@@H]1C[C@H]1c1ccccc1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with trans-2-phenyl-1-cyclopropanecarboxylic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(trans-2-phenyl-1-cyclopropylcarbonyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 510 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16]Br>>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Fc1ccc(CBr)cc1F
Product: O=Cc1cn(Cc2ccc(F)c(F)c2)c2ccccc12

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-3-carbaldehyde and 3,4-difluorobenzyl bromide in place of the benzyl bromide used in Example 1 to give 1.59 g of 1-(3,4-difluorobenzyl)indole-3-carbaldehyde as pale brown crystals. The yield thereof was found to be 98%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.O.[NH2:25][NH2:26].CCOC(C)=O.CCCCCC>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:26][N:25]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(Nc3ccccc3)nc(N)n2)cc1F
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1nc(Nc2ccccc2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
To 4-[2-amino-6-(phenylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (366 mg, 1.2 mmol) in EtOH (10 mL) was added hydrazine monohydrate (1.0 mL, 32 mmol) and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto water and EtOAc. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford crude product (230 mg). This material was dissolved in EtOH. Hexane was added until a precipitate began to form (a spatula was used to scratch the walls). The mixture was decanted and the solid was dried under vacuum to afford the title compound (100 mg, 26%) as a tan solid. LC-MS (ES) m/z=302, 304 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 6.51 (s, 1H), 7.04 (m, 1H), 7.32 (m, 2H), 7.46 (dd, J=8.6, 1.3 Hz, 1H), 7.66 (m, 2H), 7.75 (dd, J=8.3, 0.8 Hz, 1H), 7.81 (s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](OC)=[O:30].Cl>O.C1COCC1.CCCCCC>[O:30]=[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccccn1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CC(=O)c2ccccn2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 11.4 %

Procedure:
A THF solution (50 mL) of diisopropylamine (12.6 mL) was cooled to 0° C., and a hexane (33 mL) solution of 2.6 M n-butyllithium was added thereto and stirred at that temperature for 10 minutes. Then this was cooled to −78° C., and a THF solution (15 mL) of 4-methylbenzenecarboxylic acid (2.3 g) was dropwise added thereto. The reaction liquid was stirred at −40° C. for 2.5 hours, and then a THF solution (4 mL) of methyl picolinate (2.0 g) was dropwise added thereto. The reaction solution was heated up to room temperature, and stirred for one day. Next, water was added to the reaction liquid, then controlled to have a pH of 4 with aqueous hydrochloric acid solution added thereto, and then extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain the entitled compound (400 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.[N:22]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[C:23]=[O:24]>>[C:25]1([N:22]2[CH2:12][CH2:13][C@H:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:21][C:23]2=[O:24])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H](O)c2ccccc2)cc1
Product: O=C1O[C@@H](c2ccccc2)CCN1c1cccc2ccccc12

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 2 using (R)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate and 1-isocyanatonaphthalene. LC-MS (10-80) tR=2.625 min, m/z=304; 1H NMR (CDCl3) δ 2.44-2.55 (m, 3H), 3.64-3.69 (m, 1H), 3.84-3.91 (m, 1H), 5.62-5.72 (m, 1 H), 7.38-7.61 (m, 9H), 7.86-7.93 (m, 3H).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.COC1C=C([Mg]Br)C=CC=1OC.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]=1.Cl>O1CCCC1>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](=[O:31])[C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[CH:4]=2)=[CH:28][N:27]=1
Reactant: COc1ccc(Br)cc1OC
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: COc1ccc([Mg]Br)cc1OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(Cl)nc2)cc1OC
Yield: 67.3 %

Procedure:
To 200 ml of tetrahydrofuran were added metallic magnesium (5.35 g) and 4-bromoveratrole (47.8 g), and the mixture was heated for 3 hours under reflux to prepare a 3,4-dimethoxyphenyl magnesium bromide solution. This solution was added, while stirring, dropwise at temperatures ranging from -50° C. to -60° C. to a solution of 6-chloronicotinic acid chloride (21.2 g) in tetrahydrofuran (200 ml) (the time required for the addition: one hour). The resultant mixture was stirred at the same temperature for 2 hours and 40 minutes, and there was then added 2N hydrochloric acid (100 ml). Precipitating crystals were collected by filtration, washed with water and dried to afford 2-chloro-5-(3,4-dimethoxybenzoyl)pyridine (22.5 g), m.p. 158° to 159° C.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[N-:27]=[N+:28]=[N-:29].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[N:27]([CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:13]([O:22][CH2:23][CH:24]2[CH2:25][CH2:26]2)[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:6])[CH3:7])=[N+:28]=[N-:29]
Reactant: CC(C)C[C@@H](CO)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CN=[N+]=[N-])NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
To a colorless solution of 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (Example 14b; 231 mg, 639 μmol) in DMF (25.6 mL) and CCl4 (6.4 mL) was added sodium azide (49.9 mg, 767 μmol) and triphenylphosphine (352 mg, 1.34 mmol). The resulting reaction mixture was stirred at 90° C. for 4 hours. After cooling to room temperature the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate; the organic phases were washed with brine, combined, dried with Na2SO4, filtered and concentrated in vacuo. The residue, a brown waxy solid, was purified by flash chromatography (silica gel, 50 g, 0% to 60% ethyl acetate in heptane) to give the title compound (110 mg, 45%) as white solid; MS (ESI) 387.3 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([C:19]2[N:20]=[C:21]3[C:27]4[CH:28]=[C:29]([C:32](O)=[O:33])[CH:30]=[CH:31][C:26]=4[O:25][CH2:24][CH2:23][N:22]3[CH:35]=2)=[N:17][CH:16]=[N:15]1.C[N:37](C)C=O.CN(C)C(=O)C>C(Cl)Cl.N>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([C:19]2[N:20]=[C:21]3[C:27]4[CH:28]=[C:29]([C:32]([NH2:37])=[O:33])[CH:30]=[CH:31][C:26]=4[O:25][CH2:24][CH2:23][N:22]3[CH:35]=2)=[N:17][CH:16]=[N:15]1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccccc3Cl)cn1CCO2
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccccc3Cl)cn1CCO2
Reaction time: 2 h
Yield: 349.8 %

Procedure:
Oxalyl chloride in methylene chloride (2.00 M, 3.0 mL) was added to a suspension of 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid (112 mg, 0.178 mmol) in 30 ml of methylene chloride. Catalytic amount of N,N-Dimethylformamide (1.0 uL, 0.013 mmol) was added and the mixture was stirred for 2 hours. The mixture was filtered, the filtrate was concentrated in vacuum and the residue dried in high vacuum for 1 hour. The above residue was dissolved in N,N-dimethylacetamide (3.0 mL, 32 mmol) and saturated with gaseous ammonia. The mixture was stirred for 20 min, concentrated in vacuum, dissolved in aqueous methanol and subjected to RP HPLC purification to yield 18.5 mg of 102 (26%), MS: 407.1. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=2.2, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 7.72-7.51 (m, 6H), 7.29 (s, 1H), 7.00 (d, J=8.5, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=O)[C:5]([CH2:22][N:23]2C(=O)C3=CC=CC=C3C2=O)=[N:4][N:3]=1.C(N)CC>>[Cl:1][C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:23][CH2:22][C:5]2=[N:4][N:3]=1
Reactant: O=C(c1ccccc1Cl)c1ccccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O
Solvent: CCCN
Product: Clc1ccccc1C1=NCc2nnc(Cl)n2-c2ccccc21

Procedure:
The 2-(3-chloro-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl)-2'-chlorobenzophenone is reacted with propylamine to form the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)=[O:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:10](=[O:12])[CH2:9][C:6]3[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=3)[CH2:23][CH2:22]2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: Fc1ccc(NC2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=Cc1ccc(CC(=O)N2CCC(Nc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A mixture of D3 (87 mg, 0.53 mmol), D2 (102 mg, 0.53 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (123 mg, 0.64 mmol), and 1-hydroxybenzotriazole (98 mg, 0.64 mmol) in DMF (2 ml) was stirred at room temperature overnight. The DMF was removed in vacuo then EtOAc and water were added. The product was extracted into EtOAc and the combined organic layers were washed with saturated aq. NaHCO3 solution (×2) and brine then dried (Na2SO4). The solvent was removed in vacuo and the resulting residue was purified by chromatography eluting with an EtOAc/petroleum ether gradient to afford the title compound (149 mg). MS (ES): MH+ 341.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([C:12]1[N:16]=[CH:15][NH:14][N:13]=1)=[O:11].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([C:12]1[N:16]=[CH:15][N:14]([C:19](=[O:20])[N:18]([CH3:22])[CH3:17])[N:13]=1)=[O:11]
Reactant: Cc1cc(C)c(S(=O)c2nc[nH]n2)c(C)c1
Reactant: CN(C)C(=O)Cl
Product: Cc1cc(C)c(S(=O)c2ncn(C(=O)N(C)C)n2)c(C)c1

Procedure:
3-(2,4,6-Trimethylphenyl)sulfinyl-1H-1,2,4-triazole and dimethylcarbamoyl chloride were employed to synthesize the title compound as in Example 22.