Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(Cl)([Cl:33])=O>>[Cl:33][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C(Cl)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Yield: 63 %

Procedure:
A mixture of ethyl 2-hydroxy-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butyrate (320 mg) and thionyl chloride (3 ml) was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-hexane (1:4, v/v) gave ethyl 2-chloro-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butyrate (210 mg, 63%) as an oil.
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:7])(C)(C)C.[C:26]([NH:31][C:32]1[CH:33]=[C:34](/[CH:38]=[CH:39]/C(O)=O)[N:35]([CH3:37])[CH:36]=1)(=[O:30])[CH2:27][CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl>CC(N(C)C)=O>[C:26]([NH:31][C:32]1[CH:33]=[C:34](/[CH:38]=[CH:39]/[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]4[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=4[C:11]=3[CH:10]([CH2:24][Cl:25])[CH2:9]2)=[O:7])[N:35]([CH3:37])[CH:36]=1)(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(=O)Nc1cc(/C=C/C(=O)O)n(C)c1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CCCC(=O)Nc1cc(/C=C/C(=O)N2CC(CCl)c3c2cc([N+](=O)[O-])c2ccccc32)n(C)c1
Yield: 61.6 %

Procedure:
Deprotection of 13 (300 mg, 0.83 mmol) as in Example C above and reaction with (E)-4-butyrylamino-1-methyl-2-pyrroleacrylic acid (197 mg, 0.83 mmol), EDCI.HCl (397 mg, 2.07 mmol) and DMA gave a product that was chromatographed on silica gel. Elution with CH2Cl2 /EtOAc (1:1), followed by crystallisation from CH2Cl2 /iPr2O gave 14i (246 mg, 62%), mp 216° C. 1H NMR [(CD3)2SO] δ 9.79 (S, 1 H, NH), 9.22 (s, 1 H, H-4), 8.32 (d, J=8.7 Hz, 1 H, H-6), 8.17 (d, J=8.1 Hz, 1 H, H-9), 7.76-7.65 (m, 2 H, H-7,8), 7.64 (d, J=14.9 Hz, 1 H, COCH=CH), 7.25 (d, J=1.6 Hz, 1 H, H-5'), 6.81 (d, J=1.6 Hz, 1 H, H-3'), 6.71 (d, J=15.0 Hz, 1 H, COCH=CH), 4.65-4.50 (m, 3 H, H-1,2), 4.08 (d, J=3.6 Hz, 2 H, CH2Cl), 3.71 (s, 3 H, NCH3), 2.22 (t, J=7.3 Hz, 2 H, COCH2), 1.60 (sextet, J=7.4 Hz, 2 H, CH2CH3), 0.90 (t, J=7.4 Hz, 3 H, CH2CH3). Anal. Calculated for C25H25ClN4O4 : C, 62.4;H, 5.2; N, 11.7. Found: C, 62.6; H, 5.2; N, 11.5%.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:22][O:21][C:19](=[O:20])[CH2:18][NH:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CNc1ccc(OCc2ccccc2)cc1

Procedure:
4-Benzyloxyaniline hydrochloride (70 g), methyl chloroacetate (49 ml) and sodium bicarbonate (75 g) in dry acetonitrile (200 ml) were heated at reflux for 6.5 h. Work up according to the method of Intermediate 8 gave a solid which was recrystallised from chloroform-hexane to give the title compound (55 g), m.p. 106°-107°.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1.C1C=CC=CC=1>CO>[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][N:24]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=3)[CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: O=C(c1ccc(F)cc1)N1CC1
Solvent: CO
Solvent: c1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNC(=O)c2ccc(F)cc2)C[C@H]1OC

Procedure:
A mixture of 11 parts of 1-(4-fluorobenzoyl)aziridine, 6.28 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 45 parts of benzene and 20 parts of methanol was stirred and refluxed for 6 hours. The reaction mixture was evaporated and the residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 5.09 parts of cis-4-amino-5-chloro-N-[1-[2-[(4-fluorobenzoyl)amino]ethyl]-3-methoxy-4-piperidinyl]-2-methyoxybenzamide; mp. 208.7° C. (compound 131).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH2:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([S:39][CH3:40])[C:27]=1[C:28](Cl)=[O:29]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH:23][C:28](=[O:29])[C:27]2[C:31]([S:39][CH3:40])=[CH:32][C:33]([C:35]([F:38])([F:36])[F:37])=[CH:34][C:26]=2[O:25][CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Reactant: NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1

Procedure:
In analogy to the procedure described for the synthesis of example 16, the title compound was prepared from rac-3-amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester (example 29, step 1) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[Li].[CH3:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:11]1[S:10][C:9]([CH3:8])=[CH:13][CH:12]=1
Reactant: BrCCCCBr
Reactant: Cc1cccs1
Agent: [Li]
Solvent: O
Product: Cc1ccc(CCCCBr)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
This procedure was used to synthesize the disubstituted synthetic intermediate 2-(n-bromoalkyl)-5-R-thiophene (2, wherein R is not H). The synthesis of 2h was accomplished by first synthesizing the 2-methylthienyllithium intermediate. A solution of n-butyllithium (2.5 M in hexane) (Aldrich Chemical Co.) (4.4 mL, 0.011 moles) was added dropwise to 2-methylthiophene (0.98 gm, 0.01 moles) (Lancaster Synthesis, Windham, N.H.) in THF (50 mL) at 0° C. to yield the lithium salt of 2-methylthiophene. The solution was stirred at room temperature for one hour. 1,4-Dibromobutane (3.24 gm, 0.015 moles) was added in one lot to the lithium salt of 2-methylthiophene at 0° C. The solution was allowed to warm to room temperature and stirred for 12 hours. Water (20 mL) was added and the layers were separated. The organic layer was diluted with ethyl acetate (50 mL) and washed with water (3×10 mL), dried over MgSO4 (anhydrous), filtered and evaporated under reduced pressure. Purification by column chromatography (silica gel, hexanes) gave 2 gm of 2-(4-bromobutyl)-5-methylthiophene (2h) (85.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22].[O-]CC.[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][S:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C(C(=O)OCC)c1ccc(F)cc1
Reactant: Fc1ccccc1S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CSc1ccccc1F)c1ccc(F)cc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
The crude product from Step A (3.9 g, 20 mmole) was taken up in 20 ml of ethanol. To this solution, being stirred at room temperature, was added 2-fluorothiophenol (2.5 g, 20 mmole) and 50 mg of solid sodium ethoxide. After stirring for eight hours the ethanol was concentrated and the residue taken up in ether. The ether mixture was washed twice with 15% NaOH solution, dried (MgSO4) and concentrated to a colorless oil (5.3 g, 82% yield).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][OH:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:30][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C:6]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:5][N:4]=2)=[CH:27][CH:26]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: CSc1ncc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1
Product: Clc1ccc(COc2ncc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)n2)cc1

Procedure:
2-Methylthio-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with 4-chlorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(4-chlorobenzyloxy)-4-(4-chloro-phenyl)-5-(2,4-dichlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=475 (M++1); Rt=5.01 min; 1H-NMR 400 MHz (CDCl3): 5.55 (s, 2H), 7.1 (d, J=9 Hz, 1H), 7.25-7.3 (m, 4H), 7.15-7.20 (m, 3H), 7.43 (m, 3H), 8.45 )s, 1H) and 2-(4-chlorobenzyloxy)-4-(4-chlorophenyl)5-(2-chloro-4-thiomethylphenyl)pyrimidine (LRf): HPLC/MS: m/e=487 (M++1); Rt=4.91 min; 1H-NMR 400 MHz (CDCl3): δ 2.52 (s, 3H), 5.55 (s, 2H), 7.15 (d, J=6 Hz, 2H), 7.25-7.30 (m, 3H), 7.55-7.40 (m, 4H), 7.45 (m, 2H), 8.42 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:42])[C@H:12]([CH3:41])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:40])[CH2:22][C@@H:23]([O:38][CH3:39])[C@@H:24]([N:29]([CH3:37])[C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@@:51]1([CH3:59])[C:56](O)=[O:57])=[O:49])([CH3:46])([CH3:45])[CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:42])[C@H:12]([CH3:41])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:40])[CH2:22][C@@H:23]([O:38][CH3:39])[C@@H:24]([N:29]([CH3:37])[C:30](=[O:36])[C@@H:31]([NH:32][C:56]([C@:51]2([CH3:59])[CH2:52][CH2:53][CH2:54][CH2:55][N:50]2[C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])=[O:57])[CH:33]([CH3:34])[CH3:35])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C

Procedure:
According to the general procedure D, from #176 (100 mg, 0.170 mmol, 1 eq.), #156 (53.8 mg, 0.221 mmol, 1.3 eq.), dichloromethane (4.5 mL), HATU (84.9 mg, 0.221 mmol, 1.3 eq.) and N,N-diisopropylethylamine (0.123 mL, 0.697 mmol, 4.1 eq.), was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0 to 100% ethyl acetate in heptane) to afford #177 (145 mg, assume quantitative yield) as a white solid. LC-MS (Protocol Q1): m/z 814.7 [M+H+], retention time=1.14 minutes.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([S:21][C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: CC(=O)Nc1cccc(Sc2ccc(C)cc2N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CC(=O)Nc1cccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (100 mg, 0.559 mmol) was reacted with the product from Example 71c (152 mg, 0.559 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (45 mg, 18%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.97 (s, 3H), 2.38 (s, 3H), 2.74 (s, 3H), 6.26 (d, J=6.99 Hz, 1H), 6.84 (d, J=8.46 Hz, 1H), 7.06 (t, J=8.09 Hz, 1H), 7.25 (d, J=8.09 Hz, 1H), 7.33-7.41 (m, 2H), 7.41-7.54 (m, 2H), 7.74 (d, J=8.82 Hz, 1H), 8.33 (d, J=6.99 Hz, 1H), 8.89 (d, J=8.82 Hz, 1H), 9.81 (s, 1H), 10.91 (s, 1H); MS (ESI+) m/z 415 (M+H)+, (ESI−) m/z 413 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([NH2:31])[CH:29]=[CH2:30]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][NH:31][CH2:28][CH:29]=[CH2:30])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: C=CCN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: C=CCNCC1COc2c(F)cc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), prop-2-en-1-amine (0.5 ml) and ACN (2.5 ml) was heated under microwave radiation at 120° C. for 20 min. MS m/z (rel. intensity, 70 eV) 301 (M+, 2), 71 (5) 70 (bp), 69 (4) 68 (5).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]([C:21]1[S:22][C:23]([S:36][CH3:37])=[C:24]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=2)(=[O:28])=[O:27])[CH:25]=1)=[NH:20])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO>[C:12]([O:16][C:17](=[O:38])[NH:18][C:19](=[NH:20])[C:21]1[S:22][C:23]([S:36][CH3:37])=[C:24]([S:26]([C:29]2[CH:30]=[C:31]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=3)[CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH:25]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
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: Cc1ccccc1
Solvent: CCO
Product: C=Cc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)cc1
Yield: 44 %

Procedure:
Following the procedure outlined in Example 1, step c, reaction of 4-vinyl-phenyl-boronic acid (181 mg, 1.22 mmol), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (300 mg, 0.61 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosphine)palladium(0) (141 mg, 0.122 mmol, Strem Chemicals, Inc., Newburyport, Mass.), Na2CO3 (2.4 mL, 2M aqueous), and toluene/EtOH mixture (2:1, 7.2 mL) afforded 138 mg (45%) of the title compound as a white glassy solid after SiO2 flash chromatography (1:3 EtOAc/hexanes). 1H-NMR (CDCl3): δ 8.21 (t, 1H, 1.7 Hz), 8.00 (brs, 1H), 7.92–7.95 (m, 1H), 7.79–7.81 (m, 1H), 7.48–7.58 (m, 5H), 6.75 (dd, 1H, J=17.7, 10.9 Hz), 5.82 (d, 1H, J=17.5), 5.31 (d, 1H, J=10.9 Hz), 2.54 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][C@H:12]1[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:13][C@H:12]1[CH3:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCN1CCCCC1
Reactant: C[C@@H]1CNC(=O)CCN1C(=O)OCc1ccccc1
Product: C[C@@H]1CN(CCCN2CCCCC2)C(=O)CCN1C(=O)OCc1ccccc1

Procedure:
The title compound could be prepared from (R)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester and 1-(3-chloropropyl)piperidine in analogy to example 33A. MS: 388.3 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1>>[Cl:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1)=[N:3]2
Reactant: Clc1ccc2c(Cl)cccc2n1
Reactant: OCCC1CCNCC1
Product: OCCC1CCN(c2ccc3c(Cl)cccc3n2)CC1

Procedure:
The process is performed as described in Example 4 (step 4.1). Starting with 4.78 g (24.14 mmol) of 2-chloro-5-chloroquinoline (J. Med. Chem., 2002, 45, 3130–3137) and 3.43 g (26.55 mmol) of 2-(4-piperidyl)ethanol, 7 g of product are obtained in the form of an oil, which is used without further purification in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1>ClCCl.[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:17]
Reactant: Cc1ccc(Br)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(Br)[n+]([O-])c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a round-bottom flask, was placed a solution of 2-bromo-5-methylpyridine (10.0 g, 58.1 mmol, 1.00 equiv) in dichloromethane (250 mL). mCPBA (15.0 g, 86.9 mmol, 1.50 equiv) was added in several batches at room temperature. The resulting solution was stirred overnight at 30° C., then diluted with 50 mL of 2N sodium hydroxide (aq.). The pH value of the solution was adjusted to 10 with 2N sodium hydroxide (aq.). The aqueous phase was extracted with 3×100 mL of dichloromethane and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield 11.0 g (91%) of 2-bromo-5-methylpyridin-1-ium-1-olate as a yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:19]([NH2:20])[C:18](=[O:21])[N:12]2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:29]([CH2:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:19]([NH:20][C:37](=[O:38])[CH2:36][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:18](=[O:21])[N:12]2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(N)C(=O)N12
Reactant: O=C(Cl)COc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12

Procedure:
The crude methyl 3-benzyl-7-amino-3-cephem-4-carboxylate was dissolved in dry dichloromethane (3 ml.) and the solution cooled to -20°. Dry triethylamine (22 mg) in dichloromethane (0.5 ml) was added followed by phenoxyacetyl chloride (36 mg) in dichloromethane (0.5 ml). After 15 minutes the solution was washed with water (× 2), dried and evaporated. Chromatography on silica afforded methyl 3-benzyl-7-phenoxyacetamido-3-cephem-4-carboxylate (II) as a white solid (61 mg). A sample recrystallised from ethyl acetate/60°-80° petroleum ether had m.p. 161°-162°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(F)cc1Cl
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(N2CCNCC2)cc1Cl
Temperature: 85 °C

Procedure:
A mixture of 7.0 mmol 2-chloro-4-fluorobenzonitrile (commercial), 10.5 mmol piperazine in 4 ml N,N-dimethylacetamide was heated for 1 h at 85° C. After cooling to RT and evaporation in vacuo, the mixture was diluted with dichloromethane and purified on silica, eluting with a gradient of dichloromethane/MeOH to yield after evaporation the title compound. MS (m/e): 222.1 (MH+, 100%)
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:14])[C:11]=1[S:12][CH3:13])[CH:7]=[O:8]>CO.C(Cl)Cl>[F:14][C:10]1[CH:9]=[C:6]([CH2:7][OH:8])[CH:5]=[C:4]([F:3])[C:11]=1[S:12][CH3:13]
Reactant: CSc1c(F)cc(C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CSc1c(F)cc(CO)cc1F
Temperature: 25 °C

Procedure:
Sodium borohydride (25 mg, 0.66 mmol) was added to a 0° C. slurry of the product of step A (124 mg, 0.659 mmol) in methanol (4.39 mL). After 30 min the reaction mixture was warmed to room temperature, and at 1.5 h the reaction was diluted with DCM and quenched with 0.1 N HCl. The aqueous was extracted with DCM (2×) and then washed with saturated aqueous NaCl (1×). The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 6.81 (d, J 7.5 Hz, 2H), 4.55 (s, 2H), 3.23 (s, 1H), 2.37 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][CH:14]([CH:18]=[CH:19][CH3:20])[CH2:15][CH2:16][OH:17]>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:17][CH2:16][CH2:15][CH:14]([CH3:13])[CH:18]=[CH:19][CH3:20])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC=CC(C)CCO
Solvent: ClCCl
Product: CC=CC(C)CCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of freshly crystallized 4-nitrobenzoyl chloride (10.1 g, 54.5 mmol) in CH2Cl2 (ml 20) was added dropwise to a solution of 3-methyl-hex-4-en-1-ol (5.4 g, 47.5 mmol) and TEA (8.6 ml, 61.8 mmol) in CH2Cl2 (ml 50) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 h and poured in ice/water (100 g). The CH2Cl2 was separated and the water phase was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was distilled at 171-173° C. 4 mmHg to give the title compound as yellow oil.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:24].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>C1COCC1>[CH3:25][N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=5)=[O:13])[CH:10]=4)[NH:5][C:4]3=[O:24])=[CH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(N4CCN(C)CC4)cc2)C(=O)N3)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 62.6 %

Procedure:
A small screw cap test tube was charged with N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (as prepared in Example 11, 50 mg, 0.155 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (32.6 mg, 0.170 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 62% (48 mg, 0.097 mmol) of the title compound.