Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[C:27][CH:28]4[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:34](=O)[CH2:35][CH3:36].[BH3-]C#N.[Na+].Cl>CO.O.CC(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[C:27][CH:28]4[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][CH3:36])[CH2:29]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC=O
Reactant: Cc1cc(Nc2ncnc3ccc(C#CC4CCCNC4)cc23)ccc1Oc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCCN1CCCC(C#Cc2ccc3ncnc(Nc4ccc(Oc5ccccc5)c(C)c4)c3c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine (114 mg, 0.2 mmol) and propionaldehyde (116 mg, 2.0 mmol) were dissolved in MeOH/H2O (5/0.5 mL) and the pH was adjusted to 5 with AcOH. The reaction was stirred at room temperature overnight and followed by the addition of NaBH3CN (13 mg, 0.2 mmol) over a period of 1 hour. After stirring for another hour, the reaction was concentrated and the residue was partitioned between CH2Cl2 (30 mL) and saturated Na2CO3 (20 mL). The separated organic layer was dried over sodium sulfate and concentrated. Purification by preparative TLC using 10% MeOH in EtOAc gave the free base product which was converted to HCl salt to yield 42 mg (38%) of yellow solid: 1H NMR (CD3OD) δ 1.03 (t, 3H), 1.78-1.87 (m, 4H), 2.01-2.08 (m, 2H), 2.28 (s, 3H), 2.96 (t, 1H), 3.07-3.19 (m, 3H), 3.31 (br, 1H), 3.59 (d, 1H), 3.80 (d, 1H), 6.94 (m, 3H), 7.09 (t, 1H), 7.34 (t, 2H), 7.53 (d, 1H), 7.63 (s, 1H), 7.80 (d, 1H), 8.05 (dd, 1H), 8.73 (s, 1H), 8.75 (s, 1H); MS m/z (MH+) 477.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH:13]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1.O.[H][H]>C1(C)C=CC=CC=1.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13][N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([CH3:16])[CH2:18]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CCCNC1
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCCN(CC(C)Cc2ccc(C(C)(C)C)cc2)C1

Procedure:
4.45 Kg. of 3-(p-tert.-butyl-phenyl)-2-methyl-propionaldehyde and 2.38 kg. of 3-methyl-piperidine are heated at reflux in 3.42 liters of toluene for 16 hours in a water-separator under nitrogen gasification until the water-cleavage has been completed. 197 G. of 5% palladium/carbon are added at room temperature under nitrogen gasification and the mixture is subsequently hydrogenated until the hydrogen uptake has been completed. The catalyst is then removed by filtration and the toluene evaporated in vacuo. By distillation of the residue, there is obtained pure 1-[3-(p-tert.-butyl-phenyl)-2-methyl-propyl]-3-methyl-piperidine, having a boiling point of 115°-117° C./0.02 Torr.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>>[Cl:1][C:2]1[N:7]=[C:6]([C:17]2[C:10]([CH3:9])=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1c(C=O)cccc1-c1ccnc(Cl)n1
Yield: 50 %

Procedure:
2,4 dichloropyrimidine and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was coupled following procedure A. The yield was 50%. LC-MS showed the product was >95% pure and had the expected M+H+ of 233. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.9 (s, 1H) 8.6 (s, 1H) 7.5 (d, 2H) 7.4 (t, 1H), 7.2 (d, 1H), 2.5 (s, 3H).
Reaction SMILES: [CH2:1]([O:8]C1C(OC)=CC(C(Cl)=O)=CC=1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:24]1CCC[C@H]1CN)C.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(=O)C1C=CC=CC=1.C1(S(O)(=O)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([NH2:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OCc1ccccc1
Reactant: CCN1CCC[C@H]1CN
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: NC(=O)c1ccccc1

Procedure:
First, 4-benzyloxy-3,5-dimethoxybenzoic acid chloride represented by Formula 85 and [(2S)-1-ethylpyrrolidin-2-yl]methanamine represented by Formula 103 were prepared in 0.2 M solution, respectively, using a toluene solvent. An amine solution (1.2 mL, 0.240 mmol) entered 10 mL vial and a sodium carbonate solution (0.4 mL, 0.200 mmol) was added thereto. Thereafter, a benzoic acid chloride solution (1.0 mL, 0.200 mmol) entered the vial, vigorously shaken and agitated at room temperature for 18 hours. After terminating the reaction, an organic layer was moved to a cartridge tube (6 mL, benzenesulfonic acid, 904030-WJ, UCT) using ethyl acetate. Impurities were removed using methanol (15 mL) while separation and purification were conducted using an elute solution (ethyl acetate/methanol/triethylamine, 20:2:1, v/v/v), resulting in a benzamide compound represented by Formula 13 as a desired product (VVZ-014; 66 mg, 83% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O.[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:16])=[O:10])=[CH:5][CH:4]=1.[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19]
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C=CC(=O)Cl)cc1
Yield: 345.4 %

Procedure:
In a 1.5-m3 reactor, 105 kg of 4-methoxycinnamic acid and 462 kg of ethyl acetate were placed to give a suspension. The suspension was combined with 73.6 kg of thionyl chloride (1.05 times the mole of 4-methoxycinnamic acid) added dropwise while maintaining the reactor inside temperature at 65° C. to 70° C. After the dropwise addition, a reaction was performed until the conversion from 4-methoxycinnamic acid reached 99% or more. After the completion of reaction, about 200 kg of ethyl acetate was distilled off together with unreacted thionyl chloride and an acidic gas at 60° C. under reduced pressure. After the concentration by distillation, the mixture was combined with ethyl acetate in an amount equal to the distilled-off amount and yielded 579.6 kg of a 4-methoxycinnamoyl chloride/ethyl acetate solution (1).
Reaction SMILES: [Cl:1][C:2]1[C:7](/C(/C)=C/C(=O)C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][CH:21]([O-:23])[CH3:22].[CH3:24][CH:25]([O-])C.CC([O-])C.[Al+3].C(O)(C)C>>[Cl:1][C:2]1[CH:7]=[C:6](/[C:24](/[CH3:25])=[CH:20]/[CH:21]([OH:23])[CH3:22])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)[O-]
Reactant: CC(=O)/C=C(\C)c1cccc(-c2ccccc2)c1Cl
Agent: [Al+3]
Solvent: CC(C)O
Product: C/C(=C\C(C)O)c1ccc(-c2ccccc2)c(Cl)c1
Reaction time: 5 h

Procedure:
80.0 Gm (0.296 mol) of (E)-4-(2-chloro-biphenylyl)-3-pentene-2-one were gently refluxed with 68.0 gm (0.333 mol) of aluminum isopropylate and 300 ml (3.92 mols) of isopropanol in a dry distillation apparatus with a 60-cm-Vigreux-column, such that only about 5 drops were distilled off per minute. After about 5 hours no acetone was found to be present in the distillate (using hydrochloric acid 2,4-dinitrophenyl-hydrazine solution) and in the reaction mixture no unreacted starting material could be found (by thin-layer-chromatography). The isopropanol was distilled off in a weak vacuum. The residue was hydrolyzed by addition of 300 gm of crushed ice. The ethereal (upper) phase, was decanted, and the aluminum hydrozide slurry was carefully washed with ether several times. The combined extracts were washed with water, with aqueous 5% sodium hydroxide and again with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized once from petroleum ether/ethyl acetate (ratio by volume = 4:1). Yield: 64.0 gm (79% of theory) of colorless crystals, m.p. 86°C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@:12]3([OH:30])[CH2:13][CH2:14][C@@H:15]2[C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)[CH2:7]1.[N+:31]([O-:34])([O-])=[O:32].CC1([C:42]([NH2:44])=[NH2+:43])C=C(C)N=N1>C(O)C>[N+:31]([O:30][C@@:12]12[C@H:11]3[C@@H:20]([C@:21]4([CH3:24])[C@H:8]([CH2:9][CH2:10]3)[CH2:7][C@@H:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:42]([NH2:44])=[NH:43])[CH2:23][CH2:22]4)[CH2:19][CH2:18][C@:16]1([CH3:17])[C@@H:15]([C:25]1[CH:29]=[CH:28][O:27][CH:26]=1)[CH2:14][CH2:13]2)([O-:34])=[O:32]
Reactant: C[C@]12CC[C@H](OCCCN)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Reactant: O=[N+]([O-])[O-]
Reactant: CC1=CC(C)(C(N)=[NH2+])N=N1
Solvent: CCO
Product: C[C@]12CC[C@H](OCCCNC(=N)N)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O[N+](=O)[O-]

Procedure:
To a solution of 0.10 g of 3β-(3-aminopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol (I-ab) in 7 ml of absolute ethanol 0.060 g of 3,5-dimethyl-1-pyrazolylformamidinium nitrate were added and the mixture was kept at reflux temperature for 24 hrs; the ethanol was concentrated under reduced pressure and 0.090 g of the title compound (I-am) crystallized as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][N:13]=[CH:14][C:8]=2[CH2:7]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[CH:4]([NH2:15])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][N:13]=[CH:14][C:8]=2[CH2:7]1
Reactant: COC(=O)C(CN1CCc2[nH]ncc2C1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(N)CN1CCc2[nH]ncc2C1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of 2-(di-tert-butoxycarbonylamino)-3-(1,4,6,7-tetrahydro-pyrazolo-[4,3-c]pyridin-5-yl)-propionic acid methyl ester (0.55 g, 1 equiv.) in methylene chloride (5 mL, 0° C.) was added trifluoroacetic acid (1.5 mL). The ice bath was removed and stirring continued for 2 h. The solution was concentrated, redissolved in methanol, and passed onto a column of strong cation exchange resin. After flushing with methanol, the product was removed from the column by eluting with 2 M ammonia in methanol to afford the product as its free base (275 mg, 95%). 1H-NMR (CDCl3, 500 MHz) δ 2.71 (dd, J=12.8, 8.6, 1H), 2.74–2.91 (m, 6H), 3.48 (s, 2H), 3.54 (d, J=13.4, 1H), 3.62 (d, J=13.4, 1H), 3.69 (dd, J=8.2, 4.9, 1H), 3.73 (s, 3H), 7.27 (s, 1H). Mass spec.: 225.16 (MH)+.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>O.O1CCOCC1.CN(C)C1C=CN=CC=1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([N:1]2[CH2:8][CH2:7][CH2:6][C@@H:2]2[C:3]([OH:5])=[O:4])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@H]1CCCN1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
D-proline (15 g, 130.3 mmol) is dissolved in a 1:1 mixture of water (150 mL) and p-dioxane (150 mL) and then triethyl amine (40 mL, 287 mmol), 4-methoxyphenylsulfonyl chloride (29.0 g, 140.3 mmol), and the 4-dimethylaminopyridine (1.5 g, 13.0 mmol) are added. The solution is stirred at room temperature overnight. The reaction mixture is then treated with 1N HCl until the solution is acidic (pH=2). The resulting solution is extracted three times with ethyl acetate. The ethyl acetate layers are washed with ammonium chloride, dried (MgSO4), filtered and evaporated to give the crude compound. Cl+ MS: m/z (rel intensity) (M+ +H 286, 100 ).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.[NH:14]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:15]1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:14]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:15]1
Reactant: COC(=O)c1cc[nH]n1
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(-c2ccc(OC)cc2OC)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4-dimethoxyphenylboronic acid 1 (2.88 g, 15.8 mmol, 1.00 equiv) in DMF (100 mL) was added methyl 1H-pyrazole-3-carboxylate (3.00 g, 23.7 mmol, 1.50 equiv), Cu(OAc)2 (5.70 g, 31.6 mmol, 2.00 equiv), and pyridine (3.76 g, 47.4 mmol, 3 equiv). The resulting solution was stirred for 2 h at 90° C. The solids were filtrated off by filtration and the filtrate was extracted by EtOAc (200 mL×3). The combined organic layers were dried by anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with PE/EA (3/1). This resulted in 1.5 g (36%) of methyl 1-(2,4-dimethoxyphenyl)-1H-pyrazole-3-carboxylate 2 as a brown solid. 1H NMR (300 MHz, CDCl3): δ 7.88 (d, J=2.4 Hz, 1H), 7.61 (d, J=9 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.59 (s, 1H), 7.73, 6.58 (d, J=8.7 Hz, 1H). LC-MS: m/z=263 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[H][H]>[Pd].CCCCC>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCCCC
Product: CC1(C)CCC(=O)CC1
Reaction time: 0.5 h

Procedure:
4,4-Dimethyl-cyclohexene-1-one (5 g, 52 mmol) and n-pentane (50 mL) were placed in a hydrogen reaction vessel and Pd/C (300 mg) was added. The hydrogen reaction vessel was purged three times with hydrogen and subsequently pressurized with hydrogen (25 psi). After shaking in a Parr hydrogenator for 30 min., the reaction mixture was filtered though Celite and the filtrate concentrated in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9][CH3:10])[CH2:7][S:8][C@H:3]12.C(O)(=O)[CH:17]([CH:19]([C:21](O)=O)O)O.[CH3:26]O>>[NH2:1][C@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([O:13][C:19]([CH3:17])([CH3:21])[CH3:26])=[O:12])=[C:6]([CH2:9][CH3:10])[CH2:7][S:8][C@H:3]12
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CO
Reactant: CCC1=C(C(=O)[O-])N2C(=O)[C@H](N)[C@H]2SC1
Product: CCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](N)[C@H]2SC1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2.84 g of tert.-butyl DL cis 7-amino-3-ethyl-3-cepheme-4-carboxylate, 1.65 g of D(-) tartaric acid and 8 ml of methanol was heated to 60°C and the temperature was returned to room temperature and held at 18°C for 10 minutes. The mixture was vacuum filtered and the precipitate was washed with a 1-1 methanol-ether mixture and then with ether and dried. The residue was then dissolved in 25ml of aqueous 10% sodium bicarbonate and 15 ml of methylene chloride and the organic phase was decanted. The aqueous phase was reextracted with methylene chloride and the combined organic phases were dried over magnesium sulfate and evaporate to dryness. The residue was taken up in ether and the mixture was vacuum filtered to obtain 1.19 g of the L (+) enantiomorph of tert.-butyl cis 7-amino-3-ethyl-3-cepheme-4-carboxylate melting at 120°C and having a specific rotation [α]D20 = + 74° ± 2.5° (c = 0.5% in chloroform).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]2[B:16]([OH:17])[O:15][CH2:14][C:13]=2[CH:18]=1)(O)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:46]([NH:48][CH2:49][CH3:50])[CH3:47]>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[C:23]([C:21]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[B:16]([OH:17])[O:15][CH2:14][C:13]=3[CH:18]=2)=[C:6]([CH:22]=1)[O:5][CH2:4][C:1]([N:48]([CH2:49][CH3:50])[CH2:46][CH3:47])=[O:2])#[N:24]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(OCC(=O)O)c1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COc1cc(C#N)ccc1Oc1ccc2c(c1)COB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A mixture of 5-[2-(Carboxymethoxy)-4-cyanophenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (D17) (1.00 g, 3.08 mmol), EDCI (1.77 g, 9.24 mmol), HOBT (1.25 g, 9.24 mmol), diethylamine (0.96 mL, 9.24 mmol), and 4-dimethylaminopyridine (75 mg, 0.62 mmol) in DMF (20 mL) was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (9:1 chloroform/methanol). The combined fractions were put under reduced pressure to remove solvent and then washed with water and toluene. The solvent was again removed under reduced pressure. Another silica gel chromatography column was used (5:5 acetone:hexane). The desired fractions were combined and the solvent was removed under reduced pressure. The residue was recrystallized using hexanes and diisopropylether. Pure 2-(5-cyano-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)phenoxy)-N,N-diethylacetamide (0.662 g, 57%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:8]([N:11]([CH2:19][C:20]([OH:22])=O)[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[C:20](=[O:22])[CH2:19][N:11]([S:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:9])=[O:10])[C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)[CH3:24]
Reactant: CCNCc1cccc(C)n1
Reactant: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)c1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1cccc(C)c1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=O.[C:19]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)([CH3:22])([CH3:21])[CH3:20].C(O)C.[BH4-].[Na+]>O.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[CH2:7][NH:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:32])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Bromo-2-benzyloxybenzoic acid [International patent application, publication no, WO 96/03380] and tert-butyl-4-aminobenzoate were heated on a steam bath for 2 hours. Ethanol (50 ml) and tetrahydrofuran (50 ml) were added to the hot reaction mixture. The solution was allowed to cool and sodium borohydride (1.4 g) was added. The reaction mixture was then stirred at ambient temperature for 3 hours, poured into water (200 ml) and extracted with dichloromethane (4×100 ml). The combined extracts were dried over magnesium sulphate to give tert-butyl 4-[5-bromo-2-benzyloxybenzylamino]benzoate which was used without further purification (18 g).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[O:31]([CH2:38][CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[O:31]([CH2:38][CH2:39][O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOc1ccccc1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: c1ccc(OCCOCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 2-phenoxyethane chloride are treated as described in Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([CH2:13][C:14]2([CH3:17])[CH2:16][CH2:15]2)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.CN(C(O[N:26]1N=[N:33][C:28]2C=CC=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]([CH2:13][C:14]2([CH3:17])[CH2:16][CH2:15]2)[C:10]([NH:33][CH2:28][C:27]#[N:26])=[O:12])=[CH:6][CH:7]=1
Reactant: CC1(CC(Sc2ccc(Br)cc2)C(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(CC(Sc2ccc(Br)cc2)C(=O)NCC#N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice cold solution of 2-[(4-bromophenyl)thio]-3-(1-methylcyclopropyl)propanoic acid (417 mg, 1.3 mmol), HATU (652 mg, 1.7 mmol), 2-aminoacetonitrile hydrochloride (171 mg, 1.8 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (0.68 mL, 3.9 mmol) dropwise. The resulting mixture was stirred at room temperature for 18 h and partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc in hexane to afford 2-[(4-bromophenyl)thio]-N-(cyanomethyl)-3-(1-methylcyclopropyl)propanamide.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:22])[NH:18][CH:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH:19]([NH:18][C:17]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH2:8])=[CH:15][CH:14]=1)=[O:22])([CH3:21])[CH3:20]
Reactant: CC(C)NC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)NC(=O)Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Dissolve N-(tert-butoxycarbonyl)-4-(iso-propylcarbamoyl-methyl)-benzylamine (426 mg, 1.4 mmol) in DCM (5 mL). Add 4M hydrogen chloride in dioxane (3.5 mL, 14 mmol) and stir at room temperature for 1 h. Concentrate in vacuo and elute the compound through a SCX column to obtain the title compound as a white solid (281 mg, 98%). MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=[O:10]
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
1,2-Dibromoethane (56 mL, 0.66 moles) was added to a mixture of 3-hydroxy-4-methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 328 mmoles) in DMF (170 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:1) to afford 9.8 g (58%) of 3-(2-bromoethoxy)-4-methoxybenzaldehyde.