Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.C[O:7][C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1>>[NH:21]1[CH:22]=[CH:23][N:24]=[C:20]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([OH:25])=[O:7]
Reactant: COC(=O)CCCCCCCCCCCc1ncc[nH]1
Agent: c1c[nH]cn1
Product: O=C(O)CCCCCCCCCCCc1ncc[nH]1

Procedure:
To this end, 12-bromo-1-dodecanol is oxidized with Jones' reagent to form 12-bromo-1-dodecanoic acid. Then the white solid acid is esterified with diazomethane to form the corresponding methyl ester. The methyl ester is treated directly with imidazole and reacted at 80° C. for five hours until it forms 12-imidazolyl-1-dodecanoic acid methyl ester. The thick mass, which is obtained in this way, is split between water and dichloromethane; and the organic phase is dried over Na2SO4 and concentrated by evaporation. The oily residue is cleaned chromatographically on silica gel and then dissolved in a mixture of methanol and tetrahydrofuran (3:4), treated with LiOH.H2O, and the mixture is heated under reflux for two hours. Following evaporation of the solvent, the white residue is dissolved again in water, extracted with dichloromethane, acidified to a pH 5-6, and extracted again with ethyl acetate. The ethyl acetate extract is dried over Na2SO4, filtered and concentrated by evaporation. The white solid is recrystallized from methanol/ether and yields 12-imidazolyl-1-dodecanoic acid.
Reaction SMILES: C1(N2CCCN([C:12]([CH:14]3[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:15]3)=[O:13])CC2)CCC1.O=S(Cl)Cl.[N:32]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:21]([O:20][C:18]([N:16]1[CH2:17][CH:14]([C:12]([N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:33][CH2:34]2)=[O:13])[CH2:15]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)C2CN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a stirred solution of benzyl 3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidine-1-carboxylate (1.0 g, 4.25 mmol) in DCM (20 mL) was added SOCl2 (0.754 g, 0.460 mL, 6.38 mmol) and the resulting mixture was stirred for 2 hours at room temperature. LCMS analysis showed incomplete conversion so a further 1.0 eq of SOCl2 (501 mg, 305 μL) was added and the reaction stirred for a further 19 hours. Volatiles were removed at reduced pressure and the crude acid chloride dissolved in DCM (10 mL) and added dropwise to a solution of tert-butyl 1,4-diazepane-1-carboxylate (0.658 g, 5.10 mmol, 1.2 eq) and DIPEA (1.67 g, 12.75 mmol, 3.0 eq) in DCM (10 mL) at 0° C. The resulting solution was stirred at room temperature for 17 hours and then quenched by addition of NaHCO3 (5 mL). The reaction was diluted with DCM (10 mL) and the phases separated. The organic was washed with brine (5 mL), dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with 98:1.2:0.8 to 97:2.7:0.3 gradient of DCM/MeOH/NH3) gave the title compound (1.54 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]([O:16][CH3:17])=[C:4]([O:18][CH3:19])[CH:3]=1.[C:20]([N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:23]1)#[N:21].O.Cl>CS(C)=O.C(OCC)(=O)C>[NH2:9][C:8]1[C:7]2[C:2](=[CH:3][C:4]([O:18][CH3:19])=[C:5]([O:16][CH3:17])[C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:1]=[C:20]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:23]2)[N:21]=1
Reactant: COc1cc(N)c(C#N)c(-c2ccccn2)c1OC
Reactant: CS(=O)(=O)Nc1cccc2c1CCN(C#N)C2
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2nc(N3CCc4c(cccc4NS(C)(=O)=O)C3)nc(N)c2c(-c2ccccn2)c1OC
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a stirred solution of 6-amino-3,4-dimethoxy-2-(2-pyridyl)benzonitrile (see Example 2 or 2A, 7 g, 27 mmol) and N-(2-cyano-1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide (see Example 3 or 3A, 9 g, 36 mmol) in DMSO (21 ml) at room temperature, was added sodium-t-pentoxide (9.5 g, 92 mmol) portionwise over 20 minutes keeping the temperature below 30° C. The resulting slurry was then stirred for 2 hours. After this time, iced water (35 ml) was added over 1 minute followed by ethyl acetate (35 ml) before reducing the pH of the biphasic mixture to 8.0 with 2M aqueous HCl (20 ml). The aqueous phase was extracted with ethyl acetate (50 ml). The combined organics were washed with saturated NaCl solution (2×30 ml), reduced in volume and stirred for 3 hours. After this time, the resulting slurry was filtered to yield 10.2 g (74%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]([CH3:45])[CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]([CH3:45])[CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][CH2:43][CH2:44]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CN(CCN1CCCC1)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(CCN1CCCC1)c1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamido)-4-phenylbenzoate (0.097 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.097 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Chloroform was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-95% chloroform/methanol] to obtain 0.048 g of tert-butyl 2-(2-hydroxy-5-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamido)-4-phenylbenzoate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH:15]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](OC(C)(C)C)=[O:23])[OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH2:37][CH2:38][C:39]([N:41]2[CH2:48][CH2:47][CH2:46][C@H:42]2C(O)=O)=[O:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH:15]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:23])[C@@H:48]2[CH2:47][CH2:46][CH2:42][N:41]2[C:39](=[O:40])[CH2:38][CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Product: O=C(CCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(OCc2ccccc2)cc1
Yield: 81.1 %

Procedure:
By the same procedure as in Example 26-D), while using (2S)-2-{2-[4-(benzyloxy)phenoxy]-1-hydroxyethyl}-1-(tert-butoxycarbonyl)pyrrolidine (1.71 g) and N-(3-phenylpropionyl)- L-proline (1.10 g), there was obtained 1.82 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Br>CN(C=O)C>[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3ccc(F)cc3F)ccc2CCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.7 %

Procedure:
To methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) dissolved in DMF (6 ml) were added potassium carbonate (415 mg, 3.00 mmol) and 2,4-difluorobenzyl bromide (0.212 ml, 1.65 mmol), and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (40 ml) was added to the residue and the resulting mixture was washed with water (5 ml×2) and an aqueous saturated solution of sodium chloride (5 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 15 g, ethyl acetate/hexane=1/25). The objective fractions were concentrated under reduced pressure to obtain methyl 2-(2,4-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (500 mg, 1.45 mmol, 97%).
Reaction SMILES: C([O:3][C:4]([CH:6]=[N:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:18]([F:32])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1)=[O:5])C.[Li+].[OH-].Cl>CO.O>[C:4]([CH:6]=[N:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:18]([F:32])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C=Nc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
The reaction of N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (0.1 g) and LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h at room temperature followed by treatment with aqueous HCl gave the solid. The resulting solid was filtered, washed with water and dried to give N2-(3-carboxymethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 18.23 min.; purity: 87.6%; MS (m/e): 412.01 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](/[O-:7])\[CH3:6].[Na+].[I-].[K+].Br[CH:13]=[CH:14][CH2:15][CH2:16][CH3:17]>>[C:5]([CH:4]([CH2:17][CH2:16][CH2:15][CH:14]=[CH2:13])[C:3]([O:2][CH3:1])=[O:8])(=[O:7])[CH3:6]
Reactant: COC(=O)/C=C(\C)[O-]
Reactant: CCCC=CBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: C=CCCCC(C(C)=O)C(=O)OC

Procedure:
Analogously to Example 14A, 10 g (72.4 mmol) of sodium (2E)-4-methoxy-4-oxo-2-buten-2-olate (Example 13A) and 0.4 g (2.41 mmol) of potassium iodide are reacted with 10.8 g (72.4 mmol) of 1-bromopentene to give methyl 2-acetyl-6-heptenoate.
Reaction SMILES: Cl[C:2]1[N:11]([CH2:12][C:13]([O:15]CC)=O)[CH:10]([CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:19])[N:3]=1.[NH3:20]>C(O)C>[CH3:18][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:19])[N:3]=[C:2]2[NH:20][C:13](=[O:15])[CH2:12][N:11]12
Reactant: CCOC(=O)CN1C(Cl)=Nc2cccc(C)c2C1C
Reactant: N
Solvent: CCO
Product: Cc1cccc2c1C(C)N1CC(=O)NC1=N2
Reaction time: 16 h
Yield: 69.1 %

Procedure:
To a solution of 4.3 g (15.4 mmole) of 2-chloro-3-(carbethoxymethyl)-4,5-dimethyl-3,4-dihydroquinazoline in 50 ml of absolute ethanol was added a solution of 2.0 g (120 mmole) of ammonia in 25 ml of absolute ethanol, the system was stoppered and immersed in an oil bath (100°). After 16 hrs. of heating, the solution was cooled, the solvent removed in vacuo and the residue crystallized from 1N hydrochloride acid affording 2.29 g (59% yield) of yellow crystals mp 235°-40°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@H:8]([NH2:16])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[C:29]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:28]=1>C(Cl)Cl>[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:32]=[CH:31][C:30]([S:33](=[O:35])(=[O:34])[NH:16][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:17])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:29]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:28]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OCc2ccccc2)c1
Reactant: CCOC(OCC)[C@@H](N)CC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(OCC)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(=O)OC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of (S)-3-amino-4,4-diethoxy-butyric acid tert-butyl ester (3.38 g, 13.7 mmol) in anhydrous methylene chloride (130 mL) was added pyridine (3.3 mL, 41 mmol) followed by 3-benzyloxy-4-chlorosulfonyl-benzoic acid methyl ester (4.66 g, 13.7 mmol). The reaction was allowed to stir at room temperature overnight. Mass spectrometry and TLC analysis showed presence of starting material. An additional 2 equivalents of pyridine (2.2 mL, 27.3 mmol) was added and allowed to stir overnight. TLC analysis showed the reaction to be completed. The methylene chloride was evaporated and the reaction mixture was dissolved in ether and 5% aqueous citric acid. The organic layer was collected and washed with 5% citric acid and then brine, dried over magnesium sulfate, filtered, and concentrated to yield 3-benzyloxy-4-(1-tert-butoxycarbonylmethyl-2,2-diethoxy-ethylsulfamoyl)-benzoic acid methyl ester (6.82 g, 12.4 mmol, 90%) as an orange tar. MS (APCI) m/z 550.3 (M−1).
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1Br.C(=O)([O-])[O-].[K+].[K+]>[Cu].C(O)CC>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]2[O:10][CH2:9][N:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]3=[N:2][C:16]=2[CH:15]=1
Reactant: Nc1cccc[n+]1COc1ccc(Cl)cc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCCO
Product: Clc1ccc2c(c1)N=C1C=CC=CN1CO2
Yield: 73.1 %

Procedure:
A mixture of 14.0 g of 2-amino-1-[(2-bromo-4-chlorophenoxy)methyl]pyridinium chloride, 11.1 g of micronized, anhydrous potassium carbonate, 0.4 g of copper bronze, and 350 ml of anhydrous n-propanol is stirred and heated under reflux for about eight hours, filtered hot, and the deep yellow filtrate is concentrated to dryness in vacuo. Workup gives about 6.8 g of 2-chloro-6H-pyrido[1,2-c][1,3,5]-benzoxadiazepine, m.p. about 175°-177°.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(N(CC)CC)C>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCCO)cc1)C(=O)OCC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCC(Cc1ccc(OCCCOS(C)(=O)=O)cc1)C(=O)OCC

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 2-butyl-3-[4-(3-hydroxypropoxy)phenyl]propionate (3.02 g), triethylamine (2.05 ml) and methanesulfonyl chloride (0.83 ml) and the reaction mixture was treated to afford the desired compound (3.49 g) as a colorless oil.
Reaction SMILES: CC(C)[C@@H](N1CC2C(=CC=C(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)C=2)C1=O)C(O)=O.[CH3:38][O:39][CH2:40][C@H:41]([N:46]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[C:51]([C:55]3[CH:60]=[CH:59][C:58]([NH:61][C:62]([NH:64][C:65]4[CH:70]=[CH:69][CH:68]=[C:67]([C:71]([F:74])([F:73])[F:72])[CH:66]=4)=[O:63])=[CH:57][CH:56]=3)[CH:52]=2)[C:47]1=[O:75])[C:42]([O:44]C)=[O:43]>>[CH3:38][O:39][CH2:40][C@H:41]([N:46]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[C:51]([C:55]3[CH:56]=[CH:57][C:58]([NH:61][C:62]([NH:64][C:65]4[CH:70]=[CH:69][CH:68]=[C:67]([C:71]([F:74])([F:72])[F:73])[CH:66]=4)=[O:63])=[CH:59][CH:60]=3)[CH:52]=2)[C:47]1=[O:75])[C:42]([OH:44])=[O:43]
Reactant: COC[C@@H](C(=O)OC)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: CC(C)[C@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Product: COC[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Yield: 89 %

Procedure:
The compound of example 385 was prepared analogous to the compound of example 361 by hydrolysis of the compound of example 384.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5](=O)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].C([O-])(=O)C.[NH4+].C([BH3-])#[N:17].[Na+].[ClH:20]>CO>[ClH:20].[CH3:1][CH:2]([CH2:4][CH:5]([NH2:17])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[ClH:20]
Reactant: [BH3-]C#N
Reactant: CC(C)CC(=O)CC(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(C)CC(N)CC(C)C

Procedure:
A solution of 2,6 -dimethyl-4 -heptanone (2.84 g, 20 mmol), ammonium acetate (15.4 g, 200 mmol) and sodium cyanoborohydride (0.93 g, 14 mmol) in methanol (75 mL) was stirred at room temperature for 20 hours. After cooling in an ice bath, the reaction mixture was acidified with concentrated HCl and concentrated under reduced pressure at 35° . The residue was partitioned between ethyl ether and water and the aqueous portion removed and made basic with 40% NaOH solution. Product was extracted into ethyl ether which was then washed with brine, dried (Na2SO4), filtered and concentrated to 1.22 g of product. Conversion to the HCl salt and recrystallation from MeOH-EtOAc gave 1.04 of pure HCl salt, mp 248°-50° dec.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[OH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=O)[CH3:38]>O1CCCC1>[OH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:38])=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)CCCCCCCO
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=CCCCCC(=O)O)CCCCCCCO
Reaction time: 0.5 h
Yield: 111.2 %

Procedure:
45.7 g (0.1 mol) of (5-carboxypentyl)triphenylphosphonium bromide were placed in 200 ml of tetrahydrofuran and 25 g (0.22 ol) of potassium t-butylate in 100 l of tetrahydrofuran were added dropwise at 0° C. Then, 15.8 g (0.1 mol) of 9-hydroxy2-nonanone were added. After stirring for 30 minutes and usual work up, 28.5 g of crude 14-hydroxy-7-methyltetradec-6-enoic acid were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C[O-].C([Sn+](CCCC)CCCC)CCC.C([O:44][C:45]([CH3:47])=[CH2:46])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:46][C:45](=[O:44])[CH3:47])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(CC(C)=O)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Yield: 61.8 %

Procedure:
A solution of 5-bromo-1-(4-nitro-benzyl)-1H-indole-2-carboxylic acid ethyl ester (3.28 g, 8.13 mmol), tributyltin methoxide (3.92 g, 3.51 ml, 12.2 mmol), isopropenyl acetate (1.22 g, 1.34 ml, 12.2 mmol), palladium (II) acetate (91 mg, 0.41 mmol) and tri-o-tolylphosphine (248 mg, 0.813 mmol) in toluene (10 ml) was heated at about 95° C. under nitrogen for about 3 hours. The reaction solution was cooled, concentrated in vacuo, and subjected to flash chromatography on silica (200 g, gradient from 10% ethyl acetate/hexane to 40% ethyl acetate/hexane), and then the partially pure product was recrystallized from toluene/heptane to give the title compound (1.91 g).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:15]([Si:18]([CH3:20])([CH3:19])[O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])([CH3:17])([CH3:16])[CH3:14]
Reactant: OCCOCCOCCOCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
Tetraethylene glycol, 4c (1.12 g, 5.77 mmol) and TBDMSCl (0.87 g, 5.77 mmol) were dissolved in dichloromethane (25 ml) followed by triethyl amine (1.46 g, 14.4 mmol). The solution was stirred at room temperature for 2 hours. After standard workup with dichloromethane, the residue was purified by silica gel column chromatography (50% ethyl acetate in hexane) to afford 5c (744 mg, 42%): 1H NMR δ 3.66 (m, 16H), 2.51 (t, 1H, J=5.86 Hz), 0.89 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: Br[C:2]1([CH2:15][N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:4][C:3]1([CH2:10][O:11]C(=O)C)[CH2:5][O:6]C(=O)C.C(=O)([O-])[O-].[K+].[K+].CO.O>CN(C)C=O>[OH:6][CH2:5][C:3]1([CH2:10][OH:11])[CH2:4]/[C:2]/1=[CH:15]/[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: CC(=O)OCC1(COC(C)=O)CC1(Br)Cn1cc(C)c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cn(/C=C2/CC2(CO)CO)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
A mixture of compound 18 (0.60 g, 1.49 mmol) from Example 17 and flame-dried potassium carbonate (616 mg, 4.47 mmol) in N,N-dimethylformamide (50 mL) was stirred at 100° C. under nitrogen for 3 h. After cooling, methanol-water (9:1, 10 mL) was added with stirring which was continued at room temperature for 1 h. The insoluble portion was filtered off and it was washed with N,N-dimethylformamide. The filtrate was evaporated in vacuo and the residue was chromatographed on a silica gel column which was first eluted with ethyl acetate and then dichloromethane-methanol (20:1) to give the Z-isomer 1f (70 mg, 38%) and E-isomer 2f (65 mg, 36%) as white solids.
Reaction SMILES: [C:1]1(=O)[O:7][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[NH2:13]C(N)=O>O>[C:1]1(=[O:7])[NH:13][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: NC(N)=O
Solvent: O
Product: O=C1Cc2ccccc2C(=O)N1
Yield: 52.8 %

Procedure:
Homophthalic anhydride (20 g) and urea (60 g) were reacted at 170° C. for 1 hr. The reaction mixture was cooled, water (500 ml) was added thereto, and then the resulting precipitates were collected by filtration. The precipitate were washed with water and dried in hot air, to give 10.5 g of homophthalimide as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)[CH:3]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:20][OH:21])[CH:3]=1
Reactant: NO
Reactant: COc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(Cc2cc(Br)ccn2)=NO)cc1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
To a solution of Example 19A (13.41 g, 43.8 mmol) in methanol (231 mL) was added hydroxylamine hydrochloride (15.22 g, 219 mmol) to give a thick slurry. The mixture was treated with a solution of sodium hydroxide (8.76 g, 219 mmol) in water (58 mL), heated at reflux for two hours, cooled and concentrated to a paste. The paste was treated with 100-150 mL of water and stirred for 15 minutes to give a solid that was collected by filtration, washed with water and dried to constant mass to give the title compound as a powder (11.86 g, 84%). MS (ESI+) m/z 321/323 (M+H)+.