Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:55])[CH2:5][NH:6][C:7]([C:9]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C:38]4[CH:39]=[N:40][C:41]([O:44][CH2:45][CH2:46][O:47][Si](C(C)(C)C)(C)C)=[CH:42][CH:43]=4)=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[N:10]=1)=[O:8])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:55])[CH2:5][NH:6][C:7]([C:9]1[C:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:32]=[CH:33][C:34]([CH2:37][C:38]4[CH:39]=[N:40][C:41]([O:44][CH2:45][CH2:46][OH:47])=[CH:42][CH:43]=4)=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)[N:10]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(Cc4ccc(OCCO[Si](C)(C)C(C)(C)C)nc4)cc3)CC2)nc(C)c1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(Cc4ccc(OCCO)nc4)cc3)CC2)nc(C)c1OCc1ccccc1
Reaction time: 1 h
Yield: 66 %

Procedure:
A crude product of ethyl({[5-(benzyloxy)-2-{[1-(4-{[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyridin-3-yl]methyl}phenyl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate was dissolved in tetrahydrofuran (20 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 1.4 mL, 4.8 mmol) was added at 0° C., followed by stirring at the same temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.50 (ethyl acetate) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.31 g, 0.47 mmol) as a yellow oil (yield 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6]P(=O)(OCC)OCC)=[CH:4][CH:3]=1.[CH:17]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[Br:29])[C:22]([O:24][CH3:25])=[O:23])=O>>[Br:29][C:28]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1/[CH:17]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][CH:15]=1
Reactant: CCOP(=O)(Cc1ccc(Cl)cc1)OCC
Reactant: COC(=O)c1ccc(Br)c(C=O)c1
Product: COC(=O)c1ccc(Br)c(/C=C/c2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from diethyl 4-chlorobenzylphosphonate and methyl 3-formyl-4-bromobenzoate in accordance with the same procedure as in the manufacturing method described in step A of Example 2-2-1.
Reaction SMILES: CC(C(=C)CC(C)C)CO.[CH2:11]([CH:13]([C:19](=[CH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[C:14](OCC)=[O:15])[CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:11]([CH:13]([C:19](=[CH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:14][OH:15])[CH3:12]
Reactant: C=C(CC(C)C)C(CC)C(=O)OCC
Agent: C=C(CC(C)C)C(C)CO
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C=C(CC(C)C)C(CC)CO

Procedure:
As described for preparation of 2,5-dimethyl-3-methylenehexan-1-ol (vide supra), from ethyl 2-ethyl-5-methyl-3-methylenehexanoate (26.8 g, 135 mmol) and LAH (5.12 g, 135 mmol) in THF (500 mL) the 2-ethyl-5-methyl-3-methylenehexan-1-ol (17.5 g, 83%) was obtained as a colourless odoriferous liquid after standard workup and purification by silica-gel flash chromatography (pentane/Et2O, 8:2, Rf=0.18). IR (neat): ν=3332 (s, ν O—H), 1463 (w, δas CH3), 1365 (w, δs, CH3), 1034 (s, ν C—O), 892 (s, δ C═H) cm−1. 1H NMR (CDCl3): δ=0.88 (t, J=7.5 Hz, 3H, 2′-CH3), 0.91 (d, J=6.5 Hz, 6H, 5-Me2), 1.38-1.49 (m, 2H, 1′-H2), 1.77 (br. s, 1H, OH), 1.78-1.83 (m, 1H, 5-H), 1.85-1.89 (m, 2H, 4-H2), 2.11 (quint, J=8.0 Hz, 1H, 2-H), 3.51-3.55 (m, 2H, 1-H2), 4.86 (d, J=1.5 Hz, 1H, 1′-HE), 4.92 (d, J=1.5 Hz, 1H, 1′-HZ) ppm. 13C NMR (CDCl3): δ=11.7 (q, C-2′), 22.4/22.7 (2q, 5-Me2), 22.9 (t, C-1′), 25.8 (d, C-5), 44.5 (t, C-4), 49.7 (d, C-2), 64.2 (t, C-1), 111.7 (d, C-1″), 148.3 (s, C-3) ppm. MS (EI): m/z (%)=156 (3) [M+], 142 (2) [M+-CH3], 125 (7) [M+-CH3O], 83 (100) [C6H11+], 69 (100) [C5H9+], 43 (31) [C3H7+]. Odour description: pleasant and fresh green-floral note with spicy undertones and a natural agrestic aspects, somewhat reminiscent of beetroot with a slightly earthy twist.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22]Br)[CH3:19]>CN(C=O)C>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][O:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:19]
Reactant: COc1cccc(C=O)c1O
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1c(C=O)cccc1OC)OCC
Yield: 36.8 %

Procedure:
To a stirred suspension containing 2-hydroxy-3-methoxybenzaldehyde (4.0 g, 26.3 mmol) and K2CO3 (4.36 g, 31.60 mmol) in DMF (15 mL), bromoacetaldehyde diethyl acetal (4.86 mL, 31.60 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography eluting with hexane/EtOAc (4:1) to give 28 (2.60 g, 36%). 1H NMR (500 MHz, CDCl3): δ: 10.53 (1H, s, CHO), 7.42 (1H, m, ArH), 7.14-7.12 (2H, m, ArH), 4.83 (1H, t, J=5.30 Hz, CH), 4.21 (2H, d, J=5.35 Hz, CH2), 3.90 (3H, s, OCH3), 3.74-3.71 (2H, m, CH2CH3), 3.60-3.57 (2H, m, CH2CH3), 1.22 (6H, t, J=7.05 Hz, 2×CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH3:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH3:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:36]([F:39])([F:37])[F:38]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1N(C)S(C)(=O)=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CN(c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)S(C)(=O)=O

Procedure:
A mixture 4-chloro-N-{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (30 mg crude) in 4 M HCl in dioxane (12 mL) and water (4 mL) were heated at 100° C. for 18 h. The reaction mixture was concentrated to dryness under reduced pressure and subsequently neutralized aqueous NaHCO3 to pH to 5-6. The aqueous layer was extracted with EtOAc, the combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (20→80% gradient of MeCN-water) to provide 4-chloro-N-{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide as a solid. MS m/z: 582.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21](I)=[CH:22][C:13]=12.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]#[CH:33])[CH2:27][CH2:26]1>C1C=CC=CC=1.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21]([C:33]#[C:32][CH2:31][N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[CH:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3sc(I)cc23)c(Cl)cc1Cl
Reactant: C#CCN1CCN(C)CC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(Nc2c(C#N)cnc3sc(C#CCN4CCN(C)CC4)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-b]pyridine-5-carbonitrile (160 mg, 0.34 mmol), 1-methyl-4-prop-2-ynyl-piperazine (70 mg, 0.5 mmol), 15 mg of tetrakis(triphenylphosphine)palladium(0) and copper iodide (8 mg, 0.016 mmol) in 7 mL of benzene and 2 mL of triethylamine is heated at reflux for 7 hours. The reaction mixture is cooled to room temperature and partitioned between water and dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is triturated with ether and hexanes to provide 110 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]thieno[2,3-b]pyridine-5-carbonitrile as an off white solid, mp 175° C. (decomposition); 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 2.37 (bs, 4H), 2.54 (bs, 4H), 3.62 (s, 2H), 3.85 (s, 3H), 7.38 (s, 1H), 7.76 (s, 1H), 7.91 (s, 1H), 8.47 (bs, 1H), 9.83 (bs, 1H); MS 486.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:23][C:24]([OH:26])=[O:25])[C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of 4-tert-butyl-N-p-tolyl-benzenesulfonamide with tert-butyl bromoacetate
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].C([O-])(O)=O.[Na+].[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1>Cl.O>[N:15]1[CH:1]=[CH:2][N:17]2[CH:18]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[CH:24]=[CH:25][C:16]=12
Reactant: CCOC(CBr)OCC
Reactant: COC(=O)c1ccc(N)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc2nccn2c1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A solution of bromoacetaldehyde diethyl acetal (3.2 mL, 21.3 mmol) in 12M HCl (0.5 mL) and water (23 mL) was heated at 90° C. for 1 hour, cooled to room temperature, treated sequentially with NaHCO3, (1.67 g, 20 mmol) and methyl 6-aminonicotinate (1.10 g, 7.0 mmol), heated at 60° C. for 30 minutes, cooled to room temperature, adjusted to pH 9, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography with 97.5:2.5 dichloromethane/methanol to provide 1.02 g (88%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=2)[N:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28]O)=[CH:22][N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([C:5]3[N:4]=[C:3]([C:2]([F:17])([F:1])[F:18])[O:7][N:6]=3)=[CH:9][C:10]=2[CH3:16])=[CH:22][N:21]=1
Reactant: OCCCc1ccc(Cl)nc1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 78.3 %

Procedure:
To a suspension of 1.12 g (4.34 mmol) of 4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol, 0.87 g (1.2 eq) of 2-chloro-5-(3-hydroxypropyl)-pyridine, 1.4 g (1.2 eq) of triphenylphosphine in 50 ml of methylene chloride under nitrogen at 0° C. was added dropwise a solution of 0.86 g (1.2 eq) of DEAD in 5 ml of methylene chloride. The mixture was stirred under nitrogen at room temperature for 60 h, concentrated in vacuo and the residue was triturated with hexane/ethyl acetate, filtered, and the filtrate was concentrated in vacuo to yield a dark brown oil. The brown oil was purified by MPLC (50 id, Kieselgel 60 column, hexane/ethyl acetate, 3:1) to afford 1.4 g (78%) of 2-chloro-5-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine, as a white crystalline solid, m.p. 89°-91° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:11][Si:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15].Cl>C1COCC1.O>[Cl:1][C:2]1[N:7]=[C:6]([O:15][CH2:14][CH2:13][Si:12]([CH3:17])([CH3:16])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)CCO
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOc1ccnc(Cl)n1
Reaction time: 16 h
Yield: 79.2 %

Procedure:
2,4-Dichloro-pyrimidine (2.00 g, 13.4 mmol) in THF (30 mL) was treated with sodium hydride (670 mg, 60% oil dispersion, 16.8 mmol) followed by 2-trimethylsilanyl-ethanol (2.01 mL, 14.1 mmol) in portions over 15 minutes. The reaction mixture was stirred for 16 hours and treated with 1 M HCl (20 mL). Water (20 mL) was added and the mixture was extracted with 1:1 ethyl acetate:hexanes (100 mL) followed by ethyl acetate (100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (10-30% EtOAc:hexanes, 80 g column), afforded 2.45 g (79% yield) of 2-chloro-4-(2-trimethylsilanyl-ethoxy)-pyrimidine as a mixture of regioisomers.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2([C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)[CH2:59][CH2:58][NH:57][CH2:56]2)=[CH:51][CH:50]=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2([C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)[CH2:59][CH2:58][N:57]([C:20](=[O:21])[CH2:19][N:3]3[CH2:4][CH2:5][C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:2]3=[O:1])[CH2:56]2)=[CH:51][CH:50]=1
Reactant: Fc1ccc(C2(c3ccc(F)cc3)CCNC2)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 3,3-bis(4-fluorophenyl)pyrrolidine from Example 203A for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.44-6.86 (m, 18H), 4.27-3.98 (m, 4H), 3.55 (dq, J=6.7, 9.6, 3H), 3.41 (t, J=6.7, 1H), 2.82 (q, J=6.5, 2H), 2.50 (dt, J=6.8, 21.3, 2H); MS (DCI) m/z 537.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:16])[C:5]2([C:12]([OH:15])([CH3:14])[CH3:13])[N+]#[C-].C1([SnH](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:16])[C@H:5]2[C:12]([OH:15])([CH3:13])[CH3:14]
Reactant: [C-]#[N+]C1(C(C)(C)O)C(=O)N2[C@@H]1CCOC2(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: c1ccc([SnH](c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(O)[C@@H]1C(=O)N2[C@@H]1CCOC2(C)C
Temperature: 25 °C
Yield: 62.3 %

Procedure:
A solution of (6R,7RS)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1-aza-3-oxabicyclo[4.2.0]-octan-8-one (920 mg), triphenyltin hydride (1.694 g) and azobisisobutyronitrile (63.4 mg) in benzene (46 ml) was heated at 50° C. for thirty minutes under a nitrogen atmosphere. The mixture was cooled to ambient temperature. The precipitates were filtered off and washed with benzene. The filtrate and washings were combined and chromatographed on silica gel (27.6 g, eluting with 10 to 25% acetone in dichloromethane) to give a crude product mixture, which was re-chromatographed on silica gel (46 g; 230-400 mesh, eluting with a 6:1 to 1:2 mixture of hexane and ethyl acetate) to give 513 mg of (6R,7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]octan-8-one after crystallization from diisopropyl ether and 170 mg of its 7S isomer as a crystalline solid.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([O:23]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[S:45]1(=[O:52])(=[O:51])[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46]1>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[N:7]([C:21]([NH:50][CH:47]2[CH2:48][CH2:49][S:45](=[O:52])(=[O:51])[CH2:46]2)=[O:23])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: NC1CCS(=O)(=O)C1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NC2CCS(=O)(=O)C2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78.0 mg, 0.125 mmol; Example 6A) was reacted with tetrahydrothiophen-3-amine 1,1-dioxide (50.6 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound (52 mg, 66% of theory).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]=O)=[CH:16][CH:15]=1>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:22]([CH2:21][CH2:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:24])[F:25])=[CH:15][CH:16]=3)[C:5]2=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C)cn1CCN
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Product: CCc1nc(C)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2-ethyl-4-methyl-imidazol-1-yl)-ethylamine with 3-(4-trifluoromethyl-phenyl)-propionaldehyde. LC-MS: tR=0.65 min.; [M+H]+=338 g/mol.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][CH2:8][C:9](=[O:20])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[O:18][CH3:19])=[O:6])=[N+:2]=[N-:3].[BH4-].[Na+].C(O)(=O)C>CO>[N:1]([CH2:4][C:5]([NH:7][CH2:8][CH:9]([OH:20])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[O:18][CH3:19])=[O:6])=[N+:2]=[N-:3]
Reactant: COc1ccc(OC)c(C(=O)CNC(=O)CN=[N+]=[N-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(OC)c(C(O)CNC(=O)CN=[N+]=[N-])c1
Temperature: 0 °C
Yield: 95 %

Procedure:
In a four neck round bottomed flask 32.4 gm (0.11 mole) of 2-azido-N-(β-Oxo-2,5-dimethoxy phenehyl)-acetamide is prepared according to the step (c) and 260 ml methanol is charged and cooled to 0° C. To this 3.24 gm (0.08 mole) sodium boro hydride is added slowly over a period. After completion of the addition, the reaction mass temperature is raised to 10° C. After completion of the reaction, 10 ml of acetic acid is added. Methanol is stripped off under reduced pressure and the residue obtained is extracted with methylene dichloride. Organic layer is washed with water and methylene dichloride is distilled off. The yield was 95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5](C(O)=O)=[N:6][N:7]([C:9]2[C:19]([F:20])=[CH:18][C:12]3[O:13][C:14]([F:17])([F:16])[O:15][C:11]=3[CH:10]=2)[CH:8]=1.C1C=CC(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:39][C:5]1[C:4](=[O:24])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[C:19]([F:20])=[CH:18][C:12]3[O:13][C:14]([F:17])([F:16])[O:15][C:11]=3[CH:10]=2)[N:6]=1
Reactant: COc1cn(-c2cc3c(cc2F)OC(F)(F)O3)nc(C(=O)O)c1=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cn(-c2cc3c(cc2F)OC(F)(F)O3)nc(N)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)-1,4-dihydropyridazine-3-carboxylic acid (1.18 g, 3.42 mmol), DPPA (1.10 mL, 5.13 mmol) and Et3N (0.715 mL, 5.13 mmol) in toluene (12 mL) was heated to 100° C. for 1 h. To the mixture was added 8 M NaOH aqueous solution (4.3 mL) at 0° C. The mixture was stirred at room temperature for 1 h, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100) and recrystallized with EtOAc/hexane to yield the title compound (704 mg, 65% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 173 (3H, s), 6.21 (2H, s), 7.85 (1H, d, J=9.4 Hz), 7.90 (1H, d, J=6.4 Hz), 8.33 (1H, s).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH:5]([C:8]([F:11])([F:10])[F:9])[CH2:4][NH:3]1.CC(N(C)C)=O.CCN(C(C)C)C(C)C.Br[CH2:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)=[CH:34][C:35]([C:39]#[N:40])=[N:36]2)=[CH:31][CH:30]=1>CCOC(C)=O>[F:47][C:44]1[CH:45]=[CH:46][C:41]([C:33]2[C:32]3[C:37](=[CH:38][C:29]([CH2:28][N:3]4[CH2:4][CH:5]([C:8]([F:11])([F:9])[F:10])[NH:6][CH2:7][C@@H:2]4[CH3:1])=[CH:30][CH:31]=3)[N:36]=[C:35]([C:39]#[N:40])[CH:34]=2)=[CH:42][CH:43]=1
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Reactant: C[C@H]1CNC(C(F)(F)F)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C[C@H]1CNC(C(F)(F)F)CN1Cc1ccc2c(-c3ccc(F)cc3)cc(C#N)nc2c1
Temperature: 50 °C

Procedure:
To the solution of (2S)-2-methyl-5-(trifluoromethyl)piperazine (4-20) was added DMA (1.76 ml), DIEA (0.614 ml, 3.52 mmol) followed by 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (300 mg, 0.879 mmol). The reaction was heated to 50° C. for 4 hours. The reaction was diluted with EtOAc and then washed with H2O, brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes to EtOAc to provide 4-(4-fluorophenyl)-7-(((2S)-2-methyl-5-(trifluoromethyl)piperazin-1-yl)methyl)quinoline-2-carbonitrile as a colorless solid. LRMS m/z (M+H)+ 429.2 found, 429.4 required.