Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([F:10])[CH:3]=1.C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[OH-].[K+]>C1COCC1>[F:10][C:4]1[CH:3]=[C:2]([B:16]([OH:21])[OH:17])[CH:7]=[CH:6][C:5]=1[S:8][CH3:9]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccc(Br)cc1F
Agent: [K+]
Agent: [Li]CCCC
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1F
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 5.2 %

Procedure:
A solution of 4-bromo-2-fluorothioanisole (0.5 g, 22.6 mmol) in dry THF (20 mL) was chilled to −78° C. under a nitrogen atmosphere. The reaction mixture was treated with 1.6 M n-butyllithium in hexanes (1.7 mL, 27.1 mmol), and the mixture was warmed to −40° C. where it was maintained for 0.5 hours. The reaction mixture was then chilled to −78° C. and three equivalents of triisopropyl borate (1.56 mL, 67.8 mmol) were added. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. At this point, 10% aqueous KOH (200 mL, 360 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was then poured into an ice/concentrated HCl mixture with stirring to yield a white precipitate. This solid was dried in a vacuum oven (65° C., 29 in Hg) overnight to provide the title compound (yield: 0.22 g; 52.4%). 1H NMR (300 MHz, DMSO-d6) δ 2.48 (s, 3H), 7.31 (t, J=9 Hz, 1H), 7.49 (dd, J=12 Hz, 1.5 Hz, 1H) 7.54 (dd, J=9 Hz, 1.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@H:20]([NH:36][C:37]([C:39]1[N:40]([CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25]C(OCC1C=CC=CC=1)=O)=[O:19]>CO.[Pd]>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@H:20]([NH:36][C:37]([C:39]1[N:40]([CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[O:19]
Reactant: COC(=O)Cn1c(C(=O)N[C@H](CCCCNC(=O)OCc2ccccc2)C(=O)NCCCCCc2c(OC)cc(C)cc2OC)cc2ccccc21
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cn1c(C(=O)N[C@H](CCCCN)C(=O)NCCCCCc2c(OC)cc(C)cc2OC)cc2ccccc21
Reaction time: 18 h
Yield: 85 %

Procedure:
5.6 g of methyl (R)-{2-[N-{1-[(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl]-5-(benzyloxycarbonylamino)pentyl}carbamoyl]indol-1-yl}acetate (EXAMPLE 66) are dissolved in 170 ml of methanol and 0.56 g of 10% Pd/C is added thereto. Hydrogenation is carried out under a pressure of 3 bar and the reaction mixture is left at 30° C., while maintaining this pressure, for 18 hours. After cooling, the catalyst is filtered over a bed of celite and evaporation is carried out to dryness. The residual oil is purified by flash chromatography on silica gel, eluent: CH2Cl2 /CH3 OH/AcOH 90/10/0.5 (v/v/v) in order to obtain white crystals of methyl (R)-{2-[N-{1-[(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl]-5-aminopentyl}carbamoyl]indol-1-yl}acetate, M.p.=78° C., [α]D20 =-47.6° (c=1, CH3OH), Yield: 85%.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12](Cl)[CH:11]=1)([CH3:9])[CH3:8])[CH3:3].Cl>>[NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]1)([CH3:9])[CH3:8])[CH3:3]
Reactant: CC(N)CCCC(C)(C)c1ccc(N)c(Cl)c1
Agent: Cl
Product: CC(N)CCCC(C)(C)[C@H]1CC[C@H](N)CC1
Reaction time: 48 h

Procedure:
5.1 Parts of 2-amino-6-(4-amino-3-chlorophenyl)-6-methylheptane were hydrogenated and worked up to the procedure of Example 1 using 60 parts of 1N aqueous hydrochloric acid and 1.0 parts of Nishimura catalyst. The hydrogenation, which ceased after 48 hours and which represented a 126% theory uptake, gave on distillation 4.0 parts of cis and trans 2-amino-6-(4-aminocyclohexyl)-6-methylheptane b16 160°-5°. Spectroscopic analysis showed that the ratio of cis and trans isomers was 3 to 1 parts respectively.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:22][N:20]2[CH2:21][C@@H:5]([CH2:6][C@:7]([C:56]([O:58][CH3:59])=[O:57])([C:23]3[CH:24]=[C:25]4[C@:33]56[C@@H:37]7[C@:38]([CH2:53][CH3:54])([C@@H:42]([O:49][C:50]([CH3:52])=[O:51])[C@:43]([OH:48])([C:44]([O:46][CH3:47])=[O:45])[C@@H:32]5[N:31]([CH3:55])[C:26]4=[CH:27][C:28]=3[O:29][CH3:30])[CH:39]=[CH:40][CH2:41][N:36]7[CH2:35][CH2:34]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=4[C:9]=3[CH2:18][CH2:19]2)[CH:4]=1.Cl.C(C[OH:66])(F)(F)F.[BH4-].[Na+]>O.O.O.O.O.O.O.C([O-])(=O)C([O-])=O.[Fe+3].C([O-])(=O)C([O-])=O.C([O-])(=O)C([O-])=O.[Fe+3].CCOC(C)=O.CO.CCN(CC)CC>[CH3:1][CH2:2][C@@:3]1([OH:66])[CH2:22][N:20]2[CH2:21][C@@H:5]([CH2:6][C@:7]([C:56]([O:58][CH3:59])=[O:57])([C:23]3[CH:24]=[C:25]4[C@:33]56[C@@H:37]7[C@:38]([CH2:53][CH3:54])([C@@H:42]([O:49][C:50]([CH3:52])=[O:51])[C@:43]([OH:48])([C:44]([O:46][CH3:47])=[O:45])[C@@H:32]5[N:31]([CH3:55])[C:26]4=[CH:27][C:28]=3[O:29][CH3:30])[CH:39]=[CH:40][CH2:41][N:36]7[CH2:35][CH2:34]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=4[C:9]=3[CH2:18][CH2:19]2)[CH2:4]1
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccc(C)cc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Reactant: OCC(F)(F)F
Agent: [Fe+3]
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccc(C)cc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A mixture of iron(III) oxalate hexahydrate (45.0 mg, 0.093 mmol) in H2O (37 mL) was cooled to 0° C. and air was bubbled through the mixture for 10 minutes. A solution of 10′-methylanhydrovinblastine (21a, 7.5 mg, 0.0093 mmol, 1 equiv) in H2O (0.5 mL), aqueous 0.1 N HCl (0.5 mL), and CF3CH2OH (0.1 mL) was transferred by pipette to the mixture and NaBH4 (14.6 mg, 0.39 mmol, 1 equiv) in H2O (1 mL) was added to the mixture at 0° C. The resulting mixture was stirred for 30 minutes before being quenched by addition of 28-30% aqueous NH4OH (10 mL). The mixture was extracted with 10% MeOH in CH2Cl2 and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. PTLC (SiO2, Et3N:MeOH:EtOAc=3:3:97) provided 10′-methylvinblastine (21b, 3.1 mg, 0.0038 mmol, 40%) as a white solid and 10′-methylleurosidine (1.5 mg, 0.0018 mmol, 19%).
Reaction SMILES: [CH2:1]([C@H:8]1[NH:13][C:12](=O)[CH2:11][N:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([C@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:16]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CC(=O)N[C@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N2CCN[C@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 0 °C
Yield: 64.9 %

Procedure:
(R)-6-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-2-one (Compound 53) (365 mg, 0.959 mmol) was dissolved in THF (10 mL), cooled to 0° C., and treated with solid lithium aluminum hydride (73 mg, 1.92 mmol). The reaction mixture was heated at 60° C. for 3 hr then cooled to 0° C. and quenched with EtOAc (2 mL) and a 1 N aqueous solution of NaOH (2 mL). The reaction was filtered with the aid of EtOAc, dried over MgSO4, filtered, and evaporated to an oil, which was purified by silica gel flash chromatography with 5% Me0H/CH2Cl2 as eluant to afford product as a brown colored oil (228 mg, 65%). LC/MS 5.12 min, [M+1]+ 367.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].C=C(OP(O)(O)=O)C(O)=O.C([O-])(=O)C(CC([O-])=O)O.C([O-])(=O)C=O.[O:33]=[CH:34][C@@H:35]([C@H:37]([C@@H:39]([C@@H:41]([CH2:43][OH:44])[OH:42])[OH:40])[OH:38])[OH:36]>>[OH:44][CH2:43][C@@H:41]([C@H:39]([C@@H:37]([C@@H:35]([CH2:34][OH:33])[OH:36])[OH:38])[OH:40])[OH:42].[C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: C=C(OP(=O)(O)O)C(=O)O
Agent: O=C(O)CCC(=O)O
Agent: O=C([O-])CC(O)C(=O)[O-]
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
Metabolic flux analysis was used to evaluate the effect of different carbon sources on succinic acid production in batch fermentations with A. succinogenes FZ45. The analyses established that the major pathway for succinic acid production in A. succinogenes FZ45 flows in the following manner: phosphoenolpyruvate (PEP)→oxaloacetate (OAA)→malate→fumarate→succinic acid. The glyoxylate shunt and the PEP-transport-system (PTS) appear not to be substantially used in the organism. Glucose fermentations reach a concentration of 61.7 g/L succinic acid with a yield of about 94% (succinic acid (g)/glucose (g)). Fermentations performed using a more reduced carbon source, such as sorbitol, produced higher amounts of succinic acid (77.3 g/L) with a higher yield (108% succinic acid (g)/glucose (g)), indicating that reducing power may become a limiting factor during the fermentation of glucose.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].CN1[C:18]([CH3:19])=[CH:17][C:15](=[O:16])N(C)C1=O>O>[CH3:19][C:18]1[NH:2][C:3]([NH2:5])=[N:4][C:15](=[O:16])[CH:17]=1
Reactant: N=C(N)N
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(=O)nc(N)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Guanidine hydrochloride (IIIc) (10 g, 0.1 mol) was added to 1 M ethanolic sodium ethoxide (100 ml) and the mixture was stirred for 10 minutes at room temperature. Sodium chloride was removed from the mixture by filtration, and the filtrate was condensed to a syrup in vacuo below 35°. To the residue was added 1,3,6-trimethyluracil (800 mg, 0.005 mol) and the mixture was heated at ~90° for 6 hours under nitrogen. The reaction mixture was dissolved in water (20 ml) and the solution added to a column of Amberlite IRC-50 (H+) (30×3 cm diameter) and the column was washed with water. The uv absorbing fractions were collected and evaporated to dryness in vacuo. The solid residue was recrystallized from water to give 6-methylisocytosine (IIb, R1 =H, R2 =methyl) (320 mg, mp 290°-292° dec.). The uv and ir characteristics were identical with those of an authentic sample of 6 -methylisocytosine.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1([S:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1.Cl>CO.C(OCC)(=O)C.CN(C)C=O>[OH:1][NH:2][C:3]([C:5]1([S:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:16][CH:17]=2)[CH2:10][CH2:9][N:8]([CH2:35][C:34]2[CH:37]=[CH:38][C:31]([Br:30])=[CH:32][CH:33]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC#CCOc1ccc(SC2(C(=O)NO)CCNCC2)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(SC2(C(=O)NO)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxy-amide (prepared by the procedure outlined in example 15) (0.15 g, 0.5 mmol) in methanol (5 mL) and dimethylformamide (2.5 mL) was treated with triethylamine (0.15 mL, 1.1 mmol) followed by 4-bromobenzylbromide (0.13 g, 0.53 mmol). After 6 h the solution was diluted with ethyl acetate, acidified to pH=6 with 1N aqueous hydrochloric acid, washed sequentially with water, aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate. Concentration in vacuo gave 1-(4-bromo-benzyl)-4-(4-but-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxyamide. 1HNMR (DMSO-d6): 1.5-1.6 (m, CHH, 2H), 1.8 (s, CH3, 3H), 1.9-2.2 (m, CHH, 4H), 2.5-2.6 (m, CHH, 2H), 3.4 (s, CH2Ar, 2H), 4.75 (s, CH2, 2H), 6.9 (d, ArH, 2H), 7.2 (d, ArH, 2H), 7.3 (d, ArH, 2H), 7.5 (d, ArH, 2H), 8.8 (s, NHOH, 1H), 10.6 (d, NHOH, 1H). Electrospray Mass Spectroscopy: ((M+H)+=489/491).
Reaction SMILES: Cl.[CH:2]1([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].CC(C)([O-])C.[Na+]>CS(C)=O>[CH:2]1([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])[CH2:13]3)[C:9]2=[O:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C1N(C2CCCCC2)CCC12CCCNC2
Reactant: Fc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1N(C2CCCCC2)CCC12CCCN(c1ccccc1F)C2

Procedure:
A mixture of 2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one hydrochloride (0.025 g, 0.000092 mol), 1-bromo-2-fluorobenzene (0.032 g, 0.00018 mol), and sodium tert-butoxide (0.026 g, 0.00027 mol) in DMSO (0.5 mL) was microwave irradiated at 180° C. for 5 min. After cooling the reaction mixture to ambient temperature the crude product was purified by prep.-HPLC. LC-MS: 331.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:37]([O:39]/[CH:40]=[CH:41]/B1OC(C)(C)C(C)(C)O1)[CH3:38]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2/[CH:38]=[CH:37]/[O:39][CH2:40][CH3:41])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCO/C=C/c1cc2c(cc1N[C@@H]1CCN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 100 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To a mixture of (R)-3-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.625 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.05 g, 0.06 mmol) and K2CO3 (0.43 g, 1.87 mmol) in dioxane (24 mL) and water (4 mL) was added 2-((E)-2-ethoxy-vinyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.123 g, 0.62 mmol) and the reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether) to give (R)-3-[(R)-7-((E)-2-ethoxy-vinyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 g, 74%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.16 (s, 1H), 6.73 (s, 1H), 6.61 (d, J=12.4 Hz, 1H), 6.07 (s, 1H), 5.56 (d, J=12.4 Hz, 1H), 4.65 (m, 1H), 4.48 (m, 2H), 3.90 (m, 1H), 3.80 (m, 2H), 3.64 (m, 1H), 3.40 (m, 2H), 3.09-3.30 (m, 1H), 2.22 (m, 1H), 1.82 (m, 1H), 1.42 (m, 12H), 1.28 (t, J=7.2 Hz, 3H). LC/MS (Table 1, Method 2) Rt=1.100 min.; MS m/z: 472 [M+H]+. SFC (Table 1, Method 37) Rt=2.183 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:43][CH3:44])=[C:5]([C:9]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:10][CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]3=[O:19])[CH2:14][C@@H:13]2[CH2:26]OC(=O)C)[CH:6]=[CH:7][CH:8]=1.N>CO>[CH3:1][O:2][C:3]1[C:4]([O:43][CH3:44])=[C:5]([C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:10][CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]3=[O:19])[CH2:14][C@@H:13]2[CH3:26])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2COC(C)=O)(c2ccccc2)c2ccccc2)c1OC
Agent: N
Solvent: CO
Product: COc1cccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2C)(c2ccccc2)c2ccccc2)c1OC
Temperature: 0 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
Compound 185 (0.70 g, 1.17 mmol) was dissolved in dry methanol. The reaction was cooled to 0° C. and NH3 in MeOH (1.5 ml, Ca. 9 M) was added dropwise via syringe. The reaction mixture was allowed to warm gradually to room temperature. After stirring for 24 hours the solution was concentrated to dryness, and the residue was chromatographed on a silica gel column with EtOAc/Hexane (6:4-8:2) as eluent to give 186 (0.40 g, 61%). 1H NMR (CDCl3): δ8.68 (br, 1 H, NH), 7.61 (m, 1 H, Tr), 7.43 (d, 1 H, J=1.1 Hz, H-6), 7.33-7.28 (m, 9 H, Tr), 6.85-6.82 (m, 4 H, Tr), 6.14 (dd, 1 H, J=4.7, 6.7 Hz, H-1'), 3.99-3.97 (m, 1 H, H-4'), 3.79 (s, 6 H, OCH3), 3.64-3.61 (m, 2 H, CH2OH), 3.51 (dd, 2 H, J=3,6, 10.5 Hz, H-5') 3.36 (dd, 1H, J=3.6, 10.5 Hz, H-5"), 2.62-2.60 (m, 1 H, H-3'), 2.35-2.31 (m, 1 H, H-2'), 2.24-2.20 (m, 1 H, H-2"), 2.12 (m, 1 H, OH), 2.05 (s, 3 H, COCH3), 1.52 (s, 3 H, CH3); 13C NMR (CDCl3): 163.7 (C4), 158.6, 150.3 (C2), 144.3, 135.7 (C6), 135.4, 130.1, 128.0 & 127.9 (d), 127.1, 113.2, 110.7 (C5), 86.9, 85.1 (C1'), 82.3 (C4'), 64.1 (C5'), 63.1, 55.2, 41.5 (C3'), 32.8 (C2'), 12.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:49][C:50]([Si:53]([CH3:64])([CH3:63])[O:54][C:55]1[CH:56]=[C:57]([CH2:61][NH2:62])[CH:58]=[CH:59][CH:60]=1)([CH3:52])[CH3:51]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:62][CH2:61][C:57]2[CH:58]=[CH:59][CH:60]=[C:55]([O:54][Si:53]([C:50]([CH3:52])([CH3:51])[CH3:49])([CH3:63])[CH3:64])[CH:56]=2)=[O:7])[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11]
Reactant: Cc1cc(C(=O)O)cc(Cl)c1O
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
A suspension of 3-chloro-4-hydroxy-5-methylbenzoic acid (4.7 g, 25.2 mmol) in dichloromethane (50 mL) was cooled to 0° C. and BOP reagent (12.3 g, 27.8 mmol) was added, followed by diisopropylethylamine (13.2 mL, 75.6 mmol). A solution of 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzene-methanamine (Example 8; 6.59 g, 27.8 mmol) in dry dichloromethane (10 mL) was added by syringe and the resulting solution was stirred at −0° C. for 3 h. The solvent was evaporated and ethyl acetate (200 mL) was added. The solution was washed with 1 M HCl (2×50 mL), aqueous sodium hydrogen carbonate (100 mL), brine (100 mL), and water (100 mL) dried (MgSO4), filtered, evaporated, and chromatographed (30% ethyl acetate/hexanes) to give 2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylphenol (6.03 g, 59%) as a pale pink solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[Cl:25][C:26]1[CH:27]=[C:28]([C:33]2[CH:40]=[CH:39][C:36](CO)=[CH:35][CH:34]=2)[CH:29]=[C:30]([Cl:32])[CH:31]=1>C(OCC)C.C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([C:33]2[CH:40]=[CH:39][C:36]([CH2:20][Br:24])=[CH:35][CH:34]=2)[CH:29]=[C:30]([Cl:32])[CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(-c2cc(Cl)cc(Cl)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1cc(Cl)cc(-c2ccc(CBr)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of triphenylphospine (636 mg, 2.42 mmol) and carbon tetrabromide (830 mg, 2.50 mmol) in diethyl ether (5 mL) was added a solution of 4-(3',5'-bis-chlorophenyl) benzyl alcohol (50 mg, 1.98 mmol) in CH2Cl2 (12 mL). The reaction was stirred at ambient temperature for 16 hours, silica gel was than added and the solvent evaporated in vacuo. The product was isolated by chromatography (Silica gel, 10-30% EtOAc in hexanes) and obtained as a white solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:11]2([OH:24])[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:26][C:27](=[O:50])[C@H:28]([C@@H:47]([CH3:49])O)[NH:29]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[CH:1]1([C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:11]2([O:24][C@H:47]([CH3:49])[C@@H:28]([C:27]([OH:50])=[O:26])[NH2:29])[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: OC1(c2sccc2C2CCCC2)c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OC1(c2sccc2C2CCCC2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(3-cyclopentylthien-2-yl)-9H-fluoren-9-ol and Nα -(9 fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH2:14]([C:21]1([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C:21]1([OH:27])[CH2:26][CH2:25][N:24]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: OC1(Cc2ccccc2)CCNCC1
Product: N#Cc1ccc(N2CCC(O)(Cc3ccccc3)CC2)c2ccccc12
Yield: 30 %

Procedure:
The title compound (12 mg, 30% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 4-benzyl-4-hydroxypiperidine (89 mg, 0.468 mmol).
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30].C(N(CC)CC)C.CN1CCCC1=O>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[N:23][C:2]([N:27]5[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: O=C1CNCCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCNC(=O)C3)cc1OCC2

Procedure:
A solution of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 317 (55.0 mg, 0.166 mmol), piperazin-2-one (0.110 g, 1.10 mmol) and triethylamine (0.275 mL, 1.97 mmol) in N-methylpyrrolidinone (3.00 mL, 31.1 mmol) was heated at 150° C. for 2 d. The reaction was filtered thru celite then rinsed with EtOAc. The filtrate was washed water and brine. The organic layer was dried Na2SO4, concentrated to give 325, analyzed by rHPLC. MS: (ESI+)=395.1. 1H NMR (400 MHz, DMSO) δ 8.55 (d, J=8.7 Hz, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 6.70 (d, J=8.8 Hz, 1H), 5.88 (dt, J=13.2, 6.6 Hz, 1H), 4.63-4.30 (m, 4H), 4.06 (d, J=8.0 Hz, 2H), 3.81-3.63 (m, 2H), 1.47 (d, J=6.6 Hz, 6H).