Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:10])[CH2:8][N:9]=1)[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:13].CN(C)[CH:18]=[O:19].[OH-].[Na+]>ClC1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:5]1[NH:6][C:7]([Cl:13])=[C:8]([CH:18]=[O:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:1]([C:5]1[NH:6][C:7](=[O:10])[CH2:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Agent: CCCCC1=NCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: CCCCc1nc(C=O)c(Cl)[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-n-Butyl-2-imidazolin-5-one (9.81 g, 70 mmol) was added to a solution of phosphoroxychloride (26.83 g, 175 mmol) in chlorobenzene (50 ml) at room temperature. The orange suspension was heated to 100° C. within 5 minutes, and then N,N-dimethylformamide (12.79 g, 175 mmol) was added within 3 minutes. The black mixture was kept for 2 hours at 100° C., cooled to 40° C. and poured on water (84 ml). After addition of ethyl acetate (42 ml), the mixture was stirred for 15 minutes at 26° to 28° C. and then adjusted to pH 7 by addition of 30 percent sodium hydroxide solution (67 ml). The phases were separated, and the aqueous phase was extracted twice with 70 ml of ethyl acetate each. The combined organic phases were dried (MgSO4), filtered and concentrated by evaporation on a Rotavapor. The title compound was obtained in a yield of 8.31 g (64 percent) relative to the 2-n-butyl-2-imidazolin-5-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)C(=O)NNc1ccc(F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1nnc2ccc(F)cn12
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of Example 21 step a (0.41 g, 2.08 mmol), triphenylphosphine (763 mg, 2.91 mmol) and triethylamine (0.87 mL, 6.24 mmol) in THF (5 mL) at 0° C. was treated with 1,2-hexachloroethane (690 mg, 2.91 mmol). The reaction mixture was stirred at 0° C. for 40 min then at RT for 20 min, quenched with water, extracted twice with EtOAc, dried (Na2SO4), evaporated and purified twice by FCC (cyclohexane/EtOAc 1/0 to 1/1) to afford the title compound (274 mg, contaminated with 20% PPh3O, 58%) as a white solid. LCMS (Method 5): Rt 2.58 min, m/z 180 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:24])[C:15]([CH3:23])([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)C.[CH2:60]([SH:64])[CH2:61][CH2:62][SH:63].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O>[SH:63][CH2:62][CH2:61][CH2:60][S:64][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:24])[C:15]([CH3:23])([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: SCCCS
Reactant: CC(C)(C(=O)c1ccc(-c2ccc(Br)cc2)cc1)N1CCOCC1
Agent: C=CC(=O)OCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)COC(=O)C=C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(-c2ccc(SCCCS)cc2)cc1)N1CCOCC1
Temperature: 25 °C

Procedure:
3.5 g (9.0 mmol) of 1-(4'-Bromo-biphenyl-4-yl)-2-methyl-2-morpholin-4-yl-propan-1-one (prepared by the method described in EP-A-3002) and 5.4 ml (54 mmol) of 1,3-propanedithiol are dissolved in 50 ml of dimethylacetamide, and the solution is stirred at around 140° C. together with 2.5 g of potassium carbonate for 2.5 h. Then the solution is cooled to room temperature and poured into water. The crude product is extracted with methylene chloride, washed with saturated sodium chloride solution, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (10:90) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.35 (s, 6H), 1.38 (t, 1H), 1.98 (tt, 2H), 2.61 (t, 4H), 2.69 (dt, 2H), 3.11 (t, 2H), 3.72 (t, 4H), 7.42 (d, 2H), 7.51 (d, 2H), 7.62 (d, 2H), 8.63 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:19])[C:9]=1[O:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=1I)[C:5]#[N:6].[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:12]1[C:13]([CH3:17])=[N:14][N:15]([CH3:16])[C:11]=1[O:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[F:19]
Reactant: Cc1nn(C)c(Oc2c(F)cc(C#N)cc2F)c1I
Reactant: OB(O)c1ccc(F)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(C)c(Oc2c(F)cc(C#N)cc2F)c1-c1ccc(F)cc1Cl

Procedure:
To a solution of 3,5-difluoro-4-[(4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)oxy]-benzonitrile (i.e. the product of Step B) (1.0 g, 2.67 mmol) in 1,4-dioxane (6 mL) was added 2-chloro-4-fluorobenzeneboronic acid (alternatively named B-(2-chloro-4-fluorophenyl)-boronic acid) (0.93 g, 5.33 mmol), dichloro (bis)triphenylphosphine palladium(II) (alternatively named bis(triphenylphosphine)palladium(II) dichloride) (93 mg, 0.13 mmol), potassium carbonate (0.74 g, 5.33 mmol), and water (4 mL). The resulting mixture was heated at reflux for 5 h, allowed to cool, and partitioned between water (20 mL) and ethyl acetate (20 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel with a gradient of hexanes/ethyl acetate to obtain the title compound, a compound of the present invention, as an off-white solid (110 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6](I)[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[CH:12]([Sn](C=C)(C=C)C=C)=[CH2:13]>CN(C=O)C.CCOC(C)=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([CH:12]=[CH2:13])[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1
Reactant: C=C[Sn](C=C)(C=C)C=C
Reactant: OCc1cc(I)c(O)c(Cl)n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cc(CO)nc(Cl)c1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
2-Chloro-6-(hydroxymethyl)-4-iodopyridin-3-ol (5.7 g, 20 mmol) is combined with bis (triphenylphosphine) palladium dichloride (1.12 g, 1.6 mmol) in 50 ml DMF under nitrogen. The mixture is treated with tetravinyl tin, is warmed to 60° C. for 6 h followed by 50° C. for 18 h, and at rt for 72 h. The mixture is diluted with 250 ml EtOAc and is extracted with 4×100 ml 2:1:1 water/saturated NaCl/saturated NaHCO3. The organic layer is dried (MgSO4) and is concentrated in vacuo to a yellow oil. The crude material is chromatographed over 200 g SiO2 (230-400 mesh) eluting with 37% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 1.45 g (39%) of 2-chloro-6-(hydroxymethyl)-4-vinylpyridin-3-ol as a pale yellow solid. MS for C8H8ClNO2 (EI) m/z: 185 (M)+.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1([CH2:24][CH2:25][CH3:26])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:19](=[O:22])[NH:20][CH3:21])[CH:16]=[CH:15][C:14]=3[CH3:23])C.[OH-].[Na+]>C1COCC1.CO>[CH3:23][C:14]1[CH:15]=[CH:16][C:17]([C:19](=[O:22])[NH:20][CH3:21])=[C:18]2[C:13]=1[NH:12][C:11]1[C:6]([CH2:5][C:4]([OH:27])=[O:3])([CH2:24][CH2:25][CH3:26])[O:7][CH2:8][CH2:9][C:10]2=1
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(C(=O)NC)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(C)ccc(C(=O)NC)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of (8-methyl-5-methylcarbamoyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (87 mg, 0.234 mmol) in THF/MeOH (1.5 mL/1.5 mL) was added 1 N NaOH (0.468 mL, 0.468 mmol). The reaction mixture was stirred at ambient temperature overnight. The most of THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give 67 mg (84%) of title compound as a white solid. Mp=89–91° C.; HRMS (ESI) [M+H]+ calculated for C19H25N2O4 345.1809, found 345.1807; 1H NMR (DMSO-d6): 300 MHz δ 10.63 (s, 1H), 8.00 (s, 1H), 6.97 (d, J=6.00 Hz, 1H), 6.84 (d, J=6.00 Hz, 1H), 3.89 (m, 1H), 3.81 (m, 1H), 2.93–2.46 (m, 10H), 2.01 (m, 2H), 1.29 (m, 1H), 0.82 (m, 1H), 0.78 (t, J=5.10 Hz, 3H). LCMS retention time: 1.936 minutes.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=1>CN(C)C=O.O>[CH3:25][O:24][C:17]1[CH:16]=[C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (151 g, 88 mmol) in dry N,N-dimethylformamide (40 mL) at 0° C. was added diethyl malonate (10.3 g, 64.3 mmol) and the mixture was stirred at room temperature for 30 minutes. A solution of 4-fluoro-2-methoxy-1-nitrobenzene (10 g, 58.5 mmol) was added and the mixture was stirred at 90° C. overnight. The mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with a gradient of 1/20 to 1/10 ethyl acetate/petroleum ether to afford the title compound.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[C:12]2[CH2:13][CH2:14][CH:15](I)[C:16](=[O:18])[NH:17][C:11]=2[CH:10]=[CH:9][CH:8]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>O>[N:20]([CH:15]1[CH2:14][CH2:13][C:12]2[C:7]([F:6])=[CH:8][CH:9]=[CH:10][C:11]=2[NH:17][C:16]1=[O:18])=[N+:21]=[N-:22]
Reactant: O=C1Nc2cccc(F)c2CCC1I
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCc2c(F)cccc2NC1=O
Reaction time: 8 h

Procedure:
DMF (300 ml) was added to a mixture of 6-fluoro-3-iodo-1,3,4,5-tetrahydro-1-benzazepin-2-one (42.5 g) and sodium azide (13.59 g, 209 mmol) at room temperature and the reaction was stirred overnight. The mixture was diluted with water (2000 mL) and a precipitate formed, which was filtered off and washed with water. The precipitate was taken up in dichloromethane and washed with brine, dried over Na2SO4, filtered, and concentrated. The crude 3-Azido-6-fluoro-1,3,4,5-tetrahydro-1-benzazepin-2-one was isolated as a dark brown solid. Residual DMF remains in the sample, which was used without further manipulation in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@H:15]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](O)C2)n1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](OS(C)(=O)=O)C2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of (S)-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Ex. 13a, 6.1 g, 21.2 mmol) and triethylamine (8.9 mL, 63.5 mmol) in methylene chloride (75 mL) at 0° C. was added methanesulfonyl chloride (2.4 mL, 31.8 mmol). The resulting solution was warmed to room temperature and stirred at room temperature for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with 1N HCl (150 mL) and diluted with water (100 mL). The layers were cut and the organic layer was washed with 1N HCl (2×100 mL), a 50% aqueous brine solution (1×100 mL) and brine (1×100 mL), dried over Na2SO4, and concentrated under reduced pressure to afford 7.8 g (99%) of (S)-5-(3-methanesulfonyloxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as an orange foam. This material was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.27 (d, 1H, J=2.0 Hz), 7.17 (d, 1H, J=2.0 Hz), 5.15-5.17 (m, 1H), 3.97 (s, 3H), 3.84 (s, 3H), 3.43-3.60 (m, 3H), 3.30-3.37 (m, 1H), 2.94 (s, 3H), 2.17-2.23 (m, 1H), 2.09-2.16 (m, 1H). mp 79-81° C. Anal. Calcd. for C12H18N2O7S2: C, 39.34; H, 4.95; N, 7.65; S, 17.50. Found: C, 39.20; H, 5.00; N, 7.56; S, 17.66.
Reaction SMILES: C[CH:2]1[NH:7][CH:6](C)[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]=[C:19]4[N:21]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:22]=[C:23]([CH2:24][CH3:25])[C:18]4=[C:17]([O:32][CH3:33])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:3]1.[C:34](OC(N1CCNCC1)=O)(C)(C)C.Cl>>[CH2:33]([O:32][C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([N:4]3[CH2:3][CH2:2][NH:7][CH2:6][CH2:5]3)=[CH:10][CH:11]=2)[N:20]=[C:19]2[N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:22]=[C:23]([CH2:24][CH3:25])[C:18]=12)[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nn(-c2ccccc2)c2nc(-c3ccc(N4CC(C)NC(C)C4)cc3)cc(OC)c12
Agent: Cl
Product: CCOc1cc(-c2ccc(N3CCNCC3)cc2)nc2c1c(CC)nn2-c1ccccc1

Procedure:
The title compound was prepared according to the procedure as described in Example 98 reacting 6-(4-bromo-phenyl)-3-ethyl-4-ethoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine (according to Example 98) and piperazine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:45][CH2:44][N:43]([CH2:46][C:47]5[CH2:52][C:51](=O)[CH2:50][CH2:49][C:48]=5[C:54]5[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=5)[CH2:42][CH2:41]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>ClCCl.CO>[Cl:60][C:57]1[CH:58]=[CH:59][C:54]([C:48]2[CH2:49][CH2:50][CH:51]([N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)[CH2:52][C:47]=2[CH2:46][N:43]2[CH2:42][CH2:41][N:40]([C:38]3[CH:37]=[CH:36][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:6]4[CH:7]=[C:8]5[C:9](=[CH:4][CH:5]=4)[NH:1][CH:2]=[CH:3]5)[CH:39]=3)[CH2:45][CH2:44]2)=[CH:55][CH:56]=1
Reactant: O=C1CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)C1
Reactant: C1COCCN1
Solvent: CO
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(N4CCOCC4)C3)CC2)cc1Oc1ccc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 249F (120 mg) in dichloromethane (2 mL) and methanol (0.5 mL) was added morpholine (37mg) and 2-picoline borane complex (15.04 mg). The mixture was stirred overnight. The mixture was then diluted with dichloromethane (200 mL) and washed with aqueous NaHCO3, water, and brine, and dried over Na2SO4. The residue, after evaporation of solvent, was dissolved in dichloromethane and chromatographed with 0-10% 7N NH3 in 5% methanol in dichloromethane to give the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.15 (s, 1H), 8.58 (m, 2H), 7.79 (dd, 1H), 7.53 (m, 1H), 7.35 (m, 4H), 7.17 (m, 1H), 7.07 (m, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (s, 1H), 6.13 (d, 1H), 3.84 (m, 2H), 3.58 (m, 5H), 3.01 (m, 5H), 2.63 (m, 6H), 2.10 (m, 14H), 1.61 (m, 3H), 1.26 (m, 3H).
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C@H:18]1[CH2:17][CH2:16][C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:14][CH:13]=2)[CH2:20][CH2:19]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Reactant: COC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
Methyl chloro(oxo)acetate (0.842 mL) was added to a stirred solution of methyl [trans-4-(4-aminophenyl)cyclohexyl]acetate (1740 mg) and pyridine (0.689 mL) in DCM (50 mL) at 0° C. After the addition was complete the mixture was allowed to warm to ambient temperature and stirred for 64 hours. The solution was diluted with DCM (100 mL), washed with water (50 mL) and brine (50 mL), then dried and concentrated in vacuo to give the title compound (2267 mg) as a solid; 1H NMR δ 7.60 (2H, d), 7.18 (2H, d), 3.83 (3H, s), 3.58 (3H, s), 2.58-35 (1H+DMSO, m), 2.21 (2H, d), 1.75 (5H, m), 1.43 (2H, m), 1.12 (2H, m); MS m/e MH− 332.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:20][C:12]3=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1F.[CH3:21][O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][O:28][CH3:29]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:20][C:12]3=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[N:25]([CH2:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:23][O:22][CH3:21]
Reactant: O=[N+]([O-])c1cnc2[nH]c(-c3ccc(F)c(F)c3)nc2c1
Reactant: COCCNCCOC
Solvent: CN1CCCC1=O
Product: COCCN(CCOC)c1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1F
Reaction time: 18 h

Procedure:
0.5 g 2-(3,4-Difluoro-phenyl)-6-nitro-3H-imidazo[4,5-b]pyridine, 0.1 ml NMP and 0.51 g bis(2-methoxyethyl)-amine were heated to 170 C with stirring for 18 hrs. Volatile materials were removed under vacuum and the residue purified by chromatography, first on silica in dichloromethane/methanol mixtures, and subsequently by preparative HPLC.
Reaction SMILES: [CH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.C([C:9]1[C:15](=O)[C:14](Cl)=[C:13](Cl)[C:11](=[O:12])[C:10]=1C#N)#N>>[C:1]1([CH:10]2[CH2:9][CH2:15][CH2:14][CH2:13][C:11]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=CCC=CC1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: O=C1CCCCC1c1ccccc1
Yield: 56 %

Procedure:
Rh2 (S-DOSP)4-catalyzed decomposition of the cyclic vinyldiazoacetate 58 in the presence of 1,3-cyclohexadiene 40 resulted in the formation of the 1,4-cyclohexadiene 59 in 73% yield and 97% ee. The absolute configuration of compound 59 was determined by DDQ oxidation and ozonolysis to afford the 2-phenylcyclohexanone in a 56% yield. Found [α]26D=−17 (c=1.66, PhH) Lit. value: [α]24D=−113.5 (c=0.60, PhH), S-isomer. (Berti et al., J. Chem. Soc., pp. 3371–3377 (1971), which is hereby incorporated by reference.) Similarly, decomposition of the dienyldiazoacetate 60 in the presence of 1,3-cyclohexadiene 40 resulted in the formation of 61 (60% yield and 99% ee), in which both diene components have moved out of conjugation.
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@@H:26]([OH:28])[CH3:27])[C:14]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[OH:28][C@@H:26]([CH3:27])[C@@H:13]([NH:12][C:6]1[C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[O:15][C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:17][N:16]=1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.4 %

Procedure:
To a solution of N′-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (0.69 g, 1.75 mmol) in THF (100 mL) were added PS-BEMP (2.39 g, 5.27 mmol, ˜2.2 mmol/g) and p-TsCl (353 mg, 1.85 mmol) at room temperature. The mixture was stirred at room temperature for 14 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (167 mg, 25%) as a foam and the dehydration product 4-(1-(5-phenyl-1,3,4-oxadiazol-2-yl)prop-1-enylamino)benzo[b]thiophene-7-carbonitrile (33 mg, 5%). Title compound: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.98 (m, 2H), 7.88 (d, J=5.7 Hz, 1H), 7.72 (d, J=5.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.51˜7.57 (m, 3H), 6.85 (d, J=8.2 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 5.22 (dd, J=4.7, 8.4 Hz, 1H), 4.80 (b, 1H), 4.65 (m, 1H), 1.42 (d, J=6.4 Hz, 3H). Dehydration product: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.05 (m, 2H), 7.95 (d, J=5.6 Hz, 1H), 7.78 (d, J=5.6 Hz, 1H), 7.55˜7.62 (m, 4H), 7.01 (q, J=7.1 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 1.93 (d, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C#N)c1
Reaction time: 0.02 h
Yield: 112.1 %

Procedure:
40% Methanolic Triton B (0.06 mL, 0.13 mM) was added to a solution of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (34.1 mg, 0.1 mM) in 5 mL DMF at room temperature. After 1 minute, tert-butyl bromoacetate (40 mg, 0.2 mM) was added and the resultant mixture stirred at room temperature for 24 h. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with hexane to afford 51 mg (100%) of the {9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (CDCl3) δ 7.55 (d, 1H, J=8 Hz), 7.5-7.2 (m, 7H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.5 (s, 2H), 4.8 (s, 2H), and 1.5 (s, 9H). IR (KBr, cm−1) 2228, 1748, and 1669. MS (ES) m/e 455, 456.