Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4].C([Li])CCC.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>CCOCC>[CH3:19][Si:20]([CH3:22])([CH3:21])[NH:4][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]=1[Cl:13]
Reactant: C[Si](C)(C)Cl
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Et2O (200 mL) was added to a Schlenk flask under nitrogen containing 2,6-dichloro-4-trifluoromethylaniline (14.39 g, 62.6 mmol) and was cooled to −78° C. n-butyllithium (2.5M in hexane, 26.3 mL, 65.7 mmol) was added over 15 min to the stirred solution. The solution was stirred at −78° C. for 2 h and was then taken out of the cold bath, during which time a dark red/brown color evolved. Trimethylsilyl chloride (15.9 mL, 125 mmol) was then added dropwise to afford a light yellow slurry. This mixture was allowed to warm to room temperature and was filtered through Celite. The yellow filtrate was concentrated under reduced pressure to give an analytically pure orange oil; yield 18.90 g, (98%): 1H NMR (C6D6, 20° C.) δ 7.24 (s, 2H, Ar), 4.21 (bs, 1H, NH), 0.16 (s, 9H, TMS); 13C NMR (C6D6, 20° C.) δ 145.68, 125.4 (m), 123.90 (q, 1JCF=271 Hz), 123.44, 121.29 (q, 2JCF=33.8 Hz), 2.23 (m); 19F NMR (C6D6, 20° C.) δ −61.77. Anal. Calcd for C10H12Cl2F3NSi: C, 39.75; H, 4.00; N, 4.64. Found: C, 40.06; H, 3.84; N, 4.42.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:69][N:70]1[CH2:75][CH2:74][S:73](=[O:77])(=[O:76])[CH2:72][CH2:71]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:68])[S:59]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[O:77]=[S:73]1(=[O:76])[CH2:72][CH2:71][N:70]([CH2:69][CH:44]2[S:43][C:47]([C:49]3[NH:50][C:51]4[C:56]([CH:57]=3)=[CH:55][CH:54]=[CH:53][C:52]=4[N:58]([CH3:68])[S:59]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=3)(=[O:60])=[O:61])=[N:46][CH2:45]2)[CH2:75][CH2:74]1
Reactant: CN(c1cccc2cc(C(=O)NCC(CN3CCS(=O)(=O)CC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CN4CCS(=O)(=O)CC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
To a solution of triphenylphosphine oxide (0.50 g) in dichloromethane (5 mL) was slowly added trifluoromethanesulfonic anhydride (0.25 mL) under ice-cooling, and the mixture was stirred for 20 min. A solution of N-[2-(benzylthio)-3-(1,1-dioxidothiomorpholino)propyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (0.37 g) in dichloromethane (5 mL) was added dropwise, and the mixture was stirred for 30 min under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-10:0). The obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (87 mg, yield: 28%) as colorless prism crystals. MS: 520 (MH+). melting point 188-189° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([C:31]3[S:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+].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.C1COCC1>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[N:6]=[CH:7][C:2]([C:25]2[CH:30]=[N:29][C:28]([C:31]3[S:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=3)=[CH:27][CH:26]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2nc3ccccc3s2)nc1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4s3)nc2)OC1(C)C
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: O
Solvent: C1CCOC1
Product: c1ccc2sc(-c3ccc(-c4ccc(-c5nc6ccccc6s5)nc4)cn3)nc2c1
Temperature: 80 °C

Procedure:
A mixture of 9 (0.591 g, 2.03 mmol), 16 (0.700 g, 2.07 mmol), tetrakis(triphenylphosphine)palladium(0) (117 mg, 102 μmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) was degassed with argon for about 20 min while stirring. The stirring reaction mixture was then maintained under argon at about 80° C. for about 19 h. Upon completion, the mixture was cooled to RT, filtered and the precipitate collected as a white solid (0.83 g, 97%). This compound was found to be insoluble in numerous common organic solvents.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]1=[O:21])[C:5]([OH:7])=O.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH:35][C:5](=[O:7])[C@@H:4]([N:8]3[CH2:12][C:11]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[CH3:20])=[CH:10][C:9]3=[O:21])[CH2:3][CH:2]([CH3:1])[CH3:22])=[N:31]2)[CH2:26][O:25]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)C1
Temperature: 0 °C
Yield: 48.4 %

Procedure:
To a solution of (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (prepared as in Example 120, 0.228 g, 0.75 mmol) in N,N-dimethylformamide (4 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.192 g, 0.97 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.663 g, 1.50 mmol). The mixture was stirred at 0° C. and triethylamine (0.153 g, 1.51 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 30% to 70% ethyl acetate/hexanes) which afforded (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.175 g, 48%) as a pink solid: HR-ES-MS m/z calculated for C26H34N4O5 [M+H]+ 483.2602, observed 483.2603, 1H NMR (200 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.36-1.66 (m, 2H), 1.68-1.81 (m, 1H), 2.19 (s, 3H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.11 (t, J=5.7 Hz, 2H), 4.20 (d, J=18.4 Hz, 1H), 4.28-4.42 (m, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.63 (s, 1H), 4.88 (dd, J=10.6, 4.8 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 7.16-7.33 (m, 3H), 7.36 (d, J=7.5 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+].C1COCC1.O>CCO.C(OCC)(=O)C.[Fe]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][N:8]([C@@H:3]([CH:2]([CH3:27])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[C:9]3=[O:26])=[CH:14][CH:13]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O

Procedure:
The compound of example 5 (0.9 g, 0.00244 mol), iron (0.32 g, 0.0057 mol) and ammonium chloride (0.551 g, 0.0103 mol) were taken in EtOH:THF:H2O (15.5 mL, 9:4.5:2.25). The reaction mixture was refluxed for about 16 h. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated to obtain a solid residue which was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography (silicagel, 30% ethyl acetate in petroleum ether).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:3]=1.[Cl-].[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([NH3+:31])[CH3:30])=[CH:25][CH:24]=1)=[O:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O.CCOC(C)=O.CCOCC>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:31][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=2)[CH3:30])=[O:9])=[C:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(C(C)[NH3+])cc1
Reactant: O=C(O)c1sc(Cl)cc1Cc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COC(=O)c1ccc(C(C)NC(=O)c2sc(Cl)cc2Cc2cccc(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The solution containing 5-chloro-3-(3-chlorobenzyl)thiophene-2-carboxylic acid from Example 1, Step 6 (200 mg, 0.696 mmol) and (±)-1-[4-(methoxycarbonyl)phenyl]ethanaminium chloride prepared according to Example 1, Steps 7 to 9 (180 mg, 0.835 mmol) in DMF was cooled to 0° C. and to it was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (317 mg, 0.835 mmol) followed by N,N-diisopropylethylamine (304 μL, 1.74 mmol, 2.5 eq) dropwise. The mixture was stirred at 0° C. for 15 min and diluted with water and EtOAc/ether. The organic layer was washed with water, brine, dried and filtered. The crude was purified by Combi Flash chromatography system (10-40% EtOAc/hexane in 15 min.) to give the desired product as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:26])[CH3:29]
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccs2)SCC(N)C1=O
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
Following the procedure described in Example 42(h), 0.40 g of t-butyl α-[6-amino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above] was N-alkylated using 0.64 g of ethyl 2-bromo-4-phenylbutyrate. The resulting product was subjected to silica gel column chromatography eluted with a 1:20 by volume mixture of ethyl acetate and methylene chloride, to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[N:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2].[Cl:15]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:15][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[N:13][C:12]([NH2:14])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: CCOc1cc2cccnc2c(N)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCOc1nc(N)c2ncccc2c1Cl
Yield: 62.8 %

Procedure:
To a 200 mL round bottom flask was added 6-ethoxy-1,7-naphthyridin-8-amine (3.42 mmol), DCM (75 mL), followed by N-chlorosuccinimide (3.77 mmol). The mixture was heated at reflux for 18 h under Ar. The mixture was then cooled, the solvent evaporated and the resultant crude residue purified by silica gel to yield 5-chloro-6-ethoxy-1,7-naphthyridin-8-amine (480 mg, 63%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.89 (d, J=3.95 Hz, 1H), 8.43 (d, J=8.79 Hz, 1H), 7.66 (dd, J=8.79, 3.95 Hz, 1H), 4.13 (s, 3H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[CH3:7].[F:20][C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.Cl([O-])(=O)(=O)=O.[Li+].O>C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[CH3:7]
Reactant: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Reactant: Cc1ccc(C[C@@H]2CCCN2)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
A mixture of methyl (2E)-3-(2-{(1R)-1-[(2R)-oxiran-2-yl methoxy]ethyl}phenyl)prop-2-enoate (237 mg, 0.90 mmol) described in WO 2004/106280, (2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidine (167 mg, 0.86 mmol), which had been obtained in Example 1 (1e), and lithium perchlorate (55 mg, 0.52 mmol) in toluene (9 mL) was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (10 mL×3). After that, the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a yellow oily substance (238 mg, yield 61%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.[OH-].[Na+].OS([O-])(=O)=O.[K+]>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(OCCCCCl)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(OCCCCCl)cc1
Temperature: 60 °C

Procedure:
A mixture of 24-2 (3.0 g, 12.4 mmol), 1N NaOH (30 mL), and ethanol was heated at 60° C. for 1.0 hour. The cooled reaction mixture was acidified with 10% KHSO4 and then extracted with EtOAc. The EtOAc portion was washed with brine, dried (MgSO4) and concentrated to give 24-3 as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([S:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])=[CH:19][CH:18]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CCOC(C)=O>CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:13]2[CH:14]=[C:9]([Cl:8])[N:10]=[C:11]([S:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[O:25])=[CH:19][CH:18]=3)[N:12]=2)[NH:4][N:3]=1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)C1CCCC1
Reactant: Cc1cc(N)[nH]n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CCCC4)cc3)n2)[nH]n1
Temperature: 80 °C

Procedure:
To a solution of 3-methyl-1H-pyrazol-5-amine (160 mg, 1.63 mmol) and N-(4-(4,6-dichloropyrimidin-2-ylthio)phenyl)cyclopentane carboxamide (600 mg, 1.63 mmol) in dimethyl formamide (10 ml) was added diisopropylethylamine (248 mg, 1.96 mmol, 0.34 ml). The mixture was then heated to 80 ° C. for 18 hrs and allowed to cool to rt. EtOAc (40 ml) was added and washed with brine, dried (MgSO4), and concentrated in vacuo. Crude product was then purified by flash chromatography 7:3 EtOAc:hexane EtOAc 5% MeOH:EtOAc to give title compound as an off white solid (431 mg, 62%). 1H NMR (DMSO-d6) 1.50-1.55 (2H, m), 1.61-1.78 (4H, m), 1.79-1.85 (2H, m), 1.90 (3H, brs), 2.72-1.81 (1H, m), 5.21 (1H, brs), 6.46 (1H, brs), 7.52 (2H, d), 7.78 (2H, d), 10.11 (1H, s), 10.18 (1H, brs), 11.95 (1H, brs). ES+ 429.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:8][CH:7]=1)=[O:5])C.O[Li].O.CCOC(C)=O.Cl>C1COCC1.O>[C:25]([O:24][C:22]([NH:21][CH2:20][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1cnc(CNC(=O)OC(C)(C)C)c2c(OC)cc(OC)cc12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 95.6 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (520 mg, 1.34 mmol) in THF (10 ml) and H2O (10 ml) under nitrogen, LiOH—H2O (95 mg, 2.3 mmol) was added. The reaction was stirred at 50° C. for 3.5 hours and at then at room temperature for 18 hours. EtOAc and water were then added and the pH was adjusted to 5 by dropwise addition of 6N HCl. The layers were then separated and the aqueous phase was extracted with EtOAc. The combined organic layers were then washed with brine, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid as a solid (464 mg, 96%). H1-NMR (DMSO): δ, 8.84 (s, 1H), 7.96 (s, 1H), 6.91 (t, 1H, J=5.4 Hz), 6.77 (s, 1H), 4.80 (d, 2H, J=5.43 Hz), 3.95 and 3.88 (s, 3H each), 1.36 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19]C(=O)CC4C=CC=CC=4)[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30][Cl:31])=[O:10])=[CH:5][CH:4]=1.CN1CCOCC1.[C:41]([O:45][C:46]([NH:48][C:49]1[S:50][CH:51]=[C:52]([C:54](=[N:58][O:59][C:60]([C:63]([O:65][CH:66]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[O:64])([CH3:62])[CH3:61])[C:55](O)=[O:56])[N:53]=1)=[O:47])([CH3:44])([CH3:43])[CH3:42].C1C=CC(OP(Cl)(Cl)=O)=CC=1>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:55](=[O:56])[C:54]([C:52]4[N:53]=[C:49]([NH:48][C:46]([O:45][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:47])[S:50][CH:51]=4)=[N:58][O:59][C:60]([C:63]([O:65][CH:66]([C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)[C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)=[O:64])([CH3:61])[CH3:62])[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30][Cl:31])=[O:10])=[CH:32][CH:33]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=NOC(C)(C)C(=O)OC(c2ccccc2)c2ccccc2)C(=O)O)cs1
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)C(=NOC(C)(C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Yield: 83.1 %

Procedure:
To a suspension of 7β-amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (1) p-toluenesulfonate (2.705 g: 5 mMol.) in dichloromethane (50 ml) are added N-methylmorpholin (0.55 ml; 1 Eq.) and 2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-1-methylethoxyimino)acetic acid (3.51 g; 1.3 Eq.) at 0° C. and then phenylphosphoric dichloride (0.97 ml; 1.3 Eq.) and N-methylmorpholin (1.65 ml; 3 Eq.) at -40° C., and the mixture is stirred at -40° to -10° C. for 1.5 hours. The reaction mixture is diluted with ethyl acetate, washed with water, diluted hydrochloric acid and water, dried, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (toluene:ethyl acetate) to give 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (2) (3.70 g).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6](C2C=CC=CC=2)=[O:7])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.OC1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1>C(#N)C>[CH3:45][C:44]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[O:7])=[CH:14][CH:15]=1)([CH2:47][CH3:48])[C:43]#[CH:42]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C#CC(C)(CC)Oc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a solution of 3-methyl-1-pentyn-3-ol 6 (0.319 mL, 2.83 mmol) in acetonitrile (3 mL) at 0° C. was added DBU (0.55 mL, 3.69 mmol). Then TFAA (0.34 mL, 2.46 mmol) was added drop wise and the solution was stirred at 0° C. for 30 min. To a solution of 4-hydroxybenzaldehyde (300 mg, 2.46 mmol) in acetonitrile at 0° C. was added DBU (0.55 mL 3.69 mmol) and CuCl2.2H2O (0.42 mg, 0.0025 mmol). The first mixture was added to the second mixture over a period of five min. The reaction was stirred overnight. The solvent was removed by rotary evaporation and the residue diluted with DCM. Then the organic layer washed with 1M HCl, 1M NaOH, sat NaHCO3 and brine, dried over MgSO4 and concentrated in vacuum to give 170 mg (32%) of product. 1H NMR (CDCl3): δ 9.91 (s, 1H), 7.83-7.81 (m, 2H), 7.36-7.34 (m, 2H), 2.69 (s, 1H), 2.06-1.92 (m, 2H), 1.66 (s, 3H), 1.12 ppm (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:3]=1.Cl.Cl.[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[CH:33][CH:32]=[C:31]([NH:37][CH2:38][CH2:39][NH2:40])[N:30]=1.CCN(C(C)C)C(C)C>CS(C)=O>[NH2:28][C:29]1[N:30]=[C:31]([NH:37][CH2:38][CH2:39][NH:40][C:2]2[N:7]3[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]3[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:3]=2)[CH:32]=[CH:33][C:34]=1[C:35]#[N:36]
Reactant: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(Cl)n2n1
Reactant: N#Cc1ccc(NCCN)nc1N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(NCCNc3ccc(C#N)c(N)n3)n2n1

Procedure:
200 mg (0.52 mmol) of ethyl 5-chloro-7-(4-trifluoromethylphenyl)[1,2,4]triazolo[1,5-c]pyrimidine-2-carboxylate (Example 149A) and 133 mg (0.62 mmol) of 2-amino-6-[(2-aminoethyl)amino]pyridine-3-carbonitrile dihydrochloride (Example 111A) are introduced into DMSO (2 ml), 0.54 ml (3.1 mmol) of DIEA is added, and the reaction solution is irradiated in a microwave reactor at 90° C. for 30 min. The reaction mixture is purified by preparative HPLC. 98 mg (38% of theory) of the product are obtained as a solid.