Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][O:5][C:6]=1[CH:7]=C.I([O-])(=O)(=O)=[O:15].[Na+]>C1COCC1.O.[Os]>[CH:7]([C:6]1[O:5][N:4]=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]=1[CH3:1])=[O:15]
Reactant: C=Cc1onc(C(=O)OCC)c1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Os]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1noc(C=O)c1C
Temperature: 25 °C

Procedure:
To ethyl 4-methyl-5-vinylisoxazole-3-carboxylate (3 g, 16.56 mmol) in THF (40 mL) and water (20 mL) at room temperature, was added sodium periodate (10.62 g, 49.7 mmol) and Osmium ENCAT 40 (828 mg, 0.248 mmol). The reaction mixture was stirred at room temperature over the weekend. The resulting mixture was filtered over Celite® (5 g), washing with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude material was suspended in DCM, sonicated and passed through a phase separating cartridge. The eluent was collected and the solvent removed under reduced pressure to afford the title compound;
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: Nc1cccc2c(Nc3ccc(C(F)(F)F)nc3)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4ccc(C(F)(F)F)nc4)ncnc23)c1F
Yield: 8.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(6-(trifluoromethyl)pyridin-3-yl)quinazoline-4,8-diamine (Intermediate-24, 150 mg, 0.49 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 170 mg, 0.59 mmol), oxalyl chloride (112 mg, 0.89 mmol), DMF (1 drop) and DIPEA (190 mg, 1.47 mmol) in CH2Cl2 (5 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.68 (s, 1H), 10.36 (s, 1H), 9.23 (s, 1H), 8.83-8.80 (d, J=7.8 Hz, 1H), 8.75 (s, 1H), 8.69-8.65 (d, J=9.6 Hz, 1H), 8.37-8.34 (d, J=8.7 Hz, 1H), 8.16 (br t, 1H), 7.97-7.94 (d, J=8.7 Hz, 1H), 7.79 (t, 1H), 7.41-7.33 (m, 2H), 4.31-4.29 (d, J=5.4 Hz, 2H), 1.13 (s, 9H); MS (m/z): 575.18 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]([OH:17])=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:18][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO>[C:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]([O:17][CH3:18])=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cnccc1NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a stirring suspension of 4-(Boc-amino)pyridine-3-carboxylic acid (1.04 g, 4.37 mmol) in methanol (3.5 mL) was added a 2 M solution of (trimethylsilyl)diazomethane in hexanes (3.5 mL, 7 mmol). After 15 min, acetic acid was added and the solvents were removed in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of 20% ethyl acetate in hexanes through 70% ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to give the title compound (0.894 g, 81%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21]>C(O)(=O)C.O.C1(C=CC(=O)C=CC2C=CC=CC=2)C=CC=CC=1.C1(C=CC(=O)C=CC2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[CH:21]=[CH:20][C:19]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Nc1ccc(F)cc1F
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=N[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C=Cc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
51.6 g (0.40 mol) or 2,4-difluoroaniline are dissolved in 240 ml of glacial acetic acid. 45 ml (0.80 mol) of concentrated sulfuric acid are added slowly with cooling. The white suspension is diazotized at 12°-15° C. using a solution of 28.0 g (0.406 mol) of sodium nitrite in 70 ml of water. 1.2 g (0.0044 mol) of palladium bis(1,5-diphenyl-1,4-pentadien-3-one) (lit.: M. F. Rettig et al., Inorg. Synth. 17 (1977), 134) are added to the resultant yellow solution at 45° C. 40.5 g (0.405 mol) of ethyl acrylate are then added dropwise. The reaction is slightly exothermic, and the temperature slowly rises to about 60° C. The reaction mixture is stirred overnight with falling temperature and then poured into about 600 ml of ice-water. The waxy precipitate is extracted with 500 ml of diethyl ether. The ether phase is separated off, washed several times with ice-water and then dried using sodium sulfate. The ether is removed by distillation on a vacuum rotary evaporator. 51.2 g (60% of theory) of a waxy crystalline product which, after recrystallization from petroleum ether, melts at 40°-40.5° C. are obtained.
Reaction SMILES: [C:1]([N:4]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[C:6]2([CH2:9]S[CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2].CO.CC(C)=O.O[O:24][S:25]([O-:27])=O.[K+]>O>[C:1]([N:4]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[C:6]2([CH2:9][S:25](=[O:27])(=[O:24])[CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CC(=O)N1CC2(CSC2)c2ccc(Br)cc21
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: CC(=O)N1CC2(CS(=O)(=O)C2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred ice-cooled solution of 1-acetyl-6-bromo-1,2-dihydrospiro[indole-3,3′-thietane] (0.288 g, 0.97 mmol) in a mixture water (2.4 mL), MeOH (18.9 mL), and acetone (4.7 mL) was added a solution of oxone (1.19 g, 1.93 mmol) in water (1.8 mL). The ice bath was removed and the solution was stirred at rt for 4 h. The mixture was poured into saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo to give 1-acetyl-6-bromo-1,2-dihydrospiro[indole-3,3′thietane]1′,1′-dioxide as a tan solid. Mass Spectrum (ESI) m/e=330.0 [(M+1) (79Br)] and 332.0 [(M+1) (81Br)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][O:12]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[CH:11]=[O:12]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(Cl)c(C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Cl)c(C)c1C=O
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
4-Chloro-3-methylanisole (15.4 g., 0.10 mole) was taken into 200 ml. of methylene chloride and cooled to 0° C. Titanium tetrachloride (37.9 g., 0.2 mole) and then 1,1-dichloromethyl methyl ether (13.8 g., 0.12 mole) were added, each over a 2 minute period. The reaction mixture was stirred at room temperature for 1 hour, poured over 500 ml. of ice and water and the organic layer separated. The aqueous layer was extracted with two portions of fresh methylene chloride and these extracts combined with the original organic layer. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated dryness (15.2 g., 82%), containing two thirds 5-chloro-2-methoxy-4-methylbenzaldehyde [Rf 0.35 (1:1 chloroform:hexane] and one third of the desired isomeric product [Rf 0.28 (1:1 chloroform:hexane]. These two compounds were separated by chromatography on 1 kg. of silica gel, eluting with 1:1 methylene chloride:hexane, collecting 15 ml. fractions and monitoring by tlc. Fractions 115-140 were combined and evaporated to dryness to yield the undesired Rf 0.35 isomer (860 mg., m.p. 86°-88° C.). Fractions 240-310 were combined to yield the desired 3-chloro-6-methoxy-2-methylbenzaldehyde [1.61 g.; m.p. 95°-97° C., pnmr/CDCl3 /delta 2.4 (s, 3H), 3.9 (s, 3H), 6.8 (s, 1H), 7.7 (s, 1H), 10.4 (s, 1H); Rf 0.28 (1:1 methylene chloride:hexane)].
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14]([C:15](O)=[O:16])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:40]1[C:44]2[CH:45]=[CH:46][C:47]([NH2:49])=[CH:48][C:43]=2[N:42]=[N:41]1.CN1CCOCC1>C(#N)C>[NH:40]1[C:44]2[CH:45]=[CH:46][C:47]([NH:49][C:15]([C@@H:14]3[CH2:13][CH2:12][N:11]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[N:10]3[C:8](=[O:9])[C@@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:16])=[CH:48][C:43]=2[N:42]=[N:41]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Nc1ccc2[nH]nnc2c1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccc3[nH]nnc3c2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 72 h
Yield: 69.3 %

Procedure:
To a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (103.1 mg, 0.192 mmol), 1H-1,2,3-benzotriazol-5-amine (56.6 mg, 0.422 mmol), and N-methylmorpholine (46.4 μl, 0.422 mmol) in acetonitrile (1.87 ml) was added DMTMM tetrafluoroborate (69.2 mg, 0.211 mmol). The solution was stirred for 3 days, and then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), and washed with 1 N aq. HCl (50 mL), followed by 5% aq. NaHCO3. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Gilson RPLC (20% to 90% MeCN in water, 8 min gradient), and the desired fractions were combined, and concentrated in vacuo. The residue was azeotroped with MeOH (2×30 mL) to give phenylmethyl (3S)-3-[(1H-1,2,3-benzotriazol-5-ylamino)carbonyl]-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-pyrazolidinecarboxylate (87.2 mg, 0.133 mmol, 69.6% yield) as a light yellow oil. LC/MS: (M+H)+: 654.5. Reference for DMTMM tetrafluoroborate: Raw, S. A. Tetrahedron Lett. 2009, 50, 946.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:26]4[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: OCCN1CCNCC1
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(CCO)CC3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 56.1 %

Procedure:
A suspension of 2.81 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 5.2 g of N-(2-hydroxyethyl)-piperazine in 25 ml of dimethylsulphoxide is heated at 135°-140° C. for 2 hours. The solvent is distilled off under a fine vacuum, the residue is boiled up with 20 ml of water, the mixture is left to stand overnight at room temperature and the precipitate is filtered off with suction, while cooling with ice, washed with water and dried over calcium chloride in vacuo at 80° C. 2.1 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(2-hydroxyethyl)-1-piperazinyl]-3-quinolinecarboxylic acid of decomposition point 237°-239° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([OH:14])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[H-].[Na+].[Cl:23][Ti:24](Cl)([Cl:35])[C:25]1([CH3:34])[C:29]([CH3:30])=[C:28]([CH3:31])[C:27]([CH3:32])=[C:26]1[CH3:33]>C1(C)C=CC=CC=1>[Cl:23][Ti:24]([Cl:35])([C:25]1([CH3:34])[C:26]([CH3:33])=[C:27]([CH3:32])[C:28]([CH3:31])=[C:29]1[CH3:30])[O:14][C:5]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: CC1=C(C)C(C)([Ti](Cl)(Cl)Cl)C(C)=C1C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Ti](Cl)(Cl)Oc2c(-c3ccccc3)cc(C)cc2-c2ccccc2)C(C)=C1C
Reaction time: 24 h
Yield: 46.2 %

Procedure:
4-methyl-2,6-diphenylphenol (400 mg, 1.53 mmol) and sodium hydride (110 mg, 4.60 mmol) were dissolved in 10 mL of toluene, and then refluxed for 4 hours. Subsequently, cooling to normal temperature was conducted, a solution in which (trichloro)(pentamethylcyclopentadienyl)titanium(IV) (376 mg, 1.30 mmol) was dissolved in 5 mL of toluene was slowly dropped thereonto, and reflux was conducted for 24 hours. After the reaction finished, volatile materials were removed, washing was conducted using purified hexane, recrystallization was conducted using a mixed solution of toluene/hexane at −35° C., filtration was conducted, and drying was conducted at reduced pressure to produce 308 mg of red solid component.
Reaction SMILES: [Na+:1].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:18]([S:22]([O-:25])(=[O:24])=[O:23])=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]=1[S:26]([O-:29])(=[O:28])=[O:27])=[O:10])([O-])=O.[H][H]>[Pd].O>[Na+:1].[Na+:1].[NH2:3][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:18]([S:22]([O-:25])(=[O:24])=[O:23])=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]=1[S:26]([O-:29])(=[O:28])=[O:27])=[O:10]
Reactant: [H][H]
Reactant: O=C(Nc1ccc2c(S(=O)(=O)[O-])cccc2c1S(=O)(=O)[O-])c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: Nc1cccc(C(=O)Nc2ccc3c(S(=O)(=O)[O-])cccc3c2S(=O)(=O)[O-])c1

Procedure:
A mixture of 25.0 g of 2-(m-(nitrobenzamido)-1,5-naphthalenedisulfonic acid disodium salt (prepared as in Example 1), 250 ml of water and 2.0 g of 10% palladium on charcoal is hydrogenated in a Parr shaker for 31/2 hours at room temperature with an initial pressure of 42 pounds of hydrogen. During this time a total of 11.5 pounds of hydrogen is absorbed.
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:35]=[CH:34][C:11]([C:12]([NH:14][C:15]3[CH:20]=[C:19]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[CH:18]=[CH:17][C:16]=3[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:13])=[CH:10][CH:9]=2)[CH2:3]1.[N+:36]([C:39]1[CH:44]=[CH:43][C:42]([S:45]([NH:48][C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)(=[O:47])=[O:46])=[CH:41][CH:40]=1)([O-:38])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N+:36]([C:39]1[CH:44]=[CH:43][C:42]([S:45]([N:48]([C@H:2]2[CH2:6][CH2:5][N:4]([CH2:7][C:8]3[CH:35]=[CH:34][C:11]([C:12]([NH:14][C:15]4[CH:20]=[C:19]([C:21]5[S:22][CH:23]=[CH:24][CH:25]=5)[CH:18]=[CH:17][C:16]=4[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:13])=[CH:10][CH:9]=3)[CH2:3]2)[C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)(=[O:46])=[O:47])=[CH:41][CH:40]=1)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cccnc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CN2CC[C@@H](O)C2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CN2CC[C@H](N(c3cccnc3)S(=O)(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
To a solution of 243 (0.98 g, 1.81 mmol) in THF (10 mL) at 0° C., was added compound 246 (0.61 g, 2.17 mmol), triphenylphosphine (0.76 g, 2.89 mmol) and diethyl azodicarboxylate (DEAD) (0.51 g, 2.90 mmol), the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was partitioned between EtOAc and H2O, organic phase was collected, washed successively with saturated NH4Cl and brine, dried over MgSO4, filtered and concentrated to give a light brown oil which was purified by flash chromatography (eluent: 50% AcOEt in hexanes to 100% AcOEt) to give intermediate 247 (0.65 g, 47% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=O)[CH2:13][NH2:14])=[CH:6][CH:5]=1.[S-:16][C:17]#[N:18].[K+]>C(O)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[NH:18][C:17]([SH:16])=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: N#C[S-]
Reactant: COc1ccc(CCC(=O)CN)cc1
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CCc2cnc(S)[nH]2)cc1
Yield: 19.2 %

Procedure:
A solution of 4-(4-methoxyphenyl)-2-oxo-1-aminobutane, hydrochloride (8.6 g, 37.7 mmole) and potassium thiocyanate (3.6 g, 37.7 mmole) in acetic acid (100 ml) was heated under reflux for 20 minutes. The reaction was cooled, diluted with water and the product was filtered and recrystallized from ethyl alcohol and dried to give the product as a solid (1.7 g, 19%).
Reaction SMILES: [NH:1]([CH3:22])[C@H:2]([C:6]([N:8](C)[C@H:9]([C:18]([NH2:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:23]([C:35]([O:37][CH2:38][CH:39]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[C@H:24]([C:32](O)=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1>[NH:23]([C:35]([O:37][CH2:38][CH:39]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[C@H:24]([C:32]([N:1]([CH3:22])[C@H:2]([C:6]([NH:8][C@H:9]([C:18]([NH2:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:4])[CH3:5])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)cc1)C(N)=O)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of N-Me-Val-N-Me-Tyr-NH2 (185 mg, 0.603 mmol) in THF (6 ml), Fmoc-Phe-OH (304 mg, 0.784 mmol), CMPI (200 mg, 0.784 mmol) and TEA (0.168 ml, 1.21 mmol) were added under cooling with ice, followed by stirring at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:1) to give the titled compound (197 mg, 48%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([O:30][CH:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1.O.C(=O)(O)[O-].[Na+]>[Si:1]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([O:30][CH:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]2)[CH:21]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(F)(F)F)n2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](OCc1cc(OC2CCNCC2)nc(C(F)(F)F)c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-{[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.19 g, 0.23 mmol, from Step B) in 1,4-dioxane (2.0 mL) was added 4.0M hydrogen chloride in dioxane (0.50 mL, 2.0 mmol). The reaction mixture was stirred for one hour. Additional 4.0M hydrogen chloride in dioxane (0.50 mL, 2.0 mmol) was added and stirring was continued for two hours. The mixture was diluted with water, saturated sodium bicarbonate was used to adjust the pH to between 7 and 8, and then the product was extracted with two portions of DCM. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-15% MeOH in DCM afforded product as an oil (62 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 7.69-7.62 (m, 4H), 7.48-7.34 (m, 6H), 7.14-7.11 (m, 1H), 6.91 (s, 1H), 5.17 (tt, J=8.7, 4.0 Hz, 1H), 4.71 (s, 2H), 3.13 (dt, J=12.7, 4.5 Hz, 2H), 2.78 (ddd, J=12.7, 9.7, 3.0 Hz, 2H), 2.07 (dq, J=12.2, 4.1 Hz, 2H), 1.67 (dtd, J=13.0, 9.4, 3.9 Hz, 2H), 1.11 (s, 9H); LCMS (M+H)+: 515.2.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O.S(=O)(=O)(O)O.O.C1(N)C=CC=CC=1.C1(N)C=CC=CC=1>C(O)(=O)C>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[NH2:11]
Reactant: Nc1ccccc1CO
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: Nc1ccccc1
Product: Nc1ccccc1CSc1nc2ccccc2[nH]1

Procedure:
A mixture of 9.0 g (60 mMol) of 2-mercaptobenzimidazole and 4.9 g (40 mMol) of 2-aminobenzyl alcohol were heated at 84° C. in a mixture of 45 ml of glacial acetic acid and 12.0 g (120 mMol) of sulfuric acid. After two hours an additional 1 g (8 mMol) of 2-aminobenzyl alcohol and 1 g of sulfuric acid were added. After one hour the reaction mixture was cooled and poured into cold benzenamine hemihydrate.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:44])([F:43])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]>>[F:19][C:20]([F:43])([F:44])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41][N:16]2[CH2:17][CH2:18][N:13]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:12]=3)[CH2:14][CH2:15]2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]
Reactant: c1ccc(-c2cccc(N3CCNCC3)n2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(-c4ccccc4)n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(6-phenyl-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1>O1CCOCC1.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:26]4[CH:27]=[CH:28][N:29]=[CH:30][C:25]4=[O:24])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cnccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Agent: I[Cu]I
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-n4ccncc4=O)ncc3O2)CC1
Temperature: 180 °C

Procedure:
A mixture of 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (60 mg), 2-hydroxypyrazine (17 mg), and copper iodide (7 mg) in 1,4-dioxan (1 mL) is sparged with argon. N,N′-Dimethylethylendiamine (8.54) and tri-potassium orthophosphate (72 mg) are added and the resulting mixture is heated in a microwave oven to 180° C. for 1 h. The reaction mixture is filtered and chromatographed on silica gel (ethyl acetate) to give the title compound. LC (method 7): tR=1.32 min; Mass spectrum (ESI+): m/z=399 [M+H]+.