Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([N:9]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C.CCOC(C)=O>[NH2:3][CH2:2][CH2:1][NH:4][C:12]1[C:13](=[O:14])[N:9]([C:5]([CH3:7])([CH3:6])[CH3:8])[S:10](=[O:23])(=[O:22])[C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCN
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C(NCCN)=C(c2ccccc2)S1(=O)=O
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
Ethylenediamine (0.60 g, 10.0 mmol) was dissolved in dry DMF (50 ml) and heated to 60° C. 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.00 g, 3.34 mmol) dissolved in DMF (10 ml) was added dropwise over 30 mins and stirred at 60° C. for 10 mins. The reaction mixture was diluted with EtOAc (300 ml) and washed with water (400 ml and 2×200 ml), dried (Na2SO4), filtered and evaporated to give the title compound (0.97 g, 90%). 1H-NMR (500 MHz, CDCl3): δ 7.50-7.45 (m, 2H), 7.42-7.37 (m, 3H), 5.83-5.76 (m, 1H), 2.84-2.78 (m, 2H), 2.67-2.62 (m, 2H), 1.71 (s, 9H); 13C-NMR (125 MHz, CDCl3): δ 159.7, 135.4, 131.6, 129.5, 128.6, 125.2, 106.9, 61.5, 46.2, 40.8, 27.7; Mass Spectrum: M+H+ 324.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]([O:21][CH3:22])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH2:19][OH:20])[CH:7]=1.[H-].[Na+].[CH3:29]I>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH2:19][O:20][CH3:29])[C:5]([O:21][CH3:22])=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1
Reactant: CI
Reactant: COc1c(/C=C/c2ccc([N+](=O)[O-])cc2CO)cc(Br)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1cc([N+](=O)[O-])ccc1/C=C/c1cc(Br)cc(C(C)(C)C)c1OC
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
step 2—To a solution of 34a (116 mg, 0.276 mmol) in DMF (5 mL) was added sodium hydride (0.022, 0.550 mmol, 60% mineral oil dispersion). After 20 min, methyl iodide (0.040 mL, 0.643 mmol) was added and the resulting suspension was stirred overnight. The reaction mixture was diluted with EtOAc, thrice washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (5% to 15% EtOAc) to afford 81 mg (68%) of 5-bromo-1-tert-butyl-2-methoxy-3-[(E)-2-(2-methoxymethyl-4-nitro-phenyl)-vinyl]-benzene (34b) as an orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][CH2:25]2)=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
1-(N-t-Butoxycarbonylamino)-2-aminobenzene (Method 17, 3.1 g, 14.7 mmol) was added to a stirred solution of 4-(1-t-butoxycarbonylpiperidin-4-yl)benzoic acid (4.1 g, 13.4 mmol) in DMF (50 ml) and the mixture stirred at ambient temperature for 10 minutes. 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride (Method 18, 4.45 g, 16.1 mmol) was added and the mixture stirred at ambient temperature for 24 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (100 ml) and washed with water. The organics were dried over magnesium sulfate, filtered and evaporated. The resultant gum was purified by flash chromatography using 1% methanol/dichloromethane to give the title compound as a foam (5.44 g, 82%); NMR Spectrum: (DMSO-d6) 1.41 (s, 9H), 1.43 (s, 9H), 1.54 (m, 2H), 1.77 (m, 2H), 2.79 (m, 3H), 4.08 (m, 2H), 7.15 (m, 2H), 7.40 (d, 2H), 7.52 (m, 2H), 7.87 (d, 2H), 8.60 (br, 1H), 9.74 (br, 1H), Mass Spectrum: (M+H+-Boc) 396.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH3:11])[CH:7]=[CH:8][CH:9]=1.[OH-:13].[Na+].[CH2:15]1[CH2:19][O:18]CC1>O.CO>[Br:3][C:4]1[CH:5]=[C:6](/[C:10](/[CH3:11])=[CH:15]/[C:19]([OH:13])=[O:18])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: C1CCOC1
Reactant: [OH-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C/C(=C\C(=O)O)c1cccc(Br)c1
Temperature: 50 °C

Procedure:
To a stirred mixture of 60% sodium hydride (2.01 g) in dry THF (100 mL) was added triethyl phosphonoacetate (10.1 mL) at 0° C. under nitrogen. The resulting mixture was added dropwise to a solution of 1-(3-bromophenyl)ethanone (10.0 g) in THF (100 mL) at reflux and the reaction heated at reflux overnight. The reaction mixture was diluted with water (300 mL), and extracted with dichloromethane (350 mL). The organic was dried (MgSO4), filtered and evaporated to afford a yellow oil. The oil was dissolved in methanol (100 mL), sodium hydroxide (6.03 g) and water (50 mL) added and the mixture was heated at 50° C. for 2 h. The reaction mixture was evaporated to leave an aqueous solution which was extracted twice with diethyl ether and the organic extracts were discarded. The aqueous solution was acidified with aqueous 2M HCl and then extracted with ethyl acetate (300 mL). The organic was dried (MgSO4), filtered and evaporated to afford the subtitle compound (11.70 g) as a solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([S:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])[CH3:5].Cl.O>CO>[CH3:16][C:13]([C:11]1[CH:10]=[C:9]([S:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[OH:24])[CH:8]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[CH:12]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(SC2CCCCC2=O)cc(C(C)(C)C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(S[C@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1
Reaction time: 1 h

Procedure:
Sodium borohydride (0.40 g, 0.0105 mole) was added to a cold (3° C.) solution of 2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexanone (3.18 g, 0.0100 mole) in methanol (150 mL). After 1 hour, 10% hydrochloric acid (5 mL) and water (50 mL) were added. The methanol was removed by rotary evaporator and the title products were extracted into ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated to an oil. Silica gel chromatography separated the two title products. The major product (first off) was identified as the "cis" product by NMR.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[C:6]([Cl:19])[N:5]=[CH:4][N:3]=1.[K+].[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH-:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[CH2:22].Cl>CO.CN(C)C=O>[Cl:19][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:32][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH:21]=[CH2:22])=[CH:24][CH:25]=2)(=[O:30])=[O:31])[C:7]=1[CH2:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18]
Reactant: COc1cccc(OC)c1Cc1c(Cl)ncnc1Cl
Reactant: C=Cc1ccc(S([NH-])(=O)=O)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: C=Cc1ccc(S(=O)(=O)Nc2ncnc(Cl)c2Cc2c(OC)cccc2OC)cc1
Temperature: 100 °C
Yield: 21 %

Procedure:
A mixture of 80 mg of 4,6-dichloro-5-(2,6-dimethoxybenzyl)pyrimidine and 170 mg of p-vinylbenzenesulfonamide monopotassium salt (J. Am. Chem. Soc. 1956, 78, 2169) from the corresponding sulfonamide with potassium t-butylate in absolute MeOH and 10 ml of dimethylformamide was heated at 100° C. for 6 hours. Thereafter, the mixture was left to cool to 25° C. overnight. Now, 30 ml of 0.5N HCl were added to the reaction solution while stirring. The precipitated substance was removed by filtration under suction and recrystallized from toluene/n-hexane. There were obtained 25 mg of N-(6-chloro-5-(2,6-dimethoxy-benzyl)-4-pyrimidinyl)-p-vinylbenzenesulfonamide, melting point 197°-198° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1.[C:16]([O-:19])(=[O:18])[CH3:17].[Na+].C(O)(=O)C>C(N(CC)CC)C>[C:16]([O:19][CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1)(=[O:18])[CH3:17]
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2o1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc2oc(S(N)(=O)=O)cc2c1

Procedure:
A mixture of 5-bromomethyl-2-sulfamoylbenzo[b]furan, anhydrous sodium acetate and glacial acetic acid (15 ml) is treated with a little triethylamine and the mixture is heated to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13](I)[C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(O[CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)C.C(OCC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCc1c(F)cccc1I
Reactant: CC(=O)OCC=Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1c(F)cccc1CC=Cc1ccccc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Under an argon atmosphere, 300 mg of t-butyl N-(2-fluoro-6-iodobenzyl)carbamate, 0.29 mL of cinnamyl acetate, 1.28 mL of bistributyltin, and 70 mg of PdCl2(dppf)2 were dissolved in 2.5 mL of DMF, followed by stirring at 120° C. for 2 hours. After completion of the reaction, to the reaction liquid was added diethyl ether, followed by filtration through Celite, and to the filtrate was added water, followed by extraction with diethyl ether. Then, the organic layer was washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (n-hexane:ethyl acetate=3:1) to obtain 121 mg (yield 52%) of a title compound as a yellow solid.
Reaction SMILES: [CH3:1][Si:2](C#C)([CH3:4])[CH3:3].C([Li])CCC.[CH3:12][C:13]([O:16][C:17]([NH:19][CH:20]1[CH2:26][CH2:25][C:23](=[O:24])[CH2:22][CH2:21]1)=[O:18])([CH3:15])[CH3:14]>C1COCC1>[C:13]([O:16][C:17](=[O:18])[NH:19][CH:20]1[CH2:21][CH2:22][C:23]([OH:24])([Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:25][CH2:26]1)([CH3:12])([CH3:14])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(O)([Si](C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A solution of trimethylsilyl acetylene at −78° C.(4.14 g, 0.042 mol) in THF (60 mL) was treated with n-butyl lithium (29 mL, 0.042 mol; 1.6 M solution in THF). The resulting mixture was stirred at −78° C. for 15 min. A solution of N-4-Boc-aminocyclohexanone (3 g, 0.014 mol; Astatech, Inc) in THF (120 mL) was added dropwise over a period of 30 min. The resulting mixture was stirred at −78° C. for 1 h and then allowed to slowly warm up to room temperature over 1 h. The reaction was quenched with a saturated solution of ammonium chloride and diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, H2O, and saturated aqueous NaCl solution. The organic layer was dried over MgSO4 and concentrated to yield an off-white foam (4.38 g, 100%).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[O:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1>C1COCC1>[CH3:1][Si:2]([C:5]#[C:6][C:15]1([OH:18])[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)([CH3:4])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trimethylsilylacetylene (5 mL, 35.4 mmol) in THF (100 mL) cooled at −78° C., a 1.6M n-butyllithium in hexanes (22.1 mL, 35.4 mmol) was added dropwise. The solution was stirred for 30 min before tetrahydro-4H-pyran-4-one (3.47 mL, 37.2 mmol) was added. The temperature was slowly raised to room temperature and the reaction was stirred overnight. The reaction was quenched with a saturated ammonium chloride solution and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 4.60 (s, 1H), 3.85-3.75 (m, 2H), 3.61-3.51 (m, 2H), 1.98-1.87 (m, 2H), 1.74-1.66 (m, 2H), 0.16 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.[C:37]([NH:40][NH2:41])(=[O:39])[CH3:38].Cl>O1CCCC1.O>[C:37]([NH:40][N:41]=[CH:1][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])(=[O:39])[CH3:38]
Reactant: CC(=O)NN
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NN=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 87.6 %

Procedure:
In a procedure similar to that described in Example I-3, diphenylmethyl 3-formyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (104 mg) and acetylhydrazine (30 mg) are left to react in a mixture of tetrahydrofuran (8 ml) and water (1.51 ml) in the presence of hydrochloric acid (2 equivalents) at room temperature overnight to give diphenylmethyl 3-(2-acetylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (101 mg). m.p. 130-138° C. Yield: 88%. IR: νmaxNujol 3250, 1782, 1715, 1670, 1597, 1535 cm-1. UV: λmaxEtOH 327nm(ε=24000). NMR: δCDCl 3 (60MHz) 220s3H, 3.72ABq(39;18Hz)2H, 3.82s2H, 5.00d(5Hz)1H, 5.87dd (9;5Hz)1H, 6.77-7.58ml5H, 8.05s1H, 9.65s1H. [α]D23 -258° (c= 0.493,CHCl3).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O-])=[O:21])=[CH:18][CH:17]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(OCC)(=O)C>O1CCCC1>[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:23][CH:24]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)[O-])cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Temperature: 0 °C
Yield: 71.4 %

Procedure:
A suspension of 1.40 g (36.8 mmol) of lithium aluminum hydride in 150 ml of tetrahydrofuran was stirred at 0° C. A solution of 13.0 g (49.0 imol) of 4-(tert-butoxycarbonylaminomethyl)benzoate in 50 ml of tetrahydrofuran was dropwise added slowly to the suspension. After completion of the dropwise addition, the solution was heated to reflux for 2 hours and then cooled to 0° C. After 20 ml of 50% tetrahydrofuran was dropwise added to the reaction mixture, 100 ml of ethyl acetate was added thereto. Insoluble matters were filtered off and the resulting filtrate was concentrated under reduced pressure. The concentrate was isolated and purified by silica gel column chromatography to obtain 8.80 g (75.7%) of 4-(tert-butoxycarbonylaminomethyl)benzyl alcohol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[CH:3][CH:2]=1.Br[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:24])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[CH:3]=[CH:2]2)=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cc(CBr)ccc1F
Reactant: Oc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cn2ccc(=O)c3ccccc32)ccc1F
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of quinolin-4-ol, methyl 5-(bromomethyl)-2-fluorobenzoate (prepared as described in US 2007/0021427 A1, 1 eq) and potassium carbonate (1.2 eq) in dry DMF (0.1 M solution) was stirred at 100° C. for 1 h. After solvent evaporation, the residue was dissolved in DCM and washed twice with H2O and once with brine. The organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting crude was purified by flash-chromatography (EtOAc/PE 9:1) to give the title compound. The O-alkylated isomer is eluted before the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=2[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:20][N:16]1[C:15]2[CH:21]=[C:11]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:12]=[CH:13][C:14]=2[O:18][C:17]1=[O:19]
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(=O)oc2ccc(Br)cc21
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: [Na+]
Solvent: COCCOC
Product: Cn1c(=O)oc2ccc(-c3cccnc3)cc21
Yield: 39.8 %

Procedure:
A mixture of pyridin-3-ylboronic acid (61.5 mg, 0.5 mmol), 5-Bromo-3-methyl-3H-benzooxazol-2-one (114 mg, 0.5 mmol), polymer-supported Pd(PPh3)4 (0.11 mmol/g, 114 mg, 0.0125 mmol), Na2CO3 (2 M in water, 0.5 mL, 1 mmol) in DME (3 mL) was heated to reflux for 6 hrs. After filtration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 1-3%) and yielded the title compound as pale yellow solid (45 mg). 1HNMR(CDCl3, 400.342 MHz): δ 3.47 (s, 3H), 7.13 (s, 1H), 7.30 (m, 2H), 7.38 (dd, J=4.8, 7.9 Hz, 1H), 7.85 (m, 1H), 8.62 (dd, J=1.5, 4.8 Hz, 1H), 8.82 (d, J=2.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21].N1C=CC=CC=1>O>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:23]([CH:20]([CH3:22])[CH3:21])(=[O:25])=[O:24])=[CH:3][C:4]=2[C:16]([F:19])([F:17])[F:18])=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1C(F)(F)F
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 10.8 %

Procedure:
5-[4-amino-2-(trifluoromethyl)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile (0.33 g, 1.25 mmol) was dissolved in isopropyl sulfonyl chloride (1.0 mL, 9.0 mmol), pyridine (0.5 mL) was added, and the mixture was heated to 100° C. for 6 hours. The mixture was cooled and diluted with water and extracted with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, and concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-(trifluoromethyl)phenyl]-propane-2-sulfonamide (50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]1[CH2:25]O.CS(OS(C)(=O)=O)(=O)=O.[CH2:37]([NH2:40])[CH:38]=[CH2:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]1[CH2:25][NH:40][CH2:37][CH:38]=[CH2:39]
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: C=CCN
Agent: CS(=O)(=O)OS(C)(=O)=O
Product: C=CCNCc1nnc(CN(C)C)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 47, 2',5-dichloro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone is treated first with methanesulfonic anhydride followed by allylamine to give 2',5-dichloro-2-[3-[(allylamino)methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:31]2[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[C:33]([O:39]C)[N:32]=2)=[CH:13]\[C@@H:14]2[N:18](CC3C=CC(OC)=CC=3OC)[C:17](=[O:30])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].O>O1CCOCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:31]2[NH:32][C:33](=[O:39])[C:34]([S:37][CH3:38])=[CH:35][CH:36]=2)=[CH:13]\[C@H:14]2[CH2:15][CH2:16][C:17](=[O:30])[NH:18]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(SC)c(OC)n2)c(OC)c1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
48% hydrobromic acid (1.5 mL) was added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[6-methoxy-5-(methylsulfanyl)pyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (53 mg) in 1,4-dioxane (2 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A solution of the residue in trifluoroacetic acid (4 mL) and anisole (2 mL) was stirred at 80° C. for six hours. The solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1→3:1) and preparative HPLC (Waters Sunfire 19×150 mm 5 μm, rate: 20 mL/min, eluent: A=acetonitrile, B=0.1% trifluoroacetic acid solution, gradient: 10 to 90%) and powdered with ethyl acetate-hexane to give the title compound as a colorless powder (10 mg, 27%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][NH:22][C:23]([NH:25][CH3:26])=[O:24])[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1.[CH2:29](N=C=O)C.CN=C=O>>[O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][NH:22][C:23]([NH:25][CH2:26][CH3:29])=[O:24])[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1
Reactant: CNC(=O)NC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCN=C=O
Agent: CN=C=O
Product: CCNC(=O)NC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 79 was prepared in the manner of compound 24 substituting ethylisocyanate for methyl isocyanate and refluxing for 16 h [MS 408 (M+1)].