Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.CN(C)CCN(C)C.C([Li])CCC.[F:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>O.O1CCCC1>[F:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)([C:5]2[N:4]([CH2:3][O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[OH:28])=[CH:25][CH:24]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COCn1ccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of 11.2 g. (0.1 mol) of 1-(methoxymethyl)imidazole and 13.9 g. (0.12 mol) of N,N,N',N'-tetramethylethylenediamine in 150 ml. of anhydrous tetrahydrofuran 51 ml. (0.12 mol) of a butyllithium solution (20% in n-hexane) was added drop-wise over the course of one hour at -60° C., and under a nitrogen atmosphere. After the addition was completed, stirring was continued for another two hours. The cooling means was then removed and 25.1 g. (0.1 mol) of 4,4'-difluorobenzophenone in 150 ml. of anhydrous tetrahydrofuran were added drop-wise. The reaction mixture was stirred for 6 hours at room temperature and it was then decomposed with 15 ml. of water. The precipitated lithium hydroxide was filtered off and the filtrate was concentrated by distilling off the solvents. 2N Hydrochloric acid was added to the residue, after which the mixture was extracted with diethyl ether. The aqueous phase was made alkaline with 2N sodium hydroxide solution. The precipitate formed was filtered off, washed with water and twice crystallised from a mixture of isopropyl alcohol and petroleum ether (boiling range 40°-60° C.). α,α-Bis(p-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol was obtained. Melting point 133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20](O)=[O:21])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[O:21])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)O)c2)=C(C)C1=O
Reactant: C1CSCCN1
Product: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)N3CCSCC3)c2)=C(C)C1=O
Yield: 40.7 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (90 mg, 0.27 mmol) obtained in Example 57 and thiomorpholine (0.040 ml, 0.41 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (47 mg, 0.11 mmol, yield 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15](/[CH:20]=[N:21]/[S@@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:16][O:17][C:18]=2[CH3:19])=[O:7])=[CH:4][CH:3]=1.C1COCC1.[Cl-].[C:36]([O:40][C:41](=[O:44])[CH2:42][Zn+])([CH3:39])([CH3:38])[CH3:37]>[NH4+].[Cl-].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([C@@H:20]([NH:21][S@@:22]([C:24]([CH3:25])([CH3:26])[CH3:27])=[O:23])[CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])=[N:16][O:17][C:18]=2[CH3:19])=[O:7])=[CH:28][CH:29]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([C@H:20]([NH:21][S@@:22]([C:24]([CH3:25])([CH3:26])[CH3:27])=[O:23])[CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])=[N:16][O:17][C:18]=2[CH3:19])=[O:7])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Cc1onc(/C=N/[S@](=O)C(C)(C)C)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1onc([C@@H](CC(=O)OC(C)(C)C)N[S@](=O)C(C)(C)C)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Product: Cc1onc([C@H](CC(=O)OC(C)(C)C)N[S@](=O)C(C)(C)C)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Reaction time: 2.5 h

Procedure:
To a round bottomed flask was added (R,E)-N-((4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (0.480 g, 1.12 mmol) and THF (6 mL). This solution was cooled to 0° C. before addition of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (4.48 mL, 2.24 mmol). The solution was stirred at 0° C. before for 3.5 h before addition of more of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (1.12 mL, 0.560 mmol). The reaction was stirred for an additional 2.5 h before being diluted with aqueous NH4Cl and EtOAc. The layers were separated and the aqueous was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (3S)-tert-butyl 3-(4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate (0.118 g, 0.216 mmol) and (3R)-tert-butyl 3-(4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate (0.094 g, 0.172 mmol). LC/MS m/z 545 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH:10]=2)[C:3]1=[O:27].[Cl:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=2)[CH:31]=1>>[CH3:1][C@@H:2]1[N:7]([CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36]3[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=3)[CH:31]=2)[CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH:10]=2)[C:3]1=[O:27].[ClH:28]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCN[C@@H](C)C3=O)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)[C@@H](C)C3=O)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
(3S)-3-Methyl-2-oxo-1-[[2-(3,4,5-trimethoxy-phenyl)pyridin-4-yl]methyl]piperazine (80 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (63 mg) were reacted in the same manner as in Example 4 to obtain the title compound as a hydrochloride.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.2 %

Procedure:
A mixture of (2R)-2-hydroxypropanamide (0.468 g, 5.26 mmol) and triethyloxonium tetrafluoroborate (0.941 g, 4.95 mmol) in tetrahydrofuran (7.2 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (3.0 mL) and added to a suspension of tert-butyl 4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate (0.57 g, 1.6 mmol) in ethanol (11 mL). The mixture was stirred at 80° C. for 1 h. The solvent was removed and the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (85 mg, 13%). LCMS calculated for C20H27N4O3S (M+H)+: m/z=403.2. Found: 403.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([Br:19])=[CH:4][N:3]=1.[Li+].[OH-].Cl.CCOC(C)=O>C1COCC1.CO>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([Br:19])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ncc(Br)cc1-c1ccc(C(=O)O)c(F)c1
Reaction time: 5 h

Procedure:
To a solution of methyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate (1.9 g, 5.84 mmol) in THF (19.48 mL) and MeOH (9.74 mL, Ratio: 1.000) was added LiOH (1 M aqueous solutionueous solution) (10.52 mL, 10.52 mmol). The reaction mixture was stirred for 5 h. After 1N HCl (1.9 mL) was added up to pH 5, the reaction mixture was worked up with EtOAc, the organic layer was dried over Na2SO4, filtered off and concentrated in vacuo. The crude 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoic acid was used for the next step without further purification. LCMS (m/z): 311.1/313.1 (MH+), 0.5 min.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12][C:13]([OH:15])=O.[C:18]([CH:21]1[CH2:26][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:24][CH2:23][NH:22]1)(=[O:20])[NH2:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[F:11][C:9]1[CH:8]=[CH:7][C:6]([CH2:12][C:13]([N:22]2[CH2:23][CH2:24][N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[CH2:26][CH:21]2[C:18](=[O:20])[NH2:19])=[O:15])=[C:5]([O:4][CH2:3][C:2]([F:1])([F:17])[F:16])[CH:10]=1
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Reactant: O=C(O)Cc1ccc(F)cc1OCC(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1ccccc1N1CCN(C(=O)Cc2ccc(F)cc2OCC(F)(F)F)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-4-fluorophenylacetic acid (0.15 g, 0.60 mmol) from Step 5 above and 2-carbamoyl-4-(2-methylphenyl)piperazine (0.13 g, 0.66 mmol) from Step 4 of Example 1 in DMF (3 mL) was added HOBT (0.11 g, 0.78 mmol), EDC (0.17 g, 0.9 mmol), and DIEA (0.16 mL, 0.9 mmol). The solution was stirred at ambient temperature for 14 h and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and 0.25 M aqueous citric acid (25 mL). The organic phase was separated and washed with H2O (10 mL) and saturated aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 5:95 MeOH:CH2Cl2 as eluant. Evaporation of the product-containing fractions gave the title compound as an amorphous solid. HPLC retention time=9.16 min (method A) TLC Rf =0.25 (5:95 MeOH:CH2Cl2); FAB MS: m/z=454 (M+ +H), 0.4 CH2Cl2 ; combustion analysis: C22H23F4N3O3, 0.4 CH2Cl2 ; Calculated C, 57.43; H, 5.12; N, 8.97; Found C, 57.44; H, 4.89; N, 9.22
Reaction SMILES: Cl.[CH2:2]([NH:4][C@H:5]([C:7]([OH:9])=[O:8])[CH3:6])[CH3:3].[CH:10](=O)[C:11]1C=C[CH:14]=[CH:13][CH:12]=1.Cl[CH2:19][CH2:20]Cl>>[CH2:19]([O:8][C:7](=[O:9])[CH:5]([NH:4][CH2:2][C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:20]
Reactant: ClCCCl
Reactant: O=Cc1ccccc1
Reactant: CCN[C@@H](C)C(=O)O
Agent: Cl
Product: CCOC(=O)C(C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl alanine hydrochloride (5.5 g, 36.8 mmol), benzaldehyde (7.9 mL, 77.8 mmol), TEA (10.8 mL, 77.8 mmol) and NaBH(Oac)3 (16.5 g, 77.8 mmol) are taken up in 1,2-DCE (200 mL) and stirred at rt for 4 h. The reaction is then partitioned between DCM and saturated aqueous NaHCO3. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue is used without further purification. MS (ESI) m/z 208.2 (M+1).
Reaction SMILES: O.[N+:2]([C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C@H:10]1[CH2:12][C@H:11]1[C:13](O)=[O:14])=O)([O-:4])=[O:3].O.[NH2:20][NH2:21]>C(O)C>[N+:2]([C:5]1[CH:6]=[C:7]([C:8]2[CH:10]3[CH:11]([C:13](=[O:14])[NH:20][N:21]=2)[CH2:12]3)[CH:16]=[CH:17][CH:18]=1)([O-:4])=[O:3]
Reactant: NN
Reactant: O=C(c1cccc([N+](=O)[O-])c1)[C@H]1C[C@H]1C(=O)O
Solvent: O
Solvent: CCO
Product: O=C1NN=C(c2cccc([N+](=O)[O-])c2)C2CC12
Yield: 69.6 %

Procedure:
4.4 g (17.4 millimoles) of cis-2-(m-nitrobenzoyl)-cyclopropanecarboxylic acid hydrate, 1.05 g (21.0 millimoles) of hydrazine hydrate and 100 ml of ethanol are refluxed for 7 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 2.8 g (70% of theory) of 2-(m-nitrophenyl)-3,4-diazabicyclo[4.1.0]hept-2-en-5-one are obtained as pale yellow crystals, of melting point 220°-221° C.
Reaction SMILES: [CH3:1][O:2]CN.C([N:7]([CH2:10]C)CC)C.[I:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>ClCCl>[CH3:1][O:2][N:7]([CH3:10])[C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([I:12])[CH:14]=1
Reactant: COCN
Reactant: O=C(Cl)c1cccc(I)c1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of N-methoxymethylamine (3.47 g) and triethylamine (10.4 mL) in dichloromethane (100 mL) at 5° C. is treated dropwise with 3-iodobenzoyl chloride (9.8 g). The reaction mixture is stirred at room temperature for 2 hours, washed twice with water (70 mL), dried over magnesium sulphate, and evaporated to give N-methoxy-N-methyl-3-iodobenzamide (9.8 g) as a brown oil.
Reaction SMILES: [OH:1][C@@H:2]([CH3:6])[C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C=O)C>[OH:1][C@@H:2]([CH3:6])[C:3]([O:5][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: C[C@H](O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)(+)2 hydroxypropionic acid (9.0 g, 100 mmole) in 100 ml dry DMF was added potassium tert-butoxide (12.34 g, 110 mmole) and the mixture was stirred for one hour at 25° C. 4-Methoxybenzyl chloride (18.8 g 120 mmole) was added and the mixture was stirred for six hours at 60° C. The mixture was evaporated under reduced pressure and 250 ml ethyl acatate was added. The organic phase was washed four times with water. The organic phase was dried with sodium sulfate and concentrated in vacuo. Yield: 15.6 g=74%
Reaction SMILES: [P:1]([NH:9][NH2:10])(=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].CC(C1C=C[C:17]([O:20][CH3:21])=[CH:16]C=1)=O.[CH:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:3]([O:2][P:1]([NH:9][N:10]=[C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:17][O:20][CH3:21])([O:5][CH2:6][CH3:7])=[O:8])[CH3:4]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: c1ccccc1
Reactant: CCOP(=O)(NN)OCC
Product: CCOP(=O)(NN=C(COC)c1ccccc1)OCC
Temperature: 115 °C

Procedure:
In experimental work involving the preparation of the bromo-methoxy substituted azine, diethyl phosphorohydrazidate was prepared by reaction of diethyl phosphite and hydrazine hydrate in accordance with the following protocol. Hydrazine hydrate (0.13 mol) was added dropwise to a stirred mixture of CCl4 (40 cm3), CH2Cl2 (70 cm3), anhydrous K2CO3 (0.10 mol ) and triethylbenzylammonium chloride (0.66 mmol). The addition was carried out at 20-25° C., and the solution was stirred for 15 min at room temperature. A solution of diethyl phosphite (66 mmol) in Ch2Cl2 (10 cm3) was then added at 20-30° C with external cooling and the was continued for 6 hours. The K2CO3 crystals were filtered off and rinsed with CH2Cl2. After removal of the solvents, the residue was kept under 0.5 Torr for 4 hours to remove volatile impurities. Product purity was verified by NMR spectroscopy. The diethyl phosphorohydrazidate was reacted with 4-methoxyacetophenone (to produce 4-methoxyacetophenone (diethoxyphosphinyl)hydrazone in accordance with the following protocol. A mixture of diethyl phosphorohydrazidate (0.62 mol), 4-methoxyacetophenone (0.062 mol) and benzene (45 cm3) was refluxed at 110-120° C. for 5 hours. Solvent evaporation yielded a crystalline sample. Recrystallization from hexane-benzene (2:1) at 0° C. afforded an analytically pure sample of methoxyacetophenone (diethoxyphosphinyl)hydrazone. This intermediate is then reacted with the para-bromoacetophenone to produce the asymmetrical 4-methoxy-4′-bromoacetophenone azine as follows. A solution of the (diethoxyphosphinyl)hydrazone (3.72 mmol) in dried benzene (12 cm3) was added dropwise to a solution of NaH (4.84 mmol) in dried benzene (10 cm3) with stirring under nitrogen. When the hydrazone had reacted completely (formation of H2 ceased), a solution of the appropriate para-substituted acetophenone (3.72 mmol) in dried benzene (8-12 cm3) was added dropwise at 25° C. The liquid was decanted and washed with cold water until pH 7 was achieved. The solution was dried with MgSO4. The solvent was evaporated off, yielding a crystalline sample. Recrystallization from hexane-benzene (2:1) at 0° C. afforded an analytically pure sample of the asymmetrical azine shown by the following structural formula. As will be understood by those skilled in the art, similar reaction routes can be followed to produce other asymmetrical azines embodying the present invention.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[CH:10]([NH2:23])[N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25].C(N(CC)CC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[CH:10]([NH:23][C:27]([NH:26][CH2:24][CH3:25])=[O:28])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN=C=O
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2N
Solvent: CCN(CC)CC
Product: CCNC(=O)NC1N=C(c2ccc(Cl)cc2)c2ccccc2-c2c(C)noc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a round bottomed flask was added 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-amine (218 mg, 0.67 mmol). The flask was purged with nitrogen, MeCN was added (7 mL), and the solution was cooled to 0° C. Ethyl isocyanate (128 μL, 1.62 mmol) and triethylamine (244 μL, 1.75 mmol) were added and the reaction was allowed to warm to ambient temperature and stirred for 2 h. The reaction was quenched with a 1:1 mixture of sat. aq. NaHCO3:brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated and purified on a Biotage (isocratic elution 40% EtOAc: 60% Hexanes) to provide the title compound as white solid (220 mg). LC/MS m/z 395 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([C:14]([F:17])=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]3[CH:33]=[CH:32][NH:31][C:28]3=[N:29][CH:30]=2)[CH:20]=1.N1C2C(=CC=CC=2)C=N1>>[CH2:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([C:14]([F:17])=[CH:15][CH:16]=1)[CH2:12][C:33]1[C:27]2[C:28](=[N:29][CH:30]=[C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[CH:26]=2)[NH:31][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Reactant: O=Cc1c(F)ccc(OCc2ccccc2)c1F
Agent: c1ccc2[nH]ncc2c1
Product: Fc1ccc(OCc2ccccc2)c(F)c1Cc1c[nH]c2ncc(-c3cccnc3)cc12

Procedure:
Additional compounds were prepared following steps 3 and 4 of Scheme 43a, replacing 3-benzyloxy-2,6-difluoro-benzaldehyde 526 with an appropriate aldehyde and/or pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with an appropriate azaindole (see Example 9 or Example 16) in Step 3. The following compounds were made following this procedure:
Reaction SMILES: C1(S[C:8]2[S:9][C:10]([CH2:13][N:14]3[C:19](=[N:20][N+:21]([O-:23])=[O:22])[N:18]([CH3:24])[CH2:17][O:16][CH2:15]3)=[CH:11][N:12]=2)C=CC=CC=1.[ClH:25].ClCl>ClC1C=CC=CC=1>[Cl:25][C:8]1[S:9][C:10]([CH2:13][N:14]2[C:19](=[N:20][N+:21]([O-:23])=[O:22])[N:18]([CH3:24])[CH2:17][O:16][CH2:15]2)=[CH:11][N:12]=1
Reactant: Cl
Reactant: CN1COCN(Cc2cnc(Sc3ccccc3)s2)C1=N[N+](=O)[O-]
Agent: ClCl
Solvent: Clc1ccccc1
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Reaction time: 2 h

Procedure:
183 g of 3-(2-phenylthio-thiazol-5-yl-methyl)-5-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine are introduced over a period of 5 minutes, with stirring, into a mixture of 300 g of hydrochloric acid (32%) and 150 g of chlorobenzene. 124 g of chlorine are introduced at 20° C. over a period of 4 hours. After 2 hours, excess chlorine is removed by the introduction of nitrogen, and the phases are then separated. The aqueous phase is adjusted to pH 5 with sodium hydroxide solution (30%) and then filtered, and the filtration residue is washed with water and dried in vacuo at 50° C. The title product is obtained in a purity of 97%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=2)[C:6]1=[O:19].C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][CH2:3][CH2:4][N:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=3)[C:6]2=[O:19])=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc2ccn(CCCBr)c(=O)c2c1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCCOc3ccc(OC)cc3)c(=O)c2c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(3-bromopropyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (80 mg, 0.25 mmol) in DMF (2.5 mL) was added potassium carbonate (68 mg, 0.50 mmol) and 4-methoxyphenol (61 mg, 0.50 mmol). The reaction mixture was heated to 40° C. and stirred overnight. The mixture was then cooled to rt, filtered and concentrated to afford methyl 2-[3-(4-methoxyphenoxy)propyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate. LC-MS: (FA) ES+ 368.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[OH:7][C:2]([CH3:6])([CH3:1])[CH2:3][CH2:4][O:5][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(O)CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reaction time: 8 h

Procedure:
3-Methyl-1,3-butanediol (1.5 mL, 14.1 mmol) is suspended in dry dichloromethane (5 mL) and pyridine (1.24 mL, 15.46 mmol) is added followed by 4-toluenesulfonyl chloride (2.68 g, 14.1 mmol). The mixture is stirred overnight then washed with 1 M aqueous hydrochloric acid, dried and the solvent removed under vacuum. The residue is purified by flash chromatography (0-30% ethyl acetate in cyclohexane) to give the title compound. (Yield 970 mg). LC (METHOD 2): tR=5.67 min; Mass spectrum (ES+): m/z=258 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:16])=[CH:13][N:12]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1

Procedure:
6-Chloro-N-(4-methoxy-phenyl)-nicotinamide was prepared from 4-methoxyaniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C13H11N2OCl [M+H]+: 263.0582. Found: 263.0582.