Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=3[C:10]3[CH:23]=[CH:24][CH:25]=[CH:26][C:9]2=3)=[CH:4][CH:3]=1.C([Li])CCC.[B:32]([O:37]C)(OC)[O:33]C.S(=O)(=O)(O)O>O1CCCC1.CCCCCC>[CH:19]1[C:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:5]3[CH:4]=[CH:3][C:2]([B:32]([OH:37])[OH:33])=[CH:7][CH:6]=3)[C:9]3[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=3[C:11]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Ic1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Reactant: COB(OC)OC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
Ten point zero (10.0) grams (22.5 mmol) of 9-(4-iodophenyl)tribenz[b,d,f]azepin was dissolved in 50 ml of tetrahydrofuran, and the solution was cooled to −78° C. Fourteen point one (14.1) ml (22.5 mmol) of a 1.6 M hexane solution containing n-butyl lithium was dropwise added thereinto. After completion of the addition, the solution was stirred for 30 minutes, and then a tetrahydrofuran solution containing 2.8 g (22.5 mmol) of trimethyl borate was dropwise added thereto over about one hour. After completion of the addition, the solution was stirred for 1 hour, then the temperature was gradually raised to room temperature, and the solution was allowed to react for further two hours. Subsequently, a dilute sulfuric acid (3 ml of sulfuric acid and 50 ml of water) was added at 0° C. and hydrolysis was performed. The reaction solution was extracted with ethyl acetate, concentrated under reduced pressure, the obtained solid of boronic acid was recrystallized with toluene and purified, thereby 6.1 g of 4-(tribenz[b,d,f]azepin-9-yl)phenyl boronic acid was obtained (yield: 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](Cl)=[C:6]2[S:5][CH:4]=1.[NH2:18][C:19]1[C:20]([CH3:25])=[CH:21][CH:22]=[CH:23][CH:24]=1>C1(OC)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])=[C:6]2[S:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2c(OC)csc2c1Cl
Reactant: Cc1ccccc1N
Solvent: COc1ccccc1
Product: CCOC(=O)c1cnc2c(OC)csc2c1Nc1ccccc1C

Procedure:
Ethyl 3-methoxy-7-chlorothieno[3,2-b]pyridin-6-carboxylate (1.5 g, 0.0055 mol) and o-toluidine (1.18 g, 0.011 mol) in anisole (30 ml) were heated under reflux in an inert atmosphere for twenty hours. The solvent was evaporated under reduced pressure and the residue was taken up in chloroform (200 ml) and washed with 2N hydrochloric acid (3×100 ml). The organic phase was then washed with sodium bicarbonate solution (2×100 ml), and water, dried over magnesium sulphate, filtered and evaporated to give an oil. The oil was purified by flash chromatography using dichloromethane as eluant. The fractions containing the product were combined and evaporated to give a colourless product, 1.12 g. Recrystallisation from ethyl acetate gave the title compound, 0.63 g, m.p. 141°-143°.
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1>C(Cl)Cl>[NH2:5][C:3](=[O:4])[CH2:2][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1
Reactant: NC(=O)CBr
Reactant: COC(=O)c1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(N)=O)cc1OC
Temperature: 85 °C
Yield: 91.4 %

Procedure:
To a sealed tube was added 2-bromoacetamide (2.272 g, 16.47 mmol), DMF (50 mL), cesium carbonate (7.15 g, 21.96 mmol) and methyl 4-hydroxy-2-methoxybenzoate (1.00 g, 5.49 mmol). The tube was sealed and heated for 16 hours at 85° C. The reaction mixture was diluted with DCM, washed sequentially with 10 mL of 1M HCl, water, and brine. The solution was dried over sodium sulfate, filtered and the solvent removed to give 1.2 grams of methyl 4-(2-amino-2-oxoethoxy)-2-methoxybenzoate (78% yield) as a yellow powder. The LC/MS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 1 minute hold at a rate of 4 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 3.71-3.76 (m, 3H), 3.80-3.84 (m, 3H), 4.45 (s, 2H), 6.56 (dd, J=8.66, 2.38 Hz, 1H), 6.65 (d, J=2.26 Hz, 1H), 6.77 (br. s., 1H), 6.92 (br. s., 1H), 7.75 (d, J=8.78 Hz, 1H). LCMS Rt=1.385 min., m/z 240.2 (M+H), 92% purity.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[C:22]1([CH3:30])[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1.CO.[OH-].[Na+]>C(OCC)(=O)C>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:30][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C=CC(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
The title compound was prepared by heating a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol), p-tolualdehyde (75 ul, 0.633 mmol), methanol (5 ml) and NaOH (200 ul, 10M) for 24 h. The mixture was cooled to room temperature, diluted with ethyl acetate (100 ml), wash with water and saturated aqueous NaCl, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by column chromatography using hexane:ethyl acetate (4:1) to give a yellow solid (32 mg, 12.2%). 1H NMR (CDCl3): 7.67 (d, J=15.6 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.40 (d, J=15.6 Hz, 1H), 7.28 (d, J=3.3 Hz, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.12 (dd, J=3.3, 9.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 4.44-4.33 (m, 4H), 2.39 (s, 3H).
Reaction SMILES: [CH2:1]([SiH:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:26]=[CH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:18]([Si:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C=CCCCCCC
Reactant: CCCCCCCC[SiH](CCCCCCCC)CCCCCCCC
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](CCCCCCCC)(CCCCCCCC)CCCCCCCC

Procedure:
A mixture of 2.0 grams trioctylsilane and 10 grams 1-octene in 5 milliliters of toluene was reacted for 2 hours at 75°-80° C. in the presence of 0.009 gram of chlorotris(triphenylphosphine)rhodium(I) to yield 80 weight percent tetraoctylsilane.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[N:18]([CH3:33])[N:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[C:21]=3[Br:22])[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[Br:22][C:21]1[C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[N:19][N:18]([CH3:33])[C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]2[CH2:5][C:4]([OH:34])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3c(Br)c(-c4ccc(C(F)(F)F)cc4)nn3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)c(Br)c1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 f], {6-[4-bromo-2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {6-[4-bromo-2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7](=[O:21])[C:6](=[O:22])[NH:5]2.C(O)(C)C.C([O-])=O.[NH4+]>O.[Pd]>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:22])[C:7](=[O:21])[N:8]2[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(N)cc21
Temperature: 75 °C
Yield: 77.7 %

Procedure:
84.3 g (0.26 mol) of 6-chloro-1-(ethoxycarbonylmethyl)-7-nitro-2,3(1H,4H)-quinoxalinedione were suspended in 1.5 1 of isopropanol, and 194.2 g (3.1 mol) of ammonium formate dissolved in 500 ml of water, and 8.5 g of palladium/carbon (10%) were successively added. The mixture was heated at 75° C. for 4 h and, after cooling, filtered, and the filter cake was extracted three times with 800 ml of dimethylformamide. The combined dimethylformamide phases were concentrated under reduced pressure, and the residue was washed with water to yield 53.2 g (79%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[C:21]([N+:18]([O-:20])=[O:19])[CH3:22]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1c[nH]c2ccc(Cl)cc12)[N+](=O)[O-]

Procedure:
12.9 g of 5-chloro-3-formylindole and 1.3 g of ammonium acetate are suspended in 26 ml of nitroethane and refluxed for 1 hour. After the whole of the reactants have dissolved a mass of orange crystals are seen to form. The reaction mixture is then cooled and filtered after dilution with di-isopropyl ether. The product is recrystallised from 96% ethyl alcohol.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[C:15]2[CH:16]=[CH:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:21][C:19]1([CH3:22])[CH2:18][CH:17]=[CH:16][C:15]2[C:10]([CH2:9][OH:8])=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:20]1
Reactant: CC1(C)CC=Cc2c(CO[Si](C)(C)C(C)(C)C)cccc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC=Cc2c(CO)cccc2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (6,6-dimethyl-6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethoxy)dimethylsilane (7.306 g, 23.08 mmol) in tetrahydrofuran (30 ml) was added a solution of 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (27.7 ml, 27.7 mmol) at room temperature, and the mixture was stirred at room temperature for 15 min. The reaction solution was poured into water, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23]CC3C=CC([N+]([O-])=O)=CC=3)=[O:22])[CH2:12][N:11]2[CH3:41])=[O:9])[CH2:4][CH2:3]1.O1CCCC1.[ClH:47]>O>[ClH:47].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:12][N:11]2[CH3:41])=[O:9])[CH2:6][CH2:7]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C)C3)[C@H](C)[C@H]12

Procedure:
A solution of 720 mg of 4-nitrobenzyl (1R, 5S,6S)-2-[(2S,4S)-2-(4-methyl-1-piperazinylcarbonyl)-1-methylpyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] in 60 ml of a 1:1 by volume mixture of tetrahydrofuran and water was mixed with 1.2 ml of 1N aqueous hydrochloric acid, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 800 mg of 10% w/w palladium-on-charcoal. The catalyst was then removed by filtration and the filtrate was washed with diethyl ether. The aqueous solution was concentrated by evaporation under reduced pressure, the residue was subjected to column chromatography using a Lobar column (Merck, LiChroprep RP-8, size B) and the column was eluted with 3% by volume aqueous methanol. Those fractions containing the title compound were combined and concentrated by evaporation under reduced pressure, to give 326 mg of the title compound as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[F:27])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CN(C=O)C.C[Si](C)(C)[C:35]#[C:36][C:37]1([CH3:41])[CH2:40][O:39][CH2:38]1>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[F:27][C:26]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:12]1[CH:13]=[C:14]2[C@@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:35]#[C:36][C:37]4([CH3:41])[CH2:40][O:39][CH2:38]4)[CH:3]=3)[O:8][C:9]2=[CH:10][CH:11]=1
Reactant: CC1(C#C[Si](C)(C)C)COC1
Reactant: NC1=N[C@@]2(CS1)c1cc(-c3cnccc3F)ccc1Oc1ncc(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: CC1(C#Cc2cnc3c(c2)[C@]2(CSC(N)=N2)c2cc(-c4cnccc4F)ccc2O3)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
A vial was charged with (S)-3-bromo-7-(4-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (120 mg, 0.27 mmol), copper(I) iodide (20.62 mg, 0.11 mmol), and tetrakis(triphenylphosphine)palladium (31.3 mg, 0.027 mmol). The vial was flushed with Ar (g), then DMF (1 mL), and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (137 mg, 0.81 mmol), DIPA (574 μL, 4.06 mmol) were added in sequence. The vial was flushed with Ar (g), sealed, and placed in a 90° C. oil bath. The mixture was stirred overnight. After cooling to rt, the crude was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-80% EtOAc in 90:10 CH2Cl2:CH3OH to provide a white solid, (S)-7-(4-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (35 mg, 0.076 mmol, 28% yield).
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:20]([O:8][CH2:7][C:3]1[CH:2]=[C:1]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cccc(CO)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cccc(CO)c1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 1,3-phenylenedimethanol (10.00 g, 72.38 mmol, Aldrich) in DCM (200 mL) was added 1H-imidazole (5.17 g, 76.0 mmol, Aldrich), followed by the addition of tert-butylchlorodiphenylsilane (19.8 mL, 76.0 mmol, Aldrich) and 4-dimethylaminopyridine (0.88 g, 7.2 mmol, Aldrich). After stirring overnight, the reaction was partitioned between DCM and water, the organic layer was dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography (gradient elution, 0 to 20% EtOAc/hexanes). Yield: (7.9 g, 29%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10].[CH2:14]([O:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:15]>C(OCC)C>[CH2:14]([O:16][C:17]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[C:18]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:15]
Reactant: CCCCCCC#COCC
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCC1=C(OCC)C(C)(C)C1=O
Reaction time: 96 h
Yield: 61 %

Procedure:
The title compound was prepared using a modification of the method of Wasserman, H. H. et al, [J. Org. Chem, 38, 1451-1455, (1973)]; triethylamine (22 ml) was added dropwise at room temperature to a well-stirred solution of isobutyryl chloride (7.3 ml, 69 mmol) and 1-ethoxy-1-octyne [prepared according to the method of Kocienski, P. et al Tetrahedron Lett. 1833, 30, (1989)] (6.5 g, 63 mmol) in diethylether (100 ml). The reaction was warmed to 35° and stirred for 96 h prior to cooling and filtration. The filtrate was concentrated in vacuo and the residual oil chromatographed (SiO2; hexanes 80:EtOAc 20) to give the title compound as a brown oil (8.6 g, 38 mmol, 61%). δH (CDCl3, 300K) 4.34 (2H, d, J 7.1 Hz), 2.05 (2H, dd, J 5.6 Hz, 7.3 Hz), 1.44 (3H, t, J 7.1 Hz), 1.27-1.12 (8H, m), 1.23 (6H, s), 0.89 (3H, t, J 2.7 Hz). m/z (ES+, 70V) 225.0 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3].Cl.[CH3:9][C:10]([O:13][C:14]([NH:16][C@H:17]([C:20](OCC1C=CC([N+]([O-])=O)=CC=1)=[O:21])[CH2:18][OH:19])=[O:15])([CH3:12])[CH3:11].ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)(Cl)Cl>[NH:16]([C:14]([O:13][C:10]([CH3:12])([CH3:11])[CH3:9])=[O:15])[C@H:17]([C:18]([NH:1][C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3])=[O:19])[CH2:20][OH:21]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C

Procedure:
25 g of H-Ala-OMe, HCl and 66 g. of Boc-Ser-ONb are dissolved in 500 ml DMF. The product is cooled in an ice bath and 25 ml of NEM, 24 g of N-hydroxy benzotriazole are added wtih magnetic stirring and the pH is maintained at 6.5 or 7 by addition of NEM. The product is stirred for 18 hrs. at ambient temperature. After TLC monitoring, the medium is evaporated to 90% (13.33 Pa 35° C.). The oil obtained is dissolved in 1.500 ml of chloroform, the product is washed with a solution of saturated sodium chloride (twice), 5% potassium sulfate/bisulfate solution (3 times), saturated sodium bicarbonate (5 times). The solution is dried over Na2 `SO4 and evaporated to dryness. An oil is obtained which is dried to constant weight (30° C.13.33 Pa)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:13]([F:18])[F:17])=[CH:6][CH:5]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(F)F)cc1
Temperature: 125 °C
Yield: 45.9 %

Procedure:
Under N2 flow, 1.3 g of 4-hydroxy-benzoic acid methyl ester (8.3 mmol, 1.0 eq) and 1.5 g of sodium chlorodifluoroacetate (10.0 mmol, 1.2 eq) were dissolved in DMF (25 mL) in a two neck round bottom flask; potassium carbonate (1.4 g, 10.0 mmol, 1.2 eq) was added and the mixture was heated at 125° C. for 3.5 hours. The mixture was then diluted with water and extracted with DCM; organic phases were dried and evaporated, the crude was purified with Si column (eluent: cycloexane/EtOAc 80/20) to obtain 0.77 g of product (yield 46%) which was used directly for the next step.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1csc(N)n1
Agent: Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1csc(NC(C)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To an ice-cold mixture of ethyl 2-amino-1,3-thiazole-4-carboxylate hydrobromide (80 g), pyridine (52.5 g) and dichloromethane (800 ml) was added acetyl chloride (27.3 g) dropwise at 0° C., and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with water (500 ml), dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed with ethyl acetate to give ethyl 2-(acetylamino)-1,3-thiazole-4-carboxylate (60 g).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11](=[O:16])[NH:12][CH:13]([CH3:15])[CH3:14])=[O:8].[CH3:21][N:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:13]([NH:12][C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:17]=[C:2]([N:25]2[CH2:26][CH2:27][CH2:28][N:22]([CH3:21])[CH2:23][CH2:24]2)[CH:3]=[CH:4][C:5]=1[N+:18]([O-:20])=[O:19])=[O:16])([CH3:15])[CH3:14]
Reactant: CN1CCCNCC1
Reactant: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NC(=O)CNC(=O)c1cc(N2CCCN(C)CC2)ccc1[N+](=O)[O-]
Yield: 100 %

Procedure:
A mixture of 5-fluoro-N-(isopropylcarbamoylmethyl)-2-nitrobenzamide (INTERMEDIATE IV.1) (400 mg, 1.4 mmol), 1-methylhomopiperazine (0.20 mL, 1.6 mmol) and potassium carbonate (1 g) in acetonitrile (20 mL) were heated at reflux temperature under an Argon atmosphere for 16 h. The mixture was cooled, filtered, the residue washed with DCM (2×1 mL) and the volatiles evaporated under reduced pressure. The red coloured residue was dissolved in DCM (15 mL), washed with 1 N NaOH (aq.) (2×5 mL) and brine (1×5 mL), dried (Na2SO4) and concentrated under reduced pressure to afford N-(isopropylcarbamoylmethyl)-5-(4-methylperhydro-1,4-diazepin-1-yl)-2-nitrobenzamide (510 mg, 1.4 mmol, 100%) as an orange-red solid. This was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([OH:20])[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17]CC)=[O:16])[CH2:10]1.[OH-].[Na+].O>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([OH:20])[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1
Reactant: CCOC(=O)[C@H]1CCCN(CC(O)(c2ccccc2)c2ccccn2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@H]1CCCN(CC(O)(c2ccccc2)c2ccccn2)C1

Procedure:
Ethyl 1-[2-(2-pyridyl)-2-phenyl-2-hydroxyethyl]piperidine-3(S)-carboxylate (0.187 g, 0.527 mmol) was dissolved in EtOH (5 mL), 1N NaOH (0.791 mL, 0.791 mmol) and H2O (5 mL) added, and the reaction mixture heated at reflux for 3 hr. Neutralization with 1N HCl (to a pH of 6) and concentration to dryness gave the title compound which was used without further purification.