Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:9]1)=O)(C)C.I[Si](C)(C)C.CO.[C:39]([O:42][CH2:43][C:44](Cl)=[O:45])(=[O:41])[CH3:40]>C(#N)C.C(Cl)Cl.C(N(CC)CC)C>[O:30]=[C:21]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:10]3[CH2:9][N:8]([C:44](=[O:45])[CH2:43][O:42][C:39](=[O:41])[CH3:40])[CH2:13][CH2:12][CH:11]=3)=[C:15]([F:31])[CH:16]=2)[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCCN(C(=O)OC(C)(C)C)C3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCCN(C(=O)COC(C)=O)C3)c(F)c2)C(=O)O1
Reaction time: 0.08 h

Procedure:
A solution of (S)-3-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-5,6-dihydro-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 70, Step 2, 158 mg) in dry acetonitrile under N2 is treated with iodotrimethylsilane (62 μL) dropwise, and the resulting solution is stirred at ambient temperature for 50 mins, during which additional iodotrimethylsilane (25 μL) is added. The reaction is then treated with methanol (59 μL), stirred for 5 mins and concentrated under reduced pressure to give the deprotected intermediate. A mixture of this intermediate and triethylamine (0.122 mL) in dry methylene chloride (3.6 mL) at 0° C. under N2 is treated with acetoxyacetyl chloride (47 μL), and the resulting mixture is stirred at 0° C. for 2 hrs and at ambient temperature for 2 hrs and then diluted with methylene chloride (20 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (70-230 mesh, 15 g), eluting with methanol/methylene chloride (5/95), and those fractions with an Rf =0.5 by TLC (methanol/chloroform, 10/90) are pooled and concentrated to give the title compound, HRMS calculated for C21H24N3F1O6 +H1 : 434.1727. Found: 434.1741.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH2:9][CH3:10])=[N:4][C:3]=1[CH2:11][OH:12]>[O-2].[O-2].[Mn+4].O1CCOCC1>[Br:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH2:9][CH3:10])=[N:4][C:3]=1[CH:11]=[O:12]
Reactant: CCCCc1nc(CO)c(Br)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCCCc1nc(C=O)c(Br)[nH]1
Temperature: 100 °C
Yield: 85.9 %

Procedure:
4.37 g of the product of Step A were introduced into 130 ml of dioxane and then 16.32 g of manganese dioxide were added with stirring. The mixture was heated to approximately 100° C. for about 2 hours, then filtered. The filtrate was rinsed with dioxane and evaporated to obtain 3.72 g of the expected product melting at 113° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9].[CH3:14]I>CN(C=O)C>[CH3:13][O:12][N:10]([CH3:11])[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][O:3][CH3:14]
Reactant: CI
Reactant: CON(C)C(=O)CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCCC(=O)N(C)OC
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To sodium hydride (60% in mineral oil, 2.6 g, 66.3 mmol) in dry DMF (40 mL) was added a solution of 5-hydroxy-N-methoxy-N-methylpentanamide (8.9 g, 55.2 mmol) in DMF (50 mL) slowly at 0° C. After 30 min, methyl iodide (4.1 mL, 66.3 mmol) was added and the reaction was stirred over night. Starting material remained and more sodium hydride ((60% in mineral oil, 1 g, 25 mmol) and methyl iodide (1.7 mL, 27.2 mmol) was added followed by additional stirring for 6 h. The solvent was evaporated under vacuum. The residue was diluted with dichloromethane and treated with brine. The aqueous layer was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (120 g column, 80% ethyl acetate in hexanes to 100% ethyl acetate) to give product (5.3 g, 55%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[H-].[Na+].[Si:12](Cl)([C:15](C)(C)C)([CH3:14])[CH3:13]>C1COCC1>[CH3:13][Si:12]([CH3:15])([CH3:14])[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9]
Reactant: OCCCCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,7-heptandiol (44 mmol) in THF (15 mL) is cooled to 0° C. and treated with sodium hydride (44 mmol) followed by tert-butyldimethylsilyl chloride (44 mmol). The reaction mixture is stirred at room temperature overnight. Concentration in vacuo and flash chromatography affords 7-trimethylsiloxy-1-heptanol. To a solution of 7-trimethylsiloxy-1-heptanol (11.6 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4-methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 7-trimethylsiloxy-1-heptyl triflate (50) which is used without further purification.
Reaction SMILES: C([NH:4][C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=O)C.[ClH:24]>>[ClH:24].[ClH:24].[NH2:4][C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: CC(=O)NC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Product: NC1(c2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
The compound prepared in stage B is hydrolyzed by refluxing for 3 hours in 6N HCl. After evaporation to dryness, the residue is dissolved in methanol, crystallized by addition of acetone, filtered and dried to give the expected compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C>CO.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH3:1][O:4][C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CO
Product: CO[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 32.8 %

Procedure:
To a solution of 3 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 30 ml of methanol is added 1.17 g of zinc acetate, and the mixture is refluxed for 30 minutes. The reaction mixture is concentrated under reduced pressure, followed by addition of ethyl acetate. The resulting insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified on a silica-gel column (ethyl acetate: n-hexane=1:1) to give 0.912 g of (3S,4R)-4-methoxy-3-tritylamino-2-oxoazetidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[O:8][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Yield: 89.6 %

Procedure:
To a mixture consisting of 5-fluoro-2-nitrophenol (47.1 g), acetonitrile (300 ml) and potassium carbonate (46 g) was added ethyl bromoacetate (60.1 g) dropwise at a temperature from 50° to 60° C., followed by a five-hour refluxing under heating and then filtration under cooling. The resulting filtrate was subjected to distillation under reduced pressure, and then dissolved in toluene (350 ml). The resulting toluene solution was washed with water, a 5% aqueous solution of potassium hydroxide, and water, in that order, followed by drying with magnesium sulfate and the toluene was distilled off therefrom under reduced pressure. The residue was distilled under reduced pressure to collect a fraction boiling at from 154° to 156° C., so as to obtain ethyl 5-fluoro-2-nitrophenoxyacetate (65.3 g). The whole quantity of the reaction product was dissolved in ethanol (8.1 l), followed by addition thereto of a solution of ammonium chloride (60 g) and water (400 ml). To the resulting mixture was added zinc dust (60.5 g) portionwise at a temperature of from 20° to 30° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[NH:11][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[CH:34]=[CH2:35]>C1COCC1>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[N:11]([CH2:35][CH:34]=[CH2:33])[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: C=CCBr
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 60 °C

Procedure:
To a solution of 5-biphenyl-4-yl-6-chloro-2-(methylsulfonyl)-1H-benzimidazole (1.72 g, 4.49 mmol) in THF (30 ml) and 1M potassium carbonate (3.10 g, 22.46 mmol) was added allyl bromide (0.6 ml, 6.89 mmol). The reaction mixture was heated to 60° C. for 20 h. Then the volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc and water. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. Chromatography of the resulting residue over silica eluting with 20-40% EtOAc/hexanes afforded the desired product. LC-MS: calculated for C23H19ClN2O2S 422.09, observed m/e: 422.94 (M+H)+ (Rt 2.52/4 min).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2C(C(=O)NC3C=CC=CC=3)=CN=C(S(C)(=O)=O)N=2)[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(S(C)(=O)=O)ncc2C(=O)Nc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 287.6 %

Procedure:
To a stirred solution of 7 (0.15 g, 0.24 mmol) in dry CH2Cl2 (5 mL) at 0° C. was added CF3COOH (1.5 mL) and the reaction mixture was stirred at 0° C. for 30 min. The reaction was allowed to come to rt and stirred at it for 1 h. It was concentrated under reduced pressure and the residue was quenched with NaHCO3 solution (3 mL) and extracted with EtOAc (3×25 mL). The combined EtOAc extract was washed with water (20 mL), brine (10 mL) and dried over Na2SO4 and concentrated under reduced pressure to give 8 (0.085 g, 86.7%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][C:16](=[O:18])[C:15]([C:19](=O)[CH2:20][CH3:21])=[C:14]([OH:23])[CH2:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:24]([O:27][NH2:28])[CH:25]=[CH2:26]>O1CCCC1>[CH2:24]([O:27][N:28]=[C:19]([C:15]1[C:16](=[O:18])[CH2:17][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=2)[CH2:13][C:14]=1[OH:23])[CH2:20][CH3:21])[CH:25]=[CH2:26]
Reactant: C=CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Solvent: C1CCOC1
Product: C=CCON=C(CC)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Reaction time: 15 h
Yield: 68.8 %

Procedure:
Into 10 ml of tetrahydrofuran was dissolved 1.0 g of 5-(4-methanesulfonamidophenyl)-3-hydroxy-2-propionyl-2-cyclohexen-1-one and to the solution was added 0.5 g of allyloxyamine. The mixture was kept at room temperature for 15 hours and then it was treated with similar process in Example 1. Thus, 0.8 g of the objective compound was obtained. It was colorless crystals having a melting point of 134°-135° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH:11]=1)[C:8](O)=[O:9])#[N:2].S(Cl)([Cl:15])=O>>[F:12][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:7]=1[C:8]([Cl:15])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(F)c(C(=O)O)c1
Product: N#Cc1ccc(F)c(C(=O)Cl)c1

Procedure:
A solution of Example 59B (535 mg, 3.24 mmol) in thionyl chloride (3855 mg, 32.4 mmol) was heated at 90° C. for 2 hours. The solution was cooled, concentrated, diluted with toluene, and concentrated to afford 2-fluoro-5-cyanobenzoyl chloride which was used without purification. The title compound was prepared and isolated as described in Example 22B, substituting 2-fluoro-5-cyanobenzoyl chloride for 2-fluoro-5-(trifluoromethyl)benzoyl chloride, in 61% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (s, 9 H) 1.58-1.72 (m, 1H) 1.82 (qd, J=7.01, 6.74 Hz, 2 H) 1.90-1.97 (m, 1 H) 3.61-3.70 (m, 1 H) 3.74-3.83 (m, 1H) 4.24-4.35 (m, 3 H) 7.33 (s, 1 H) 7.52 (dd, J=10.71, 8.72 Hz, 1 H) 8.02-8.07 (m, 1 H) 8.40 (dd, J=6.94, 2.18 Hz, 1 H); MS (DCI/NH3) m/z 388 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[O:18][CH2:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[F:15])[N:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH2:65]([O:67][C:68](=[O:76])[C:69]1[C:74]([NH2:75])=[CH:73][CH:72]=[N:71][CH:70]=1)[CH3:66].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:65]([O:67][C:68](=[O:76])[C:69]1[C:74]([NH:75][C:2]2[C:3]3[O:18][CH2:17][CH2:16][C:4]=3[N:5]=[C:6]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=3[F:15])[N:7]=2)=[CH:73][CH:72]=[N:71][CH:70]=1)[CH3:66]
Reactant: CCOC(=O)c1cnccc1N
Reactant: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)CCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Temperature: 80 °C
Yield: 21.3 %

Procedure:
To a solution of 4-chloro-2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidine (320 mg, 1.13 mmol, 1 eq) in dioxane (5 ml) was added Pd(OAc)2 (13 mg, 0.06 mmol, 0.05 eq) followed by BINAP (53 mg, 0.08 mmol, 0.075 eq), 4-aminonicotinic acid ethyl ester (206 mg, 1.24 mmol, 1.1 eq) and Cs2CO3 (478 mg, 1.46 mmol, 1.5 eq). The reaction mixture was heated to 80° C. for 15 h. The reaction mixture was cooled to rt and filtered through Celite® and the crude material was purified by flash column chromatography (0-5%MeOH in CHCl3) to afford 4-[2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ylamino]-nicotinic acid ethyl ester (100 mg, 21%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[OH:18])[O:9][C:6]2=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[F:32][CH:33]([F:43])[CH2:34]OS(C(F)(F)F)(=O)=O>O>[F:32][CH:33]([F:43])[CH2:34][O:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:10]1[O:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=2
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)COc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Temperature: 60 °C
Yield: 26.3 %

Procedure:
To a mixture of 0.31 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.23 g of potassium carbonate and 3 ml of DMF, a mixture of 0.50 g of trifluoromethanesulfonate (2,2-difluoroethyl)ester and 7 ml of DMF was added at room temperature, and then stirred while heating at 60° C. for six hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.10 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as “active compound 162”).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:16])=[C:4]([CH3:17])[N:3]=1)[C@@H:13]([CH3:15])[CH2:12][O:11][CH2:10]3.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.Cl.N1C=CC=CC=1.C(Cl)(Cl)Cl>FC(F)(F)CO>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:2]2[C:7]3[N:8]=[C:9]4[N:14]([C:6]=3[C:5]([CH3:16])=[C:4]([CH3:17])[N:3]=2)[C@@H:13]([CH3:15])[CH2:12][O:11][CH2:10]4)=[CH:22][CH:21]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1nc(Cl)c2nc3n(c2c1C)[C@@H](C)COC3
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: OCC(F)(F)F
Product: COc1ccc(CNc2nc(C)c(C)c3c2nc2n3[C@@H](C)COC2)cc1
Temperature: 160 °C
Yield: 92.8 %

Procedure:
A conical microwave vial was charged with a solution of (4S)-9-chloro-4,6,7-trimethyl-3,4-dihydro-1H-pyrido[3′,4′:4,5]imidazo[2,1-c][1,4]oxazine (270 mg, 1.07 mmol) dissolved in 3.5 mL of 2,2,2-trifluoroethanol. 4-Methoxybenzylamine (1.4 mL, 10.7 mmol) and pyridine hydrochloride (620 mg, 5.35 mmol) were added and the vial was sealed. The solution was heated in an Emrys Optimizer microwave (Personal Chemistry) at 160° C. for 120 minutes. The solvent was removed under reduced pressure, and the resulting residue was partitioned between 20 mL of CH2Cl2 and 20 mL of 10% aqueous Na2CO3. The layers were separated, and the organic portion was washed with 10% aqueous Na2CO3 solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressures to give a crude oil. Chromatography (SiO2, 0-20% CMA/CHCl3) afforded (4S)—N-(4-methoxybenzyl)-4,6,7-trimethyl-3,4-dihydro-1H-pyrido[3′,4′:4,5]imidazo[2,1-c][1,4]oxazin-9-amine (350 mg) as an orange syrup.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.Cl[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:34].CCN(CC)CC.O>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.[CH2:36]([O:35][C:33](=[O:5])[O-:34])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCOC(=O)Cl
Agent: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCOC(=O)[O-]
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To the solution of budesonide (750 mg, 1.74 mmol) in DCM (7.5 mL) was added dodecyl chloroformate (513 mL, 1.617 mmol) and Et3N (533 μL, 3.825 mmol) at room temperature. The reaction mixture was stirred at room temperature for 7 hours. During this 7 hours more dodecyl chloroformate (510 μL, 1.616 mmol) and Et3N (440 μL, 3.18 mmol) were added. The reaction was followed by HPLC. The reaction mixture was poured into water (20 mL) and DCM (10 mL); the aqueous phase was extracted with DCM (10 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude budesonide dodecylcarbonate. The product was purified by chromatography, eluted with Hexane: AcOEt=9:1 to 3:1 to provide 983 mg of 1:1 mixture of epimers (originated from budesonide) (96.78 area % purity on HPLC). 1H NMR (CDCl3) δ 0.80-2.25 (m, 45H), 2.36 (d, 1H, 13.4 Hz), 2.58 (t, 1H, 13.2 Hz), 4.19 (t, 2H, 6.7 Hz), 4.52 (bs, 1H), 4.6-5.2 (m, 5H), 6.03 (s, 1H), 6.30 (d, 1H, 10.1 Hz), 7.29 (d, 1H, 10.1 Hz). 13C NMR (CDCl3) δ 14.21, 14.38, 17.22, 17.35, 17.50, 17.78, 21.35, 22.94, 25.86, 28.83, 29.45, 29.60, 29.74, 29.80, 29.88, 30.57, 31.24, 32.16, 33.18, 33.68, 34.26, 35.26, 37.36, 41.17, 41.41, 44.24, 46.18, 47.61, 50.01, 53.14, 55.41, 55.52, 69.12, 69.18, 70.11, 70.22, 82.32, 83.57, 97.76, 98.62, 104.88, 108.63, 122.83, 128.24, 156.14, 169.81, 169.92, 186.74, 202.16 and 203.46. Mass spectrum (m/e) 643 (M+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[S:10][C:11]([CH3:17])=[C:12]([CH3:16])[C:13]=1[C:14]#[N:15])[C:2]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(I)C>C(#N)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]1[S:10][C:11]([CH3:17])=[C:12]([CH3:16])[C:13]=1[C:14]#[N:15])[CH3:2]
Reactant: Cc1sc(NCc2ccccc2)c(C#N)c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCI
Solvent: CC#N
Product: CCNc1sc(C)c(C)c1C#N
Reaction time: 0.25 h

Procedure:
To a mixture of 2-(benzylamino)-4,5-dimethylthiophene-3-carbonitrile (302 mg, 10 mmol), potassium carbonate (276 mg, 2.0 mmol), and a catalytic amount of potassium iodide in acetonitrile (1 mL) in a 20 mL microwave vial was added ethyl iodide (310 mg, 2.0 mmol). The reaction vial was placed in a microwave reactor for 15 minutes at 165° C. The reaction mixture was dissolved in ethyl acetate and washed with water and brine. The ethyl acetate portion was dried over sodium sulfate and solvent was evaporated under reduced pressure, and the product was purified by prep HPLC using acetonitrile/water as solvent. MS 181 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:21])[CH2:10][N:9]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccccc2Br)c2ccccc2N1
Product: S=C1CN=C(c2ccccc2Br)c2ccccc2N1

Procedure:
A mixture of 1,3-dihydro-5-(o-bromophenyl)-2H-1,4-benzodiazepin-2-one and P2S5 can be reacted in the same manner as in Preparation I to produce 1,3-dihydro-5-(o-bromophenyl)-2H-1,4-benzodiazepine-2-thione. This latter compound can then be substituted in the procedure of Example 1 to produce 6-(o-bromophenyl)-1-methyl-4H-s-triazolo[4,3-a] [1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:25][C:26](=[O:28])[CH3:27]>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:25][C:26](=[O:28])[CH3:27])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)COc1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.5 %

Procedure:
2-Methyl-8-hydroxyquinoline (0.80 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and dry N,N-dimethylformamide (DMF) (40 ml) were stirred at room temperature for 30 min. To this solution was added chloroacetone (0.46 g, 5 mmol) in dry THF (10 ml) in one portion. The resulting mixture was stirred at room temperature for 24 h. (monitored by TLC) and then poured into ice water (100 ml). The pale yellow solid thus obtained was collected and crystallized from dichloromethane and ether to afford 2-methyl-8-(2-oxopropoxy)quinoline (10a) (0.77 g, 72%). mp: 99°-100° C.; 1H-NMR (CDCl3): δ2.35 (s, 3H, 2'-CH3), 2.79 (s, 3H, 2-CH3), 4.86 (s, 2H, OCH2), 6.88-7.44 (m, 3H, Ar--H), 7.33 (d, 1H, 3-H), 8.03 (d, 1H, 4-H).