Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]Br.[Mg:7].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:21]>[Li+].[Li+].[Cl-].[Cl-].[Cl-].[Cl-].[Cu+2].O1CCCC1>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][Mg:7][Br:8].[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:21]
Reactant: BrCCCCCCCCCCCCBr
Reactant: [Mg]
Reactant: CC(C)CCBr
Agent: [Cu+2]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCCCCCCCCCCCCCBr
Product: CC(C)CC[Mg]Br
Reaction time: 1 h

Procedure:
A solution of 3-methylbutylmagnesium bromide is prepared by treating 15 g. (0.1 mole) 3-methylbutyl bromide with 2.7 g. (1.1 eq) magnesium turnings in 50 ml. dry tetrahydrofuran. The resultant Grignard reagent is dropwise added to a cold (-10° C.) solution of 36.1 g. (1.1 eq) 1,12-dibromododecane and 0.2 g. (1 m mole) dilithiumtetrachloro cuprate in 75 ml. dry tetrahydrofuran. The solution is stirred for one hour, evaporated, and fractionally distilled in vacuo to yield 15-methylhexadecylbromide as a colorless liquid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7].[CH3:17][NH:18][CH3:19]>C(O)C.Cl>[CH3:17][N:18]([CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7]
Reactant: CNC
Reactant: CCCCCCCCNC(=O)CCCCBr
Agent: Cl
Solvent: CCO
Product: CCCCCCCCNC(=O)CCCCN(C)C
Reaction time: 3 h
Yield: 70 %

Procedure:
5-Bromo-N-octylpentanamide (17.25 g) was dissolved in ethanol (50 ml) and a 33% solution of dimethylamine in ethanol (20 ml) was added. The solution was allowed to stand at room temperature for 3 hours, more dimethylamine (10 ml) added and the solution allowed to stand at room temperature for 18 hours. The solution was evaporated to give an oil, which was dissolved in dilute HCl and the solution at pH 5.5 was washed with dichloromethane. The pH was then raised to 7.5 and extracted twice with dichloromethane at this pH. The combined latter organic extracts were dried over MgSO4 and evaporated to give 5-dimethylamino-N-octylpentanamide as an oil (10.6 g, 70%).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:9][C:10]1[CH:25]=[CH:24][C:13]2[CH:14](O)[C:15]3[C:16]([CH:21]=[CH:22][C:12]=2[CH:11]=1)=[N:17][CH:18]=[CH:19][CH:20]=3>C(O)(=O)C>[CH3:9][C:10]1[CH:25]=[CH:24][C:13]2[CH:14]([C:7]3[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=3)[C:15]3[C:16]([CH:21]=[CH:22][C:12]=2[CH:11]=1)=[N:17][CH:18]=[CH:19][CH:20]=3
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: Cc1ccc2c(c1)C=Cc1ncccc1C2O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C=Cc1ncccc1C2c1c[nH]c(=O)[nH]c1=O

Procedure:
A solution of uracil (1.87 g) and the product of step (iii) (3.73 g) in glacial acetic acid (30 ml) was heated at 120° C. under nitrogen for 40 hr. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and saturated. sodium bicarbonate solution. The organic phase was separated, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 0-20% methanol in ethyl acetate.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl[C:10]1[N:15]([CH3:16])[C:14](=[O:17])[CH:13]=[C:12]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:11]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH:35]2[CH2:37][C@H:32]1[CH2:33][NH:34]2)=[O:30])([CH3:27])([CH3:26])[CH3:25].O>CN(C)C=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH:35]2[CH2:37][C@H:32]1[CH2:33][N:34]2[C:10]1[N:15]([CH3:16])[C:14](=[O:17])[CH:13]=[C:12]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:11]=1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC2C[C@H]1CN2
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(N2C[C@@H]3CC2CN3C(=O)OC(C)(C)C)nc(-c2ccncc2)cc1=O
Temperature: 20 °C
Reaction time: 6 h
Yield: 72.1 %

Procedure:
A mixture containing 10.7 ml (78.14 mmol) of triethylamine, 13.6 g (52.7 mmol) of 2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one hydrochloride (1:1), 6.0 g (30.24 mmol) of (1S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in 500 ml of anhydrous dimethylformamide is stirred at 20° C. for 6 h. Water is added to the cooled mixture and the resulting solution extracted with ethyl acetate. The combined extracts are washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride then-evaporated. The crude product is refluxed in diethylether for 1 h to afford 8.36 g of pure product as a brown solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][Br:15])[CH:8]=1>>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:9]([CH2:13][CH2:14][Br:15])[CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: BrCCc1cccc(Br)c1
Product: O=S(=O)(Cl)c1ccc(Br)cc1CCBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chlorosulfonic acid (17 mL) was added dropwise to 1-bromo-3-(2-bromo-ethyl)-benzene (5 g, 19 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h then an additional 3 h at rt. The mixture was poured into an ice-water slowly and extracted with methylene chloride, and the combined organic layers were evaporated under reduced pressure to give 4.3 g of crude 4-Bromo-2-(2-bromo-ethyl)-benzenesulfonyl chloride which was used directly for next reaction. MS (ESI) 342.9 (M-Cl+OH)−.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[F:17][C:18]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:19]=1[CH:20]=[C:21](Cl)[C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:17][C:18]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:19]=1[CH:20]=[CH:21][C:22]([NH:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:5]=1)[CH3:3])=[O:23]
Reactant: C[C@H](N)c1cccc(Nc2ccncc2)c1
Reactant: O=C(O)C(Cl)=Cc1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1cc(F)ccc1F)c1cccc(Nc2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A mixture of (S)-[3-(1-amino-ethyl)-phenyl]-pyridin-4-yl-amine (0.1 mmol), 2.5-difluoro-chlorocinnamic acid (0.1 mmol), EDAC.HCl (0.2 mmol), DMAP (0.1 mmol), triethylamine (0.3 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The reaction mixture was purified by flash chromatography with 5% methnol in ethyl acetate to provide the title compound (31 mg) as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[NH:15][C:16](=[O:20])/[CH:17]=N/O)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:22]>>[C:11]([C:9]1[CH:8]=[C:7]2[C:6](=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)[NH:15][C:16](=[O:20])[C:17]2=[O:22])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)c1ccc(NC(=O)/C=N/O)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)NC(=O)C2=O
Temperature: 0 °C
Yield: 42 %

Procedure:
N-(2,4-Di-tert-butyl-phenyl)-2-[(E)-hydroxyimino]-acetamide (500 mg, 1.7 mmol) in concentrated sulfuric acid (3.8 mL) was heated at 90° C. for 2 h. This solution was cooled at 0° C. and slowly added to ice-water (15 mL), the brown precipitate was filtered off and purified by chromatography on silica gel with a gradient of 0% to 25% of ethyl acetate in heptane to afford 200 mg (42%) of an orange powder, MS: m/z=259 (M).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12])(=[O:3])[CH3:2].[CH:13]1([C:19](OC)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[H-].[Na+].Cl>C1(C)C=CC=CC=1.O>[Cl:10][C:8]1[CH:7]=[C:6]([CH3:11])[C:5]([OH:12])=[C:4]([C:1](=[O:3])[CH2:2][C:19]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:20])[CH:9]=1
Reactant: CC(=O)c1cc(Cl)cc(C)c1O
Reactant: COC(=O)C1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc(C(=O)CC(=O)C2CCCCC2)c1O

Procedure:
2-Acetyl-4-chloro-6-methylphenol (1.84 g) and methyl cyclohexanecarboxylate (1.7 g) were dissolved in toluene (36 ml) and to the solution was added 60% sodium hydride (0.96 g). Then, the mixture was heated under reflux for 16 hours. The mixture was poured into cold water. Diluted hydrochloric acid was added and crystals precipitated were filtered and recrystallized from methanol to obtain the title compound, yield 1.54 g (52.2%). The melting point and IR and NMR spectra were identical with those of the compound of Reference Example 5.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:27])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52])=[CH:46][CH:45]=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)=[S:55])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)CC1
Reaction time: 0.08 h
Yield: 18.4 %

Procedure:
After dissolving 4-dimethylaminopiperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (89.3 mg) in ethanol (2 ml), D-10-camphorsulfonic acid (55.3 mg) was added and the mixture was stirred for 5 minutes under a nitrogen atmosphere. A 0.24 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.4 ml) was then added and the mixture was stirred for 1 hour. Then, a 0.24 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.4 ml) was further added to the reaction mixture and stirring was continued for 1 hour. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=8:1), and then fractions containing the target compound were concentrated under reduced pressure. Diethyl ether (0.5 ml) and hexane (4.0 ml) were added to the resultant residue to produce a suspension. After filtering the solid, it was subjected to aeration drying to provide the title compound (24.9 mg, 18.4%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C[N:10]([CH:12](OC)OC)C.Cl.N[OH:19]>CC(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:12]=[N:10][OH:19])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: NO
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CC(C)O
Product: ON=CNc1ccc(Br)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a 1 L round-bottom flask was added 2-amino-5-bromopyridine (100 g, 578 mmol), DMF-DMA (101 mL, 751 mmol) and 2-propanol (200 mL). The mixture was heated to reflux for 3 h to give a clear dark solution. It was then cooled to 50° C. and hydroxylamine hydrochloride (52.2 g, 751 mmol) was added. The mixture was stirred at 50° C. overnight to give a yellow suspension. The precipitate was collected by filtration. The black filtrate was concentrated and the residue was stirred in EtOH (20 mL) for 20 min. The solid was collected by filtration. The combined solids were dried in an oven to give N-(5-bromopyridin-2-yl)-N′-hydroxyformimidamide as a sandy solid (94 g, 75% yield).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19].[NH2:22]/[C:23](/[CH3:29])=[CH:24]\[C:25]([O:27][CH3:28])=[O:26].C(O)(=O)C>CC(O)C>[C:18]([C:17]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([CH3:29])[NH:22][C:16]=1[CH3:15])(=[O:20])[CH3:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(C)=O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(C)=C(C(C)=O)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 93.1 mg (0.93 mmol) of 2,4-pentanedione, 61.1 mg (0.53 mmol) of methyl 3-aminocrotonate and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated to reflux under argon for 10 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 77 mg (39% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: CC1SC=C(/C=C(/[C@H]2[O:28][C:26](=[O:27])[CH2:25][C@H:24]([OH:29])[C:23]([CH3:31])([CH3:30])[C:21](=[O:22])[C@H:20](C)[C@@H:19](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)\C)N=1.N1CCCCC1.C(Cl)Cl.CC(C)=O>C(Cl)Cl>[CH3:31][C:23]([CH3:30])([C:21](=[O:22])[CH2:20][CH3:19])[C@@H:24]([OH:29])[CH2:25][C:26]([OH:28])=[O:27]
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: C1CCNCC1
Product: CCC(=O)C(C)(C)[C@@H](O)CC(=O)O
Reaction time: 16 h

Procedure:
1 g (2.03 mmol) of epothilone A is dissolved in 168 mL of CH2Cl2. After adding 86 μl (0.88 mmol) of piperidine and 254 μl (0.88 mmol) of titanium tetra-isopropylate, the reaction solution is strirred for 16 h at RT. After concentration in vacuo, the product is purified by FC (200 g of silica gel, CH2Cl2→CH2Cl2/acetone=4:1) giving a colorless oil: Rf (CH2Cl2/acetone=85:15): 0.55; M+H=494.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]>CN(C)C=O.C(OCC)(=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][CH:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccnc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
Sodium hydride (7.2 g, 180.4 mmol) was slowly added at 0° C. to a solution of 4-fluorophenol (17.11 g, 152.6 mmol) in 200 ml of N,N-dimethylformamide and then the reaction mixture was stirred for 30 minutes at room temperature. 4-Chloro-3-nitropyridine (22.0 g, 138.8 mmol) prepared in Step 1 of Preparation 1 was added at 0° C. to the reaction mixture, which was stirred for 1 hour at room temperature, diluted with 200 ml of ethyl acetate, and then washed with 200 ml of water three times. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound as a pale yellow solid (25.2 g, 76.8%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.S(C1NC=CN=1)(C1NC=CN=1)=O.[C:22]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:34]1([CH2:40]O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[CH:25]1[CH:24]=[CH:23][C:22]([C:28]2[CH:29]=[CH:30][C:31]([CH:40]([N:1]3[CH:2]=[N:3][CH:4]=[CH:5]3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:32][CH:33]=2)=[CH:27][CH:26]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: c1c[nH]cn1
Reactant: OCc1ccccc1
Agent: O=S(c1ncc[nH]1)c1ncc[nH]1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: c1ccc(-c2ccc(C(c3ccccc3)n3ccnc3)cc2)cc1
Yield: 56 %

Procedure:
The second and third stage of synthesis consists of making imidazole react with thionyl chloride, using acetonitrile as solvent; the operation is performed at 10° C. To the resulting thionylbisimidazole solution, biphenyl-phenyl-carbinol is added in a 1:4 molar relation to the thionyl. After fifteen hours at room temperature, the solvent is removed by vacuum distillation. The remaining is dissolved in chloroform and washed with water, the organic phase is dried over sodium sulfate; after filtering, the solvent is vacuum distilled. The resulting solid is purified by recrystallization in acetonitrile. Bifonazole is obtained in 56% yield in relation to the theoretical.
Reaction SMILES: Br[CH:2]([CH:8](Br)[CH3:9])[C:3]([O:5]CC)=O.[NH2:11][C:12]1[N:16]=[C:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:14][N:13]=1>N1C=CC=CC=1>[CH2:18]([S:17][C:15]1[N:16]=[C:12]2[N:11]=[C:3]([OH:5])[CH:2]=[C:8]([CH3:9])[N:13]2[N:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CCOC(=O)C(Br)C(C)Br
Solvent: c1ccncc1
Product: Cc1cc(O)nc2nc(SCc3ccccc3)nn12
Temperature: 65 °C

Procedure:
Ethyl 2,3-dibromobutyrate (1.33 g, 48.5 mmol) was added dropwise over 15 minutes to a solution of 10 g (49 mmol) of 3-amino-5-benzylthio-1,2,4,-triazole in 20 ml of pyridine heated to 65° C. After the addition was complete, the reaction mixture was heated at 65° C. for 20 hours, cooled to room temperature and filtered. The filtrate was concentrated by evaporation at reduced pressure. The residue was triturated with methanol to separate 1.64 g (13%) of the desired product as a colorless crystalline solid, m.p. 219°-220° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20].C(N(CC)CC)C>C1COCC1>[CH3:12][O:13][CH2:14][CH2:15][N:16]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:17][CH2:18][O:19][CH3:20]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COCCNCCOC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCN(CCOC)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of p-nitrobenzyl bromide (10 g) in THF (50 ml) was added dropwise to a solution of bis(2-methoxyethyl)-amine (6.8 g) and triethylamine (10 ml) in THF (50 ml). Under nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous-magnesium sulfate. Under reduced pressure, the solvent was evaporated to give N,N-bis(2-methoxyethyl)-4-nitrobenzylamine (10.8 g) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:36]([NH:35][C:27]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:37])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from the previous step (94 mg, 0.3 mmol) in THF (3 mL) was added phenyl 3-methoxy-5-(trifluoromethyl)phenylcarbamate from Example 115A (140 mg, 0.45 mmol), diisopropylethylamine (80 uL, 0.45 mmol), and 4-dimethylaminopyridine (4 mg, 0.03 mmol). The solution was stirred at 50° C. overnight, allowed to cool to room temperature, and diluted with EtOAc. The solid was then filtered to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-methoxy-5-(trifluoromethyl)phenyl)urea (89 mg, 0.17 mmol, 56%). 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.48 (s, 1H), 7.44 (t, 1H), 7.35 (s, 1H), 7.34 (s, 1H), 7.29-7.24 (m, 2H), 6.85 (s, 1H), 3.99 (s, 6H), 3.81 (s, 3H); LC-MS (ESI) m/z 531 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH:19]([OH:21])[CH2:18][CH2:17][N:16]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:14].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.CCN(CC)CC>[CH3:11][O:12][C:13]([CH:15]1[CH2:20][C:19](=[O:21])[CH2:18][CH2:17][N:16]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:14]
Reactant: COC(=O)C1CC(O)CCN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a mixture of oxalyl chloride ((15 mL, 30 mmol, 2 M dichloromethane) in CH2Cl2 (100 mL) cooled to −78° C. was added DMSO (4.5 mL, 63.4 mmol). The mixture was stirred at this temperature for 1 h, after which 4-hydroxy-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2.0 g, 7.71 mmol dissolved in CH2Cl2) as added. The mixture stirred for a further 1 h and Et3N (20 mL) was then added and the mixture stirred for another 30 min. The mixture was then allowed to warm to −40° C. and poured into a solution of 10% NaHSO4. The reaction mixture was then extracted with ethyl acetate. The organic extract was then washed with brine and dried over MgSO4 (anhydrous) and the solvent was removed in vacuo and the crude residue was purified by silica gel flash column chromatography giving 1.75 g (88%) of the product as a yellow oil. 1H-NMR (CDCl3), δ(ppm): 4.85 (br, d, 1H), 4.02 (m, 1H), 3.61 (s, 3H), 3.58 (br, 1H), 2.75 (m, 2H), 2.44 (br, 2H), 1.43 (br, s, 9H).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:19]
Reactant: O=C(NOC1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NOC1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 96.2 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-N-(tetrahydro-2H-pyran-4-yloxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 32 (0.26 g, 0.69 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2S,5R)-6-hydroxy-7-oxo-N-(tetrahydro-2H-pyran-4-yloxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 33 (0.19 g, 99%) as a colorless foam.