Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][NH:12][C:13](=O)[C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:16]([CH2:29][CH3:30])[CH:15]=2)=[O:10])=[CH:7][C:6]=1[CH3:34])([CH3:3])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.C(OCC)C>[CH2:22]([O:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([C:13]2[O:10][C:9]([C:8]3[CH:32]=[CH:33][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH3:34])[CH:7]=3)=[N:11][N:12]=2)=[CH:15][C:16]=1[CH2:29][CH3:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCc1cc(C(=O)NNC(=O)c2ccc(OC(C)C)c(C)c2)cc(C)c1OCc1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cc(-c2nnc(-c3ccc(OC(C)C)c(C)c3)o2)cc(C)c1OCc1ccccc1
Yield: 83.1 %

Procedure:
A solution of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid N'-(4-isopropoxy-3-methyl-benzoyl)-hydrazide (1.57 g, 3.40 mmol) and Burgess reagent (1.06 g, 4.43 mmol) in THF (30 mL) is heated to 110° C. under microwave irradiation for 3 min. The mixture is cooled, diluted with diethyl ether, washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 5:1 to give 2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-5-(4-isopropoxy-3-methyl-phenyl)-[1,3,4]oxadiazole (1.25 g) as a colourless oil; LC-MS: tR=1.24 min, [M+1]+=443.58.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=1.[CH:16](O)=O>O>[CH:9]1[C:10]([C:13]([OH:15])=[O:14])=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]=[CH:16]2
Reactant: O=CO
Reactant: Nc1ccccc1-c1cc(C(=O)O)n[nH]1
Solvent: O
Product: O=C(O)c1cc2c3ccccc3ncn2n1
Reaction time: 0.5 h

Procedure:
3.0 g (0.0148 mole) of 5-(2-aminophenyl)-1H-pyrazole-3-carboxylic acid is suspended in 21 ml of 97+% HCOOH, and the reaction mixture heated in an oil bath at 100° for 2 hours. The reaction mixture is cooled, diluted with water (75 ml), stirred for 30 minutes and filtered, washing the precipitates well with water. The crude product is dried overnight in vacuo at 90°. Yield: 2.9 g. Percent crude yield: 91.8%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH4+].O[N:40]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]([NH2:40])=[O:35])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)O)CC2)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(N)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylic acid (0.5 g), 1-hydroxybenzotriazole ammonium salt (0.21 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 67%).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:5][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)=[C:7]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[CH:16][N:17]=3)[CH:14]=2)[N:8]=1.C([O-])(O)=O.[Na+]>Cl>[N:17]1[CH:16]=[N:15][N:13]2[CH:14]=[C:9]([C:7]3[N:8]=[C:4]([CH:3]=[O:2])[NH:5][C:6]=3[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)[CH:10]=[CH:11][C:12]=12
Reactant: COC(OC)c1nc(-c2ccc3ncnn3c2)c(-c2cccc(C)n2)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cccc(-c2[nH]c(C=O)nc2-c2ccc3ncnn3c2)n1
Temperature: 70 °C
Yield: 90 %

Procedure:
6-(2-(Dimethoxymethyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (6.00 g, 17.12 mmol) was dissolved in 1 N HCl (120 mL), and the mixture was heated at 70° C. for 3 h. The reaction mixture was allowed to cool to 0° C., and then it was neutralized with saturated aqueous NaHCO3 solution. The mixture was extracted with 10% MeOH in CHCl3 (3×200 mL), and the organic phase was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure to give the titled compound (4.69 g, 90%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.82 (s, 1H), 9.01 (br s, 1H), 8.41 (s, 1H), 7.85 (dd, 1H, J=9.2, 0.8 Hz), 7.82 (dd, 1H, J=9.2, 1.6 Hz), 7.55 (t, 1H, J=7.8 Hz), 7.33 (br s, 1H), 7.16 (d, 1H, J=8.0 Hz), 2.60 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br)([O-:11])=[O:10]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)[CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Nc1ccc(F)cc1
Product: O=[N+]([O-])c1cccc(CN(Cc2cccc([N+](=O)[O-])c2)c2ccc(F)cc2)c1

Procedure:
4-Fluoroaniline and 3-nitrobenzyl bromide were processed using the method described in Example 32A to afford the title compound. LC/MS Rt 2.15 m/z 423 (M+CH3CN)+.
Reaction SMILES: [H-].[K+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C1COCC1>[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][C:5]1([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: ClCc1cccnc1
Reactant: O=C1CCCC1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCCC1(Cc1cccnc1)C(=O)OCc1ccccc1
Temperature: -78 °C

Procedure:
In a 1-liter three-necked flask provided with magnetic stirring and a condenser, under an inert nitrogen atmosphere, potassium hydride 32% (25 g; 200 mmoles; 1.1 eq.) is suspended in anhydrous THF (200 mL). The reaction mixture is cooled to −78° C. and then benzyl 2-oxocyclopentanecarboxylate (39.7 g; 182 mmoles) is added dropwise whilst keeping the temperature below −78° C. The reaction mixture is stirred for 1 hour at ambient temperature. A solution of 3-(chloromethyl)-pyridine base (38.7 g; 226 mmoles; 1.24 eq.) in 100 mL of anhydrous THF is added to the clear yellow solution. The reaction mixture is stirred at reflux for 12 hours. After coming back to ambient temperature, the reaction mixture is evaporated to dryness and taken up in 80 mL of water and 500 mL of ethyl acetate. The aqueous phase is extracted three times with 50 mL of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and then dried over MgSO4, filtered and concentrated. The product is purified on silica gel using a mixture of dichloromethane/ethanol (gradient of 98/2 to 95/5) as eluant to yield the expected product in the form of a yellow oil.
Reaction SMILES: [O:1]1CC[CH2:3][CH2:2]1.[NH2:6][C:7]1[C:8]([Cl:25])=[CH:9][C:10]([F:24])=[C:11]([N:13]2[C:21](=[O:22])[C:16]3=[CH:17][CH2:18][CH2:19][CH2:20][N:15]3[C:14]2=[O:23])[CH:12]=1.C(OC(=O)C)(=O)C.Cl>N1C=CC=CC=1.C(OCC)(=O)C>[C:2]([NH:6][C:7]1[C:8]([Cl:25])=[CH:9][C:10]([F:24])=[C:11]([N:13]2[C:21](=[O:22])[C:16]3=[CH:17][CH2:18][CH2:19][CH2:20][N:15]3[C:14]2=[O:23])[CH:12]=1)(=[O:1])[CH3:3]
Reactant: Nc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Reactant: C1CCOC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To an tetrahydrofuran (5 mL) solution of 2-(5-amino-4-chloro-2-fluorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.50 g, 1.69 mmol) were dropwise added acetic anhydride (0.18 mL, 1.86 mmol) and pyridine (8 drops) with stirring at room temperature. The reaction mixture was stirred for 8 hours at room temperature and further stirred for 13 hours at 80° C. 1N Hydrochloric acid (20 mL) and ethyl acetate (20 mL) were added to the resulting mixture, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL×2 times). The organic layer combined was washed with saturated sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane =1/1) to obtain a white solid of 2-(5-acetylamino-4-chloro-2-fluorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.34 g, yield:59.6%).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][Br:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(CBr)c1Br
Reaction time: 23 h
Yield: 90.4 %

Procedure:
A stirred solution of 1-bromo-2-methyl-6-nitrobenzene (16.2 g, 0.075 mole) in 200 ml of carbon tetrachloride was irradiated and heated at reflux with a 250 watt brooder lamp. N-bromosuccinimide (13.5 g, 0.075 mole) was added to the refluxing reaction mixture, and the mixture was stirred for approximately 23 hours. The mixture was cooled, filtered, and washed with two 200 ml portions of saturated aqueous sodium chloride solution. The organic phase was passed through phase separation filter paper. The filtrate was evaporated under reduced pressure to give 2-bromo-1-bromomethyl-3-nitrobenzene (20 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])N=[CH:4]1.[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14].[CH3:21]N(C=O)C>>[CH3:12][Si:13]([CH3:15])([CH3:14])[CH2:16][CH2:17][O:18][CH2:19][N:3]1[CH:4]=[CH:21][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7]1
Reactant: COC(=O)c1c[nH]cn1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccn(COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (1.0 g, 0.025 mol) in 50 mL of DMF was added methyl 4-imidazolecarboxylate (2.95 g, 0.023 mol) portionwise at room temperature. The mixture was stirred at room temperature for 0.5 hours. Then SEM-Cl (4.17 g, 0.025 mol) was added dropwise over 5 minutes. The reaction mixture was stirred for 4 hours and quenched by adding water. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 8:2) to give 4.0 g of the major regioisomer as a clear oil. Step 2: Preparation of 4-[1-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-3-(4-fluorophenyl-5-[[(2-trimethysilyl)ethoxy]methyl-1H-imidizol-4-yl]-1H-pyrazol-4-yl]pyridine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[N:8][C:7](=O)[C:6]=2[CH:20]=1.[NH:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[NH2:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])[N:21]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=3)[N:22]=2)[CH:20]=1
Reactant: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CCO
Product: O=C(O)c1ccc(-n2nc(-c3cc(Cl)ccc3O)nc2-c2cc(Cl)ccc2O)cc1

Procedure:
3.0 g of 6-chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 1.7 g of 4-hydrazinobenzoic acid are boiled under reflux for 2 h in 40 ml of ethanol. The crystals precipitating on cooling are recrystallized from isopropanol. After drying, 4-[3,5-bis(5-chloro-2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid remains as colorless crystals of m.p. 275-278 C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:18][C:19]([F:30])([F:31])[O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)nc23)CC1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.012 mL (0.053 mMol) 4-trifluoromethoxybenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:26]([N+:27]([O-])=O)=[CH:25][C:12]2[N:13]=[C:14]([CH3:24])[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=2[CH:10]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[NH2:27][C:26]1[C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:3][C:2]=2[Cl:1])=[CH:10][C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[C:14]([CH3:24])=[N:13][C:12]=2[CH:25]=1
Reactant: COC(=O)Cc1ccc(Oc2cc3c(cc2[N+](=O)[O-])nc(C)n3COCC[Si](C)(C)C)c(Cl)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(Oc2cc3c(cc2N)nc(C)n3COCC[Si](C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under an N2 atmosphere, methyl 2-(3-chloro-4-(2-methyl-6-nitro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-benzo[d]imidazol-5-yloxy)phenyl)acetate (0.220 g, 0.435 mmol) was dissolved in ethyl acetate (10 mL) and tin chloride dihydrate (0.392 g, 0.174 mmol) was added. The reaction was allowed to stir at room temperature for 2.5 h. The reaction was diluted with 10% NaHCO3 (aq) and ethyl acetate. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo, afforded the title compound. LC-MS ESI (pos.) m/z: 476.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C>[OH:18]/[N:17]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NO
Reactant: CCOC(=O)C(=O)c1ccc(OC)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C(=N\O)c1ccc(OC)cc1
Yield: 55.9 %

Procedure:
A mixture of ethyl 4-methoxyphenylglyoxylate (15.0 g), hydroxylamine hydrochloride (6.00 g), sodium acetate (8.86 g) and ethanol (150 ml) was heated under reflux for 12 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel and ethyl Z-2-hydroxyimino-2-(4-methoxyphenyl)acetate (8.99 g, yield 56%) was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless crystals. m.p. 81-82° C.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[F:14][C:15]1([F:22])[CH2:21][CH2:20][CH2:19][CH:18]2[CH:16]1[O:17]2.[F-].[Na+]>ClCCl>[F:14][C:15]1([F:22])[CH2:21][CH2:20][CH2:19][C@H:18]([NH:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[C@H:16]1[OH:17]
Reactant: FC1(F)CCCC2OC21
Reactant: C[C@@H](N)c1ccccc1
Agent: C[Al](C)C
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](N[C@H]1CCCC(F)(F)[C@@H]1O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A solution of (1R)-1-phenylethanamine (22, 72 mL, 0.57 mol) in dichloromethane (200 mL) was cooled to 0° C. and treated with trimethylaluminum (260 mL, 0.52 mol) and the resulting solution was stirred for 1 hour at 0° C. To this solution was added a solution of 2,2-difluoro-7-oxabicyclo[4.1.0]heptane (66 g, 0.49 mol) in dichloromethane (200 mL) and the resulting mixture stirred at 0° C. for 3 hours. The reaction was then warmed to ambient temperature for 16 hours. The reaction was cooled to 0° C., treated with 103 g of sodium flouride and then quenched with water (90 mL, slow addition). The reaction was warmed to ambient temperature, the solids filtered and the solution evaporated in vacuo, Purification by flash chromatography (50-100% ethyl acetate in hexanes) gave 36.3 g (29%) of (1S,6R)-2,2-difluoro-6-{[(1R)-1-phenylethyl]amino}cyclohexanol 23 (plus 32 g of 1R,6S diastereomer) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.32 (5H, s), 3.90 (1H, q, =6.6 Hz), 3.39 (1H, ddd, J=19.8, 9.8, 4.2 Hz), 2.70 (1H, m), 2.11 (1H, m), 1.80 (1H, m), 1.62 (2H, m), 1.43 (1H, m), 1.36 (3H, d, J=6.6 Hz), 0.96 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1.[CH:18]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19]1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:22](=[O:23])[NH:21][CH:18]3[CH2:20][CH2:19]3)[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1
Reactant: CCN1CCC(O)N(c2nnc(OC)s2)C1=O
Reactant: O=C=NC1CC1
Solvent: CCN(CC)CC
Product: CCN1CCC(OC(=O)NC2CC2)N(c2nnc(OC)s2)C1=O
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and cyclopropyl isocyanate (3.5 ml; 0.07 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-cyclopropylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>O>[CH2:18]1[O:19][CH:17]1[CH2:15][O:3][C:4]1[C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:14]
Reactant: O=c1ccc2c(O)cccc2[nH]1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1ccc2c(OCC3CO3)cccc2[nH]1
Reaction time: 5 h

Procedure:
0.6 g of sodium hydroxide was dissolved in 40 ml of water, and 2.0 g of 5-hydroxycarbostyril and 2.5 g of epichlorohydrin were added to the solution. The mixture was stirred at a temperature of from 60° to 70°C for 5 hours followed by cooling to precipitate the product. The precipitated crystals were washed with water, dissolved in ethanol and then subjected to thin layer chromatography using acetone as an eluate to obtain two spots having a Rf value of 0.58 and 0.65, respectively, The spot having a Rf value of 0.58 was extracted with ethanol and crystallized to obtain 5-(2,3-epoxy)propoxycarbostyril which was used as the starting material in Examples 1 and 2. The spot having a Rf value of 0.65 was worked up in the same manner as described above to obtain 5-(2-hydroxy-3-chloro)propoxycarbostyril which was used as the starting material in Example 3.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>CO>[CH:11](=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCc2ccccc21
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2ccccc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-indanone (5.0 g) and benzaldehyde (4.1 g) in methanol (40 ml), was added 2.2 ml of 48% aqueous sodium hydroxide solution. The reaction mixture was stirred at room temperature for 0.5 hr. The resulting precipitate was filtered and washed with water. The yield was 7.9 g.
Reaction SMILES: [Br-].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:38])[CH2:12][N+:13]23[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]2)[C@@H:15]([O:21][C:22](=[O:37])[C@@H:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:14]3)=[CH:7][CH:6]=1)([O-])=O>C1COCC1>[CH:22]([O-:37])=[O:21].[NH2:2][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:38])[CH2:12][N+:13]23[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20]2)[C@@H:15]([O:21][C:22](=[O:37])[C@@H:23]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:14]3)=[CH:7][CH:6]=1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccc([N+](=O)[O-])cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Product: O=C[O-]
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A solution of (R)-1-[2-(4-nitro-phenyl)-2-oxo-ethyl]-3-((R)-2-phenyl-2-phenylamino-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide (Diastereoisomer 1 of C179) (88 mg, 0.152 mmol) in THF (30 mL) is hydrogenated in presence of a catalytic amount of Pt2O at 15 psi for 2 hours and then at 20 psi for additional 2 hours (UPLC-MS monitoring: complete conversion). Catalyst is removed by filtration and the solution evaporated to dryness. The crude is purified by preparative HPLC to give the title compound as a pale yellow solid (31 mg, 37% yield, formate formate anion, single diastereoisomer).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:38](Br)[C:39]#[CH:40]>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH2:40][C:39]#[CH:38])[C:5]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:30])([F:31])[F:29])[CH:21]=1
Reactant: C#CCBr
Reactant: C=CCOCC1(c2ccc(F)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(COCC=C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.42 g of 4-[2,5-dioxo-4-(4-fluorophenyl)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile in 3 mL of DMF, 160 mg of potassium carbonate and 0.2 mL of propargylbromide (80% solution in toluene) are added. The mixture is stirred at room temperature for 4 hours under argon atmosphere. Then 0.04 mL of propargylbromide (80% solution in toluene) is added and the mixture is stirred 1 hour at room temperature, evaporated to dryness, diluted with water and brine and extracted with ethyl acetate. The organic layer is dried over sodium sulfate filtered and evaporated.