Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9].[C:14]([CH2:16][C:17](O)=[O:18])#[N:15]>CC(C)=O>[C:14]([CH2:16][C:17]([NH:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9])=[O:18])#[N:15]
Reactant: N#CCC(=O)O
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: O
Solvent: CC(C)=O
Product: Cn1c(N)c(NC(=O)CC#N)c(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
A mixture of 5,6-diamino-1,3-dimethyluracil hydrate (19.0 g, 0.11 mole) and cyanoacetic acid (19.0 g, 0.22 mole) is heated to 120°-130° C. under a nitrogen atmosphere. The mixture melts and resolidifies within thirty minutes. The resolidified residue is cooled to room temperature and is taken up in acetone. The residue is collected on a filter, recrystallized in water using decolorizing carbon, dried, and triturated under vacuum to yield 5-cyanoacetamido-6-amino-1,3-dimethyluracil as a solid (14.2 g; 54%).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:38]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Cl:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:42]=1[C:48]1[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:38][NH:54][C:51]2[CH:50]=[CH:49][C:48]([C:42]3[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:41]=3[Cl:40])=[CH:53][CH:52]=2)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Reactant: Nc1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (4.9 g, 22.9 mmol) was added to a DCE solution (37 mL) of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate, prepared as in Example 6, (4.1 g, 11.5 mmol), 2′,4′-dichloro-[1,1′-biphenyl]-4-amine, prepared as in example x (3.0 g, 12.6 mmol), and AcOH (2.6 mL, 45.8 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:17])=[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:6]2.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([N:6]1[C:7]2[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=2)[C:4]([CH3:17])=[C:5]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(-c2ccccc2)[nH]c2cccc(Br)c12
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(Br)c12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 4-bromo-3-methyl-2-phenyl-1H-indole (1.467 g, 5.126 mmol) was reacted with k-t-butoxide (0.604 g, 5.383 mmol) and benzyl bromide (0.924 g, 5.383 mmol) in DMF (15 ml) to give the product (1.286 g, 3.651 mmol, 71%) as a colorless oil. 1H DMSO-d6) δ 2.40 (s, 3H), 5.27 (s, 2H), 6.79-6.81 (m, 2H), 6.98 (t, J=7.6 Hz, 1H), 7.15-7.21 (m, 3H), 7.23 (dd, J=0.8, 7.5 Hz, 1H), 7.36-7.38 (m, 3H), 7.43-7.53 (m, 3H); [ESI(+)], m/z 376/378 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[Sn](CCCC)(CCCC)CCCC)([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2Br)[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C1(PC2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:28]([O:32][C:33]([N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:27])[CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccc1NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(-c2ccccc2PC2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccncc1-c1cccc2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 100 °C
Reaction time: 24 h
Yield: 29.4 %

Procedure:
A mixture of (3-tributylstannyl-pyridin-4-yl)-carbamic acid tert-butyl ester (0.7 g, 1.44 mmol), 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.45 g, 1.44 mmol), tris(dibenzylideneacetone)dipalladium(O) (0.066 g, 0.072 mmol) and 2-(cyclohexylphosphino)biphenyl (0.075 g, 0.216 mmol), in toluene was heated with stirring to 100° C. for 24 h. The solvent was evaporated and the residue purified by flash chromatography eluting with 50% ethyl acetate in hexanes to yield 0.18 g 5-(4-tert-butoxycarbonylamino-pyridin-3-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#N)=[CH:17][CH:16]=2)[CH2:10]1.B(F)(F)F.CC[O:29][CH2:30]C.C[OH:33]>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]([O:29][CH3:30])=[O:33])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: CO
Reactant: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3N)C2)cc1
Reactant: CCOCC
Agent: FB(F)F
Product: COC(=O)c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3N)C2)cc1
Yield: 100 %

Procedure:
To a solution of 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (70 mg, 0.235 mmol) in MeOH (1 mL) at was added BF3.OEt2 (0.2 mL, 1.578 mmol) at rt. The reaction was stirred at reflux for 16 h. LC/MS showed only ˜22% of the desired products formed. More BF3.OEt2 (100 μL, 0.789 mmol) was added. The reaction was stirred at reflux for another 6 days. The reaction mixture was concentrated. The residue was diluted with EtOAc, washed with saturated aq NaHCO3, saturated aq NaCl solution. The organic extracts were concentrated under vacuum to give the crude product methyl 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzoate (78 mg, 0.235 mmol, 100% yield). The product was used without further purification.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.Cl.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37](O)=[O:38])[CH:31]=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:37](=[O:38])[CH2:36][C:32]6[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=6)[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1cccnc1)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1

Procedure:
To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine tri-HCl (137 mg, 0.300 mmol), 3-pyridinylacetic acid-HCl (78.1 mg, 0.450 mmol), and EDC (115 mg, 0.600 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.261 mL, 1.50 mmol). The mixture became a clear solution after being stirred for a few minutes and was stirred overnight. The products, which precipitated from the solution during the reaction, were collected by filtration, washed with dichloromethane (2×1 mL), and dried in vacuo to afford the title compound as a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ=2.73 (s, 2H), 2.89 (s, 2H), 3.78 (dt, J=4.0, 18.8 Hz, 2H), 3.86 (d, J=20 Hz, 2H), 4.19 (s, 1H), 4.33 (s, 1H), 6.45 (d, J=5.2 Hz, 1H), 6.84 (d, J=16.8 Hz, 1H), 7.33-7.36 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.87 (dt, J=2.0, 8.0 Hz, 1H), 7.95 (s, 1H), 8.04 (d, J=9.2 Hz, 1H), 8.34 (d, J=3.6 Hz, 1H), 8.44-8.48 (m, 1H), 8.92 (s, 1H), 9.24 (s, 1H), 9.62 (d, J=7.6 Hz, 1H). MS (ES+): m/z 467.94 [MH+]. HPLC: tR=1.98 min (ZQ2000, polar—5 min).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].Cl.[CH3:12]O>CO>[O:1]([CH3:12])[C@H:2]1[O:10][CH2:9][C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: CO
Agent: Cl
Product: CO[C@H]1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Yield: 201.4 %

Procedure:
To a suspension of L-arabinose (100 g, 667 mmol) in anhydrous MeOH (450 mL) was added a HCl /MeOH solution (7.3 g dry HCl in 50 mL MeOH) at room temperature under argon atmosphere. The mixture was refluxed for 2 h and cooled down to room temperature. The solution was concentrated to about 3/4 of its volume to give a suspension. The solid precipitated was filtered and washed with cold MeOH (20 mL) to give the first crop as a crystalline powder (35.23 g). The filtrate was concentrated (35° C.) to 1/4 of its volume. The solid precipitated was filtered, washed and dried as above to give the second crop (9.66 g) as a colorless crystalline powder. The concentration and filtration were repeated to afford additional 28.31 g of the product (total 73.2 g, 67%). 1H NMR (D2O) δ 3.30 (s, OCH3, 3H), 3.56 (dd, 1H, H5), 3.73 (m, 1H, H4), 3.77 (dd, 1H, H5), 3.82 (bs, 1H, H2), 4.73 (m, 1H, H1).
Reaction SMILES: O.[OH-].[Li+].[C:4]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([O:25]C)=[O:24])=[N:21][CH:22]=3)=[CH:14][CH:15]=2)[C@H:10]([NH:27][C:28]2[CH:33]=[N:32][C:31]([C:34]#[N:35])=[CH:30][N:29]=2)[CH2:9][C@@H:8]1[CH3:36])(=[O:6])[CH3:5].C(O)(=O)C>O.O1CCOCC1>[C:4]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[N:21][CH:22]=3)=[CH:14][CH:15]=2)[C@H:10]([NH:27][C:28]2[CH:33]=[N:32][C:31]([C:34]#[N:35])=[CH:30][N:29]=2)[CH2:9][C@@H:8]1[CH3:36])(=[O:6])[CH3:5]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2cnc(C#N)cn2)C[C@H](C)N3C(C)=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)nc3)cc2[C@H](Nc2cnc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 43 %

Procedure:
Lithium hydroxide monohydrate (83 mg, 1.97 mmol) in water (5 mL) was added to methyl 5-((2S,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinate (for a preparation, see Intermediate 52) (435 mg, 0.983 mmol) in 1,4-dioxane (5 mL) and the reaction mixture stirred at room temperature for 70 mins. Acetic acid (0.169 mL, 2.95 mmol) was added and the resulting mixture stirred for 10 mins. The mixture was filtered, the solid collected was washed with water, then dried in a vacuum oven to give 5-((2S,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinic acid (181 mg, 0.422 mmol, 43% yield) as a brown solid. LCMS: (Formate, 2 min) Rt=0.66 mins, MH+=429.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=O.O.[NH2:11][NH2:12].C(O[C:16](=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17])C>CO>[CH3:17][C:16]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]([C:2]([F:1])([F:8])[F:9])=[N:12][N:11]=1
Reactant: CCOC(C)=Nc1ccccc1
Reactant: NN
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: O
Product: Cc1nnc(C(F)(F)F)n1-c1ccccc1
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
Ethyl trifluoroacetate (4.3 g) was added to hydrazine hydrate (1.5 g, 99-100%) in methanol (30 ml) at 5°-10° and stirred for 15 min. Ethyl-N-phenylacetimidate (3.9 g) was added keeping the temperature below 10° for 1 hr and then at room temperature for another hour. The mixture was evaporated to dryness under reduced pressure and the residue heated at 90°-100° with glacial acetic acid (50 ml) for 1 hr. Evaporation under reduced pressure and crystallization of the residue from methyl cyclohexane gave 3-methyl-4-phenyl-5-trifluoromethyl-1,2,4-triazole (2.8 g, 41.2%) m.p. 118°. (Found: C, 52.73%; H, 3.72%; F, 25.3%; N, 18.78%. C10H8F3N4 requires: C, 52.87%; H, 3.55%; F, 25.1%; N, 18.50%). δ(CDCl3): 7.47 (5H, m); 2.33 (3H, s). m/e, 227.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.C[O:9][C:10]1[C:11](=[O:28])[C:12]([C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1.O>C(#N)C>[OH:9][C:10]1[C:11](=[O:28])[C:12]([C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1
Reactant: COc1cn(-c2ccccc2)nc(-c2ccnn2C)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cn1nccc1-c1nn(-c2ccccc2)cc(O)c1=O
Temperature: 25 °C
Yield: 35.4 %

Procedure:
To a solution of sodium iodide (7.49 g) in acetonitrile (300 mL) was added chlorotrimethylsilane (6.35 mL) at room temperature with stirring, and the mixture was stirred for 30 min. Then, 5-methoxy-3-(1-methyl-1H-pyrazol-5-yl)-1-phenylpyridazin-4(1H)-one (2.82 g) was added, and the mixture was stirred for 30 min at the same temperature and further refluxed for 7 hr. The reaction mixture was allowed to cool to room temperature, poured into water and the mixture was stirred for 30 min. The resulting precipitate was collected by filtration, washed successively with water, methanol, and diisopropyl ether, and dried to give the title compound (0.95 g) as pale-yellow needles. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (1.70 g) as pale-yellow needles.
Reaction SMILES: [CH2:1]([Sn:5]([Cl:11])(Cl)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].O.[NH4+].[Cl-].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.[Zn]>[CH2:15]([Sn:5]([Cl:11])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](Cl)(CCCC)Cc1ccccc1

Procedure:
In a round-bottom two-necked flask equipped with a condenser and a dropping funnel, 31.25 mmol (9.5 g) of dibutyltindichloride were dissolved in 25 ml of tetrahydrofurane (THF). Then 125.1 mmol (8.18 g) of zinc (zinc granules: −30+100 mesh, Sigma-Aldrich) and 50 ml of water saturated with NH4Cl were added. With vigorous stirring 125.1 mmol (21.4 g) of benzylbromide (in 1:1 stoichometric ratio with respect to zinc) were added drop wise at a rate sufficient to keep temperature below 27° C. The reaction flask was cooled down with ice. First a brown benzyldibutyltin chloride was formed as an intermediate. The addition took about 30 min. The resulting heterogeneous colorless mixture was stirred for a further 60-120 min to complete disappearance of Zn powder. The organic layer was separated, washed with saturated aqueous NaCl and dried over MgSO4. Solvent was removed by distillation under reduced pressure up to 45° C. for 5 hours. An oil like liquid remained, which was distilled under vacuum to afford the pure compound.
Reaction SMILES: Br[CH:2]([CH:8]=O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH2:10][C:11]([NH2:13])=[O:12]>CN(C=O)C>[NH2:13][C:11]1[O:12][C:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])=[CH:8][N:10]=1
Reactant: NC(N)=O
Reactant: COC(=O)CC(Br)C=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cnc(N)o1
Temperature: 110 °C
Yield: 18 %

Procedure:
A 250-mL round bottom flask was charged with methyl 3-bromo-4-oxobutanoate (5.00 g, 25.6 mmol) and urea (2.08 g, 34.6 mmol) in DMF (15 mL) and heated to 110° C. for 30 minutes. After this time, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was absorbed onto silica and purified by chromatography on silica using dichloromethane/(89:9:1 dichloromethane/methane/conc. NH4OH) (10:0 to 0:10) as eluent, to afford the title compound (0.72 g, 18%) as a red oil. MW=156.14. 1H NMR (DMSO-d6, 300 MHz) δ 9.54 (s, 1H), 6.48 (s, 2H), 6.45 (s, 1H), 3.64 (s, 2H), 3.62 (s, 3H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([SH:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].[Na].Br[CH2:23][CH2:24][Cl:25]>C(O)C.C1(C)C=CC=CC=1>[Cl:25][CH2:24][CH2:23][S:16][CH:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: SC1c2ccccc2CCc2ccccc21
Reactant: ClCCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: ClCCSC1c2ccccc2CCc2ccccc21
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of the above crude thiol (4.53 g, 0.020 mol) in absolute ethanol (7 ml) was added dropwise to a stirred solution of sodium ethoxide, freshly prepared from absolute ethanol (25 ml) and sodium (0.46 g, 0.020 mol). Stirring was continued for 0.5 h at ambient temperature. 1-Bromo-2-chloroethane (8.60 g, 0.060 mol) was added dropwise and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with toluene (20 ml) and filtered. The filtrate was evaporated in vacuo and stripped with toluene, affording 5.72 g (99%) of crude 5-(2-chloroethylsulfanyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[CH2:21][O:22]S(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[CH2:21][O:22][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[Cl:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1COc1ccccc1Cl

Procedure:
12.5 Reaction of 1.5 g of 1-tert-butyloxycarbonyl-(2R,4S)-2-(methylsulfonyloxymethyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine with 560 μl of 2-chlorophenol and 1.19 g of caesium carbonate in 15 ml of DMF under standard conditions gives 751 mg of (2R,4S)-1-tert-butyloxycarbonyl-2-(2-chlorophenoxymethyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine. 223 mg of the silyl-eliminated product (2R,4S)-1-tert-butyloxycarbonyl-2-(2-chlorophenoxymethyl)-4-hydroxypyrrolidine are formed as by-product.
Reaction SMILES: [C:1]1([N:11]2[C:15]([OH:16])=[CH:14][CH:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:24][C:18]([O:16][C:15]1[N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:12]=[CH:13][CH:14]=1)([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Oc1ccnn1-c1cccc2ccccc12
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccnn1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(naphthalen-1-yl)-1H-pyrazol-5-ol (250 mg, 1.2 mmol), ethyl bromoisobutyrate (0.2 mL, 1.3 mmol) and potassium carbonate (318 mg, 1.3 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Water was then added to the reaction mixture, extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% dichloromethane/5% methanol) afforded ethyl 2-methyl-2-(1-(naphthalen-1-yl)-1H-pyrazol-5-yloxy)propanoate as a solid.
Reaction SMILES: [Cl:1][C:2]1(C2C=CC=C(C(=O)NC)C=2)[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[O:10])=[C:4](NC(O)=O)[CH2:3]1.[CH3:36][NH:37][C:38]([C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])=[O:39].C1C=CC2N(O)N=NC=2C=1.O.CN1CC[O:62][CH2:61]C1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[Cl:1][C:2]1([C:61](=[O:62])[NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[C:40]([C:38](=[O:39])[NH:37][CH3:36])[CH:41]=2)[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])=[O:10])=[CH:4][CH2:3]1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: CN1CCOCC1
Reactant: CNC(=O)c1cccc(C2(Cl)C=CC(NC(=O)Nc3ccccc3C(F)(F)F)=C(NC(=O)O)C2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cccc(NC(=O)C2(Cl)C=CC(NC(=O)Nc3ccccc3C(F)(F)F)=CC2)c1
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBT-H2O (0.14 g, 1.07 mmol), and N-methylmorpholine (0.5 mL, 1.07 mmol) in DMF (3 mL) at 0° C. was added EDCI.HCl (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temp. and was stirred overnight. The resulting mixture was treated with water (10 mL), and extracted with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10% MeOH/90% EtOAc) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N-(4-(3-methylcarbamoylphenyl) carbamoylphenyl) urea as a white solid (0.097 g, 41%): mp 225-229; TLC (100% EtOAc) Rf 0.23.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH3:4].C([O-])(O)=O.[Na+].Cl.[NH2:12][NH:13][C:14]([NH2:16])=[O:15]>O.C1COCC1>[N:12](=[C:3]([CH3:4])[CH2:2][Cl:1])[NH:13][C:14]([NH2:16])=[O:15]
Reactant: NNC(N)=O
Reactant: CC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CCl)=NNC(N)=O

Procedure:
Add 1.0 gm chloroacetone and a solution of 0.84 gm NaHCO3 in 10 ml water to a solution of 1.1 gm semicarbazide hydrochloride in 25 ml THF and stir overnight. Two layers form. Separate the top layer and concentrate to obtain an off-white solid, 2-semicarbazono-1-chloropropane.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[C:22](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[C:18]([O:17][C:15]([NH:1][C@@H:2]([CH2:3][CH2:4][C:5]([O:6][CH3:22])=[O:7])[C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.0 g of Boc-Glu-OtBu (39.6 mmol) are dissolved in 200 mL of DMF. Under argon atmosphere, 7.09 g of cesium carbonate (21.8 mmol, 0.55 eq.) are added and the resulting suspension is stirred for 1 hour at RT. After this time, 2.47 mL of methyl iodide (39.6 mmol) are added and stirred at RT overnight. The solvent is removed in vacuo and the obtained residue is taken up in 400 mL of ethyl acetate. The undissolved solid is filtered and the filtrate is washed with respectively 75 mL of 10% citric acid, 10% NaHCO3 solution and brine 3 times. After drying of the organic phase over Na2SO4 the solvent is removed in vacuo. The product is obtained as yellow oil. The product can be used without further purification in the following reaction.