Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11](/[N:14]=[C:15]2/[C:16]([Cl:20])=[N:17][S:18][S:19]/2)=[C:10]([Br:21])[C:9]=1[C:22]#[N:23])(C)(C)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(O)(=O)C>[NH2:7][C:8]1[C:9]([C:22]#[N:23])=[C:10]([Br:21])[C:11](/[N:14]=[C:15]2/[C:16]([Cl:20])=[N:17][S:18][S:19]/2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(/N=c2\ssnc2Cl)c(Br)c1C#N
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: N#Cc1c(N)ccc(/N=c2\ssnc2Cl)c1Br

Procedure:
The thiazolo[5,4-f]quinazoline-2-carbonitriles VIIIaa-ib were prepared following scheme 1: N-Boc Protection of 2-amino-5-nitrobenzonitrile using di-tert-butyl dicarbonate in a suitable solvent, such as dichloromethane, in presence of suitable bases such as triethylamine and 4-(dimethylamino)pyridine and preferably at room temperature, provides tert-butyl (2-cyano-4-nitrophenyl)carbamate I in high yield. Reduction of the nitro intermediate I, for example by treatment with ammonium formate and a catalytic amount of 10% palladium charcoal preferably in ethanol under microwave irradiation for preferably 30 min at 600 W, provides tert-butyl 4-amino-2-cyanophenylcarbamate II in high yield. Treatment of intermediate II by a solution of bromine in dichloromethane in a suitable solvent, such as acetic acid, preferably at room temperature provides tert-butyl 4-amino-3-bromo-2-cyanophenylcarbamate III in a quantitative yield. Intermediate III is reacted with Appel's salt (4,5-dichloro-1,2,3-dithiazolium chloride) (Appel, R. et al., Chem. Ber., 1985, 118, 1632) preferably in dichloromethane at room temperature to afford (Z)-tert-butyl-3-bromo-4-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-2-cyanophenylcarbamate IV. N-Boc deprotection of intermediate IV using di-tert-butyl dicarbonate in a suitable solvent, such acetic acid, preferably under microwave irradiation at 118° C. provides (Z)-6-amino-2-bromo-3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzonitrile V in a quantitative yield. Cyclization of intermediate V may be accomplished by treatment with copper iodide in a suitable solvent, such as pyridine, preferably under microwave irradiation at 400 W at 130° C. for 20 min to obtain 6-aminobenzo[d]thiazole-2,7-dicarbonitrile VI in good yield (Besson, T. et al., J. Chem. Soc., Perkin Trans. 1, 1998, 3925). Treatment of intermediate VI in a suitable solvent, such as dimethylformamide dimethylacetal, preferably under microwave irradiation at 70° C. (600 W) gives (E)-N′-(2,7-dicyanobenzo[d]thiazol-6-yl)-N,N-dimethylformimidamide VII in good yield. Cyclization of intermediate VII in thiazolo[5,4-f]quinazoline-2-carbonitriles VIIIaa-ib may be accomplished by a Dimroth rearrangement using the appropriate aniline or primary amine R3NH2 (preferably 1.5 equivalent) in a suitable solvent, such acetic acid and preferably under microwave irradiation at 118° C. (600 W) (Foucourt, A. et al., Tetrahedron, 2010, 66, 4495).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:22]2[O:23][C:24]([CH3:27])=[CH:25][N:26]=2)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:22]2[O:23][C:24]([CH3:27])=[CH:25][N:26]=2)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1
Reactant: CCOC(=O)CC(c1ccc(OCc2ccccc2)cc1)c1ncc(C)o1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(O)cc1)c1ncc(C)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 3-(4-(benzyloxy)phenyl)-3-(5-methyloxazol-2-yl)propanoate (M5.3) (2.47 mmol) and Pd—C (270 mg) in EtOH was stirred under hydrogen atmosphere at room temperature for 4 hours. The Pd—C was removed by filtration through silica gel eluting with EtOH. After concentration, product M5 was obtained. MS ESI (pos.) m/e 276 (M+H).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:13][C@@H:14]([CH3:33])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=2)=[N:17]1>>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:6][CH:7]=3)=[O:12])[CH3:33])[N:17]=2)=[CH:22][C:23]=1[C:29]([F:30])([F:32])[F:31])#[N:26]
Reactant: CC(C)(O)c1nc(C(=O)O)co1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1)NC(=O)c1coc(C(C)(C)O)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(2-hydroxypropan-2-yl)-oxazole-4-carboxylic acid (0.3 g, 1.75 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile (0.516 mg, 1.75 mmol). The product was purified by column chromatography. Yield 270 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 1.51 (s, 6H), 4.30-4.52 (m, 3H), 5.67 (s, 1H), 7.05 (s, 1H), 7.86 (d, 1H), 8.17 (d, 2H), 8.28 (d, 2H), 8.47 (s, 1H).
Reaction SMILES: [N:1]1([CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].I[CH3:31]>CN(C)C=O>[CH3:31][N:13]1[C:14]2[C:9](=[CH:8][C:7]([CH:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]1=[O:17]
Reactant: O=c1ccc2cc(C(c3cccc(C(F)(F)F)c3)n3cncn3)ccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)ccc2cc(C(c3cccc(C(F)(F)F)c3)n3cncn3)ccc21
Temperature: 25 °C
Yield: 28 %

Procedure:
A mixture of compound 3 (10 g) in N,N-dimethylformamide (100 ml) was stirred at room temperature under N2. Sodium hydride (0.51 g) was added portionwise and the mixture was stirred for 15 minutes. The mixture was cooled, iodomethane was added dropwise and the reaction mixture was stirred for 12 hours. The solvent was evaporated and the residue was partitioned between CH2Cl2 and water. The separated organic layer was dried over MgSO4, filtered and the filtrate evaporated. The oily residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 98/2/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from methyl ethyl keton/diethyl ether, yielding 2.9 g(28%) (±)-1methyl-6-[1H-1,2,4-triazol-1-yl[3-(trifluoromethyl)phenyl]methyl]-2(1H)-quinolinone (compound 12; mp. 186.7° C.). In a similar manner, the following compounds were prepared:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N+:40]([CH2:42][C:43]([O:45][CH3:46])=[O:44])#[C-:41]>CN(C)C=O>[CH3:46][O:45][C:43]([C:42]1[N:40]=[CH:41][O:16][C:14]=1[CH:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:13][CH2:12]1)=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: [C-]#[N+]CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ncoc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To an ice-cold mixture of 1-Boc-4-piperidinecarboxylic acid (9.65 g, 42.1 mmol) and K2CO3 (23.3 g, 168.4 mmol) in N,N-dimethylformamide (60 mL) were added diphenylphosphoryl azide (16.1 g, 58.5 mmol) and methyl isocyanoacetate (5.0 g, 50.5 mmol). After being stirred at room temperature for 16 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated NaHCO3 solution, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 20:80) to give the title compound (9.07 g, 69%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([O:17][CH3:18])=[CH:7][C:6]=1/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])[CH2:2][CH2:3][CH3:4].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:22][C:21](=[O:23])/[CH:20]=[CH:19]/[C:6]2[CH:7]=[C:8]([O:17][CH3:18])[C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: CCCCc1c(/C=C/C(=O)O)cc(OC)c2ccc(OC)cc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)cc(OC)c2ccc(OC)cc12

Procedure:
As in Example 113, (E)-3-(1-butyl-4,7-dimethoxy-2-naphthalenyl)-2-propenoic acid (0.71 g) was treated with 4-nitrophenol (0.35 g) in dichloromethane (10 mL) in the presence of 1,3-dicyclohexylcarbodiimide (0.475 g) to furnish, after the normal work up and crystallization of the crude product from 2-propanol, 1.17 g of (E)-3-(1-butyl-4,7-dimethoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester., mp 144°-145.5° C. Anal. Calcd for C25H25NO6 : C, 68.95; H, 5.79; N, 3.22 Found: C, 69.05; H, 5.74; N, 3.25
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:22][CH:21]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: OB(O)c1ccc(Br)cc1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(Br)cc2)cn1
Yield: 13 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 4-bromophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (15 mg, 13%) which was obtained as an off-white solid. MS: m/e=399.6[M+H]+.
Reaction SMILES: [Na].[CH2:2]([N:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5]([C:7]1[C:8](=[O:20])[N:9]([CH3:19])[C:10]2[C:15]([C:16]=1[OH:17])=[C:14]([Cl:18])[CH:13]=[CH:12][CH:11]=2)=[O:6])[CH3:3].O.C([O-])(=O)C.[Ca+2:32].C([O-])(=O)C>C(O)C.O>[Ca:32].[CH2:2]([N:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5]([C:7]1[C:8](=[O:20])[N:9]([CH3:19])[C:10]2[C:15]([C:16]=1[OH:17])=[C:14]([Cl:18])[CH:13]=[CH:12][CH:11]=2)=[O:6])[CH3:3]
Reactant: [Ca+2]
Agent: CC(=O)[O-]
Agent: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: [Ca]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
N-Ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide sodium salt (2.63 mmol, 1.0 g) was dissolved in a mixture of ethanol (10.5 ml) and water (5.3 ml). The solution was heated to 70° C. and a solution of calcium acetate hydrate in water (1M solution, 1.05 eq., 1.38 mmol, 1.38 ml) was added. The resulting suspension was stirred for 30 minutes, then cooled, and the crystals were isolated by filtration, washed with water, and dried under vacuum (966 mg, 98% yield). Anal. Calcd for C38H32Cl2N4O6Ca: C, 60.7; H, 4.29; N, 7.45. Found C, 60.5; H, 4.34; N, 7.41.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25](O)=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.C[O:39][C:40](=[O:43])[CH2:41][NH2:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]([NH:42][CH2:41][C:40]([OH:39])=[O:43])=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)NCC(=O)O)cc2c1
Yield: 48.6 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carboxylic acid (730 mg, 1.672 mmol) in CH2Cl2 (30 mL) and DMAP (612 mg, 5.02 mmol), EDC (481 mg, 2.51 mmol), and glycine methyl ester hydrochloride (313 mg, 2.51 mmol) are reacted and hydrolyzed analogous to Example 7 to yield title compound (401 mg, 47%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23]>>[CH3:20][N:21]([CH3:26])[S:22]([NH:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH:17]=[CH:18][C:9]([NH:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[N:10]2)(=[O:24])=[O:23]
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Reactant: CN(C)S(=O)(=O)Cl
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)N(C)C)cccc3n2)o1

Procedure:
The title compound, MS: m/e=361.0 (M+H+), was prepared in accordance with the general method of example 19 from N2-(5-Methyl-furan-2-ylmethyl)-quinoline-2,5-diamine and dimethylsulfamoyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH3:11])[S:6][C:7]=1[C:8](O)=[O:9])[CH3:2].Cl>C1COCC1>[CH2:1]([C:3]1[N:4]=[C:5]([CH3:11])[S:6][C:7]=1[CH2:8][OH:9])[CH3:2]
Reactant: CCc1nc(C)sc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CCc1nc(C)sc1CO
Reaction time: 8 h
Yield: 34 %

Procedure:
To a borane tetrahydrofuran complex solution (1.2 M in THF, 5 mL) was added 4-ethyl-2-methylthiazole-5-carboxylic acid (400 mg) at 0° C. The mixture was stirred at 0° C. to room temperature under argon atmosphere overnight. To the mixture was added 1N HCl at room temperature, and the mixture was extracted with EtOAc. The organic layer was separated, washed successively with brine and water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (125 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([C@H:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH3:31])=[CH:26][CH:25]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][N:11]([CH2:22][C:24]3[CH:25]=[CH:26][C:27]([C@H:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH3:31])=[CH:28][CH:29]=3)[CH2:10]2)=[CH:7][CH:8]=1
Reactant: C[C@@H](NS(C)(=O)=O)c1ccc(C=O)cc1
Reactant: Fc1ccc([C@H]2CNCCO2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H](NS(C)(=O)=O)c1ccc(CN2CCO[C@@H](c3ccc(F)cc3)C2)cc1
Reaction time: 3 h
Yield: 81.1 %

Procedure:
Under a nitrogen atmosphere, suspend (2S)-2-(4-fluorophenyl)morpholine hydrochloride (29.5 g, 128.8 mmol) in DCM (17 L) at 22° C. and add triethylamine (35.89 mL, 257.5 mmol). Add N-[(1R)-1-(4-formylphenyl)ethyl]methanesulfonamide (29.26 g, 128.8 mmol) and stir the resulting solution for 30 min. Add acetic acid (8.85 mL, 154.5 mmol), then sodium triacetoxyborohydride (86.17 g, 386.3 mmol) portion-wise in 3 batches. Stir for 3 h; monitor the reaction via LCMS until completion. Quench the reaction via the slow addition of a saturated aqueous solution of sodium bicarbonate (259.31 mL) to give a solution with a pH of 8. Separate the layers, and extract the aqueous layer with 200 mL DCM. Combine the organic layers, wash with saturated sodium bicarbonate, water, brine, and then dry over MgSO4. Filter; collect the filtrate; and concentrate to give a residue. Purify the residue via silica gel flash column chromatography, using a gradient of 100% DCM to DCM:MeOH (95:5). Combine the product fractions, and concentrate to provide the title product as a yellow thick oil (41 g, 81.13%). MS (m/z): 393 (M+1)
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C:17](=[C:28]([F:30])[F:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C=C1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[F:29][C:28]([F:30])=[C:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:50])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16]1
Reactant: C[C@]12CCCCC1C(=C(F)F)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C[C@]12CCC(=O)CC1C(=C(F)F)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 99 %

Procedure:
The title compound II-ak was prepared in 99% yield from 3,3:17,17-bis(ethylendioxy)-6-difluoromethyleneandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 2.85-0.95 (20H, m), 1.12 (3H, s), 0.88 (3H, s).
Reaction SMILES: C([C:4]1[C:8](C)=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6][C:5]=1[NH:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])(O)=O.[Li+].[I-].C1(C(O)=O)CCCCC1>N1C(C)=CC(C)=CC=1C>[C:10]1([C:7]2[S:6][C:5]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[CH:4][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1c(-c2ccccc2)sc(NC(=O)C2CCCCC2)c1C(=O)O
Agent: [I-]
Agent: [Li+]
Solvent: O=C(O)C1CCCCC1
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(Nc1ccc(-c2ccccc2)s1)C1CCCCC1

Procedure:
This compound (m.p. 174° C.) was prepared from N-(3-carboxy-methyl-5-phenyl-2-thienyl)-cyclohexane carboxamide (31.1 g, 0.1 mole) and LiI. 2H2O (48.1 g, 0.32 mole) by refluxing in collidine (125 ml.) according to the procedure of Example 53 (a). This compound was also prepared according to the procedure of Example 53(b), using cyclohexane carboxylic acid as the acylating agent. The products of the two processes were spectrally identical and had a melting point of 175° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].[C:13]([C@@H:15]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1)#[N:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:13]([C@@H:15]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:12])[CH:5]=2)=[CH:19][CH:18]=1)#[N:14]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H](C#N)Cc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](C#N)Cc1ccc(-c2ccc(C#N)c(F)c2)cc1
Reaction time: 0.17 h
Yield: 38.3 %

Procedure:
A solution of 4-cyano-3-fluorophenylboronic acid (0.736 g) dissolved in dioxane (10 mL) was added to a stirred solution of (S)-tert-butyl 1-cyano-2-(4-iodophenyl)ethylcarbamate (1.51 g) and bis[bis(1,2-diphenylphosphino)ethane]palladium (0) (0.037 g) in dioxane (20 mL) under nitrogen. The resulting mixture was stirred for 10 min. A solution of potassium carbonate (1.121 g) in water (5 mL) was added and the resulting solution was stirred at 75° C. for 3 h. The cooled mixture was evaporated to dryness. The residue was taken up in ethyl acetate (150 mL) and washed with saturated brine (3×50 mL), dried over sodium sulfate and adsorbed onto silica. The crude product was purified by flash silica chromatography, eluting with 20% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the subtitle compound as a colourless solid (0.568 g).
Reaction SMILES: O=C(NN[C:13]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][C:17]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]1=2)=[O:14])CCC1C=CC=CN=1.FC(F)(C(O)C1C=CN=CC=1)C(NN)=[O:34].ClC1C=CC2OC3C=CC=CC=3CN(C(Cl)=O)C=2C=1>C(O)(=O)C.Cl>[Cl:30][C:28]1[CH:27]=[CH:26][C:17]2[O:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[CH2:21][N:15]([C:13]([OH:14])=[O:34])[C:16]=2[CH:29]=1
Reactant: O=C(CCc1ccccn1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: NNC(=O)C(F)(F)C(O)c1ccncc1
Agent: Cl
Agent: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CC(=O)O
Product: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
The free base of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[2,2-difluoro-3-hydroxy-1-oxo-3-(4-1-oxo-3-(4-pyridinyl) propyl]hydrazide (51) was prepared in the same manner as 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(2-pyridinyl)propyl]hydrazide (6), as described above in Example 6, on a 1.75 mmol scale from α,α-difluoro-β-hydroxy-3-(4-pyridinyl)-propanoic acid, hydrazide (50), prepared in the manner described above in Example 50, and 8-chlorodibenz-[b,f][1,4]oxazepine-10 (10H)-carbonyl chloride (2), prepared in the manner described above in Example 2, for a yield of 0.098 g (12%) of product. The free base was taken up in acetic acid (1.5 mL) and 1M HCl (1.5 mL). The material was lyophilized to yield 0.049 mg of the hydrochloride salt. Analysis calculated for C22H17N4O4F2Cl.HCl.0.25 H2O (M.W. 514.83): C, 51.23; H, 3.62; N, 10.86. Found: C, 50.85; H, 3.67; N, 10.94.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([CH:15]=[O:16])[C:9]2=[O:17])=[CH:4][CH:3]=1.[OH:18]P([O-])(O)=O.[Na+].CC(=CC)C.Cl([O-])=O.[Na+].Cl>C1COCC1.CC(O)(C)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15]([OH:18])=[O:16])[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=Cc1c(I)ccn(-c2ccc(F)cc2)c1=O
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A 0° C. mixture of 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (8 g, 23 mmol) and sodium phosphate monobasic (8 g, 58.4 mmol) in 1:1:1 THF/t-BuOH/water (105 mL) was treated with 2-methyl-2-butene (2.0 M in THF, 36.1 mL, 72.2 mmol) followed by sodium chlorite (4.8 g, 53.7 mmol) and the vigorously stirred mixture warmed to RT and stirred for 1 h. HCl (1 M, 20 mL) was added, the mixture stirred for 5 minutes and the solid was collected via filtration and washed with water, EtOAc, then Et2O. The layers of the filtrate were separated and the aqueous layer extracted with additional EtOAc. The combined organics were dried over MgSO4, concentrated to dryness, the residue suspended in EtOAc, the solid collected via filtration and combined with the above-isolated solid. The combined material was dissolved in a minimum amount of 1N NaOH, treated with EtOAc, stirred vigorously for 5 minutes and the layers separated. The aqueous layer was washed with EtOAc, acidified to pH=1 with conc. HCl and the resulting solid was collected via filtration, washed with water, EtOAc and Et2O and dried to afford 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (5.4 g, 65%). 1H NMR (400 MHz, DMSO-d6): δ 13.5 (brs, 1H), 7.43-7.47 (m, 3H), 7.30-7.35 (m, 2H), 6.76 (d, J=7.2 Hz, 1H).