Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:27]5[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:25]([F:24])[CH:26]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cc(F)cc(C(F)(F)F)c1
Yield: 87.5 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (309 mg, 1.00 mmol), 3-fluoro-5-(trifluoromethyl)benzoic acid (312 mg, 1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg, 1.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (437 mg, 88%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[C:26](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[C:31]([F:34])([F:33])[F:32])=[CH:24][CH:23]=2)[CH:29]=[N:28]1)[CH3:13]
Reactant: O=c1[nH]ncn1-c1ccc(OCC(F)(F)C(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 36.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.94 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.16 g of 4-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.68 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[C:14]3[C:22](O)=[O:23])[CH:8]=2)=[CH:4][CH:3]=1.Cl.[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)([CH3:28])[CH3:27].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(N(CC)CC)C>[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:22]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[O:23])[CH2:31][CH2:30]1)([CH3:28])[CH3:27]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1cc2ncccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(NC(=O)c2cc3ncccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reaction time: 16 h

Procedure:
To a suspension of 50 mg 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid, 36 mg 1-isopropyl-piperidin-4-ylamine hydrochloride and 35 mg bis(2-oxo-3-oxazolidinyl)phosphinic chloride in 1 mL dichloromethane, 77 μl triethylamine were added at room temperature and the mixture was stirred for 16 hours. After removing of the solvent under reduced pressure, the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoroacetic acid). The fractions containing the product were evaporated and lyophilized to yield a white residue which was partitioned between 5 mL aqueous 0.1 N sodium hydroxide solution and 5 mL ethyl acetate. The organic layer was washed with additional water and then dried over sodium sulphate. After filtration and removal of the solvent under reduced pressure, a white solid was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>>[CH3:17][O:16][C:7]1[C:6]([O:18][CH3:19])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][NH:25][CH2:24][CH2:23][N:22]([CH2:26][CH3:27])[CH2:20][CH3:21])[N:8]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNCc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12

Procedure:
The title compound can be prepared as described under Example 39 a), that is to say from 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline and 2-diethylaminoethylamine. The title compound is obtained in the form of a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](OS(C)(=O)=O)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH2:1]([C:8]1[N:9]=[CH:10][N:11]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCc1ccccc1
Reactant: c1ccc(Cc2c[nH]cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(CCn2cnc(Cc3ccccc3)c2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-benzyl-1H-imidazole (example 110C) (1.23 g, 7.78 mmoles) in ACN (20 mL) are added K2CO3 (1.29 g, 9.34 mmoles), Cs2CO3 (253 mg, 0.778 mmole) and methanesulfonic acid phenethyl ester (example 4D) (1.86 g, 9.34 mmole). The reaction mixture is heated at reflux overnight, then cooled to room temperature, filtered, cake washed with ACN and filtrate concentrated under reduced pressure. The residue is purified by silica gel chromatography using (toluene:acetone) (90:10) to give 4-benzyl-1-phenethyl-imidazole.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[SH:34][CH2:35][CH2:36][OH:37]>C(Cl)Cl>[OH:37][CH2:36][CH2:35][S:34][CH:2]1[C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: OCCS
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CC2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(SCCO)c1ccccc1CC2
Temperature: 25 °C

Procedure:
In 15.3 ml of methylene chloride was suspended 0.51 g of methyl 5-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate. Under ice cooling, 0.27 ml of trifluoroacetic anhydride was added to the suspension followed by stirring at room temperature for an hour. Then, 0.14 ml of 2-mercaptoethanol was added to the mixture followed by stirring for further an hour. After 10 ml of methylene chloride was added to the reaction mixture, the mixture was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) and recrystallized from toluene to give 0.51 g of the objective compound as light yellow crystals.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([OH:16])[C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:7][CH:8]=1.Br[CH:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:2][C:3]1[CH:4]=[C:5]([O:16][CH:22]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21]2)[C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)C1
Reactant: Cc1csc(Nc2ncc(Br)cc2O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(Nc2ncc(Br)cc2OC2CCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A mixture of 5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ol-hydrochloride (1.0 g, 3.10 mmol), tert-butyl 3-bromopyrrolidine-1-carboxylate (WO 2003/062224) (1.01 g, 4.03 mmol), K2CO3 (1.29 g, 9.30 mmol), and DMF (20 mL) were reacted at 50° C. over the weekend. The reaction was cooled to room temperature, poured into water (250 mL) and extracted with EtOAc:ether (1:1). The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (40% EtOAc in hexanes) to afford tert-butyl 3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidine-1-carboxylate (584 mg, 41.4% yield) as a tan solid. 1H NMR (CDCl3) δ 8.42 (bs, 1H), 8.02 (s, 1 h), 7.10 (d, 1H), 6.42 (s, 1H), 4.95 (m, 1H), 3.75-3.44 (m, 4H), 2.35 (d, 3H), 2.21 (m, 2H), 1.50 (s, 9H); Mass spectrum (apci) m/z=456.9 (M+H).
Reaction SMILES: Br[C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]([CH3:22])=[N:17]2.[CH3:28][Zn]C>O1CCOCC1.C(Cl)Cl>[C:24]([NH:23][C:15]1[C:16]([CH3:22])=[N:17][C:18]2[C:13]([N:14]=1)=[C:12]([C:3]1[NH:4][C:5]3[CH2:10][CH2:9][NH:8][C:7](=[O:11])[C:6]=3[C:2]=1[CH3:28])[CH:21]=[CH:20][CH:19]=2)([CH3:27])([CH3:26])[CH3:25]
Reactant: C[Zn]C
Reactant: Cc1nc2cccc(-c3[nH]c4c(c3Br)C(=O)NCC4)c2nc1NC(C)(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc2cccc(-c3[nH]c4c(c3C)C(=O)NCC4)c2nc1NC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (349) (61 mg, 0.14 mmol), dimethylzinc in hexanes (0.39 mL of 10% wt. in hexanes, 0.570 mmol, Strem Chemicals, Inc.,), and (A-Phos)2PdCl2 (10 mg, 0.014 mmol) in dioxane (1.42 mL) was stirred at 80° C. for 2 h when product was observed via lcms. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-4% of 2 M NH3 in MeOH/DCM to give impure 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one contaminated with starting material. The impure product was purified via SFC [IC (3×15 cm, 5 μm), 60% 0.2% DEA in MeOH: EtOH: isopropanol (1:1:1) (NH4OH)/CO2, 100 bar; 65 mL/min, 220 nm; inj vol.: 1.5 mL, 3.5 mg/mL in MeOH] to give 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (350, 10 mg, 0.028 mmol, 19% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.60 (s, 9H) 2.55 (s, 3H) 2.69 (s, 3H) 2.95 (t, J=6.85 Hz, 2H) 3.61 (td, J=6.85, 2.54 Hz, 2H) 4.79 (s, 1H) 5.18 (br. s., 1H) 7.42 (t, J=7.92 Hz, 1H) 7.68 (dd, J=8.12, 1.27 Hz, 1H) 7.85 (dd, J=7.53, 1.08 Hz, 1H) 11.62 (br. s., 1H). MS (ESI, pos. ion) m/z: 364.2 (M+1).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:37]=[C:23]4[C@@H:24]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[CH2:25][C:26](=C)[CH2:27][CH2:28][N:22]4[N:21]=3)=[CH:15][C:14]=2[O:38][CH3:39])[CH:12]=1>O.C1COCC1.[Cl-].[Na+].O.[Os](=O)(=O)(=O)=O>[Cl:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:37]=[C:23]4[C@@H:24]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[CH2:25][C:26](=[O:2])[CH2:27][CH2:28][N:22]4[N:21]=3)=[CH:15][C:14]=2[O:38][CH3:39])[CH:12]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C1CCn2nc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2[C@@H](c2ccc(F)cc2)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3n(n2)CCC(=O)C[C@@H]3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A solution of sodium periodate (276 mg, 1.29 mmol) in water (5.0 mL) was added over a 10 min period to a vigorously stirred solution of the (R)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-9-(4-fluorophenyl)-7-methylene-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (200 mg, 0.430 mmol, from example 134) and osmium tetroxide (10.9 mg, 0.043 mmol) in THF (5.0 mL). The reaction was stirred for 1 h and then diluted with water (150 mL)/brine (100 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford (R)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (192 mg, 77% yield). LC-MS (M+H)+ 467.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH:8](O)[N:7]1[CH:21]=[O:22])=[O:5])[CH3:2].CO.[H][H]>[Ni].C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:5])[C:6]([NH:7][CH:21]=[O:22])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][C:9]1[C:11]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:17][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(c2ccccc2[N+](=O)[O-])C(O)N1C=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1c[nH]c2ccccc12)(NC=O)C(=O)OCC
Temperature: 25 °C
Yield: 97.9 %

Procedure:
50.0 g (0.13 mol) of the compound of Example 4 in 500 ml. of methanol and 1 ml of acetic acid was hydrogenated in a rocking autoclave at room temperature and 200 psi in the presence of 6 g. of Raney nickel. After the hydrogen uptake (3 equivalents) was complete the filtered reaction mixture was concentrated in vacuo to a volume of 140 ml. Toluene (600 ml.) was added and the remaining methanol was removed by azeotropic distillation. The mixture was heated at reflux for an additional 30 minutes and then allowed to cool to room temperature. The precipitate was collected, washed with toluene and dried to yield 42.3 g (97%) of white crystals, m.p. 179-180° (lit. m.p. 179°). The analytical sample was prepared by recrystallization from ethaniol: m.p. 180-181°.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:28])[N:5]([C:9]([NH:11][CH:12]2[CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([S:22](=[O:25])(=[O:24])[NH2:23])[CH:19]=3)[O:14][CH2:13]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:35][N:36]=[C:37]=[S:38]>CS(C)=O>[CH2:1]([C:3]1[C:4](=[O:28])[N:5]([C:9]([NH:11][CH:12]2[CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([S:22]([NH:23][C:37]([NH:36][CH3:35])=[S:38])(=[O:24])=[O:25])[CH:19]=3)[O:14][CH2:13]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCC1=C(C)CN(C(=O)NC2COc3cc(OC)c(S(N)(=O)=O)cc3C2)C1=O
Reactant: CN=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC1=C(C)CN(C(=O)NC2COc3cc(OC)c(S(=O)(=O)NC(=S)NC)cc3C2)C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2.05 g (5 mmol) of 3-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-6-sulfamoyl-7-methoxychroman, 2.07 g (15 mmol) of finely powdered potassium carbonate and 0.44 g (6 mmol) of methyl isothiocyanate were suspended or dissolved in 20 ml of DMSO. The reaction mixture was stirred at 80° C. for 1 hour. The mixture was poured onto ice-water and the product was precipitated by acidification with hydrochloric acid. After the crude product had been filtered off with suction and dried, it was purified by chromatography over silica gel (eluting agent methylene chloride/glacial acetic acid 19:1). The product had a melting point of 205° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)[CH2:2][CH3:3].[N+:15]([C:18]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[Br:35])=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16].O>CN(C)C=O>[N+:15]([C:18]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[Br:35])=[CH:23][C:19]=1[C:20]([N:10]1[C:11](=[O:12])[C:6]2=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=[C:7]2[C:8]1=[O:9])=[O:21])([O-:17])=[O:16]
Reactant: O=C(Cl)c1cc(Oc2ccc(Br)cc2Br)ccc1[N+](=O)[O-]
Reactant: CCCc1ccc2c(c1)C(=O)NC2=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1ccc2c(c1)C(=O)N(C(=O)c1cc(Oc3ccc(Br)cc3Br)ccc1[N+](=O)[O-])C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of 4-propylphthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-nitro-5-(2,4-dibromophenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-nitro-5-(2,4-dibromophenoxy)benzoyl]-4-propylphthalimide.
Reaction SMILES: C(C[O:4][C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)#N.[NH3:20]>O1CCCC1>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([NH2:20])=[O:4])=[CH:11]1
Reactant: N
Reactant: N#CCOC(=O)CCCCc1c[nH]c2ccccc12
Solvent: C1CCOC1
Product: NC(=O)CCCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
A solution of 5-(1H-indol-3-yl)pentanoic acid cyanomethyl ester (4.5 g, 17.5 mmol) in tetrahydrofuran (110 ml) was added to a 25 percent strength ammonia solution (80 ml) and the mixture was stirred at room temperature for 3 d. Working up of the mixture was carried out by phase separation and extraction of the aqueous phase with tetrahydrofuran (2×30 ml). The organic phases were combined, washed with saturated sodium chloride solution (50 ml), dried and concentrated. The residue was washed with water (2×10 ml) and ether (2×10 ml) and dried. The product remained as a colourless solid in a yield of 68% (2.56 g) with an m.p. of 134-139° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5]>C1COCC1.[OH-].[Na+]>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)Nc1ccc(O)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 60 °C

Procedure:
The methyl 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoate was then dissolved in THF (15 mL) and 3 N NaOH (5 mL). The mixture was heated (60° C., 2 h) and then concentrated and acified to pH 3 with 2 N HCl. The product was extracted with ethyl acetate, and the combined organic extracts were washed with brine and dried over MgSO4. The crude product was purified by silica chromatography (0-15% MeOH/CH2Cl2) to afford 0.3 g of as 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoic acid an orange solid. Mass calculated for C27H37NO4=439.59. found: [M−H]+=438.3.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:17]1[CH:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)C.O>[CH2:3]([N:17]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCn1ccc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCn1ccc(C(=O)O)c1
Yield: 79.9 %

Procedure:
To a solution of 2.58 g (61.3 mmol) of 95% sodium hydroxide in 100 ml of ethanol and 40 ml of water was added 5.43 g (15.3 mmol) of ethyl 1-tetradecylpyrrole-3-carboxylate obtained in Example 56. After the mixture was heated under reflux for 5 hours, the ethanol was removed under reduced pressure and 100 ml of water was added thereto. Then the mixture was acidified with concentrated hydrochloric acid to precipitate crystals, which were extracted with 70 ml and with 50 ml of ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the remaining crystals were recrystallized from hexane to give 3.76 g (79.9% yield) of 1-tetradecylpyrrole-3-carboxylic acid as white crystals, m.p. 66°-67° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].O[N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][N:8]1[C:12](=[O:13])[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]1=[O:18]
Reactant: COCCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Product: COCCCON1C(=O)c2ccccc2C1=O
Yield: 94.9 %

Procedure:
2-(3-Methoxypropoxy)isoindoline-1,3-dione (2C) was prepared from 3-methoxypropan-1-ol and N-hydroxyphthalimide by a procedure analogous to Example 2A, Step 1 (3.71 g, 94.9% yield). ESI-MS: m/z 236.3 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[N:21]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:25]=[CH:24][N:23]=[CH:22]1>>[N:21]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:28][CH:27]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: CCOC(=O)C(Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc(-n2ccnc2)cc1
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-n3ccnc3)cc2)cc1)C(=O)O

Procedure:
3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 173, Step A) and 4-(imidazol-1-yl)phenol were treated under ester J to give the title compound. 1H-NMR (CDCl3, 200.15 MHz): δ 8.11 (s, 1H), 7.31–7.16 (m, 7H), 6.99 (d, 2H, J=8.9), 6.82 (d, 2H, J=8.6), 4.19 (t, 2H, J=6.2), 4.12 (t, 2H, J=5.9), 3.95 (dd, 1H, J=7.3, 4.8), 3.39 (s, 3H), 3.08 (dd, 1H, J=14.4, 4.8), 2.96 (dd, 1H, J=14.2, 7.6), 2.26 (qn, 2H, J=5.9).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:16][CH:15]=2)[C:7]([Cl:12])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:16][CH:15]=2)[C:7]([Cl:12])=[C:8]([CH:10]=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO)c(Cl)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCCc1nc(C=O)c(Cl)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A mixture of 2-butyl-1-[(2'-t-butoxycarbonylbiphen-4-yl)methyl]-5-chloro-1H-imidazole-4-methanol (European Patent Applications 253,310) (145 mg, 319 mmol), MnO2 (550 mg, 6.4 mmol), 3A powdered sieves (500 mg) in CH2Cl2 (10 mL) was stirred at room temperature for 3 hours. The mixture was filtered and evaporated to give 142 mg of the title compound as a glass. 1H NMR (300 MHz, CD3OD)δ 9.82 (s, 1H), 7.70 (dd, 1H, J=7 and 1.5 Hz), 7.50 (td, 1H, J=7 and 1.5 Hz), 7.40 (td, 1H, J=7 and 1.5 Hz), 7.31-7.26 (m, 3H), 7.15 (apparent d, 2H, J=3 Hz), 5.38 (s, 2H), 2.73 (t, 2H, J=7.5 Hz), 1.72-1.62 (m, 2H), 1.45-1.30 (m, 2H) 1.21 (s, 9H), 0.90 (t, 3H, J=7 Hz).