Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([CH3:13])([CH3:12])[O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[C-:14]#[N:15].[Na+].C(Cl)(Cl)Cl>CS(C)=O.[Cl-].[Na+].O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]([CH3:13])([CH3:12])[CH2:2][C:14]#[N:15])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: CC(C)(CBr)Oc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(CC#N)Oc1ccc(Cl)cc1

Procedure:
A crude solution of 1-(2-bromo-1,1-dimethylethoxy)-4-chlorobenzene (60.3 mmol) in dimethyl sulfoxide (60 mL) is treated with sodium cyanide (180.7 mmol). The reaction mixture is heated to 95 degrees Celsius overnight under nitrogen. The reaction mixture is transferred into a separatory funnel using brine (150 mL) and chloroform (300 mL). The reaction mixture is equilibrated and the aqueous layer is removed. The aqueous layer is extracted an additional two times with chloroform (2×300 mL). The combined organic extracts are dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford 3-(4-chlorophenoxy)-3-methylbutyronitrile. This crude material is used in the next step (hydrolysis of the nitrile into the corresponding amide) without further purification. [Alternatively, the corresponding carboxylic acid can be obtained from this material by acid hydrolysis (e.g., using sulfuric acid).]
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH2:20]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[CH:18][CH:19]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1ccc(Oc2ncccc2C(N)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cccnc1Oc1ccc(CCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1107.4 %

Procedure:
Take up 2-[4-(2-aminoethyl)phenoxy]nicotinamide (0.0555 g, 0.216 mmol) in methanol (2.1 mL). Add benzaldehyde (0.022 mL, 0.216 mmol) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (0.0082 g, 0.216 mmol) and stir for 6 hours before loading directly onto an SCX column. Wash the column with methanol then elute with 2.0 M NH3 in methanol. Purify by flash chromatography, eluting with 4% (2.0 M NH3 in methanol) in dichloromethane to give the title compound (0.831 g, 79%): TOF MS ES+ 348.2 (M+H)+, HRMS calcd for C21H22N3O2 348.1712 (M+H)+, found 348.1721, time 0.35 min; TLC [silica gel 60 F254, 5% (2.0 M NH3 in methanol) in dichloromethane] Rf=0.20.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=3)[CH2:19][N:20]3[C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:29]([OH:31])=O)[C:23]=4[CH:22]=[CH:21]3)=[O:15])=[C:9]([C:35]3[CH:40]=[C:39]([C:41](=[O:54])[NH:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=4)[CH:38]=[CH:37][N:36]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:31]=[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[CH:22]=[CH:21][N:20]2[CH2:19][C:18]1[CH:32]=[CH:33][CH:34]=[C:16]([C:14](=[O:15])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][C:9]=2[C:35]2[CH:40]=[C:39]([C:41](=[O:54])[NH:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:51])([F:52])[F:53])[CH:45]=3)[CH:38]=[CH:37][N:36]=2)[CH:17]=1)[NH:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68]
Reactant: NCCOCCOCCOCCC(=O)O
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(Cn3ccc4c(C(=O)O)cccc43)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCOCCOCCOCCNC(=O)c1cccc2c1ccn2Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h
Yield: 36.5 %

Procedure:
A mixture of 3 mg of 1-(3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)-benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)-1H-indole-4-carboxylic acid 9.1, 1.7 mg of 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoic acid, and 2.5 mg of HATU in 300 μL of DMF was treated with 1.5 μL of diisopropylethylamine. After 2 h the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate, and the combined organic extracts were washed with brine and dried (Na2SO4). The solvent was evaporated and a fraction of the product was dissolved in 1:1 dichloromethane/TFA. After stirring for 1 h the solvent was evaporated and the residue was purified by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to yield 1.4 mg of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.57 (t, J=5.7 Hz, 1H), 8.98 (d, J=5.1 Hz, 1H), 8.51 (d, J=8.7 Hz, 1H), 8.40 (s, 1H), 7.93 (s, 1H), 7.89 (d, J=5.1 Hz, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.72 (s, 1H), 7.65 (m, 2H), 7.60-7.52 (m, 3H), 7.48 (t, J=7.7 Hz, 1H), 7.24-7.14 (m, 3H), 7.03-6.94 (m, 1H), 4.64 (d, J=5.8 Hz, 2H), 4.36 (s, 2H), 3.47 (s, 4H), 2.15 (t, J=7.3 Hz, 2H), 1.83 (br, 4H), 1.81-1.67 (m, 2H), 1.64 (br, 2H). MS (ES, m/z) 935.32 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([CH2:9][CH2:10][C:11](=O)[CH3:12])[CH:8]=1.[CH2:22]([NH2:34])[CH2:23][C:24]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:26]([O:27][CH3:28])[CH:25]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:28][O:27][C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][NH:34][CH:11]([CH3:12])[CH2:10][CH2:9][C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:33]=[CH:32][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(C#Cc2ccccc2)c(CCC(C)=O)c1
Reactant: COc1ccc(CCN)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C#Cc2ccccc2)c(CCC(C)NCCc2ccc(OC)c(OC)c2)c1
Yield: 90.2 %

Procedure:
4-[5-Methoxy-2-(phenylethynyl)phenyl]-2-butanone (0.5 g, 1.8 mmole), the product of Example 1d, and homoveratryl amine (0.33 g 1.8 mmole) were combined in 10 mL of absolute methanol. With stirring, sodium cyanoborohydride (0.21 g, 3.3 mmole) was added in three portions. During this addition, the pH was adjusted to 6 with glacial acetic acid. After stirring for 5 hr, the reaction mixture was concentrated in vacuo and the resulting residue dissolved in methylene chloride. The methylene chloride solution was washed with 1N sodium hydroxide, water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.72 g of the title compound as a golden oil. The free base was dissolved in absolute methanol (5 mL) and treated with oxalic acid (0.2 g). After stirring for several hours, ether (50 mL) was added and the solution was cooled and filtered to give 1.0 g of the title compound as the oxalate salt.
Reaction SMILES: C[Li].[CH2:3]([C:9]1[C:10](=O)[CH2:11][CH2:12][CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].BrCBr.C([Mg]Cl)(C)(C)C.C([O:26][CH2:27][CH3:28])C>>[CH2:3]([C@@:4]12[CH2:5][C@@H:6]1[CH2:7][CH2:8][C:27]2([CH3:28])[OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC1=CCCC1=O
Reactant: CCOCC
Agent: CC(C)(C)[Mg]Cl
Agent: [Li]C
Solvent: BrCBr
Product: CCCCCC[C@@]12C[C@@H]1CCC2(C)O
Yield: 60 %

Procedure:
Methyl lithium 1.6 M in diethyl ether (4 ml, 7 mmol) is added dropwise to 2-hexylcyclopent-2-enone (Isojasmone B11) (1 g, 6 mmol) in diethylether (4 ml) at −78° C. At 0°-5° C. dibromomethane (3×0.6 ml, 24 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (3×4 ml, 24 mmol) are added. Work-up after 18 h at 25° C. (as described in example 1) and bulb-to-bulb distillation gives 0.7 g (60%) of a colorless oil (cisltrans=93:7). 1H NMR (CDCl3): δ 0.3 (m, 1H), 0.7 (m, 1H), 0.9 (t, 3H), 1.05 (m, 1H), 1.2-2 (15H), 1.3 (s, 3H) ppm. 13C-NMR (CDCl3): δ 11.0 (t), 14.0 (q), 22.6 (t), 23.4 (d), 24.7 (t), 25.15 (q), 27.5 (t), 29.9 (t), 31.2 (t), 31.8 (t), 34.3 (s), 37.9 (t), 81.05 (s). cis-configuration assigned by COSY, HMBC, HSQC, NOESY in CDCl3. MS (EI): m/z (%) 196 (M+, 2), 181 ([M-15]+, 14), 155 (24), 138 (15), 135 (27), 125 (32), 110 (34), 107 (38), 93 (92), 79 (50), 57 (14), 43 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)=[N:8]2.[NH:27]1[CH2:32][CH2:31][CH:30]([N:33]2[C:37]3=[N:38][CH:39]=[N:40][C:41]([NH2:42])=[C:36]3[CH:35]=[N:34]2)[CH2:29][CH2:28]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.CO>[CH3:1][O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:7]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[C:37]5=[N:38][CH:39]=[N:40][C:41]([NH2:42])=[C:36]5[CH:35]=[N:34]4)[CH2:29][CH2:28]3)=[CH:19][CH:20]=1)=[N:8]2
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Reactant: COc1nccc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1nccc2nc(-c3ccc(CN4CCC(n5ncc6c(N)ncnc65)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(5-methoxy-3-phenyl-1,6-naphthyridin-2-yl)benzaldehyde (80 mg, 0.235 mmol) and 1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-4-amine (58 mg, 0.26 mmol) in dry DMF (1 mL) containing acetic acid (70 μL, 1.25 mmol) was stirred at room temperature 16 hours. Sodium triacetoxyborohydride (91 mg, 0.43 mmol) was then added to the semi-solid mixture and stirred for three hours. The mixture was diluted with methanol and the solvent evaporated. The residue was purified by column chromatography on silica gel eluting with a 0.5 to 5% methanol/ethyl acetate (sat'd NH3) gradient. The combined fractions were concentrated and the residue was digested with acetonitrile to afford upon cooling the pure title compound. 1H-NMR (500 MHz, CDCl3): δ 8.55 (1H, s), 8.39 (1H, s), 8.23 (1H, d, J=6 Hz), 7.92 (1H, s), 7.56 (1H, d, J=6 Hz), 7.41 (2H, d, J=7.8 Hz), 7.24-7.33 (5H, m), 5.40 (2H, br s), 4.75 (1H, m), 4.17 (3H, s), 3.57 (2H, br s), 2.31-2.41 (2H, m), 2.18-2.28 (2H, m), 1.96 (2H, br d, J=10.7 Hz). m/e (m+1): 543.3.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[N:14](OS(=O)(=O)O)=O.S(=O)(=O)(O)O.[CH2:26]([CH:28]([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:29][O:30][C:31]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH:40]([CH2:45][CH3:46])[CH2:41][CH2:42][CH2:43][CH3:44])=[CH:34][C:32]=1[NH2:33])[CH3:27]>C(O)(=O)C.C(O)(=O)CC.S(=O)(=O)(O)N>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[N:6]=[N:14][C:36]1[C:35]([O:38][CH2:39][CH:40]([CH2:45][CH3:46])[CH2:41][CH2:42][CH2:43][CH3:44])=[CH:34][C:32]([NH2:33])=[C:31]([O:30][CH2:29][CH:28]([CH2:26][CH3:27])[CH2:47][CH2:48][CH2:49][CH3:50])[CH:37]=1)([O-:3])=[O:2]
Reactant: CCCCC(CC)COc1ccc(OCC(CC)CCCC)c(N)c1
Reactant: O=NOS(=O)(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: NS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCC(=O)O
Product: CCCCC(CC)COc1cc(N=Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(OCC(CC)CCCC)cc1N
Temperature: 3 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
2,4-Dinitroaniline (3.7 g, 0.02 mol) is suspended in a mixture of acetic acid (20 ml) and propionic acid (10 ml) and cooled to 3° C. 40% (w/w) nitrosyl sulfuric acid in sulfuric acid (6.4 g, 0.02 mol) is added dropwise and stirring continued for 30 minutes to give a pale yellow solution. Crude 2,5-bis(2-ethylhexyloxy)aniline (0.02 mol) solution is diluted with IMS (200 ml) and 10% sulfamic acid solution (20 ml) added, followed by ice (200 g). The above pale yellow diazonium salt solution is slowly added with stirring and a dark oil rapidly separated. The mixture is stirred overnight and the water is decanted off. The crude product (8.3 g) is dissolved in 25/75 dichloromethane/hexane and purified over silica gel, the required product eluting with 50/50 hexane/dichloromethane. Evaporation and trituration with methanol gave 4-((2,4-dinitrophenyl)diazenyl)-2,5-bis(2-ethylhexyloxy)-aniline as a violet-blue crystalline solid (4.2 g, 39%).
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[F:13].[C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#N.Cl.[OH-:23].[Na+]>ClC=C(Cl)Cl.O.ClCCl>[NH2:12][C:9]1[C:10]([C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:23])=[CH:11][C:6]([F:5])=[C:7]([F:13])[CH:8]=1
Reactant: [OH-]
Reactant: Nc1ccc(F)c(F)c1
Reactant: N#Cc1cccnc1
Agent: Cl
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: ClC=C(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Nc1cc(F)c(F)cc1C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
BCl3 (6.2 ml, 1M in DCM) was added dropwise to 1,2-difluoro-4-aminobenzene (0.5 g, 0.004 mol) in trichloroethylene (6.5 ml) at 0° C., the reaction mixture stirred for 15 min, then 3-Cyanopyridine (0.48 g, 0.005 mol) added and the solution warmed to room temperature and stirred for 30 min. The solution was then heated at 80-90° C. for 1 h. The resulting solution was refluxed at 160° C. for 4 hr, then stirred at room temprature over night, then 3N HCl was added to the reaction mixture and again refluxed at 110° C. for 1.5 h. The reaction mixture was cooled to RT and made basic (pH=12) with 6N NaOH. The reaction mixture was diluted with water and dichloromethane. The resulting two layers were separated and the aqueous layer was extracted with dichloromethane, dried over sodium sulfate and concentrated. The compound was purified by column chromatography on silica gel. 1H NMR (CDCl3): 6.29 (bs, 2H, NH2), 6.56 (m,1H), 7.25 (m,1H), 7.46 (m,1H), 7.93 (m,1H), 8.80 (m,1H), 8.85 (s, 1H). 13C NMR (CDCl3): 104.5, 104.7, 112.7, 121.3, 123.3, 135.1, 136.1, 142.5, 149.3, 149.5, 152.0, 153.8, 153.9, 156.3, 194.7. LC-MS m/e=235 (M+H)+. HPLC [c18 BDS 25 min column, flow=0.8 ml/min (70:30; ACN:0.1% TFA), rt=4.34 min].
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:11]=[C:8](C=O)[C:7](O)=[C:6]([CH2:13][CH3:14])[CH:5]=1.[OH:15]O>O1CCCC1>[Br:3][C:4]1[CH:11]=[C:8]([OH:15])[CH:7]=[C:6]([CH2:13][CH2:14][OH:1])[CH:5]=1
Reactant: [OH-]
Reactant: OO
Reactant: CCc1cc(Br)cc(C=O)c1O
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1cc(O)cc(Br)c1
Reaction time: 0.5 h

Procedure:
A 2L flask was charged with tetrahydrofuran (600 mL) and one normal aqueous sodium hydroxide (260 mL). To this solution was added 5-bromo-3-ethylsalicylaldehyde (58 g, 0.25 mol, prepared by the procedure described by S. A. Weerawarna et al., J. Het. Chem., 1991;28:1400). With good stirring, hydrogen peroxide (400 mL of 3% solution, 0.35 mol) was slowly added. After 30 minutes, tlc (silica plate eluted with hexane:ethyl acetate, 7:3) showed no more starting material. The reaction mixture was brought to a pH of ˜5.0 by addition of acetic acid. The tetrahydrofuran was removed under vacuum, then the aqueous mixture was extracted twice with 300 mL portions of methyl t-butyl ether. The ether solution was dried over magnesium sulfate, filtered, and concentrated to a dark oil (54.8 g). This material was not further purified, but used directly in the next reaction.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:30](=[O:40])[N:31]([CH3:39])[CH2:32][CH2:33][C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)C)(C)(C)C.C(=O)([O-])O.[Na+].O>ClCCl>[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][C:18]([CH2:17][C@@H:16]([NH:14][CH3:13])[C:30]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:40])=[CH:23][CH:22]=1
Reactant: CN(CCc1cccs1)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N(C)CCc1cccs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
At 0° C., trifluoroacetic acid (4 ml) was added to a solution of N-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)ethyl)-N-methylcarbamic acid tert-butyl ester (910 mg, 1.90 mmol) in dichloromethane (4 ml). The reaction mixture was stirred for 3 h at 0° C. A saturated solution of sodium hydrogen carbonate (8 ml) was added. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. Water was added, until a clear solution was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (2×30 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude produduct was purified by flash chromatogrphy on silica (60 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 674 mg of (2R)-3-(biphenyl-4-yl)-N-methyl-2-(methylamino)-N-(2-(2-thienyl)ethyl)propionamide.
Reaction SMILES: [Mg:1].Br[C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[Br:12]C(Br)C>C1COCC1>[S:7]1[CH:8]=[CH:9][C:5]2[CH:4]=[C:3]([Mg:1][Br:12])[CH:11]=[CH:10][C:6]1=2
Reactant: CC(Br)Br
Reactant: [Mg]
Reactant: Brc1ccc2sccc2c1
Solvent: C1CCOC1
Product: Br[Mg]c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of magnesium (34 mg, WAKO) in dehydrated THF (0.7 ml) was added dropwise with a solution of 5-bromobenzo[b]thiophene (149.2 mg, MAYB) and dibromoethane (30 μl, WAKO) in dehydrated THF (0.7 ml) under an argon atmosphere, and the mixture was stirred at room temperature for 2 hours to obtain a THF solution of the title compound (Compound No. MG01).
Reaction SMILES: C[Si]([C:5]#[C:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])(C)C.[Br:17]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:17][C:5]#[C:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)C#C[Si](C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)C#CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a stirred solution of trimethylsilyl p-tolylsulfonylacetylene (10 g, 40 mmol) in acetone (300 mL) was added silver nitrate (0.68 g, 4 mmol) followed by the addition of N-bromosuccinimide (7.6 g, 44 mmol) in one portion. The mixture was stirred at room temperature for 1 h. The resulting precipitate was filtered and washed with acetone. Silica gel (20 g) was added to the filtrate and the solvent was removed under reduced pressure. The residue was subjected to column chromatography with hexane/EtOAc (5:1) to afford the product as a light yellow solid (10 g, 96%). Mp. 99-101° C. 1H NMR (CDCl3) δ 7.87 (d, 2H, J=7.8 Hz), 7.39 (d, 2H, J=7.8 Hz), 2.47 (s, 3H); 13C NMR (CDCl3) δ 146.19, 138.16, 130.34, 127.83, 78.14, 61.70, 21.97.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].O>O1CCCC1>[C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(O)cc1
Yield: 85.4 %

Procedure:
109 g (1 mole) of 4-amino-phenol and 101 g of triethylamine were dissolved in 700 ml of tetrahydrofuran. 120.5 g (1 mole) of pivalyl chloride were added dropwise at 10°-15° C., with stirring. The mixture was subsequently stirred at room temperature for 2 hours and then poured into 3 liters of water. The crystals precipitated were filtered off with suction and dried in air. 165 g (85.5% of theory) of 4-pivaloylamino-phenol were obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][CH2:22][CH3:23])[C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(OC(C)(C)C)=O.Cl>O1CCOCC1>[CH3:1][N:2]([CH2:20][CH2:21][CH2:22][CH3:23])[C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: CCCCN(C)C(=O)CCCCCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCN(C)C(=O)CCCCCCCN
Reaction time: 1 h

Procedure:
Combine 8-(t-butoxycarbonyl)amino-octanoic acid methyl-butyl-amide and 4M hydrochloric acid in dioxane (10 mL). After 1 hour, the reaction mixture is evaporated to a residue. Partition the residue between toluene and 1M sodium hydroxide solution. Extract the aqueous layer with toluene. Combine the organic layers, dry over MgSO4, and filter to give the title compound as a toluene solution. Evaporate in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:27]1([CH2:33][S:34][CH:35]([C:39](O)=[O:40])[C:36](O)=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:36](=[O:37])[C:35]([S:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:39]([OH:40])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cc(C)cc(C)c1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3',5'-dimethylacetophenone (0.785 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 170° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.33 (s, 6 H), 3.99 (s, 2 H), 6.67 (s, 1 H), 7.21 (m, 6 H), 7.39 (s, 2 H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8](=[O:17])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.CS(C)=O>[O:17]1[CH2:4][CH:8]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CCCc1ccccc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: c1ccc(CCC2CO2)cc1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Dimethyl sulphoxide (100 ml) was added over 5 minutes to sodium hydride (6.76 g of a 55% oil dispersion, 0.155 mol) under a nitrogen atmosphere. The mixture was stirred vigorously for 10 minutes, then diluted with anhydrous tetrahydrofuran (80 ml). The mixture was cooled to 5° C. and a solution of trimethylsulphonium iodide (31.63 g, 0.155 mol) in dimethyl sulphoxide (80 ml) was added slowly keeping the temperature of the reaction mixture at 5° C. After addition the reaction mixture was stirred at 5° C. for 2 minutes then a solution of hydrocinnamaldehyde (20.0 g, 0.149 mol) in anhydrous tetrahydrofuran (20 ml) was added over 1 minute. After 15 minutes at 5° C. the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (200 ml), then extracted with ethyl acetate (3×100 ml). The combined extracts were washed with saturated sodium chloride solution (200 ml), dried (potassium carbonate) then evaporated to give an orange oil which was purified by distillation under vacuum. (±)-(3,4-Epoxybutyl)-benzene was obtained as a colourless oil (5.2 g, 23%), bp 80°-85° C. (4 mbar).