Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:13](=O)[CH2:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na].C(O)(=O)C.[NH3:22]>>[N:1]1([C:7]2[CH:8]=[C:9]([CH:13]([NH2:22])[CH2:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCC(=O)c1cccc(N2CCOCC2)c1
Reactant: N
Agent: [Na]
Solvent: CC(=O)O
Product: CCC(N)c1cccc(N2CCOCC2)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3-morpholin-4-yl-phenyl)propan-1-one (4.06 g, 18.5 mmol), powdered 3A molecular sieves (4 g), in ammonia (2.0 M solution in methanol) (61.2 mL) was stirred in sealed vessel at 65° C. for 2 hours, at which time sodium cyanoboronhydride (2.33 g, 37 mmol) and glacial acetic acid (8.47 mL) was added and the mixture was stirred at 65° C. for another 2 hours. After cooling down, the reaction mixture was filtered to remove molecular sieves and the filtrate was concentrated under vacuum. Solids was re-dissolved in dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (15 mL). The aqueous layer was extracted with dichloromethane (2×25 mL) and the combined organic layer was dried over magnesium sulfate, and concentrated under vacuum. The crude pale yellow oil was purified by Biotage flash chromatography with 90:10:10 dichloromethane:methanol:triethylamine to afford the title compound as a pale yellow clear oil (2.56 g).
Reaction SMILES: [N:1]1([CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:21](=[O:36])[CH:22]=[C:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]1([CH:6]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:21](=[O:36])[CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Cl)C=C(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(C=C(c1ccccc1)c1ccccc1)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 140.2 %

Procedure:
A mixture of intermediate (1-b) (8.92 g) and 1-chloro-3,3-diphenyl-2-propen-1-one (10.42 g) in DCM (100 ml) was stirred at room temperature overnight. The mixture was poured into a 10% NaHCO3 -solution. This mixture was extracted with DCM and separated. The organic layer was dried (MgSO4), filtered and evaporated, yielding 22.85 g (100%) of (±)-N-[4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]-3,3-diphenyl-2-propenamide (interm. 1-c). The product was used without further purification.
Reaction SMILES: C[C:2]1([CH:13]=[CH:12][C:8]([C:9]([O-:11])=[O:10])=[CH:7][CH:6]1[N+:14]([O-:16])=[O:15])[C:3]([O-])=[O:4].CCOCC.CO.[Li+].[BH4-]>C1COCC1>[OH:4][CH2:3][C:2]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CC1(C(=O)[O-])C=CC(C(=O)[O-])=CC1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a suspension of 1-methyl-2-nitroterephthalate (10.2 g, 45.1 mmol) and 150 mL of anhydrous ether was added 5.2 mL of anhydrous MeOH at which point most of the solid went into solution. The solution was cooled to 0° C. and LiBH4 (in THF, 57.0 mL, 114.0 mmol, Aldrich) was added slowly over 50 min. Bubbles were generated. The resulting mixture was stirred at RT for 5 h, then heated to 35° C. TLC showed ˜20% conversion. 100 mL of anhydrous THF was added and the reaction was heated to 55° C. After 3 days, TLC showed reactions to be complete. The reaction was carefully quenched with the addition of H2O, and neutralized with 1N HCl. The organic layer was separated and the aqueous layer was extracted with ether (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a light yellow solid. MS m/z: 196.1 (M−1).
Reaction SMILES: [CH3:1][P:2](=[O:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[Li]CCCC.[CH:15]1([S:18]([NH:21][C:22]23[CH2:29][CH2:28][C:25](C(OC)=O)([CH2:26][CH2:27]2)[CH2:24][CH2:23]3)(=[O:20])=[O:19])[CH2:17][CH2:16]1.[NH4+].[Cl-]>C1COCC1>[CH2:4]([O:3][P:2]([CH2:1][C:25]12[CH2:24][CH2:23][C:22]([NH:21][S:18]([CH:15]3[CH2:17][CH2:16]3)(=[O:20])=[O:19])([CH2:27][CH2:26]1)[CH2:29][CH2:28]2)(=[O:9])[O:6][CH2:7][CH3:8])[CH3:5]
Reactant: COC(=O)C12CCC(NS(=O)(=O)C3CC3)(CC1)CC2
Reactant: CCOP(C)(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC12CCC(NS(=O)(=O)C3CC3)(CC1)CC2)OCC
Temperature: -78 °C
Reaction time: 3 h
Yield: 122.8 %

Procedure:
A solution of diethyl methylphosphonate (1.27 g, 8.36 mmol) was dissolved in THF (20 mL) and cooled to about −78° C. in a dry ice-acetone bath under nitrogen. Then n-BuLi (9.77 mmol, 3.9 mL, 2.5M in hexane) was added dropwise over about 5 min. The reaction mixture was stirred for about 3 h, keeping the temperature below about −70° C. Then a solution of methyl 4-(cyclopropanesulfonamido)bicyclo[2.2.2]octane-1-carboxylate (800 mg, 2.79 mmol) in THF (10 mL) was added, keeping the temperature at about −78° C. The solution was stirred for about 15 h, allowing the temperature to rise slowly to rt. To the reaction mixture was added saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (3×30 mL). The organic layers were combined and washed with brine, dried over anhydrous Na2SO4 and concd to provide diethyl(4-(cyclopropanesulfonamido)bicyclo[2.2.2]octan-1-yl)methylphosphonate (1.30 g, 100% yield). The crude product was used in next step without further purification. LC/MS (Table 1, Method p) Rt=1.62 min; MS m/z: 408 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1.[CH3:22][C:23]1([CH3:32])[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25](=O)[CH2:24]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[C:16]1([C:14](=[C:25]2[CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28][C:23]([CH3:32])([CH3:22])[CH2:24]2)[C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])=[CH:9][CH:10]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(c1ccccc1)c1ccc(OCCOCCO)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(OCCOCCO)cc2)CC(C)(C)C1
Temperature: 25 °C

Procedure:
To a stirred suspension of Zn (0.59 g, 8.94 mmol) in THF (10 mL) was added TiCl4 (0.50 mL, 4.47 mmol) dropwise. The mixture was refluxed under nitrogen for 2.5 h. Cooled to room temperature, a solution of 7 (0.32 g, 1.12 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.53 g, 3.35 mmol) in THF (15 mL) was added and the reaction mixture was refluxed for another 2.5 h. Cooled to room temperature, the reaction was quenched with 10% K2CO3 (40 mL). The quenched reaction mixture was filtered through a pad of celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel, the layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to a pale yellow oil. The residue was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 45% EtOAc:hexanes to give 8 as a white solid. Crystallization from 10:1 hexanes:EtOAc yielded colorless needles (0.27 g, 59%). mp 116-117° C. 1H NMR (400 MHz, CD3OD): δ0.91 (s, 6H), 0.93 (s, 6H), 1.29 (s, 2H), 1.95 (s, 2H), 1.99 (s, 2H), 3.60-3.65 (m, 2H), 3.65-3.70 (m, 2H), 3.80-3.85 (m, 2H), 4.05-4.15 (m, 2H), 6.85 (d, J=8.6 Hz, 2H), 7.06 (d, J=8.6 Hz, 2H), 7.10-7.20 (m, 3H), 7.20-7.30 (m, 2H). LRMS (ESI): m/z 409 (M+H)+. Anal. Calcd for C27H36O3: C, 79.37; H, 8.88. Found: C, 79.23; H, 8.95.
Reaction SMILES: Br.Br.C([NH:10][C@H:11]1[C@H:16]2[CH2:17][CH2:18][C@H:13]([CH2:14][NH:15]2)[CH2:12]1)C1C=CC=CC=1.[CH:19]1([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:33])=[C:29](F)[CH:30]=3)[C:25](=[O:34])[C:24]([C:35]([OH:37])=[O:36])=[CH:23]2)[CH2:21][CH2:20]1.C1CCN2C(=NCCC2)CC1>>[NH2:10][C@H:11]1[C@H:16]2[CH2:17][CH2:18][C@H:13]([CH2:14][N:15]2[C:29]2[CH:30]=[C:31]3[C:26]([C:25](=[O:34])[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]3[CH:19]3[CH2:21][CH2:20]3)=[CH:27][C:28]=2[F:33])[CH2:12]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: c1ccc(CN[C@@H]2C[C@@H]3CC[C@H]2NC3)cc1
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Product: N[C@@H]1C[C@@H]2CC[C@H]1N(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2

Procedure:
In a manner similar to that of Example 14, the title compound of Example 13 (0.80 g) was coupled to 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the presence of DBU and the product was subjected to catalytic hydrogenation to remove the benzyl group, yielding 0.16 g of the title compound as a solid, mp 268°-271° , [α]D20 -69.3°(DMSO). NMR data was the same as for the
Reaction SMILES: Cl[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])[CH:9]=2)[NH:4][C:3]1=[O:18].CCN(C(C)C)C(C)C.[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C1COCC1.O>[CH3:17][C:12]1[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3](=[O:18])[C:2]3([N:37]2[CH2:36][CH2:35][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:15]([CH3:16])[O:14][N:13]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccccc1)C(=O)N2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)(N1CCN(C(=O)OC(C)(C)C)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
676 mg (2.0 mmol) of 3-chloro-5-(3,5-dimethylisoxazol-4-yl)-3-phenylindolin-2-one and 774 mg (6.0 mmol) of DIPEA were dissolved in 20 ml of THF, after the addition of 774 mg (4.0 mmol) of tert-butyl piperazine-1-carboxylate, the reaction solution was stirred for 0.5 h at room temperature. Subsequently, the solution was diluted with water. The aqueous phase was extracted with CH2Cl2 (2×30 mL). The combined organic phases were washed with aqueous NaHCO3 and with water, dried and concentrated in vacuum. The resulting residue was purified by chromatography (eluent: CH2Cl2/MeOH=20/1) to give product (940 mg, 96%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δH 10.75 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.25-7.38 (m, 6H), 6.98 (d, J=8.0 Hz, 1H), 3.27-3.29 (m, 4H), 2.47-2.38 (m, 4H), 2.36 (s, 3H), 2.18 (s, 3H), 1.35 (s, 9H). MS (ESI) m/e [M+1]+ 489.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH2:14]1[O:17][CH:15]1[CH3:16]>C(O)C>[CH3:1][N:2]([CH2:14][CH:15]([OH:17])[CH3:16])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Reactant: CC1CO1
Solvent: CCO
Product: CC(O)CN(C)CCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of N-methyl-4-nitrophenethylamine (1.8 g) and propylene oxide (0.66 g) in ethanol (50 ml) was stirred at reflux for 5 hours. After evaporation to dryness the residual orange oil was chromatographed on silica ("Kieselgel 60"--Trade Mark) eluting with ethyl acetate followed by collection and evaporation of suitable fractions to give the title compound as a yellow oil.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].Cl.[Cl:8][C:9]1[CH:10]=[C:11]([N:26]([C:31]2[C:50]([CH:51]3[CH2:53][CH2:52]3)=[CH:49][C:34]3[C:35]([C:45]([NH:47][CH3:48])=[O:46])=[C:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[O:37][C:33]=3[CH:32]=2)[S:27]([CH3:30])(=[O:29])=[O:28])[CH:12]=[CH:13][C:14]=1[CH2:15][CH2:16][B:17]1[O:21]C(C)(C)C(C)(C)[O:18]1>C1COCC1.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([N:26]([C:31]2[C:50]([CH:51]3[CH2:53][CH2:52]3)=[CH:49][C:34]3[C:35]([C:45](=[O:46])[NH:47][CH3:48])=[C:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[O:37][C:33]=3[CH:32]=2)[S:27]([CH3:30])(=[O:28])=[O:29])[CH:12]=[CH:13][C:14]=1[CH2:15][CH2:16][B:17]([OH:18])[OH:21]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(CCB4OC(C)(C)C(C)(C)O4)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(CCB(O)O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
Sodium periodate (722 mg, 3.37 mmol) and 1N aqueous HCl (2.70 mL, 2.70 mmol) were added to a cold (0° C.) solution of 6-(N-(3-chloro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (150 mg, 0.225 mmol) in THF (3 mL). The mixture was stirred at 0° C. for 10 min and then warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate. The organic layer was separated, washed with 5% aqueous sodium thiosulfate and brine and dried over sodium sulfate. The solvent was evaporated and the residue was subjected to reverse phase HPLC (C18, acetonitrile:water with 0.1% formic acid) to give 33 mg (25%) of the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41-8.51 (m, 1H) 8.14 (s, 1H) 7.92-8.02 (m, 2H) 7.59 (s, 2H) 7.46-7.51 (m, 1H) 7.35-7.44 (m, 3H) 7.29-7.35 (m, 1H) 7.17 (s, 1H) 3.37 (s, 3H) 2.79-2.87 (m, 3H) 2.62-2.74 (m, 2H) 2.11-2.24 (m, 1H) 0.93-1.09 (m, 1H) 0.75-0.93 (m, 4H) 0.46 (m, 1H). LCMS (m/z, ES+)=585 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH:7]=[O:8])[CH3:2].[N+](C1C=CC=CC=1C(O)=O)([O-])=O.N1CCCC1.[OH:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:29]=1[CH:30]=O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:5]1[C:6]([CH:7]=[O:8])=[CH:30][C:29]2[C:28](=[CH:35][CH:34]=[CH:33][C:32]=2[O:36][CH3:37])[O:27]1)=[O:9])[CH3:2]
Reactant: CCOC(=O)/C=C/C=O
Reactant: COc1cccc(O)c1C=O
Agent: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: C1CCNC1
Solvent: CS(C)=O
Product: CCOC(=O)C1Oc2cccc(OC)c2C=C1C=O
Temperature: 25 °C
Reaction time: 78 h
Yield: 13.1 %

Procedure:
(E)-4-oxo-but-2-enoic acid ethyl ester (7.63 mL, 63.09 mmol), 2-nitro benzoic acid (1.77 g, 10.52 mmol), and pyrrolidine (0.87 mL, 10.52 mmol) were added simultaneously to a solution of commercially available 2-hydroxy-6-methoxy-benzaldehyde (8.0 g, 52.58 mmol) in dimethysulfoxide (50 mL) at 25° C. and the solution was stirred for 78 hours at 25° C. The reaction was quenched by the addition of water. The reaction mixture was then partitioned between water and ethyl acetate. The combined organics were washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtered, rinsed and concentrated in vacuo. The residue obtained was purified on a silica gel flash column chromatography using ethyl acetate-hexanes as eluants, yielding 5-methoxy-3-formyl-2H-chromene-2-carboxylic acid ethyl ester as a solid (1.80 g, 51.9%).
Reaction SMILES: [CH3:1][CH:2]([NH2:6])[CH:3]([NH2:5])[CH3:4].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.CS(O)(=O)=O.[CH:43]1[CH:48]=[CH:47][C:46]([CH2:49][O:50][C:51](Cl)=[O:52])=[CH:45][CH:44]=1>O.C(O)C.COCCOC.C(O[K])(C)=O>[NH2:5][CH:3]([CH3:4])[CH:2]([NH:6][C:51](=[O:52])[O:50][CH2:49][C:46]1[CH:47]=[CH:48][CH:43]=[CH:44][CH:45]=1)[CH3:1]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)C(C)N
Agent: CC(=O)O[K]
Agent: CS(=O)(=O)O
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CC(N)C(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
To a mixture of butane-2,3-diamine (4.8 g, 54.5 mmol) in water (50 mL) containing bromocresol green as indicator was slowly added a solution of methane sulfonic acid (10.46 g) in water (50 mL) until a blue to yellow color transition was observed. The mixture was diluted with ethanol (100 mL) and to it was added a solution of Cbz-Cl (7.61 g, 45.5 mmol) in DME (50 mL) and aqueous AcOK (w/v=50%) to maintain the pale-green color. The reaction mixture was stirred (RT, 1 h), concentrated under reduced pressure, treated with water and filtered. The solution was washed with toluene, basified with 40% aqueous NaOH and extracted with toluene (4×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford benzyl 3-aminobutan-2-ylcarbamate (4.2 g, 35%) as a colorless oil. Mass calculated for C12H18N2O2=222.28. found: [M−H]+=221.2.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[C:31]3[CH:32]=[CH:33][C:34]([C:37]([NH:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])=[O:38])=[N:35][CH:36]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[C:31]3[CH:32]=[CH:33][C:34]([C:37]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:38])=[N:35][CH:36]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)c(-c2ccc(C(=O)NCCC(=O)O)nc2)c1
Temperature: 55 °C

Procedure:
A 1M aqueous solution of NaOH (2.0 mL, 2.0 mmol) was added to a THF (1 mL) and MeOH (5 mL) solution of ethyl 3-(5-(2-((4′-chloro-[1,1′-biphenyl]-4-yl)carbamoyl)-5-methylphenyl)picolinamido)propanoate (50 mg, 0.09 mmol) and the resulting mixture was heated to 55° C. After 10 min the resulting mixture was neutralized with 2M aqueous HCl, concentrated and extracted with EtOAc. The combined extracts were concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[C:12]=3[CH:19]([CH3:21])[CH3:20])[S:10][C:6]=2[CH:5]=[C:4]([O:22]C)[CH:3]=1.B(Br)(Br)Br>>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:12]=3[CH:19]([CH3:20])[CH3:21])[S:10][C:6]=2[CH:5]=[C:4]([OH:22])[CH:3]=1
Reactant: COc1cc(Br)c2nc(-c3cccc(OC)c3C(C)C)sc2c1
Agent: BrB(Br)Br
Product: CC(C)c1c(O)cccc1-c1nc2c(Br)cc(O)cc2s1
Yield: 53.8 %

Procedure:
4-Bromo-6-methoxy-2-(2-isopropyl-3-methoxy-phenyl)-benzothiazole (60 mg, 0.153 mmol) was treated with boron tribromide under standard condition to give the title compound (30 mg, 54% yield) as a yellow solid. Mass spec: MH+=364.
Reaction SMILES: C1C(=O)N([O:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]2[S:19][CH2:18][C@@H:17]3[NH:20][C:21]([NH:23][C@H:16]23)=[O:22])=[O:10])C(=O)C1>CN(C=O)C.C([O-])(O)=O.[Na+]>[OH:10][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[C@@H:16]2[C@@H:17]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:19]1)=[O:8]
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)ON2C(=O)CCC2=O)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 1 h

Procedure:
Histone H1 was biotinylated to different degrees with increasing amounts of BHSE. 5 μg BHSE (dissolved in 10 μl DMF), 25 μg BHSE (in 10 μl DMF) and 250 μg BHSE in 10μl DMF were added to three solutions containing the same amount of histone H1 (1 mg in 300 μl of 50 mM NaHCO3) and incubated for 1 hour at 20° C. After dialysis against 5 mM sodium phosphate (pH 6.8) the three samples are stored at -20° C. The concentrations of the biotin-labelled histone H1 solutions are determined by comparison with unmodified histone H1 by SDS-polyacrylamide gel electrophoresis. The number of biotin residues in the three preparations was estimated by the tritium marker contained in BHSE and was found to be between 2.7 and 20 per histone H1 molecule.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>C(Cl)Cl>[NH2:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[C:2]#[C:1][C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Nc1ccccc1I
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccccc1N)O2

Procedure:
This compound was obtained by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-iodoaniline under the conditions described in Example 26. The product was isolated by chromatography over the 40 fold amount of silica gel using methylene chloride. Crystallization from ether/hexane and recrystallization from cyclohexane gave pale yellow crystals with m.p. 110°-112°.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]([CH3:21])([O-])[CH3:19].[K+]>CN(C=O)C>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=[CH:17][C:18]2[CH:21]=[CH:21][C:18]([CH:17]=[CH:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:19][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C(=Cc1ccc(C=CC=C(c2ccccc2)c2ccccc2)cc1)C=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 15.5 %

Procedure:
In 100 ml of DMF were dissolved 5.53 g of 3,3-diphenylacrolein and 5.0 g of p-xylene-α,α'-diylbis(diethyl phosphonate), and 3.87 g of potassium tert-butoxide was added to the solution at room temperature. Thereafter, the reaction was carried out for 4 hours at room temperature with stirring and the reaction mixture was poured into 100 ml of ice-water with stirring. Then, precipitates thus deposited were collected by filtration, dissolved in benzene, and separated and purified by silica gel column chromatography (eluent: benzene). After distilling off benzene from the effluent, the residue was recrystallized from ethyl acetate to provide 1.00 g (yield 15.6%) of yellow crystals having a melting point of from 237.0° C. to 249.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:33]2(O)[CH2:38][CH2:37][CH2:36][CH:35]=[CH:34]2)=[CH:8][C:9]=1[N:10]([C:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]1)=[O:25])[C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:13][CH2:12]1)=[O:4].C([SiH](CC)CC)C.FC(F)(F)C(O)=[O:50].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:33]2[CH2:38][CH2:37][CH2:36][CH:35]([OH:50])[CH:34]=2)=[CH:8][C:9]=1[N:10]([C:24]([C@H:26]1[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]1)=[O:25])[C@H:11]1[CH2:12][CH2:13][C@H:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][CH2:16]1)=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1sc(C2(O)C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1sc(C2=CC(O)CCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1
Reaction time: 3.5 h

Procedure:
A solution of 5-(1-hydroxy-cyclohex-2-enyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (48 mg, 0.086 mmol) in DCM (1 mL) was cooled to −50° C. Triethylsilane (43 μl, 0.27 mmol) was added followed by gradual addition of trifluoroacetic acid (total 22 μl, 0.28 mmol) (4 μl to 6 μl every 30 min). The mixture was stirred at −40° C. to −50° C. for 3.5 h. Aqueous NaHCO3 was added and the mixture was allowed to come to room temperature. It was extracted with DCM, washed with brine, dried (MgSO4) and evaporated. The crude was left at room temperature for 2 days and purified by chromatography over silica gel (hexane-EtOAc mixtures) yielding 5-(3-Hydroxy-cyclohex-1-enyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (22 mg, 45%).