Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:18][N+:19]([O-:21])=[O:20])[C:2]([CH2:13][O:14][N+]([O-])=O)([CH2:8][O:9][N+:10]([O-:12])=[O:11])[CH2:3][O:4][N+:5]([O-:7])=[O:6].O.NN>O1CCOCC1.C(O)C>[CH2:13]([OH:14])[C:2]([CH2:8][O:9][N+:10]([O-:12])=[O:11])([CH2:3][O:4][N+:5]([O-:7])=[O:6])[CH2:1][O:18][N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])OCC(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: O=[N+]([O-])OCC(CO)(CO[N+](=O)[O-])CO[N+](=O)[O-]

Procedure:
158 g (0.5 mol) of pentaerythrityl tetranitrate (PETN) are dissolved in a boiling mixture of 300 ml of dioxane and 300 ml of ethanol, and different amounts of aqueous hydrazine hydrate solution (1.5-4 mol) are added in portions over 1 hour. The reaction mixture is then refluxed for a further 2.5 hours. The solvents are evaporated off at 15 mm Hg and the residue is extracted by shaking several times with 100 ml portions of water, as required, until the volume of the oil layer no longer decreases on extraction. The aqueous extracts (A) are collected and the residual oily layer is dissolved in twice its volume of ethanol. Any white precipitate of PETN which has separated out is filtered off after 24 hours; m.p.=132° C., nitrogen content: 17.35%; m.p.=141° C. (2×acetone); nitrogen content: conforms. Ethanol is evaporated off from the filtrate at 15 mm Hg. The viscous oily residue consists of crude pentaerythrityl trinitrate (PETriN); nitrogen content: conforms.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2S[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.Cl[C:31]1C([N+]([O-])=O)=C(Cl)N=C[N:32]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[N:32]=[CH:31][C:15]3[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:17]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl(trans-3-(quinazolin-2-ylamino)cyclobutyl)carbamate, which was synthesized analagous to intermediate 10, (1.71 g, 5.44 mmol) was dissolved in dichloromethane (20 mL) and treated with trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 20 minutes after which the solution was evaporated to dryness under reduced pressure. The crude oil was further dried under high vacuum then dissolved in dry dimethylsulfoxide (40 mL). 4,6-Dichloro-5-nitropyrimidine (1.5 g, 7.73 mmol) was added followed by potassium carbonate (1.8 g, 13.02 mmol) and the reaction heated at 60° C. After 2 hours the mixture was cooled and diluted with water (300 mL). The product precipitated out and was filtered off using a sintered glass frit. It was dried on the frit and used without purification.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][CH:29]1[C:34](=O)[CH2:33][CH2:32][O:31][CH2:30]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:34]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[5-(trifluoromethyl)-3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (9.0 mg, 0.024 mmol), 3-methyltetrahydro-4H-pyran-4-one (8.1 mg, 0.071 mmol) and triethylamine (0.0066 mL, 0.047 mmol) in dry methylene chloride (2.0 mL) was added sodium triacetoxyborohydride (15.0 mg, 0.071 mmol). After being stirred at room temperature overnight, the reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The organic layers were combined, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified by silica gel column (30:70 MeOH/EtOAc) to provide pure product. MS calculated for C26H36F3N3O2: (M+H) 480; found 480.1.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](O)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O.CN(C)C(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([Cl:22])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Agent: CN(C)C(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
Alternative A. 4′-(Trifluoromethyl)[1,1′-biphenyl]-2-carboxylic acid (133 g), commercially available, thionyl chloride (89 g) and a catalytic amount of N,N-dimethylbenzamide (2.3 g) were combined in toluene (665 mL) at 55-60° C. over 2 hours, and the mixture heated at 80° C. for 1 hour. The excess reagent was removed by atmospheric co-distillation with toluene (600 ml distillate removed), providing a solution of 4′-(trifluoromethyl)[1,1′-biphenyl]-2-carbonyl chloride, which was combined with ethyl 5-amino-1-methyl-1H-indole-2-carboxylate (109 g) from the previous step, ethyl acetate (4660 ml) and N,N-diisopropylethylamine (131 mL) at 18-29° C. The resulting slurry was cooled, filtered and the crude product solids were washed with propan-2-ol (330 mL). The crude product was twice reslurried in a 70/30 mixture of demineralized water and propan-2-ol (2×1500 mL), and the solids were filtered, washed with propan-2-ol (400 mL) and dried, yielding the title compound, ethyl 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylate (167 g, 71.8%).
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:10]=[CH:11][C:12]2[O:13]C(C3C=CC=CC=3)[O:15][CH2:16][C:17]=2[N:18]=1)[CH2:3][NH:4][C:5]([CH3:8])([CH3:7])[CH3:6].[ClH:25]>CC(C)=O.O>[ClH:25].[ClH:25].[OH:15][CH2:16][C:17]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH:2]([OH:1])[CH2:3][NH:4][C:5]([CH3:7])([CH3:6])[CH3:8])[N:18]=1
Reactant: CC(C)(C)NCC(O)c1ccc2c(n1)COC(c1ccccc1)O2
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)NCC(O)c1ccc(O)c(CO)n1

Procedure:
One and five-tenths grams (4.8 m moles) of the above intermediate 6-(1-hydroxy-2-t-butylaminoethyl)-2-phenyl-4H-pyrido[3,2-d]-1,3-dioxin is dissolved in 20 ml. of acetone-water (1:1 v/v) and is treated with 1 ml. of 12N hydrochloric acid. After heating the solution to reflux for 5 hrs. the mixture is concentrated to an oil and dissolved in 100 ml. of ethanol. The water is azeotroped with 3 × 100 ml. portions of ethanol and the free base of the product generated by the addition of triethylamine. The solution is concentrated in vacuo to an oily slurry and the free base extracted from the triethylamine hydrochloride by extraction with acetone. The acetone extracts are combined, concentrated to an oil and the oil dissolved in 10 ml. of dry ethanol. Ethanol (0.184 ml.) containing hydrogen chloride (188 gm. HCl/ml. ethanol) is added and the solution added dropwise to 2 l. of dry isopropyl ether. The product is filtered and dried, 1.05 g. Further purification by recrystallization from methanol-acetone provides 950 mg. of the product which by infrared and nuclear magnetic resonance spectroscopy and thin-layer chromatography are identical to that in U.S. Pat. No. 3,700,681.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Br[CH:14]([CH3:18])[C:15]([NH2:17])=[O:16].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:8]=[CH:7]2
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CC(Br)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(N)=O)n1ccc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A dispersion of 60% NaH (6.85 g, 0.17 mol) was added to an ice-cooled solution of 5-chloroindole (20 g, 0.13 mol) in 250 ml of dry DMF. The stirring was continued for 20 minutes at room temperature, and the mixture was cooled again with an ice bath. After portionwise addition of solid 2-bromopropanamide (24.1 g, 0.15 mol), the reaction mixture was stirred for 1 h 30 at room temperature, then poured into cold water and extracted 3 times with AcOEt. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (AcOEt/hexane 50/50) to give pure 2-(5-chloro-1H-indol-1-yl)propanamide 25 as a white solid.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][SH:7].Cl[C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]>CN1CCCC1=O>[CH3:16][C:11]1[C:10]([CH3:17])=[C:9]([S:7][CH2:6][CH2:5][CH2:4][OH:3])[CH:14]=[CH:13][N+:12]=1[O-:15]
Reactant: OCCCS
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1c(SCCCO)cc[n+]([O-])c1C
Reaction time: 0.25 h

Procedure:
6 g (60% pure) of NaOH are added in portions to 50 ml of dry N-methylpyrrolidone (NMP), the mixture is stirred for 15 min, 9.5 g (0.11 mol) of 3-hydroxypropyl mercaptan are metered in over a period of 20 min. and the mixture is stirred again for 30 min. until the evolution of gas has ended. A solution of 14.4 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine N-oxide in 100 ml of NMP is then added dropwise in the course of 20 min. and the reaction mixture is stirred at room temperature for 1 hour, subsequently at 70° C. for 1 hour and thereafter at 100° C. for a further hour.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]([CH2:19][CH3:20])[CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1>C1COCC1.C(O)(=O)C>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([N:17]([CH2:19][CH3:20])[CH3:18])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CCN(C)c1nc(Cl)nc2c1CCC2c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(C)c1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
2-Chloro-N-ethyl-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (160 mg, 0.556 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (124 mg, 0.556 mmol) in THF (1.5 mL) and acetic acid (1.5 mL). The reaction mixture was stirred overnight at 80° C. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (85.3 mg, 0.171 mmol, 30.7% yield). LC-MS (M+H)+=475.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.49-7.61 (1H, m), 7.38 (1H, br. s.), 7.23-7.34 (6H, m), 7.13 (1H, d, J=8.5 Hz), 7.05 (1H, s), 4.35 (1H, dd, J=9.3, 4.1 Hz), 3.69-3.82 (4H, m), 3.47 (2H, br. s.), 3.27-3.38 (4H, m), 3.11-3.23 (1H, m), 2.56-2.72 (1H, m), 2.24 (1H, ddd, J=9.0, 4.4, 4.3 Hz), 1.31 (3H, t, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(-c2nc3ccccc3o2)ccc1CBr

Procedure:
To a solution of 5.1 gm. of 2-(3-fluoro-4-methyl-phenyl) benzoxazole in 60 ml. of carbon tetrachloride is added 6.23 gm. N-bromosuccinimide and 100 mg. of dibenzoyl peroxide. The reaction mixture is refluxed for 6 hours, filtered to remove succinimide and the filtrate concentrated to dryness. The residue is chromatographed on 500 gm. of silica gel. Elution with 1% ether in petroleum ether gives 2-(4-bromomethyl-3-fluorophenyl)benzoxazole, m.p. 150°-152°C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:22]([OH:25])[CH2:23][CH3:24])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:6]=2[N:7]=1.[CH3:26][N:27]=[C:28]=[O:29].CN(C1C=CC=CN=1)C>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([CH:22]([O:25][C:28](=[O:29])[NH:27][CH3:26])[CH2:23][CH3:24])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:14]([CH3:21])=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=3[CH3:19])[C:6]=2[N:7]=1
Reactant: CCC(O)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Reactant: CN=C=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCC(OC(=O)NC)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-propan-1-ol(62 mg, 0.184 mmol), methyl isocyanate (0.25 ml), dimethylaminopyridine (20 mg) in dichloromethane (2 ml) was heated at reflux for 1 hr. Additional methyl isocyanate (0.25 ml) was added and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give a yellow foam (95 mg). The foam was purified by preparative thin layer chromatography plate in 10% methanol in chloroform, then in 20% methanol in chloroform as solvent to give the title compound (29 mg) as an off-white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)(=[O:4])=[O:3].Br[C:15]1[N:16]=[C:17]([O:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[S:18][CH:19]=1>>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][CH:21]([O:20][C:17]2[S:18][CH:19]=[C:15]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)[N:16]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc(Br)cs2)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(N3CCc4cc(S(C)(=O)=O)ccc43)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using 5-(methylsulfonyl)indoline (intermediate 26) and tert-Butyl 4-((4-bromothiazol-2-yl)oxy)piperidine-1-carboxylate (intermediate 46).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([N:9]=[C:10]=S)[CH:3]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)[CH:3]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: S=C=Nc1cc(Cl)c(Cl)cn1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1cnc(NC2=NC[C@@]3(CN4CCC3CC4)O2)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
To 4,5-dichloro-2-isothiocyanatopyridine (0.25 g, 1.22 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.43 mL, 3.05 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.29 g, 1.24 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.57 mL, 3.66 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(4,5-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.09 g, 0.27 mmol, 22% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.81 (s, 1 H), 8.32 (d, J=6.10 Hz, 1 H), 7.03 (s, 1 H), 3.83 (d, J=9.46 Hz, 1 H), 3.57 (d, J=9.77 Hz, 1 H), 2.98 (s, 2 H), 2.71-2.79 (m, 2 H), 2.65 (t, J=7.78 Hz, 2 H), 1.99 (s, 1 H), 1.86 (s, 1 H), 1.53-1.61 (m, 2 H), 1.41-1.49 (m, 1 H). MS (LC/MS) R.T.=0.78; [M+H]+=327.0.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:29]([C:23]1([C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[Cl:15])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:30])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCCC1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(c2ccc(F)cc2Cl)CCCCC1

Procedure:
The product from Example 92B and (2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid (Acros) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ 0.76 (t, J=7.3 Hz, 3H), 1.06-1.18 (m, 2H), 1.33-1.53 (m, 8H), 1.56 (s, 9H), 1.71-1.81 (m, 2H), 1.92-2.00 (m, 2H), 2.34-2.42 (m, 2H), 7.14-7.22 (m, 2H), 7.57 (dd, J=8.6, 6.3 Hz, 1H), 8.46 (s, 1H). MS (ESI+) m/z 451 (M+H)+. Anal. calcd. for C24H32ClFN2OS: C, 63.91; H, 7.15; N, 6.21. Found: C, 64.04; H, 7.08; N, 6.10.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][C:6]=2[C:5]([Cl:15])=[CH:4][C:3]=1[F:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)CCc2ccc(F)c(N)c2O1
Solvent: CN(C)C=O
Product: CC1(C)CCc2c(Cl)cc(F)c(N)c2O1
Yield: 51.2 %

Procedure:
By a method analogous to that of Example 11, Step J, 6.7 grams (0.034 mole) of 8-amino-3,4-dihydro-2,2-dimethyl-7-fluoro-2H-1-benzopyran was reacted with 4.6 grams (0.035 mole) of N-chlorosuccinimide in 100 mL of N,N-dimethylformamide. The crude reaction product was purified with column chromatography on silica gel, with hexane and 1:4 methylene chloride:hexane as the eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.0 grams of 8-amino-5-chloro-3,4-dihydro-2,2-dimethyl-7-fluoro-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([F:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([F:17])=[CH:11][C:10]=1[Br:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc(OCc2ccccc2)ccc1F
Solvent: CN(C)C=O
Product: COc1nc(OCc2ccccc2)c(Br)cc1F
Reaction time: 2 h
Yield: 37.3 %

Procedure:
step 3—A solution 142 (1 g, 4.29 mmol) in DMF (10 mL) was cooled in ice-bath and NBS (0.763 g, 4.29 mmol) was added. The colorless mixture was stirred for 2 h and then quenched with H2O. The mixture was extracted with EtOAc (2×50 mL). The combined extracts were washed sequentially with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography to afford 0.5 g of 6-benzyloxy-5-bromo-3-fluoro-2-methoxy-pyridine (144).
Reaction SMILES: Cl.C(ON)C.[OH-].[Na+].C([C:13]1[C:14](=[O:26])[CH2:15][CH:16]([C:20]2[S:24][C:23]([CH3:25])=[N:22][CH:21]=2)[CH2:17][C:18]=1[OH:19])(=O)CCC>C(O)C.O>[OH:19][C:18]1[CH2:17][CH:16]([C:20]2[S:24][C:23]([CH3:25])=[N:22][CH:21]=2)[CH2:15][C:14](=[O:26])[CH:13]=1
Reactant: CCCC(=O)C1=C(O)CC(c2cnc(C)s2)CC1=O
Agent: CCON
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ncc(C2CC(=O)C=C(O)C2)s1
Reaction time: 20 h
Yield: 143 %

Procedure:
Ethoxyamine hydrochloride (0.3 g) and then aqueous sodium hydroxide (0.12 g in 1 ml of water) were added to a solution of 2-butyryl-3-hydroxy-5-(2-methyl-5-thiazolyl)cyclohex-2-en-1-one (0.7 g) in ethanol (50 ml) at 20° C. with stirring. After 20 hours, the mixture was diluted with water (200 ml) and then extracted with chloroform (2×100 ml). The dried (MgSO4) organic extract was evaporated to give 2-[1-ethoxyimino)butyl]-3-hydroxy-5-(2-methyl-5-thiazolyl)cyclohex-2-en-1-one (0.75 g, 95%) as a nearly colourless oil which was characterised by proton magnetic resonance spectroscopy (CDCl3 ; δ in ppm); 0.96 (3H, t); 1.31 (3H, t); 1.7 (2H, m); 2.65 (3H, s); 2.5-3.8 (7H, m); 4.10 (2H, q); 7.37 (1H, s); 15.1 (1H, brs).
Reaction SMILES: N#N.[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([C:18]([OH:20])=O)[N:17]=2)[O:8][CH2:7][CH2:6][O:5]1.CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C1(C)C=CC=CC=1>[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([C:18]([Cl:29])=[O:20])[N:17]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(CCCCc2nc(C(=O)O)co2)OCCO1
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1(CCCCc2nc(C(=O)Cl)co2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-oxazole-4-carboxylic acid (489 mg, 1.92 mmol) in toluene (20 mL) was treated with a drop of DMF followed by oxalyl chloride (0.20 mL, 2.30 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-oxazole-4-carbonyl chloride as a yellow oil. LC-MS-conditions 02: tR=0.96 min [M+H]+=274.37.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].[Al+3].C1C(O)=CC=C(S(O)(=O)=O)C=1.O>[CH2:7]([O:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH:9]1[O:11][CH2:10]1
Reactant: CC(C)CCO
Reactant: ClCC1CO1
Agent: CC(C)[O-]
Agent: O=S(=O)(O)c1ccc(O)cc1
Agent: [Al+3]
Solvent: O
Product: CC(C)CCOCC1CO1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
3-Methylbutanol (158 g, 1.78 mol), aluminum triisopropoxide (3.61 g, 17.7 mmol) and p-phenolsulfonic acid (9.40 g, 54 mmol) were charged into a 1-liter reaction vessel and the whole was heated to 90° C. with stirring. After an additional. 1 hour of stirring under reduced pressure (266 hPa). The vessel was heated to 100° C. and epichlorohydrin (170 g, 1.78 mol) was added dropwise thereto over a period of 30 minutes, followed by an additional 3 hours of stirring. The reaction mixture was kept at a 50° C. and 50% sodium hydroxide aqueous solution (285 g, 3.56 mol) was added dropwise thereto over a period of 1 hour. After an additional 3 hours of stirring, 400 ml of water was added to the mixture and the mixture was allowed to separate into layers. After removal of the water layer, 100 ml of toluene was added to the oil layer and the resulting solution was washed with 300 ml of 5% brine three times and concentrated to obtain a crude reaction product (218 g). Distillation of the product gave 3-methylbutyl glycidyl ether (150 g) (bp: 63–64° C./5 hPa, yield 98%).