Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:8]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=2[OH:19])=[CH:7][N:6]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[C:34](F)=[CH:35][C:36]([F:55])=[C:37]([S:39]([N:42]([C:50]2[N:51]=[CH:52][S:53][CH:54]=2)[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=[O:41])=[O:40])[CH:38]=1>CS(C)=O.C(OCC)(=O)C.ClC1C(F)=CC(F)=C(S(N(C2N=CSC=2)C(=O)OC(C)(C)C)(=O)=O)C=1>[Cl:32][C:33]1[C:34]([O:19][C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]=2[C:8]2[C:4]([N+:1]([O-:3])=[O:2])=[N:5][N:6]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:7]=2)=[CH:35][C:36]([F:55])=[C:37]([S:39]([N:42]([C:50]2[N:51]=[CH:52][S:53][CH:54]=2)[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=[O:41])=[O:40])[CH:38]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2-c2cn(C3CCCCO3)nc2[N+](=O)[O-])cc1F
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
To a solution of 2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenol (Preparation 868, 28.73 g, 80.41 mmol) in dimethyl sulfoxide (175 mL) was added potassium carbonate (22.3 g, 161 mmol). After stirring for 10 minutes, tert-butyl [(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 453, 33.02 g, 80.37 mmol) was added. After stirring for 14 hours at room temperature, additional potassium carbonate (4.7 g, 34 mmol) and tert-butyl [(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (1.25 g, 3.0 mmol) were added and the reaction mixture heated at 45° C. for 7 hours. The mixture was allowed to cool, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by manual flash column chromatography using 25% ethyl acetate/hexanes and an 8×46 cm column provided product as a yellow oil (40 g, 70%).
Reaction SMILES: CCOCC.[CH3:6][N:7]([CH3:21])[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[CH2:22]1[CH2:26]O[CH2:24][CH2:23]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC>[CH:26](=[C:11]1[CH2:12][CH2:13][C:8]([N:7]([CH3:21])[CH3:6])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: C1CCOC1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: CCCC=C1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium tert-butylate (2.75 g, 23.7 mmol) was provided in abs. ether (50 mL) in argon and mixed with butyl-triphenyl phosphonium bromide (9.45 g, 23.7 mmol). The batch was heated for 30 min to 40° C. 4-dimethylamino-4-phenyl cyclohexanone (5.00 g, 23.0 mmol) dissolved in abs. THF (50 mL) was then added carefully in drops (exothermic reaction). The batch was heated for 6.5 h to 50° C. and stirred overnight at room temperature. The batch was then concentrated in a vacuum until dry, taken up in dioxan (20 mL) and mixed with HO/dioxan (5 mL). A precipitate separated out during this. This was filtered off, washed with ether (10 mL), then basified with 2N NaOH and extracted with dichloromethane (2×40 mL). The organic phase was dried over Na2SO4, filtered and concentrated in a vacuum until dry.
Reaction SMILES: NN.[N+:3]([C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][NH:18][CH:17]3[CH2:21][S:22](=[O:25])(=[O:24])[CH2:23][CH:16]23)[C:9]2O[CH:12]=[CH:11][C:10]=2[CH:14]=1)([O-])=O.CC#N.C1C[O:32]CC1>CCO.[Ni]>[O:25]=[S:22]1(=[O:24])[CH2:21][CH:17]2[CH:16]([N:15]([C:8]3[O:32][C:11]4[CH:12]=[CH:7][C:6]([NH2:3])=[CH:14][C:10]=4[CH:9]=3)[CH2:20][CH2:19][NH:18]2)[CH2:23]1
Reactant: O=[N+]([O-])c1cc(N2CCNC3CS(=O)(=O)CC32)c2occc2c1
Reactant: C1CCOC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: CC#N
Product: Nc1ccc2oc(N3CCNC4CS(=O)(=O)CC43)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (204 mL, 4.20 mmol) were added to 1-(5-nitro-1-benzofuran-7-yl)octahydrothieno[3,4-b]pyrazine 6,6-dioxide (0.354 g, 1.05 mmol; Intermediate 35) in a mixture of THF (20 mL) and EtOH (80 mL). The resulting mixture was stirred at room temperature overnight and then more Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (204 mL, 4.20 mmol) were added and stirring was continued overnight. The mixture was filtered through Celite and the solvent was removed in vacuo to afford 0.338 g (quantitative). HPLC 90%, RT: 0.782 (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) δ ppm 2.79 (dd, J=12.49, 7.30 Hz, 1H) 2.90-3.25 (m, 4H) 3.43-3.64 (m, 3H) 3.91-3.94 (m, 1H) 5.01-5.07 (m, 1H) 6.33 (d, J=1.98 Hz, 1H) 6.61 (dd, J=12.99, 2.10 Hz, 2H) 7.62 (d, J=1.98 Hz, 1H). LC-MS 308 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:8]([OH:9])=[CH:7][CH:6]=[N:5]1)[CH3:3].C(N(CC)CC)C.[O:17]1[CH2:21][CH2:20][C:19]([C:22]2[C:23]([CH3:35])=[C:24]([CH:28]=[CH:29][C:30]=2[S:31]([CH3:34])(=[O:33])=[O:32])[C:25](Cl)=[O:26])=[N:18]1.CC(C)(O)C#N>C(Cl)(Cl)Cl>[O:17]1[CH2:21][CH2:20][C:19]([C:22]2[C:23]([CH3:35])=[C:24]([CH:28]=[CH:29][C:30]=2[S:31]([CH3:34])(=[O:33])=[O:32])[C:25]([C:7]2[CH:6]=[N:5][N:4]([CH2:2][CH3:3])[C:8]=2[OH:9])=[O:26])=[N:18]1
Reactant: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1C1=NOCC1
Reactant: CCn1nccc1O
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To 2.75 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoic acid were added 30 ml of benzene, then 1.7 ml of thionyl chloride and a drop of pyridine to heat at reflux for 3 hours. The reaction solution was cooled down. The solvent was distilled out under reduced pressure to give 2.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride. Separately 0.93 g of 1-ethyl-5-hydroxypyrazole hydrochloride was dissolved in 20 ml of chloroform, and 1.60 g of triethylamine was added, while cooling with ice. Into the obtained solution was added dropwise 10 ml of a chloroform solution containing 1.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride to stir at room temperature for 30 minutes, and 0.76 g of triethylamine and 0.16 g of acetone cyanohydrin were added to further stir overnight. The reaction solution was washed with dilute hydrochloric acid, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the residue. The obtained crystals were separated by filtration to give 1.59 g of the title compound as white crystals. m.p. 183~184.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[NH2:16][C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:26]([O:25][C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([NH:16][CH2:2][CH2:3][C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)([OH:8])[CH2:5][CH:6]=[CH2:7])[CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: C=CCC(O)(CCCl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(O)(CCN[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccc(F)cc1
Yield: 38.6 %

Procedure:
A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (760 mg, 3.3 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (1.0 g, 5 mmol), KI (1.1 g, 6.7 mmol) and K2CO3 (920 mg, 6.7 mmol) in acetonitrile (33 mL) was heated to reflux overnight. The reaction mixture was filtered. The filtrate was condensed to give the crude product, which was purified by preparative TLC to afford (3S)-tert-butyl-3-(3-(4-fluorophenyl) -3-hydroxyhex-5-enylamino)piperidine-1-carboxylate (500 mg, 38%). 1H NMR: (CDCl3): 1.23 (m, 1H), 1.38 (d, 9H), 1.57 (m, 1H), 1.75 (broad, 1H), 1.94 (m, 2H), 2.37 (m, 1H), 2.43 (m, 2H), 2.56 (m, 1H), 2.80 (broad, 3H), 3.49 (broad, 1H), 3.71 (broad, 3H), 4.95 (d, 2H), 5.56 (m, 1H), 6.95 (t, 2H), 7.32 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.C(O)(=O)C>CO.[Fe]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ncc([N+](=O)[O-])cn2)CC1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCN(c2ncc(N)cn2)CC1
Yield: 78.1 %

Procedure:
A mixture of 2-(4-methyl-piperazin-1-yl)-5-nitro-pyrimidine (446 mg, 2 mmol), iron powder (432 mg, 7.6 mmol), acetic acid (0.884 mL, 14 mmol) in methanol (8 mL) is heated at 65 C for 2 h. It is worked up as before to yield 302 mg (78%) of the title compound. MS (ESI) m/z 194 (M+H)+1.
Reaction SMILES: C1(C2C=C(F)C=C[C:5]=2[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH:20]2[CH2:22][CH2:21]2)=O)CC1.C[Mg]Br.C1C[O:29]CC1>CCOCC>[CH:20]1([C:14]([C:13]2[CH:11]=[CH:5][C:16]([F:19])=[CH:17][CH:18]=2)([OH:29])[CH3:15])[CH2:21][CH2:22]1
Reactant: C1CCOC1
Reactant: O=C(c1ccc(F)cc1C1CC1)c1ccc(F)cc1C1CC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)(c1ccc(F)cc1)C1CC1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a solution of cyclopropyl-4-fluorophenyl ketone (523 mg, 3.19 mmol) in THF (10 mL) at 0° C. under N2 was added 3 M methyl magnesium bromide (1.7 mL, 5.1 mmol) in Et2O. After 90 minutes at 0° C., the reaction was quenched by addition of brine (10 mL) and diluted with Et2O (100 mL). The organic solution was washed with saturated NaHCO3 (100 mL) and brine (100 mL). Column purification (hexanes:EtOAc 9:1) yielded 1-cyclopropyl-1-(4-fluorophenyl)ethanol (512 mg, 89%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.Cl[C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:19](=[O:20])[O:21][CH3:22]
Reactant: COC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
A solution of 2-bromo-5-nitroaniline (500 mg, 2.30 mmol) in THF (40 mL) was treated with pyridine (0.19 mL, 2.3 mmol) and methyl chloroformate (0.27 mL, 3.5 mmol) at room temperature. After 4 hours, additional methyl chloroformate (0.27 mL, 3.5 mmol) was added, and the reaction mixture was stirred at room temperature for an additional 3 hours. The reaction mixture was concentrated to dryness and then taken up in EtOAc (30 mL) and washed with 1 N HCl (3×25 mL), dried (Na2SO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 0% ethyl acetate/hexanes to 30% ethyl acetate/hexanes, 40 g column, 30 min. gradient) to afford Intermediate 60A (390 mg, 61.5%). HPLC: Rt=3.215 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=274.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.39 (1H, s), 8.44 (1H, d, J=2.52 Hz), 7.92-7.96 (1H, m), 7.88-7.92 (1H, m), 3.71 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][N:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.Cl[CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH:17]1([C:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:1]5[CH2:28][CH2:29][CH2:30][S:31]5(=[O:33])=[O:32])=[CH:3][C:4]=4[O:25][CH3:26])=[N:13][C:12]=3[N:14]([CH3:23])[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc(N2CCCS2(=O)=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a 2 ml pyridine solution of 100 mg (0.280 mmol) of the compound obtained in Example 44, 85.2 μl (0.700 mmol) of 3-chloropropanesulfonyl chloride was added, and the mixture was stirred at room temperature for 8 hours. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. To the residue, 2 ml of ethanol and a 1M aqueous solution of sodium hydroxide were added, and the mixture was stirred at room temperature for 48 hours. Then, the reaction mixture was neutralized with a 1M aqueous solution of hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 68 mg (53%) of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[C:22]([Br:29])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+]>CO.O.ClCCl>[Cl:1][C:2]1[C:3]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[C:22]([Br:29])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2
Reactant: CCOc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(C(=O)C(F)(F)F)CC3)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc(C(=O)Nc2ccc3c(c2Cl)CNCC3)cc1Br
Reaction time: 12 h
Yield: 79.4 %

Procedure:
A solution of N-(8-chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide (0.28 g) in methanol/water (5 ml 9:1) was treated with potassium carbonate (0.38 g) and stirred 12 h. The mixture was diluted with dichloromethane and washed with water. The organic phase was dried (MgSO4) solvent removed at reduced pressure. The residue was chromatographed (silica gel, dichloromethane/methanol/ammonia up to 9:1:0.1 eluant) to give the title compound (0.18 g) as a colourless solid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[C:21](Cl)=[O:22].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: CN(C(=O)Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN1CCC(OC(=O)N(C)c2ccc(Cl)c(Cl)c2)N(c2nnc(C(C)(C)C)s2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N-methyl-N-(3,4-dichlorophenyl)carbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[N-methyl-N-(3,4-dichlorophenyl)carbamoyloxy]-2(1H)-pyrimidinone.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.CCOCC.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)c2ccccc2n1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 101A (5.9 g) in N,N-dimethylformamide (50 mL) was added 1-(bromomethyl)-4-methoxybenzene (4.85 g) and Cs2CO3 (25 g). The mixture was stirred overnight at room temperature. The mixture was diluted with ether (300 mL) and water (200 mL). The aqueous layer was extracted with ether twice. The combined extracts were washed with water (×3), brine and dried over Na2SO4. Concentration of the solvent gave EXAMPLE 101B.
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](/[CH:14]=[C:15]1/[C:16](=[O:28])[N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH2:18][CH2:19]/1)=[C:7]2[C:11]([OH:13])=[O:12].C[Si](/N=C(/O[Si](C)(C)C)\C(F)(F)F)(C)C.[Br:44][CH2:45][C:46](Br)=[O:47].C(OCC)C>ClCCl>[Br:44][CH2:45][C:46]([NH:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](/[CH:14]=[C:15]1/[C:16](=[O:28])[N:17]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=3)[CH2:18][CH2:19]/1)=[C:7]2[C:11]([OH:13])=[O:12])=[O:47]
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4ccc(O)cc4)C3=O)CS[C@H]12
Reactant: O=C(Br)CBr
Agent: C[Si](C)(C)/N=C(/O[Si](C)(C)C)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CBr)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4ccc(O)cc4)C3=O)CS[C@H]12

Procedure:
(E)-(6R,7R)-7-amino-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (736.0 mg, 1.83 mmol) was suspended in 20 ml dichloromethane and N,O-bis(trimethylsilyl)-trifluoroacetamide (1.94 ml, 7.32 mmol) was added. After 45 min bromoacetyl bromide (167 ml, 1.92 mmol) was added dropwise. After 1 h the reaction mixture was poured on 200 ml diethyl ether containing 160 ml water. After 15 min the solid material was collected by filtration, washed with diethyl ether and dried in high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:27]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:25]=[C:26](/[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)\[CH3:27])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)c1ccc(Cl)c(Cl)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (69 mg, 0.31 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (6 mg, 0.032 mmol) L-proline (7 mg, 0.063 mmol) and potassium phosphate (134 mg, 0.63 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) followed by HPLC. Yield: 13 mg as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.82 (d, 1H), 7.62 (d, 2H), 7.58 (d, 1H), 7.22 (m, 2H), 7.10 (s, 1H), 4.80 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.62 (m, 1H), 3.20 (m, 2H), 3.15 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[Br:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)(C)C)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1Br
Temperature: 0 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
To a solution of 20.80 g (108.7 mmol) of N-acetyl-4-tert-butyl aniline and 0.33 g (2 mmol) of ferric chloride in 70 ml of acetic acid is added dropwise 17.9 g (112 mmol) of bromine while the temperature is kept between 30° C. and 40° C. Then the reaction mixture is stirred 4 hours and poured into 500 ml of ice water. The precipitate is filtered off, washed with water and recrystallized from 70% ethanol. Thus is obtained 24.33 g (83%) of title compound.
Reaction SMILES: [Br:1][C:2]([F:10])([C:6]([Br:9])([F:8])[F:7])[C:3](F)=[O:4].[Cl-:11].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]([F:10])([C:6]([Br:9])([F:8])[F:7])[C:3]([Cl:11])=[O:4]
Reactant: O=C(F)C(F)(Br)C(F)(F)Br
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(Cl)C(F)(Br)C(F)(F)Br
Yield: 57 %

Procedure:
A 163-g (0.56 mole) sample of 2,3-dibromo-2,3,3-trifluoropropionyl fluoride was added dropwise to a mechanically stirred suspension of 76 g (0.56 mole) of aluminum chloride in 282 ml of methylene chloride. The reaction mixture warmed spontaneously to 40°. After cooling, the volatile portion of the reaction mixture was distilled under reduced pressure into a Dry Ice-cooled trap. Redistillation gave 97.5 g (57%) of 2,3-dibromo-2,3,3-trifluoropropionyl chloride as a colorless liquid: bp 128°-129°; nD25 1.4436; ir (liquid) 5.57 μ (COCl); 19F nmr (CCl3F) δ 55.7 ppm (d, J = 175 Hz to d, J = 14.5 Hz, 1F), 57.9 ppm (d, J = 175 Hz to d, J = 16 Hz, 1F) and 116.5 ppm (d, J = 16 Hz to d, J = 14.5 Hz, 1F).
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:7]=[C:8]([C:23]2[S:27][C:26]([C:28]3([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][CH:24]=2)[CH:9]=[C:10]([NH:12][C:13]2[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=2)[CH:11]=1.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[OH:34][C:28]1([C:26]2[S:27][C:23]([C:8]3[CH:9]=[C:10]([NH:12][C:13]4[N:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][N:14]=4)[CH:11]=[C:6]([CH3:5])[CH:7]=3)=[CH:24][N:25]=2)[CH2:29][CH2:30][N:31]([C:1](=[O:3])[CH3:2])[CH2:32][CH2:33]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Reactant: CC(=O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1

Procedure:
To a mixture of acetic acid (9 μL, 0.15 mmol) and Si-carbonyl diimidazole (266 mg, 0.287 mmol) was added a solution of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) and hydroxybenzotriazole (26 mg, 0.17 mmol) dissolved in N,N-dimethylformamide, and the resultant suspension was shaken in a Bohdan block overnight at room temperature. The reaction mixture was filtered and concentrated in vacuo, and the resultant residue was dissolved in DMSO and purified via HPLC (30-64% CH3CN:H2O) to provide 1-{4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone. MS EST: [M+H]+ m/z 478.1. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 7.95 (s, 2H), 7.44 (s, 1H), 7.26 (d, J=5.1 Hz, 1H), 7.14 (s, 1H), 6.30 (s, 1H), 4.25-3.99 (m, 1H), 3.73 (m, 1H), 3.41-3.34 (m, 1H), 3.07-2.97 (m, 1H), 2.47 (s, 3H), 2.32 (s, 3H), 2.25-2.14 (m, 1H), 1.93 (m, 2H), 1.75 (m, 1H). rhSYK activity=+++