Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[CH:2]([O:5][C:6]1[N:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[N:7]=1)([CH3:4])[CH3:3].[CH3:17][O:18][CH:19]=[C:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Br)[C:21]([O:23][CH3:24])=[O:22].C(OCC)(=O)C>CCCCCCCC>[CH3:17][O:18][CH:19]=[C:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][O:12][C:10]1[CH:9]=[C:8]([C:13]([F:15])([F:16])[F:14])[N:7]=[C:6]([O:5][CH:2]([CH3:4])[CH3:3])[N:11]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: CC(C)Oc1nc(O)cc(C(F)(F)F)n1
Agent: [K]
Solvent: CCCCCCCC
Solvent: CCOC(C)=O
Product: COC=C(C(=O)OC)c1ccccc1COc1cc(C(F)(F)F)nc(OC(C)C)n1
Temperature: 25 °C

Procedure:
3.04 g of potassium salt of 2-isopropoxy-6-trifluoromethyl-4-hydroxypyrimidine and 3.65 g of methyl 3-methoxy-2-(2-bromomethylphenyl)acrylate were suspended in 50 ml of octane. The resulting suspension was reacted at reflux of octane for 5 hours and cooled down to room temperature. 30 ml of ethyl acetate was added and insoluble matter was filtrated. The precipitate separated by filtration was washed with 20 ml of etyl acetate. A mixed solution of the obtained filtrate and washing was analyzed with high-performance liquid chromatography. The yield of the target compound was 13.3% and 75.0% for a byproduct of methyl 3-methoxy-2-[2-(2-isopropoxy-6-trifluoromethylpyrimidin-4-on-3 -ylmethyl)phenyl]acrylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:24][CH2:23]2)=[CH:4][C:5]([CH2:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].[CH:35]1([C:38]2[O:39][CH:40]=[C:41]([C:43](O)=[O:44])[N:42]=2)[CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH2:20]([C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:43]([C:41]2[N:42]=[C:38]([CH:35]3[CH2:37][CH2:36]3)[O:39][CH:40]=2)=[O:44])=[C:3]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:26][CH2:27]2)[CH:4]=1)[CH3:21]
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: CCc1cc(N2CCN(c3ccccc3C)CC2)c(N)cc1C(=O)NCCCN1CCCC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2coc(C3CC3)n2)cc1C(=O)NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
5-Amino-2-ethyl-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 6b (36.0 mg, 0.08 mmol, 100 mol %), 2-cyclopropyl-oxazole-4-carboxylic acid 1 h (17.8 mg, 0.12 mmol, 150 mol %) and N,N-diisopropylethylamine (0.04 ml, 0.23 mmol, 300 mol %) were combined in N,N-dimethylformamide (2.0 ml) and HATU (44.3 mg, 0.12 mmol, mol %) was added and the reaction was stirred at room temperature for 16 h. The reaction was then diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate and then concentrated to a residue that was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford 2-cyclopropyl-oxazole-4-carboxylic acid [4-ethyl-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 6c (23.4 mg; 0.04 mmol, 50.3%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(N(CC)CC)C.[Cl-].C(OC(=O)O)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][C:31]2[N:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[N:32]=2)=[CH:26][CH:25]=1.Cl>O1CCCC1.O>[CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([S:30][C:31]2[N:32]=[C:33]([CH3:38])[CH:34]=[C:35]([CH3:37])[N:36]=2)=[CH:28][CH:29]=1)=[O:5]
Reactant: Cc1cc(C)nc(Sc2ccc(N)cc2)n1
Reactant: COC(C)(C)C(=O)O
Agent: CCOC(=O)O
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(C)(C)C(=O)Nc1ccc(Sc2nc(C)cc(C)n2)cc1
Yield: 82.7 %

Procedure:
11.8 g (0.1 mole) of α-methoxy-isobutyric acid were dissolved in 150 ml of tetrahydrofuran, and 10.1 g (0.1 mole) of triethylamine were added. 10.85 g (0.1 mole) of carbonic acid ethyl ester-chloride were added dropwise at 10°-15° C., with stirring. The mixture was subsequently stirred at room temperature for 2 hours and 23.1 g (0.1 mole) of 2-(4-aminophenylmercapto)-4,6-dimethyl-pyrimidine were then added in portions. The mixture was subsequently stirred at room temperature for 1 hour and boiled under reflux for a further 2 hours. The reaction mixture was cooled and then stirred into one liter of water rendered slightly acid with hydrochloric acid. The crystals precipitated were filtered off with suction, washed with water and dried in air. 27.4 g (83% of theory) of 2-(4-(α-methoxy-isobutyrylamino)-phenylmercapto)-4,6-dimethyl-pyrimidine were obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C@H:4]1[CH2:6][NH:5]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CCOCC>[CH3:1][CH:2]([CH3:7])[CH2:3][CH:4]1[CH2:6][N@@:5]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)C[C@H]1CN1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)CC1CN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A solution of 24.3 g of (S)-2-(2-methylpropyl)aziridine [Bull. Chem. Soc. (Japan) 35, 1004 (1962).] in 500 ml of ether is treated with 34.2 ml of triethylamine and cooled in ice. While stirring rapidly 40.4 ml (a 10% excess) of benzyl chloroformate is added dropwise over a 30 minute period. After stirring for one hour at 0°, the triethylamine, hydrochloride is filtered off and the ether removed under reduced pressure. The residue is distilled under reduced pressure. After a forerun of benzyl chloride, the product distills at 105°-122°/0.6 mm. There is obtained 51.66 g (90.5% yield) of (S)-2-(2-methylpropyl)-1-aziridinecarboxylic acid, phenylmethyl ester.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH:15][C:18](=[O:20])[CH3:19])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1

Procedure:
introducing an acyl group at the N4 position of 1-β-D-arabinofuranosyl cytosine with an acylating agent, for example using acetic anhydride under conditions suitable for obtaining 1-β-D-arabinofuranosyl-N4-acetyl cytosine,
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].C(=O)([O-])[O-].[K+].[K+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].[CH2:27](I)[CH3:28]>CN(C)C=O>[N+:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:27][CH3:28])=[O:9])([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCI
Reactant: O=C(O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1Sc1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
In 100 ml of N,N-dimethylformamide was dissolved 15.4 g of thiosalicylic acid followed by addition of 42 g of potassium carbonate and 14.8 g of 2-fluoronitrobenzene, and the mixture was stirred at 100° C. for 3 hours. After the reaction mixture had cooled to room temperature, 18.7 g of ethyl iodide was added thereto and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was then poured into ice-water and extracted with ether. The ether layer was washed with water twice, dried and concentrated. Finally the residue was crystallized from ethanol to give 25.5 g of the title compound as yellow crystals.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=2)[CH2:3][CH2:2]1.[CH:14]1([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([O:26][CH3:27])[CH:19]=2)[CH2:16][CH2:15]1.C(C1C=CC=CC=1)=CC>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH:4]2[CH2:1][CH:3]2[CH3:2])[CH:10]=[CH:9][C:8]=1[OH:11].[CH3:15][CH:16]1[CH2:14][CH:17]1[C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:27][O:26][C:20]=2[CH:19]=1
Reactant: COc1cc(CC2CC2)ccc1O
Reactant: COc1ccc(CC2CC2)cc1OC
Agent: CC=Cc1ccccc1
Product: CC1CC1c1ccc2c(c1)OCO2
Product: COc1cc(C2CC2C)ccc1O

Procedure:
4-Cyclopropylmethyl-2-methoxy-phenol (B); 4-Cyclopropylmethyl-1,2-dimethoxy-benzene (C); 2-Methoxy-4-(2-methyl-cyclopropyl)-phenol (D) and 5-(2-methyl-cyclopropyl)-benzo[1,3]dioxole (E) were synthesised by reacting the corresponding propenyl benzene in a procedure analogous to that of Example 1.
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:24]=[CH:23]4)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH2:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.[CH:44](OCC)=[O:45]>>[F:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:25]1[C:26]2[C:22](=[CH:21][C:20]([NH:19][C:17]3[C:18]4=[C:10]([CH2:9][N:41]5[CH2:42][CH2:43][CH:38]([NH:37][CH:44]=[O:45])[CH2:39][CH2:40]5)[CH:11]=[CH:12][N:13]4[N:14]=[CH:15][N:16]=3)=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: NC1CCNCC1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)c1ccccc1
Reactant: CCOC=O
Product: O=CNC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A mixture of (5-benzenesulfinylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (200 mg, 0.4 mmole) and 4-amino-piperidine (1.2 g, 30 equiv.) in a vial was placed in microwave reactor (Personal Chemistry's Smith Creator) and irradiated at 150° C. for 20 min. Ethyl formate (3 ml) was added to above mixture and irradiation was continued at 135° C. for 30 min. Concentration of the reaction mixture followed by preparative HPLC purification afforded N-(1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidin-4-yl)-formamide (71 mg, 36%). This was dissolved in dry THF (0.3 ml) and added dropwise to a stirred solution of LiAlH4 (1M in ether, 0.57 ml, 4 equiv.). Water (0.5 mL) was slowly added after 20 hr and the title compound (16 mg, 23%) was isolated by preparative HPLC. MS: 485 (M+H)+; HPLC Ret Time: 1.02 min (Xterra 3.0×50 mm S7 C18 column, 2 min gradient, 5 ml/min).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Br:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:38][CH2:39][NH2:40])([CH3:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:38][CH2:39][NH:40][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:3][CH2:2]5)[C:15]=4[CH:14]=3)[C:21]([Br:22])=[CH:20][N:19]=2)([CH3:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Reactant: CC1(CCN)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1(CCNc2ncc(Br)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 100.1 %

Procedure:
A stirred mixture of 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (400 mg, 0.979 mmol), 4-(2-aminoethyl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (474 mg, 1.96 mmol) and diisopropylethylamine (253 mg, 1.96 mmol) in 1,4-dioxane (10 mL) is heated at 90° C. under nitrogen for 18 hours. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with 3% 2 M NH3/MeOH in dichloromethane, to give 602 mg of 4-{2-[5-bromo-4-(4-cyclopropylcarbamoylbenzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-4-methylpiperidine-1-carboxylic acid tert-butyl ester. It is then subject to deprotection by dissolving the material (132 mg, 0.220 mmol) in MeOH (10 mL) and dichloromethane (5 mL) and bubbling anhydrous HCl gas for 5 minutes. The hot, yellow solution is allowed to sit at room temperature for 1.5 hours, then concentrated to give the title compound as a yellow solid (126 mg, 100% yield). ES+(m/z) 514 (79Br) and 516 (81Br) [M(free base)+H].
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.[NH:18]1[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19]1.C(N(CC)CC)C>C(#N)C>[ClH:1].[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([N:7]2[C:3]([CH2:2][N:18]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19]3)=[N:4][N:5]=[N:6]2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#CC1CCNC1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cl
Product: N#CC1CCN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)C1
Temperature: 120 °C

Procedure:
Preparative procedure: To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (200 mg, 0.762 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (4 mL) was added 3-pyrrolidinecarbonitrile (202 mg, 1.52 mmol, J&W Pharmlabs, Levittown, USA) and triethylamine (0.329 mL, 2.36 mmol). The reaction mixture was heated at 120° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled then the solvent removed under vacuum. The residue was purified by MDAP. Fractions containing the desired product were combined and the solvent removed. The product was dissolved in 1 ml of DCM and 0.5 ml of 1M HCl in ether was added. Solvent was removed and the product was dried in a vacuum oven over the weekend to afford the title compound as a white solid (170 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH2:42][CH2:43][CH2:44][CH3:45])[C:3]([NH:5][CH2:6][C@@H:7]1[O:11]C(C)(C)[N:9](C(OC(C)(C)C)=O)[C@H:8]1[CH2:21][C@H:22]([CH:26]([OH:41])[C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][N:33]2[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:29][CH:28]=1)[CH:23]([CH3:25])[CH3:24])=[O:4].[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[NH2:9][C@@H:8]([CH2:21][C@H:22]([CH:26]([OH:41])[C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][N:33]2[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:29][CH:28]=1)[CH:23]([CH3:25])[CH3:24])[C@@H:7]([OH:11])[CH2:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([CH3:46])[CH2:42][CH2:43][CH2:44][CH3:45].[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]
Reactant: CCCCC(C)(C)C(=O)NC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C(C)C)C(O)c1ccc2cnn(CCCOC)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCC(C)(C)C(=O)NC[C@H](O)[C@@H](N)C[C@@H](C(C)C)C(O)c1ccc2cnn(CCCOC)c2c1
Reaction time: 1 h

Procedure:
To a stirred solution of (4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-(hydroxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (45 mg, 0.07 mmol) in CH2Cl2 (8 mL) at 0° C. was added TFA (2 mL). The mixture was stirred for ˜1 h and concentrated. The residue was purified by preparative HPLC to give N-((2S,3S,5S)-3-amino-2-hydroxy-5-(hydroxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-6-methylheptyl)-2,2-dimethylhexanamide as its TFA salt (15 mg, 42%). 1H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.55 (m, 1H), 7.17 (m, 1H), 4.50 (m, 2H), 3.84-3.68 (m, 2H), 3.45 (m, 1H), 3.27 (s, 3H), 3.25-3.18 (m, 3H), 2.13 (m, 2H), 1.89-1.72 (m, 2H), 1.55 (m, 3H), 1.32-1.11 (m, 9H), 0.99-0.80 (m, 12H); MS: 489 (M++1).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[NH:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].O>C1COCC1>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([N:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(F)c1)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 27 h
Yield: 9.7 %

Procedure:
To a solution of the above crude Boc-Tyr(3-F)-OH (1.18 g), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.10 g, 3.03 mmol) and CMPI (1.16 g, 4.55 mmol) in THF (6 ml), TEA (1.27 ml, 12.1 mmol) was added under cooling with ice and stirred at room temperature for 27 hours. The reaction mixture was mixed with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:concentrated aqueous ammonia=30:1:0.05), giving the titled compound (0.19 g, 10%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[I-].[CH2:18]([N:25]([CH3:34])[C:26](N1C=C[N+](C)=C1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:26](=[O:27])[N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:34])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: CN(Cc1ccccc1)C(=O)n1cc[n+](C)c1
Agent: [I-]
Product: CN(Cc1ccccc1)C(=O)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from 4-(3,5-dichloro pyridin-2-yloxy)-phenol and 3-(benzyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][C@@H:3]1[OH:33].N1C=CN=C1.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[CH2:9]([O:8][C@H:7]1[C@H:6]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][C@H:3]([O:33][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44])[C@@H:2]1[NH2:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@@H]1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1N
Yield: 71.8 %

Procedure:
A solution of (1S,2S,3R,4R,5R)-2-amino-3,4-bis(benzyloxy)-5-(benzyloxymethyl)cyclohexanol (1 g, 2.23 mmol) and imidazole (338 mg, 3.35 mmol) in DCM (20 mL) was treated with tert-butylchlorodimethylsilane (371 mg, 2.46 mmol) for 12 h at room temperature. The reaction was quenched by addition of satd. aqueous NaHCO3 (5 mL), and was extracted by DCM (2×10 mL). The organic layers were combined, dried over anhydrous MgSO4, and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% of MeOH in DCM to give (1R,2R,3R,4R,6S)-2,3-bis(benzyloxy)-4-(benzyloxymethyl)-6-(tertbutyldimethylsilyloxy)cyclohexanamine as a yellow oil (0.9 g, 68%). MS (ES, m/z): 562.3; 1H NMR (300 MHz, CDCl3) δ 7.24-7.37 (m, 15H), 4.80-4.95 (m, 2H), 4.55-4.71 (m, 2H), 4.40-4.51 (m, 2H), 4.05 (s, 1H), 3.62-3.67 (m, 1H), 3.44-3.50 (m, 3H), 2.43-2.46 (m, 1H), 2.15 (s, 1H), 1.82-1.85 (m, 1H), 1.52-1.59 (m, 1H), 0.92 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[NH:8][C:7](C(OC)=O)=[CH:6][C:5]=1C1C2C(=CC=CC=2)N=CC=1)([O-])=O.CO.CO[C:27]1[CH:32]=CC(C(C=O)C=O)=C[CH:28]=1>[Pd].CC(O)=O>[N:1]1[C:4]2[N:8]([CH:7]=[CH:6][CH:5]=2)[CH:28]=[CH:27][CH:32]=1
Reactant: COC(=O)c1cc(-c2ccnc3ccccc23)c([N+](=O)[O-])[nH]1
Reactant: COc1ccc(C(C=O)C=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: c1cnc2cccn2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 253.9 %

Procedure:
A mixture of methyl 5-nitro-4-quinolin-4-yl-1H-pyrrole-2-carboxylate (23, 90 mg, 0.3 mmol), Pd/C (5%, 45 mg), and MeOH (15 mL) was stirred under argon for 5 min, then under hydrogen for 40 min before removal of the catalyst by filtration through celite. To the orange color filtrate was added 2-(4-methoxyphenyl)malondialdehyde (54 mg, 0.3 mmol) followed by AcOH (2 mL). The resulting reaction mixture was stirred overnight at 82° C., then cooled to rt, quenched with sat. NaHCO3, and extracted with ethyl acetate and CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2/MeOH (90:10) to give 25 as a yellow solid (90 mg, 73%). 1H NMR (DMSO-d6, 500 MHz) δ 9.80 (d, J=3.0 Hz, 1H), 8.97 (d, J=5.0 Hz, 1H), 8.87 (d, J=3.0 Hz, 1H), 8.10 (m, 1H), 8.04 (s, 1H), 7.80 (m, 1H), 7.75 (d, J=5.0 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.61 (m, 1H), 7.15 (d, J=8.5 Hz, 2H), 3.94 (s, 3H), 3.84 (s, 3H); nip 230-231° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][O:9]2)[CH:7]=1.B(F)(F)F.CCOCC.[CH3:20][C:21]([CH3:23])=[O:22]>O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][O:9][C:21]([CH3:23])([CH3:20])[O:22]2)[CH:7]=1
Reactant: CC(C)=O
Reactant: Brc1cncc(C2CO2)c1
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: CC1(C)OCC(c2cncc(Br)c2)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.2 %

Procedure:
To a solution of 3-bromo-5-(oxiran-2-yl)pyridine (1.00 g, 5.00 mmol) in acetone (25 mL) was added BF3.OEt2 (0.950 mL, 7.50 mmol) dropwise and the reaction mixture was stirred at ambient temperature for 14 h. The reaction mixture was diluted with water (15 mL) and the resulting mixture extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 25% EtOAc/hexanes) to obtain 3-bromo-5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine (0.700 g, 54.2%). LCMS Condition B-26: retention time 2.17, [M+2]=260.0. 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 3H), 1.55 (s, 3H), 3.72 (dd, J=7.6 Hz, J=8.4 Hz, 1H), 4.36 (dd, J=6.4 Hz, J=8.4 Hz, 1H), 5.08 (dd, J=6.4 Hz, J=7.6 Hz, 1H), 7.85-7.86 (m, 1H), 8.49 (d, J=1.6 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H).