Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](I)=[CH:14]2)[C@H:9]([OH:12])[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])=[CH:14]2)[C@H:9]([OH:12])[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H](O)[C@H](c1cccc(F)c1)n1cc(I)c2ccccc21
Reactant: OB(O)c1ccccc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC[C@@H](O)[C@H](c1cccc(F)c1)n1cc(-c2ccccc2F)c2ccccc21
Temperature: 90 °C
Yield: 60.5 %

Procedure:
A mixture of (2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol (0.25 g, 0.61 mmol), 2-fluorobenzeneboronic acid (0.12 g, 0.85 mmol), and potassium phosphate (0.39 g, 1.83 mmol) in N,N-dimethylformamide (10 mL) was degassed with nitrogen for 5 minutes then a catalytic amount (0.02 g) of [1,4-bis-(diphenylphosphine)butane]palladium (II) dichloride was added. The solution was heated to 90° C. for 3 hours then cooled and poured into 100 mL of water. The aqueous mixture was extracted 3 times with ethyl acetate and the combined extracts were then washed 2 times with water. The ethyl acetate was dried by filtration through a plug of silica gel then concentrated. The residue was purified by Biotage chromatography (FlasH40i, silica, 40% ethyl acetate/hexane) to yield 0.14 g of (2S,3S)-3-(3-fluorophenyl)-3-{3-[2-fluorophenyl]-1H-indol-1-yl}propane-1,2-diol as an oil, which was used in the next step without further purification.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(Cl)([Cl:23])=O>>[C:1]([Cl:23])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)Cl

Procedure:
Stearic acid (25 g) was reacted with thionylchloride (30 g) to form stearoylchloride, which was further reacted with indigo (5.2 g) in pyridine to obtain N,N'-distearoylindigo in per se conventional manners.
Reaction SMILES: [NH:1]1[C:9](=[O:10])[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.[CH2:11]1[O:13][CH:12]1[CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>>[NH:1]1[C:9](=[O:10])[C:8]2[N:7]=[CH:6][N:5]([CH2:11][CH:12]([OH:13])[CH2:14][OH:15])[C:4]=2[N:3]=[CH:2]1
Reactant: OCC1CO1
Reactant: O=c1[nH]cnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1[nH]cnc2c1ncn2CC(O)CO

Procedure:
Hypoxanthine is treated as in the procedure of Example 1 with glycidol in the presence of potassium carbonate to give 1-(hypoxanthine-9-yl)-2,3-propandiol. The resulting 1-(9-hypoxanthine)-2,3-propandiol is treated with dimethoxytrityl chloride in pyridine as in Example 2 to give 1-(9-hypoxan-thine)-3-O-dimethoxytrityl-2-propanol. The resulting 1-(9-hypoxanthine)-3-O-dimethoxytrityl-2-propanol is phosphitylated with chloro-β-cyanoethoxy-N,N-diisopropylaminophosphine as per Example 3 to give the title compound.
Reaction SMILES: [F-:1].[K+].I([C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:10])(=O)=O.C1OCCOCCOCCOCCOCCOC1.C(#N)C>CCOC(C)=O>[F:1][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:10]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(I(=O)=O)c1)OCc1ccccc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(F)c1)OCc1ccccc1
Yield: 61 %

Procedure:
A mixture of spray-dried KF (614 mg, 10.59 mmol), intermediate 7 (1 g, 2.12 mmol), 18-crown-6 (40 mg) and dry acetonitrile (20 mL) was refluxed for 40 min. After completion of reaction (TLC), the mixture was diluted with EtOAc (75 mL). The solution was successively washed with water (50 mL) and brine (50 mL) and dried over anhyd Na2SO4. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform:hexane (75:25) as eluents to give the product as a colorless solid (430 mg, 61%), mp 118-120° C. 1H NMR (400 MHz, CDCl3): δ 8.13 (1H, t, J=7.8 Hz), 7.75 (1H, d, J=10.8 Hz), 7.68 (1H, d, J=8.0 Hz), 7.38 (5H, br s), 6.68 (1H, br s), 5.25 (2H, s), 4.29 (2H, d, J=4.8 Hz); LC-MS negative ion mode): m/z 331 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([CH:8]([CH2:21][CH2:22][CH3:23])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:11](OCC)=[O:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>C(OCC)C>[F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([CH:8]([CH2:21][CH2:22][CH3:23])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:11]=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(CC(O)(C(=O)OCC)C(F)(F)F)c1cccc(F)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCC(CC(O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
698 mg (2.56 mmol) of 1,1′-bi-2-naphthol are admixed with 2.56 ml (1.28 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred at room temperature for 2 hours. 4.26 g (21.9 mmol) of 2-fluoro-6-(1-methylenbutyl)anisole and 5.7 ml (44 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 18 hours. After cooling it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 0-15%) to give 5.82 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hept-4-enoate. 2.6 g (7.1 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hept-4-enoate are dissolved in 65 ml of methanol and the solution is admixed with 260 mg of palladium on carbon (10%). The suspension is shaken under a hydrogen atmosphere at atmospheric pressure for 4 hours until the hydrogen uptake is 155 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 2.6 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanoate. 2.6 g (7.1 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-heptanoate in 150 ml of diethyl ether are cooled to −10° C. and over 15 minutes 520 g (14.2 mmol) of solid lithium aluminum hydride are added in portions. The mixture is stirred at −15° C. for 1.5 hours, followed by dropwise addition in succession of ethyl acetate and water and by a further hour of stirring until a readily filterable precipitate is formed. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/diisopropyl ether 0-15%) yields 2.1 g of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanal as a mixture of the diastereomers.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:6][O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]5[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=5)=[CH:24][CH:23]=4)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]4[N:39]=[CH:40][N:41]=[C:15]34)[CH2:10][CH2:9]2)[CH2:5][O:4]1.[FH:42].[K].CCCC[N+](CCCC)(CCCC)CCCC.F.F.[F-]>ClC1C=CC=CC=1>[F:42][CH2:5][C:3]([CH2:2][F:1])([OH:4])[CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:19](=[O:20])[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]3[N:39]=[CH:40][N:41]=[C:15]23)[CH2:10][CH2:9]1
Reactant: F
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(CF)CO3)CC2)c2ncnn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K]
Solvent: Clc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)(CF)CF)CC2)c2ncnn12
Temperature: 120 °C
Reaction time: 14 h

Procedure:
A mixture of 4′-{[4-(trans-4-{[2-(fluoromethyl)oxiran-2-yl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.17 g), potassium hydrogen fluoride (0.15 g), tetra-n-butylammonium dihydrogentrifluoride (0.097 g) and chlorobenzene (0.5 mL) was stirred at 120° C. for 14 hr. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.16 g, 87%).
Reaction SMILES: [O:1]=[C:2]([C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[NH2:5])[OH:3].[C:15](OC(=O)C)(=[O:17])C>C(O)(=O)C>[C:15](=[N:5][C@@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[C:2]([OH:3])=[O:1])=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Solvent: CC(=O)O
Product: O=C=N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O

Procedure:
In another exemplary particular, L-DOPA is reacted with a carboxylic anhydride (e.g., a mixture of acetic acid and acetic anhydride), to thereby produce a N-carbonyl L-DOPA derivative (e.g., N-acetyl L-DOPA).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:12]1[C:17](Cl)=CC=C(Cl)[CH:13]=1>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:13][CH2:12][CH3:17])[CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Clc1ccc(Cl)cc1
Product: CCCc1cc(C(=O)OC)ccc1O

Procedure:
The synthesis begins with the allylation of readily available methyl-4-hydroxybenzoate (Scheme 1). The allylated phenol is then thermally rearranged in dichlorobenzene and subsequently hydrogenated to provide the desired Methyl-4-hydroxy-3-n-propylbenzoate in good overall yield. ##STR27##
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: C1CCNC1
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2n(c1CN1CCCC1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with pyrrolidine similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide to afford 10-bromo-9-fluoro-3-(pyrrolidin-1-ylmethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 15 mg (17%) of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-(pyrrolidin-1-ylmethyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=423.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C@@H:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22](OS(C)(=O)=O)[CH2:21]1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:9])=[O:8])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Li+]>CN(C)C=O.O>[CH2:1]([O:3][C:4]([CH:5]1[C@H:22]2[CH2:21][CH:20]([CH2:26][CH2:25][CH2:24][CH2:23]2)[N:6]1[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:9])=[O:8])=[O:32])[CH3:2]
Reactant: CCOC(=O)CN([C@@H]1CCCCC(OS(C)(=O)=O)C1)S(=O)(=O)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1[C@@H]2CCCCC(C2)N1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 80 °C
Yield: 77 %

Procedure:
To a solution of (R)—N-naphthalene-2-sulfonyl (3-methanesulfonyloxy-cycloheptyl)glycine ethyl ester (0.60 g, 1.24 mmol) in N,N-dimethylformamide (5 mL) is added cesium carbonate (1.21 g, 3.71 mmol) followed by lithium iodide (0.249 g, 1.86 mmol), and the reaction is heated to 80° C. for 3 hours. The reaction is cooled to ambient temperature, diluted with water, and extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product is purified by column chromatography (20% hexanes-ethyl acetate) to afford the title compound as a white solid (0.37 g, 77% yield). LCMS (m/z): 388.10 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7]/[CH:8]=[CH:9]/C(N)CC2CCCCC2)[N:3]=[CH:2]1.[ClH:19]>>[ClH:19].[CH2:6]([C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[CH2:7][C:8]#[CH:9]
Reactant: NC(/C=C/CCc1c[nH]cn1)CC1CCCCC1
Agent: Cl
Product: C#CCCc1c[nH]cn1

Procedure:
4-But-3-ynylimidazole HCl was prepared from the deprotection of compound 26 by treatment with 2N HCl.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=1[F:24].[C:25](=[O:27])=[O:26]>C1COCC1.O.[OH-].[Na+]>[Br:16][C:17]1[C:18]([F:24])=[C:19]([CH:20]=[C:21]([Br:23])[CH:22]=1)[C:25]([OH:27])=[O:26]
Reactant: O=C=O
Reactant: Fc1ccc(Br)cc1Br
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)cc(Br)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Butyllithium (1.6M solution in hexanes, 12.3 ml, 19.7 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (3.32 ml, 19.7 mmol) in THF at −78° C. The reaction was stirred for 10 min. prior to the addition of 2,4-dibromofluorobenzene (5 g, 19.7 mmol). Stirring was continued for 2 h. The solution was then poured onto freshly crushed dry ice and allowed to warm to room temperature. The resulting solution was diluted with water (100 ml) and NaOH (2M, 10 ml) was added. This was extracted with ether (2×) and the aqueous layer was acidified to pH 1 (2M HCl) to afford a gummy solid which was triturated from ether to afford the title compound (D37) as a colourless solid (1.23 g).
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)C.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:20][CH2:1][C:3]1[N:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ncc2ccccc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: BrCc1ncc2ccccc2n1
Yield: 12.2 %

Procedure:
To a solution of the title compound from Step B (1.39 g 8.79 mmol) in chloroform (50 ml) was added NBS (1.56 g, 8.79 mmol) and benzoyl peroxide (213 mg, 0.88 mmol) and the resulting mixture heated at reflux for 5 h. The mixture cooled and evaporated, the residue purified by MPLC (Biotage Horizon: FLASH 25+M) eluent: 100% Hexanes (90 ml), gradient rising from 100% Hexanes to 10% EtOAc in Hexanes (1200 ml) to afford the title compound 240 mg (11.5%) as a red oil. 1H NMR (CDCl3): 2.25 (d, J 6.9 Hz, 3H), 5.51 (q, J 6.9 Hz, 1H), 7.64 (m, 1H), 7.71 (m, 1H), 7.97 (m, 1H), 8.08 (d, J 8.6 Hz, 1H), 9.49 (s, 1H).
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:44][CH2:45][C:46]([OH:48])=O)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:60]2[N:61]=[CH:62]C=CC=2N=N1.CNC.C1COCC1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:44][CH2:45][C:46]([N:61]([CH3:62])[CH3:60])=[O:48])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CCC(=O)O)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CCC(=O)N(C)C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
The 3-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)propanoic acid (63 mg, 0.094 mmol) obtained in Example 57 was dissolved in chloroform (2 mL), and stirred overnight at room temperature after adding O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; Aldrich; 71 mg, 0.187 mmol), a 2 mol/L dimethylamine THF solution (0.234 mL, 0.469 mmol), and diisopropylethylamine (0.082 mL, 0.469 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) to give compound 58 (60.7 mg, 92.6%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:11]CC)[CH3:10]>[Br-].[Zn+2].[Br-]>[C:1]1([C@H:9]([OH:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOCC
Agent: [Br-]
Agent: [Zn+2]
Product: C[C@@H](O)c1ccccc1
Temperature: -5 °C

Procedure:
Anhydrous zinc bromide (11.37 g) was charged to a dry, stirred 250 ml flask filled with nitrogen. Dried diethylether (75 ml) was added and the slurry heated to reflux until a homogenous solution. A 3molar ethereal solution of phenylmagnesium bromide (33.3 ml) was slowly added. Solvent was distilled from the reaction mixture at ambient pressure, whilst maintaining a constant volume by addition of toluene until a distillate temperature of 110° C. was reached. The hot slurry was screened under a nitrogen atmosphere using an in-line sintered glass filter. The filtrates were received into a dry, stirred 250 ml flask and cooled to −5° C. D(+) diethyinorephedrine (0.64 g) was added and the acetaldehyde (2.2 g) in toluene (5 ml) charged from a dropping funnel. The reaction mixture was warmed to ambient temperature, stirred for a total of 12 hours, then cooled on an ice bath and quenched by addition of dilute hydrochloric acid. The organic layer was separated, washed with an equal volume of water and concentrated to yield a crude product (4.62 g). This was further purified by chromatography to give 3.86 g (R)phenylethanol of 17% ee, measured by chiral GC. The product was identified by gas chromatographic comparison with authenticated material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=2)[CH:17]=1.[CH3:28][C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:33][C:29]3([CH3:28])[CH2:32][O:31][CH2:30]3)=[O:24])=[CH:20][N:19]=2)[CH:17]=1
Reactant: CC1(N)COC1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC3(C)COC3)cn2)cn1
Yield: 74 %

Procedure:
As described for example 22, 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (69 mg, 0.189 mmol) was converted, using 3-methyl-3-oxetaneamine instead of 4-aminotetrahydropyran, to the title compound (61 mg, 74%) which was obtained as a white foam after purification by chromatography (silica, 0 to 10% methanol in dichloromethane). MS: m/e=434.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:30]=[CH:29][C:13]([C:14]([NH:16][C@H:17]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=3[N:20]=2)[CH3:18])=[O:15])=[CH:12][C:11]=1[Cl:31])=[O:9].[C:32](OC(=O)C)(=[O:34])[CH3:33].ClCCl.C(O)C.ClCl>C(O)(=O)C>[C:32]([NH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:30]=[CH:29][C:13]([C:14]([NH:16][C@H:17]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=3[N:20]=2)[CH3:18])=[O:15])=[CH:12][C:11]=1[Cl:31])=[O:9])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)NC[C@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 78 %

Procedure:
Prepared analogously to Example 124 from 4-((2R)-2-aminomethylpyrrolidin-1-ylcarbonyl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide and acetic anhydride in glacial acetic acid. Yield: 78%; Rf value: 0.30 (silica gel; dichloromethane/ethanol=9:1); C24H25Cl2N5O3 (502.40); mass spectrum: (M+H)+=502/504/506 (chlorine isotope) and (M−H)−=500/502/504 (chlorine isotope).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:7]=[N:6][CH:5]=[N:4]1.[OH-].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)=[O:20]
Reactant: NCCCCn1cncn1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCCn1cncn1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of about 2.13 g of 1H-1,2,4-triazole-1-butanamine, dihydrochloride, about 75 ml of methylene chloride, about 30 ml of approximately 1N sodium hydroxide and about 1.41 ml of 3,4-dichlorobenzoyl chloride was stirred at room temperature overnight. An additional, about 5 ml of approximately 1N sodium hydroxide and about 50 ml of methylene chloride were added and the layers were separated. The organic layer was washed with water, dried and concentrated. The oil was collected and crystallized from ether, giving about 2.3 g of the desired product as white crystals, mp 97°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:20])=[O:7])=[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)cc1Sc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(Cl)cc1Sc1ccccc1

Procedure:
To a stirred suspension of 59.2 g. (0.224 mole) of 4-chloro-2-(phenylthio)benzoic acid in 200 ml. of benzene is added dropwise 41.6 g. (0.35 mole) of thionyl chloride during a 1 hour period, and the reaction mixture is heated under reflux for an additional hour. The reaction mixture is then concentrated to dryness under reduced pressure, and the residue is recrystallized from 300 ml. of boiling hexane to yield 41.9 g. of pale yellow product, melting point 94°-96°C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]4[C:18]5[CH:19]=[CH:20][C:21]([C:25](O)=[O:26])=[CH:22][C:23]=5[CH2:24][C@H:13]34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:28][NH2:29]>>[CH3:28][NH:29][C:25]([C:21]1[CH:20]=[CH:19][C:18]2[C@@H:14]3[C@@H:13]([N:12]([C:10]([C:8]4[CH:7]=[CH:6][C:5]5[NH:1][CH:2]=[N:3][C:4]=5[CH:9]=4)=[O:11])[CH2:17][CH2:16][CH2:15]3)[CH2:24][C:23]=2[CH:22]=1)=[O:26]
Reactant: O=C(O)c1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Reactant: CN
Product: CNC(=O)c1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 19 %

Procedure:
The title compound is prepared from cis-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-7-carboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Example 1. Yield: 19% of theory; LC (method 1): tR=1.86 min; Mass spectrum (ESI+): m/z=375 [M+H]+.