Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:37]3[CH2:36][CH2:35][N:34]([CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH2:39][CH2:38]3)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N3CCN(C4CCN(C)CC4)CC3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AM using 5-({cyclopropyl[(4-methoxy-2,6 dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (47 mg, 0.12 mmol), 1-(1-methylpiperidin-4-yl)piperazine (21 mg, 0.11 mmol), DIC (0.3 mL, 1.87 mmol), HOBt (29 mg, 0.19 mmol) and TEA (0.07 mL, 0.48 mmol) in DCM (5 mL). The crude product was purified using Isolute SCX-2 cartridge, washing with MeOH (3 mL) and eluting with 7N NH3 in MeOH (3 mL) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[CH2:17][OH:18])[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[C:9]([CH2:17][OH:18])[CH:10]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2CO)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN1CCN(c2ccc(N)cc2CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
[2-(4-Methylpiperazin-1-yl)-5-nitrophenyl]methanol prepared in step A of example 1 (1.00 g, 3.98 mmol) was hydrogenated using ammonium formate (2.51 g, 10 eq) and Pd/C (10% Pd, 0.43 mg, 0.1 eq) in 50 mL of EtOH. The mixture was stirred overnight at room temperature and then filtered through a celite pad. The filtrate was evaporated and the residue was dissolved in DCM and washed with an saturated aqueous solution of Na2CO3. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to yield expected compound as a pale yellow oil (0.85 g, 97% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:10]1[CH2:15][CH2:14][N:13]([CH:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)(=O)[CH3:8].O.[OH-].[Na+]>C1COCC1>[CH2:7]([N:10]1[CH2:11][CH2:12][N:13]([CH:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[CH2:18][CH2:17]2)[CH2:14][CH2:15]1)[CH3:8]
Reactant: COc1ccc2c(c1)C(N1CCN(C(C)=O)CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1CCN(C2CCc3ccc(OC)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
Lithium aluminum hydride (0.14 g) was suspended in THF. Into the resultant suspension was added dropwise a solution of 1-(4-acetylpiperazin-1-yl)-6-methoxyindan (0.50 g) in THF and the reaction mixture was heated under reflux while monitoring the reaction by TLC. Then the reaction solution was ice cooled and water (0.14 ml), a 5 N aqueous solution (0.14 ml) of sodium hydroxide and further water (0.42 ml) were successively added thereto followed by stirring at room temperature for 1 hr. The resulting precipitate was filtered off and washed with THF. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (methylene chloride/methanol system) to give 1-(4-ethylpiperazin-1-yl)-6-methoxyindan (0.30 g) as an oil (yield: 63%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:28]2[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=2)([OH:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:37].[Na+]>CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:28]2[CH:29]=[CH:30][C:31]([S:34]([CH3:35])=[O:37])=[CH:32][CH:33]=2)([OH:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(C(O)(CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a stirred solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(4-methylsulfanyl-phenyl)-ethanol (5 g, 10 mmol) in methanol (100 mL) and water (30 mL) was added sodium metaperiodate (4.3 g, 20 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 h, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(4-methaneylsulfinyl-phenyl)-ethanol (5.1 g, quant.) as a light yellow solid: LC/MS m/e calcd for C27H27FN2O4S2 [M+H]+ 527.65, observed 527.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][N:10]1[C@@H:15](/[CH:16]=[CH:17]/[C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13][CH2:12][C:11]1=[O:27].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C@@H:15]([CH2:16][CH2:17][C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13][CH2:12][C:11]1=[O:27]
Reactant: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)COCCCCN1C(=O)CCC[C@@H]1CCC(=O)Cc1ccccc1
Reaction time: 19 h
Yield: 85.2 %

Procedure:
Palladium on carbon (10 wt. %, 2 mg) was added to a solution of {(Z)-4-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-but-2-enyloxy}-acetic acid methyl ester (9.7 mg, 0.025 mmol) in MeOH (1.5 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 8.3 mg (85%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[N:21]1([CH2:30][C:31]2[C:32](=[O:38])[NH:33][C:34](=[S:37])[NH:35][CH:36]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:37][C:34]3[NH:35][CH:36]=[C:31]([CH2:30][N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22]4)[C:32](=[O:38])[N:33]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Reactant: O=c1[nH]c(=S)[nH]cc1Cn1ccc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cn1ccc2ccccc21
Temperature: 80 °C
Yield: 8.9 %

Procedure:
A mixture of 1-chloro-4-(4-(chloromethyl)phenoxy)-2-(trifluoromethyl)benzene (200 mg, 0.623 mmol), 5-(1H-indol-1-ylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (160 mg, 0.623 mmol), and K2CO3 (200 mg, 1.447 mmol) in DMF (5 mL) was heated at 80° C. for 3 h. Purification via MDAP then afforded the title compound (30 mg, 8.44% yield). LCMS: rt=4.19 min, [M+H+]=542
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:32])[CH3:2].[CH2:34](I)[CH3:35].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([CH2:34][CH3:35])[CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: CCOC(=O)COc1c(C)cc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1c(C)cc(N(CC)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.102 g (0.21 mmol) of the above prepared (2,6-dimethyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester was dissolved in 1.5 ml of abs. DMSO and treated with 0.066 g (0.43 mmol) of ethyl iodide and 0.032 g (0.23 mmol) of K2CO3. After vigorously stirring for 18 h at ambient temperature, the reaction mixture was poured onto crashed ice/aqueous 10% KHSO4, extracted twice with EtOAc, the organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/EtOAc=8/2), yielded finally 0.067 g of the title compound as yellow oil, MS: 507.6 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:16]=[C:15]([CH3:17])[C:12]([CH:13]=O)=[C:11]([CH3:18])[CH:10]=2)[CH2:4][O:3]1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][C:37]=1[NH2:38])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=1)=[O:25].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[CH3:34][C:29]1[CH:28]=[C:27]([NH:26][C:24]([C:23]2[CH:35]=[CH:36][C:37]3[N:38]=[C:13]([C:12]4[C:15]([CH3:17])=[CH:16][C:9]([O:8][CH2:7][C@@H:5]5[CH2:4][O:3][C:2]([CH3:19])([CH3:1])[O:6]5)=[CH:10][C:11]=4[CH3:18])[NH:20][C:21]=3[CH:22]=2)=[O:25])[CH:32]=[CH:31][C:30]=1[CH3:33]
Reactant: Cc1cc(OC[C@@H]2COC(C)(C)O2)cc(C)c1C=O
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OC[C@@H]5COC(C)(C)O5)cc4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2,6-dimethylbenzaldehyde (145 mg, 0.55 mmol) and 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide (153 mg, 0.55 mmol) in DMSO (8 mL) was added Yb(OTf)3 (68 mg, 0.11 mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was partioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, filtered and concentrated. Purification by flash chromatography using heptane/EtOAc (1:2) as eluent gave 2-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2,6-dimethylphenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a pale yellow solid 1H NMR (Methanol-d4, 400 MHz): δ 8.30 (d, 1H), 7.90 (d, 1H), 7.77 (dd, 1H), 7.47 (s, 1H), 7.44 (dd, 1H), 7.13 (d, 1H), 6.79 (s, 2H), 4.51 (m, 1H), 4.19 (q, 1H), 4.07 (d, 2H), 3.91 (q, 1H), 2.29 (s, 3H), 2.26 (s, 3H), 2.15 (s, 6H), 1.44 (s, 3H), 1.38 (s, 3H). MS (m/z) 500.3 (M+1); Retention time: 1.51 min (Method 10).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26](C(OC)=O)[CH:25]=2)=[C:14]([NH2:34])[N:13]=1)[CH2:8][CH2:9][CH3:10].[OH-:35].[Na+].S(Cl)(Cl)=O.[C-]#N.[Na+].[Cl-].[NH4+]>C1COCC1.O.CN(C=O)C>[CH2:7]([O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:8][C:7]([O:11][CH3:12])=[O:35])[CH:25]=2)=[C:14]([NH2:34])[N:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: [OH-]
Reactant: CCCCOc1nc(N)c2ncn(CCOc3cccc(C(=O)OC)c3)c2n1
Agent: [Al+3]
Agent: [C-]#N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCCOc1nc(N)c2ncn(CCOc3cccc(CC(=O)OC)c3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
To a suspension of lithium aluminum hydride (150 mg, 4.0 mmol) in THF (15 ml) was added a solution of 2-butoxy-9-[2-(3-methoxycarbonylphenoxy)ethyl]adenine (540 mg, 1.4 mmol) obtained in Reference Example 2 in THF (5 ml) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. 1N Aqueous sodium hydroxide solution was added thereto, followed by filtration through celite pad and concentration under reduced pressure. The residue was dissolved in chloroform (10 ml), and thionyl chloride (336 μl, 4.62 mmol) was added thereto at room temperature, followed by stirring at 60° C. for 10 minutes. To the reaction mixture was added 1N aqueous sodium hydroxide solution, and the mixture was diluted with water and extracted with chloroform (methanol 5%). The organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give chloromethyl product as a pale yellow crystal, 380 mg. To a solution of the chloromethyl product (380 mg) in DMF (10 ml) was added sodium cyanide (99 mg, 2.02 mmol) at room temperature, followed by stirring at room temperature for 1 hour. To the reaction mixture was added saturated ammonium chloride and the mixture was concentrated under reduced pressure. To the residue was added water and the mixture was extracted with chloroform (methanol 5%). The organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. To the residue were added methanol (7 ml) and 5N aqueous potassium hydroxide solution (7 ml) and the mixture was stirred at 95° C. for 3.5 hours. The reaction solution was neutralized with concentrated hydrochloric acid, and concentrated under reduced pressure. Methanol (20 ml) and concentrated sulfuric acid (0.3 ml) were added thereto, followed by stirring at 90° C. for 3.5 hours. After cooling, the resultant was concentrated under reduced pressure, and to the residue was added water. The solution was extracted with chloroform (methanol 5%). The organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 160 mg (0.40 mmol) of the titled compound as a pale yellow oil. Yield: 29%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:23][OH:24])[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C(OCC)(=O)C>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:23][OH:24])[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@](CO)(c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC[C@@]1(c2ccc(Cl)c(Cl)c2)CCNCCO1
Reaction time: 8 h
Yield: 157 %

Procedure:
To a solution of tert-butyl (7S)-7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (206.2 mg) in ethanol (2 mL) was added 4 N hydrogen chloride/ethyl acetate solution (2 ml), and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from ethanol and ethyl acetate to give the title compound (134.5 mg).
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](\[C:5]([O:7][C@@H:8]1[C@:16]2([CH3:38])[C@@H:17]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@:18]3([CH3:32])[C:22]4=[C:23]([CH3:31])[C@H:24]([C:26]5[CH:27]=[CH:28][O:29][CH:30]=5)[CH2:25][C@H:21]4[O:20][C@@H:19]3[C@H:14]3[C@H:15]2[C@:11]([CH3:39])([CH2:12][O:13]3)[C@H:10]([O:40][C:41]([CH3:43])=[O:42])[CH2:9]1)=[O:6])/[CH3:4]>C(O)C.[Pd]>[CH3:1][CH2:2][CH:3]([C:5]([O:7][C@@H:8]1[C@:16]2([CH3:38])[C@@H:17]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@:18]3([CH3:32])[C:22]4=[C:23]([CH3:31])[C@H:24]([C:26]5[CH:27]=[CH:28][O:29][CH:30]=5)[CH2:25][C@H:21]4[O:20][C@@H:19]3[C@H:14]3[C@H:15]2[C@:11]([CH3:39])([CH2:12][O:13]3)[C@H:10]([O:40][C:41]([CH3:43])=[O:42])[CH2:9]1)=[O:6])[CH3:4]
Reactant: C/C=C(/C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C)CO[C@H]3[C@H]4O[C@@H]5C[C@@H](c6ccoc6)C(C)=C5[C@@]4(C)[C@H](CC(=O)OC)[C@]1(C)[C@@H]32
Agent: [Pd]
Solvent: CCO
Product: CCC(C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C)CO[C@H]3[C@H]4O[C@@H]5C[C@@H](c6ccoc6)C(C)=C5[C@@]4(C)[C@H](CC(=O)OC)[C@]1(C)[C@@H]32
Yield: 77.4 %

Procedure:
Salannin (25 mg., 0.041 mmol) in 0.5 ml of ethanol was stirred with 13 mg of 5% palladium on alumina at 25° C. under hydrogen (5 atm) for 15 min. The reaction mixture was then filtered and evaporated in vacuo. The residue was chromatographed by silica gel preparative HPLC (solvent = isopropanol-n-hexane, 2:23) to afford 2',3'-dihydrosalannin (19 mg): IR max (cm-1) 1735 (s), 1500 (w), 870 (m); 1H-NMR (CDC13) δ 0.95 (t, J =7.4 Hz, 1 H, 4' -Me), 0.96 (t, J =7.4 Hz, 2 H, 4' -Me), 1.23 (d, J =6.5 Hz, 2 H, 5' -Me), 1.30 (d, J =6.9 Hz, 1 H, 5' -Me), 1.45-1.70 (m, 2 H, H-3'ab), 1.75-1.95 (m, 1 H, H-2'), 2.07 (s, 3 H, 3-Ac), 3.60 (apparent br s, 2 H, H-28a,b), 4.87 (dd, J =2.9, 2.9 Hz, 1 H, H-3); EI-MS, m/z 598 (M+, 100%), 583 (M-CH3, 7), 567 (M-OCH3, 2), 513 (M-COCH(CH3) Ch2Ch3, 4), 504 (10), 496 (M-HOCOCH(CH3)CH2CH3, 5), 421 (17), 397 (5), 283 (30), 259 (23), 235 (17), 230 (9), 202 (9), 185 (9) 173 (14), 147 (13 ), 119 (8), 85 (CH3CH2CH(CH3)CO+, 14), 57 CH3CH2CH(CH3)+, 46).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:12])=[N:11][C:6]2=[CH:5][CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)C(C(C(O)=O)O)[OH:25].[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[CH:1]([C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:12])=[N:11][C:6]2=[CH:5][CH:4]=1)=[O:25]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: Cc1nc2ccc(C#N)nc2s1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc2ccc(C=O)nc2s1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a suspension of the product of Step 4 (4.42 g, 25 mmol) in 100 mL of anhyd. THF at -78° C. was added dropwise 1.5M diisobutylaluminum hydride in toluene (40 mL) and the mixture was stirred at -78° C. for 2 hr. A solution of tartaric acid 10% was then added and the mixture was stirred at room temperature for 2 hr, neutralized with 10N NaOH and extracted with EtOAc. The title product was dried over Na2SO4 and purified by flash chromatography on silica with EtOAc:hexane 20:80 to yield 3.733 g (83%) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][CH2:8][CH2:9][C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][C:14]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:13]1=2)=O.O.[OH-].[Na+]>O1CCCC1>[Cl:27][C:25]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:12]([CH2:10][CH2:9][CH2:8][Cl:7])[C:13]=2[CH:26]=1
Reactant: O=C(CCCl)N1c2ccccc2CCc2ccc(Cl)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: ClCCCN1c2ccccc2CCc2ccc(Cl)cc21
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
A 1.0 M solution of lithiumaluminium hydride in tetrahydrofuran (18.7 ml, 18.7 mmol) was introduced into a 250 ml dry, three-necked, roundbottom flask under a nitrogen atmosphere. The solution was cooled on an icebath. Concentrated sulphuric acid (0.5 ml) was added dropwise, with caution, over 10 minutes. More dry tetrahydrofuran (20 ml) was added to compensate for evaporated solvent and the mixture was stirred for 15 minutes. Additional tetrahydrofuran was added (20 ml) and the icebath was removed. The mixture was stirred for 75 minutes at room temperature. The above amide (3.0 g, 9.3 mmol) was dissolved in dry tetrahydrofuran (25 ml) and dropwise added over 20 minutes. The reaction mixture was stirred for 1 h. Water (0.7 ml) was added, followed subsequently by 4 N sodium hydroxide (0.7 ml) and water (2.1 ml). Stirring was continued for 30 minutes. The mixture was filtered (hyflo) and evaporated in vacuo, affording 2.70 g (95%) 3-chloro-5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36]O[CH2:34][CH2:33]3)[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(N2C=C(CCOS(C3C=CC(C)=CC=3)(=O)=O)N=N2)C=CC=1C)=O.C(NCC)C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][N:32]([CH2:33][CH3:34])[CH2:37][CH3:36])[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18]
Reactant: Cc1ccc(-n2cc(CCN3CCOCC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)OCCc2cn(-c3ccc(C)c(C(=O)c4ccc(Nc5ccc(F)cc5F)cc4Cl)c3)nn2)cc1
Solvent: CCNCC
Product: CCN(CC)CCc1cn(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 138, using compound 435 (0.24 mmol) and diethylamine (0.5 mL). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 15:85 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [O:1]=[S:2]1(=[O:40])[CH2:6][CH2:5][CH:4]=[C:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:37])[N:19]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C@@H:20]4[C@H:25]([C:26]=3[OH:27])[C@@H:24]3[CH2:28][C@H:21]4[CH2:22][CH2:23]3)=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1>CO.[Pd]>[O:40]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:37])[N:19]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[C@@H:20]4[C@H:25]([C:26]=3[OH:27])[C@@H:24]3[CH2:28][C@H:21]4[CH2:22][CH2:23]3)=[N:13][S:14](=[O:15])(=[O:16])[C:9]=2[CH:8]=1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: O=C1C(C2=NS(=O)(=O)c3cc(C4CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
(1R,2S,7R,8S)-5-[7-(1,1-Dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 20, 30 mg, 0.05 mmol) was dissolved in methanol (15 mL) and 5% palladium on charcoal (100 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite, rinsed with 10% methanol dichloromethane, and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (1R,2S,7R,8S)-5-[7-(1,1-dioxo-tetrahydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (26 mg, 0.044 mmol, 86%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.19 (2H, m), 1.40-1.60 (4H, m), 2.12 (1H, m), 2.67 (1H, m), 2.36 (1H, m), 2.50 (1H, m), 2.65 (1H, m), 3.03 (1H, m), 3.23 (1H, m), 3.32 (1H, m), 3.53 (1H, d, J=10.0 Hz), 4.42 (1H, d, J=15.2 Hz), 4.56 (1H, dd, J=11.6, 6.8 Hz), 4.97 (1H, d, J=15.6 Hz), 7.14 (2H, m), 7.33 (2H, m), 7.58 (1H, d, J=8.8 Hz), 7.69 (1H, dd, J=8.8, 2.4 Hz), 7.82 (1H, d, J=2.4 Hz); LC-MS (ESI) calcd for C28H28FN3O6S2585.14, found 586.3 [M+H+].