Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[CH:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([O:17][S:33]([CH3:32])(=[O:35])=[O:34])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)O)[C@H]2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1

Procedure:
p-Nitrobenzyl (5R,6R)-3-(2-acetamidoethylthio)-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e10) (80 mg) was treated with methanesulphonyl chloride and triethylamine in dichloromethane as described in Example 1. After work-up, evaporation of the dichloromethane solution afforded p-nitrobenzyl (5R,6R)-3-(2-acetamidoethylthio)-6-[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e11) as a pale-yellow foam (67 mg); νmax (CH2Cl2) 1780, 1700, 1675, 1425, 1245 and 1175 cm-1.
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.[O:15]([CH2:19][CH2:20][NH2:21])[N+:16]([O-:18])=[O:17].C(OC(C)C)(C)C>>[O:15]([CH2:19][CH2:20][NH:21][C:8](=[S:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[N+:16]([O-:18])=[O:17]
Reactant: OC(=S)Cc1ccccc1
Reactant: NCCO[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])OCCNC(=S)Cc1ccccc1
Yield: 66.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.72 g of phenylthioacetic acid and 0.60 g of 2-nitroxyethylamine nitrate, 0.57 g of the title compound was obtained as colorless powdery crystals (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C@@:10]([C:14](Cl)=[O:15])([CH2:11]2)[C@@H:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]([F:47])([F:46])[C:32]1[CH:33]=[C:34]([C@@H:42]([NH:44][CH3:45])[CH3:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>C(=O)(O)[O-].[Na+]>[F:30][C:31]([F:46])([F:47])[C:32]1[CH:33]=[C:34]([C@@H:42]([N:44]([CH3:45])[C:14]([C@@:10]23[CH2:11][CH:12]2[CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:9]3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH3:43])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1
Reactant: O=C(Cl)[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Reactant: CN[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C[C@@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(=O)[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
To racemic Intermediate 40, one enantiomer being (1S,2S)-3-benzyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-1-carbonyl chloride (0.17 g, 0.56 mmol) in MC (5 mL) was added triethylamine (0.24 mL, 1.7 mmol) and (S)-1-(3,5-bis(trifluoromethyl)phenyl)-N-methylethanamine 0.15 g, 0.56 mmol) in MC (1 mL). The reaction was stirred at room temperature overnight. The reaction was diluted with saturated sodium bicarbonate solution and the phases separated. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to an oil. This material was flash chromatographed on silica using a gradient of 5 to 10% EtOAc/Hexanes to afford the title compound (0.06 g, 19% yield).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11](Cl)[O:12][CH3:13]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][O:12][CH3:13])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1
Yield: 95.1 %

Procedure:
Add sodium hydride (2.78 g of 95% dry, 0.116 mol) in portions to a 500 mL three-necked flask equipped with a nitrogen inlet, magnetic stir bar and DMF (200 mL) at −10 to −15° C. Add a solution of 4-bromophenol (20.00 g, 0.116 mol) in DMF (100 mL) over about 20 minutes, maintaining the internal temperature of the reaction below −5° C. Stir the reaction for 1 hour and then add MOMCl (8.81 mL, 0.116 mol) in portions to maintain the internal temperature below −5° C. Stir the mixture for 3 hours and then add ice until gas evolution ceases. Pour the reaction into ice-H2O (500 mL) and extract with EtOAc (2×300 mL). Wash the combined organic extracts with 1 N NaOH (500 mL), H2O (500 mL) and brine (400 mL). Dry the solution (MgSO4), filter and concentrate to obtain the title product (23.94 g, 93%) as an oil which may be used without further purification. 1H NMR (CDCl3) δ 3.46 (s, 3H), 5.14 (s, 2H), 6.92 (d, J =9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].[C:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@@H:28]4[CH2:33][CH2:32][C@H:31]([N:41]5[CH2:42][CH2:43][N:38]([C:35](=[O:37])[CH3:36])[CH2:39][CH2:40]5)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn(C4CCC(=O)CC4)c3C)cc12
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@@H](N5CCN(C(C)=O)CC5)CC4)c3C)cc12
Temperature: 60 °C

Procedure:
A mixture of 4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanone (12.0 mg, 0.0250 mmol), 1-acetylpiperazine (31.98 mg, 0.2495 mmol), sodium triacetoxyborohydride (10.58 mg, 0.04990 mmol) and 1,2-dichloroethane (3 mL, 40 mmol) was heated to 60° C. in a sealed tube for 6 h. The solution was extracted with DCM and sat. NaHCO3, and the organic layer was loaded onto silica gel for column chromatography, eluting with 3-7% (7N NH3 in MeOH)/DCM. The fractions containing the product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.63-1.73 (m, 3H), 1.81 (d, J=7.1 Hz, 3H), 2.00 (s, 3H), 2.10-2.14 (m, 4H), 2.25-2.43 (m, 4H), 2.58-2.66 (m, 4H), 3.59-3.70 (m, 8H), 4.34 (tdd, J=9.3, 9.3, 4.7, 4.3 Hz, 1H), 5.12 (q, J=6.8 Hz, 1H), 6.90 (dd, J=9.1, 4.3 Hz, 1H), 7.09 (t, J=8.8 Hz, 1H), 7.36 (d, J=1.0 Hz, 1H), 7.42 (s, 1H), 7.47 (s, 1H), 8.12 (s, 1H). MS (ES+): m/z=593.27/595.27 (100/50) [MH+]. HPLC: tR=1.19 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][C:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CC)=[O:13])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[N+]([O-])([O-])=O>>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][C:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: CCCCCCCC(=O)OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: O=[N+]([O-])[O-]
Product: CCCCCC(=O)OC(Cn1ccnc1)c1ccc(Cl)cc1Cl

Procedure:
1-[2,4-dichloro-β-(n-heptylcarbonyloxy)phenethyl]imidazole, as nitrate mp 99°-100.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]([CH3:34])[CH3:33])[S:7][C:6]=2[CH:35]=1.Cl[CH2:37][N:38]1[C:42](=[O:43])[C:41]2[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=2[S:39]1(=[O:49])=[O:48].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[O:48]=[S:39]1(=[O:49])[C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[C:42](=[O:43])[N:38]1[CH2:37][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15][CH:16]=3)=[C:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]([CH3:33])[CH3:34])[S:7][C:6]=2[CH:35]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCl
Reactant: CC(C)c1ccccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1ccccc1-c1sc2cc(OCN3C(=O)c4ccccc4S3(=O)=O)ccc2c1Oc1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.7 %

Procedure:
To a solution of (E)-tert-butyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (68 mg, 0.140 mmol) in acetone (2 mL) was added 2-(chloromethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (32.4 mg, 0.140 mmol), potassium carbonate (19.31 mg, 0.140 mmol) and potassium iodide (23.2 mg, 0.140 mmol). The resulting mixture was stirred at room temperature for 48 hours. The solvent was removed in vacuo. The resulting solid was retaken in ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution followed by brine. The organic layer was dried over anhydrous MgSO4 filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (SiO2, 0-30% EtOAc/Heptane) to afford (E)-tert-butyl 3-(4-((6-((1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)methoxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (67.4 mg, 0.099 mmol, 71% yield). 1H NMR (400 MHz, (CD3)2SO) δ 8.37 (d, J=7.4 Hz, 1H), 8.18 (dd, J=7.4, 1.3 Hz, 1H), 8.11 (td, J=7.7, 1.3 Hz, 1H), 8.04 (t, J=7.6 Hz, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.61-7.54 (m, 2H), 7.48-7.34 (m, 3H), 7.34-7.30 (m, 2H), 7.23-7.15 (m, 2H), 6.89-6.81 (m, 2H), 6.33 (d, J=16.0 Hz, 1H), 5.90 (s, 2H), 3.13 (q, J=6.9 Hz, 1H), 1.45 (s, 9H), 1.13 (d, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:16]>>[C:1]1([CH2:11][C:12]([Cl:16])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)Cl
Reactant: O=C(O)Cc1cccc2ccccc12
Product: O=C(Cl)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Naphthylacetyl chloride is prepared according to the method described in Example 8 using 1-naphthylacetic acid (2.0 g, 10.8 mmol) to give a yellow oil which is dissolved in chloroform (10 mL). This solution is added to a solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanethiol (2 g, 10 mmol) in chloroform (10 mL), and the mixture is stirred at room temperature for 8 hours under nitrogen. The solvent is removed and the residue is partitioned between 1M hydrochloric acid (100 mL) and ether (80 mL). The organic layer is separated and the aqueous is washed with more ether (2×60 mL). The aqueous mixture is basified to pH>12 by the addition of 50% sodium hydroxide solution, and extracted with ether (1×80 mL, 2×50 mL). These ether extracts of the basic aqueous solution are washed repeatedly with water to remove any unreacted aminothiol, dried over sodium sulfate, and the solvent is removed to leave the crude free thioester. This is converted to the hydrochloride salt by dissolving it in 1M hydrochloric acid (60 mL), adding sodium chloride (12 g), and extracting with chloroform (3×75 mL). The chloroform is removed in vacuo and the residue is recrystallised from ethyl acetate/methanol to yield the title compound.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:28][CH:29]([F:31])[F:30])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[F:27])[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[F:27])=[C:8]2[O:28][CH:29]([F:30])[F:31]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Cl)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of [8-chloro-3-(4-chloro-2-fluorobenzyl)-4-difluoromethoxy-2-ethyl-quinolin-5-yloxy]acetic acid methyl ester (0.075 g), tetrahydrofuran (2.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.20 mL) was stirred at room temperature for 2 hour. The solvent was removed under reduced pressure and the residue diluted with water. The pH of mixture was adjusted to 4 by the addition of sodium dihydrogenphosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and solvent removed under reduced pressure. The residue was crystallised from a mixture of acetonitrile and water to afford title compound, 0.057 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:17]([O:18]C(=O)C)[C@H:12]3[O:13]C(=O)C)[CH:9]=[N:10][C:5]2=[C:4]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)[CH:3]=1.N>CO>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C@@H:11]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([OH:18])[C@H:12]3[OH:13])[CH:9]=[N:10][C:5]2=[C:4]([S:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)[CH:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(SCc4ccc([N+](=O)[O-])cc4)cc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1ccc(CSc2cc(Cl)nc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1
Yield: 88 %

Procedure:
A mixture of 57 (75 mg, 0.17 mmol), p-nitro-benzylthiol (0.85 g, 0.5 mmol) and 0.1 mL of Et3N in 5 mL of DMF was stirred at room temperature for 18 h. under N2 atmosphere. The solution was extracted with ether, dried and purified by flash chromatography (PE/EA. 1:1), yielding 72 mg of 5-chloro-7-(4-nitrobenzylsulfanyl)-3-(2′, 3′, 5′-tri-O-acetyl-β-D-ribofuranosyl)-3H-imidazo[4,5-b]pyridine 59 (75%). 1H NMR (CDCl3): δ 8.19 (d, 2H, J=8.0), 8.15(s, 1H), 7.60 (s, 1H), 755 (d, 2H, J=8.0, 2H), 6.21 (d, 1H, J=5.1 Hz), 5.83 (dd, 1H, J=5.1, 5.9 Hz), 5.64 (dd, 1H, J=5.1, 5.9 Hz), 4.63 (s, 2H), 4.38 (m, 2H), 2.14, 2.12, 2.08 (3×s, 3H). Deprotection of 59 with saturated solution of ammonia in methanol at 0° C. for 18 h, gave 50 mg 61 (88%). 1H NMR (CDCl3): δ 8.74 (s, 1H), 8.14 (d, 2H, J=8.0), 7.66 (d, 2H, J=8.0, 2H), 7.18 (s, 1H), 6.03 (d, 1H, J=5.1 Hz), 4.89 (s, 2H), 4.69 (dd, 1H, J=5.1, 5.9 Hz), 4.43 (m 1H), 3.88-3.78 (m, 2H). 13C NMR (CD3OD): 147.15, 145.80, 145.101, 144.324, 137.180, 130.02, 129.78, 128.75, 115.495, 90.91, 87.49, 75.46, 72.16, 63.13, 36.07; Mp: 162-165° C.; HRMS calc. for C18H18N4O6ClS m/z=453.0635 (M+H), found 453.0614.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O)([O-:3])=[O:2].O.[CH3:12][NH:13][CH3:14]>CO>[CH3:12][N:13]([CH3:14])[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][N+:1]([O-:3])=[O:2]
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: CNC
Solvent: O
Solvent: CO
Product: CN(C)C(=O)CCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.9 %

Procedure:
To a solution of methyl 4-nitrobutyrate (1.0 g, 6.80 mmol) in methanol (10 ml) was added 40% dimethylamine water solution (12.5 ml, 102 mmol). The solution was stirred at room temperature for 48 h, concentrated by vacuum, and diluted with ethyl acetate (20 ml). The organic layer was dried and evaporated. The residue was purified by flash chromatography over silica gel (Hexane-EtOAc, 1:1) to give the title product (0.99 g, 91%). 1H NMR (CDCl3): 4.53 (t, J=6.6 Hz, 2H), 3.02-2.94 (m, 6H), 2.48-2.43 (m, 2H), 2.36-2.31 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+:17]>CO.C1COCC1>[F:15][C:2]([F:1])([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1)[C:3]([O-:5])=[O:4].[Na+:17]
Reactant: CCOC(=O)C(F)(F)c1ccc(F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])C(F)(F)c1ccc(F)cn1
Reaction time: 0.17 h
Yield: 100.9 %

Procedure:
To ethyl 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate (560 mg, 2.55 mmol) in 1:1 MeOH/THF (10 mL) at rt was added 1 M NaOH (2.8 mL, 2.8 mmol). The solution was stirred for 10 min and then concentrated to dryness to afford sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate (548 mg, quantitative). 1H NMR (300 MHz, DMSO-d6) δ 7.66 (dd, 1H), 7.79 (dt, 2H), 8.54 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([C@@H:12]1[C@H:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.O=C1CCC(=O)N1[O:26][C:27](=O)[CH2:28][C:29]#[N:30]>C(O)C>[CH3:18][C@@H:17]1[CH2:16][CH2:15][N:14]([C:27](=[O:26])[CH2:28][C:29]#[N:30])[CH2:13][C@@H:12]1[N:2]([CH3:1])[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: C[C@@H]1CCNC[C@@H]1N(C)c1ncnc2[nH]ccc12
Solvent: CCO
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a stirred solution of the product from Method B (1.0 g) dissolved in 30 mL of ethanol was added 0.82 g of cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester and the resulting mixture stirred at room temperature for 2 h. The reaction mixture was filtered through Celite® and concentrated in vacuo. The residue was redissolved in dichloromethane, washed with saturated, aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to dryness in vacuo affording 1.1 g (86%) of the title compound as a yellow foam. LRMS: 313 (M+1).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[CH:13][CH:12]=2)(O)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>Cl>[N:17]1([C:14]2[CH:13]=[CH:12][C:11]([C:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH:6]=3)=[CH:16][CH:15]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CC(=O)N1CCC(O)(c2ccc(-n3ccnc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C1=C(c2ccc(-n3ccnc3)cc2)CCNC1
Yield: 76 %

Procedure:
To 2.5 g of 1-acetyl-4-(4-imidazol-1-ylphenyl)-4-hydroxypiperidine, 30 ml of concentrated hydrochloric acid was added, followed by heating at reflux for 4 hours. After the completion of the reaction, the reaction solution was cooled, neutralized with an aqueous 1N sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the resulting crystal was washed with hexane and then dried to obtain 1.5 g of the objective 4-(4-imidazol-1-ylphenyl)-1,2,3,6-tetrahydropyridine (mp: 150-153° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1C=CCC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1CC[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.5 %

Procedure:
A mixture of 3,4-dichlorophenylboronic acid (488 mg, 2.56 mmol), bis(norbornadiene)rhodium tetrafluoroborate (14.6 mg, 0.0390 mmol) and S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (25.8 mg, 0.0410 mmol) in dioxane (6.6 mL) was sparged with Ar three times and stirred at rt for 2 h. To the reaction mixture was added water (1.015 mL) followed by the addition of cyclopent-2-enone (200 mg, 2.44 mmol) and TEA (0.340 mL, 2.44 mmol). The reaction mixture was stirred at room for 18 h. The reaction mixture was diluted with DCM, washed with H2O, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography 40 g using hexanes/EtOAc (0-100% over 15 min, flow rate 40 mL/min) to give Intermediate 41A (585 mg, 2.55 mmol, 100% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 1.86-2.02 (1H, m), 2.18-2.38 (2H, m), 2.38-2.55 (2H, m), 2.67 (1H, dd, J=18.2, 7.4 Hz), 3.28-3.49 (1H, m), 7.09 (1H, dd, J=8.0, 2.5 Hz), 7.34 (1H, d, J=1.8 Hz), 7.41 (1H, d, J=8.3 Hz).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[C:7]([C:13]([O:15][CH3:16])=[O:14])#[C:8][C:9]([O:11][CH3:12])=[O:10]>O>[CH3:3][C:2]1[CH2:1][C:7]([C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][C:4]=1[CH3:6]
Reactant: C=C(C)C(=C)C
Reactant: COC(=O)C#CC(=O)OC
Solvent: O
Product: COC(=O)C1=C(C(=O)OC)CC(C)=C(C)C1
Temperature: 25 °C
Yield: 78 %

Procedure:
2,3-dimethylbutadiene (9.84 g, 0.12 mol) and dimethyl acetylenedicarboxylate (14.2 g, 0.1 mol) were stirred together in water (50 ml) at 60° C. for 24 hours. The emulsion was cooled to room temperature and filtered. The filtered solid was recrystallised from diethyl ether to give the title compound in 78% yield. N.m.r: δH (90 MHz, CDCl3) 3.70 (s,6H), 1.71 ppm (s,6H)
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:9]1[CH2:14][CH2:13][CH:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(CCN2CCC(Nc3ccccc3)CC2)cc1

Procedure:
The title compound was prepared by the method outlined in Example 1 using 1-phenethyl-4-piperidone (5.3 g, 0.026 mol), aniline (5.01 ml, 0.55 mol), acetic acid (3 ml) 1,2-dichloroethane (100 ml) and sodium triacetoxyborohydride (5.82 g, 0.027 mol). The title compound was obtained as a white solid (74% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]=[C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[S:24][C:25]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:15]=2[CH:14]=[CH:13]1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:41][S:42]([N:33]([C:25]1[S:24][C:16]2[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12](=[O:11])[CH:13]=[CH:14][C:15]=2[C:26]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1)S(C)(=O)=O
Temperature: 25 °C
Yield: 92.6 %

Procedure:
Sodium bis(trimethylsilyl) amide (0.25 mL of a 1M solution in THF, 0.25 mmol) was added to a solution of the compound of Example 80 (105 mg, 0.25 mmol) in dry THF (5 mL) under a nitrogen atmosphere at 0°. After 30 min methane sulfonyl chloride (28.6 mg, 0.25 mmol) was added. The reaction mixture was allowed to warm to r.t. over 1 h then poured into saturated NaHCO3(aq) (20 mL) and the product extracted with DCM (2×20 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by radial chromatography on silica (EtOAc) to give the title compound (115 mg, 92%). δH (CDCl3) 7.6–7.28 (11H, m), 6.55 (1H, d, J 9 Hz), 2.68 (3H, s), 1.32 (9H, s). m/z (ES+) 497 (M+H)+.