Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(BC(C(C)C)C)(C(C)C)C.[CH3:12][C:13]([CH3:28])([CH2:24][CH2:25][CH2:26][CH3:27])[CH:14]([O:17]C1CCCCO1)[C:15]#[CH:16].C([N+]([O-])(CC)CC)C.[OH-].[Na+].[I:39]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.O1CCCC1>[CH3:12][C:13]([CH3:28])([CH2:24][CH2:25][CH2:26][CH3:27])[CH:14]([OH:17])/[CH:15]=[CH:16]/[I:39]
Reactant: II
Reactant: C#CC(OC1CCCCO1)C(C)(C)CCCC
Agent: CC(C)C(C)BC(C)C(C)C
Agent: CC[N+]([O-])(CC)CC
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(C)(C)C(O)/C=C/I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 233 ml. of a 0.43% solution of disiamylborane in diglyne cooled to 0° C. under an inert atmosphere is added 23.8 g. (0.100 mole) 4,4-dimethyl-3-tetrahydropyramyloxy-1-octyne (Example 995). The mixture is allowed to come to room temperature and is stirred at ambient temperature for 3 hours. The solution is cooled to 0° C. and 22.5 g. (0.30 mole) of triethylamine oxide is added portionwise such that the temperature is maintained at 0°-5° C. The mixture is stirred at 0° C. for 1 hour and is then poured into 150 ml. of 1 N sodium hydroxide followed immediately by a solution of 25.4 g. (0.100 mole) of iodine in 60 ml. of tetrahydrofuran. The mixture is stirred at ambient temperatures for 0.5 hour and poured into 500 ml. of water. The mixture is decolorized by addition of sodium thiosulfate solution and is extracted into ether. The organic phase is washed with water and the solvent is removed in vacuo. The residue is stirred at room temperature for 20 hours with 900 ml. 3:1:1 tetrahydrofuran-acetate acid-water. The solution is evaporated in vacuo and the residue is chromatographed on silica gel in benzene using 10-20% ethylacetate in benzene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)/C=C/c1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(CN)cc1
Yield: 86.2 %

Procedure:
To solution of methyl (2E)-3-(4-cyanophenyl)acrylate (18 g, 0.096 mol) in methanol (200 ml) was added Pd/C (1.8 g) and hydrogenated under a pressure of 50 psi of hydrogen for 12 h. The catalyst was filtered off and the filtrate was concentrated to a residue. The residue was purified by chromatography (SiO2, chloroform/methanol 9/1) to yield the title compound as a liquid (16 g, 86%). TLC:CHCl3/MeOH (9/1); Rf: 0.3
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[N+:27]([C:30]1[CH:40]=[CH:39][C:33]([CH:34]=[CH:35][C:36](O)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:36](=[O:37])[CH:35]=[CH:34][C:33]1[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:40][CH:39]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CN([C@@H](CCCCNC(=O)C=Cc1ccc([N+](=O)[O-])cc1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 49 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 4-nitrocinnamic acid under the conditions described in example 86 to yield 49% of the desired product.
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:29])OC(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CN1CCCC1>O1CCOCC1>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:24]([NH:23][C:19]2[CH:18]=[C:17]([O:16][C:13]3[CH:14]=[N:15][C:10]([NH:9][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3])=[O:30])=[CH:11][CH:12]=3)[CH:22]=[CH:21][N:20]=2)=[O:29])[CH2:34][CH2:33]1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Reactant: CN1CCNCC1
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)CC1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
A mixture of Example C2 (0.145 g, 0.351 mmol) 1-methylpiperizine (0.105 g, 1.052 mmol) and N-methylpyrrolidine (2.99 mg, 0.035 mmol) in dioxane (3 mL) was heated at 80° C. overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide (60 mg, 38%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (s, 1H), 9.25 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.12 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.39 (m, 4H), 2.24 (m, 4H), 2.14 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 456.2 (M+H+).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].CC(C)[O-].[Al+3:13].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Al+3:13].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Al+3:13]
Reactant: Oc1ccccc1O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: [O-]c1ccccc1[O-]
Temperature: 100 °C

Procedure:
A solution of catechol (3.30 g, 30.0 mmol) and toluene (45 ml) was dehydrated by distilling 5 mL of the solution. Thereafter, 4.08 g (20.0 mmol) of aluminum(III) isopropoxide was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, volatile components of the residual mixed solution were vaporized under reduced pressure by a rotary evaporator. The residual solid content was further heated to 100° C. under vacuum using a vacuum dryer so that the remaining volatile components were completely removed. The solid content (catechol-aluminum complex) was green in color. The yield amount was 3.78 g (20.0 mmol), and the yield percentage was 100%. 1.89 g of catechol-aluminum complex was dissolved into 100 mL of 1:4 acetylacetone/toluene to produce a coating liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]=O)=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1>>[O:20]1[C:25]2[CH:26]=[CH:27][C:28](/[CH:30]=[C:17](/[C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:16][CH:15]=3)\[C:18]#[N:19])=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: N#CCc1ccc(OCCCCCCCCO)cc1
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: N#C/C(=C\c1ccc2c(c1)OCCO2)c1ccc(OCCCCCCCCO)cc1
Yield: 41 %

Procedure:
(2Z)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-{4-[(8-hydroxyoctyl)oxy]phenyl}prop-2-enenitrile is prepared starting from {4-[(8-hydroxyoctyl)oxy]phenyl}acetonitrile and commercial 1,4-Benzodioxan-6-carboxaldehyde according the same procedure following for example 1 in 41% yield.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.[OH-].[K+]>O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: c1cn[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(CCn2cccn2)cc1
Temperature: 140 °C
Reaction time: 0.13 h
Yield: 7.8 %

Procedure:
A mixture of 1-(2-bromoethyl)-4-nitrobenzene (18.7 g), pyrazole (5.53 g) and potassium hydroxide (4.56 g) was stirred at 140° C. for 8 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give 1-[2-(4-nitrophenyl)ethyl]-1H-pyrazole (1.37 g, 8%) as crystals from a fraction eluted with hexane-ethyl acetate (1:2, v/v). Recrystallization thereof from ethyl acetate-hexane gave yellow prism crystals. melting point: 92-93° C.
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([CH2:13][CH2:14][O:15][CH2:16][O:17][CH3:18])[CH:6]=1.[CH:19]([C@@H:22]1[CH2:26][C@@H:25]([C@@H:27]([N:35]=[N+:36]=[N-:37])[CH2:28][C@@H:29]([CH:32]([CH3:34])[CH3:33])[CH:30]=[O:31])[O:24][C:23]1=[O:38])([CH3:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.BrCCBr.O.C(O)(=O)C>[CH:19]([C@@H:22]1[CH2:26][C@@H:25]([C@@H:27]([N:35]=[N+:36]=[N-:37])[CH2:28][C@@H:29]([CH:32]([CH3:33])[CH3:34])[CH:30]([OH:31])[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([CH2:13][CH2:14][O:15][CH2:16][O:17][CH3:18])[CH:6]=2)[O:24][C:23]1=[O:38])([CH3:20])[CH3:21]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](C[C@H](C=O)C(C)C)N=[N+]=[N-])OC1=O
Reactant: COCOCCc1cc(Br)ccc1OC
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COCOCCc1cc(C(O)[C@@H](C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OC
Reaction time: 0.5 h

Procedure:
Several iodine crystals am added to a suspension of 763 mg of magnesium chips in 0.5 ml of tetrahydrofuran, and the mixture is activated in an ultrasound bath for 30 minutes. Then 4 drops of 1,2-dibromoethane and then a solution of 8.64 g of 4-bromo-2-(2-methoxymethoxyethyl)-anisole in 30 ml of tetrahydrofuran are added dropwise in such a manner that the reaction mixture boils under reflux. When the addition is complete, the mixture is maintained under reflux for a further one hour. The reaction mixture is then added dropwise within a period of 45 minutes, with stirring, to a solution, cooled to -75° C., of 2.85 g of 3(S)-isopropyl-5(S)-[1(S)-azido-3(S)-isopropyl-4-oxobutyl]-tetrahydrofuran-2-one in 20 ml of tetrahydrofuran. The reaction mixture is stirred for a further 150 minutes at -75° C., and there are then added thereto, at the same temperature, a solution of 1.4 ml of glacial acetic acid in 1 ml of tetrahydrofuran and then 25 ml of saturated ammonium chloride solution. The reaction mixture is then brought to room temperature, poured onto 60 ml of water and extracted three times with 100 ml of ethyl acetate. The organic phases are washed with 50 ml of saturated sodium chloride solution, combined, dried over magnesium sulfate and concentrated by evaporation. Purification of the residue by means of FC (400 g of silica gel, hexane/ethyl acetate=8:2) yields the title compound: Rf (hexane/ethyl acetate=7:3)=0.25; HPLC Rt =48.10 and 50.29 minutes (diastereoisomeric mixture).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[I:15][C:16]1[CH:29]=[C:28]([I:30])[CH:27]=[C:26]([I:31])[C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Cl.O>CN(C=O)C>[I:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[C:26]([I:31])=[CH:27][C:28]([I:30])=[CH:29][C:16]=1[I:15]
Reactant: ClCCCCCCOc1c(I)cc(I)cc1I
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cccc(OCCCCCCOc2c(I)cc(I)cc2I)c1
Temperature: 110 °C
Yield: 53.8 %

Procedure:
A mixture of potassium carbonate (3.0 g, 21.9 mmol, 1.1 eq), 3-iodophenol (4.4 g, 19.9 mmol) and 6-(2,4,6-triiodophenoxy)-1-chlorohexane (11.75.g, 19.9 mmol) in 50 ml of DMF was heated to 110° C. for 1.5 hours and then cooled. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried (magnesium sulfate) and evaporated to give a solid which was filtered through basic alumina (hexanes-ethyl acetate). The filtrate was concentrated under vacuum leaving the crude product as a solid. Recrystallization from cyclohexane afforded 8.29 g (54%) of the desired product after drying at room temperature under high vacuum, mp 65°-66° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=[C:4]([O:17][CH3:18])[CH:3]=1.C([SH:23]1(CCCC)(CCCC)[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:24]1)CCC.[SnH4].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([C:24]2[S:23][CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[N:25]=2)[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=1
Reactant: CCCC[SH]1(CCCC)(CCCC)C=NC(C(C)C)=C1
Reactant: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(C(C)C)cs2)nc(-n2ccc(C(F)(F)F)n2)n1
Temperature: 90 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
To a solution of compound 305 (892 mg, 3.2 mmol) in dry DMF (15 mL) were added tributyl(4-isopropyl-thiazole)-stannane (2 g, 4.8 mmol), PdCl2(PPh3)2 (224 mg, 0.32 mmol), and potassium carbonate (530 mg, 3.84 mmol). The mixture was stirred at 90° C. for 48 hrs, and the concentrated under reduced pressure. Water and ethyl acetate were added. Organics were washed with water, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to yield compound 307h as a beige solid in 76% yield. MS (ESI, EI+) m/z=370 (MH+).
Reaction SMILES: Cl.[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10]Cl)([CH3:4])[CH3:3].[NH2:36][CH:37]([C:41]([OH:43])=[O:42])[CH2:38][CH2:39][SH:40]>>[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:34][CH:35]=1)[C:9](=[O:12])[CH2:10][S:40][CH2:39][CH2:38][CH:37]([C:41]([OH:43])=[O:42])[NH2:36])([CH3:3])[CH3:4]
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: NC(CCS)C(=O)O
Agent: Cl
Product: CC(C)OCCN(C(=O)CSCCC(N)C(=O)O)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 1, 1-{4-[N-(2-isopropoxyethyl)-N-chloroacetylamino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine hydrochloride is reacted with DL-homocysteine (=2-amino-4-mercaptobutyric acid), yielding (±)-1-{4-[N-(2-isopropoxyethyl)-N-(3carboxy-3-amino-propylmercapto-acetyl)-amino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:7]2[CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])[CH2:26][CH2:25]1)=[O:23].I[CH3:39].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:39])[C:8]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[C:7]2[CH2:20][CH2:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])[CH2:28][CH2:29]1)=[O:23]
Reactant: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)[nH]c3ccc(Cl)cc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)n(C)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% suspension in mineral oil, 40 mg, 1 mmol) was added to a solution of 1-{3-[5-chloro-2-(4-chlorophenyl)-1H-indol-3-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine (Description 33, 270 mg, 0.53 mmol) in dimethylformamide (10 mL) and the mixture was stirred at room temperature for 10 min. Iodomethane (165 μl, 376 mg, 2.65 mmol) was added and the mixture was stirred at room temperature for 1 h. Water (100 mL) was added and the mixture was extracted with ether (2×40 mL). The combined organic fractions were washed with water (3×40 mL) and brine (40 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a beige foam. 1H NMR (360 MHz, CDCl3) δ 7.60 (1H, d, J 1.7 Hz), 7.48 (2H, d, J 8.4 Hz), 7.32 (2H, d, J 8.4 Hz), 7.24 (1H, d, J 8.5 Hz), 7.20 (1H, dd, J 8.5, 1.7 Hz), 7.02 (1H, t, J 7.8 Hz), 6.94-6.82 (3H, m), 3.86 (3H, s), 3.75 (2H, t, J 5.0 Hz), 3.54 (3H, s), 3.40 (2H, t, J 5.0 Hz), 3.02 (2H, t, J 8.1 Hz), 2.95 (2H, t, J 5.0 Hz), 2.80 (2H, t, J 5.0 Hz), and 2.55 (2H, t, J 8.1 Hz). m/z (ES+) 522, 524 (M+1).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Mg].C1C(C(O[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O)=CC=CC=1.Cl>O1CCCC1>[C:21]([O:20][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: C=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc(OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 20 %

Procedure:
There was added dropwise with vigorous stirring under a nitrogen atmosphere, 62.9 grams (0.34 mole) of 4-chlorostyrene and 250 ml. of dry distilled tetrahydrofuran to 8.9 grams (0.37 mole) of magnesium metal turnings under enough tetrahydrofuran to cover the turnings. The exothermic reaction was controlled by external cooling to keep the temperature below 60° C. After the exotherm had subsided, the reaction mixture was heated at 60° C. for 0.5 hour until most of the magnesium had been consumed. Using a salt-ice bath, the reaction mixture was cooled to 0° C. and a solution of 44 grams (0.23 mole) of t-butyl perbenzoate in 80 ml. of tetrahydrofuran was added a such a rate to maintain the temperature between 0° C. and 5° C. After the addition had been completed, the temperature was allowed to rise to 25° C. with stirring over the course of 2 hours. Reaction mixture was then poured into 1000 ml. of a 3% aqueous hydrochloric acid solution. The oil which formed was extracted from the aqueous solution with 200 ml. portions of ethylether. The ether layers were washed twice with a 10% aqueous sodium hydroxide solution and then with water until the washings were neutral. The ether layer was then dried over sodium sulfate and the ether removed using a rotary evaporator. To the pale-yellow oil which remained was added a small amount of ionol as an inhibitor and the product fractionally distilled. There was obtained 20% yield of 4-t-butoxystyrene having a boiling point of 45°-46° C. at 0.03 millimeters. The proton NMR spectrum was recorded and is in agreement with the structure of the product. Elemental analysis calculated for C12H16O: %C, 81.82; %H, 9.09. Found: %C, 81.64; %H, 8.89.
Reaction SMILES: [N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[CH2:35][C@@:25]4([C:33]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:27][C:26]4=[O:34])[CH2:24][C:21]3=[N:22][CH:23]=2)=[O:17])[CH2:7][CH2:6][C@H:5]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[F:43])=[N+]=[N-].CP(C)C>C1(C)C=CC=CC=1>[NH2:1][C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[CH2:35][C@@:25]4([C:33]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:27][C:26]4=[O:34])[CH2:24][C:21]3=[N:22][CH:23]=2)=[O:17])[CH2:7][CH2:6][C@H:5]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[F:43]
Reactant: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)CC[C@H]1c1cccc(F)c1F
Agent: CP(C)C
Solvent: Cc1ccccc1
Product: N[C@@H]1c2cccnc2[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(6S)—N-[(5S,6S,9R)-5-Azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide (13 mg, 0.022 mmol) was azeotroped with dry toluene and dried under high vacuum. The azide was dissolved in THF (1 mL), trimethylphosphine (1 M in toluene, 0.25 mL, 0.25 mmol) was added, and the resulting solution was stirred at ambient temperature for 1.5 h. The reaction solution was concentrated to dryness in vacuo, resuspended in THF (2 mL) and water (0.5 mL) and heated at 85° C. in a sealed vial for 4 h. The mixture was allowed to cool, most of the THF was removed by evaporation and the residual solution was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H2O:CH3CN:TFA-95:5:0.1 to 0:100:0.1. Product-containing fractions were combined and neutralized with saturated aqueous sodium bicarbonate and the acetonitrile was removed by evaporation under reduced pressure. The resulting mixture was extracted with ethyl acetate (2×50 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=553.3 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.95 (d, 1H, J=2.0 Hz); 8.48 (dd, 1H, J=4.9, 1.6 Hz); 8.24 (d, 1H, J=2.0 Hz); 8.08 (dd, 1H, J=5.3, 1.6 Hz); 8.00 (d, 1H, J=7.9 Hz); 7.42-7.35 (m, 2H); 7.28 (s, 1H); 7.25-7.15 (m, 2H); 6.96 (dd, 1H, J=7.4, 5.3 Hz); 5.58 (dd, 1H, J=10.1, 3.3 Hz); 4.74 (d, 1H, J=9.4 Hz); 3.65-3.55 (m, 2H); 3.40-3.30 (m, 2H); 3.06 (br s, 1H); 2.41-2.24 (m, 2H); 2.04-1.94 (m, 1H); 1.71-1.53 (m 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][S:14][CH:15]=[C:11]2[N:10]=[C:9]1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:26]C1C=CC(COC(N2C3=CSC=C3N=C2S(CC2C=CC(C)=CN=2)=O)=O)=CC=1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][S:14][CH:15]=[C:11]2[N:10]=[C:9]1[S:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC(=O)n2c(S(=O)Cc3ccc(C)cn3)nc3cscc32)cc1
Reactant: Cc1ccc(CSc2nc3cscc3n2C(=O)OC(C)(C)C)nc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(CS(=O)c2nc3cscc3n2C(=O)OC(C)(C)C)nc1

Procedure:
1.1 g (3 mmol) of the title compound from Example 23 were dissolved in 50 ml of CH2Cl2, and 50 ml of the KH2PO4 /Na2HPO4 buffer solution from Example 22 were added. At 10° C. a total of 900 mg (4.5 mmol) of m-chloroperbenzoic acid in CH2Cl2 was added dropwise in portions until the precursor has been completely used up.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:20][C:21]([O:23]CC1C=CC=CC=1)=O)[C:9]([N:11]1[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH:38][CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>C(O)C.[Pd]>[CH2:1]([C@H:8]([CH2:20][C:21]([N:38]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:39])=[O:23])[C:9]([N:11]1[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OCc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccccc1
Reaction time: 6 h
Yield: 97.7 %

Procedure:
A solution of 1.03 g (2.52 mmole) of 3-[2(R)-benzyl-3-(benzyloxycarbonyl)propionyl]-4(S)-isopropyl-2-oxazolidinone (prepared as described in Preparation 13) in 20 ml of ethanol was stirred at room temperature for 4 hours under an atmosphere of hydrogen and in the presence of 100 mg of 10% w/w palladium-on-charcoal. The catalyst was then removed by filtration, and the filtrate was concentrated by distillation under reduced pressure. The residue was dissolved in 50 ml of anhydrous tetrahydrofuran, and 0.39 ml (3.02 mmole) of N-benzyl-N-methylamine, 0.46 ml of 95% diethyl cyanophosphonate and 0.42 ml of triethylamine were added, in that order, to the solution, whilst ice-cooling and under an atmosphere of nitrogen, after which the mixture was stirred for 6 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure column chromatography through silica gel using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent), followed by recrystallization from diisopropyl ether, to afford 1.04 g (yield 98%) of the title compound as white crystals, melting at 60°-62° C.