Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:21]=[CH:20][C:15]3[O:16][C:17]([CH3:19])=[CH:18][C:14]=3[CH:13]=2)=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:33]=[C:32](OC/C=C(/C2C=CC(C#CCN3CCOCC3)=CC=2)\C2C=CC=CC=2)[CH:31]=[CH:30][C:24]=1[O:25][CH2:26][C:27]([OH:29])=[O:28].[C:59]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:21]=[CH:20][C:15]3[O:16][C:17]([CH3:19])=[CH:18][C:14]=3[CH:13]=2)=[CH:9]/[CH2:10][O:11][C:32]2[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([O:29][CH3:59])=[O:28])=[C:23]([CH3:22])[CH:33]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(OC/C=C(\c2ccccc2)c2ccc(C#CCN3CCOCC3)cc2)ccc1OCC(=O)O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc2cc(/C(=C\CO)c3ccc(I)cc3)ccc2o1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(I)cc2)c2ccc3oc(C)cc3c2)cc1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The above allyl alcohol (2.20 g, 5.64 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (1.20 g, 6.1 mmol; prepared as in example 2) and triphenylphosphine (1.70 g, 6.48 mmol) were dissolved in a mixture of anhydrous toluene (20 mL) and tetrahydrofuran (10 mL). The mixture was cooled to 0° C., kept under nitrogen and diisopropyl azodicarboxylate (1.50 g, 7.0 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 3 h and then at ambient temperature for 72 h. The solvents were evaporated in vacuo and the residue was submitted to column chromatography (silica gel Fluka 60, benzene) affording methyl (Z)-[4-[3-(4-iodophenyl)-3-(2-methylbenzo[b]furan-5-yl)allyloxy]-2-methylphenoxy]acetate as solid mass.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([C:34]5[NH:35][C:36]6[C:41]([CH:42]=5)=[CH:40][CH:39]=[CH:38][CH:37]=6)[CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[CH3:43][C:44]1[CH:45]=[CH:46][C:47](S(O)(=O)=O)=[CH:48][CH:49]=1.C(=O)C1C=CC=CC=1.O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])[C:18]([C:27]4[CH:28]=[C:29]5[C:34]6[NH:35][C:36]7[C:41]([C:42]=6[CH:43]([C:44]6[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=6)[O:33][C:30]5=[CH:31][CH:32]=4)=[CH:40][CH:39]=[CH:38][CH:37]=7)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(-c4cc5ccccc5[nH]4)c3)cc12
Solvent: O=Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(c3)-c3[nH]c5ccccc5c3C(c3ccccc3)O4)cc12
Temperature: 130 °C
Reaction time: 2 h
Yield: 175.1 %

Procedure:
A mixture of 2-(4-fluorophenyl)-5-(4-hydroxy-3-(1H-indol-2-yl)phenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 g, 0.08 mmol), PTSA (3.0 mg, 0.017 mmol), and benzaldehyde (42 mg, 0.41 mmol) in xylene (2 mL) was stirred at 130° C. for 2 h under microwave. Water was added, extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4. After concentrated, the resulting residue was purified using prep-TLC to provide the product of compound 63 (20 mg, yield: 38%). 1H-NMR (CDCl3, 400 MHz) δ 8.96 (s, 1H), 7.88˜7.92 (m, 2H), 7.76 (s, 1H), 7.65 (s, 1H), 7.50 (s, 1H), 7.32˜7.47 (m, 6H), 7.14˜7.17 (m, 4H), 6.96˜6.99 (m, 2H), 6.86 (s, 1H), 6.55 (s, 1H), 5.91 (d, J=4.8 Hz, 1H), 3.02 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.94 (s, 3H). MS (M+H)+: 672.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:19])[CH:17]=[CH2:18]>CCCCCC.C(OCC)(=O)C>[C:1]([C:9]1([CH2:18][CH2:17][C:16]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCc1ccc(OC)cc1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(COC(=O)CCC2(C(=O)c3ccccc3)CCCCC2=O)cc1
Yield: 65.5 %

Procedure:
The title compound was prepared in 65.5% yield after chromatography (silica gel, hexane/ethyl acetate 4:1) from 2-benzoylcyclohexanone and p-methoxybenzyl acrylate using a similar method to that used in Preparation 2. (M+ 394.13, 53%). Rf. 0.39 (silica, hexane/ethyl acetate 2:1). 1H-NMR (300 MHz, CDCl3):=1.38-1.49 (m, 1H), 1.68-1.82 (m, 3H), 1.98-2.57 (m, 7H), 2.82-2.91 (m, 1H), 3.82 (s, 3H), 5.03 (s, 2H), 6.87 (d, 2H), 7.26 (d, 2H), 7.42 (t, 2H), 7.56 (t, 1H), 7.88 (d, 2H) ppm. Analysis %: Found: C, 73.05; H, 6.74; C24H26 O5 requires: C, 73.08; H, 6.64.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[I:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C1COCC1>[I:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O:1][CH2:2][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][CH:4]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: O=c1cccc(CO)[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1cccc(=O)[nH]1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.2021 g (1.615 mmol) of the 6-hydroxymethyl-2-pyridone was suspended in 15 mL of THF in a 100 mL RBF under the presence of argon gas and was placed in a −80° C. methanol bath. 1.03 mL (1.648 mmol) of BuLi was added dropwise to the reaction which was stirred for 20 min. 0.4374 grams (1.641 mmol) of 4-iodobenzoyl chloride was dissolved in 15 mL of THF and brought to −80° C. before being added dropwise to the reaction mixture. The reaction was allowed to stir at −80° C. for 48 hours before being warmed to room temperature. The reaction was quenched with 20 mL of water and extracted with ethyl acetate (4×20 mL), the organic layers combined and washed with brine (3×20 mL), and dried over MgSO4. The solvent was removed in vacuo to produce a brown solid. The product was purified by crystallization from toluene. The yield of the reaction was 0.032 g (5.58% Yield). MP: 206-208° C. IR (cm−1) 3426.48 (m, broad), υ (O—H), 3126.38 (m, broad), υ (N—H), 1722.45 (m), υ (C═O), 1656.57 (s), 1392.33 (m) υ (C═C aromatic). 1H NMR (DMSO-d6, 500 MHz) δ: 5.12 (s, 2H), 6.35 (d, J=9.1 Hz, 2H), 7.45 (t, J=7.0 Hz, 1H), 7.76 (d, J=4.8 Hz, 2H), 7.94 (d, J=9.0 Hz, 2H), 11.75 (s, 1H). HRMS: m/e, found 377.9598 (M+Na+). Calc. for C13H10INO3Na: 377.9603.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:20])[C:7]([S:18][CH3:19])=[C:8]2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH3:3].[OH:21]O>C(O)C.C(Cl)Cl>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:20])[C:7]([S:18]([CH3:19])=[O:21])=[C:8]2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH3:3]
Reactant: OO
Reactant: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CCO
Solvent: ClCCl
Product: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 18 h

Procedure:
To a solution of allyl (4R,5S,6S)-6-((1R)-1-hydroxyethyl)-4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (100 mg) in ethanol (1.0 ml) was added a 30% aqueous solution of hydrogen peroxide (0.5 ml) and the mixture was allowed to stand at the ambient temperature for 18 hours. The solution was diluted with methylene dichloride and washed with water, 5% aqueous sodium thiosulfate solution and brine successively. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford allyl (4R,5S,6S)-6-((1R)-1-hydroxyethyl)-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=1)[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.[OH-].[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=2)[C:15]([CH:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
4-Fluorobenzoyl chloride (0.98 ml, 8.3 mmol) was added dropwise to a 0° C. solution of 4-[3-aminobenzoyl]-1-methylpiperidine (1.64 g, 7.5 mmol) and triethylamine (1.3 ml, 9.0 mmol) in tetrahydrofuran (20 ml). The reaction mixture stirred 2 h at room temperature, diluted with ethyl acetate and 1N sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, brine, then dried over sodium sulfate. Solvent was removed under reduced pressure to give 2.5 g (98%) of a foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(OCC)(=O)C>[C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc(Br)cc1)c1ccccc1
Yield: 86.7 %

Procedure:
To a solution of 360 g of 4-bromophenol in 4.3 liters of ethyl acetate, was added 326 ml of triethylamine. To the mixture, while being cooled in ice and stirred, was added dropwise 300 g of benzoyl chloride over a period of 90 minutes. After two hours of stirring, water was added to the reaction mixture to remove the triethylamine hydrochloride. The ethyl acetate layer was washed successively with a dilute aqueous alkali solution, dilute hydrochloric acid, and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and freed from the solvent by distillation. The residue was washed with ethanol and dried to obtain 500 g of 4-bromophenyl benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:47](O)(=[O:50])[C:48]#[CH:49].O>C(Cl)(Cl)Cl>[Cl:25][C:24]1[C:23]([O:26][CH3:27])=[CH:22][C:21]([O:28][CH3:29])=[C:20]([Cl:30])[C:19]=1[NH:18][C:16](=[O:17])[N:15]([C:11]1[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:47](=[O:50])[C:48]#[CH:49])[CH:10]=1)[CH3:31]
Reactant: C#CC(=O)O
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C#CC(=O)Nc1ccccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
The compound was synthesized following the approach outlined in Procedure 2C (Example 108) modifying step (g) to the following procedure: To a solution of 1-[6-(2-amino-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-urea (50 g, 0.108 mmol) and DCC (46 g, 0.22 mmol) in chloroform (50 mL) was added a solution of propiolic acid (16 mg, 0.22 mmol) in chloroform (50 mL) at 0° C., and the resulting mixture was stirred at room temperature overnight. Water (1 mL) was added to quench the reaction. The mixture was concentrated and the residue was purified by reverse phase column and prep-TLC to obtain the title compound (5 mg, yield: 9.1%). 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 10.36 (s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 7.30-7.25 (m, 2H), 6.96 (s, 1H), 6.50 (s, 1H), 4.42 (s, 1H), 4.00 (s, 6H), 3.35 (s, 3H); MS (ESI): 515 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[N:11]1.CN(C)C=O.[Br:33]Br>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([Br:33])[C:12]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[N:11]1
Reactant: O=C(NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1)c1cccc([N+](=O)[O-])c1
Reactant: BrBr
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br)c1cccc([N+](=O)[O-])c1
Yield: 96.6 %

Procedure:
428 g (1.0 mol) of 1-(2,4,6-trichlorophenyl)-3-(3-nitrobenzamido)-5-oxo-2-pyrazoline was added to 2.2l of dimethylformamide and the mixture was stirred under cooling with ice. Next, 160 g (1.0 mol) of bromine was added dropwise, followed by stirring for about 1 hour. The reaction solution was then poured into 9 l of water, and thereafter the precipitated crystals were filtered to obtain 489.5 g (96.6 %) of 1-(2,4,6-trichlorophenyl)-3-(3-nitrobenzamido)-4-bromo-5-oxo-2-pyrazoline.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@H:23]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[CH2:49]([O:48][CH:47]([O:51][CH2:52][CH3:53])[C@@H:46]([N:34]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[C:32](=[O:33])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH3:54])[CH3:50]
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 94 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-4-oxobutanoate (Compound IV-16) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](O)=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1>ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[CH2:10][CH2:11][O:12][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:17]([NH2:16])=[N:18][CH:19]=[CH:20]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CCO
Reactant: Nc1nccc2cc(O)ccc12
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CCOc1ccc2c(N)nccc2c1

Procedure:
This compound was prepared from N-tert-butoxycarbonyl-L-β-homoprolinol [Leyendecker, F.; Jesser, F.; Laucher, D.; Tetrahedron Lett. 1983, 24, 3513-3516; 590 mg, 2.75 mmol] and 1-amino-6-hydroxy-isoquinoline (1e, 320 mg, 2.0 mmol) by the Mitsunobu procedure described in Example 1f. Yield: 650 mg (91%). ESI-MS: 358.0 (M+H)+. Rf (silica gel; dichloromethane/methanol, 9:1, v/v): 0.37.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[N+:31]([O-:33])=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[C:22]([N+:31]([O-:33])=[O:32])[CH:23]=2)(=[O:28])=[O:29])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Product: CCOC(=O)C1=CN(S(=O)(=O)c2ccc(C)c([N+](=O)[O-])c2)CCc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 70 by using ethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-methyl-3-nitrobenzenesulfonyl chloride (˜3.4 mg); MS (ES): 456 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[C:8]3[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH2:13][CH2:14][CH3:15])[C:7]=3[O:6]N=2)[CH2:3][CH2:2]1.ClC1C=C(CC(OC)=[O:31])C=CC=1NCCCBr.C(=O)([O-])[O-].[Cs+].[Cs+].CCCCCC.C(OCC)(=O)C>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]([C:8]2[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH2:13][CH2:14][CH3:15])[C:7]=2[OH:6])=[O:31])[CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(NCCCBr)c(Cl)c1
Reactant: CCCc1c(O)ccc2c(C3CC3)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCc1c(O)ccc(C(=O)C2CC2)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 128.1 %

Procedure:
To a solution of 3-cyclopropyl-6-hydroxy-7-propylbenz-[4,5]-isoxazole (34 mg, 0.156 mmole) and methyl 3-chloro-4-(3-bromopropylamino)phenylacetate (Example 21, Step C, 50 mg, 0.156 mmole) in DMF (0.70 mL) was added cesium carbonate (54 mg , 0.164 mmole), and the mixture stirred at 80° C. in a nitrogen atmosphere for 2 hours. The cooled mixture was dissolved in ethyl acetate and washed with water, brine, dried over magnesium sulfate and concentrated in vacuo to give an oil. Thin layer chromatography on silica gel eluting with hexane:ethyl acetate (2:1) afforded the title compound (44 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@H:19]1[CH2:24][CH2:23][C@H:22](/[CH:25]=[C:26](\[CH3:29])/[CH2:27][OH:28])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:18][C@H:19]1[CH2:20][CH2:21][C@H:22](/[CH:25]=[C:26](\[CH3:29])/[CH:27]=[O:28])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: C/C(=C\[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C/C(C=O)=C\[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a -78° C. solution of oxalyl chloride (105 μL, 1.2 mmol) in 1.0 mL of methylene chloride was added dimethylsulfoxide (170 μL, 2.4 mmol). The resulting solution was stirred for 5 min and then 170 mg (0.6 mmol) of the alcohol 135 was added in 1.0 mL of methylene chloride. The reaction mixture was stirred at -78° C. for 45 min at which time 500 μL (3.6 mmol) of triethylamine was added and the solution was allowed to warm to ambient temperature. The reaction was quenched with 1.0N HCl and the aqueous layer was extracted with three portions of methylene chloride. The combined organic extracts were dried over MgSO4 and evaporated to dryness to give the crude aldehyde 136 which was used directly in the next reaction. 1H NMR consistent with structure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([OH:14])=O)=[C:7]([Cl:15])[CH:6]=[CH:5][C:4]=2[N:3]=1.C[N:17]([CH3:20])C=O.[C:21](Cl)(=[O:25])[C:22](Cl)=O>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:17][CH2:20][C:21]3([OH:25])[CH2:22][CH2:6][CH2:5][CH2:4][CH2:9][CH2:8]3)=[O:14])=[C:7]([Cl:15])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(NCC1(O)CCCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2,6-dichloroquinoline-5-carboxylic acid (40.0 g) (WO2004/106305, Example 76, step b) under nitrogen at room temperature in dichloromethane (600 ml) was added dimethylformamide (0.13 ml) and oxalyl chloride (36.2 ml) dropwise over 2 hours in 3 portions. The mixture was then stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, dichloromethane (400 ml) was added and the mixture was added dropwise to a solution of 1-(aminomethyl)cycloheptanol hydrochloride (32.7 g) (W. C. Vincek, C. S. Aldrich, R. T. Borchardt and G. L. Grunewald, J. Med. Chem., 1981, 21(1), 7-12) and triethylamine (69.1 ml) in dichloromethane (600 ml) at 0° C. over 15 minutes. The mixture was stirred for 1 hour and then water (400 ml) was added. The mixture was filtered under vacuum and the solid washed sequentially with water (2×400 ml), acetonitrile (400 ml) and diethyl ether (400 ml), then dried in vacuo to afford the subtitle product as a colourless solid (59.0 g).
Reaction SMILES: C1(O)C=CC=CC=1.BrCCCCCCCCCCCO.[O:21]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O(CCCCCCCCCCC(O)=O)C1C=CC=CC=1.Cl.Cl.[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH2:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>>[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH:77][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:73][N:74]([CH3:75])[CH3:76])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: OCCCCCCCCCCCOc1ccccc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(O)CCCCCCCCCCOc1ccccc1
Agent: OCCCCCCCCCCCBr
Solvent: Oc1ccccc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCCOc1ccccc1

Procedure:
The title compound, m/e=405.7 ([M−H]−), was produced in analogy with example 18, steps 1 to 4. Thus, phenol was alkylated in step 1 with 11-bromo-1-undecanol, leading to 11-phenoxy-undecan-1-ol, which was oxidized in step 2 to 11-phenoxy-undecanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[11-phenoxy-undecanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: O[CH:2]([C:18]1[N:19]=[CH:20][N:21](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:22]=1[CH3:23])[CH:3]1[C:15](=[O:16])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:17])[C:6]=2[CH2:5][CH2:4]1.O.C1(C)C=CC(S(O)(=O)=[O:51])=CC=1.[C:55]([OH:58])(=[O:57])[CH3:56]>>[C:15]([OH:16])(=[O:51])/[CH:3]=[CH:56]\[C:55]([OH:58])=[O:57].[CH3:17][N:7]1[C:6]2[CH2:5][CH2:4]/[C:3](=[CH:2]\[C:18]3[N:19]=[CH:20][NH:21][C:22]=3[CH3:23])/[C:15](=[O:16])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: Cc1c(C(O)C2CCc3c(c4ccccc4n3C)C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)O
Solvent: O
Product: Cc1[nH]cnc1/C=C1\CCc2c(c3ccccc3n2C)C1=O
Product: O=C(O)/C=C\C(=O)O

Procedure:
A solution of 1,2,3,9-tetrahydro-3-[hydroxy[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-9-methyl-4H-carbazol-4-one (2.7070 g) in glacial acetic acid (100 ml) was treated with p-toluenesulphonic acid monohydrate (10.80 g) and the stirred solution heated at reflux for 4 h. The cool, dark liquid was evaporated, treated with aqueous saturated sodium bicarbonate (250 ml) and extracted into ethyl acetate (4×250 ml). The combined, dried organic extracts were evaporated, and purified by SPCC. Elution with System A (978:20:2→945:50:5) afforded the free base of the title compound as a light yellow-brown solid (488 mg). A hot solution of the free base (87 mg) in ethanol (ca. 16 ml) was treated with a hot solution of maleic acid (38 ml) in ethanol (1 ml), and on cooling the precipitate was collected to give the title compound (81 mg), m.p. 205°-209° C.