Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C1COCC1>[Cl:23][CH2:24][C:25]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][CH:3]=1)=[O:26]
Reactant: Cc1cc(O)nc(-c2ccc(N)cn2)n1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(-c2ccc(NC(=O)CCl)cn2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound of example 13 (0.10 g, 0.49 mmol) in THF (5 mL) was added triethylamine (0.075 g, 0.742 mmol) and chloroacetylchloride (0.0559 g, 0.495 mmol), and the reaction mixture was stirred at room temperature for 2 hours. THF was removed under reduced pressure, and the reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by crystallization from ethyl acetate and petroleum ether to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[F-].[K+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[Pd]Cl>[CH2:14]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cccc2cnccc12
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
5-Bromoisoquinoline (Preparation 6, Step 1, 1.04 g, 5.0 mmol) was mixed with allyltributyltin (1.7 mL, 5.5 mmol) and dichloropalladium bis(triphenylphosphine) (176 mg, 0.25 mmol) in toluene (20 mL) under a nitrogen atmosphere. The mixture was heated at reflux for 16 h. After cooling to room temperature, a saturated aqueous solution of potassium fluoride (20 mL) was added with stirring, resulting in the formation of a precipitate. Following 15 min of stirring, the mixture was filtered and the organic layer was separated from the aqueous layer, was concentrated in vacuo and was purified by silica gel chromatography (6:1 hexanes-ethyl acetate) to give 778 mg (92% yield) of 5-allylisoquinoline; 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.54 (d, J=5.8 Hz, 1H), 7.85 (m, 1H), 7.79 (d, J=5.8 Hz, 1H), 7.56 (m, 2H), 6.1 (m, 1H), 5.15 (m, 1H), 5.05 (m, 1H), 3.81 (d, J=6.2 Hz, 2H); MS (AP/CI): 170.1 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].C(N(CC)CC)C.[C:12]([C:16]1[O:17][C:18]2[C:24]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([Cl:29])[CH:22]=[CH:21][C:19]=2[N:20]=1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[CH3:4][O:3][N:2]([CH3:1])[S:25]([C:24]1[C:18]2[O:17][C:16]([C:12]([CH3:14])([CH3:13])[CH3:15])=[N:20][C:19]=2[CH:21]=[CH:22][C:23]=1[Cl:29])(=[O:26])=[O:27]
Reactant: CNOC
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Temperature: 0 °C

Procedure:
N,O-dimethylhydroxylamine (1.98 g, 2 equiv) was suspended in dry THF (20 ml) and cooled to 0° C. in an ice bath while stirring vigourously. Triethylamine (4.51 ml, 2 equiv) was added maintaining the temperature at 0° C. followed by dropwise addition of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (US 2007/0249672 page 9) (5 g, 16.22 mmol, 1 equiv) in THF (10 ml) over 30 minutes. The reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to room temperature overnight. The resulting mixture was filtered and concentrated in vacuo and the resulting solid was dissolved in EtOAc (75 ml), washed with water (3×20 ml), sat. brine (30 ml) dried (MgSO4) and concentrated in vacuo to afford the title compound as a solid; [M+H]+ 333.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:16](=[O:17])[O:15][CH:14]2[CH2:18][CH:19]=[CH:20][CH:13]12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:31](Br)[CH:32]=[CH2:33]>C1COCC1>[CH2:33]([C@:12]1([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:16](=[O:17])[O:15][C@H:14]2[CH2:18][CH:19]=[CH:20][C@H:13]12)[CH:32]=[CH2:31]
Reactant: O=C1OC2CC=CC2C1Cc1ccc2ccccc2c1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@]1(Cc2ccc3ccccc3c2)C(=O)O[C@H]2CC=C[C@@H]21

Procedure:
Analogously to the procedure of Example 3, the title compound was prepared from 0.79 g (3 mmol) of the compound from Example 7, 3 ml of 1 molar lithium bis(trimethylsilyl)-amide solution in THF and 0.36 g (3 mmol) of allyl bromide in 10 ml of THF. Chromatographic purification was carried out using a mixture of dichloromethane and petroleum ether (40-60) in a ratio of 100:4. Yield: 684 mg (74.8%) of a pale yellow oil; Diastereomeric purity: >99% de (HPLC). MS (DCI/NH3) [m/e]: 322 (100, M+NH4+) 1H-NMR (200 MHz; CDCl3): δ[ppm]=2.24 (dd,1H); 2.37 (dd,1H), 2.72 (m,2H), 3.16 (d,1H), 3.28 (d,1H), 3.48(m,1H), 5.03 (dd,1H), 5.05 (m,1H), 5.12 (dd,1H), 5.78 (ddt,1H), 5.89 (m,1H), 6.04 (m,1H), 7.4-7.5 (br m,3H), 7.75 (s,1H), 7.8 (m,3H)
Reaction SMILES: O.[C:2]([C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][C@@H:11]([NH:26][C:27](=[O:38])[NH:28][C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([OH:34])=[O:33])[C:10]1=[O:39])=[O:7])([CH3:5])([CH3:4])[CH3:3].[Cl-].[Ca+2:41].[Cl-].O>C(O)C.N>[C:2]([C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][C@@H:11]([NH:26][C:27](=[O:38])[NH:28][C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([O-:34])=[O:33])[C:10]1=[O:39])=[O:7])([CH3:5])([CH3:3])[CH3:4].[Ca+2:41].[C:2]([C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][C@@H:11]([NH:26][C:27](=[O:38])[NH:28][C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([O-:34])=[O:33])[C:10]1=[O:39])=[O:7])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Nc2cccc(C(=O)O)c2)CN(C2CCCCC2)c2ccccc21
Agent: N
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Nc2cccc(C(=O)[O-])c2)CN(C2CCCCC2)c2ccccc21
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
In 220 ml of ethanol was suspended 22.0 g of (R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoic acid monohydrate. Under ice cooling, the resulting suspension was dissolved in 26.4 ml of concentrated aqueous ammonia. To the reaction mixture was added 22 ml of an aqueous solution of 3.05 g of calcium chloride, followed by stirring for 30 minutes. Water was added. The precipitate was collected by filtration and washed with a mixed solvent of water and ethanol (2:1), whereby 21.0 g of the title compound as powder was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:21][OH:22])=[C:4]([N:8]2[C:12](=[O:13])[C:11]3[S:14][C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:16][C:10]=3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([O:22][CH2:21][C:3]1[C:4]([N:8]2[C:12](=[O:13])[C:11]3[S:14][C:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:16][C:10]=3[CH2:9]2)=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:31])[CH3:30]
Reactant: CC(C)(C)c1cc2c(s1)C(=O)N(c1cccc(Br)c1CO)C2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1c(Br)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 114g (240 mg, 0.633 mmol), pyridine (150 mg, 1.90 mmol) and methylene chloride (10 mL). The solution was cooled to 0° C., and acetyl chloride (75 mg, 0.950 mmol) was added. The cooling bath was then removed, and the reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was partitioned between water (5 mL) and methylene chloride (5 mL), and the layers were separated. The aqueous phase was extracted with methylene chloride (2×10 mL), and the combined organic extracts were washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) and brine (10 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 114h in 86% yield (231 mg) as a white solid: mp 172-173° C.; 1H NMR (500 MHz, CDCl3) δ 7.63 (d, 1H, J=8.0 Hz), 7.34-7.21 (m, 2H), 6.87 (s, 1H), 5.21 (s, 2H), 4.64 (s, 2H), 2.05 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: F[C:2]([F:14])(F)[C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)=[O:4].N=C=N.Cl.[NH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].CCN(CC)CC>C(Cl)Cl>[O:22]=[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][NH:19][C:10]([C:8]1[S:9][C:5]([C:3](=[O:4])[CH2:2][F:14])=[CH:6][CH:7]=1)=[O:12]
Reactant: O=C(O)c1ccc(C(=O)C(F)(F)F)s1
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Agent: N=C=N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(C(=O)CF)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 1, A1 in DCM was added Pol-supported carbodiimide (2 eq) and the suspension was stirred at RT for 30 min. A solution of 2-aminoacetophenone HCl (1.1 eq) and Et3N (1.1 eq) in DCM was added and the resulting suspension was stirred at RT overnight. The resin was filtered, washed with DCM, and the filtrate was evaporated at reduced pressure. Purification by flash chromatography on silica gel eluting with DCM gave the title compound as a solid.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.Cl.Cl.[N:36]1([CH:41]2[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:43]4[CH2:44][CH2:45][CH:41]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH2:42]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: C1CCN(C2CCNC2)C1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N5CCCC5)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-pyrrolidinyl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 472 [M+H]
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15]1)(C1C=CC(C)=CC=1)(=O)=O.[OH:23][C:24]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[OH:23][C:24]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][CH2:28][N:27]([CH2:12][CH2:13][CH:14]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:26][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3ccccc3O2)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: OC1(c2ccccc2)CCN(CCC2Cc3ccccc3O2)CC1

Procedure:
The mixture of 4.6 g of 2-(2-tosyloxyethyl)-2,3-dihydrobenzofuran, 2.64 g of 4-hydroxy-4-phenylpiperidine, 10 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is refluxed for 48 hours. It is filtered, evaporated and the residue recrystallized from isopropanol-petroleum ether, to yield the 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-2,3-dihydrobenzofuran melting at 107°.
Reaction SMILES: C([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[C:15]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)[C:5]1=[O:24])(C)=C.O1CCOCC1.O.Cl>CO.C(Cl)Cl>[CH3:23][C:22]1[C:15]2[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[NH:4][C:5]3=[O:24])=[CH:18][S:17][C:16]=2[CH:19]=[CH:20][CH:21]=1
Reactant: C=C(C)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Temperature: 65 °C
Yield: 100.1 %

Procedure:
1-Isopropenyl-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (630 mg, 1.9 mmol) is dissolved in methanol (2.0 mL), 1,4-dioxane (10 mL) and water (2.0 mL). Then 37% HCl (1.6 mL) is added and the reaction mixture is heated at 65° C. for 6 hr. A white solid is formed during the heating. Then water (80 mL) and CH2Cl2 (80 mL) are added. The organic layer is separated and the aqueous layer is extracted with CH2Cl2 (3×50 mL). The organic layers are combined, washed with Sat. NaHCO3 (100 mL), Sat. NH4Cl (100 mL) and water (3×100 mL), dried over MgSO4 and concentrated to give 560 mg (99%) of 1-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one which is used for the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:39]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[O:11])=[CH:7][CH:8]=1)(=[O:39])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To the solution of rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.5 g, 0.91 mmol) prepared in Example 64 in DMSO (15 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.56 mL, 18 mmol), then aqueous solution (1N) of NaOH (4 mL, 4 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatograph (50-100% EtOAc in CH2Cl2) to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid (Yield 0.3 g, 58%)
Reaction SMILES: ON1C(=O)CCC1=O.[NH:9]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][C:11]([O:13]N1C(=O)CCC1=O)=O.[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30].C(N(CC)CC)C>CS(C)=O.O>[NH:9]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:10][C:11]([NH:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30])=[O:13]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: C[C@H](N)C(=O)O
Agent: O=C1CCC(=O)N1O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h
Yield: 41.5 %

Procedure:
Boc-Gly-Ala-OH was prepared by an N-hydroxysuccinimide coupling procedure. Boc-Gly-OSu (7.67 g, 28.2 mmol) was dissolved in 10 mL of dimethylsulfoxide and the resulting solution was added to a solution consisting of H-Ala-OH (3.76 g, 42.3 mmol) and triethylamine (5.89 mL, 42.3 mmol) in 20 mL of water. After stirring overnight, a precipitate was removed by filtration. The remaining solution was diluted with water and then acidified with hydrochloric acid. An aqueous phase separated from which product was extracted by addition of ethyl acetate. The ethyl acetate extract was washed with 0.2N hydrochloric acid and then saturated sodium chloride prepared in 0.2N hydrochloric acid. The washed ethyl acetate solution was then dried over sodium sulfate and filtered. Solvent was then evaporated, leaving a foamy product, which was crystallized from ethyl acetate:hexane to yield 2.88 g of Boc-Gly-Ala-OH (m.p. 128°-130°).
Reaction SMILES: N1C=CN=C1.S(Cl)([Cl:8])=O.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18](O)([C:25]([F:28])([F:27])[F:26])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:8][C:18]([C:12]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=1[F:10])([C:25]([F:28])([F:27])[F:26])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: O=S(Cl)Cl
Reactant: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CC#N
Product: Fc1ccc(C(Cl)(Cn2cncn2)C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Imidazole (0.53 g, 7.8 mmole) was dissolved in dry acetonitrile (4 ml) and thionyl chloride (0.3 ml, 4.1 mmole) was added dropwise over 2 minutes followed by a solution of 2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3,3,3-trifluoropropan-2-ol (0.389 g, 1.25 mmole) in dry acetonitrile (12 ml). The mixture was stirred at room temperature for 24 hours and then heated to 70° C. for 1/2 hour. The cooled mixture was then poured into sodium bicarbonate solution and extracted with dichloromethane (3×100 ml). The combined dichloromethane extracts were washed once with water, dried over magnesium sulphate and evaporated. Chromatography of the residue on silica (230-400 mesh), eluting with 40:60 (by volume) ethyl acetate:hexane gave, after recrystallization from ethyl acetate/hexane, the title compound, 170 mg (41%), m.p. 87°-88° C.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[CH2:23][N:24]1[C:30](=[O:31])[C@@H:29]2[C@H:25]1[C@@H:26]([OH:42])[CH2:27][N:28]2[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[CH2:23][N:24]1[C:30](=[O:31])[C@@H:29]2[C@H:25]1[C:26](=[O:42])[CH2:27][N:28]2[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]
Reactant: COc1ccc(CN2C(=O)[C@@H]3[C@H]2[C@@H](O)CN3C(=O)OCc2ccccc2)cc1OC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)[C@@H]3[C@H]2C(=O)CN3C(=O)OCc2ccccc2)cc1OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
3.7 g (47 mmol) of DMSO were dissolved in 50 ml of methylene chloride and cooled to −78° C. under argon. Then, 5 ml (35 mmol) of trifluoroacetic acid anhydride were added dropwise thereto, the mixture was stirred for 15 minutes and a solution of 9.7 g (23.5 mmol) of benzyl (1S,4S,5S)-6(3,4-dimethoxybenzyl)-4-hydroxy-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate in 50 ml of methylene chloride was slowly added dropwise thereto and left to react for 1.5 hours. Before it was left to warm to room temperature, 12 ml (70 mmol) of ethyldiisopropylamine were added thereto. The reaction mixture was then washed once each time with dilute aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and the organic phase was dried over magnesium sulphate. After concentration there were obtained 9.5 g (98%) of a yellow oil.
Reaction SMILES: CCC[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13]S([O-])(=O)=O.[Na+].[SiH4]>>[CH:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Agent: [SiH4]
Product: CCCCCCCCC=O
Reaction time: 0.17 h

Procedure:
Targets are complementary oligonulceotides labeled with fluorescent dye Cy3. Slides were hybridized with targets in hybridization buffer (2×SSC, 0.1% SDS and complementary target at 100 nM) at room temperature for 1 hr and washed in 2×SSC, 0.1% SDS for 5 min., 0.1×SSC, 0.1% SDS for 10 min., and finally in 0.1×SSC for 1 min. All washings were carried out at room temperature. Results show that the aldehyde slides prepared from photoactivatable silane gave much higher hybridization signal than non-aldehyde slides.
Reaction SMILES: [OH:1][C:2]([CH3:43])([CH3:42])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[N:17][C:18]([C:22]4[CH:23]=[N:24][C:25]([NH:28]C(=O)OC(C)(C)C)=[N:26][CH:27]=4)=[N:19]3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4].FC(F)(F)C(O)=O>CO.C(Cl)Cl>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([C:18]2[N:17]=[C:16]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:15]3[C:20](=[CH:21][C:12]([C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([OH:1])([CH3:43])[CH3:42])[CH:11]=[CH:10][CH:9]=4)=[CH:13][CH:14]=3)[N:19]=2)=[CH:23][N:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ccc(-c4cccc(NC(=O)C(C)(C)O)c4)cc3n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(O)C(=O)Nc1cccc(-c2ccc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 0 %

Procedure:
In a 25 mL round bottom flask, tert-butyl (5-(7-(3-(2-hydroxy-2-methylpropanamido)phenyl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-yl)carbamate (0.06 g, 0.0001 mol) and DCM (10 mL) were added. To the flask was added trifluoroacetic acid (0.5 mL) and the reaction stirred at room temperature for 5 hours. The volatiles were evaporated under reduced pressure to provide the residue. The residue was dissolved in 5% methanol in DCM and washed with saturated sodium bicarbonate. The organic layer was washed with water, brine, dried over sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by preparative HPLC (10 mM NH4OAc and 1:1 MeOH:ACN) to obtain the title compound (0.007 mg, 14%). 1H NMR (DMSO-d6, 400 MHz): δ 9.76 (s, 1H), 9.22 (s, 2H), 8.32 (s, 1H), 8.11 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.48 (t, J=8.8 Hz, 1H), 7.16 (s, 2H), 3.85 (s, 8H), 1.39 (s, 6H): LC-MS (ESI): Calculated mass. 485.2, Observed mass [M+H]+: 486.2. (RT=0.11 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C@@H:9]([C:17](=O)[NH2:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].II.[Cl-].[NH4+].[OH-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:20])[N:7]([C@@H:9]([CH2:17][NH2:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(N)=O
Agent: II
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CN)Cc1ccccc1
Temperature: 5 °C
Yield: 17.5 %

Procedure:
N-((1R)-1-Carbamoyl-2-phenylethyl)-N-methylcarbamic acid tert.-butylester (2.73 g, 9.81 mmol) was dissolved in tetrahydrofuran (10 ml). The solution was cooled to 5° C. A suspension of sodium borohydride (816 mg, 21.58 mmol) in tetrahydrofuran (10 ml) was added. A solution of iodine (1.24 g, 4.91 mmol) was added dropwise. After the addition was completed, the solution was heated to reflux for 16 h. It was cooled to 5° C. A 10% solution of ammonium chloride in water (60 ml) was added dropwise. The solution was warmed to 50° C. for 1 h. It was cooled to room temperature. 1 N sodium hydroxide solution was added until pH 14. It was extracted with tert-butyl methyl ether (4×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (150 g) using dichloromethane/methanol/25% aqueous ammonia 100:10:1 as eluent to give 453 mg of N-((1R)-1-aminomethyl-2-phenylethyl)-N-methylcarbamic acid tert-butylester.