Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:15]=2)[N:3]=1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O.O>C1COCC1>[NH2:1][C:2]1[C:7]([N:8]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:15]=2)[N:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(CC(F)(F)F)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1N
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A quantity of 3.470 g (8.138 mmol) of the compound from Example 1 was suspended in 35 ml of THF, admixed at 0° C. with 358 mg (8.952 mmol) of sodium hydride (60% suspension in mineral oil) and stirred at 0° C. for 90 min, in the course of which a solution was formed. A quantity of 2.519 g (8.952 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate was added and the mixture was stirred at RT for 48 h. It was then stirred with water and concentrated on a rotary evaporator. The residue was taken up in ethyl acetate, and the organic phase was washed twice with water and dried over sodium sulphate. This gave 5.005 g of the target compound (79% of theory, purity by HPLC 65%). A quantity of 250 mg of the residue was purified by means of preparative HPLC (mobile phase: methanol/water, gradient 30:70→90:10).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C@H:47]([CH2:50][CH2:51][CH2:52][CH2:53][NH:54]C(OCC1C=CC=CC=1)=O)[CH2:48][OH:49].Cl.NCC(N)=O>>[NH2:54][CH2:53][CH2:52][CH2:51][CH2:50][C@@H:47]([NH:46][C:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[CH:36][CH:35]=1)=[O:42])[CH2:48][OH:49]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: N[C@@H](CO)CCCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)N[C@@H](CO)CCCCN)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and (R)-2-amino-6-benzyloxycarbonylamino-1-hexanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=1)[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([O:41][CH2:42][CH3:43])[C:35]=1[N:36]1[CH:40]=[CH:39][CH:38]=[CH:37]1)[CH:31]=O)[CH3:26].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([O:41][CH2:42][CH3:43])[C:35]=1[N:36]1[CH:40]=[CH:39][CH:38]=[CH:37]1)[CH2:31][N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[C:5]2[CH:15]=[C:16]([O:18][CH2:19][C:20]3[NH:21][N:22]=[N:23][N:24]=3)[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13]1)[CH3:26]
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Reactant: COc1cc(OCc2nnn[nH]2)cc(C(=O)NC2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCc4nnn[nH]4)c3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), 3-methoxy-N-piperidin-4-yl-5-(1H-tetrazol-5-ylmethoxy)-benzamide (example 170c) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 576.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:19]=[CH:18][C:9]2[C:10]3[C:15](=O)[NH:14][CH:13]=[N:12][C:11]=3[S:17][C:8]=2[CH:7]=1)[CH3:2].C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:19]=[CH:18][C:9]2[C:10]3[C:15]([Cl:32])=[N:14][CH:13]=[N:12][C:11]=3[S:17][C:8]=2[CH:7]=1)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1nc[nH]c(=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc2c(c1)sc1ncnc(Cl)c12
Temperature: 80 °C
Yield: 58.3 %

Procedure:
To a solution of (4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl)-acetic acid ethyl ester (1.78 g, 6.17 mmol, 1 equiv, from step 3) in toluene (15 mL) were added diisopropylethylamine (1.18 mL, 6.79 mmol, 1.1 equiv) and phosphorous oxychloride (0.63 mL, 6.79 mmol, 1.1 equiv) at 0° C. under argon. The flask was equipped with a reflux condenser and heated at 80° C. for 5 h. The reaction mixture was cooled to rt and quenched with ice/saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (20% EtOAc/hexane) to yield 1.12 g (3.6 mmol, 56%) of a light yellow solid. 1H-NMR (DMSO-d6) δ 9.01 (s, 1H), 8.64 (d, J=8.6 Hz, 1H), 8.15 (s, 1H), 7.61 (d, J=8.6 Hz, 1H), 4.10 (q, 2H), 3.92 (s, 2H), 1.20 (t, 3H), LCMS RT=3.19 min, [M+H]+=307
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[I:12][CH3:13]>CO>[I-:12].[CH3:13][N+:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1
Reactant: CI
Reactant: Cc1ccnc2ccccc12
Solvent: CO
Product: Cc1cc[n+](C)c2ccccc12
Product: [I-]
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution mixture of lepidine (0.66 g, 4.65 mmol) and iodomethane (1.32 g, 9.3 mmol) in methanol (30 mL) was heated to reflux in a sealed tube overnight. After cooling to room temperature, methanol was removed under vacuum. Anhydrous acetone was added to the residue and filtered. The resulting solid was washed with acetone and dried to afford iodide 4 (1.1 g) as yellow solid in 83% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J=6 Hz, 1H), 8.54 (d, J=8.8 Hz, 1H), 8.49 (d, J=8.8 Hz, 1H), 8.27 (t, J=7.2 Hz, 1H), 8.07 (t, J=4.8 Hz, 1H), 8.05 (d, J=6 Hz, 1H), 4.57 (s, 3H), 3.00 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 158.1, 148.9, 137.6, 134.9, 129.6, 128.4, 126.8, 122.4, 119.5, 44.9, 19.6. MS (FAB) m/z Calcd for C11H12N+158.0. Found 158.2 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH3:11].N1C=CN=C1.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18].Cl>CN(C=O)C.C(OCC)(=O)C>[C:17]([Si:21]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][CH3:11])[CH:4]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1cc(CO)ccc1F
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 9.17 g of (4-fluoro-3-methoxyphenyl)methanol [CAS No. 128495-45-4] in 100 ml of DMF, 5 g of imidazole and 17 g of t-butyl-chlorodiphenylsilane were added and the mixture was stirred overnight at room temperature. Next, 1N hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give t-butyl-(4-fluoro-3-methoxybenzyloxy)diphenylsilane as an oil.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[OH-].[Na+].C(Cl)Cl.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27](=[O:31])[C:28](Cl)=[O:29])=[CH:19]1>O>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[C@H:4]([NH:3][C:28](=[O:29])[C:27](=[O:31])[C:20]1[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([CH3:17])[CH:19]=1)[CH2:5]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1cc(C(=O)C(=O)N[C@@H]2CN3CCC2CC3)c2ccccc21
Yield: 30.8 %

Procedure:
(S)-3-amino-1-azabicyclo[2.2.2]octane dihydrochloride salt (7.5 g; 37.5 mmol) and sodium hydroxide (2.0 g; 50.0 mmols) were dissolved in 50 ml of water. The solution was cooled in an ice bath and 100 ml of methylene chloride was added. The mixture was stirred while approximately one third of a solution containing 1-methy-α-oxo-3-indoleacetyl chloride (10.8 g; 48.7 mmol) was added in a dropwise fashion, after which additional sodium hydroxide (3.0 g; 75.0 mmol) in 20.0 ml of water was mixed in. The remaining 1-methy-α-oxo-3-indoleacetyl chloride was then added and the reaction mixture was stirred for 10 minutes. The aqueous layer was then separated from the organic phase and rinsed with methylene chloride. The combined organic phase was dried over potassium carbonate. Filtration and evaporation of the solvent resulted in 5.1 g of crude product. The crude product was purified by chromatography (silica gel 60; 7% MeOH in CH2Cl2 containing approximately 0.5 % NH4OH) to yield 3.6 g (11.5 mmmol) of (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-1-methyl-α-oxo-3-indoleacetamide, m.p. 186°-187° C., [α]D25 -41° (CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[Li+].[Cl-].[CH:27]1([Mg]Cl)[CH2:31][CH2:30][CH2:29][CH2:28]1>S(Cl)(Cl)=O.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl[Mg]C1CCCC1
Reactant: O=C(O)CCc1cccc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(CCc1cccc(OCc2ccccc2)c1)C1CCCC1
Temperature: 25 °C

Procedure:
3-(3-Benzyloxy-phenyl)-propanoic acid (5 g, 19.5 mmol) from Example XXXX was taken up in thionyl chloride (20 mL) and refluxed for 2 hours. The excess thionyl chloride was removed under reduced pressure and carbon tetrachloride added and removed several times under reduced pressure to remove any excess thionyl chloride. The resulting oil was taken up in freshly distilled THF (50 mL), MnCl2 (0.49 g, 3.9 mmol) and LiCl (0.331 g, 7.8 mmol) were added. This was allowed to stir under nitrogen at room temperature until homogenous. The solution was then cooled to 0° C. with an ice bath and 2.0M cyclopentyl magnesium chloride (11.0 mL, 22 mmol) in Et2O was added dropwise to the solution over 0.5 hour. The reaction was allowed to stir for 10 minutes after addition was complete and was then quenched with 1N HCl and brine until acidic. The organics were extracted into EtOAc and then washed with brine and dried with MgSO4. The solvent was removed under reduced pressure and the residue submitted to flash chromatography (3:7 EtOAc:hexane, silica gel) to yield the title compound as a viscous oil. 1H NMR (CDCl3) δ 1.54-1.80 (br m, 8 H), 2.76 (m, 2 H), 2.80 (m, obscured, 1 H), 2.86 (m, 2 H), 5.05 (s, 2 H), 6.81 (br m, 3 H), 7.21 (br m, 1 H), 7.43 (br m, 5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH2:15]1CCN2C(=NCCC2)CC1.IC.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:15])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of 4-methoxy-2-nitrobenzoic acid (10.0 g, 50.7 mmol) in DMF (200 mL) at 0° C. was added DBU (15.2 mL, 101 mmol) followed by iodomethane (9.47 mL, 152 mmol). The reaction mixture was allowed to stir at 0° C. for 15 min then at rt overnight. The mixture was poured into water and extracted with EtOAc. The organic solutions were combined, washed with brine and dried over MgSO4. The residue was purified by column chromatography to give methyl 4-methoxy-2-nitrobenzoate (50.7 mmol, 85%) as a yellow solid. LCMS (FA): m/z=212.1 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[C:10](Cl)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11].[O-:20][OH:21].C1(C(C)C)C=CC=CC=1.[OH-].[Na+]>>[C:2]([O:20][O:21][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:1])[CH3:3]
Reactant: [O-]O
Reactant: CC(C)(Cl)c1ccccc1
Reactant: C=C(C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)c1ccccc1
Product: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
Into a 100 ml. open-top, jacketed reactor was placed 19.2 g. (0.162 m.) of α-methylstyrene, 4.4 g. (0.0285 m.) of distilled cumyl chloride and 37 g. (0.20 m.) of 82% assay cumene hydroperoxide. The mixture was stirred at 40°±2° C. for 5 hours. The reaction mixture was cooled to 20° and then stirred for 15 minutes with 40 ml. of 20% sodium hydroxide solution. The aqueous layer was discarded. The washing with caustic was repeated twice and the organic layer washed with 50 ml. portions of 20% sodium chloride solution until neutral. The organic layer was added to 400 ml. of water and the mixture distilled at 80-90 mm. on a steam bath until no further oil came over with the water. The pot residue was stirred vigorously and cooled to 0° by adding ice.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:15]1([N:18]2[C:24]3[N:25]=[CH:26][C:27]([CH2:29][CH2:30][OH:31])=[CH:28][C:23]=3[C:22](=[O:32])[NH:21][C:20]3[C:33]([CH3:37])=[CH:34][CH:35]=[N:36][C:19]2=3)[CH2:17][CH2:16]1.O[C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=[CH:41][CH:40]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH:15]1([N:18]2[C:24]3[N:25]=[CH:26][C:27]([CH2:29][CH2:30][O:31][C:39]4[C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[N:42]=[CH:41][CH:40]=4)=[CH:28][C:23]=3[C:22](=[O:32])[NH:21][C:20]3[C:33]([CH3:37])=[CH:34][CH:35]=[N:36][C:19]2=3)[CH2:17][CH2:16]1
Reactant: Cc1ccnc2c1NC(=O)c1cc(CCO)cnc1N2C1CC1
Reactant: Oc1ccnc2ccccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccnc2c1NC(=O)c1cc(CCOc3ccnc4ccccc34)cnc1N2C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
Diisopropyl azodicarboxylate (DIAD) (167 μL, 0.85 mmol) was added drop-wise to a solution of 11-(cyclopropyl)-5,11-dihydro-8-(2-hydroxyethyl)-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (175 mg, 0.57 mmol), 4-hydroxyquinoline (123 mg, 0.85 mmol) and Ph3P (223 mg, 0.85 mmol) in THF (2.8 mL) at room temperature. The mixture was stirred at room temperature for 3 h then was concentrated under reduced pressure. The residue was dissolved in EtOAc (60 mL) and the solution was successively washed with 3 N aqueous NaOH (3×20 mL), aqueous saturated NH4Cl (20 mL) and brine (20 mL) then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:MeOH; 95:5) to give the title compound (74 mg, 30% yield) as a white solid: MS (ESI) m/z 438 (MH)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1)#[N:13].N1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.Cl>[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=C(Cl)c1cccc(I)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CNC(=O)c2cccc(I)c2)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
An aliquot of 3-iodobenzoyl chloride (1.1 g, 4.2 mmol) was taken up in tetrahydrofuran (“THF”, 25 mL), and cooled to approximately 0° C. in an ice-water bath. To the cold solution were added 4-cyanobenzylamine hydrochloride (0.71 g, 4.2 mmol) and pyridine (0.66 g, 8.3 mmol). The solution gradually warmed to room temperature, and was stirred for 72 hours. The reaction mixture was diluted with ethyl acetate (25 mL) and aqueous HCl (25 mL). The organic phase was separated, dried (MgSO4), filtered, and rotary evaporated. The resulting crude product was purified using silica gel chromatography (elution with dichloromethane/THF [9:1]) to give N-(4-cyano-benzyl)-3-iodo-benzamide (0.76 g, 51%) as a white solid. 1H-NMR (DMSO-d6) δ 9.2 (t, 1H), 8.2 (s, 1H), 7.9 (m, 2H), 7.8 (d, 2H), 7.5 (d, 2H), 7.3 (m, 1H), 4.5 (d, 2H) ppm.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:8][C@H:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([CH3:16])[CH:10]=2)[O:6][C:5]1=[O:17])[CH:2]=[CH2:3].[OH-:18].[K+].Cl>O1CCOCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C@H:7]([OH:6])[CH2:8][C@H:4]([CH2:1][CH:2]=[CH2:3])[C:5]([OH:17])=[O:18])=[CH:10][C:11]=1[CH3:16]
Reactant: C=CC[C@H]1C[C@H](c2ccc(F)c(C)c2)OC1=O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: C=CC[C@@H](C[C@@H](O)c1ccc(F)c(C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 150 mg (3S,5R)-3-allyl-5-(4-fluoro-3-methylphenyl)dihydrofuran-2(3H)-one in 5 mL dioxane was added 5 mL aq. 5% KOH at 25° C. The mixture was stirred for 30 min at 25° C. then hydrolyzed with 10 mL of 1M HCl. The resulting mixture was extracted twice with ethyl acetate (10 mL). The combined organic layers were then extracted with 5 mL 5% K2CO3 three times and the combined aqueous layers acidified with 1M HCl to pH3. The resulting mixture was extracted with ethyl acetate (3×30 mL), the combined organic layers washed with brine (2×20 mL) before being concentrated under reduced pressure. The crude product residue was used for the next step without further purification.
Reaction SMILES: CON(C)[C:4](=[O:19])[CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:21][C:22]1[C:23](I)=[CH:24][C:25]([F:28])=[N:26][CH:27]=1>>[Cl:21][C:22]1[C:23]([C:4](=[O:19])[CH2:5][CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:24][C:25]([F:28])=[N:26][CH:27]=1
Reactant: Fc1cc(I)c(Cl)cn1
Reactant: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Product: O=C(CC(c1ccccc1)c1ccccc1)c1cc(F)ncc1Cl

Procedure:
In analogy to example 55, step 2, the title compound was prepared from N-methoxy-N-methyl-3,3-diphenyl-propionamide and 5-chloro-2-fluoro-4-iodopyridine as a light yellow liquid, MS (EI): m/z=339 ([M]+, 1Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[OH-].[Na+]>C(O)C>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:3][C:2]=1[CH3:1].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-n2ccnc2)ccc1N
Product: c1c[nH]cn1

Procedure:
Stannous chloride dihydrate (55.0 g) was added portionwise to a stirred suspension of 1-(3-methyl-4-nitrophenyl)imidazole (10.0 g) in absolute ethanol (100 cm3). After heating under reflux for 4 hours, the cooled mixture was basified to pH8 with aqueous 2.5M sodium hydroxide solution and filtered. The filtrate was evaporated in vacuo, partitioned between chloroform (100 cm3) and water (50 cm3), and the aqueous phase was further extracted with chloroform (3×50 cm3). The combined and dried (MgSO4) extracts were concentrated in vacuo to give a solid which was recrystallised from ethyl acetate to afford 1-(4-amino-3-methylphenyl)imidazole)imidazole, m.p. 131°-134°, (4.7 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=1)(=[O:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:7][CH2:6]2)=O.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[S:24]([NH:23][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][C:14]([NH:13][CH:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:1][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)=[O:37])(=[O:26])=[O:25]
Reactant: C1CCNCC1
Reactant: O=Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Product: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCCc2cc(CN3CCCCC3)ccc21

Procedure:
The title compound was prepared from N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Step G) by reductive amination with piperidine similar to that described in Example 1, Step H. MS (+ESI m/z): 582 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27]([OH:29])=O.[CH3:34][C:35]1[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([C:42]2([NH2:45])[CH2:44][CH2:43]2)[N:36]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:41][C:39]1[CH:40]=[C:35]([CH3:34])[N:36]=[C:37]([C:42]2([NH:45][C:27]([C:26]3[C:25]([O:31][CH3:32])=[CH:24][C:23]([CH3:33])=[C:22]([C:3]4[CH:4]=[CH:5][C:6]5[O:10][C:9]([C:11]6[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=6)=[C:8]([C:18]([NH:19][CH3:20])=[O:21])[C:7]=5[C:2]=4[F:1])[CH:30]=3)=[O:29])[CH2:43][CH2:44]2)[N:38]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Reactant: Cc1cc(C)nc(C2(N)CC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nc(C)cc(C)n5)CC4)c(OC)cc3C)c(F)c12
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (50 mg, 0.11 mmol), crude 1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (100 mg) in 2 ml DMF at room temperature was added BOP (100 mg, 0.22 M, 2.0 eq.) and triethyl amine (0.046 ml 0.33 M, 3.0 eq.), and the mixture stirred overnight under an N2 atmosphere. The mixture was poured into crushed ice, and the solid precipitate was filtered and dried. The product obtained was further purified by preparative HPLC. Yield: 15 mg (24%) 1H NMR (400 MHz, CD3OD): δ 7.97-7.94 (m, 2H), 7.89 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 7.14 (s, 1H), 4.11 (s, 3H), 2.96 (s, 3H), 2.48 (s, 6H), 2.31 (s, 3H), 1.86-1.83 (m, 2H), 1.55-1.52 (m, 2H). 19F NMR (376.57 MHz, CD3OD) δ−77.40 (TFA), −112.33, −122.75 (CFCl3 as reference).