Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[O-:16][C:17]#[N:18].[K+].C(O)(=O)C>O1CCOCC1.O>[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[C:17]([NH2:18])=[O:16])=[CH:15][CH:14]=1)#[N:13]
Reactant: N#C[O-]
Reactant: N#Cc1ccc(OCCNCCO)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc(OCCN(CCO)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(2-hydroxyethylamino)ethoxy]benzonitrile (5 g, 0.0242 mol; see Preparation C(ii) above) in dioxane (65 mL) and water (65 mL) was added, at rt, potassium cyanate (4.92 g, 0.0606 mol), followed by acetic acid (4.36 g, 0.0726 mol). The reaction mixture was then stirred at rt overnight, before being concentrated under reduced pressure. The resulting residue was partitioned between water and dichloromethane. The organic layer was separated, washed with water and brine, dried over sodium sulfate and then concentrated. The crude product was further purified by column chromatography. Yield: 3.5 g.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][N:28]2[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)[CH:17]=[C:12]3[CH:11]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH2:34][CH2:33]1
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC2CC2)CC1
Yield: 51 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-h]pyridin-2-yl]-methanone (example 13), sodium hydride and cyclopropylmethyl bromide, to give the desired product as a light brown oil (51%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[C:10]=1[F:19])C1C=CC=CC=1>CO.C1COCC1.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:19])[C:11]=1[F:18]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(O)c(F)c1F
Temperature: 32 °C
Reaction time: 13 h
Yield: 840.2 %

Procedure:
To a suspension of 1-(benzyloxy)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) in CH3OH (45 mL) and THF (9 mL) was added Pd/C (333 mg, 6% Pd content, 53%˜55% water content). The mixture was stirred at 32° C. for 13 hours under H2 atmosphere. The mixture was filtered through a CELITE® pad, which was washed with 50 mL of EtOAc. The filtrate was concentrated in vacuo, washed with 30 mL of CH2Cl2 to give the title compound as a dark brown solid (0.89 g, 84%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C@@H:8]([OH:9])[C@@H:7]([OH:10])[CH:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13]>CO>[CH3:1][O:2][C@@H:3]1[C@@H:4]([OH:13])[C@@H:5]([OH:12])[C@H:6]([OH:11])[C@H:7]([OH:10])[C@H:8]1[OH:9]
Reactant: COC1[C@@H](O)[C@@H](O)C(O)[C@H](O)[C@H]1O
Solvent: CO
Product: CO[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 70 °C
Yield: 47.4 %

Procedure:
3-O-methyl-D-chiro-inositol (D-pinitol) (283 mg, 1.457 mmol, 1 equiv) was dissolved in methanol (15 mL), then 1,2-cyclohexane diacetal (507 mg, 2.458 mmol, 1.7 equiv), trimethyl orthoformiate (200 mL, 1.752 mmol, 1.2 equiv) and 1-(S)-(+)-10-camphorsulfonic acid (24 mg, 0.102 mmol, 0.07 equiv) were added. The reaction mixture was heated at 70° C. for 24 h whereupon it was diluted with MeOH and quenched with solid NaHCO3. The residue was concentrated and purified by flash chromatography (Hex/EtOAc 1:15) to give 6 (222 mg, 0.664 mmol, 45%; 89% based on 134 mg of recovered D-pinitol). Rf(Hex/EtOAc 1:20):0.22; [α]20D −22.9 (c=1.05, CHCl3); 1H NMR (CDCl3, 300 MHz): d=4.12 (Ys, 1H, H1), 4.10 (s, 2H, H4, H5), 4.07 (Ys, 1H, H6), 3.81 (dt, 1H, J2-3=9.0 Hz, J2-1=3.6 Hz, J2-OH=1.8 Hz, H2), 3.47 (t, 1H, J=9.0 Hz, H3), 3.23 (s, 3H, OCH3), 3.21 (s, 3H, OCH3), 2.76 (d, 1H,JOH-2=1.8 Hz, OH2), 2.60 (s, 1H, OH1), 2.56 (s, 1H, OH−6), 1.86-1.78 (m, 1H, CDA), 1.77-1.66 (m, 3H, CDA), 1.57-1.50 (m, 2H, CDA), 1.42-1.34 (m, 2H, CDA); 13C-NMR (CDCl3, 75 MHz); d=98.9 (C), 98.0 (C), 80.2 (C3), 71.5(C2), 70.8, 70.4, 70.3 (C1, C4, C6), 68.7 (C5), 61.1 (OCH3), 47.0(OCH3, CDA), 46.8 (OCH3, CDA), 27.1 (CH2), 27.0 (CH2), 21.5 (CH2), 21.4 (CH2); HRFABMS Calcd. for C15H26O8: 357.3571 found: 357.1528; MALDI-TOF Calcd. for C15H2O8+Na+: 357.4. found: 357.5. calcd. for C15H26O8+K+: 373.5. found: 374.1
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([S:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[NH:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: Sc1ccccc1
Product: N=C(Sc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and thiophenol, there is obtained phenyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-thiocarboximidate as a syrup, mass spectrum m/e: M+ 330 (3), 220 (70), 179 (100), 165 (85), 110 (74);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=2)=[O:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.CO.[OH-].[Li+].Cl>O1CCCC1.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:29])[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)=[O:14])[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[CH2:7][C:6]=2[CH:12]=1
Reactant: CCOC(=O)C(C)Cc1ccc(NC(=O)c2cc(F)cc3c2OC(C)(C)C3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1ccc(NC(=O)c2cc(F)cc3c2OC(C)(C)C3)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (803) (Compound was prepared in a similar manner as that described for the synthesis of (735) (101.3 mg, 0.482 mmol) was dissolved in dichloromethane (4 mL) and ethyl 3-(4-aminophenyl)-2-methylpropanoate (646) (100 mg, 0.482 mmol), triethyl amine (0.4 mL, 2.89 mmol), and 1-propanephosphonic acid cyclic anhydride (0.34 mL, 0.58 mmol, 50% in ethyl acetate) were added and stirred overnight at room temperature. The reaction was purified in vacuo and purified by flash column chromatography on silica gel with hexanes and EtOAc to give ethyl 3-(4-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoate. The ester was dissolved in tetrahydrofuran (1.0 mL), methanol (1.0 mL) and water (3 mL). Lithium hydroxide was added and the reaction was stirred at room temperature for 4 h. The mixture was acidified with 1M HCl and diluted with EtOAc (3 mL). The organic layer was washed with brine (3 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 3-(4-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoic acid (97). 1H NMR (400 MHz, CDCl3) δ 9.53 (br, 1H), 7.66 (dd, J=9.9, 2.6 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.02 (dd, J=9.9, 2.6 Hz, 1H), 3.13-3.00 (m, 3H), 2.72 (m, 2H), 1.60 (s, 6H), 1.19 (d, J=8.0 Hz, 3H).
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:3]=1[C:24]#[N:25].[C:26]([O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:26]([O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([C:2]2[N:11]=[C:10]3[N:4]([CH2:5][CH2:6][C:7]4[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=4[CH:9]3[O:12][CH:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[C:3]=2[C:24]#[N:25])=[CH:34][CH:33]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN1CCC(OC2c3ccccc3CCn3c2nc(I)c3C#N)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccc(C(=O)OC(C)(C)C)cc2)c3C#N)CC1
Temperature: 85 °C

Procedure:
To a solution of 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carbonitrile (example 221) (215 mg, 0.48 mmole) in THF (3 mL) are added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid tert-butyl ester (191 mg, 0.63 mmole), 1M aqueous K2CO3 (2 mL) and PdCl2(dppf)2 (20 mg). The flask is evacuated and filled with argon. The reaction mixture is heated at 85° C. for 24 hours. AcOEt is added and the organic phase is washed with water, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) (100:0) to (95:5) to give 4-[1-cyano-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-benzoic acid tert-butyl ester melting at 95° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[O:10][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[CH:17]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: COc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(COc2c(Br)cc(C=O)cc2[N+](=O)[O-])c1
Reaction time: 17 h

Procedure:
To a solution of 3-bromo-4-hydroxy-5-nitro-benzaldehyde (87.4 mg) in dry dichloromethane (7.5 ml) was added 3-methoxybenzyl alcohol (35 μl), triphenylphosphine (103 mg) and diethyl azodicarboxylate (45 μl). The mixture was stirred under a nitrogen atmosphere for 17 h and then concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 9/1→1/1 (v/v) as eluent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([C:17]([OH:19])=O)[C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:26]C=2C=1.CN1CCOCC1.C(Cl)CCl.[OH-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1([C:17](=[O:19])[NH2:26])[C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CC12CCCC2
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC1(C(N)=O)CC12CCCC2
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of 1-(tert-butoxycarbonylaminomethyl)-spiro[2.4]heptane-1-carboxylic acid (12.5 g, 46.6 mmol) in THF (450 mL) was added HOBT (6.6 g, 48.9 mmol), 4-methylmorpholine (5.4 mL, 48.9 mmol) and EDC (9.83 g, 51.3 mmol). The reaction mixtured was stirred for 3 hours and then concentrated aqueous ammonium hydroxide (6.3 mL, 93.2 mmol) was added. The reaction mixture was stirred for 48 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (500 mL) and half saturated potassium hydrogen sulfate solution. The layers were separated. The organic layer was washed with half saturated potassium hydrogen sulfate, saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated to give 9.7 g (78%) of (1-carbamoyl-spiro[2.4]hept-1-ylmethyl)-carbamic acid tert-butyl ester as a white solid: 1H NMR (300 MHz, CDCl3) δ 0.74 (d, J=4.5 Hz, 1H), 1.38 (d, J=4.5 Hz, 1H), 1.44 (s, 9H), 1.6-1.8 (m, 7H), 1.83 (m, 1H), 3.15 (dd, J=5.1, 14.8 Hz, 1H), 3.65 (dd, J=5.1, 14.8 Hz, 1H), 5.0 (br s, 1H), 5.49 (br s, 1H), 6.45 (br s, 1H); MS (APCI) m/z 169 [M+H-100(Boc)]+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Br[CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.O>CN(C)C=O.C(OCC)C>[CH:8]1([S:1][CH2:2][CH2:3][OH:4])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: OCCS
Reactant: BrC1CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: OCCSC1CCCCCC1
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
2.32 g of 2-mercaptoethanol, dissolved beforehand in 10 cm3 of dimethylformamide, were slowly added, under an inert atmosphere and at a temperature in the region of 20° C., to a stirred suspension of 0.91 g of 60% sodium hydride in 10 cm3 of anhydrous dimethylformamide. After stirring for 20 minutes, 3.5 g of bromocycloheptane, dissolved in 10 cm3 of dimethylformamide, were added. The reaction was brought to completion by stirring at a temperature in the region of 20° C. for 1 hour 30 minutes. The reaction mixture was poured onto 150 cm3 of water to which have been added 100 cm3 of diethyl ether. The ethereal phase was separated by settling and the aqueous phase was extracted once with 50 cm3 of diethyl ether. The organic phases were combined and then washed with 2 times 100 cm3 of water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 3.2 g of 2-hydroxyethyl cycloheptyl sulfide were obtained in the form of an oil with a yellow color.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35](=[O:52])[CH2:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=1)[CH3:33]>>[CH2:32]([O:34][C:35](=[O:52])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:15])[C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=4)[CH:20]=3)=[CH:6][CH:7]=2)=[CH:39][CH:38]=1)[CH3:33]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2cccc(C(F)(F)F)c2)nn1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(O)c3cn(Cc4cccc(C(F)(F)F)c4)nn3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]1([OH:13])[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.[I:14]I>O>[I:14][C:7]1[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:6]=1[OH:13]
Reactant: Oc1cccc(O)c1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1cccc(O)c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
Add sodium bicarbonate (27.9 g, 333 mmol) to a solution of benzene-1,3-diol (33.0 g, 300 mmol), and iodine (81.5 g, 321 mmol) in water (225 mL) chilled to 0° C. and stir. Warm the solution to ambient temperature gradually over 1 hour. Extract with diethyl ether, combine organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield a white solid. Triturate the solid in chloroform (100 mL) chilled to −10° C. After 30 minutes, filter the precipitate, washing with cold chloroform to yield the title compound as a white solid (49.0 g, 69%): 1H NMR (DMSO-d6) δ 6.33 (d, 2H), 6.93 (t, 1H), 10.03 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[NH2:16][C:17]([CH2:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[O:20]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:16][C:17]([CH2:23][CH3:24])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:10](=[O:12])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCC(N)=CC(=O)OC
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Product: CCc1[nH]c(-c2ccc(Cl)cc2)cc(=O)c1C(=O)OC

Procedure:
2.00 g (8.82 mmol) of ethyl 3-(4-chlorophenyl)-3-oxopropanoate and 1.25 g (9.71 mmol) of methyl 3-aminopent-2-enoate [Pena et al., J. Am. Chem. Soc. 124, 14552-14553 (2002)] were taken up in 12 ml of xylene, 3.50 g molecular sieve (4 Å) which had been dried by heating were added and the mixture was reacted at reflux temperature overnight. The molecular sieve was removed by filtration and washed with methanol/chloroform (1/1). The combined organic phases were concentrated on a rotary evaporator and the crude product was purified by preparative MPLC (Biotage 40M cartridge; mobile phase: isohexane/ethyl acetate 4/1). This gave 550 mg (21% of theory) of the target compound.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:54]([O:61][C:62]1[CH:70]=[CH:69][C:65]([C:66](O)=[O:67])=[CH:64][N:63]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C=O)C.O>[CH2:54]([O:61][C:62]1[CH:70]=[CH:69][C:65]([C:66]([NH:11][CH2:12][C:13](=[O:14])[N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]2)=[O:67])=[CH:64][N:63]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(OCc2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 45.1 %

Procedure:
DIPEA (253 mg, 0.34 mL, 1.9 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (184 mg, 0.52 mmol) in DMF (4 mL). HOBT (64.8 mg, 0.479 mmol) and EDCI (167 mg, 0.87 mmol) were then added at room temperature. After 2 minutes, 6-benzyloxy-nicotinic acid (100 mg, 0.43 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 102 mg (45.33% yield) 6-benzyloxy-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-nicotinamide. LCMS Purity: 98.91%. 1H NMR (DMSO-d6): δ 8.7 (d, 2H), 8.2-8.1 (d, 1H), 7.9-7.64 (m, 5H), 7.62-7.5 (m, 1H), 7.5-7.3 (m, 3H), 7.0-6.9 (d, 1H), 5.4 (s, 2H), 4.24-4.06 (d, 2H), 3.8-3.56 (m, 4H), 3.54-3.4 (m, 2H), 3.2-3.02 (m, 2H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1([NH:13][C:14]([C:16]2[O:17][C:18]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]>O.O1CCCC1.CO>[C:26]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:18]2[O:17][C:16]([C:14]([NH:13][C:8]3([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])=[CH:20][CH:19]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(COc3ccc(-c4ccccc4)cc3)o2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(NC1(C(=O)O)CCCC1)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A solution of lithium hydroxide monohydrate (0.085 g, 2.0 mmol) in water (1 mL) was added to a solution of 1-{[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-amino}-cyclopentanecarboxylic acid methyl ester (0.092 g, 0.22 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL). The mixture was stirred overnight at room temperature and then the solvents were evaporated under reduced pressure. 0.5 M NaOH was added and the solution was extracted with ether. The aqueous layer was acidified with 1 M HCl and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered, and evaporated to give 1-{[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-amino}-cyclopentanecarboxylic acid (61 mg, 69%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]=[CH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:45])C=1.CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH:28]([CH2:29][CH2:30][C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[O:45]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=CCCc4ccccc4)cc3)cc2)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4OC4CCc4ccccc4)cc3)cc2)CC1
Reaction time: 8 h

Procedure:
1-{4′-[3-Methyl-4-(4-phenyl-but-1-enyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.343 g, 0.718 mmol) and m-chloroperbenzoic acid (0.181 g, 0.79 mmol) were stirred in CH2Cl2 overnight. An additional portion of m-chloroperbenzoic acid was added and the reaction stirred overnight again. Standard aqueous workup and silica gel chromatography (0-100% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]2=[C:10]([C:27]#[N:28])[N:11]=1)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1F
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1F

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 496 (M+H)+.