Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].O>C(#N)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(CCc1ccccc1O)NCCOc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCC(=O)NCCOc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 96 h

Procedure:
N-(4-Chlorophenoxyethyl)-3-(2-hydroxyphenyl)propanamide (11.6 g, 36.3 mmol) was dissolved in acetonitrile (15 mL), and potassium carbonate (15.0 g, 109 mmol) was added thereto. Subsequently, tert-butyl 2-bromoisobutyrate (20.2 g, 90.7 mmol) was added thereto, followed by stirring for 4 days at 70° C. Subsequently, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with brine, and the resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=50/1), whereby the target compound was obtained (7.4 g, 44%).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br.Br[CH:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:12]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)C(Br)c1cccnc1
Reactant: Oc1ccc(Cl)cc1
Agent: Br
Agent: [Na]
Solvent: CO
Product: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)c1cccnc1
Yield: 61.9 %

Procedure:
6.9 g (0.3 mol) of sodium metal were added to a solution of 38.6 g (0.3 mol) of 4-chlorophenol in 200 ml of absolute methanol. When the sodium had dissolved completely, the solution was heated under reflux and 33.7 g (0.1 mol) of 1-bromo-3,3-dimethyl-1-pyridin-3-yl-butan-2-one hydrobromide were added. The reaction mixture was heated under reflux overnight. It was allowed to cool and was concentrated in vacuo. The residue was taken up in diethyl ether and the ether mixture was washed twice with 2 N sodium hydroxide solution, once with water and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue was recrystallized from n-hexane. 18.8 g (62% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-pyridin-3-yl-butan-2-one of melting point 50° C. were obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:26][C:27]1[CH:28]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:30]=[N:31][CH:32]=1.NC1C=NC=C(C)C=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH3:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:35])[CH:30]=[N:31][CH:32]=1
Reactant: Cc1cncc(NC(=O)Oc2ccccc2)c1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cc1cncc(N)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenyl 5-methylpyridin-3-ylcarbamate (0.274 g, 1.2 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-amino-5-methylpyridine) in DMSO (2.5 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and the mixture was heated to 60° C. After 4 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined and were washed with brine and dried over sodium sulfate, filtered and concentrated to form a residue. The residue was purified by silica gel chromatography (10% of the 1N NH3 in MeOH, in dichloromethane) to afford the title compound as a white foam (300 mg, 64%). MS (APCI 10V) AP+ 458.16; 1H NMR (400 MHz, DMSO) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H) 3.29 (s, 3H) 3.46 (t, J=5.46 Hz, 2H) 3.54 (t, J=5.46 Hz, 2H) 6.38 (s, 1H) 7.03 (m, 2H) 7.13 (d, J=7.80 Hz, 1H) 7.21 (d, J=8.58 Hz, 1H) 7.4 (dd, J=7.8 Hz, 2 Hz, 1H) 7.70 (s, 1H) 7.96 (d, J=2 Hz, 1H) 8.20 (dd, J=8.8 Hz, 2.5 Hz, 1H) 8.41 (d, J=2.2 Hz, 1H) 8.55 (s, 1H) 8.64 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]1[C:33](=[O:34])[N:15]2[C:16]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11])=O>C(O)C.O>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:4]=1
Reactant: NC(N)=S
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Solvent: O
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 27.4 %

Procedure:
Thiourea (0.14 g.) was added to a solution of 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.8 g.) in ethanol (20 ml.) and water (5 ml.), and stirred at room temperature for 3.5 hours. The resultant solution was concentrated under reduced pressure, and to the residue were added water and ethyl acetate. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product (0.6 g.) The product was purified by column chromatography on silica gel (eluent: benzene and ethyl acetate (8:2) to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.21 g.), mp 165° to 170° C. (dec.)
Reaction SMILES: C(OC(=O)C[C@@H](N1C=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)C(N[C@@H](CC1C=CC=CC=1)CO)=O)C1C=CC=CC=1.[CH2:43]([O:50][C:51](=[O:72])[CH2:52][C@@H:53]([NH:64][C:65](OC(C)(C)C)=O)[C:54]([NH:56][C@@H:57]1[CH2:62][CH2:61][CH2:60][CH2:59][C@H:58]1[OH:63])=[O:55])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C1(C2C=CC=CC=2)C=CC(C2CC(OC)OC2OC)=CC=1>C(O)(=O)C>[CH2:43]([O:50][C:51](=[O:72])[CH2:52][C@@H:53]([N:64]1[CH:65]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:28]1)[C:54]([NH:56][C@@H:57]1[CH2:62][CH2:61][CH2:60][CH2:59][C@H:58]1[OH:63])=[O:55])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCCC[C@H]1O
Agent: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: CC(=O)O
Product: O=C(C[C@H](C(=O)N[C@@H]1CCCC[C@H]1O)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Yield: 41 %

Procedure:
As described in Example 1(a) for the preparation of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-(3-(biphenyl-4-yl)-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-t-butoxycarbonylamino-N-(2(R)-hydroxycyclohex-1(R)-yl)succinamic acid benzyl ester and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in acetic acid to furnish in 41% yield 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-(2(R)-hydroxycyclohex-1(R)-yl)succinamic acid benzyl ester as an amorphous off-white solid. 1H NMR (CDCl3): δ 7.63-7.54 (m, 6H), 7.45 (t, 2H, J=7.5 Hz), 7.36-7.26 (m, 6H) 1H), 6.76 (t, 1H, J=2.4 Hz), 6.58 (s, 1H), 5.46 (d, 1H, J=7.0 Hz), 5.15-5.10 (m, 3H), 3.61-3.55 (m, 1H), 3.49 (dd, 1H, J=5.5, 16.6 Hz), 3.27-3.21 (m, 1H), 3.06 (dd, 1H, J=8.3, 16.7 Hz), 2.04-1.98 (m, 1H), 1.85-1.78 (m, 1H), 1.71-1.51 (m, 2H), 1.32-1.02 (m, 4H). Anal. Calculated for C33H34N2O4.H2O: C, 73.31; H, 6.71; N, 5.18. Found: C, 72.93; H, 6.72; N, 4.93.
Reaction SMILES: Cl.O1CCOCC1.C(=[N:15][C:16]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)([CH2:22][CH:23]=[CH2:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C1C=CC=CC=1>O>[NH2:15][C:16]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)([CH2:22][CH:23]=[CH2:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C=CCC(N=Cc1ccccc1)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C=CCC(N)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
4N HCl-1,4-dioxane (308 mL) and water (65 mL) were added to ethyl 2-(benzylidene-amino)-2-(3,4-dichlorophenyl)-4-pentenoate (518 g), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Water (1 L) and 1N aqueous hydrochloric acid (500 mL) were added to the residue, and the mixture was washed with diisopropyl ether (500 mL) three times. 25% Aqueous sodium hydroxide (250 mL) was added to the aqueous layer to adjust the pH to 9. The resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure, to thereby give the title compound (231 g). The title compound was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([OH:15])[CH3:14].[O-]CC.[Na+]>O>[CH2:13]([O:15][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=1)[CH3:14]
Reactant: CCO
Reactant: CNC(=O)c1cnc(C)cc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1cc(C)ncc1C(=O)NC
Reaction time: 8 h

Procedure:
4-Chloro-6,N-dimethylnicotinamide (2.4 g) was dissolved with stirring in abs. ethanol (40 ml) and treated with sodium ethoxide (1.8 g). After stirring at RT for 4 h, the mixture was allowed to stand overnight. After addition of water, it was extracted 3 times with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 2.2 g of the desired compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C(NC(C)C)(C)C.[CH:33]#[C:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C.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.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:33]#[C:34][CH2:35][CH2:36][CH3:37])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C#CCCC
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCCC#Cc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 24 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (693 mg, 1.54 mmol) in anhydrous DMF (5 mL) and DIPA (diisopropylamine, 10 mL) is added Pd(PPh3)4 (89 mg, 7.7% mmol), CuI (29 mg, 0.154 mmol) and pent-1-yne (1.5 mL, 15.4 mmol). The resulting solution is covered in argon and run in a microwave reaction: 110° C., 35 minutes. After the removal of DMF and DIPA in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 0%-40% EtOAc in heptane) to give a pure product (122) as a pale yellow solid (144 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cccc(C)c1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Agent: N
Product: Cc1cccc(-c2cc(-c3cncc(Cl)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-ethynyl-3-methylbenzene (Aldrich, 35 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 2.42 (s, 3H), 7.38 (d, J=7.5 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.66-7.75 (m, 2H), 7.75 (s, 1H), 8.44 (t, J=2.1 Hz, 1 H), 8.80 (d, J=2.4 Hz, 1H), 9.09 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 271 (M+H)+, 273 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([C@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:21]2[C:22]3[C:18](=[CH:17][C:16]([Cl:15])=[CH:24][C:23]=3[Cl:25])[CH2:19][CH2:20]2)[C:3](=[O:14])[N:4]([C@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=1
Reactant: COC[C@@H](C)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Product: COC[C@@H](C)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 93–95° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (s, 1 H), 7.11 (s, 1 H), 7.06 (s, 1 H), 4.35 (t, J=7.9 Hz, 2 H), 3.62–3.56 (m, 3 H), 3.36 (s, 3 H), 3.12 (t, J=8.1 Hz, 2 H), 0.90–0.86 (m, 3 H); HRMS (ESI) calcd for C16H17N3O2Cl3 (M+H)+: 388.0386; found m/z 388.0358.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: C1CCNCC1
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.8 %

Procedure:
To a cooled (0° C.) solution of 1.75 g (10.0 mmol) of 4-chloro-2-fluoronitrobenzene in 15 mL of EtOH was added 2.97 mL (30.0 mmol) of piperidine dropwise over 5 min. The solution stirred at 0° C. for 10 min and then at 23° C. for 30 min. The mixture was poured into water (225 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with saturated aq NaHCO3 and brine (30 mL each) and then dried (Na2SO4). Concentration afforded 2.33 g (97%) of the title compound as an orange oil which crystallized on standing: Mass spectrum (ESI, m/z): Calcd. for C11H13ClN2O2, 241.1 (M+H), found 241.1.
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4].[CH3:38][C:39]1([CH3:42])[CH2:41][O:40]1.CCN(C(C)C)C(C)C>CC#N>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][N:22]([CH2:38][C:39]([CH3:42])([OH:40])[CH3:41])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4]
Reactant: CC1(C)CO1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCNC3)n(C)c2n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 90 °C
Yield: 34.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine dihydrochloride (150 mg, 0.27 mmol), 2,2-dimethyloxirane (242 μL, 2.73 mmol) and DIPEA (187 μL, 1.09 mmol) in MeCN (3 mL) was heated at 70° C. r.t. for 3 h before further 2,2-dimethyloxirane (242 μL, 2.73 mmol) was added and the mixture heated at 90° C. for 6 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) affording 791 (51 mg, 34%). LCMS (method I): RT 2.72 min, [M+H]+ 549.3. 1H NMR (DMSO, 400 MHz): δ 8.03-8.02 (1 H, m), 7.64-7.63 (1 H, m), 7.25-7.24 (2 H, m), 4.26 (4 H, brd s), 4.08 (1 H, s), 3.91 (3 H, s), 3.79 (4 H, t, J=4.72 Hz), 3.27-3.26 (2 H, m), 3.20-3.15 (1 H, m), 3.06 (3 H, s), 3.01-2.97 (1 H, m), 2.69-2.61 (1 H, m), 2.46-2.38 (1 H, m), 2.25 (2 H, s), 2.17-2.14 (1 H, m), 1.92-1.75 (3 H, m), 1.33 (3 H, t, J=7.43 Hz), 1.03 (3 H, s), 0.94 (3 H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[CH:18]1([NH:24][C:25]([CH:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH3:28])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:32]1[CH2:33][CH2:34][N:29]([CH:27]([C:25]([NH:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:26])[CH3:28])[CH2:30][CH2:31]1)=[O:9]
Reactant: CC(C(=O)NC1CCCCC1)N1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC(=O)N2CCN(C(C)C(=O)NC3CCCCC3)CC2)cc(OC)c1OC
Reaction time: 0.33 h

Procedure:
0.64 g of 3,4,5-trimethoxycinnamoyl chloride is added to a solution of 0.50 g of 1-[1-(cyclohexylaminocarbonyl)ethyl]piperazine and 0.27 g of triethylamine in 15 ml of chloroform, and the resulting solution is kept standing at room temperature for 20 minutes.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:21]=[CH:20][C:11]([CH:12]=[C:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1.[OH:22][C@@H:23]([CH2:36][NH2:37])[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[OH:22][C@H:23]([CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:36][NH:37][CH:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:21]=[CH:20][C:11]([CH:12]=[C:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:2][CH2:7]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1NC(=O)C(=Cc2ccc(N3CCCCC3=O)cc2)S1
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 36) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 73 as a pale yellowish solid; mp>240° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.45–1.60 (m, 2 H), 2.00–2.15 (m, 2 H), 2.86 (brt, J=9.0 Hz, 2 H), 2.90–3.60 (m, 3 H), 3.91 (brd, J=9.4 Hz, 1 H), 3.93–4.10 (m, 3 H), 5.40 (brs, 1 H), 6.59 (d, J=6.0 Hz, 1 H), 6.63 (d, J=6.0 Hz, 1 H), 6.86 (t, J=6.0 Hz, 1 H), 7.02 (d, J=6.6 Hz, 2 H), 7.36 (s, 1 H), 7.40 (d, J=6.6 Hz, 2 H), 11.60 (s, 1 H), 11.70 (brs, 1 H); MS (ES) m/z: 509.9 (MH+); HRMS Calcd. for C25H28N5O5S (MH+): 510.1811. Found: 510.1861.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:31])[CH2:14][CH2:15][C:16]1([OH:30])[CH2:21][CH:20]2[CH2:22][CH2:23][CH:17]1[CH:18]=[C:19]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(CC)CC.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:31])[CH2:14][CH2:15][C@:16]1([O:30][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:21][C@H:20]2[CH2:22][CH2:23][C@@H:17]1[CH:18]=[C:19]2[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)C(=O)Cl
Reactant: CN(CCCc1nc2ccccc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)O[C@@]1(CCN(C)CCCc2nc3ccccc3[nH]2)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 150 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol and 0.176 mL of NEt3 in 4 mL DCM 0.1 mL of isobutyrylchloride was added at 0° C. The yellow reaction mixture was stirred for 3 h at rt and then quenched with sat. aq. NaHCO3. The product was extracted with DCM, the organic phase was evaporated to dryness. The residue was dissolved in EtOAc, silica gel and a few drops of MeOH were added and the mixture was stirred vigorously for 5 h. The mixture was filtered, the filtrate evaporated and the residue purified by CC with EtOAc-MeOH (3:1) to yield 86 mg of pure rac-isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as colorless foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:18][C:19](=[O:36])[C@@H:20]([CH2:28][S:29]([C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([OH:17])=O)[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][C@@H:38]([CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)[C@@H:39]([OH:45])[C@H:40]([CH:42]1[CH2:44][CH2:43]1)[OH:41].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.ON1C(=O)CCC1=O>[C:32]([S:29]([CH2:28][C@@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C@H:14]([C:15](=[O:17])[NH:37][C@@H:38]([CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)[C@@H:39]([OH:45])[C@H:40]([CH:42]1[CH2:44][CH2:43]1)[OH:41])[CH2:13][C:11]1[N:10]=[CH:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:12]=1)=[O:36])(=[O:30])=[O:31])([CH3:35])([CH3:33])[CH3:34]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](O)C2CC2)c1
Reaction time: 17 h
Yield: 87.2 %

Procedure:
89 g (170 mmol) of (S)-1-(t-butoxycarbonyl)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionic acid, 1 g (8.5 mmol) of N-hydroxysuccinimide, 35.5 g (155 mmol) of (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-butane-1,2-diol and 800 ml of ethyl acetate were stirred at 20°. A solution of 37 g (178 mmol) of dicyclohexylcarbodiimide in 110 ml of ethyl acetate was added within 10 minutes. The reaction had finished after stirring at 20° for 17 hours. The solid (dicyclohexylurea) was filtered off and the filtrate was treated while stirring firstly with 68 ml of deionized water and then with 1100 ml of hexane. After one hour at 0° the crystallizate was filtered off under suction and triturated in methanol at 20°. The suspension was cooled to -15° and the product was filtered off. 98.8 g (86%) of t-butyl 4-[(S)-2-[(S)-2-t-butanesulphonylmethyl-3-phenylpropionylamino]-2-[(1S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl]ethyl]-1H-imidazole-1-carboxylate were obtained.