Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][NH2:16])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:20])[CH:3]=1.CCN(CC)CC.Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][NH:16][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:20])[CH:3]=1
Reactant: NCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 155.3 %

Procedure:
To a mixture of 2-(2-(4,5-dichloro-2-iodophenoxy)pyridin-4-yloxy)ethanamine (30 mg, 0.07 mmol), Et3N (35.7 mg, 0.35 mmol) in DCM (5 mL), 2-chloroethanesulfonyl chloride (11.5 mg, 0.07 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. Then solvent was removed under reduced pressure. The residue was taken in THF (2 mL) and H2O (2 mL), then K2CO3 (100 mg) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was partitioned between DCM and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/ethyl acetate=5:1) to afford the desired product (56 mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ: 7.98 (d, J=5.6 Hz, 1H), 7.92 (s, 1H), 7.25 (s, 1H), 6.61-6.57 (m, 2H), 6.47 (d, J=2.0 Hz, 1H), 6.32 (d, J=16.4 Hz, 1H), 6.00 (d, J=10.0 Hz, 1H), 4.77 (t, J=5.2 Hz, 1H), 4.18 (t, J=5.2 Hz, 2H), 3.51-3.47 (m, 2H). ESI-MS m/z: 515.0[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[N:5]=[C:4]([N:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[N:3]=1.[S:17](=[O:20])(=[O:19])=[O:18].N1C=CC=CC=1.O>CN(C=O)C>[OH-:8].[NH2:1][C:2]1[N:3]=[C:4]([N:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[N:5]=[C:6]([NH2:9])[N+:7]=1[O:8][S:17]([OH:20])(=[O:19])=[O:18]
Reactant: O=S(=O)=O
Reactant: C=CCN(CC=C)c1nc(N)[n+]([O-])c(N)n1
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: C=CCN(CC=C)c1nc(N)[n+](OS(=O)(=O)O)c(N)n1
Product: [OH-]
Reaction time: 2 h
Yield: 135 %

Procedure:
A mixture of 3.00 grams (0.0148 mols) of 2,4-diamino-6-(di-2-propenylamino)-1,3,5-triazine-3-oxide and 4.50 grams of pyridine sulfur trioxide in 3 ml of DMF is stirred for 2 hr. Water (240 ml) is added and the mixture is warmed on a steam bath for 4 min. The white crystals are filtered and dried to yield 3.20 grams of the titled product, a 71% yield. The crystals are homogeneous by TLC. A sample recrystallized from methanol-water decomposes at 258° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([F:20])[CH:13]=2)[CH:9]=[N:8][CH:7]=1)(=O)C.O.[OH-].[Li+].Cl>C1COCC1.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:6]([CH2:5][OH:4])=[CH:7][N:8]=[CH:9]2)=[CH:13][C:14]=1[F:20])#[N:19]
Reactant: CC(=O)OCc1cncn1Cc1ccc(C#N)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CO)cc1F
Reaction time: 4 h

Procedure:
To a solution of 5-(acetoxymethyl)-1-(4-cyano-3-fluorobenzyl)imidazole, as described above in Step E, (19.8 g, 72.5 mmol) in 5:1 THF/water (430 mL) at ambient temperature was added lithium hydroxide monohydrate (3.33 g, 79.4 mmol). After 4 hrs, the solution was adjusted to pH 7 with 1.0 N hydrochloric acid and concentrated in vacuo. The residue was concentrated from toluene in vacuo (3×100 mL) to give the titled product as a pale solid.
Reaction SMILES: C([Li])CCC.CCCCCC.[NH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:19].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1.O>[C:21]1([CH2:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][NH:12][C:13]2=[O:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCCN1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1NCCCCC1Cc1ccccc1
Temperature: -50 °C
Reaction time: 3 h

Procedure:
A solution of n-butyl lithium in hexane (2.5 M, 178 ml, 0.444 mol) was added dropwise to a mechanically stirred solution of hexahydroazepin-2-one (22.8 g, 0.202 mol) in tetrahydrofuran (400 ml) over a period of 90 minutes at 0° C. The solution was stirred for 3 hours and then cooled to -50° C. Benzyl bromide (24 ml, 0.202 mol) in tetrahydrofuran (100 ml) was then added dropwise over a period of 1 hour and the reaction mixture allowed to warm slowly to room temperature and stirred for 15 hours. Addition of water (100 ml) and saturated aqueous ammonium chloride (100 ml) was followed by extraction of the aqueous phase with ethyl acetate (3×100 ml). The combined organic phases were washed with brine, dried with sodium sulphate and evaporated in vacuo. Flash column chromatography upon silica gel of the resulting oily solid using ethyl acetate: methanol (25:1) as eluant afforded a solid which was recrystallised from benzene/hexanes to give the desired product as an off white solid, 10.3 g, M.pt. 99°-104° C., M+ found: 203.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[C:2]1([CH2:1][C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][N+:16]([O-:27])=[CH:17][CH:18]=3)[N:12]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(Cc2nc(-c3ccncc3)cs2)cc1
Solvent: ClCCl
Product: [O-][n+]1ccc(-c2csc(Cc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 328 %

Procedure:
To a suspension of n-chloroperbenzoic acid (14.5 g) in dry methylene chloride (150 mL) was added a solution of 2-benzyl-4-(4-pyridyl)thiazole (15.1 g, 0.06 mol) in methylene chloride (125 mL) over thirty minutes. The mixture was allowed to stir overnight at room temperature then an additional portion of m-chloroperbenzoic acid (3.00 g) was added. After an additional six hours of stirring the mixture was extracted with saturated sodium bicarbonate (3×100 mL). The organic layer was dried over sodium sulfate, and concentrated to a total volume of 75 mL. Dilution with ether (200 mL) afforded 4-[2-(phenylmethyl)-4-thiazolyl]pyridine -1-oxide (15.3 g, 95%). Recrystallization from ethanol/ether afforded an analytical sample. mp. 170°-172° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:25])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([Cl:25])(=[O:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4′-bromobiphenyl-4-sulfonic acid 13a (18.8 g, 78.1 mmol) in thionyl chloride (150 mL) is added a catalytic amount of N,N-dimethylformamide (0.3 mL). The reaction mixture is heated to reflux for 4 hr. The mixture is then cooled to room temperature, and concentrated under reduced pressure. Toluene is then added and the mixture is concentrated under reduced pressure. The solid crude product is then recrystallized with ethyl acetate and hexanes to give the solid desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Reaction time: 0.67 h
Yield: 60.6 %

Procedure:
The (2-amino-ethyl)-carbamic acid tert-butyl ester (5.00 g, 31.2 mmol) and 4-chloro-benzaldehyde (4.61 g, 32.77 mmol) were dissolved in 60 mL of 1,2-dichloroethane at room temperature. The reaction mixture was allowed to stir for 40 minutes prior to treatment with sodium triacetoxyborohydride (9.90 g, 46.8 mmol). The mixture was allowed to stir overnight to completion and quenched with a saturated NaHCO3 solution. The aqueous was extracted with DCM, separated, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with hexanes/EtOAc plus 2% triethyl amine) to afford the pure [2-(4-chlorobenzylamino)-ethyl]-carbamic acid tert-butyl ester as a viscous yellow oil (5.38 g, 61%). 1H NMR (CDCl3, 400 MHz) δ 7.29 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.92 (brs, 1H), 3.75 (s, 2H), 3.23 (appd, J=5.6 Hz, 2H), 2.73 (appt, J=6.0 Hz, 2H), 1.44 (s, 9H), 1.36 (brs, 1H). LCMS (APCI+) m/z 285 [M+H]+; Rt=2.30 min.
Reaction SMILES: [C:1]([C:9]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH:10]1[CH:12]=[CH2:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.C1(C(C2CC2)=O)CC1>>[C:14]([C:9]1[CH2:11][CH:10]([CH:12]=[CH2:13])[O:8][C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C=CC1CC1(C(=O)OCC)C(=O)c1ccccc1
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: O=C(C1CC1)C1CC1
Agent: [Cl-]
Product: C=CC1CC(C(=O)OCC)=C(c2ccccc2)O1

Procedure:
4-Carbethoxy-5-phenyl-2-vinyl-2,3-dihydrofuran was obtained in the usual manner by isomerizing ethyl 1-benzoyl-2-vinylcyclopropane-1-carboxylate. To catalyze the isomerization, tricaprylylmethylammonium chloride was employed at a 20 percent weight level. The mixture was heated at 150° C. for about two hours after which time only about 7 percent of the cyclopropyl ketone remained. After two distillations, essentially pure 4-carbethoxy-5-phenyl-2-vinyl-2,3-dihydrofuran was obtained. The product (B.P. 110° C. @ 0.1 mm Hg: nD25° 1.5570) had a pleasing aroma that was somewhat coumarin-like in odor character. Nuclear magnetic resonance and infrared spectroscopic analysis confirmed the structure ##STR16##
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:16]([OH:17])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:17][C@@H:16]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NC(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CNC[C@H]1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-(benzyloxycarbonylamino)-4-hydroxypyrrolidine-1-carboxylate (4.91 g, 14.60 mmol) in DCM (20 mL) was added TFA (11.25 mL, 146.0 mmol) and the mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure. 6 N HCl in water (10 mL) was added. The mixture was stirred at ambient temperature for 30 minutes and neutralized with saturated sodium bicarbonate to about pH 8. It was extracted with DCM:IPA=4:1 (50 mL). The organic layer was separated, dried (sodium sulfate), filtered and concentrated under reduced pressure to give benzyl (3R,4R)-4-hydroxypyrrolidin-3-ylcarbamate (2.45 g, 71.0%) as a solid.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:15][C:14](=S)[CH2:13][CH2:12][S:11](=[O:18])(=[O:17])[CH:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]=2[CH:26]=1>O1CCCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:15]=[C:14]([NH:2][NH2:3])[CH2:13][CH2:12][S:11](=[O:18])(=[O:17])[CH:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]=2[CH:26]=1
Reactant: O=S1(=O)CCC(=S)Nc2ccc(Cl)cc2C1c1ccccc1F
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of 0.9 ml of hydrazine hydrate in 134 ml of tetrahydrofuran is treated with 6.2 g of 8-chloro-6-(2-fluorophenyl)-1,3,4,6-tetrahydro-2-thiono-2H-5,1-benzothiazocine 5,5-dioxide. The solution is stirred at room temperature under a stream of argon for 1.25 hours and then evaporated in vacuo. The residue is crystallized from diisopropyl ether, there being obtained 8-chloro-6-(2-fluorophenyl)-2-hydrazino-3,6-dihydro-4H-5,1-benzothiazocine 5,5-dioxide of melting point 159°.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C:3]([NH:5][C:6]1[CH:24]=[CH:23][C:9]2[N:10]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:11]([C:14]([F:17])([F:16])[F:15])[CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].C([Li])(C)(C)C.C([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])(=O)C>C(OCC)C>[F:38][C:37]([F:40])([F:39])[C:36]([C:7]1[C:8]2[O:13][CH2:12][CH:11]([C:14]([F:17])([F:15])[F:16])[N:10]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:9]=2[CH:23]=[CH:24][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:26])([CH3:25])[CH3:1])=[O:35]
Reactant: CC(C)(C)C(=O)Nc1ccc2c(c1)OCC(C(F)(F)F)N2CC(F)(F)F
Reactant: CC(=O)OCC(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1ccc2c(c1C(=O)C(F)(F)F)OCC(C(F)(F)F)N2CC(F)(F)F
Temperature: -10 °C
Yield: 16 %

Procedure:
To a solution of (±)-7-(2,2-dimethylpropionamido)-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine (200 mg, 0.52 mmol) in 3 mL of dry diethyl ether at −30° C. was added t-butyllithium (1.7M/pentane, 0.80 mL, 1.35 mmol) was added dropwise over of 30 min and then stirred at −10° C. The deep yellow solution was allowed to stir at −10° C. for 5–6 hours and then recooled to −30° C. and trifluoroethyl acetate (0.186 mL, 1.56 mmol) was slowly added. The reaction was allowed to gradually warm to room temperature over the course of 12 hours. The reaction was quenched with saturated ammonium chloride (2 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a brown oil. The substrate was purified via flash chromatography (4:1 hexanes:EtOAc) to afford 40 mg (15%) of (±)-3,4-dihydro-8-(trifluoroacetyl)-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-7-(trimethylacetamido)-2H-1,4-benzoxazine. 1H NMR (400 MHz, CDCl3) d 8.92 (s, 1H), 7.81 (d, 1H), 7.06 (d, 1H), 4.68 (d, 1H, J=12), 4.22–4.38 (m, 1H), 4.05–4.12 (m, 1H), 3.93–4.20 (m, 1H), 3.78–3.91 (m, 1H), 1.28 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[C@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CC(O)=O>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:20])[C:9]([N:11]2[C@H:15]([CH:16]([CH3:17])[CH3:18])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[C@@H]1COC(=O)N1C(=O)[C@H](C)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (4R)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one (2.80 g, 9.96 mmol) in dry THF (80 mL) at −78° C. under argon, was added dropwise 1.0M solution of NaHMDS in THF (11.0 mL, 11.0 mmol) over a period of 10 min. After stirring at −78° C. for 1 h, Mel (1.9 mL, 30.0 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 1 h and −40° C. for 2 h, quenched with HOAc (30.0 mmol) in ether (20 mL), filtered over celite. The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2 (100 mL) and washed with H2O following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (5%–10% EtOAc in hexane) to give 1.58 g (5.35 mmol, 54%) of (4R)-3-[(2R)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.30–7.23 (m, 4H), 5.11 (q, 1H, J=7.9 Hz), 4.35 (quintet, 1H, J=3.7 Hz), 4.16–4.09 (m, 2H), 2.46–2.36 (m, 1H), 1.49 (d, 3H, J=7.3 Hz), 0.91 (apparent t, 6H, J=6.9 Hz); ESMS m/e: 296.1 (M+H)+.
Reaction SMILES: [H-].[K+].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10].[CH2:11](B(CC)CC)C.CI>O1CCCC1>[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10]
Reactant: CC1CCCCC1=O
Reactant: CCB(CC)CC
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C)CCCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of potassium hydride (5.5 mmol) and 2-methylcyclohexanone (5 mmol) in dry tetrahydrofuran (10 ml) is stirred for 30 mins at room temperature. Triethylborane (6.25 mmol) is slowly added dropwise and the mixture is stirred for 16 hours at room temperature. After addition of methyl iodide stirring is continued for another 8 hours, the reaction is then quenched with saturated aqueous ammonium chloride solution and twice extracted with diethyl ether. The combined organic phases are dried over sodium sulphate and concentrated to dryness in a vacuum and produce the title compound, which can be reacted without [without] purification (JACS 1985, 107, 19, 5391-5396).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].[F:7][C:8]([F:36])([F:35])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=O)=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH2:16][CH2:17][C:12]2=[N:11][N:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:6])[C:30](=[O:32])[CH2:29][O:28][C:27]1[CH:26]=[CH:25][C:24]([CH:21]2[CH2:22][CH2:23][N:18]([C:15]3[CH2:16][CH2:17][C:12]4[N:13]([C:9]([C:8]([F:7])([F:36])[F:35])=[N:10][N:11]=4)[N:14]=3)[CH2:19][CH2:20]2)=[CH:34][CH:33]=1
Reactant: O=C(O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Reactant: CNCCOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)C(=O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
N-(2-methoxyethyl)methylamine (25 mg, 0.28 mmol) was added to 2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetic acid (100 mg, 0.24 mmol), HATU (108 mg, 0.28 mmol) and DIPEA (0.123 mL, 0.71 mmol) in DMF (2 mL). The resulting solution was stirred at ambient temperature for 3 hours then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(2-methoxyethyl)-N-methyl-2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)acetamide (38 mg, 32%) as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.[NH2:39][C:40]1[CH:45]=[CH:44][N:43]([CH3:46])[C:42](=[O:47])[CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:46][N:43]1[CH:44]=[CH:45][C:40]([NH:39][C:35]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17]2)=[O:36])=[CH:41][C:42]1=[O:47]
Reactant: Cn1ccc(N)cc1=O
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1=O
Yield: 14.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.2 g, 0.43 mmol) was vented with 4-amino-1-methyl-1H-pyridin-2-one (Molbridge) (0.11 g, 0.86 mmol), HATU (0.29 g, 0.77 mmol) and iPr2NEt (0.15 mL, 0.86 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a white solid (35 mg, 14%).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[C:17](=[O:18])[NH:16][C:10]2[N:11]=[C:12]([CH3:15])[N:13]=[CH:14][C:9]=2[C:8]=1[NH2:19])=[O:6])[CH3:3].CN(C)C=O.[CH2:25](I)[CH3:26]>O>[CH2:2]([O:4][C:5]([C:7]1[C:17](=[O:18])[N:16]([CH2:25][CH3:26])[C:10]2[N:11]=[C:12]([CH3:15])[N:13]=[CH:14][C:9]=2[C:8]=1[NH2:19])=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(N)c2cnc(C)nc2[nH]c1=O
Reactant: CCI
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N)c2cnc(C)nc2n(CC)c1=O
Reaction time: 72 h

Procedure:
To a solution containing 5.4 g. (0.02 mole) of the sodium salt of 5-amino-7,8-dihydro-2-methyl-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester in 50 ml. of dimethylformamide was added 9.35 g. (0.06 mole) of ethyl iodide. The reaction mixture was heated to 50° for 4 hours; cooled in ice and then poured into one liter of water. The reaction mixture was kept in a cold room for 3 days and was then filtered. The product amounted to 3.4 g. (m.p. 230°-231°). The analytical sample was obtained by recrystallization from ethanol.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH2:4][S:3]1.[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:17]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH2:4][S:3]1)(=[O:19])[CH3:18]
Reactant: N=C1SCCN1c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N=C1SCCN1c1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
0.52 g (2 mmoles) of 2-imino-3-(4'-chloro-2-nitrophenyl)-thiazolidine is dissolved in 20 ml of anhydrous chloroform. 0.24 g (0.21 ml, 3 mmoles) of acetyl chloride and 0.4 ml (0.3 g, 3 mmoles) of triethylamine are added to the solution and it is boiled for 30 minutes. The solution is then evaporated in vacuo, the oily residue is dissolved in 30 ml of dichloromethane and extracted twice with 10 ml of saturated aqueous sodium chloride solution each. The solution is dried and evaporated, the oily residue is crystallized from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:20]4[O:26][C:25](=[O:27])[C:24]5[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=5[CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:20]([OH:26])[CH2:21][CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=4[C:25]([N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:27])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C1OC(c2cccc(/C=C/c3ccc4ccc(Cl)cc4n3)c2)CCc2ccccc21
Product: O=C(c1ccccc1CCC(O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)N1CCCC1
Yield: 61.6 %

Procedure:
A stirred solution of lactone 49 (21.0 g, 49.0 mmol) in pyrrolidine (20 ml, 241 mmol) was heated at 90° C. for 3 hours. Excess pyrrolidine was distilled off and the residue was dissolved in dichloromethane (200 ml) followed by FC to give desired hydroxy pyrrolidinamide 50 (15.0 g, 61%) as a pale yellow solid.