Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]([C:24]#[N:25])([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH3:23])[CH:14]=1)[CH2:7][CH2:8][C:9](OC)=[O:10].COCCOC.[H-].[Na+]>O>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][C:6]([C:24]#[N:25])([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH3:23])[CH:14]=2)[CH2:7][CH2:8][C:9]1=[O:10])=[O:26]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C1CC(C#N)(c2ccc([N+](=O)[O-])c(OC)c2)CCC1=O
Temperature: 25 °C

Procedure:
Into a 1-Neck round-bottom flask, 4-Cyano-4-(3-methoxy-4-nitro-phenyl)-heptanedioic acid dimethyl ester (4.20 g, 11.5 mmol), 1,2-Dimethoxyethane (80 mL, 800 mmol), and Sodium Hydride (60% dispersion mineral oil)(6:4, Sodium hydride:Mineral Oil, 1.38 g, 34.6 mmol) were added, and heated to reflux overnight. The reaction was cooled to room temperature. Water was added to quenched the excess NaH. 2N HCl was added to adjust pH to 2. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc. The collected fractions afforded 5-Cyano-5-(3-methoxy-4-nitro-phenyl)-2-oxo-cyclohexanecarboxylic acid methyl ester as an off white solid (2.00, 59%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[O:10][CH:9]([CH3:26])[CH2:8]2)(=[O:3])[CH3:2].[OH-:27].[Na+].Cl>CS(C)=O.CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C:11]([OH:27])([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[O:10][CH:9]([CH3:26])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: COc1cc2c(cc1NC(C)=O)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1NC(C)=O)CC(C)OC2(O)c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h

Procedure:
A solution of 14 (1.8 g) in 5 ml of DMSO and 30 ml of DMF was cooled to 8-12° C. and air was passed through the mixture. To the solution was added 1.2 ml of 50% aqueous sodium hydroxide in one portion and the resulting mixture was stirred for 5 hours. HCl (1 N) was added, and extracted with ethyl acetate three times. The combined organic phase was washed with water, dried over Na2SO4. Removal of the solvent afforded 22 (1.9 g) as a syrup, which was used directly for the next step.
Reaction SMILES: [N:1]([CH:4]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:5]1=[O:21])=[N+]=[N-]>C(O)C.[Pd]>[C:8]([CH:7]1[N:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:5](=[O:21])[CH:4]1[NH2:1])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1C(N=[N+]=[N-])C(=O)N1c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C(N)C(=O)N1c1ccc(OC)cc1

Procedure:
A solution of 2.16 g of 3-azido-4-carboethoxy-1-(p-methoxyphenyl)-azetidine-2-one in ethanol was hydrogenated with palladium to yield 4-carboethoxy-1-(p-methoxyphenyl)-3-aminoazetidin-2-one. This amine was acylated with 1.1 ml of trifluoro acetic anhydride in 10 ml CH2Cl2 containing 1.5 ml pyridine, followed by methylation using 1 ml dimethyl sulfate in 30 ml acetone containing 3 g potassium carbonate. After isolation, the crude product was crystallized to give 2.2 g of 4-carboethoxy-1-(p-methoxyphenyl)-3-(N-methyltrifluoroacetamido)-azetidine-2-one, m.p. 102°-104°.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:12]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:36])=[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=1.CO>C1COCC1.C(Cl)Cl>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])=[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=2)[N:20]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CN(c1cc(N)ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cc(Nc2nc(Cl)ccc2C(N)=O)ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Reaction time: 21 h
Yield: 58.1 %

Procedure:
A 1 M THF solution of LiHMDS (0.762 mL, 0.762 mmol) was added dropwise to a suspension of 2,6-dichloronicotinamide (54.0 mg, 0.283 mmol) and N-(5-amino-2-(morpholine-4-carbonyl)phenyl)-N-methylmethanesulfonamide (68.2 mg, 0.218 mmol) in THF (0.5 mL) at 0° C. After 21 h at room temperature, LCMS analysis showed that the reaction was less than 50% complete. Additional portions of LiHMDS (0.054 mL) were added at 22, 23, and 24 h time points. After a total of 28 h, the mixture was quenched by saturated NH4Cl (2 mL) and extracted with EtOAc (3×2 mL). The combined extracts were loaded onto a silica gel cartridge and dried in vacuo. The dry cartridge was then connected to an ISCO cartridge and eluted with 30-100% EtOAc in hexanes, then 10% MeOH in CH2Cl2 to give a brown powder (59.3 mg, 58% yield). LCMS: (M+H)+=468.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (1H, s), 8.38 (1H, br. s.), 8.21 (1H, d, J=8.28 Hz), 7.95 (1H, d, J=2.26 Hz), 7.85 (1H, br. s.), 7.55 (1H, dd, J=8.41, 2.13 Hz), 7.30 (1H, d, J=8.28 Hz), 7.01 (1H, d, J=8.03 Hz), 3.64-3.78 (2H, m), 3.45-3.59 (4H, m), 3.23 (2H, m), 3.16 (6H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]3)[CH2:10][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28]>>[NH2:20][C:13]1[CH2:14][O:15][CH2:16][C:17]([F:19])([F:18])[C@@:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:27]#[N:28])[CH:3]=3)[O:8][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10]2)[N:12]=1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)COC1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2ccc3c(c2)[C@@]2(CC(c4ccccc4)O3)N=C(N)COCC2(F)F)c1
Yield: 10 %

Procedure:
The cross coupling reaction of (2RS,4R)-6-bromo-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepin]-3′-amine (intermediate C3.4) with 3-cyanophenylboronic acid yielded the title compound (10% yield) as a colorless solid. MS (ISP): m/z=446.0 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]1[CH:4]=[C:5]([C:16]([NH:18][C@@H:19]([C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[CH3:20])=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:2]([C:3]1[CH:4]=[C:5]([C:16]([NH:18][C@@H:19]([C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[CH3:20])=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1)(=[O:1])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C)nc3)cc(C(O)c3ccccc3)c2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C)nc3)cc(C(=O)c3ccccc3)c2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(hydroxy(phenyl)methyl)-4′-methyl-N—((R)-1-(6-methylpyridin-3-yl)ethyl)biphenyl-3-carboxamide (20 mg, 0.04 mmol) in methylene chloride (2.0 mL) was added Dess-Martin periodinane (26 mg, 0.061 mmol). The reaction mixture was stirred for 2 hours at 40° C., and LC-MS indicated the reaction was complete. The reaction solution was diluted with CH2Cl2, washed with 10% Na2S2O3, sat. aq. NaHSO3 and brine. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was purified by silica gel column to afford a white solid.
Reaction SMILES: [F:1][CH2:2][C@@H:3]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH2:4][C:5](OCC1C=CC=CC=1)=[O:6].[H-].C([Al+]CC(C)C)C(C)C>CCOCC>[F:1][CH2:2][C@@H:3]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH2:4][CH:5]=[O:6]
Reactant: O=C(C[C@@H](CF)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: O=CC[C@@H](CF)N1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (S)-benzyl 4-fluoro-3-(1,3-dioxoisoindolin-2-yl)butanoate (19-4, 0.5 mmol) in dry ether (5 ml) was added dropwise diisobutylaluminum hydride (1.0 M in toluene, 1.5 mmol) at −78° C. The reaction was stirred at −78° C. for approximately 30 min as monitored by LC-MS. After completion, the reaction was quenched by adding water (10 ml) at −78° C. Extracted with ethyl acetate, washed with water (×3), brine (×2), dried over sodium sulfate, filtered and concentrated. The crude product 19-5 was used in the next reaction step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5].C(N(C(C)C)CC)(C)C.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:29]([O:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:30])=[O:5]
Reactant: COC(=O)[C@@H]1CCCCN1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred suspension of (S)-piperidine-2-carboxylic acid methyl ester hydrochloride salt (5.0 g, 27.8 mmol) in dichloromethane (DCM) (35 mL ) at 0° C. was added diisopropylethylamine (DIPEA) (10.1 mL, 58.4 mmol) followed by N-(benzyloxycarbonyloxy)succinimide (7.63 g, 30.6 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The residue was diluted with DCM and washed with 1.0-M HCl. The organic layer was washed with brine, dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (20% ethyl acetate in hexane) to afford the title compound as a pale yellow oil (7.72, 100%): 1H NMR (400 MHz, CD3OD) δ 1.19–1.88 (5H, m), 2.15–2.28 (1H, m), 2.91–3.12 (1H, m), 3.70–3.73 (3H, 2s), 4.00–4.07 (1H, m), 4.82–4.87 (1H, m), 5.03–5.21 (2H, m), 7.24–7.39 (5H, m); 13C NMR (100 MHz, CD3OD) δ 22.0, 22.1 (CH2), 26.0, 26.1 (CH2), 28.1 (CH2), 43.4, 43.5 (CH2), 53.1 (CH3), 56.2, 56.5 (CH), 68.8, 68.9 (CH2), 129.2 (CH), 129.5 (CH), 129.9 (CH), 138.4 (C), 167.0 (CO), 173.7 (CO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]([CH3:27])([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]23)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[I:31]N1C(=O)CCC1=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]([CH3:27])([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=3)[N:11]3[C:28]([I:31])=[CH:29][N:30]=[C:10]23)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2nccn21
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(I)n21
Temperature: 25 °C
Reaction time: 17 h
Yield: 64.5 %

Procedure:
A solution of (R)-1-(3,5-dichloro-phenyl)-3-methyl-3-(4-trifluoromethoxy-benzyl)-1H-imidazo[1,2-α]imidazol-2-one (Example 1) (1.54 g, 3.38 mmol) in 30 mL of THF was treated with N-iodosuccinimide (0.846 g, 3.76 mmol) and pyridinium p-toluenesulfonate (0.086 g, 0.37 mmol). The mixture was stirred at room temperature for 17 h, then diluted with EtOAc and washed with 10% Na2S2O3 solution and water. The combined aqueous layers were extracted with 10 mL of EtOAc. The combined organic phases were washed with 25 mL of brine, dried over Na2SO4, filtered and concentrated. The crude orange oil was purified by silica gel chromatography to provide 1.27 g (65%) of (R)-1-(3,5-dichloro-phenyl)-5-iodo-3-methyl-3-(4-trifluoromethoxy-benzyl)-1H-imidazo[1,2-α]imidazol-2-one as an off-white oil (582.0, M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][CH:13]=[O:14])=[CH:5][CH:4]=1.C=O.[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[S:9][CH2:10][CH2:11][N:12]([CH:13]=[O:14])[CH2:17][C:5]=2[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(SCCNC=O)cc1
Agent: C=O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CN(C=O)CCS2
Temperature: 72.5 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
A mixture of compound 14 (100 mg), paraformaldehyde (100 mg), p-toluenesulfonic acid (60 mg) in benzene (5 mL) was stirred at 70-75° C. for 2 days. Filtration, washing with sat. NaHCO3 and concentration gave crude product 15 in an estimated yield of ˜70% by TLC and NMR.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:40][C:17]3=[N:18][CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:37]=[CH:38][CH:39]=4)[C:25]([NH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([CH3:30])[CH3:29])=[O:26])[CH:21]=[C:16]3[C:15]=2[CH:41]=[O:42])=[CH:10][CH:9]=1>CN(C=O)C.CCOC(C)=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:40][C:17]3=[N:18][CH:19]=[C:20]([C:22]4[CH:39]=[CH:38][CH:37]=[C:24]([C:25](=[O:26])[NH:27][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)([CH3:30])[CH3:29])[CH:23]=4)[CH:21]=[C:16]3[C:15]=2[C:41]([OH:1])=[O:42])=[CH:10][CH:9]=1
Reactant: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1)c1ccccc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C(=O)O)c3c2)c1)c1ccccc1
Reaction time: 72 h
Yield: 33.3 %

Procedure:
Oxone (28 mg, 0.046 mmol) was added to a stirring solution of 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (20 mg, 0.042 mmol) in DMF (0.5 mL) at room temperature. It was allowed to stir for 3 days. An additional amount of Oxone (28 mg, 0.046 mmol) was added and the reaction was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 2-(4-fluorophenyl)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxylic acid (7 mg, 0.014 mmol, 34% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, MeOD) δ ppm 7.42 (1H, d, J=2.14 Hz), 7.31-7.39 (2H, m), 6.93-7.02 (2H, m), 6.87 (1H, s), 6.59 (2H, t, J=8.70 Hz), 6.34 (1H, t, J=7.63 Hz), 6.20 (2H, d, J=7.63 Hz), 5.97-6.07 (4H, m), 5.92 (1H, t, J=7.32 Hz), 0.52 (6H, s). LC-MS retention time: 1.15 min; m/z (MH+): 495. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Cl-].BrC1C(Br)=C(C)SC=1C[P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:30][CH2:31][C:32]1[S:33][C:34](C)=[C:35]([Br:38])[C:36]=1[Br:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl-:30].[Br:38][C:35]1[C:36]([Br:37])=[C:32]([CH3:31])[S:33][C:34]=1[P+:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1sc(CCl)c(Br)c1Br
Reactant: Cc1sc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Br)c1Br
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1sc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Br)c1Br

Procedure:
(3,4-Dibromo-5-methyl-2-thenyl)triphenyl phosphonium chloride can be prepared in a manner analogous to that described in Example 13 by reaction of 2-chloromethyl-3,4-dibromo-5-methyl-thiophene with triphenyl phosphine, m.p. 215°-216° C.
Reaction SMILES: C1(C([C:8]2[CH:9]=[C:10]([NH:14]C(C3C=CN4C=3CSC4C3C=NC=CC=3)=O)[CH:11]=[CH:12][CH:13]=2)=O)SC=CC=1.[C:31]1(C(C2C=C([N+]([O-])=O)C=CC=2)=O)[S:35][CH:34]=[CH:33]C=1.Cl.[OH-].[Na+].[CH2:50]([OH:52])[CH3:51]>C(OCC)C.O>[CH:31]1[S:35][CH:34]=[CH:33][C:51]=1[C:50]([C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][C:10]=1[NH2:14])=[O:52]
Reactant: O=C(c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1)c1cccs1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1cccs1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Nc1ccccc1C(=O)c1ccsc1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
The 3-(2-thenoyl)aniline may be prepared as follows: Stannous chloride in the dihydrate form (22.8 g) is added, at a temperature in the vicinity of 4° C., to a suspension of 3-(2-thenoyl)nitrobenzene (6.8 g) in a 3.7N solution (130 cc) of hydrogen chloride in ethanol, in the course of 40 minutes. After stirring at a temperature in the vicinity of 4° C. for 1 hour and then at a temperature in the vicinity of 20° C. for 1 hour, the solution obtained is heated at a temperature in the vicinity of 78° C. for 1 hour. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. The residue obtained is taken up with a mixture of distilled water (50 cc) and diethyl ether (100 cc), to which an aqueous 10N sodium hydroxide solution (130 cc) is added at a temperature in the vicinity of 15° C. The organic phase is separated and the aqueous phase is extracted 4 times with diethyl ether (400 cc in total). The ether extracts are combined, washed 3 times with distilled water (300 cc in total), dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 40° C. 2-(3-Thenoyl)aniline (5.7 g) in the form of yellow crystals m.p. 105° C., is thereby obtained.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].[CH2:6]([N:10]=[C:11]=[N:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:7][CH2:8][CH3:9].O.Cl>CO>[ClH:1].[CH2:13]([NH:12][C:11]([NH:4][C:3]([NH2:5])=[NH:2])=[N:10][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:14][CH2:15][CH3:16]
Reactant: N=C(N)N
Reactant: CCCCN=C=NCCCC
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCCN=C(NCCCC)NC(=N)N

Procedure:
0.715 g. (7.5 mmol) of guanidine hydrochloride, 1.54 g. (10 mmol) of di-n-butyl carbodiimide, 5 ml. of water, and 15 ml. of methanol is heated for 16 hours under reflux. After evaporation, the oily residue is taken up in 15 ml. of water and extracted three times with respectively 20 ml. of ether in order to remove the 1,2-di-n-butyl urea formed as a by-product. The aqueous phase is mixed with concentrated hydrochloric acid to a pH of 4 and crystallizes during evaporation. The crude product having a melting point of 102°-105° C. is still contaminated by guanidine hydrochloride and minor amounts of 1,2-di-n-butyl urea. The product is suspended in dry chloroform, the remaining guanidine hydrochloride is filtered off, the chloroform solution is concentrated by evaporation, and the solid residue is recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:31])[N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=3)[N:21]=[C:8]2[N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:6]=1[CH3:42])=[O:4].[CH3:43][NH:44][CH3:45]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:31])[N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:44]([CH3:45])[CH3:43])=[CH:25][CH:24]=3)[N:21]=[C:8]2[N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:6]=1[CH3:42])=[O:4]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(Cc3ccc(CBr)cc3)c(=O)n2C1c1ccc(C#N)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(Cc3ccc(CN(C)C)cc3)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
Intermediate 15 (105 mg, 0.16 mmol) was dissolved in THF (3 ml), and then dimethylamine (2 M in THF, 400 μl, 0.8 mmol) was added. The reaction mixture was stirred at RT for 16 hours and then filtered. The filtrate was collected and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 5-8% MeOH in DCM and gave the title compound as a white solid (72 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:11]1[CH2:15][CH:14]([CH3:16])[CH:13]([C:17]2[N:21]3[C:22]4[CH:28]=[CH:27][NH:26][C:23]=4[N:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:36][Si:37]([CH2:40][CH2:41][O:42][CH2:43]Cl)([CH3:39])[CH3:38]>CN(C=O)C>[CH2:29]([N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:11]1[CH2:12][CH:13]([C:17]2[N:21]3[C:22]4[CH:28]=[CH:27][N:26]([CH2:43][O:42][CH2:41][CH2:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[C:23]=4[N:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]([CH3:16])[CH2:15]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1c1cnc2cnc3[nH]ccc3n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.3 %

Procedure:
To the suspension of sodium hydride (60% dispersion in mineral oil, 0.382 g, 9.55 mmol) in DMF (50 mL) was added drop-wise a solution of N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine (3.96 g, 9.09 mmol) in DMF (50 mL) at 0° C. The resulting solution was stirred at ambient temperature for about 10 min. SEM chloride (1.774 mL, 10.0 mmol) was added drop-wise and the solution was stirred for about 1 h. The solvent was removed under reduced pressure and the residue was partitioned between water and EtOAc (200 mL each). The organic layer was washed with brine (100 mL), dried over anhydrous MgSO4, filtered and concd. The residue was purified by silica gel chromatography eluting with 10-80% EtOAc in DCM to yield N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (3.1 g, 60% yield) as an off-white amorphous solid. LC/MS (Table 1, Method a) Rt=3.32 min; MS m/z 566 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18].[CH3:19][S-:20].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[CH2:8][S:20][CH3:19]
Reactant: C[S-]
Reactant: Fc1ccc(Oc2ccc(CBr)cc2Br)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Yield: 99.9 %

Procedure:
A mixture of Example 287c (1.512 g, 4.00 mmol) and sodium thiomethoxide (0.280 g, 4.00 mmol) in dimethylformamide (8 mL) was stirred at ambient temperature for 6 hours. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride twice, dried with anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (1.38 g, 100%).