Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Li+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([O:14][CH:15]1[CH2:19][CH:18]([C:20]([O:22]C)=[O:21])[NH:17][C:16]1=[O:24])[CH:8]=[CH:7]2.Cl>O.O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([O:14][CH:15]([C:16]([OH:24])=[O:1])[CH2:19][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:17])[CH:8]=[CH:7]2
Reactant: COC(=O)C1CC(Oc2ccc3cc(Br)ccc3c2)C(=O)N1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CC(Oc1ccc2cc(Br)ccc2c1)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of lithium hydroxide (0.156 g) in water (2.0 ml) and tetrahydrofuran (6.6 ml) was treated with methyl 3-(6-bromo-2-naphthyloxy)-2-pyrrolidone-5-carboxylate (0.615 g), and heated to 60° C. After about 3.0 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was treated with 5N HCl (1.30 ml). The insolubles were collected by filtration, washed with 1:1 THF:water (10 ml), THF (10 ml), and water (5 ml). The insolubles were dried overnight in at vacuum oven at 60° C. to afford the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][N+:12]([O-:14])=[O:13])(C)(C)C.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[CH3:15][C:8]([NH2:7])([CH3:16])[CH2:9][CH2:10][CH2:11][N+:12]([O-:14])=[O:13]
Reactant: CC(C)(CCC[N+](=O)[O-])NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)CCC[N+](=O)[O-]
Temperature: 25 °C
Yield: 88 %

Procedure:
To (1,1-Dimethyl-4-nitro-butyl)-carbamic acid tert-butyl ester (1.0 g, 4.0 mmol) in 25 mL CH2Cl2 at −10° C. was added 2.5 mL TFA. The mixture was warmed to rt and monitored by TLC. When judged complete by TLC analysis, the mixture was concentrated to give the 518 mg (88%) of the title compound as an orange oil: mass spectrum m/e=147 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[N+:21]([O-])=O)[CH:10]([CH2:24][C:25]([O:27]C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[NH:21][C:25](=[O:27])[CH2:24][CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1c1ccc(C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)NC(=O)CC1CN(Cc3ccccc3)CCN21
Temperature: 80 °C

Procedure:
To a solution of Example 49A (150 mg, 0.392 mmol) in acetic acid (5 mL) was added iron powder (65.5 mg, 1.17 mmol), and the reaction was heated to 80° C. for 14 hours. The solution was then concentrated onto silica gel and purified via flash chromatography (0-30% methanol/dichloromethane). The pure fractions were partitioned between dichloromethane and 1 M NaOH. The organic layer was collected and dried with MgSO4 to afford title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.41 (s, 1H), 7.20-7.41 (m, 5H), 6.86-7.01 (m, 2H), 6.73 (s, 1H), 3.53 (s, 2H), 3.02-3.27 (m, 2H), 2.67-3.00 (m, 3H), 2.42-2.48 (m, 1H) 2.04-2.30 (m, 5H), 1.84 (d, J=13.22 Hz, 1H); MS (APCI+) m/z 322 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1>[Pd].C(OCC)(=O)C>[F:29][C:2]([F:1])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of (E)-ethyl 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate (C17) (1.08 g, 2.68 mmol) and palladium on carbon (10%, 0.285 g, 0.270 mmol) in ethyl acetate (10.7 mL) was stirred at room temperature. The reaction flask was evacuated under vacuum, backfilled with nitrogen, evacuated under vacuum again, and then backfilled with hydrogen by balloon (˜1 atm). The reaction was stirred at room temperature overnight and then filtered through a pad of Celite® and concentrated to afford the title compound as a gray oil that solidified to a wax upon standing at room temperature (0.999 g, 87%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.14-8.07 (m, 2H), 7.80 (d, J=9.1 Hz, 2H), 7.42-7.36 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.02 (t, J=7.8 Hz, 2H), 2.67 (t, J=7.8 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 406 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH2:24])[CH3:23])[C:19]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:26]2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:23])[C:19]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:26]2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2
Reactant: Brc1ncnc2[nH]cnc12
Reactant: COCCN1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COCCN1CCN(c2c(C(C)Nc3ncnc4[nH]cnc34)cc(Cl)c3cccnc23)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.0274 g, 0.138 mmol), 1-{5-chloro-8-[4-(2-methoxyethyl)piperazin-1-yl]quinolin-7-yl]ethanamine (0.024 g, 0.069 mmol), and N,N-diisopropylethylamine (0.02396 mL, 0.1376 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the desired product as a tris-TFA salt. LCMS calculated for C23H28ClN8O(M+H)+: m/z=467.2; found: 467.1. 1H NMR (DMSO-d6, 400 MHz) δ 9.70 (1H, br s), 8.98 (1H, s), 8.50 (1H, d, J=8.0 Hz), 8.21 (2H, m), 8.02 (1H, s), 7.66 (1H, dd, J=8.4 and 4.4 Hz), 6.41 (1H, m), 4.42˜3.02 (12H, m), 3.33 (3H, s), 1.55 (3H, d, J=6.4 Hz) ppm.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 186.1, 92 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (49.6 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M Na2CO3 (0.300 mL, 0.6 mmol) was added, the mixture was flushed with argon, heated to 100° C. in a pressure safe vial, then Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) was added. The RM was stirred under argon at 80-90° C. for 2 h. After cooling at RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue that was purified by flash chromatography (RediSep® Silica gel column, (DCM/MeOH 98:2)/MeOH, from 0 to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a beige crystalline powder. HPLC (Condition 4) tR=5.02 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, 5 μm, eluent: EtOH/MeOH (50:50), 1 mL/min, UV 220 nm, tR=10.32 min, UPLC-MS (Condition 3) tR=1.00 min, m/z=462.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.79 (m, 1H) 1.78-1.91 (m, 1H) 2.87 (d, J=1.00 Hz, 1H) 3.21 (m, J=6.60 Hz, 2H) 3.32-3.42 (m, 1H) 4.14-4.24 (m, 1H) 4.87 (d, J=3.13 Hz, 1H) 7.68 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.60 Hz, 2H) 8.09 (d, J=1.95 Hz, 1H) 8.76-8.80 (m, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.26 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:11][Mg]Br>O1CCCC1>[Cl:1][C:2]1[C:3]([CH:9]([OH:10])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ncc(Cl)nc1Cl
Solvent: C1CCOC1
Product: CC(O)c1ncc(Cl)nc1Cl
Reaction time: 0.17 h

Procedure:
3,5-Dichloro-pyrazine-2-carbaldehyde (5.0 g) was dissolved in dry tetrahydrofuran (100 ml) in a reaction vessel equipped with a magnetic stirring bar under an argon atmosphere. The solution was cooled on an ice-bath before slow addition of 10.3 ml methylmagnesium bromide solution (3M in tetrahydrofuran), keeping the internal temperature in the reaction vessel below 5° C. After the addition the cooling bath was removed and the reaction mixture stirred for another 10 min. Then the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (100 ml) and extracted with EtOAc (3×200 ml). The combined aqueous phases were dried over sodium sulfate, filtered and evaporated to afford 1-(3,5-dichloro-pyrazin-2-yl)-ethanol as a dark brown oil. Yield: 5.23 g (96%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[C:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:25]([CH3:35])[CH:24]=3)=[C:20](C3C=CC(OCCC4CCCN4)=NC=3)[S:19][C:18]=2[CH:50]=1.[N:51]1([CH2:56][CH2:57][O:58][C:59]2[CH:64]=[CH:63][C:62](Br)=[CH:61][C:60]=2[CH3:66])[CH2:55][CH2:54][CH2:53][CH2:52]1>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[CH3:66][C:60]1[CH:61]=[C:62]([C:20]2[S:19][C:18]3[CH:50]=[C:14]([OH:13])[CH:15]=[CH:16][C:17]=3[C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:25]([CH3:35])[CH:24]=2)[CH:63]=[CH:64][C:59]=1[O:58][CH2:57][CH2:56][N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: Cc1cc(Cc2c(-c3ccc(OCCC4CCCN4)nc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Reactant: Cc1cc(Br)ccc1OCCN1CCCC1
Agent: O=C(O)C(=O)O
Product: Cc1cc(Cc2c(-c3ccc(OCCN4CCCC4)c(C)c3)sc3cc(O)ccc23)ccc1CN1CCCC1
Yield: 59 %

Procedure:
The title compound was prepared from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-methyl-4-[(1-pyrrolidinyl)methyl]phenyl ketone (Example 124, Part C) and 4-bromo-2-methylphenyl 2-(1-pyrrolidinyl)ethyl ether (Part A) in 59% yield after PrepLC (SiO2; gradient of 85:10:5 to 75:20:5 hexanes-THF-TEA) by essentially following the procedure detailed in Example 123, Part A.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Nc1cc(Cl)ccn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Temperature: 160 °C
Reaction time: 41 h
Yield: 19.5 %

Procedure:
2-Amino-4-chloropyridine (8.00 g) was dissolved in N-methylpyrrolidone (65 ml), and 2-fluoro-4-nitrophenol (19.55 g) and N,N-diisopropylethylamine (43.36 ml) were added thereto, followed by stirring at 160° C. for 41 hr. The reaction mixture was allowed to cool down to room temperature, and was partitioned between ethyl acetate-tetrahydrofuran (1:1) and a 2N aqueous solution of sodium hydroxide. The organic layer was washed with water and brine in this order. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2, then ethyl acetate). Fractions containing the target compound were concentrated, and crystals were precipitated by addition of ethyl acetate to the residue. The crystals were collected by filtration and dried under aeration to provide the titled compound as opalescent crystals (3.02 g, 20%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:14](=[O:16])[CH3:15])=[CH:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].C1C(=O)N(Br)C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:16][C:14]=1[CH3:15])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=CCC1CCCCC1)C(C)=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(C2CCCCC2)oc1C
Temperature: 25 °C
Reaction time: 68 h
Yield: 76.5 %

Procedure:
A solution of 2-acetyl-4-cyclohexyl-but-2-enoic acid ethyl ester (1.79 g, 7.52 mmol) in 40 mL CCl4 was added to a slurry of NBS (1.338 g, 7.52 mmol) in 40 mL CCl4. The mixture was refluxed under argon for 12 hours, stirred at room temperature for 68 hours and then cooled in an ice bath. The precipitated solid was filtered off and the filtrate was evaporated to an oil that was purified by short-path distillation (165-185° C., 1 mm Hg) yielding 5-cyclohexyl-2-methyl-furan-3-carboxylic acid ethyl ester (1.36 g, 77%).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Bi+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>O1CCCC1>[N+:1]([C:21]1[CH:20]=[CH:19][C:18]([OH:23])=[C:17]([O:16][C:15]([F:14])([F:25])[F:24])[CH:22]=1)([O-:4])=[O:2]
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: [Bi+3]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(O)c(OC(F)(F)F)c1
Temperature: 50 °C
Yield: 31 %

Procedure:
3.0 g (7.5 mmol) of anh. bismuth nitrate was added to a solution of 891 mg (5.0 mmol) of 2-trifluoromethoxyphenol in 20 mL of tetrahydrofuran (redistilled) under argon atmosphere with stirring. The mixture was slowly heated to 50° C. and allowed to react at this temperature for 10 min. The reaction was stopped, cooled, filtered under reduced pressure and the filter cake was washed with 20 mL of tetrahydrofuran. The filtrate was concentrated, and 40 mL of water and 45 mL of ethyl acetate were added. The organic layer was isolated, and the water layer was extracted with 40 mL×2 of ethyl acetate. The organic layers were combined, successively washed with 110 mL of water and 110 mL of saturated saline, dried over anh. MgSO4, filtered and concentrated. The residue was purified by silica column chromatography (mobile phase: petroleum ether: ethyl acetate=15:1) to obtain 346 mg of a yellow oil. Yield 31.4%.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][S:10][C:11](SC)=[C:12]([C:15]#[N:16])[C:13]#[N:14].CS>C(OCC)(=O)C>[CH2:1]([NH:8][C:11]([S:10][CH3:9])=[C:12]([C:15]#[N:16])[C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CSC(SC)=C(C#N)C#N
Agent: CS
Solvent: CCOC(C)=O
Product: CSC(NCc1ccccc1)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
43.6 ml (400 mmol) of benzylamine are added to a suspension of 68.4 g (400 mmol) of 3,3-bis-methylmercapto-2-cyano-acrylonitrile [3,3-bis(methylsulfanyl)-2-cyano-acrylonitrile] (Maybridge) in 400 ml of ethyl acetate. The clear solution is heated slowly to 70° C. (→ evolution of MeSH!), stirred at that temperature for 1.5 hours, cooled to RT and concentrated by evaporation, yielding crystalline 3-benzylamino-3-methylmercapto-2-cyano-acrylonitrile; 1H-NMR: (CD3OD) 7.36 (m, 5H), 4.77 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: C1(C)C=CC=CC=1.CSC.B.[Br:12][CH2:13][CH2:14][CH:15]=[C:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][C:19](=[O:27])[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]1=2.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[Br:12][CH2:13][CH2:14][CH:15]=[C:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][C@H:19]([OH:27])[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]1=2
Reactant: O=C1Cc2ccccc2C(=CCCBr)c2ccccc21
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O[C@H]1Cc2ccccc2C(=CCCBr)c2ccccc21
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
In a dry 40 mL vial with a septum cap, R-CBS catalyst, 1 M in toluene (3.98 mL, 3.98 mmol), 2.0 M borane-dimethyl sulfide in tetrahydrofuran (1.69 mL, 3.37 mmol), and 10 mL dry tetrahydrofuran were premixed. The premix was cooled to −20° C. in an acetonitrile/dry ice bath. A tetrahydrofuran solution of 5-(3-bromo-propylidene)-5,11-dihydro-dibenzo[a,d]cyclohepten-10-one (6) (1.00 g, 3.06 mmol) which had been stored over molecular sieves was then added dropwise. The reaction was allowed to slowly come to room temperature over ˜90 minutes. When complete, the reaction was cooled to 0° C. and 1 mL methanol added to quench the reaction. After 15 minutes of further stirring, 1 mL saturated sodium bicarbonate was added. The reaction mixture was then concentrated under reduced pressure and the residue separated between water (50 mL) and dichloromethane (50 mL). The organic layer was then separated, evaporated, and the crude residue was purified by silica gel chromatography using a 5-25% hexanes:ethyl acetate gradient. 0.90 g (89%) (S)-5-(3-Bromo-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ol (7a) was obtained as a faintly yellow oil. ESI MS m/z 623.3 (2(M−H2O)+H)+.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][S:13][CH2:12][CH2:11][NH:10]1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:28]Br>O.CCOC(C)=O>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:28][N:10]1[C:9](=[O:8])[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:14][S:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Reactant: Fc1cc(F)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CSCCN(Cc2cc(F)cc(F)c2)C1=O
Yield: 79 %

Procedure:
121 mg of sodium hydride as a 60% suspension in oil (3.05 mmol) are introduced at room temperature into a 50 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of DMF and 500 mg of 26 (2.03 mmol). The medium is stirred for 1 hour and 454 mg (2.03 mmol) of 3,5-difluorobenzyl bromide are then added. The medium is stirred for 3 hours, 50 ml of EtOAc and 50 ml of water are added to the reaction medium and, after separation of the phases by settling, the organic phase is washed with 50 ml of water. The organic phase is dried, filtered and then evaporated to dryness. 1.5 g of crude product are recovered, which product is chromatographed on a silica cartridge (20 g, eluent: 80/20 heptane/EtOAc). 600 mg of product 33 are recovered (yield=79%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[CH3:12].CCN(CC)CC>C(Cl)Cl.O>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]=[O:27])=[CH:24][CH:25]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: CCN1CCN(Cc2ccc(CO)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN1CCN(Cc2ccc(C=O)cc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), N-ethyl piperazine (3.76 g, 32.92 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed to give 4.61 g of crude 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (100% yield). LAH (0.792 g, 20.86 mmol) was taken up in a 3-neck dry flask and THF (60 mL) was added on cooling. A solution of 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (4.61 g, 16.69 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to 0° C., 10% NaOH solution was added, and then water was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give 2.78 g of crude (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol in 78% yield. To a 3-neck flask containing anhydrous CH2Cl2 (100 mL) cooled to the −78° C. oxalyl chloride (1.8 g, 14.25 mmol) and DMSO (1.85 g, 23.76 mmol) were added and the mixture was stirred for 15 min at −78° C. The solution of (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol (2.78 g, 11.88 mmol) in CH2Cl2 (10 mL) was added at −78° C. and stirred at −78° C. for 1 h. Then Et3N (4.8 g, 47.52 mmol) was added at −78° C. The reaction mixture was allowed to come to room temperature. Water was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then, solvent was removed to give crude 4-(4-ethyl piperazin-1-ylmethyl)benzaldehyde (2.5 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:8]([O:10]C)=O)=[CH:5][S:6][CH:7]=1.O.[NH2:13][NH2:14]>CO>[CH3:1][O:2][C:3]1[C:4]([C:8]([NH:13][NH2:14])=[O:10])=[CH:5][S:6][CH:7]=1
Reactant: COC(=O)c1cscc1OC
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1cscc1C(=O)NN

Procedure:
Methyl 4-methoxy-3-thiophenecarboxylate (50.8 g, 0.295 mol) was refluxed with hydrazine hydrate (30 ml) in methanol (250 ml) overnight. The solvent was evaporated and the residue was diluted with water (300 ml) and extracted with dichloromethane (5×100 ml). The dichloromethane extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure to give the title compound as an off white solid, 49.5 g, m.p. 91°-92°.