Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:18])=[CH:12]3)[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][S:27]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1>>[CH3:34][N:33]([CH3:35])[CH2:32][CH2:31][NH:30][S:27]([CH2:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][C:13]([CH3:18])=[CH:12]4)[CH:5]=[CH:4][N:3]=2)[CH:21]=1)(=[O:29])=[O:28]
Reactant: Cc1cc2cc(Oc3ccnc(Cl)n3)ccc2[nH]1
Reactant: CN(C)CCNS(=O)(=O)Cc1cccc(N)c1
Product: Cc1cc2cc(Oc3ccnc(Nc4cccc(CS(=O)(=O)NCCN(C)C)c4)n3)ccc2[nH]1

Procedure:
The title compound of Formula A can be synthesized as the crude product of the compound of Formula A by the reaction of Compound 3 with 1-(3-aminophenyl)-N-(2-(dimethylamino)ethyl)methane-sulfonamide (Compound 4) in the presence of an acid, such as but not limited to acetic acid, formic acid, HCl, H2SO4, toluenesulfonic acid, trifluoroacetic acid, or ethanesulfonic acid acidic, and in a solvent, such as but not limited to, N,N-dimethylformamide (DMF), acetonitrile, tetrahydrofuran, ethanol, isopropanol, or toluene. The reaction can be carried out at a suitable temperature, such as a temperature ranging from 40 to 100° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C@@H:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[C@H:16]([OH:25])[CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:28](Br)[CH:29]=[CH2:30].CCOCC.[ClH:37]>C1COCC1.CCOCC>[ClH:37].[CH2:30]([O:25][C@H:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH2:19][CH2:20][C@@H:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH2:15]1)[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: O[C@@H]1C[C@H](CN2CCC(c3ccccc3)CC2)CCc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCO[C@@H]1C[C@H](CN2CCC(c3ccccc3)CC2)CCc2ccccc21
Reaction time: 0.5 h

Procedure:
0.2 g (0.596 mmol) of (±)-cis-7-[(4-phenylpiperdin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol dissolved in 5 ML THF were added dropwise to a suspension of 0.029 g (0.715 mmol) of NaH (60% dispersion in mineral oil) in 10 mL THF. After 30 min at room temperature, 0.12 mL of allyl bromide were added and the reaction mixture was refluxed 8 h. After cooling, the reaction mixture was quenched by addition of MeOH and the solvent was removed in vacuo. The residue was taken up in 1 N NaOH and extracted with CH2Cl2; the organic phase was dried and the solvent was removed in vacuo. The resulting crude product was purified by chromatography, eluting with a mixture CH2Cl2/MeOH 100:2 respectively, yielding an oil which was dissolved in Et2O; the solution was brought to acidic pH with Et2O/HCl and the solvent was removed in vacuo. The resulting solid was triturated with Et2O, yielding 65 mg of the title product. m.p. 126-128° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N+:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([NH:20][NH2:21])=[O:19])([O-:15])=[O:14]>C(O)(=O)C>[N+:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([NH:20][N:21]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:19])([O-:15])=[O:14]
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 73 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3dione in acetic acid was added 2-nitrobenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 159 mg of the title compound (73%) as a yellow solid in 99.2% purity by HPLC (Rt: 5.67, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([SH:10])=[CH:3][CH:2]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>S(=O)(=O)(O)O>[F:11][C:12]1[C:17]2[C:7](=[O:8])[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[S:10][C:16]=2[C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1S
Reactant: Oc1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: O=c1c2ccccc2sc2c(O)ccc(F)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a solution of 2-thiosalicylic acid (39.32 g, 255 mmol) in concentrated sulfuric acid (700 ml) was added 4-fluorophenol (32.0 g, 280 mmol). The red solution was then stirred at room temperature for 18 hours. Upon completion, the mixture was poured directly onto 4 liters of crushed ice and the resulting red solid was filtered off, and then suspended in water (1 L)and treated with ammonia solution until pH 6 attained whereupon the precipitate was re-filtered to give the title compound as an orange solid (44.48 g, 70.8%) m/z (LC-MS, ESP): 247 [M+H]+, R/T=3.99 mins
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][S:10](O)(=[O:12])=[O:11].C(Cl)(=O)C([Cl:19])=O>C1COCC1.CN(C=O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][S:10]([Cl:19])(=[O:12])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=S(=O)(O)Cc1ccccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)Cc1ccccc1C(F)(F)F
Yield: 87.5 %

Procedure:
To a suspension of (2-trifluoromethylphenyl)methanesulfonic acid (20.3 g, 84 mmol) in THF (1.9 L) and DMF (5.0 mL) at −20° C. was added oxalyl chloride (44.7 mL, 0.5 mol) slowly dropwise over 1 hr. The bath temperature was maintained below 0° C. for 4 h, at which point the reaction was evaporated to a volume of ˜250 mL and diluted with 500 mL of ethyl acetate. This solution was washed with brine in a separatory funnel and dried over magnesium sulfate. The solution was then evaporated to a brown oil. This oil was taken up in 500 mL of pet ether (30-50°) and heated with a heat gun until the oil went into solution. The solution was then placed into a dry-ice acetone bath to cool resulting in formation of a white crystalline material. This material was collected via filtration and dried to afford 19 g (85%) of (2-trifluoromethylphenyl)methanesulfonyl chloride as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:16][C:17]([OH:19])=O)[CH:7]([CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][CH3:9])=[O:5])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:8]([CH:7]1[CH2:10][C:11]2[S:12][CH:13]=[CH:14][C:15]=2[C:17](=[O:19])[CH2:16][N:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:9]
Reactant: CCOC(=O)N(CC(=O)O)C(CC)Cc1cccs1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)N1CC(=O)c2ccsc2CC1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
To a solution of Compound 1036 (2.25 g, 7.885 mmol) in DCM (35 mL) was added 0.1 mL of DMF followed by addition of oxalyl chloride (1.502 g, 1.032 mL, 11.83 mmol). The reaction mixture was stirred at RT for 1 hour and the volatiles were removed in vacuo. The residue was taken up in benzene and the volatiles were again removed in vacuo (2×), followed by drying under vacuum. The residue was taken up in dry DCM (35 mL) and AlCl3 (3.679 g, 27.59 mmol) was added at RT. The mixture was stirred at RT for 1.5 hours and the reaction quenched with ethanol. The resulting solution was poured into ice water and extracted with DCM (2×). The combined organic layers were dried over Na2SO4, concentrated under vacuum, and the residue purified by silica gel chromatography, using a 5%-20% ethyl acetate/hexanes gradient as eluant, to produce ethyl 7-ethyl-4-oxo-7,8-dihydro-4H-thieno[2,3-d]azepine-6(5H)-carboxylate (Compound 1037, 671 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][N:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:14][C:13]([CH3:28])([CH3:27])[C:12]=3[N:11]=[C:10]([CH:29]([CH3:31])[CH3:30])[C:9]=2[CH:32]=[O:33])=[CH:4][CH:3]=1.C[Si]([C:38]#[N:39])(C)C.CO.Cl>C(Cl)Cl.[I-].[Zn+2].[I-]>[C:38]([CH:32]([OH:33])[C:9]1[C:10]([CH:29]([CH3:30])[CH3:31])=[N:11][C:12]2[C:13]([CH3:28])([CH3:27])[CH2:14][N:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[O:19])[CH2:16][C:17]=2[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[N:39]
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C=O)CN(C(=O)OCC[Si](C)(C)C)CC2(C)C
Reactant: C[Si](C)(C)C#N
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(O)C#N)CN(C(=O)OCC[Si](C)(C)C)CC2(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
A mixture of 2-(trimethylsilyl)ethyl 4-(4-fluorophenyl)-3-formyl-2-isopropyl-8,8-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (intermediate 1) (4.28 g, 9.09 mmol), trimethylsilyl cyanide (1.46 ml, 10.91 mmol) and zinc iodide (0.145 g, 0.455 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 2.5 h. MeOH (100 mL) was added and the reaction stirred 22 h at room temperature. Additional trimethylsilyl cyanide (2 mL) was added and stirring continued at room temperature for 24 h. 1M HCl (10 mL) was added and stirring continued for 24 h. The reaction mixture was concentrated and the residue taken up in Et2O (200 mL), washed with satd NaHCO3 (50 mL), water (25 mL), brine (25 mL), dried (Na2SO4), filtered and solvent removed to give 2-(trimethylsilyl)ethyl 3-(cyano(hydroxy)methyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (4.16 g) as a tan powder contaminated with about 20% of starting material. This was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].I[C:38]1[CH:43]=[CH:42][NH:41][C:40](=[O:44])[CH:39]=1>>[CH3:36][C:2]([CH3:1])([CH2:5][C@@:6]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:43]=[CH:42][NH:41][C:40](=[O:44])[CH:39]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: O=c1cc(I)cc[nH]1
Product: C[C@@H](c1ccc(-c2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 4. LC-MS Method 1 tR=1.36 min, m/z=456 (M+1); 1H NMR (CDCl3) 7.77 (d, 1H), 7.43-7.32 (m, 7H), 7.01 (t, 4H), 5.67 (q, 1H), 2.99 (dd, 1H), 2.57-2.43 (m, 2H), 2.32 (m, 1H), 2.17 (s, 2H), 1.57 (d, 3H), 1.40 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([CH3:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:6][CH2:7][CH2:8][C:9](=[O:26])[CH2:10][CH2:11][CH2:12][C:13]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16]CC)=[O:15])C.[OH-].[K+]>O.C(O)C>[CH3:25][C:13]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:12][CH2:11][CH2:10][C:9](=[O:26])[CH2:8][CH2:7][CH2:6][C:5]([CH3:33])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:4]([OH:34])=[O:3])[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)C(C)(CCCC(=O)CCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CCCC(=O)CCCC(C)(C(=O)O)c1ccccc1)(C(=O)O)c1ccccc1
Yield: 31.3 %

Procedure:
According to the procedure given for 210f, 209b (14.5 g, 31.1 mmol) was saponified with KOH (85%, 7.2 g, 108.6 mmol) in water (15 mL) and ethanol (45 mL) at reflux for 6 h. After the usual extractive workup, the crude material was purified by flash chromatography (silica gel; ethyl acetate/hexanes=1/20, 1/10, 1/2) to give 210b (4.0 g, 31%) as a white solid. Mp 44-46° C. 1H NMR (CDCl3): 10.25 (br., 2H), 7.35-7.22 (m, 10H), 2.32 (m, 4H), 1.94-1.86 (m, 4H), 1.57 (s, 6H), 1.51-1.22 (m, 4H). 13C NMR (CDCl3): δ 210.64, 182.66, 142.69, 128.66, 127.18, 126.29, 50.07, 42.97, 38.62, 22.20, 19.11. HRMS (LSIMS, gly): Calcd for C25H31O5 (MH+): 411.2171, found: 411.2144. HPLC: 95.2% pure.
Reaction SMILES: Br[C:2]([CH3:23])([CH3:22])[C:3]([NH:5][C:6]1[S:7][C:8]([CH3:21])=[C:9]([CH3:20])[C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:4].[OH-].[NH4+:25]>O1CCCC1>[NH2:25][C:2]([CH3:23])([CH3:22])[C:3]([NH:5][C:6]1[S:7][C:8]([CH3:21])=[C:9]([CH3:20])[C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:4]
Reactant: Cc1sc(NC(=O)C(C)(C)Br)c(C(=O)c2ccc(Cl)cc2)c1C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(NC(=O)C(C)(C)N)c(C(=O)c2ccc(Cl)cc2)c1C
Temperature: 60 °C

Procedure:
A round bottomed flask was charged with 2-bromo-N-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-2-methylpropanamide (5 g, 12.06 mmol) and a stir bar, followed by tetrahydrofuran (25 mL, 0.5 M) and ammonium hydroxide (30%, 7.82 ml, 60.3 mmol, 5 equiv). The solution was stirred at 60° C. 4 h, at which point LC/MS analysis indicated complete consumption of the starting material. The solution was diluted with ethyl acetate, washed successively with water and brine, and purified by column chromatography (eluting with hexanes/ethyl acetate) to yield 2-amino-N-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-2-methylpropanamide as a yellow amorphous solid (m/z=351), which was used in the subsequent reaction.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15](Cl)=[O:16].[NH2:18][C:19]1[S:20][C:21]([CH3:24])=[CH:22][N:23]=1.O>CN(C)C=O>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:18][C:19]1[S:20][C:21]([CH3:24])=[CH:22][N:23]=1)=[O:16]
Reactant: Cc1cnc(N)s1
Reactant: CN1C(C(=O)Cl)=C(O)c2ccccc2S1(=O)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.23 gm (4.5 millimols) of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid chloride-1,1-dioxide were dissolved in 10 ml of dimethylformamide and 1.0 gm (9 millimols) of 2-amino-5-methyl-thiazole was added in portions. The reaction mixture was stirred at room temperature for 24 hours, and then 40 ml of water were added. The mixture was stirred at room temperature for 20 minutes, and the precipitate which had formed was filtered off, washed and dried. After recrystallization from ethylene chloride 0.4 gm (25% of theory) of 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH:35]([CH2:38][CH2:39][CH3:40])[CH2:36][OH:37]>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:34][CH:35]([CH2:36][OH:37])[CH2:38][CH2:39][CH3:40])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reactant: CCCC(N)CO
Product: CCCC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-1-pentanol using conditions similar to those employed in Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.31 (1H, d, J=8 Hz), 8.55 (1H, s), 8.12 (1H, s), 7.40 (2H, dd, J=6, 9 Hz), 7.13 (2H, t, J=9 Hz), 4.93 (1H, t, J=5 Hz), 4.30-4.46 (2H, m), 4.15 (2H, s), 3.94-4.03 (1H, m), 3.32-3.53 (6H, m), 1.88-2.05 (2H, m), 1.68-1.82 (2H, m), 1.42-1.64 (2H, m), 1.25-1.36 (2H, m), 0.88 (3H, t, J=7 Hz); ES+ MS: 511 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.[F:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)=O)=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:15]([C:14]2[CH:22]=[CH:23][C:11]([F:10])=[CH:12][CH:13]=2)[CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNC1
Reactant: Nc1ccc(F)cc1
Agent: Cl
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCNC2)cc1

Procedure:
The title compound is prepared from 4-fluoroaniline and 3-(4-fluorobenzoyl)pyrrolidine hydrochloride according to the procedure of Example 31.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]([OH:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]1>>[OH:35][C:32]([CH:29]1[CH2:30][CH2:31][N:26]([C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]4[CH:25]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:10]=[C:11]4[C:17]=3[CH:18]=2)=[O:23])[CH2:27][CH2:28]1)([CH3:34])[CH3:33]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: CC(C)(O)C1CCNCC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)N3CCC(C(C)(C)O)CC3)ccc1OCC2

Procedure:
Following the procedure for 109, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 2-(piperidin-4-yl)propan-2-ol gave 113. MS: (ESI+)=465.2. 1H NMR (400 MHz, DMSO) δ 8.40 (d, J=1.6 Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.35 (dd, J=8.4, 1.9 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 5.87-5.69 (m, 1H), 4.56 (s, 4H), 4.15 (s, 1H), 1.75 (s, 2H), 1.48 (d, J=6.6 Hz, 7H), 1.19 (dd, J=23.3, 11.1 Hz, 2H), 1.05 (s, 7H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([N:1]([S:30]([CH3:29])(=[O:32])=[O:31])[C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N(S(C)(=O)=O)S(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.374 g) was dissolved in dichloromethane (25 mL) and cooled to 0° C. Triethyl amine (0.5 mL) was added to the solution and methanesulfonyl chloride (0.12 mL) in dichloromethane (5 mL) was added dropwise. After stirring the mixture for 15 miutes, another portion of triethyl amine (0.25 mL) and methanesulfonyl chloride (0.12 mL) were added sequentially. After 15 minutes, the process was repeated and the examination showed a single new product. The reaction mixture was evaporated to dryness and purified by silica gel chromatography, eluting with ethyl acetate/hexane mixture. The colorless crystalline material was recrystallized from hexane-ether to afford 2-(bis-methanesulfonyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, (354 mg), m.p. 143.8-144.2° C.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[CH2:13]([O:15][P:16](Cl)([O:18][CH2:19][CH3:20])=[S:17])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[P:16](=[S:17])([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:2]1[CH2:3][CH2:4][CH2:5][S:1]1)([O:18][CH2:19][CH3:20])[O:15][CH2:13][CH3:14]
Reactant: Oc1ccccc1C1CCCS1
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=S)(OCC)Oc1ccccc1C1CCCS1

Procedure:
A mixture of 3 g. of 2-(tetrahydro-2-thienyl) phenol, 4 g. of diethylchlorothiophosphate, 50 ml. of methyl ethyl ketone and 10 g. of anhydrous potassium carbonate was refluxed for 5 hours. Thereafter, the solids were recovered by filtration and the solvent was removed. The residue was treated with ether and water resulting in the formation of a two-layer liquid. The water layer was removed and the ether layer was washed twice with water. The ether layer resulting therefrom was dried over magnesium sulfate and the solvent removed.
Reaction SMILES: COC[O:4][C:5](=O)[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:14][O:15][CH3:16])=[CH:8][C:7]=1[O:17][CH2:18][O:19][CH3:20].O.[NH2:23][NH2:24]>C(O)C>[Br:12][C:10]1[C:9]([O:13][CH2:14][O:15][CH3:16])=[CH:8][C:7]([O:17][CH2:18][O:19][CH3:20])=[C:6]([CH:11]=1)[C:5]([NH:23][NH2:24])=[O:4]
Reactant: NN
Reactant: COCOC(=O)c1cc(Br)c(OCOC)cc1OCOC
Solvent: CCO
Solvent: O
Product: COCOc1cc(OCOC)c(C(=O)NN)cc1Br
Temperature: 70 °C
Reaction time: 27 h
Yield: 45.1 %

Procedure:
5-bromo-2,4-bis-methoxymethoxybenzoic acid methoxymethylester (IM3-d: 4.36 g, 11.9 mmol), ethanol (15 mL) and hydrazine monohydrate (0.96 mL, 29.8 mmol) were placed in a 100 mL eggplant shaped flask and stirred at 70° C. for 27 hours. After completing the reaction, the reaction mixture was extracted with methylene chloride, and the organic layer was washed with saturated sodium chloride solution and then concentrated under reduced pressure. The solid material thus obtained was suspended in hexane for purification to obtain the title compound (IM4-d: 1.8 g, 46%).
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH:10]1([Mg]Br)[CH2:12][CH2:11]1.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:3][P:4]([CH:10]1[CH2:12][CH2:11]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: Br[Mg]C1CC1
Reactant: CCOP(=O)(Cl)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C1CC1
Temperature: -78 °C
Yield: 50.7 %

Procedure:
To a 200 mL round-bottom flask equipped with a magnetic stir-bar was added phosphorochloridic acid diethyl ester (17.25 mL, 120 mmole) and THF (200 mL). The mixture was cooled to −78° C. and a solution of cyclopropylmagnesium bromide (200 mL, 0.5 M in THF, 100 mmol) was added dropwise over 30 minutes using an addition funnel. The reaction was allowed to slowly warm to room temperature overnight. The resulting clear reaction mixture was poured into saturated NH4Cl (200 mL) and partitioned. The product was extracted from the aqueous layer with diethyl ether (1×100 mL). The organic fractions were combined, dried over sodium sulfate, and concentrated in vacuo. The resulting yellow oil was further purified by vacuum distillation (65-75° C. at 500 mTorr) to provide cyclopropylphosphonic acid diethyl ester (9.025 g, 51%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.11-4.03 (m, 4H), 1.32-1.29 (m, 6H), 0.90-0.77 (m, 5H); 13C NMR (100 MHz, CDCl3) δ ppm 61.7 (d, J=5.3 Hz), 16.4 (d, J=6.1 Hz), 3.3 (d, J=196.3 Hz), 3.0 (d, J=4.6 Hz).