Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](/[C:3](=[CH:6]\[CH2:7][C@@H:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])/[CH:4]=[O:5])[CH3:2].CC1C2C(C)(C)C(C2)CC=1>>[CH2:1](/[C:3](=[CH:6]\[CH2:7][C@@H:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:14])[CH3:15])/[CH2:4][OH:5])[CH3:2]
Reactant: CC/C(C=O)=C\C[C@@H]1CC=C(C)C1(C)C
Agent: CC1=CCC2CC1C2(C)C
Product: CC/C(=C\C[C@@H]1CC=C(C)C1(C)C)CO

Procedure:
(E)-(S)-2-Ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-al synthesized from 1R,5R)-α-pinene having an optical purity of 97% e.e. (available from Aldrich) was hydrogenated in the same manner as in Example 2 to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[Na+].O>CS(C)=O>[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CC(C)(C)C(=O)CBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)CC(=O)C(C)(C)C)cc1
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of 1-bromo-3,3-dimethyl-2-butanone (33.3 g, 0.19 mole) in dimethylsulfoxide (330 ml), sodium p-toluenesulfinate (34.9 g, 0.20 mole) was added at 30°-40° C., and reacted with stirring at 60°-70° C. for 18 hours. The reaction mixture was poured into cold H2O (2 liter). The precipitate was filtered, washed with H2O and dried to afford 41.6 g of 1-(p-toluenesulfonyl)-3,3-dimethyl-2-butanone as white crystals. m.p. 119°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([CH2:14][CH3:15])[C:9](=[O:13])[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:33][CH2:34]Br>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([C:9]2[O:13][CH2:33][CH2:34][C:10]=2[C:11]#[N:12])[CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCC(C(=O)CC#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C1=C(C#N)CCO1)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of N-(1-(3-(4-chlorophenyl)-1-cyano-2-oxopentan-3-yl)-1H-indol-4-yl)methanesulfonamide (50 mg, 0.116 mmol, enantiomer A), as described in Example 28 step A, in DMF (2 mL) was added NaH (9 mg, 0348 mmol, 60% in oil) at 0° C. After stirring for 30 min, 1,2-dibromoethane (22 mg, 0.116 mmol) was added to the mixture at 0° C. The resulting mixture was stirred at 0° C. for another 1 h, and then quenched with water (15 mL), extracted with ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with PE/EA (5/1 to 3/1, v/v) to give the title compound as a colorless amorphous solid. LC/MS m/z=456.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][C:20]([OH:22])=[O:21])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1
Yield: 98.9 %

Procedure:
A solution of t-butyl 3-methoxy-4-phenylureidophenylacetate (0.108 g, 0.303 mmol) in trifluoroacetic acid (5.0 mL) was stirred for 30 min. The reaction was concentrated and the residue coevaporated with methylene chloride (2×) then ether to afford 3-methoxy-4-phenylureidophenylacetic acid (0.090 g, 99%) as a white foam: 1H NMR (CD3SOCD3, 300 MHz, ppm) 9.28 (s,1H), 8.18 (s, 1H), 8.02 (d, 7.5 Hz, 1H), 7.58-7.15 (m, 5H), 6.91 (bm, 2H), 6.77 (d, 7.5 Hz, 1H), 3.85 (s, 3H), 3.49 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:11]=[C:12]([CH3:25])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)=O>C(O)(=O)C>[CH3:25][C:12]1[CH:11]=[N:1][C:2]2[N:3]([N:4]=[CH:5][C:6]=2[C:7]#[N:8])[C:13]=1[C:15]1[CH:16]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:19][CH:20]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: Cc1cnc2c(C#N)cnn2c1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 1.08 g. of 3-aminopyrazole-4-carbonitrile, 25 ml. of glacial acetic acid and 2.57 g. of 3-dimethylamino-2-methyl-3'-(trifluoromethyl)acrylophenone is refluxed for 8 hours and then evaporated to a crystalline solid. A methylene chloride solution of this solid is treated as described in Example 1, giving the desired product, m.p. 191°-193° C.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].S(Cl)(=O)(=O)N.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+].[Cl-]>CN1C(=O)CCC1.C(O)=O>[C:13]1([O:19][S:2](=[O:3])(=[O:4])[NH2:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: NS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O=CO
Product: NS(=O)(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A three necked round bottom equipped with a reflux condensor was charged with chlorosulfonyl isocyanate (5.25 ml, 0.06 mol) and cooled to 0° C. Formic acid (2.25 mL, 0.06 mol) was added dropwise with rapid stirring with rapid gas evolution observed. Upon complete addition of formic acid, the reaction was let warm to room temperature. After 2 h, the resultant reaction vessel containing the solid sulfamoyl chloride was cooled to 0° C. and phenol (1.88 g, 0.02 mol) dissolved in NMP (25 mL) was added dropwise via an addition funnel. The reaction was let warm to room temperature. After 3 h stirring, the reaction mixture was poured into cold saturated aqueous NaCl (120 mL) and extracted with EtOAc. After removal of the separated organic solvent, the crude product was purified by column chromatography on silica (35% EtOAc/hexane) to provide sulfamic acid phenyl ester (2.8 g, 81%): LCMS found 173.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:68]1([CH2:74][C@H:75]([C:77]([OH:79])=[O:78])[NH2:76])[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]1.[BH4-].[Na+]>CN(C=O)C.C(O)(=O)C.C(#N)C.C([O-])(=O)C.[NH4+].CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:76][C@@H:75]([C:77]([OH:79])=[O:78])[CH2:74][CH:68]3[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]3)=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Agent: CC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (30 mg, 0.0555 mmol) and N-methylmorpholine (30 mg, 0.296 mmol) were dissolved in DMF (0.5 ml). TBTU (23 mg, 0.0717 mmol) was added and the mixture was stirred for 15 min at room temperature. 3-Cyclohexyl-D-alanine (15 mg, 0.0876 mmol) was added and the stirring was continued overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol (1 ml). NaBH4 (10 mg, 0.264 mmol) was added and the mixture was stirred for 10 min at room temperature. Three drops of acetic acid was added to the reaction mixture. The product was isolated by preparative HPLC using acetonitrile/ammonium acetate buffer (40:60) as eluent. After freeze-drying 19 mg (49%) of the title compound was obtained. 1H-NMR, 300 MHz, DMSO): 0.68-0.93 (m, 2H), 1.0-1.75 (m, 1H), 2.78-3.00 (m, 2H), 3.73 (s, 2H), 4.00-4.14 (m, 1H), 4.23-4.35 (m, 1H), 4.51 (s, 2H), 4.65-4.78 (m, 1H), 4.99-5.09 (m, 1H), 6.90-7.44 (m, 12H), 7.72-7.86 (m, 1H), 8.26 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:16]([O:18][C:19](=[O:25])[CH:20]=[CH:21][N:22]([CH3:24])[CH3:23])[CH3:17].C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH2:16]([O:18][C:19](=[O:25])[C:20]([C:7]([C:4]1[CH:3]=[C:2]([Cl:1])[O:6][N:5]=1)=[O:9])=[CH:21][N:22]([CH3:24])[CH3:23])[CH3:17]
Reactant: O=C(O)c1cc(Cl)on1
Reactant: CCOC(=O)C=CN(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
A solution of 5-chloro-isoxazole-3-carboxylic acid (791 mg, 5.43 mmol) (preparation described in WO03093250 A2) in dichloromethane (27.2 mL, 0.2M) cooled to 0° C. was treated with oxalyl chloride (0.71 mL, 8.15 mmol, 98%) followed by a few drops of N,N-dimethylformamide. The reaction was allowed to gradually warm up to 25° C. The reaction was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The resulting residue was dissolved in dichloromethane and re-concentrated twice to remove residual oxalyl chloride. The residue was then dissolved in dichloromethane (16 mL, 0.34M) and treated dropwise with a solution of ethyl-3-(dimethylamino)acrylate (0.79 g, 5.51 mmol) in triethylamine (1.6 mL, 11.47 mmol). The resulting red/orange reaction solution was heated to 60° C. overnight. At this time, the reaction was cooled to 25° C. and then partitioned between water (50 mL) and dichloromethane (100 mL). The organics were then washed with water (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Biotage chromatography (40M column, 50-60% ethyl acetate/hexanes) afforded 2-(5-chloroisoxazole-3-carbonyl)-3-dimethylamino-acrylic acid ethyl ester (300.6 mg, 20%) as a red oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH2:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br.C(O)(=O)C>O>[NH2:13][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(O)cc(C(F)(F)F)c1
Temperature: 140 °C
Yield: 81 %

Procedure:
To a round bottom flask was added 3-methoxy-5-trifluoromethyl-phenylamine (1.0 g, 5.23 mmol), 10 mL HBr (49% aq.), and 8 mL glacial acetic acid. A reflux condenser was attached and the solution heated to 140° C. for 20 h. The reaction was then diluted with water and neutralized to ˜pH 7 by slow addition of saturated NaHCO2. The aqueous solution was then extracted into EtOAc twice. The organic layers were combined, washed once with brine, dried over Mg2SO4, filtered, and concentrated in vacuo to yield the title compound as a tan solid (750 mg). MS (M+H)+=178; Calc'd 177.12 for C7H6F3NO.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C>[N:25]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:23]=[CH:22][S:21][CH:20]=4)=[CH:13][C:12]3=[O:24])=[CH:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=c1cc(OCc2ccsc2)ccn1CCc1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: CC#N
Product: O=c1cc(OCc2ccsc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 150 mg (0.37 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(thiophen-3-ylmethoxy)-1H-pyridin-2-one (example 4.1b) in 1.5 mL acetonitrile is added at RT 122 μL (1.48 mmol) pyrrolidine. The reaction mixture is stirred for 2 h at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccc(C(=O)OC)cc1OC
Solvent: CC(=O)O
Product: CCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Temperature: 50 °C

Procedure:
Dissolved 5.00g (23.7 mmol) methyl 4-ethoxy-3-methoxybenzoate in 25 ml acetic acid under N2 and added 6.1 ml (95.1 mmol) 69% nitric acid dropwise over 30 minutes. Heated to 50° C. for 1.5 hours and poured onto ice bath. Extracted with chloroform, washed with dilute sodium hydroxide solution and filtered through magnesium sulfate. Stripped solvent and dried in vacuo, giving 5.268 of off-white solid: mass spectrum (electrospray m/e): M+H=255.8.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][S:24](=[O:35])[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: C[C@]1(COc2ccc(N3CCSCC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@]1(COc2ccc(N3CCS(=O)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.4 %

Procedure:
(R)-2-Methyl-6-nitro-2-[4-(thiomorpholin-4-yl)phenoxymethyl]-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 137 (85 mg, 0.23 mmol) was dissolved in methylene chloride (5 ml). To the solution, m-chloroperbenzoic acid (59 mg, 0.24 mmol) was added followed by stirring at room temperature for 20 minutes. The reaction mixture was diluted with methylene chloride. The solution was washed with a sodium thiosulfate solution, a saturated sodium hydrogencarbonate solution and a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was crystallized from methylene chloride-isopropyl ether to afford (R)-2-methyl-6-nitro-2-[4-(1-oxothiomorpholin-4-yl)phenoxymethyl]-2,3-dihydroimidazo[2,1-b]oxazole (59 mg, yield 67%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:34])[C:11]([O:32][CH3:33])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:31])=[C:18]([CH:27]=[CH:28][C:29]=3[CH3:30])[O:19][CH2:20][C:21]([O:23]C(C)C)=[O:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:34])[C:11]([O:32][CH3:33])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:31])=[C:18]([CH:27]=[CH:28][C:29]=3[CH3:30])[O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(C)ccc(OCC(=O)OC(C)C)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(C)ccc(OCC(=O)O)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
To a solution of isopropyl 2-[3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]-2,4-dimethyl-phenoxy]acetate (155 mg, 0.33 mmol, 1.0 eq) in THF (4 mL) was added LiOH (2M aqueous solution, 4 mL, 8 mmol). The reaction mixture was stirred at room temperature for 2 h then the THF was removed under reduced pressure. The aqueous solution that remained was diluted with water and the pH adjusted to 4-6 with diluted HCl. The solid precipitate that formed was collected by filtration, washed with water and dried in vacuo to give a partially purified product. This material was further purified by preparative HPLC to give the title compound as a yellow solid (30 mg, 21%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:5]=1[C:6](OCC)=[O:7])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OC(=O)C)C.Cl>O1CCCC1.CCCCCC.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:5]=1[CH2:6][OH:7])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1CO

Procedure:
Ethyl 2-ethoxy-6-pentadecyl-benzoate (10.9 g, 27 mmol) was dissolved in dry tetrahydrofuran (60 mL). This solution was transferred to dry 250 mL three neck round bottom flask fitted with reflux condenser, mechanical stirrer and it was maintained under nitrogen atmosphere through out the reaction. To this lithium aluminum hydride (2.04 g, 54 mmol) was added slowly. Reaction was highly exothermic. After addition the solution was slowly brought to the reflux temperature and maintained at that temperature for about two hours and TLC was checked in hexane:EtOAc (8:2). After completion of reaction, excess lithium aluminum hydride was decomposed by drop-wise addition of ethylacetate (80 mL). To this 5 M HCl (100 mL) was added and organic layer was separated, dried over anhydrous sodium sulphate, concentrated under vacuum to give a light brownish solid. This was recrystallised from petroleum ether (40-60° C.) to give white solid. Yield: 8 g.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:24]([O-:26])=[O:25])[NH2:23].[Na+].CO>COCCOC.Cl>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:16]=2)([C:24]([OH:26])=[O:25])[NH2:23])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC(C(=O)[O-])c1ccccc1F
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: Cl
Agent: [K]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: NC(C(=O)O)(c1ccccc1)P(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
A solution of 3.07 g (16.5 mmol) of diphenylphosphine in 60 ml of 1,2-dimethoxyethane was admixed with 0.64 g (16.5 mmol) of potassium. After the metallation reaction was complete, 3.0 g (15.7 mmol) of sodium 2-(2-fluorophenyl)glycinate were added and the reaction mixture was heated at 80° C. for 3 hours. Subsequently, 10 ml of methanol were added and the volatile constituents were removed at 80° C. at a pressure of 10−2 bar. The residue obtained was suspended in 500 ml of dilute aqueous hydrochloric acid (pH=4) and filtered, and then dried at 20° C. and 10−2 bar. The yield was 4.7 g (89%). For the further work-up, the product was recrystallized from a 3:1 mixture of water and methanol. The 1H, 13C{1H} and 31P{1H} NMR spectra were recorded on a Bruker AC 250 spectrometer; the mass spectra were recorded on a Varian MAT 311 A instrument.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:31]=[CH:30][C:11]([CH2:12][N:13]2[C:17]3([CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:18]3=[O:28])[CH2:16][C@@H:15]([OH:29])[CH2:14]2)=[CH:10][CH:9]=1.[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C1(C)C=CC=CC=1.C(O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]1([N:19]2[CH2:20][CH2:21][C:17]3([N:13]([CH2:12][C:11]4[CH:30]=[CH:31][C:8]([C:35]5[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=5)=[CH:9][CH:10]=4)[CH2:14][C@H:15]([OH:29])[CH2:16]3)[C:18]2=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2Cc1ccc(Br)cc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2Cc1ccc(-c2ccncc2)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A solution of sodium carbonate (10.0 mg, 0.0000943 mol) in water (0.1 mL) was added to a mixture of (3R)-1-(4-bromobenzyl)-7-cyclohexyl-3-hydroxy-1,7-diazaspiro[4.4]nonan-6-one (19.0 mg, 0.0000466 mol; prepared as Example 37), 4-pyridinylboronic acid (8.60 mg, 0.0000700 mol) and tetrakis(triphenylphosphine)palladium(0) (1.6 mg, 0.0000014 mol) in toluene (200 μL, 0.002 mol) and ethanol (100 μL, 0.002 mol). After stirring the mixture at 120° C. for 6 h, the inorganics were separated by filtration and the filtrate was diluted with methanol and adjusted to a pH of ˜2.0 with TFA. The crude product was purified by prep. HPLC to afford the desired product. LC/MS 406.2 (M+1H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=1O.CCN=C=NCCCN(C)C.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>O1CCOCC1.O.C(Cl)(Cl)Cl.CN(C=O)C>[C:28]([C:26]1[CH:25]=[CH:24][C:23]2[O:20][C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)=[N:21][C:22]=2[CH:27]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Reactant: CC(C)(C)c1ccc(O)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1nc2cc(-c3nc4cc(C(C)(C)C)ccc4o3)ccc2n1C1CCOCC1
Yield: 48.8 %

Procedure:
2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (250 mg, 0.842 mmol), 2-amino-4-tert-butylphenol (139 mg, 0.842 mmol), DMF (2 mL), chloroform (5 mL) and WSC (178 mg, 0.926 mmol) were stirred for 22 hours. Water was added, and the solid obtained was filtered off, washed with water, and dried to give a solid that was taken up in dioxane (5 mL) to which was added methanesulfonic acid (140 mg, 1.46 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water and saturated aqueous sodium hydrogen carbonate solution were added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (160 mg, 49% yield) as white crystals.