Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=1)#N.[OH2:20].C(OCC)(=O)C.[OH2:27]>Cl>[F:17][C:16]([F:19])([F:18])[C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:5]1[N:4]=[C:3]([C:1]([OH:27])=[O:20])[CH:8]=[CH:7][CH:6]=1
Reactant: O
Reactant: N#Cc1cccc(Oc2cccc(C(F)(F)F)c2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-cyano-6-[3-(trifluoromethyl)phenoxy] pyridine (3.00 g, 0.011 mol) was suspended in about 15 ml of concentrated hydrochloric acid. The obtained suspension was stirred at about 100° C. for about 2 hours. After being allowed to stand for cooling, the obtained reaction solution was mixed with water, and then distributed in ethyl acetate-water. The organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6](N)[CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1.[C:19]1(=O)[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[C:17]2[C:5]3=[C:4]([O:9][CH2:8][CH:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:6]3[C:19]3[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C:20]2=3)[CH:3]=1
Reactant: Cc1ccc2c(c1)OCC(c1ccccc1)N2N
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2c3c(c1)c1c(n3C(c3ccccc3)CO2)CCCC1=O
Temperature: 106 °C
Yield: 51.6 %

Procedure:
To a mixture of 7-methyl-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-amine (5.95 g, 24.8 mmol) in toluene (175 mL) is added while stirring 1,3 cyclohexandione (2.86 g, 25.5 mmol). The mixture is heated to 95° C. for 20 min, at which time p-toluenesulfonic acid monohydrate (4.71 g, 24.8 mmol) is added and the temperature is increased to 106° C. for 1 h. The mixture is refluxed for 12 h, then cooled to room temperature and concentrated. The residue is partitioned between CH2Cl2/1N NaOH. The organic layer is washed with brine, dried over magnesium sulfate and concentrated to dryness. Column chromatography (100 g silica gel) using acetone/hexane (25/75) as eluent gave 4.06 g (51%) of 5-methyl-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one; mp 171° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH2:23])[N:15]([C:24]3[C:25]4[CH:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23][CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:15]([C:24]3[C:25]4[CH:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC5CCCC5)cccc43)c21
Reaction time: 0.33 h
Yield: 91 %

Procedure:
A stirring solution of (1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methanamine (0.250 g, 0.433 mmol) in DCE (3 mL) was treated with cyclopentanone (0.192 mL, 2.17 mmol). The reaction was allowed to stir for 20 minutes, followed by the addition of NaBH(OAc)3 (0.184 g, 0.867 mmol). The reaction was stirred at room temperature overnight. An additional 2.5 equivalents of cyclopentanone and 1.0 eq of NaBH(OAc)3 were added to the reaction and stirred an additional 2 hours. The reaction was quenched by the addition of saturated NaHCO3 and diluted with DCM. The combined organics were washed with brine, dried Na2SO4, filtered, and concentrated under reduced pressure to yield N-((1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)cyclopentanamine (0.211 g, 91%), which was used without further purification. LCMS (APCI+) m/z 536.4 [M+H]+; Rt=3.61 min.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[N+:21]([O-])([OH:23])=[O:22].CCC1(C2C=CC=CC=2)C(=O)NC(=O)NC1=O>C(O)(=O)C>[OH:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Solvent: CC(=O)O
Product: C[C@]12CC[C@@H]3c4ccc(O)c([N+](=O)[O-])c4CC[C@H]3[C@@H]1CCC2=O
Temperature: 120 °C
Yield: 13 %

Procedure:
To a suspension of estrone (11, 8.11 g, 30 mmol) in acetic acid (250 mL) was heated to 120° C. and cooled to 50° C. To the reaction mixture was added 70% nitric acid (2.27 mL, 36 nunol, in an acetic acid (8.0 mL) solution) at 50° C., and stirred for 20 h at room temperature. The precipitate was filtered and washed with acetic acid, H2O, Et2O to afford 1.18 g of 76a (13% yield) mp: >250° C. To the filtrate was added H2O; it was then extracted with Et2O. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (2:1, v/v) to afford 3.25 g of 76b (34% yield) mp: 178-180° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[C:19](P(=O)(OCC)OCC)([F:21])[F:20]>C(#N)C.O.C(OCC)(=O)C>[F:20][CH:19]([F:21])[O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:16][CH2:17]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc2ccc(O)cc2cn1)C1CC1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Nc1cc2ccc(OC(F)F)cc2cn1)C1CC1
Temperature: -78 °C
Yield: 38.5 %

Procedure:
A solution of N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamide (91.2 mg, 0.40 mmol), diethyl bromodifluoromethylphosphonate (212 mg, 0.80 mmol) in acetonitrile/water (1:1, 5 mL) was mixed and stirred at −78° C. After the reaction mixture was warmed to room temperature and stirred for 20 minutes, the reaction mixture was diluted with ethyl acetate, and the organic phase was separated. The water phase was extracted with ethyl acetate, and the combined organic layer was dried, concentrated and purified by prep-HPLC to give product (42.8 mg, 26%). LCMS (ESI): RT (min)=0.994, M+H+=279.0, method=A. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.54 (s, 1H), 8.37 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.54 (s, 1H), 7.43 (dd, J=2.4, 8.8 Hz, 1H), 6.61 (t, J=73.2 Hz, 1H), 1.71-1.57 (m, 1H), 1.15-1.11 (m, 2H), 0.95-0.89 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([C:10]#[N:11])=[CH:6][CH:7]=[CH:8][CH:9]=1)#[N:2].[BrH:12].C([O-])(=O)C>C(O)(=O)C>[NH2:2][C:1]1[N:11]=[C:10]([Br:12])[C:5]2[C:4]([CH:3]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: N#CCc1ccccc1C#N
Reactant: Br
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Nc1cc2ccccc2c(Br)n1
Yield: 90.8 %

Procedure:
To a suspension of α-cyanotolunitrile (20.0 g) in acetic acid (50 ml) was added 25% hydrogen bromide/acetate solution (150 ml), and the mixture was reacted at room temperature overnight. The resulting precipitates were collected by filtration and then added to a 10% aqueous solution of potassium carbonate. The yellow powder was changed to a pale yellow powder. The resulting powder was collected by filtration, washed with water and hexane, and dried at 50° C. under reduced pressure, to give 3-amino-1-bromoisoquinoline (28.5 g; 90.8%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[N:4]=[C:3]1[CH2:12][OH:13].CC(O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O)=O.C1C=CC=CC=1>C(O)CO>[CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[N:4]=[C:3]1[CH:12]=[O:13]
Reactant: Cn1c(CO)nc([N+](=O)[O-])c1C#N
Agent: CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O
Solvent: c1ccccc1
Solvent: OCCO
Product: Cn1c(C=O)nc([N+](=O)[O-])c1C#N

Procedure:
0.91 G. (0.05 moles) of 1-methyl-2-hydroxymethyl-4-nitro-5-cyanoimidazole and 2.66 g. of leadtetraacetate are combined in 35 ml. of benzene and refluxed for 12 hours. 0.3 G. of ethylene glycol is added to the reaction mixture to consume excess leadtetraacetate and the reaction mixture is filtered. The benzene solution is washed with water and sodium bicarbonate solution, dried and evaporated to dryness. The residue is recrystallized from isopropanol affording 1-methyl-2-formyl-4-nitro-5-cyanoimidazole, m.p. 130° to 133C.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([NH2:45])[CH:42]=[CH:41][N:40]=1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:45][C:43]1[CH:42]=[CH:41][N:40]=[C:39]([O:38][CH3:37])[CH:44]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(N)ccn1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)ccn1
Temperature: 50 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (38.9 mg, 0.141 mmol) in dry dichloromethane (2 mL) was added triethylamine (0.049 mL, 0.352 mmol), 2-chloro-1-methylpyridinium iodide (53.3 mg, 0.209 mmol), and 2-methoxy-4-aminopyridine (20.2 mg, 0.163 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 50° C. for 1.5 hours. LC/MS showed reaction complete. The reaction mixture was concentrated and purified by HPLC on a 30×100 mm Waters Sunfire column to afford the title compound as an orange solid after lyophilization.
Reaction SMILES: [NH:1]([CH2:8][C:9]1C=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1C=CC=CC=1)C1C=CC=CC=1.C(=O)C1C=CC=NC=1>>[NH:1]([C:8]1[CH:9]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(NCc2cccnc2)cc1
Agent: O=Cc1cccnc1
Agent: c1ccc(CNc2ccccc2)cc1
Product: c1ccc(Nc2ccccn2)cc1

Procedure:
The synthesis of 3-anilinomethylpyridine precursors should proceed similar to the synthesis of N-benzylaniline described in Example 7 except with nicotin-aldehyde as the reagent:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([Br:8])[CH:7]=1.C[Si]([C:14]#[N:15])(C)C.CN(C)C(Cl)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:14]([C:3]1[C:2]([Br:1])=[CH:7][C:6]([Br:8])=[CH:5][N:4]=1)#[N:15]
Reactant: [O-][n+]1cc(Br)cc(Br)c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ncc(Br)cc1Br

Procedure:
A mixture of 3,5-dibromopyridine N-oxide (prepared in the above (1)) 2.26 g, trimethylsilylcyanide 1.06 g and dimethylcarbamic acid chloride 1.15 g in methylene chloride 25 ml is refluxed under heating for 1 day. To the mixture are added trimethylsilylcyanide 443 mg and dimethylcarbamic acid chloride 480 mg, and the mixture is refluxed under heating for 20 hours. An aqueous sodium hydrogen carbonate solution is added to the reaction mixture cooled, and the mixture is extracted with methylene chloride. The combined extract is washed, dried and the solvent is removed in vacuo. The residue is purified by silica gel chromatography (solvent; n-hexane:ethyl acetate=1:1) to give 2-cyano-3,5-dibromopyridine 1.38 g. mp 109–112° C.
Reaction SMILES: [CH3:1][N:2](C)C=O.C(Cl)(=O)C(Cl)=O.[C:12]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH2:32][OH:33])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.C[Si](C#N)(C)C>C(Cl)Cl.C1C=CC=CC=1.CO>[C:12]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]([C:1]#[N:2])[OH:33])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: C[Si](C)(C)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
To a solution of N,N-dimethylformamide (2.54 ml, 35.8 mmol) and methylene chloride (34.5 ml) was added oxalyl chloride (1.53 ml, 17.5 mmol) at -78° C., and the mixture was stirred for 15 min at the same temperature. To the mixture was added dropwise a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-hydroxymetylpyrrolidine (3.92 g, 11.8 mmol) in methylene chloride (34.5 ml) over a 10 min period. After stirring for 30 min, triethylamine (8.27 ml, 59.3 mmol) was added to the mixture, and the mixture was allowed to warm to room temperature. After stirring for 15 min, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give an oily residue, which was dissolved in benzene (20 ml). To the solution was added trimethylsilylcyanide (1.75 ml, 13.1 mmol), and the mixture was stirred for 12 h at room temperature. To the mixture was added methanol (15 ml), and further stirred. The solvent was removed in vacuo. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=5:1) to give (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(1-cyano-1-hydroxymethyl)pyrrolidine (3.8 g, yield: 88.1%).
Reaction SMILES: [C:1](=[S:9])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](=O)[CH2:13]Cl>CCO.C1COCC1>[Cl:10][CH2:11][C:12]1[N:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:9][CH:13]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C(CCl)CCl
Solvent: C1CCOC1
Solvent: CCO
Product: ClCc1csc(-c2ccccc2)n1
Temperature: 65 °C
Yield: 72.9 %

Procedure:
Benzothioamide (0.8 g, 5.83 mmol) was dissolved in a mixture EtOH (26.0 ml) and THF (10.4 ml), and the solution was heated to 65° C. 1,3-Dichloropropan-2-one (0.81 g, 6.41 mmol) was added, and the mixture was heated to reflux overnight (UPLC-MS: complete conversion). The solvents were evaporated, and the residue was taken up with EtOAc (100 ml) and washed with an aqueous solution of NaHCO3. The organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude was purified by flash chromatography eluting with petroleum ether/EtOAc=97/3 to obtain 4-chloromethyl-2-phenyl-thiazole (891 mg, 72.9% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][O:18][CH2:19]Cl.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][CH2:17][O:18][CH3:19])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: OCc1coc(-c2ccc(Cl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOCc1coc(-c2ccc(Cl)cc2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1.32 g (7.54 mmol) of [2-(4-chlorophenyl)-1,3-oxazol-4-yl]methanol (Example 100A) are initially charged in 18.5 ml of dry THF and cooled to 0° C., and 0.33 g (8.29 mmol) sodium hydride (60% strength in mineral oil) are added. The mixture is stirred at 0° C. for 10 min and then at RT for 1 h. The reaction mixture is again cooled to 0° C., and 0.69 ml (9.04 mmol) of chlorodimethyl ether is added. The mixture is stirred at 0° C. for 10 min and then at RT for 2 h. 5 ml of water are then added, and the reaction mixture is extracted three times with in each case 25 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The product obtained is used without further purification in the subsequent reaction.
Reaction SMILES: [Cl-].[Li+].Br[CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:20]=[C:21](Br)[CH:22]=[CH:23][CH:24]=1.CC(C1C=CC=C(C(C)C)C=1N1[C-]=[N+](C2C(C(C)C)=CC=CC=2C(C)C)CC1)C.[Cl-].[NH4+]>[Zn].CC(C1C=CC=C(C(C)C)C=1N1[CH-]N(C2C(C(C)C)=CC=CC=2C(C)C)CC1)C.C1C=NC=C(Cl)C=1.Cl[Pd]Cl.BrCCBr.C[Si](Cl)(C)C.C1COCC1>[F:16][C:17]([F:26])([F:27])[O:18][C:19]1[CH:24]=[C:23]([CH:22]=[CH:21][CH:20]=1)[CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1
Reactant: FC(F)(F)Oc1cccc(Br)c1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cccc(C(C)C)c1N1[C-]=[N+](c2c(C(C)C)cccc2C(C)C)CC1
Agent: CC(C)c1cccc(C(C)C)c1N1[CH-]N(c2c(C(C)C)cccc2C(C)C)CC1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Cc2cccc(OC(F)(F)F)c2)cc1
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
A mixture of zinc (807 mg, 12.3 mmol) and lithium chloride (523 mg, 12.3 mmol) under argon was warmed for 10 minutes using a hot air gun, allowed to cool and then anhydrous THF (50 mL) added. The zinc was activated by treatment with 1,2-dibromoethane (39 mg, 0.21 mmol) and TMSCl (4.3 mg, 0.04 mmol). To the resulting mixture at 25° C. was added ethyl 4-(bromomethyl)benzoate (1.0 g, 4.15 mmol) and the mixture stirred for 15 minutes. 3-(Trifluoromethoxy)bromobenzene (694 mg, 2.88 mmol) was added, followed by (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride [PEPPSI™-SIPr] (28 mg, 0.04 mmol) and the mixture stirred at 25° C. for 1 hour. Saturated ammonium chloride solution was added and the crude product extracted with ether. The ether extract was washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by silica gel column chromatography eluting with 7:3 hexane:ethyl acetate to afford the title compound (950 mg, 71%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8]#[N:9])[CH3:5]>CO.O>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8](=[NH:9])[O:2][CH3:1])[CH3:5]
Reactant: CCOC(C#N)OCC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(OCC)C(=N)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a solution of sodium methoxide (13.38 g, 248 mmol) in MeOH (300 mL) was added dropwise 2,2-diethoxyacetonitrile (17.22 mL, 124 mmol). The resulting mixture was stirred at rt for 16 h. The reaction was then diluted with 300 mL of water and the product was extracted with 3×250 mL of Et2O. The combined Et2O layers were washed with 100 mL of brine, dried over sodium sulfate, and evaporated to give the desired product as a colorless liquid (15.3 g, 95 mmol, 77% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (1H, br. s.), 4.77 (1H, s), 3.78 (3H, s), 3.55 (4H, qd, J=6.97, 4.28 Hz), 1.21 (7H, t, J=7.05 Hz).
Reaction SMILES: N1([CH:10]=[O:11])C2C=CC=CC=2N=N1.[C:12]1([CH2:18][O:19][NH:20][CH2:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.O>[CH:10]([N:20]([CH2:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])[O:19][CH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: O=Cn1nnc2ccccc21
Reactant: CCCC[C@H](CNOCc1ccccc1)C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 1H-1,2,3-benzotriazole-1-carbaldehyde (26 g, 0.18 mol) in THF (200 ml) at 0° C. was added dropwise a solution of (2R)-2-({[(phenylmethyl)oxy]amino}methyl)hexanoic acid (8) (40 g, 0.16 mol) in THF (200 mL). The reaction mixture was warmed up to rt and stirred overnight. LC/MS indicated completion of the reaction. To the reaction mixture at 0° C. was added water (400 mL), Na2CO3 (36 g), and Boc2O (43.6 g, 0.36 mol). The mixture was stirred for 3 h. THF was removed under vacuum. The aqueous mixture was washed with ether and then acidified to pH ˜2.0 with acetic acid, and extracted with ethyl acetate. The extracts were dried and concentrated to provide the title compound (36.8 g, 80%). LCMS: (M+H)+: 280.2.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[CH:29]=3)=[C:26]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[N:25]=[CH:24]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[OH-].[Na+]>CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([O:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH:29]=3)=[C:26]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[N:25]=[CH:24]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(Cl)c2)CC1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(Oc3ccccc3)c2)CC1
Temperature: 120 °C
Yield: 63.2 %

Procedure:
To a stirring suspension of NaH (120 mg, 3.0 mmol) in DMA (1.3 mL) was added phenol (0.40 g, 4.25 mmol). After the bubbling cease, 1-(1-t-butoxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-chloro-4-pyridinyl)imidazole (0.20 g, 0.44 mmol) was added and the resulting solution was heated at 120° C. until no evidence of starting material was seen by mass spectroscopy (1-3 days). To the cooled solution was added 1M NaOH and the mixture was extracted thrice with EtOAc. The combined organic layers were washed with NaCl (sat.), dried over MgSO4, filtered, and evaporated under reduced pressure to give a light yellow solid. The solid was then chromatographed with 50-80% EtOAc/Hex to give the title compound as a white solid (143 mg, 64% yield). ES (+) MS m/e=515 (MH+)
Reaction SMILES: [CH2:1]([C:6]1([CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[CH2:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH2:17][CH2:18][CH3:19])[C:8]=2[O:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].[C:26]1([O:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:21]([C:6]1([CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:15]([O:20][CH2:39][CH2:38][CH2:37][O:36][C:26]3[C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=4[CH:29]=[CH:28][CH:27]=3)=[C:16]([CH2:17][CH2:18][CH3:19])[C:8]=2[O:7]1)[CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: C=CCCCC1(CCCC=C)CC(=O)c2ccc(O)c(CCC)c2O1
Reactant: BrCCCOc1cccc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCCC1(CCCC=C)CC(=O)c2ccc(OCCCOc3cccc4c3CCCC4)c(CCC)c2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of 3.0 g (9.55 mmol) of the title product of Example 69 and 4.01 g (11 mmol) of the title product of Example 12 in 56 ml of dry dimethylformamide (DMF) was added 2.77 g (20.1 mmol) of anhydrous potassium carbonate. The resulting mixture was stirred overnight at room temperature. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and 3N hydrochloric acid. The aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were washed with water and with brine, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. Chromatography of the residue over silica gel, using 10% ethyl acetate/hexane as eluent, gave the title compound (4.19 g) as an oil.