Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][S:18][CH2:19][C@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.O.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:17][S:18][CH2:19][C@H:20]([NH:27][C:13](=[O:15])[C@@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CSC[C@H](N)c1ccccc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CSC[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-tert-butoxycarbonyl-D-valine (2.39 g, 11.0 mmols) and 10.0 mmols of the above-obtained (R)-α-methylthiomethylbenzylamine hydrochloride were dissolved in 60 ml of methylene chloride. Triethylamine (1.53 ml, 11.0 mmols), 2.11 g (11.0 mmols) of water-soluble carbodiimide hydrochloride and 1.49 g (11.0 mmols) of HOBt were added to the solution while being cooled to 0° C. The mixture was stirred for 1 hour while being cooled, and then overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, 100 ml of water were added to the residue, and the solution was extracted twice with 100 ml of ethyl acetate. The organic layer was washed twice with a 5% citric acid aqueous solution, with 50 ml of a saturated aqueous solution of sodium chloride, twice with a 5% sodium hydrogencarbonate aqueous solution and with 50 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain N-tert-butoxycarbonyl-D-valine (R)-α-methylthiomethylbenzylamide as a solid in a quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.O.[NH2:14][NH2:15]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:11])[NH:15][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC(=O)c1cccc(Br)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2cccc(Br)c2)n[nH]1
Reaction time: 0.08 h
Yield: 80.8 %

Procedure:
A mixture of 3-(3-bromophenyl)-3-oxopropanenitrile (35 g, 156 mmol) and hydrazine hydrate (11.34 mL, 234 mmol) in ethanol (600 mL) was refluxed for 16 h. Mixture was then cooled and concentrated in vacuuo. Crude product was diluted with dichloromethane and stirred for 5 min. Solids were filtered and dried to afford 3-(3-bromophenyl)-1H-pyrazol-5-amine (30 g, 126 mmol, 81% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.02 (br. s., 0.4H), 11.66 (br. s., 0.6H), 7.86 (t, J=1.6 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.45 (d, J=6.8 Hz, 1H), 7.37-7.18 (m, 1H), 5.78 (br. s., 1H), 5.08 (br. s., 1.2H), 4.68 (br. s., 0.8H). LCMS (M+H)=240.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[K+].[K+].C(=O)(OC)OC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH3:17])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: Cn1c(-c2ccc(Br)cc2)nc2ccccc21
Temperature: 3 °C
Reaction time: 3.5 h
Yield: 150.8 %

Procedure:
12.69 g (46 mmole) of 2-(4-bromophenyl)-1H-benzo[d]imidazole, 3.17 g of K2CO3 (23 mmole), 120 ml of DMF, and 11.6 ml of dimethyl carbonate (138 mmole) were mixed together and heat to reflux. The reaction was completed in 3.5 hours. The reaction mixture was cooled to 3° C., and 250 ml of ice cold water was slowly added, The precipitated was filtered, and wash with 3*50 ml of water, this wet cake was dried under vacuum to get 9.96 g of product (yield=75.44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH:15][C:16](=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:10][C:9]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:10][C:11]2[N:12]([C:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:15][N:14]=2)[N:13]=1
Reactant: O=C(CC1CCCCC1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(-c2cc3nnc(CC4CCCCC4)n3nc2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 102.9 %

Procedure:
To a suspension of N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-cyclohexylacetohydrazide (46 mg, 0.1 mmol) in THF (2 mL) at room temperature was added diisopropylethylamine (0.14 mL, 0.8 mmol). After 5 min, triphenylphosphine dichloride (110 mg, 0.33 mmol) was added, and the reaction mixture stirred at room temperature for 16 h. Analysis by HPLC/MS indicated the reaction was complete. The reaction was diluted with EtOAc (40 mL), washed with H2O, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated. The obtained residue was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-30%) in hexanes to yield 45 mg of the desired product with 80% purity (contaminated with triphenylphosphine oxide). The product was further purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 70% to 100% B, 8 min gradient, 100% B hold for 7 min, (A 90% H2O, 10% MeOH and B=10% H2O, 90% MeOH); Flow rate at 20 mL/min, UV detection at 220 nm) to afford 30 mg (68%) of the title compound as a white powder. HPLC/S (method A): retention time=4.22 min, (M+H)+=437.1. 1H NMR (CDCl3, 400 MHz): δ 8.03 (s, 1H), 7.33-7741 (m, 4H), 7.21-7.28 (m, 2H), 7.07 (d, J=8.31 Hz, 2H), 3.14 (d, J=7.09 Hz, 2H), 2.01-2.12 (m, 1H), 1.69-1.80 (m, 4H), 1.21-1.29 (m, 3H), 1.10-1.17 (m, 3H).
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29]([NH:31][CH2:32][CH2:33][S:34][C:35](=[O:37])[CH3:36])=[O:30])[CH2:8][S:9]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N[C@H](C(NCCSC(=O)C)=O)CS)(=O)C.C(Cl)Cl.CCOCC>C(Cl)(Cl)Cl>[C:1]([NH:6][C@H:7]([C:29]([NH:31][CH2:32][CH2:33][S:34][C:35](=[O:37])[CH3:36])=[O:30])[CH2:8][SH:9])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(=O)SCCNC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)C(C)C
Agent: CC(=O)N[C@@H](CS)C(=O)NCCSC(C)=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(=O)SCCNC(=O)[C@H](CS)NC(=O)C(C)C
Yield: 70 %

Procedure:
This compound is obtained by the S-detritylation of 14 (2.56 mmol). The protocol used is the same as that described in example 1 for the synthesis of I-152. After the various treatments, a gum is collected, which gum is purified by flash chromatography on a silica gel column (eluent: CH2Cl2/ether 30%). I-203 is isolated in the form of white solid with a yield of 70%. Rf CH2Cl2/ether, 5/5): 0.44. M.p.=117-120° C. [α]D20=−36.5° (c 1.04, CHCl3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:16]1([S:22]([C:25]2[CH:30]=[CH:29][C:28](F)=[C:27]([F:32])[CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:32][C:27]1[CH:26]=[C:25]([S:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:23])=[O:24])[CH:30]=[CH:29][C:28]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(F)c1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from example 24 step (i).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.[N+:17]([C:20]1[CH:21]=[C:22]([NH2:30])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)([O-:19])=[O:18].Cl>O.O1CCOCC1>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:30][C:22]3[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Reactant: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc([N+](=O)[O-])cc(C(F)(F)F)c3)nc21
Temperature: 25 °C
Yield: 49 %

Procedure:
2-Chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one of (2 g; 8.30 mmol) and 3-nitro-5-trifluoromethyl-phenylamine (1.71 g; 8.30 mmol) were diluted in 10 ml of water and 10 ml of 1,4-dioxane. 2 ml of HCl 37% were added. The reaction mixture was refluxed 48 h, then cooled to room temperature. The desired product precipitated from the reaction mixture, so, it was filtered, washed with water and dried in vacuo. Recrystallisation with 1,4-dioxane/water 1:1 gave 1.65 g (4.04 mmol; 49% yield) of white-yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14](=[O:20])[CH2:15][O:16]C(=O)C)[CH3:2]>Cl>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14](=[O:20])[CH2:15][OH:16])[CH3:2]
Reactant: CCOc1ccc2ccccc2c1C(=O)COC(C)=O
Agent: Cl
Product: CCOc1ccc2ccccc2c1C(=O)CO
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A solution of acetic acid 2-(2-ethoxy-naphthalen-1-yl)-2-oxo-ethyl ester (6.1 g), industrial methylated spirits (40 mL) and 1M hydrochloric acid (30 mL) was heated at reflux for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure to afford a brown oil. Purification by column chromatography, eluting with 30% to 40% ethyl acetate in cyclohexane, afforded 1-(2-ethoxy-naphthalen-1-yl)-2-hydroxy-ethanone (3.7 g, 71%) as an orange solid. 1H NMR (CDCl3): 1.4 (3H, t, J=7.0 Hz), 3.5 (1H, t, J=5.1 Hz), 4.2 (2H, q, J=7.0 Hz), 4.75 (2H, d, J=5.1 Hz), 7.25 (1H, d, J=9.0 Hz), 7.35 (1H, m), 7.5 (1H, m), 7.75 (1H, d, J=8.1 Hz), 7.85 (1H, d, J=7.8 Hz), 7.9 (1H, d, J=9.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:36]2[S:40][C:39]([C:41]3([O:45]COC)[CH2:44][CH2:43][CH2:42]3)=[N:38][CH:37]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:25])[CH2:21][N:22]([CH3:24])[CH3:23])[CH2:15][CH2:14]4)[N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([C:36]2[S:40][C:39]([C:41]3([OH:45])[CH2:44][CH2:43][CH2:42]3)=[N:38][CH:37]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:25])[CH2:21][N:22]([CH3:23])[CH3:24])[CH2:15][CH2:14]4)[N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:27])=[O:28])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc5c(c3)CCN5C(=O)CN(C)C)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc4c(c3)CCN4C(=O)CN(C)C)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 65 °C

Procedure:
A solution of Example 52C (0.083 g, 0.118 mmol) in tetrahydrofuran (0.8 mL) was treated with 10% aqueous HCl solution (0.25 mL), and the reaction was heated at 65° C. for 4 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The concentrate was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound. MS ESI(+) m/z 662.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N+](CC)(CC)CC)C1C=CC=CC=1.[N+](C1C=CC([O:41][C:42](=O)[C@H:43]([CH2:55][C:56](=[O:58])[NH2:57])[NH:44][C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])=CC=1)([O-])=O.N1C=CC=CC=1>CN(C)C=O>[CH2:48]([O:47][C:45]([NH:44][C@H:43]([C:42]([NH:14][C@H:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:41])[CH2:55][C:56](=[O:58])[NH2:57])=[O:46])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
51 g Nε-tert.butyloxycarbonyl-L-lysine were converted in a conventional manner into the benzyltriethylammonium salt and then stirred in 700 ml dimethylformamide with 81 g benzyloxycarbonyl-L-asparagine-4-nitrophenyl ester with the addition of 1 equivalent of pyridine for 48 hours at 20°. The residue left after vacuum evaporation was treated with ethyl acetate and potassium hydrogen sulfate solutions simultaneously; the thick precipitate formed was filtered off and then recrystallised from ethanol/petroleum ether. F = 174° - 175° (Z);[α]D20 = + 13.8° (c = 1.0; in pyridine). Yield = 70 g (71 % of the theoretical amount).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]([CH3:15])[CH2:7][C:6]2=[O:16].N1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(Cl)(Cl)Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH:8]([CH3:15])[CH2:7][C:6]2=[O:16]
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)N2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a stirred solution of 10.0 g. (0.45 mol.) of 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline in 76 ml. of pyridine, at 0° C., was added, dropwise, during a 30 minute period, 45 ml. of benzyl chloroformate. Stirring was continued for 15 minutes, and then an additional 10 ml. of benzyl chloroformate was added. After a further 10 minutes, a further 10 ml. of benzyl chloroformate was added. The reaction mixture was heated on a steam bath for 30 minutes, cooled to room temperature and then poured into a mixture of 950 ml. of chloroform and 300 ml. of water. The separated chloroform layer was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, and water, and then it was dried (MgSO4) and concentrated to dryness in vacuo. The residue was an oil which solidified after trituration with ehtyl acetate-hexane. The resulting solid was then recrystallized from the same solvent system, giving 11.4 g. of the title compound, m.p. 127.5°-129.5° C. (71% yield). Further recrystallization of a small portion of the product from ethyl acetate-hexane raised the melting point to 128.5°-130° C.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[O:10][C:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:7]=2[O:6]1)=[NH:4].C[O-].[Na+].[C:31](=O)(OCC)[O:32]CC>C(O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:7]2[O:6][CH:5]([C:3]3[NH:4][C:31](=[O:32])[O:1][N:2]=3)[O:10][C:9]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:8]=2[CH:23]=1
Reactant: N=C(NO)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: CCOC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(C2Oc3ccc(Cl)cc3C(C3CCCCC3)(C3CCCCC3)O2)no1
Temperature: 25 °C

Procedure:
To a solution of 500 mg N-hydroxy-6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carboxamidine in 3.7 ml ethanol was added 0.7 ml of a sodium methoxide solution (30% in methanol) and then 0.617 ml diethyl carbonate. The mixture was refluxed for 2 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was dissolved in 3.4 ml water and 1M aqueous HCl was added until pH7 was reached. The obtained precipitate was filtered, washed with water, dissolved in EtOAc and dried with MgSO4. Then the solvent was removed in vacuo and the crude product purified by preparative HPLC (C18 reverse phase column, elution with water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a solid. Yield: 257 mg.
Reaction SMILES: S(Cl)(C)(=O)=O.[CH3:6][O:7]/[N:8]=[C:9](/[C:13]1[NH:14][N:15]([NH:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:16][CH:17]=1)\[C:10]([OH:12])=O.C(N(CC)C(C)C)(C)C.[NH2:47][C@@H:48]1[C:72](=[O:73])[N:50]2[C:51]([C:60]([O:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][CH:65]=3)=[O:61])=[C:52]([C@@H:55]3[CH2:59][CH2:58][CH2:57][O:56]3)[CH2:53][S:54][C@H:49]12>ClCCl.N1C=CC=CC=1>[CH3:6][O:7]/[N:8]=[C:9](/[C:13]1[NH:14][N:15]([NH:18][C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:16][CH:17]=1)\[C:10]([NH:47][C@@H:48]1[C:72](=[O:73])[N:50]2[C:51]([C:60]([O:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][CH:65]=3)=[O:61])=[C:52]([C@@H:55]3[CH2:59][CH2:58][CH2:57][O:56]3)[CH2:53][S:54][C@H:49]12)=[O:12]
Reactant: COc1ccc(COC(=O)C2=C([C@@H]3CCCO3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: CO/N=C(\C(=O)O)C1=CSN(NC(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCCO3)CS[C@H]12)C1=CSN(NC(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Temperature: -20 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
Mesyl chloride (65μl) was added to 2-(Z)-methoxyimino-2-(2-tritylaminothiadiazol-4-yl)acetic acid (370mg) and N,N-diisopropylethylamine (146μl) in dichloromethane (5ml) at -20° C. The reaction mixture was stirred at -20° C. for 1 hour then added to an ice cold solution of 4-methoxybenzyl (6R,7R)-7-amino-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (335mg) and pyridine (70μl) in dichloromethane (5ml). The reaction was stirred for 1 hour, concentrated and flash chromatographed on silica gel eluting with 30,50,60 and 70% ethyl acetate in hexane to afford the title compound as a foam (300mg); vmax (CHCl3) 3398, 1784, 1724, 1691, 1516, 1134 and 1107 cm-1 ; δH (CDCl3, 250MHz) 1.55-1.75 (1H,m), 1.80-2.05 (2H,m), 2.25-2.45 (1H,m), 3.30 and 3.61 (2H, ABq, J 18.3Hz), 3.75-4.00 (2H,m), 3.81 (3H,m), 4.16 (3H,m), 4.85-5.00 (1H,m), 5.00 (1H,d, J 4.8Hz), 5.17 (2H,s), 5.92 (1H,dd, J 4.8Hz), 6.72 (1H,d,J 7.8Hz) and 6.88 and 7.30 (19H,m). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (839)].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH:10]1([CH2:16]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([CH2:16][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: BrCC1CCCCC1
Reactant: OCc1ccc(O)cc1
Product: OCc1ccc(OCC2CCCCC2)cc1

Procedure:
3-3 was prepared as described for the synthesis of 1-6 except 4-hydroxy-benzyl alcohol (3-1) and cyclohexylmethyl bromide (3-2) were used in Step A to yield 4-(cyclohexylmethoxy)benzyl alcohol directly. mp: 241°-3° C.;
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][C:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[O:31][N:30]=1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C:32]5[O:31][N:30]=[C:29]([CH3:28])[CH:33]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)on1

Procedure:
The title compound, white solid (17 mg, 54%), MS (ISP) m/z=455.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2-(3-methyl-isoxazol-5-yl)acetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[N:16]1[CH2:21][CH2:20][CH:19]([CH:22]([N:24]([CH3:26])[CH3:25])[CH3:23])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:13])=[O:14])=[C:5]3[N:16]2[CH2:17][CH2:18][CH:19]([CH:22]([N:24]([CH3:26])[CH3:25])[CH3:23])[CH2:20][CH2:21]2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]
Reactant: CC(C1CCN(c2c(S(C)(=O)=O)cnc3ccc(Br)cc23)CC1)N(C)C
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(S(C)(=O)=O)c(N4CCC(C(C)N(C)C)CC4)c3c2)cc(Cl)c1O
Yield: 55.2 %

Procedure:
Following general procedure D, 1-{1-[6-bromo-3-(methylsulfonyl)quinolin-4-yl]piperidin-4-yl}-N,N-dimethylethanamine (35 mg, 0.079 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.150 mmol) to afford the desired product (22.6 mg, 55%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.22 (s, 1H), 8.41 (s, 1H), 8.20-8.15 (m, 2H), 7.33 (d, J=2.1 Hz, 1H), 7.25 (d, J=2.1 Hz, 1H), 4.00 (s, 3H), 3.71 (t, J=11.8 Hz, 2H), 3.56 (d, J=11.9 Hz, 2H), 3.49-3.42 (m, 3H), 2.96 (s, 1H), 2.64 (s, 6H), 2.10-1.90 (m, 3H), 1.82-1.63 (m, 2H), 1.26 (d, J=6.7 Hz, 3H); ESI MS m/z 518 [C26H32ClN3O4S+H]+; HPLC 98.8% (AUC), tR=10.97 min.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1.[CH2:21]([S:24](Cl)(=[O:26])=[O:25])[CH2:22][CH3:23].CCN(CC)CC>C(Cl)Cl>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]([C@H:7]2[CH2:8][CH2:9][C@H:4]([NH:3][S:24]([CH2:21][CH2:22][CH3:23])(=[O:26])=[O:25])[CH2:5][CH2:6]2)=[O:11])[CH2:17][CH2:16]1)([CH3:20])[CH3:19]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](N)CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)N[C@H]1CC[C@H](C(=O)N2CCN(C(C)C)CC2)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of 32.6 mg (0.1 mmol) trans-(4-amino-cyclohexyl)-(4-isopropyl-piperazin-1-yl)-methanone, dihydrochloride, 28 mg (0.2 mmol) propane-1-sulfonyl chloride and 101 mg (1 mmol) NEt3 in 2 ml DCM was stirred for 16 h at 40° C. After evaporation methanol and DMF were added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.1% NEt3). The combined product fractions were evaporated to dryness to yield 13.9 mg (39%) of the title compound. MS (m/e): 360.4 (MH+).