Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:26]([CH3:25])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CNc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (132 mg, 0.36 mmol), N-methylaniline (0.1 mL, 99 mg, 0.92 mmol) and DMAP (120 mg, 0.98 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (4:1) on silica gel to give 59 mg (38% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.42-1.60 (m, 4 H), 1.63 (s, 9 H), 2.24-2.43 (m, 1 H), 3.19 (s, 3 H), 3.28-3.41 (m, 2 H), 3.92 (m, 2 H), 4.48 (d, J=7.42 Hz, 2 H), 7.03-7.12 (m, 2 H), 7.20-7.35 (m, 3 H), 7.60 (dd, J=8.79, 1.76 Hz, 1 H), 7.82 (d, J=1.17 Hz, 1 H), 7.94 (d, J=8.79 Hz, 1 H); MS (ESI) (M+H)+=442.0; Anal. Calcd for C24H31N3O3S+1.00 TFA+0.20 EtOAc+0.10H2O (575.04): C, 55.98; H, 5.92; N, 7.31. Found: C, 55.89; H, 5.87; N, 7.30.
Reaction SMILES: [CH:1]12[CH2:11][CH:4]([CH:5]3[C:10]1=[CH:9][CH2:8][CH2:7][CH2:6]3)[CH2:3][CH2:2]2.[H][H]>[Pd].CO>[CH:4]12[CH2:11][CH:1]([CH:10]3[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:2][CH2:3]2
Reactant: C1=C2C3CCC(C3)C2CCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C1CCC2C3CCC(C3)C2C1
Reaction time: 0.75 h
Yield: 257.6 %

Procedure:
A 400 ml autoclave was charged with octahydro-1,4-methanonaphthalene (122 g, prepared as described above), methanol (100 ml, Burdick & Jackson, HPLC grade), and palladium on activated carbon (1.5 g containing 10% Pd, Alfa products, powder). The autoclave was closed and sealed, then shaken under 50 psig hydrogen pressure for 20 minutes at room temperature. The hydrogen pressure was increased to 200 psig for 10 minutes at room temperature followed by 600 psig at 70° C. for 45 minutes. The reaction mixtures from three identical reactions were combined and filtered to remove the catalyst. The filtrate separated into two layers. The MeOH layer (top layer) was isolated and concentrated to give a residue, which was combined with product layer (the bottom layer). The combined crude product was distilled at reduced pressure to give decahydro-1,4-methanonaphthalene (318.6 g, bp 71–73° C./0.2 Torr, yield 86%).
Reaction SMILES: CO[C:3]1[CH:27]=[CH:26][C:25](C)=[CH:24][C:4]=1[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6].Cl.FC(F)(F)C1N=C[C:35]([NH:38][C@H:39]2[CH2:43][CH2:42]C[C@@H]2N)=[N:36]C=1.N1C=CC=NC=1C1C=CC=CC=1C(O)=O>>[N:38]1[CH:39]=[CH:43][CH:42]=[N:36][C:35]=1[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][N:15]=1)=[O:6]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C(O)c1ccccc1-c1ncccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 75 mg, 0.27 mmol) and 2-(pyrimidin-2-yl)benzoic acid (CAS number 400892-62-8; 64 mg, 0.32 mmol) to afford the title compound.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[O:2]2.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH:1]12[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:4][CH:3]([OH:9])[O:2]2
Reactant: O=C1CC2CCCC2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC1CC2CCCC2O1

Procedure:
The compound (52) (12.1 g) was reduced with diisobutylaluminum hydride (1.5M, 65.1 ml) in toluene (500 ml) at -78° C. and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (53). Yield: 11.1 g (91%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].Br[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Br.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: BrCCOCCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Temperature: 120 °C
Yield: 100 %

Procedure:
To a solution of 3-nitroaniline (42)(5.52 g, 40.00 mmol) in anhydrous dimethylacetamide (15 ml) was added 2-bromoethylether (7.52 ml, 60.00 mmol) and N,N-diisopropylethylamine (13.94 ml, 80.0 mmol). The mixture was then heated to 120° C. for 6 hours. After this time the reaction was cooled to room temperature which saw the mixture take the form of a slurry. The slurry was dissolved in CH2Cl2 (80 ml) and washed with 0.2 M HCl (3×30 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to give a brown semi-solid residue that was triturated with Et2O to give the desired product (8.33 g, 79.7%) in suitably clean form to be used without any further purification. m/z (LC-MS, ESP): 209 [M+H]+, R/T=3.46 mins
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1ccc(-c2ncco2)cc1F
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2ncco2)cc1F
Reaction time: 16 h
Yield: 81.9 %

Procedure:
A stirred solution of 2-(3-fluoro-4-nitro-phenyl)oxazole (500 mg, 2.40 mmol) in methanol (10 mL) was added to stannous chloride (2.7 g, 12.01 mmol) under nitrogen atmosphere and stirred for 16 h. The reaction mixture was diluted with water and filtered through Celite. The filtrate was basified with bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-fluoro-4-oxazol-2-yl aniline (350 mg, 83%) as a yellow colour solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[C:23]2[CH:22]=[CH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[CH:18]([C:28]#[N:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1.Br[CH2:31][CH2:32][CH2:33][C:34]#[N:35]>C1COCC1>[C:34]([CH2:33][CH2:32][CH2:31][C:18]1([C:28]#[N:29])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:23]=2[CH:22]=[CH:21][C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]1=2)#[N:35]
Reactant: N#CC1c2ccccc2C=Cc2ccccc21
Reactant: N#CCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CCCCC1(C#N)c2ccccc2C=Cc2ccccc21
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 78.1 %

Procedure:
To a −5° C. solution of diisopropylamine (0.143 ml, 1 mmol) in THF (1 ml) was added dropwise nBuLi (0.67 ml, 1.06 mmol, 1.6 M in hexane). After 20 minutes stirring at −5° C., a solution of 5H-dibenzo[a,d]cycloheptene-5-carbonitrile (prepared according to: Regnier G. J. et al. J. Med. Chem. 1992, 35, 2481–2496) (0.2 g, 0.9 mmol) in THF (1 ml) was added dropwise. After 15 minutes at −5° C., a solution of 4-bromobutyronitrile (0.1 ml, 1 mmol) in THF (1 ml) was added slowly. The reaction mixture was allowed to warm up slowly to room temperature, stirred overnight and quenched with water and ether. Aqueous phase was extracted with ether and the combined organic phases were washed with water, dried with Na2SO4 and concentrated in vacuo. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide 5-(3-cyano-propyl)-5H-dibenzo(a,d]cycloheptene-5-carbonitrile (0.2 g, 76%) as a colorless oil, MS: m/e=284 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:20]1[N:24]2[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:23]2=[N:22][CH:21]=1)CCC>>[F:14][C:5]1[CH:4]=[CH:3][C:2]([C:20]2[N:24]3[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[N:28][C:23]3=[N:22][CH:21]=2)=[CH:7][C:6]=1[C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Fc1ccc(Br)cc1-c1cnccn1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1cnccn1

Procedure:
2-(5-Bromo-2-fluorophenyl)pyrazine was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 4% methanol followed by crystallisation from hot toluene gave 3-[4-fluoro-3-(pyrazin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, DMSO) 9.31 (1H, d, J 7), 9.14 (1H, m), 8.85 (1H, dd, J 2 and 1.5), 8.73 (1H, d, J 2), 8.32 (1H, s), 8.27 (1H, dd, J 7 and 2), 7.96 (1H, m), 7.68 (1H, dd, J 11 and 9), 7.54 (1H, d, J 7); m/z (ES+) 360 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]([Br:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]([Br:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]21[O:21][CH2:20][CH2:19][O:15]2
Reactant: OCCO
Reactant: CC(Br)c1ccc(CC2CCCCC2=O)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(Br)c1ccc(CC2CCCCC23OCCO3)c(Cl)c1

Procedure:
Forty-five (45) grams of 1-[3-chloro-4-(2-oxocyclohexane-1-yl methyl)phenyl]ethylbromide were dissolved in 200 ml of benzene and then incorporated with 12.7 g of ethylene glycol and 0.12 g of p-toluenesulfonic acid, after which the whole was refluxed under agitation for 4 hours. After the end of the reaction, the reaction mixture was washed with water, an aqueous solution of sodium hydrogen carbonate and water in this order. Then, the organic layer obtained was dried and thereafter freed of the solvent at a reduced pressure thereby to obtain 51 g of 1-[3-chloro-4-(2,2-ethylenedioxycyclohexane-1-yl methyl)phenyl]ethylbromide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:11]2=[O:22])[S:5][C:6]=1[C:7]([OH:9])=O.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(C(C)C)CC)(C)C.[NH2:59][CH2:60][C:61]1[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:11]2=[O:22])[S:5][C:6]=1[C:7]([NH:59][CH2:60][C:61]1[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=1)=[O:9]
Reactant: Cc1nc(N2CCN(Cc3ccncc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(Cc3ccncc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.6 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)thiazole-5-carboxylic acid (0.67 g, 2.12 mmol) in anhydrous N,N-dimethyl formamide (10 mL) was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.94 g, 2.12 mmol), diisopropylethylamine (1.12 mL, 6.35 mmol) and 3-(aminomethyl)pyridine (0.22 mL, 2.12 mmol). The resulting solution was stirred at ambient temperature for 24 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (15 mL) and brine (15 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 10-20% methanol in ethyl acetate as an eluent to afford the title compound as a colorless solid (10%, 0.092 g): mp 233-235° C. (dichloromethane/hexanes): 1H NMR (300 MHz, CDCl3) δ 8.57-8.49 (m, 4H), 7.67 (d, J=7.7 Hz, 1H), 7.26-7.17 (m, 3H), 6.36 (br s, 1H), 4.56 (d, J=5.8 Hz, 2H), 4.45 (s, 2H), 4.12-4.07 (m, 2H), 3.50-3.45 (m, 2H), 2.58 (s, 3H): MS (ES+) m/z 409.2 (M+1).
Reaction SMILES: O.[OH-].[Li+].[Br:4][C:5]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:6]=1[CH2:7][C:8]1[N:13]=[C:12]([C:14]([O:16]C)=[O:15])[C:11]([OH:18])=[C:10]([OH:19])[N:9]=1>O.C1COCC1>[Br:4][C:5]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:6]=1[CH2:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([OH:18])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: COC(=O)c1nc(Cc2ccc(F)cc2Br)nc(O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(Cc2ccc(F)cc2Br)[nH]c(=O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.6 %

Procedure:
A solution of lithium hydroxide monohydrate (23.5 mg, 560 μmol) in water (1 ml) was added to a stirred solution of methyl 2-(2-bromo-4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxylate (50 mg, 140 μmol) in THF (4 ml). The resulting mixture was stirred at room temperature for 24 h. The mixture was then acidified by the addition of Amberlyst resin, filtered and evaporated to dryness. The residue was triturated with Et2O to give the title compound as a white solid (0.02 g; 41%). LCMS: m/z=344 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[OH-].[O-:15]S(S([O-])=O)=O.[Na+].[Na+]>O>[NH2:10][C:5]1[C:6]([C:8]([NH2:9])=[O:15])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=S([O-])S(=O)[O-]
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1nc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
To a suspension of 6-chloro-3-nitropicolinonitrile (2.54 g, 13.8 mmol) in water (27.0 mL) was added NH4OH (5.61 mL, 36.0 mmol) at room temperature. After stirring for 20 min at room temperature, Na2S2O4 (13.7 g, 79.0 mmol) was added to the mixture. After stirring for 3 hours at room temperature, the reaction mixture was filtered, and washed with water. The filtercake was dried under vacuum to give 3-amino-6-chloropicolinamide (1.67 g, 70%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 5.36 (1H, brs), 6.00 (2H, brs), 7.00 (1H, d, J=8.8 Hz), 7.18 (1H, d, J=8.8 Hz), 7.63 (1H, brs).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[Cl:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:17]2[CH2:18][C@@H:14]([N:12]3[N:11]=[N:10][C:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[N:13]3)[CH2:15][C@H:16]2[C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[C:29]#[N:30])[CH2:25][CH2:26]2)=[O:20])=[CH:38][CH:37]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Reactant: O=Cc1ccc(Cl)cc1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2ccc(Cl)cc2)CC1
Yield: 10.8 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 4-chloro-benzaldehyde (20 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (8.3 mg, 11%) as light yellow oil. MS m/e=589.1 (75%); 591.1 (25%) [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][NH2:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][NH:21][C:29]([NH:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:30])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C=NC1CCCCC1
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCN
Product: CCCCc1nc2cnc3ccccc3c2n1CCCNC(=O)NC1CCCCC1
Yield: 90.8 %

Procedure:
Using the general method of Example 146 Part B, 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08 mmol) was reacted with cyclohexyl isocyanate (1.0 g, 7.98 mmol) to provide 2.62 g of N-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-cyclohexylurea.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([C:33]2[CH:38]=[CH:37]C=CC=2)(=[N:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])=[CH:21][CH:20]=1>>[CH2:31]([O:30][C:28]([N:27]=[S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH:33]1[CH2:38][CH2:37]1)=[O:26])=[O:29])[CH3:32]
Reactant: CCOC(=O)N=S(=O)(c1ccccc1)c1ccc(N)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: CCOC(=O)N=S(=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1)C1CC1
Yield: 43 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (155 mg, 0.57 mmol) with (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-phenyl-sulfoximide (159 mg, 0.52 mmol) according to procedure 5c, the desired product is obtained in 43% yield (120 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[OH:7])=[O:5].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[C:18]([O:7][N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:4](=[O:5])[C:3]([CH3:17])([CH3:16])[CH2:2][Cl:1])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(CCl)C(=O)N(O)Cc1ccccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)N(Cc1ccccc1Cl)OC(=O)c1ccccc1
Temperature: 0 °C
Yield: 154 %

Procedure:
A stirred solution of 2.0 grams (0.007 mole) of 3-chloro-N-(2-chlorophenyl)methyl-N-hydroxy-2,2-dimethylpropanamide (prepared in Example 1) in 25 ml of methylene chloride was placed under an argon atmosphere and cooled to 0° C. To this was added 0.98 gram (0.007 mole) of benzoyl chloride in 5 ml of methylene chloride followed by 0.63 gram (0.008 mole) of pyridine. Upon completion of addition the reaction mixture was heated under reflux for 16 hours. The reaction mixture was diluted with methylene chloride and washed with 100 ml of water, 100 ml of aqueous 10% hydrochloric acid and finally 100 ml of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residual oil. The oil was subjected to column chromatography on silica gel. The appropriate fraction was concentrated under reduced pressure to give 4.1 grams of solid. The solid was recrystallized from ethyl acetate/cyclohexane. A precipitate was collected by filtration; mp 117°-120°. Nuclear magnetic resonance spectroscopy indicated the precipitate to be benzoic acid. The mother liquor was concentrated under reduced pressure and the residue redissolved in 60 ml of methylene chloride. The solution was washed with five portions of 20 ml each of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. Volatiles were removed from the oil under reduced pressure using a short-path distilling system. There remained as a residue 1.0 gram of N-benzoyloxy-3-chloro-N-(2-chlorophenyl)methyl-2,2-dimethylpropanamide.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:32]([F:34])[F:33])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.S(Cl)(C)(=O)=O.[NH2:49][CH:50]1[C:67](=[O:68])[N:52]2[C:53]([C:64]([OH:66])=[O:65])=[C:54]([CH2:57][S:58][C:59]3[S:60][CH:61]=[N:62][N:63]=3)[CH2:55][S:56][C@H:51]12.C[Si](C)(C)NC(=O)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:32]([F:33])[F:34])[C:27]([NH:49][CH:50]2[C:67](=[O:68])[N:52]3[C:53]([C:64]([OH:66])=[O:65])=[C:54]([CH2:57][S:58][C:59]4[S:60][CH:61]=[N:62][N:63]=4)[CH2:55][S:56][C@H:51]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Agent: CC(=O)N[Si](C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)C1=C(CSc2nncs2)CS[C@@H]2C(NC(=O)C(=NOC(F)F)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of 2-(2-tritylaminothiazol-4-yl)-2difluoromethoxyiminoacetic acid (syn isomer) (0.8 g) and diisopropylethylamine (0.43 g) in N,N-dimethylformamide (20 ml) was added mesyl chloride (0.38 g) at -20° C. and the mixture was stirred at the same temperature for 30 minutes to give an activated acid solution. To a solution of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (0.57 g) and N-trimethylsilylacetamide (1.8 g) in tetrahydrofuran (20 ml) was added the activated acid solution obtained above all at once at -10° C. After being stirred at the same temperature for an hour, the mixture was poured into water and adjusted to pH 2.5 with an aqueous solution of sodium bicarbonate. The precipitates were collected by filtration and washed with water to give 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)COCC1(c2ccc(F)cc2)CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COCC1(c2ccc(F)cc2)CCCCC1
Yield: 95.7 %

Procedure:
A solution of tert-butyl 2-((1-(4-fluorophenyl)cyclohexyl)methoxy)acetate (100 mg, 310 μmol) in trifluoroacetic acid (1 mL) was stirred at room temperature for 85 min. TFA was removed under reduced pressure, followed by co-evaporation with ether to obtain the crude 2-((1-(4-fluorophenyl)cyclohexyl)methoxy)acetic acid (79 mg, 96% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.30-7.43 (m, 2H), 6.93-7.17 (m, 2H), 3.91 (s, 2H), 3.46 (s, 2H), 2.13 (d, 2H), 1.60-1.76 (m, 2H), 1.55 (dd, 3H), 1.26-1.44 (m, 3H).