Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.[CH2:20]([O:22]/[CH:23]=[CH:24]/[C:25](Cl)=[O:26])[CH3:21]>C(Cl)Cl.N1C=CC=CC=1>[CH2:20]([O:22]/[CH:23]=[CH:24]/[C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2)=[O:26])[CH3:21]
Reactant: CCO/C=C/C(=O)Cl
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCO/C=C/C(=O)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of (±)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (3.06 g, 12.2 mmol, described in Intermediate 4) in CH2Cl2 (100 mL) and pyridine (40 mL) was added a solution of (E)-3-ethoxyacryloyl chloride [Tietze et al., Synthesis, 1993, 1079-1080] (1.64 g, 12.2 mmol) in CH2Cl2 (100 mL). The resulting mixture was stirred at ambient temperature for 1 h, then concentrated to dryness in vacuo. The residue was suspended in H2O (350 mL) with sonication and the solid was isolated by filtration and dried to give the title compound. MS: m/z=350 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35][CH2:36][CH2:37]O)[CH3:23].C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:37][CH2:36][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: CCc1oc(-c2ccccc2)nc1CCCO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1oc(-c2ccccc2)nc1CCCOc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 79 %

Procedure:
Intermediate 60 was prepared as described above for the preparation of intermediate 52. From 266 mg of N-(Boc)-L-Tyrosine methyl ester and 208 mg of Intermediate 8F was prepared 360 mg of BOC-protected intermediate methyl ester (79% yield; 1H NMR (CDCl3, 300 MHz) δ8.06-8.03 (m, 2H), 7.46-7.44 (m, 3H), 7.04 (d, 2H, J=8.4), 6.85 (d, 2H, J=8.4), 4.97 (d, 1H, J=7.6), 4.57 (m, 1H), 3.99 (t, 2H, J=6.0), 3.74 (s, 3H), 3.05 (m, 2H), 2.77-2.65 (m, 4H), 2.19 (t, 2H, J=6.6), 1.45 (s, 9H), 1.24 (t, 3H, J=7.5); From 352 mg of BOC-protected ester intermediate was prepared the crude TFA salt of intermediate 60. The TFA salt was suspended into water and the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered and dried to yield intermediate 60; 1H NMR (DMSO-d6, 400 MHz) δ7.88-7.85 (m, 2H), 7.48-7.43 (m, 3H), 7.11 (d, 2H, J=8.5), 6.82 (d, 2H, J=8.5), 3.92 (t, 2H, J=6.2), 3.55 (m, 1H), 3.0 (dd, 1H, J=14.3, 4.8), 2.8 (dd, 1H, J=14.3, 7.7), 2.67-2.56 (m, 4H), 2.02-1.96 (m, 2H), 1.13 (t, 3H, J=7.4); low resolution MS (ES+)m/e 392.9 (MH+); TLC Rf=0.44 (4/1, DCM/MeOH).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][N:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:18]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OC1C(OCC2C=CC=CC=2)=C(C(OCC)=O)N(C2C=CC(OC)=CC=2)C=1C([O-])=O)C1C=CC=CC=1.C([NH+](CC)CC)C>CN(C=O)C>[CH2:9]([O:16][C:17]1[C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([I:1])[N:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:18]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)cn1-c1ccc(OC)cc1
Reactant: O=C1CCC(=O)N1I
Agent: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)[O-])n1-c1ccc(OC)cc1
Agent: CC[NH+](CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(I)n1-c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
N-Iodosuccinimide (1.77 g, 7.57 mmol) was added to a solution of ethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (27) [prepared using the same procedure as Example E step (i) using (5) as starting material] (3.0 g, 6.56 mmol) in DMF (60 mL) and stirred at 0° C. for 10 min. The mixture was partitioned between sat. Na2S2O3 (aq.) (100 mL) and Et2O (250 mL), the organic layer was separated and washed with sat. Na2S2O3 (aq.) (100 mL), brine (100 mL) dried (MgSO4), filtered and solvents removed in vacuo. The crude residue was purified by silica gel chromatography (120 g, 0-40% Et2O in isohexane) to afford ethyl 3,4-bis(benzyloxy)-5-iodo-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (28) (2.92 g, 76%) as a white solid: m/z 584 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.51-7.29 (m, 10 H), 7.14-7.05 (m, 2H), 7.03-6.92 (m, 2H), 5.12 (s, 2H), 5.00 (s, 2H), 3.97 (q, J=7.1 Hz, 2H) 3.82 (s, 3H), 0.99 (t, J=7.1 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1COCC1.C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>CCCCCCC>[CH3:21][Si:20]([CH3:23])([CH3:22])[N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: Ic1cn[nH]c1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: C[Si](C)(C)n1cc(I)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a flask equipped with a reflux condenser, a nitrogen inlet, mechanical stirrer, and a thermowell was charged 4-iodopyrazole (14, 200 g, 1.03 mol) and THF (2 L). To this solution was added triethylamine (TEA, 158 mL, 1.13 mol, 1.1 equiv) and the resulting solution was cooled to 0° C. in an ice-brine bath. To this solution was added chlorotrimethylsilane (TMS-Cl, 137 mL, 1.08 mol, 1.05 equiv) with rapid stirring allowing the temperature to reach 18° C. (The reaction becomes very thick and difficult to stir, but becomes manageable after over time). When the exotherm had subsided, the cold bath was removed and the reaction was warmed to room temperature. The reaction was followed by GC and was found to be deemed complete after about 1 hour (Sampling of reaction must be done out of air and diluted with dry solvent to prevent TMS hydrolysis). The reaction mixture was then diluted with heptane (2 L) before being filtered under nitrogen. The solvent was removed from the filtrate under reduced pressure venting the rotovap with nitrogen. The residual oil was diluted with heptane (1 L) and re-concentrated. If the solids formed upon adding the heptane, a second filtration is necessary. The residue was then distilled under the reduced pressure (70-90° C. at about 0.5 Torr) using a Kugelohr to afford 1-trimethylsilyl-4-iodopyrazole (15, 263 g, 274.1 g theoretical, 96%) as a colorless oil. (This material must be kept under nitrogen at all times since the TMS group rapidly hydrolyzes.) Subsequently, we have found that 1-trimethylsilyl-4-iodopyrazole can be prepared by heating the iodopyrazole (14) with 2 equivalents of hexamethyldisilazane for 1 hr.
Reaction SMILES: C1(C2C(OC3C=CC(C4C=CC=CC=4C4N=NNN=4)=CC=3)=[C:12]([C:32]([O:34][CH:35](OC(=O)CC)[CH:36](C)C)=[O:33])[C:11]3C(=CC=CC=3)N=2)CC1.[CH:44]1([C:47]2[C:56]([O:57][C:58]3[CH:63]=[CH:62][C:61]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=4[C:70]4[N:71]=[N:72][N:73]([C:75]([C:88]5[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=5)([C:82]5[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=5)[C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=5)[N:74]=4)=[CH:60][CH:59]=3)=[C:55]([C:94]([OH:96])=[O:95])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:48]=2)[CH2:46][CH2:45]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.C(OCC)(=O)C>[CH:44]1([C:47]2[C:56]([O:57][C:58]3[CH:59]=[CH:60][C:61]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=4[C:70]4[N:71]=[N:72][N:73]([C:75]([C:88]5[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=5)([C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=5)[C:82]5[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=5)[N:74]=4)=[CH:62][CH:63]=3)=[C:55]([C:94]([O:96][CH:35]([O:34][C:32](=[O:33])[CH2:12][CH3:11])[CH3:36])=[O:95])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:48]=2)[CH2:45][CH2:46]1
Reactant: O=C(O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12
Reactant: CCC(=O)OC(OC(=O)c1c(Oc2ccc(-c3ccccc3-c3nn[nH]n3)cc2)c(C2CC2)nc2ccccc12)C(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)OC(C)OC(=O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of the title A compound of Example 28, 2-cyclopropyl-3-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]oxy]-4-quinolinecarboxylic acid (1.55 mmol), the title A compound (1.1 g, 8.05 mmol), potassium carbonate (521 mg, 3.77 mmol), potassium iodide (375 mg, 2.26 mmol), and 18-crown-6 (100 mg, 0.378 mmol) in dimethylformamide (3.7 mL) were heated at 65° C. for 45 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (75 mL) and filtered. The organic filtrate was rinsed with aq. 5% sodium bisulfite and brine, dried (magnesium sulfate), and concentrated in vacuo to give a crude product (2 g). Flash chromatography on silica gel (50 g) eluted with 1 column volume of hexanes followed by 1.8 L of 6:1, hexanes:ethyl acetate yielded the title compound (930 mg, 76%).
Reaction SMILES: [O:1]([CH:8]([OH:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.O.O>[Br:16][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:8]([OH:10])[CH3:9])=[CH:3][CH:4]=1
Reactant: CC(O)Oc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(O)Oc1ccc(Br)cc1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
Phenoxyethanol (440 g, 3.1874 mol) was dissolved in 880 ml of a mixed solution of acetic acid/water =7/3. Sodium acetate (340 g, 4.1436 mol) was added and cooled to 15° C. A solution resulting from dissolving bromine (514.5 g, 3.22 mol) in 1760 ml of a mixed solution of acetic acid/water=7/3 was dropped while keeping at 15-20° C. and then was stirred at 10-20° C. for 30 minutes. Yellow color remained a little. Six milliliter of a 10 W/W% aqueous sodium sulfite solutions was dropped. The mixture became colorless. Dropping 2200 ml of water caused clouding. Crystallization was conducted by addition of seed crystals and stirring at room temperature for 30 minutes. After adding 4400 ml of water, stirring was done at room temperature for 30 minutes and at 0-10° C. for 1.5 hours. The crystals were filtered and washed with 3 L of water. After overnight air-drying and vacuum drying (35-40° C.) for 16 hours, 631 g (Yield 91.3%) of p-bromophenoxyethanol was obtained as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]([S:14]([CH3:17])(=[O:16])=[O:15])S(C)(=O)=O)[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+].[C:66]1([C:72]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[NH:73])[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:5]1[C:4]([NH:9][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:3][C:2]([N:73]=[C:72]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[CH:7][N:6]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)N(c1cc(Br)cnc1Cl)S(C)(=O)=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(N=C(c2ccccc2)c2ccccc2)cnc1Cl
Temperature: 120 °C
Yield: 76.7 %

Procedure:
To a 20 mL microwave reaction tube was added N-(5-bromo-2-chloropyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (Step 0) 1.11 g, 3.04 mmol), xantphos (0.179 g, 0.308 mmol), NaOtBu (1.18 g, 12.3 mmol), Pd2dba3 (0.139 g, 0.152 mmol) and diphenylmethanimine (0.62 mL, 3.7 mmol) in DMF (10 mL). The mixture was degassed by bubbling argon through for 10 min. The tube was heated in Initiator microwave reactor (Biotage) at 120° C. for 30 min. The reaction mixture was partitioned between tris-HCl buffer (1 M, pH 7.0) (80 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×60 mL). The combined organic phases were washed with water (200 mL) and saturated aqueous sodium chloride (150 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100 g, eluent: EtOAc in hexanes 0% to 50%) to afford N-(2-chloro-5-(diphenylmethyleneamino)pyridin-3-yl)methanesulfonamide (0.90 g, 77% yield) as a light brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.72-7.77 (m, 3H) 7.50-7.56 (m, 1H) 7.43 (t, J=7.53 Hz, 2H) 7.32-7.37 (m, 3H) 7.28-7.31 (m, 1H) 7.11-7.16 (m, 2H) 6.66 (s, 1H) 2.78 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]4[O:23][C:24]([NH:27][C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=5)=[N:25][N:26]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1.[OH-].[Na+]>CO>[Cl:34][C:30]1[CH:29]=[C:28]([NH:27][C:24]2[O:23][C:22]([C:19]3[CH:20]=[CH:21][C:15]4[N:14]=[C:13]([C:9]5[C:8]([CH3:35])=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:11][C:10]=5[CH3:12])[NH:17][C:16]=4[CH:18]=3)=[N:26][N:25]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)CCc1cc(C)c(-c2nc3ccc(-c4nnc(Nc5cccc(Cl)c5)o4)cc3[nH]2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CCC(=O)O)cc(C)c1-c1nc2ccc(-c3nnc(Nc4cccc(Cl)c4)o3)cc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(4-{6-[5-(3-chlorophenylamino)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazol-2-yl}-3,5-dimethylphenyl)-propionic acid methyl ester (190 mg, 0.38 mmol) in MeOH (10 mL) was added 1.0 N NaOH (1.14 mL, 1.14 mmol) and the mixture was stirred at RT for 24 h. The solvent was removed under reduced pressure and water was added. The resulting solution was washed with EtOAc and 1.0 N HCl (1.14 mL) was added to the aqueous phase. The mixture was extracted with EtOAc and the organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure and the resulting gum was triturated with MeCN to give the title compound as a beige solid. MS: m/z 488.1 (M+1). H1-NMR (DMSO-d6): δ ppm 12.91 (s, broad, 0.6H), 12.12 (s, broad, 0.7H), 10.93 (s, 0.6H), 8.17-7.95 (m, 1H), 7.90-7.65 (m, 3H), 7.53 (d, J=9.47 Hz, 1H), 7.41 (t, 1H), 7.12-7.05 (m, 3H), 2.84 (t, 2H), 2.59 (t, 2H), 2.10 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[CH2:29]([N:36]1[CH2:40][CH2:39][CH:38](O)[CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:38]4[CH2:39][CH2:40][N:36]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:37]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCN(Cc4ccccc4)C3)cc2)cc1
Yield: 95.2 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), 1-benzyl-3-hydroxypyrrolidine (1.06 g, 6.00 mmol), triphenyiphosphine (1.57 g, 6.00 mmol), and DEAD (6.0 mmol) were converted to product by the procedure of Example 1 to g ive 1.57 g of the title compound. Yield: 95.3%. MS(FD) 549(M+). IR (CHCl3) ν max 3033, 3010, 2971, 2842, 1646, 1599, 1476, 1254, 1167.
Reaction SMILES: C(OC([N:8]1[CH2:26][C@@H:25]([CH3:27])[N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21])=O)(C)(C)C.[ClH:28]>CCOCC.O>[ClH:28].[CH3:27][C@H:25]1[N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9][NH:8][CH2:26]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2c3cccc(OC(F)(F)F)c3C(=O)N12
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: C[C@@H]1CNC[C@H]2c3cccc(OC(F)(F)F)c3C(=O)N12
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(4R,10bR)-1,3,4,10b-tetrahydro-4-methyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one (30 mg, 0.08 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 21 mg of a white solid. MS (ESI) 271 (M−Cl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[N:19]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[N:19]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:10])[F:12])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccc(Cl)n2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3cccc(Cl)n3)n2)CN1

Procedure:
75 mg (0.16 mmol) of the compound of Example 38A is reacted analogously to the synthesis of the compound of Example 1 with 22 mg (0.18 mmol) of 4-imidazolinone-hydrochloride. 65 mg (75% of theory) of the title compound is obtained.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1.[ClH:40]>CO>[ClH:40].[ClH:40].[NH2:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]3([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NCCn1c(=O)n(C2CCN(C3(c4ccccc4)CCCCCC3)CC2)c2ccccc21
Agent: Cl
Solvent: CO
Product: NCCn1c(=O)n(C2CCN(C3(c4ccccc4)CCCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A mixture of t-butyl N-(2-{2-oxo-3-[1-(1-phenylcycloheptyl)-4-piperidyl]-2,3-dihydro-1H-benzimidazol-1-yl}ethyl)carbamate (35 mg, 0.0657 mmol, this was prepared as Preparation 18) and HCl solution in MeOH (2 ml) was stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo to give 33.2 mg (100%) of white solid.
Reaction SMILES: [C:1]([O-])([O-:7])([O:4][CH2:5][CH3:6])[CH2:2][CH3:3].[CH3:9][C:10]([CH3:19])=[CH:11][CH2:12][CH2:13][C:14](O)([C:16]#[CH:17])[CH3:15].C(O)(=O)C(C)C>>[CH3:3][CH:2]([CH:17]=[C:16]=[C:14]([CH3:15])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:19])[CH3:9])[C:1]([O:4][CH2:5][CH3:6])=[O:7]
Reactant: C#CC(C)(O)CCC=C(C)C
Reactant: CCOC([O-])([O-])CC
Solvent: CC(C)C(=O)O
Product: CCOC(=O)C(C)C=C=C(C)CCC=C(C)C
Yield: 98.5 %

Procedure:
In the same manner as in the preceeding Examples, 50 g of ethyl ortho-propionate, 21.6 g of dehydrolinalool and 2.1 g of isobutyric acid were reacted at 135° to 140°C. for 4 hours and the resulting reaction mixture was subjected to distillation under reduced pressure. Ethyl 2,5,9-trimethyl-3,4,8-decatrienoate was obtained in a yield of 98.5% from a fraction boiling at 129 to 130°C. under 2.3 mm Hg.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][N:9](C)[CH2:10]CO.C(Cl)(Cl)Cl.[OH-].[Na+]>C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][N:9]([CH3:10])[CH3:8])(=[O:3])[CH3:2]
Reactant: CN(C)CCO
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCN(C)C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
With gentle cooling, 168.5 g of acetic anhydride are added dropwise to 133.6 g of 2-dimethylaminoethanol in the course of 20 minutes, whereupon the temperature rises from 20° C. to a maximum of 105° C. The reaction mixture is kept for 30 minutes at 100° C. and then cooled. Then 750 ml of CHCl3 are added and the acetic acid formed is neutralised with 380 ml of 20% sodium hydroxide solution at 30°-35° C. with cooling. The two phases are separated and the organic phase is washed with a small amount of H2O. Distillation of the residue affords 151.7 g (77.7%) of product with a boiling point of 114° C./225 torr.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]3[CH:29]=[C:30]([C:34]4[N:38]([CH3:39])[C:37]5[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=5[N:35]=4)[CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:14][CH:15]=3)[C:7]3[CH:29]=[C:30]([C:34]4[N:38]([CH3:39])[C:37]5[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=5[N:35]=4)[CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39](O)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH:39]2[CH2:38][CH2:37][N:36]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:41][CH2:40]2)=[O:11])=[CH:8][N:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc(NC(=O)C(F)(F)F)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cn1
Reaction time: 2 h
Yield: 72.4 %

Procedure:
0.1 g (0.00043 mol) of 6-trifluoroacetamido-nicotinic acid was dissolved in 10 ml of THF, treated with 0.073 g (0.00045 mol) of carbonyldiimidazole and stirred at 60° for 2 hrs. Then, 0.086 g (0.00045 mol) of 1-benzyl-4-hydroxypiperidine was added and the mixture was stirred at 60° overnight. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.097 g (72%) of 1-benzyl-piperidin-4-yl 6-amino-nicotinate was obtained as white crystals; m.p. 135°-136°.