Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[C:38]([C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][C:41]=1B(O)O)#[N:39].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:38]([C:40]1[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=[CH:42][C:41]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2)#[N:39]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Reactant: N#Cc1cc(C(F)(F)F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 100 °C
Yield: 1.4 %

Procedure:
A pressure vessel was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D) (150 mg, 0.288 mmol), potassium carbonate (199 mg, 1.441 mmol), (2-cyano-4-(trifluoromethyl)phenyl)boronic acid (124 mg, 0.576 mmol), tetrakis(triphenylphosphine)palladium(0) (33.3 mg, 0.029 mmol), dioxane (1922 μl) and water (961 μl). The reaction was heated in a microwave to 100° C. for 60 min. Additional (2-cyano-4-(trifluoromethyl)phenyl)boronic acid (124 mg, 0.576 mmol) and tetrakis(triphenylphosphine)palladium(0) (33.3 mg, 0.029 mmol) were added and the resulting mixture was heated in a microwave at 100° C. for an additional hour. After heating the mixture was allowed to cool to room temperature, the organic layer was separated and the organic layer was concentrated. The resulting product was purified by MPLC (40 g silica gel column, eluting with 0% to 50% EtOAc in heptane) to afford a white solid that was further purified by reverse phase HPLC (Column: Xbridge 19×100 mm, 5 μm, Waters, Milford, Mass., Flow rate: 40 mL/min, Mobile phase: 0.1% NH4OH in ACN and water). The fractions containing product were dried under a vacuum to afford 5-(2-cyano-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (2.1 mg, 0.004 mmol) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.58 (d, J=8.76 Hz, 1H) 7.69-7.74 (m, 1H) 7.75-7.83 (m, 2H) 7.87 (d, J=8.01 Hz, 1H) 8.16-8.24 (m, 2H) 8.34 (d, J=8.34 Hz, 1H) 8.52-8.57 (m, 2H); m/z (ESI) 461.0 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([C:7]1[C:8]([CH2:24][CH:25]2[CH2:27][CH2:26]2)=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]([CH:17]([F:19])[F:18])=[N:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[CH2:4][CH:5]=[CH2:6])#N.[H-].C([Al+]CC(C)C)C(C)C.Cl.CC[O:41]CC>>[CH:25]1([CH2:24][C:8]2[C:7]([CH:3]([CH:1]=[O:41])[CH2:4][CH:5]=[CH2:6])=[C:12]([C:13]([F:15])([F:16])[F:14])[N:11]=[C:10]([CH:17]([F:18])[F:19])[C:9]=2[C:20]([O:22][CH3:23])=[O:21])[CH2:26][CH2:27]1
Reactant: C=CCC(C#N)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC1CC1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Product: C=CCC(C=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC1CC1
Reaction time: 0.5 h

Procedure:
To a solution of 16.5 g (68.3 mmol) of methyl 5-(1-cyano-3-butenyl)-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 16 of U.S. Pat. No. 5,169,432) in 250 ml of ether cooled in an ice bath was added 91 ml (136 mmol) of diisobutylaluminum hydride (1.5 M in toluene). The reaction mixture was stirred on an ice bath for 30 min and was treated with 200 ml of 2.4 M HCl. The organic layer was washed with brine, dried (MgSO4), and filtered through silica gel. The filtrate was concentrated in vacuo and the residue was purified by HPLC (17% EtOAc in hexane) to give 8.1 g of methyl 4-(cyclopropylmethyl)-2-(difluoromethyl)-5-(1-formyl-3-butenyl)-6-(trifluoromethyl)-3-pyridinecarboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[CH3:14][S-:15].[Na+].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][S:15][CH3:14])[CH:3]=1
Reactant: C[S-]
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Br)cc1CSC
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (12 g) and sodium thiomethoxide (2.5 g) in toluene was stirred at 100° C. for 2 hours. The mixture was then cooled, poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (anhydrous sodium sulphate) and evaporated to afford a brown oil which was purified by column chromatography on silica gel giving methyl 4-bromo-2-(methylsulphenylmethyl)benzoate (4.1 g) as white crystals, m.p. 79.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[O:17][CH3:18])[N:5]=[CH:4][N:3]=1.C(O)(=O)C>CCO.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[O:17][CH3:18])[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cc(Cl)ncn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(N)ccc1-c1cc(Cl)ncn1
Temperature: 80 °C
Yield: 93.9 %

Procedure:
A suspension of 4-chloro-6-(2-methoxy-4-nitrophenyl)pyrimidine (0.6 g, 2.259 mmol) in EtOH (Ratio: 2.000, Volume: 10 mL) was stirred at 80° C. to make most of the material solublized, Acetic Acid 20% (Ratio: 1.000, Volume: 5 mL) and iron powder (0.883 g, 15.81 mmol) were added. The resulting mixture was refluxed for 1 h. The reaction was concentrated under vacuum. The residue was partitioned between EtOAc/1.0 M aqueous NaOH. The aqueous layer was extracted with EtOAc (3×20 ml). The combined organic layers were washed with aqueous sodium bicarbonate (2×20 ml) and brine (20 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified via Biotage Horizon system (25 g column of Thomson Single Step, EtOAc/Hexane, Griadient: 0%˜80%). Desired fractions were collected, concentrated and the residue was triturated with DCM to get 0.5 g (82%) of product as light-yellow solid. LC-MS (M+H)+=236. 1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3H) 4.07 (br. s., 2H, NH2) 6.27 (d, J=2.26 Hz, 1H) 6.40 (dd, J=8.53, 2.26 Hz, 1H) 8.04 (d, J=1.25 Hz, 1H) 8.07 (d, J=8.28 Hz, 1H) 8.91 (d, J=1.25 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(O)[CH2:8][CH2:9][CH2:10][CH2:11]OC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[BrH:25]>O>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH2:9][CH2:10][CH2:11][Br:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCCCC(O)(c1ccccc1)c1ccccc1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: BrCCCC=C(c1ccccc1)c1ccccc1

Procedure:
A mixture of the pentanol prepared as above (8.88 g., 0.0328 mole) in 132 ml. of glacial acetic acid and 66 ml. of distilled hydrobromic acid was stirred at ambient temperature for two hours and then refluxed for 90 minutes. The reaction mixture was cooled, diluted with water and extracted with ether. The ether extract was washed with 5% sodium carbonate solution, water, dried and concentrated to obtain an oil which is chromatographed on silica to yield 5,5-diphenyl-4-pentenyl bromide.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C.C(=O)(O)[O-].[Na+].CC1(C)C(C)(C)OB([C:44]2[CH:49]=[CH:48][C:47]([C:50]3([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:53][CH2:52][CH2:51]3)=[CH:46][CH:45]=2)O1>C1(C)C=CC=CC=1>[CH2:20]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]3[N:16]=[CH:17][CH:18]=[CH:19][C:7]=3[N:6]2[C:2]=1[C:44]1[CH:45]=[CH:46][C:47]([C:50]2([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:59])([CH3:58])[CH3:60])[CH2:51][CH2:52][CH2:53]2)=[CH:48][CH:49]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: Brc1c(CCc2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CCc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
To a suspension of 3-bromo-2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.197 g, 1 eq.) in a mixture of toluene (10 mL), ethanol (10 mL), and saturated sodium bicarbonate (4 mL) was added tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (0.353 g, 2 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.054 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (100 mL). The aqueous phase was extracted with dichloromethane (2×100 mL) and the organic extracts were combined and washed with brine (1×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (10-60% ethyl acetate in hexanes) gave tert-butyl (1-(4-(2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.042 g, 15%) as a yellow solid. LCMS: 584 [M+H].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].C1(=O)N([CH:37]([CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:60])[CH2:47][CH2:48][CH2:49][CH2:50][C@H:51]2[C@@H:59]3[C@@H:54]([NH:55][C:56]([NH:58]3)=[O:57])[CH2:53][S:52]2)[C:38]([O-])=[O:39])C(=O)CC1>CN(C=O)C>[CH3:12][C:10]1[N:11]=[C:7]([NH:6][C:4]([CH2:3][CH2:2][NH:1][C:38](=[O:39])[CH2:37][CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:60])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]2[CH:59]3[CH:54]([NH:55][C:56](=[O:57])[NH:58]3)[CH2:53][S:52]2)=[O:5])[S:8][C:9]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[N:14]=1
Reactant: Cc1nc(NC(=O)CCN)sc1-c1ccnc(Nc2ccc(N3CCOCC3)cc2)n1
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCC(C(=O)[O-])N1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)CCNC(=O)CCCCCNC(=O)CCCCC2SCC3NC(=O)NC32)sc1-c1ccnc(Nc2ccc(N3CCOCC3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-amino-N-{4-methyl-5-[2-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-thiazol-2-yl}-propionamide (75 mg, 0.17 mmol) in DMF (1 mL) was treated with succinimidyl-6-(biotinamido)hexanoate (32 mg, 0.085 mmol). After stirring at room temperature for 3 h, the reaction mixture was purified by preparative RP-HPLC (0-60% MeCN in 0.1% aq CF3COOH over 40 min, 9 mL/min) to afford the title compound as an orange solid. Anal. RP-HPLC: tR=13.2 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>97%). MS (ESI+) m/z 776 (C37H50N10O5S2 requires 778.9).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([O:16][CH3:17])=[N:11][C:10]=1[C:18]([O:20]C(C)(C)C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([O:16][CH3:17])=[N:11][C:10]=1[C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(C(=O)OC(C)(C)C)c(OCc2ccccc2)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(C(=O)O)c(OCc2ccccc2)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of Compound 43c (1.1 g, 3.2 mmol) in MeOH (20 mL) and THF (20 mL) was added 7 N NaOH (4.0 mL, 28 mmol) and the solution stirred at 50° C. for 3 h. The reaction mixture was cooled in an ice bath then acidified by the addition of 1 N HCl (20 mL). The resulting precipitate was filtered, rinsed with water then dried under vacuum to give Compound 43a (790 mg, 89% yield) as a white solid. LCMS=1.41 min using analytical method (Q), 277.0 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 13.49 (br. s., 1H), 12.91 (br. s., 1H), 7.90-6.67 (m, 5H), 5.01 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.C1COCC1.[O:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C:36](O)=[O:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:36]([C@@H:32]2[CH2:33][CH2:34][CH2:35][O:31]2)=[O:37])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: O=C(O)[C@@H]1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)[C@@H]1CCCO1
Yield: 11.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-107 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol), THF:DMF (5 mL:1 mL), (S)-(−)tetrahydrofuran-2-carboxylic acid (0.032 g, 0.283 mmol), TBTU (0.182 g, 0.567 mmol), and TEA (3.0 mL). The obtained crude was purified by column chromatography on basic alumina by eluting solution of 2% ammonia in 10.0% MeOH:DCM to afford 0.010 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.80 (m, 3H), 2.15 (m, 1H), 3.75 (m, 1H), 3.94 (m, 1H), 4.27-4.32 (m, 3H), 7.42 (d, 1H), 7.60 (d, 2H), 7.85 (d, J=5.4 Hz, 2H), 8.20 (d, J=4.5 Hz, 2H), 8.52 (s, 1H), 12.50 (s, 1H); MS (m/z): 467.08 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH3:21])[C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C(N1CCOCC1)C.[CH2:38]([NH2:41])[CH2:39][CH3:40]>O1CCCC1.C(OCC)(=O)C>[CH2:38]([NH:41][C:14](=[O:16])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:20][CH3:21])[CH2:39][CH3:40]
Reactant: CCCN
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CC)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
2 g of 1-(N-(tert-butoxycarbonyl)-2(S)-amino-butyryl)-L-proline (6.6 mmol) prepared as in Example 2 c) are dissolved in tetrahydrofuran (40 ml). 0.86 ml of isobutyl chloroformate (6.6 mmol) and 0.85 ml of N.-ethylmorpholine (6.6 mmol) are then added to this solution, at −10° C. and under nitrogen. After stirring at −10° C. for 20 minutes, 2.75 ml of n-propylamine (33.0 mmol) are added. The mixture is left stirring at 0° C. for one hour and then at room temperature overnight. The solvent is evaporated off under vacuum and a white semi-solid material is obtained. It is dissolved in ethyl acetate (150 ml) and washed with 5% citric acid (30 ml), saturated sodium bicarbonate solution (30 ml) and brine (20 ml). After drying (Na2SO4) the mixture is filtered and the solvent is evaporated off. An oil is obtained, which is purified by liquid chromatography on a column (eluent: ethyl acetate) and a white solid is obtained.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:38])=[C:23]([NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:27])[CH:24]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:38])=[C:23]([NH:25][C:26]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[N:34]=[CH:33][CH:32]=[CH:31]4)=[O:27])[CH:24]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1NC(=O)c1ccc2ncccc2c1
Yield: 49.5 %

Procedure:
Triethylamine (0.28 ml) was added to a stirred mixture of 4-chlorobenzoyl chloride (0.29 g), N-(5-amino-2-methylphenyl)quinoline-6-carboxamide (0.28 g) and methylene chloride (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with water and with methylene chloride. There was thus obtained the title compound as a solid (0.208 g); NMR Spectrum: (DMSOd6) 2.24 (s, 3H), 7.24 (d, 1H), 7.52-7.62 (m, 4H), 7.87 (s, 1H), 7.98 (d, 2H), 8.12 (d 1H) 8.46 (d, 1H), 8.52 (d, 1H), 8.65 (s, 1H) 9.00 (s, 1H), 10.15 (s, 1H) 10.31 (s, 1H); Mass Spectrum: M+H+ 416.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=O.C([N+](CC)(CC)S(NC(=O)OC)(=O)=O)C>O1CCCC1>[CH2:3]([C:4]1[O:18][C:8]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[N:7][N:6]=1)[C:2]([CH3:20])([CH3:19])[CH3:1]
Reactant: CC(C)(C)CC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Solvent: C1CCOC1
Product: CC(C)(C)Cc1nnc(-c2ccc([N+](=O)[O-])cc2)o1
Temperature: 120 °C

Procedure:
A mixture of N′-(3,3-dimethylbutanoyl)-4-nitrobenzohydrazide (0.556 g, 1.991 mmol) and methyl N-(triethylammoniumsulfonyl)carbamate (0.572 g, 2.389 mmol) in tetrahydrofuran (10 ml) was heated to 120° C. in a microwave (Biotage Initiator) for 45 minutes. The crude reaction mixture was concentrated and purified by normal phase chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[F:11].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:13])=[CH:6][C:5]=1[F:11]
Reactant: COC(=O)c1ccc(C)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1F
Temperature: 60 °C
Yield: 82 %

Procedure:
To a solution of 2-fluoro-4-methyl-benzoic acid methyl ester (1.12 g, 6.66 mmol) in carbon tetrachloride (12 mL) add N-bromosuccinimide (1.18 g, 6.66 mmol) and benzoyl peroxide (10 mg). Heat the resulting mixture to 60° C. for 15 hours then concentrate under vacuum to half and filter. Concentrate the filtrate under vacuum and purify the resulting crude product by flash chromatography on silica gel (eluting with 5/1 heptane/ethyl acetate) to give the title compound (1.35 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[C:10](Cl)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C(C)=CC=CC=1C.BrC1C=C(NC(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:19])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(Br)c1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C(/C=C/c1ccccc1)Nc1cccc(Br)c1
Solvent: Cc1cccc(C)n1
Product: O=C(/C=C/c1ccccc1)Nc1cc(F)cc(Br)c1
Yield: 85 %

Procedure:
The compound was prepared from 3-bromo-5-fluoroaniline (Intermediate 180, 5.3 g, 27.9 mmol) and cinnamoylchloride (5.6 g, 33.5 mmol) in the presence of 2,6-lutidine (5.0 mL, 41.9 mmol) as described for Intermediate 18 to give the product as a colorless solid, 7.6 g (85% yield).
Reaction SMILES: [C:1]([NH2:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O.[OH-].[Na+]>OS(O)(=O)=O>[CH2:2]([C:1]1[O:7][CH:13]=[C:11]([CH2:10][Cl:9])[N:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(CCl)CCl
Reactant: CCCCCC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCc1nc(CCl)co1
Temperature: 120 °C
Yield: 19.2 %

Procedure:
The synthesis of 3 was performed similarly to example 1 above. The solids, hexanoamide (5 g) and 1,3-dichloroacetone (5.5 g), were mixed together in a round bottomed flask and heated at 120° C. under an argon atmosphere for 2 hours. The mixture was cooled to 25° C. for 1 hour, followed by the addition of concentrated H2SO4 (50 mL). The resulting syrup was poured onto ice and the pH was adjusted to 10 with NaOH (1M). The resulting solution was extracted with CHCl3, dried (Na2SO4) and evaporated to yield a brown liquid (1.56 g). This material was chromatographed according to Still et al. (J. Org. Chem., 1978, 43, 2923) on silica gel in EtOAc to yield 3 as a yellow liquid (1.4 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:18]=3)=[CH:15][C:14]([C:28]([O:30]CC)=[O:29])=[N:13]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[OH-].[Na+].O.Cl.[CH2:37]([OH:39])[CH3:38]>>[CH2:37]([O:39][C:6]1[CH:5]=[C:4]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:18]=3)=[CH:15][C:14]([C:28]([OH:30])=[O:29])=[N:13]2)[CH:3]=[CH:2][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10])[CH3:38]
Reactant: CCO
Reactant: CCOC(=O)c1cc(-c2ccc(-c3ccco3)cc2)n(-c2ccc(S(C)(=O)=O)c(F)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc(-n2nc(C(=O)O)cc2-c2ccc(-c3ccco3)cc2)ccc1S(C)(=O)=O
Yield: 73 %

Procedure:
To a stirred solution of ethyl 1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylate (0.57 g, 1.25 mmol) in ethanol (15 mL) was added 2N-NaOH solution in water (1.6 mL, 3.14 mmol), and the mixture was heated at reflux temperature for 30 minutes. After cooling, 2N-HCl solution (4 mL) and water (30 mL) were added to the mixture. The whole was extracted with ethyl acetate (20 mL×3), the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting solid was washed with methylene chloride to give the title compound (0.413 g, 73.0%, yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][OH:24])[O:20][C:19]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][O:24][S:34]([CH3:33])(=[O:36])=[O:35])[O:20][C:19]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CCN1CCF
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CCN(CCF)C(=O)C3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]phenyl)-5-hydroxymethyloxazolidin-2-one (0.8 g) is dissolved in pyridine (15 ml) and the mixture cooled to 0°. Triethylamine (0.38 ml) and methanesulfonyl chloride (0.19 ml) are added to the mixture, and stirring continued at 20–25° for 2 hours. The solvent is removed and the residue dissolved in dichloromethane, washed with water, saline, dried over magnesium sulfate and concentrated. The resulting residue is triturated with ether to give (5R)-3-(3-fluoro-4-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (0.76 g) which is used without further purification.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>C(O)C>[CH2:2]([O:1][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])[CH3:3]
Reactant: CC[O-]
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncccc1C(=O)O
Temperature: 170 °C

Procedure:
A solution of sodium ethoxide (14.2 mL) was added to a solution of 2-chloronicotinic acid (2.00 g) in ethanol (13 mL). The mixture was heated in a sealed vessel at 170° C. for 2 days. After cooling, the mixture was concentrated in vacuo and the residue taken in water and acidified with hydrochloric acid to pH 3. The precipitated solids were collected by filtration and washed with water to obtain the title compound (1.32 g) having the following physical data.