Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6][NH2:7].[F:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH:7][CH2:6][CH2:5][C:4]#[C:3][Si:2]([CH3:9])([CH3:8])[CH3:1])=[O:19]
Reactant: O=C(O)c1cccc(Cc2cccc(F)c2)c1
Reactant: C[Si](C)(C)C#CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#CCCNC(=O)c1cccc(Cc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.3 %

Procedure:
A mixture of 4-(trimethylsilyl)but-3-yn-1-amine (0.184; 1.30 mmol), 3-(3-fluorobenzyl)benzoic acid, (0.200 g; 0.869 mmol), HATU (0.363 g; 0.955 mmol) and N,N-diisopropylethylamine (0.374 mL; 2.17 mmol) in DMF (20 mL) was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was washed with water, dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) to afford 0.13 g (42%) of 3-(3-fluorobenzyl)-N-(4-(trimethylsilyl)but-3-ynyl)benzamide which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C([BH3-])#N.[Na+]>>[O:22]=[C:11]1[N:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:3][CH2:4]2)[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Yield: 16.4 %

Procedure:
4-[2-(4-aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 58) (0.8 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (140 mg, 0.79 mmol) and sodium cyanoborohydride (83 mg, 1.32 mmol) were reacted as described under Example 21 to give 60 mg (19%) product as a solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[N:11]=[C:10]3[CH:13]=[C:14]([N:18]4[CH2:23][CH2:22][NH:21][CH:20]([CH3:24])[CH2:19]4)[C:15]([F:17])=[CH:16][C:9]3=[CH:8][C:7]=2[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2].[CH2:29]=O>C(O)=O>[CH3:24][CH:20]1[N:21]([CH3:29])[CH2:22][CH2:23][N:18]([C:14]2[C:15]([F:17])=[CH:16][C:9]3[C:10]([CH:13]=2)=[N:11][C:12]2[N:3]([CH2:1][CH3:2])[CH:4]=[C:5]([C:26]([OH:28])=[O:27])[C:6](=[O:25])[C:7]=2[CH:8]=3)[CH2:19]1
Reactant: C=O
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(C)C4)cc3nc21
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(C)C(C)C4)cc3nc21

Procedure:
8-(3,4-Dimethyl-1-piperazinyl)-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 21 but starting from 2.3 g of 1-ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid, 2.26 cm3 of 98% formic acid and 5.6 cm3 of a 30% aqueous solution of formaldehyde. 1.75 g of 8-(3,4-dimethyl-1-piperazinyl)-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 293°-294° C.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][C:3](Cl)=[O:4].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[NH:17][C:18]([NH2:20])=[O:19]>O1CCOCC1>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[N:17]1[C:3](=[O:4])[CH:2]=[C:1]([OH:6])[NH:20][C:18]1=[O:19]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: NC(=O)Nc1c(Cl)cc(Cl)cc1Cl
Solvent: C1COCCO1
Product: O=c1cc(O)[nH]c(=O)n1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 0 °C
Yield: 76.3 %

Procedure:
1.7 g of malonic acid dichloride was added dropwise to a 50 ml 1,4-dioxane solution of 2.4 g of 2,4,6-trichlorophenylurea with stirring at 0° C. The solution was stirred at room temperature for 3 hours and then the solvent was distilled away under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (developing solvent: chloroform) to obtain 2.35 g of 3-(2,4,6-trichlorophenyl)-6-hydroxy-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:22][C@@H:23]([C@@H:25]2[CH2:29][O:28]C(C)(C)[O:26]2)[CH3:24])[N:7]=1.C(O)(C(F)(F)F)=O>CO>[F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:22][C@H:23]([CH3:24])[C@@H:25]([OH:26])[CH2:29][OH:28])[N:7]=1
Reactant: C[C@@H](Oc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N-(2-[(2,3-difluorobenzyl)thio]-6-{(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}pyrimidin-4-yl)morpholine-4-sulfonamide (0.20 g) in MeOH (2 ml) was added TFA (0.4 ml) and the reaction was stirred at room temperature for 20 h. The mixture was evaporated, suspended in saturated sodium carbonate solution and then re-acidified to pH5 with glacial acetic acid with stirring. The resulting solid was collected, washed with H2O and dried to give the title compound as a white solid. Yield 0.15 g.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:52]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16][Br:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCC(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCC(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Reaction time: 1 h
Yield: 69.5 %

Procedure:
First, 13.8 g of 2,2-bis(6-benzyloxyhexyl)ethanol, 10.2 g of triphenylphosphine, and 50 ml of methylene chloride were placed in a 200 ml flask. Then, 50 ml of a methylene chloride solution containing 16.1 g of carbon tetrabromide was added dropwise to the reaction mixture at room temperature, and the reaction mixture was stirred for 1 hour. The reaction mixture was washed with an aqueous solution of sodium bicarbonate and water in this order. The resultant reaction mixture was dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 11 g of 2,2-bis(6-benzyloxyhexyl)ethyl bromide (Y: 69%). The compound thus obtained had a purity of 97.5% by GC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16]S(C)(=O)=O)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:21])([F:31])[F:32])[CH:25]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1cccc(OC(F)(F)F)c1
Product: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(OC(F)(F)F)c2)C1
Yield: 101.5 %

Procedure:
The title compound (D107) (112 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 5-chloro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D63) (100 mg, 0.311 mmol) and 3-(trifluoromethoxy)phenol (0.036 ml, 0.284 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[C:29](B(O)O)=[C:28]([CH3:33])[O:27][N:26]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1.O>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[C:25]([CH3:24])=[N:26][O:27][C:28]=3[CH3:33])=[CH:3][CH:4]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Oc1ccc(C(=C2CCCCCCC2)c2ccc(Br)cc2)cc1
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1-c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1
Yield: 76.7 %

Procedure:
The procedure described for 202 was used. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol (9) (0.150 g, 0.404 mmol), PdCl2(PPh3)2, (0.028 g, 0.40 mmol), (3,5-dimethyl-4-isoxazolyl)boronic acid (0.113 g, 0.80 mmol), Na2CO3 (0.086 g, 0.808 mmol), and THF/H2O (4:1, 5 mL). The reaction mixture was refluxed for 10 h. Standard workup and purification by flash silica gel chromatography provided 0.120 g (77%) of the title compound 205 as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 9.27 (s, 1H), 7.30 (d, J=6.00 Hz, 2H), 7.21 (d, J=6.30 Hz, 2H), 6.96 (d, J=6.0 Hz, 2H), 6.69 (d, J=6.0 Hz, 2H), 2.37 (br s, 3H), 2.19 (s, 7H), 2.60 (br s, 2H), 1.50 (br s, 8H). LCMS (ESI): m/z 386 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])=[CH-:3].[K+].[CH3:9][Si:10](Cl)([CH3:12])[CH3:11]>C1COCC1>[CH3:9][Si:10]([CH3:12])([CH3:11])[CH2:3][C:2]([CH3:1])=[CH:4][C:5]([CH3:7])=[CH2:6]
Reactant: [CH-]=C(C)C=C(C)C
Reactant: C[Si](C)(C)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C=C(C)C[Si](C)(C)C
Reaction time: 8 h

Procedure:
A solution of 15.1 g (112 mmol) of potassium 2,4-dimethylpentadienide in 250 mL of THF was added to a -35° C. solution of 36.0 g (33.1 mmol) of trimethylsilyl chloride in 200 mL of THF. The yellow-orange color of the pentadienyl anion faded instantly upon addition. The reaction mixture was stirred overnight. The solvent was removed under reduced pressure, the residue was extracted with pentane, the resulting solution was filtered from insolubles and concentrated under reduced pressure to give the product as a pale yellow liquid. The yield was 11.65g, 61.5%. 1H NMR(C6D6) δ 5.63 (s, 1H), 4.95 (s, 1H), 4.92 (s, 1H), 1.83 (s, 3H), 1.81 (s, 2H), 1.68 (s, 3H), 0.03 (s, 9H). 13C NMR (C6D6) δ 142.5, 136.0 125.2, 113.1, 27.8, 24.5, -0.2.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)CCl>C1COCC1>[C:7]([C:3]1[N:2]([NH:1][C:19](=[O:20])[CH2:18][NH:17][C:15](=[O:16])[O:14][C:10]([CH3:11])([CH3:12])[CH3:13])[CH:6]=[CH:5][CH:4]=1)(=[O:8])[NH2:9]
Reactant: NC(=O)c1cccn1N
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nn1cccc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.3 %

Procedure:
1-Amino-1H-pyrrole-2-carboxamide (5.00 g, 40.0 mmol) and 2-(tert-butoxycarbonylamino)acetic acid (7.70 g, 44.0 mmol) were combined and dissolved in THF (250 mL). To this solution was added EDC (8.43 g, 44.0 mmol). The reaction was stirred at room temperature for 16 h, after which the reaction was concentrated in vacuo. The residue was partitioned between EtOAc (250 mL) and water (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (150 mL). The combined organics were dried (MgSO4) and filtered. The filtrate was treated with activated charcoal and filtered over Celite. The filtrate was concentrated in vacuo to remove most of the solvent, then diluted with hexanes to ˜1 L. A solid was filtered off and dried to give 21A (8.73 g). The aqueous layer was extracted again with EtOAc (2×100 mL). A second crop was obtained similarly to above to give 465 mg, for a total yield of 9.20 g (82%). 21A had an analytical HPLC retention time=1.75 min (Phenomonex-Luna (4.6×50 mm S10); 10-90% MeOH/H2O (0.1% TFA) over 4 min; flow=4 mL/min) and a LC/MS M+-Boc+1=183.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][NH:8][C:9](=[O:15])[C@H:10]([CH:12]([CH3:14])[CH3:13])[NH2:11].O>CCCCC>[CH3:7][NH:8][C:9](=[O:15])[C@H:10]([CH:12]([CH3:14])[CH3:13])[N:11]=[CH:1][C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CNC(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)C=O
Solvent: O
Solvent: CCCCC
Product: CNC(=O)[C@@H](N=CC(C)(C)C)C(C)C

Procedure:
There were added 95.7 ml (870 mmols) of pivalaldehyde to 112.0 grams (864 mmoles) of (S)-valine monomethylamide dissolved in 300 ml of n-pentane. The reaction mixture was boiled at a water separator until the formation of water was ended (4 hours). The solvent was removed under reduced pressure and there remained behind 130 grams (76% of theory) of (S)-N-(2',2'-dimethyl-propylidene)-valine monomethylamide, which could be further worked without purification. To ascertain the exact material data, a test of sample was purified by distillation.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 41 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide hydrochloride and n-octyl chloroformate. Yield: 41% of theory, C36H44N6O5 (640.8); Rf value: 0.43 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=641; (M+Na)+=663.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C=O)C>[F:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[C:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1)=[O:29]
Reactant: OB(O)c1c(F)cccc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cccc3F)ccc2c1
Temperature: 100 °C

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.0 g, 3.7 mmol), 2,6-difluorophenyl boronic acid (1.17 g, 7.4 mmol), tetrakis(triphenylphosphine)palladium (0) (855 mg, 0.74 mmol) and potassium phosphate (4.7 g, 22.2 mmol) add 100 mL of dry DMF and heat under nitrogen at 100° C. for two hours. Cool the reaction and filter. Purify on an SCX column eluting with 2N ammonia/methanol. Purify further on a silica gel column eluting with a gradient of 0-10% methanol/methylene chloride. The yield is 1.5 g (81%). 1H-NMR (CDCl3, 400 MHz) δ7.90 (d, J=8.4 Hz, 1H); 7.63 (d, J=8.4 Hz, 1H); 7.62 (d, J=9.2 Hz, 2H); 7.39 (d, J=8.4 Hz, 1H); 7.23 (d, J=2.8 Hz, 1H); 7.18-7.08 (m, 2H); 6.78 (d, J=10.4 Hz, 2H); 6.74 (s, 2H); 4.11-4.08 (m, 2H); 3.95 (s, 3H); 2.75 (t, J=6.4 Hz, 2H); 2.49-2.49 (m, 4H); 1.63-1.58 (m, 4H); 1.47-1.44 (m, 2H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]([CH3:37])([O:29][Si](CC)(CC)CC)[CH3:28])[CH3:22])[CH2:12][C@@H:11]([O:45][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]([OH:29])([CH3:28])[CH3:37])[CH3:22])[CH2:12][C@@H:11]([OH:45])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C/CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](OC/C=C/C(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 34.3 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(E)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)}pregna-5,7,16-triene (83.0 mg, 0.108 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to give the title compound as a pale yellow oil (15.9 mg, 34%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>CC(C)=O.O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:21][C:22](=[O:24])[CH3:23])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(S)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc(SCC(C)=O)cc1
Temperature: 25 °C

Procedure:
To a solution of (4-mercaptophenyl)-acetic acid ethyl ester (10 g, 0.051 mol) in 150 mL of acetone is added potassium carbonate (anhydrous, 8.51 g, 0.061 mol) at 0° C., followed by dropwise addition of chloroacetone (5 mL, 0.061 mol) in 10 mL of acetone at 0° C. The reaction is then maintained at RT for 2 h. The reaction is filtered and the filtrate is concentrated under vacuum. The residue thus obtained is diluted with 15 mL of water and extracted with ethyl acetate (2×50 mL). The organic layer is then washed with water and brine, dried over sodium sulfate, filtered and evaporated under vacuum to give [4-(2-oxo-propylsulfanyl)-phenyl]-acetic acid ethyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:32])[C@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34]>O1CCOCC1.O>[ClH:34].[CH2:1]([O:8][C:9](=[O:33])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:32])[C@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
N-t-butyloxycarbonyl-L-phenylalanyl-L-proline benzylester (29.87 g, 66 mmole) was dissolved in 4.5N hydrochloric acid in dioxane solution (220 ml), and stirred for 1.5 hours at room temperature. The solvent was distilled off under reduced pressure, and gelatinous solid material thus obtained was dissolved in water (250 ml). The solution was washed with diethyl ether and the water layer was freeze-dried to obtain L-phenylalanyl-L-proline benzylester hydrochloride(yield: 26.53 g, 100%).
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[S:12])[NH:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:16][CH2:17][CH2:18]Br.Cl.[OH-].[Na+]>C(O)C.CN(C=O)C>[S:12]1[C:10]2[N:11]([C:7]3[C:8]([N:9]=2)=[CH:13][CH:14]=[C:5]([CH2:3][OH:4])[CH:6]=3)[CH2:18][CH2:17][CH2:16]1
Reactant: BrCCCBr
Reactant: COC(=O)c1ccc2[nH]c(=S)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: OCc1ccc2nc3n(c2c1)CCCS3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
To a round bottomed flask was added 4.06 grams of 2-Thioxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester, 4.04 grams of 1,3-dibromopropane and 50 ml DMF and 50 ml ethanol. The mixture was refluxed for 10 hours. Then it was concentrated to dry on a rotary evaporator. The solid was next dissolved in 100 ml THF and 20 ml of 1M LiAlH4 (in THF) was next injected within five minutes. The reaction media was stirred at room temperature for one hour. Ethanol was next added (˜10 ml), followed by 50 ml 2N HCl. The aqueous layer was adjusted to basic Ph=14 with 10N sodium hydroxide. The aqueous was extracted with 2×500 ml ethyl acetate. The combined organic layers was dried over magnesium sulfate. Filter off the drying agent and concentrate yielded 3 grams (68%) product. NMR (DMSO): δ 7.91 (m, 3H), 4.13 (m, 2H), 3.93 (s, 1H), 3.23 (m, 2H, CH2), 2.48 (m, 2H, CH2). MS: 221.0 (M+H).
Reaction SMILES: P(Cl)(Cl)[Cl:2].[N:5]([CH:8]1[C:14](=[O:15])[N:13]2[CH:9]1[CH2:10][C:11](=O)[CH:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[N+:6]=[N-:7]>CN(C)C=O.C1(C)C=CC=CC=1>[N:5]([CH:8]1[C:14](=[O:15])[N:13]2[CH:9]1[CH2:10][C:11]([Cl:2])=[C:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[N+:6]=[N-:7]
Reactant: ClP(Cl)Cl
Reactant: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Reaction time: 5 h

Procedure:
Phosphorus trichloride (1 mmol) is added to a solution of benzyl 6-azido-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (0.5 mmol) in anhydrous dimethylformamide (2.5 ml) and the mixture is left to stand at room temperature. After 5 hr, the mixture is diluted with toluene, washed with water, 1 N hydrochloric acid, 5% sodium bicarbonate solution, and brine, dried over magnesium sulfate, and filtered. Evaporation of the solvent under vacuum yields benzyl 6-azido-3-chloro-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate.