Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]2[CH:32]=[CH:31][C:19]([C:20]([N:22]3[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([OH:30])=[O:29])[CH2:23]3)=[O:21])=[CH:18][CH:17]=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:33])[CH:3]=1.[C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)#[N:35].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:22]4[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([OH:30])=[O:29])[CH2:23]4)=[O:21])=[CH:31][CH:32]=3)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:33])[CH:3]=2)=[CH:38][CH:37]=1)#[N:35]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccc(C#N)cc2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Yield: 17.8 %

Procedure:
To (3R)-1-(4-((1-(4-bromo-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoyl)piperidine-3-carboxylic acid (42 mg) was added a solution of 4-cyanophenylboronic acid (24 mg) in DME (0.5 mL), polymer-supported triphenylphosphinepalladium(0) (0.1 mg), and a solution of potassium carbonate (16 mg) in water (0.2 mL), and the mixture was stirred at 80° C. overnight. The reaction solution was passed through a filter, and washed twice with THF (2 mL). The solvent was evaporated from the obtained solution by an air blowing apparatus. The residue was purified by HPLC (C18, mobile phase: water/acetonitrile (0.1% TFA-containing system)), and the solvent was evaporated from the obtained solution by an air blowing apparatus. The residue was purified by HPLC (C18, mobile phase: water/acetonitrile (10 mM ammonium acetate-containing system)) to give the title compound (7.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14]([OH:16])=O)=[N:11][NH:12][CH:13]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:14]([C:10]3[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:13][NH:12][N:11]=3)=[O:16])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1
Reactant: CN1CCN(c2ccc(CN)cc2)CC1
Reactant: O=C(O)c1n[nH]cc1-c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(CNC(=O)c3n[nH]cc3-c3ccc(Cl)cc3Cl)cc2)CC1
Yield: 28.3 %

Procedure:
A solution of 4-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid (70 mg; 0.27 mmol), 4-(4-methyl-piperazin-1-yl)-benzylamine (62 mg; 0.3 mmol), EDAC (63 mg; 0.33 mmol) and HOBt (45 mg; 0.33 mmol) in 5 ml of DMF was stirred at room temperature for 48 hours. The reaction was evaporated and the residue partitioned between ethyl acetate and brine. The ethyl acetate layer was separated, dried (MgSO4), filtered, evaporated then dried further under vacuum to give 34 mg of 4-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid 4-(4-methyl-piperazin-1-yl)-benzylamide. (LC/MS: Rt 2.42 [M+H]+ 444).
Reaction SMILES: CS(C)=O.F[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:15])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O>[CH3:15][C:8]1[CH:7]=[C:6]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:11]=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: C1COCCN1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a DMSO solution (8 ml) of 4-fluoro-2-methyl-1-nitro-benzene (500 mg), potassium carbonate (668 mg) and morpholine (0.42 ml) were added, followed by stirring at 80° C. for 18 hours. This was cooled to room temperature, and water (30 ml) was added, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. After the magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure, to obtain the desired compound as a yellow solid (680 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1.C(OC(N1CCOC[C@H]1C(=O)NC1C=CC(C#CC2C(C3C=C(Cl)C=CC=3O)=NN(CCO)C=2)=CC=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@@H:24]4[CH2:29][O:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)C1COCCN1
Agent: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@@H]1COCCN1

Procedure:
Using the same procedure for the preparation of 17A, treatment of compound 20A with TFA in methylene chloride to give the title compound 21A as white powder in similar yield. Its 1H NMR and LCMS data are identical with those of compound 17A.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].C(Cl)(=O)C(Cl)=O.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:13]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[CH3:16])=[O:15])([CH3:25])[CH3:24]
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Reactant: CC(C)N
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc2c(C(=O)NC(C)C)c(C)n(C)c2c1

Procedure:
This material was prepared from 1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, oxalyl chloride and isopropylamine in a manner as previously described for example 16d. 1H NMR (300 MHz, CDCl3) δ 7.53 (1H, d, J=8.7 Hz), 6.85 (1H, dd, J=2.3, 8.7 Hz), 6.77 (1H, d, J=2.3 Hz), 4.35 (1H, m), 3.87 (3H, s), 3.63 (3H, s), 2.69 (3H, s), 1.30 (3H, s), 1.27 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 261. found 261.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24](Cl)=[CH:25][C:26]5[N:27]4[CH:30]=[N:31][N:32]=5)=[CH:22][CH:21]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:12]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([C:36]5[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=5)=[CH:25][C:26]5[N:27]4[CH:30]=[N:31][N:32]=5)=[CH:22][CH:21]=3)[CH:14]=[C:15]([F:17])[CH:16]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Cl)cc5nncn5c4c3)c2)CCOCC1
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: O
Solvent: COCCOC
Product: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(-c5cccnc5)cc5nncn5c4c3)c2)CCOCC1
Temperature: 80 °C

Procedure:
To 5d (50 mg, 0.11 mmol) in DME:H2O (2:1, 2 mL) was added 3-pyridineboronic acid (20 mg, 0.16 mmol) and potassium carbonate (37 mg, 0.27 mmol). The mixture was degassed with N2 for 5 minutes, and then Pd(PPh3)4 (12 mg, 0.01 mmol) was added, and the mixture was degassed with N2 for an additional 5 minutes. The reaction was then heated to 80° C. overnight. After cooling to room temperature, the reaction was concentrated and purified by silica gel chromatography (10% MeOH in EtOAc) to give the desired product, 5e.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]([CH3:35])([CH3:34])[NH:5][C:6](=[O:33])[C@H:7]([CH2:28][O:29][C:30]#[C:31][CH3:32])[NH:8][C:9](=[O:27])[C:10]([CH3:26])([CH3:25])[NH:11][C:12](=[O:24])[C:13]([CH3:23])([CH3:22])[NH:14]C(OC(C)(C)C)=O.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH3:1][O:2][C:3](=[O:36])[C:4]([CH3:35])([CH3:34])[NH:5][C:6](=[O:33])[C@H:7]([CH2:28][O:29][C:30]#[C:31][CH3:32])[NH:8][C:9](=[O:27])[C:10]([CH3:26])([CH3:25])[NH:11][C:12](=[O:24])[C:13]([CH3:22])([CH3:23])[NH2:14]
Reactant: CC#COC[C@H](NC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#COC[C@H](NC(=O)C(C)(C)NC(=O)C(C)(C)N)C(=O)NC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
N-tert-butoxycarbonyl α,α-dimethylglycyl α,α-dimethylglycyl O-propynyl-L-seryl α,α-dimethylglycine methyl ester 16 (4.79 g, 9.35 mmol) was dissolved in 50% (v/v) TFA in CH2Cl2 (70 mL) and the reaction mixture stirred for 1 h 30 min at room temperature. The solvent and bulk of excess TFA were evaporated and CH2Cl2 (2×70 mL) added and evaporated. The residue was washed with Et2O (3×35 mL), redissolved in CH2Cl2 (100 mL), the solvent evaporated and the residue washed with Et2O (70 mL). Finally, CH2Cl2 (3×120 mL) was added and evaporated and the residue dried under high vacuum affording a white solid (4.93 g, 100%); 1H NMR (200 MHz, DMSO-d6) δ 8.38-8.00 (m, 5H, NH3+/NH(Aib2)/NH(Aib4)), 7.25 (d, J=7.8 Hz, 1H, NH(propSer)), 4.33 (q, J=5.4 Hz, 1H, CαH), 4.11 (d, J=2.4 Hz, 2H, CH2CCH), 3.62 (d, J=5.4 Hz, 2H, CH2), 3.54 (s, 3H, OCH3), 3.43 (t, J=2.3 Hz, 1H, CCH), 1.49 (s, 6H, CH3), 1.40 (s, 6H, CH3), 1.35 (s, 6H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 174.2, 173.2, 171.3, 168.6, 158.4 (q, JCF=32 Hz), 117.1 (q, J=297 Hz), 80.1, 77.3, 69.0, 57.7, 56.7, 56.6, 55.1, 52.4, 51.9, 25.0, 24.8, 24.7, 24.6, 23.3, 23.3; HRMS (m/z): M+ calcd. for C19H33N4O6, 413.2400. found, 413.2391; Anal. Calcd. for C21H33F3N4O8: C, 47.91; H, 6.32; N, 10.64. Found: C, 47.2; H, 6.2; N, 10.5.
Reaction SMILES: [N:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19]([O:21]CC)=[O:20].[O-]CC.[Na+].O>C(O)C>[CH2:24]([C:17]1[N:1]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:14][CH:15]=2)[N:2]=[N:3][C:18]=1[C:19]([OH:21])=[O:20])[CH2:25][CH3:26]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CCCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
4-Azido-N-propylbenzamide (2.0 g) obtained in Example 55a) and ethyl 3-oxohexanoate (1.09 ml, 6.50 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (491 mg, 6.50 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 14 hr. Water (20 ml) was added to the reaction mixture. After concentration, the mixture was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.58 g, 4.99 mmol, 96.0%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:15][N:12]([CH2:13][CH2:14]2)[CH2:11][CH:10]=[CH:9]3)=[CH:4][N:3]=1.[C:16]1([C:22]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:23]2[CH:27]=[C:26]([Sn](CCCC)(CCCC)CCCC)[N:25]=[CH:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:47]1([C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:23]2[CH:27]=[C:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]45[CH2:15][N:12]([CH2:13][CH2:14]4)[CH2:11][CH:10]=[CH:9]5)=[CH:4][N:3]=3)[N:25]=[CH:24]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: Brc1ccc(C23C=CCN(CC2)C3)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C1=CC2(c3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)nc3)CCN(C1)C2
Temperature: 85 °C

Procedure:
0.25 g (0.94 mmol) of 5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]oct-3-ene (WO 03/057 697) dissolved in 3 ml of tetrahydrofuran, 1.24 g (2.07 mmol) of 1-triphenylmethyl-4-tributylstannylimidazole and 0.06 g (0.08 mmol) of bis(triphenylphosphine)dichloropalladium are successively introduced into a 10 ml three-necked round-bottomed flask. The mixture is then heated at 85° C. for 15 hours and then diluted in 10 ml of chloroform and 10 ml of saturated aqueous sodium carbonate solution.
Reaction SMILES: [C:1]1([C:7]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:27]1[CH:28]=[CH:29][CH:30]=[N:31][C:26]=1[N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]1
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Reactant: Clc1ncccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccccc2)CCN(c2ncccn2)CC1
Yield: 47 %

Procedure:
To a mixture of 4.0 gms (0.017 mole) 4-phenyl-4-carboethoxy-piperidine and 1.72 gms (0.017 mole) of triethylamine in 50 ml. toluene was added dropwise 2.0 gms (0.017 mole) 2-chloropyrimidine. Triethylamine hydrochloride started to precipitate out almost immediately. The reaction mixture was warmed to 70°-80° for a period of two hours, and then allowed to cool. The triethylamine hydrochloride was filtered off and the filtrate washed with water (to remove the last traces of triethylamine hydrochloride). The residue was recrystallized from acetone to yield 2.5 gms (47% yield), m.p. 119°-120°.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:23])([F:22])[S:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:21][C:18]1[CH:19]=[N:20][C:15]([S:14][C:13]([F:23])([F:22])[F:12])=[CH:16][CH:17]=1)=[O:9]
Reactant: Nc1ccc(SC(F)(F)F)nc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.3 using 5-bromo-6-chloronicotinic acid and 6-(trifluoromethylthio)pyridin-3-amine to afford an off-white powder. HPLC (Condition 4) tR=6.43 min, UPLC-MS (Condition 3) tR=1.15 min, m/z=411.9 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[CH:7]([CH2:10][C:11]([O:13]CC)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:31][NH2:32]>CO.CCO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[CH:7]([CH2:10][C:11]([NH:32][CH3:31])=[O:13])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CN
Reactant: CCOC(=O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Solvent: CCO
Solvent: CO
Product: CNC(=O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2

Procedure:
A slurry of ethyl {7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 21, 0.39 g, 0.91 mmol) in a mixture of MeOH (5 mL) and a 33% solution of methanamine (15 mL, 0.91 mmol) in EtOH was stirred at rt over night giving clean conversion to the amide. The reaction mixture was concentrated under reduced pressure giving the title compound (0.370 g, 98%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[O-:6].[K+].Br[C:14]1[CH:19]=[C:18]([NH:20][C:21]([CH3:23])=[O:22])[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]=1[O:27][CH3:28]>CN(C=O)C.O>[NH:20]([C:18]1[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]([O:27][CH3:28])=[C:14]([O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[CH:19]=1)[C:21]([CH3:23])=[O:22]
Reactant: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1Br
Reactant: [O-]c1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1Oc1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
To the above solid 7 under argon, was added a solution of 3.0 g (10.4 mmol) of bromide 6 in 20 mL of DMF via cannula. The resulting solution was stirred at 120° C. for 1 day. TLC and NMR indicated the presence of a small amount of starting material 6. The reaction solution was cooled to room temperature and 2 mmol of compound 7 was added. The solution was stirred at 120° C. for 12 hour, diluted with 200 mL of ice and water, and the solid was collected by filtration, washed with water, dried under vacuum, and crystallized from ethanol to give 3.04 g (79% yield) of compound 8. 1H NMR (CDCl3) δ 10.4 (s, 1 H, NH), 8.39 (s, 1 H), 7.83 (s, 1 H), 7.5 (m, 2 H), 7.3 (m, 2 H), 3.93 (s, 3 H, OMe), 2.23 (s, 3 H, CH3). 13C NMR (CDCl3) δ 174, 155.7, 153.9, 142.4, 141.6, 130.9, 123.0, 121.7, 121.6, (116.9, 116.8, 116.7, 116.6 q for CF3), 108.7, 106.6, 56.7, 21.8.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][C:9]=2[CH3:27])[CH2:6][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C#Cc2ccc(C(=O)O)cc2)ccc1C1(OC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound 83, 60.0 mg, 0.17 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 38.0 mg (69%) of the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1cc(Br)cnc1NCC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
A mixture of 5-bromo-2-chloro-3-nitropyridine (Step B, 5.0 g, 21.1 mmol), cyclopropanemethylamine (2.8 mL, 31.7 mmol) and N,N-diisopropylethylamine (5.5 mL, 31.7 mmol) in ethanol (20 mL) was stirred at room temperature for 24 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate as eluent) to afford the title compound (5.5 g, 96%) as a yellow solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([Cl:17])[CH:11]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:8])=[C:12]([Cl:17])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)ccc1CBr
Temperature: 90 °C
Reaction time: 144 h
Yield: 60.4 %

Procedure:
Add NBS (13.171 g, 74 mmol) and benzoyl peroxide (152 mg, 0.63 mmol) to a solution of 4-bromo-2-chlorotoluene (15.2 g, 74 mmol) in carbon tetrachloride (152 mL) and stir for 6 days at 90° C. Cool to 0° C., filter the mixture and concentrate the filtrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (99:1) to obtain the desired intermediate as a yellow oil (12.7 g, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH:10]1[C:16](=[O:17])[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:10]2[C:16](=[O:17])[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCOC(=O)N1CCC(=O)C(Br)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(=O)C(Sc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
60.5 g (320 mmol) 4-bromothiophenol in 300 mL chloroform are added to a solution of 84.5 g (320 mmol) ethyl 4-bromo-5-oxo-azepan-1-carboxylate and 32.4 g (320 mmol) triethylamine in 80 mL chloroform over 45 min, so that the internal temperature does not exceed 40° C. The reaction solution is stirred for 1.5 h at RT. The reaction mixture is washed twice with dilute ammonia solution and twice with water. The organic phase is dried over Na2SO4 and K2CO3 and the solvent is eliminated i.vac. The purification is carried out by repeated column chromatography on silica gel.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:25])[CH2:4][C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[N:26]([O-])=[O:27].[Na+]>C(O)(=O)C>[Br:1][CH2:2][C:3](=[O:25])[C:4](=[N:26][OH:27])[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]2SC1
Reaction time: 0.33 h

Procedure:
While a solution of 0.15 g of 7-(4-bromo-3-oxobutyrylamino)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in 2 ml of acetic acid was stirred at room temperature, 0.0.3 g of sodium nitrite was added dropwise over a period of five minutes. Then, the mixture was further stirred for 20 minutes, after which time it was concentrated to dryness under reduced pressure. The resultant vitreous solid was applied to a Merck silica gel plate No. 5715 and developed with ethyl acetate-acetic acid-water (8:1:1). The color reaction with a 0.5% solution of copper chloride gave a single yellow spot at Rf=0.327. Therefore, the product was assumed to be substantially the captioned compound and was subjected to the next reaction.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:15])=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[F:16][C:17]([F:25])([F:24])[C:18](=[O:23])[CH2:19][C:20](=O)[CH3:21]>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:15][C:4]1[S:3][C:2]2=[N:1][C:20]([CH3:21])=[C:19]([C:18](=[O:23])[C:17]([F:25])([F:24])[F:16])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]2[CH:5]=1
Reactant: Nc1sc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc(Cl)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 21.6 %

Procedure:
To a stirred solution of 30 mg (0.13 mmol) (2-amino-5-chloro-thiophen-3-yl)-phenyl-methanone in 2 ml acetic acid was added 0.016 ml (0.13 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 70° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CE-CN/H20) afforded 10 mg (23%) 1-(2-chloro-6-methyl-4-phenyl-thieno[2,3-b]pyridin-5-yl)-2,2,2-trifluoro-ethanone as a light brown solid. ES-MS m/e (%): 356 (M+H+, 100).