Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.CC(C)([O-])C.[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>C(#N)C.CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[N:11]1
Reactant: OCCCCCCCBr
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2Cl)n1)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2ccc(OCCCCCCCO)cc2Cl)n1)c1c(F)cccc1F
Temperature: 100 °C

Procedure:
To a solution of N-{1-[(2-chloro-4-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Example 31)(30 mg, 0.082 mmol) in acetonitrile (0.5 ml) was added potassium t-butoxide (9.4 mg, 0.084 mmol) and then 7-bromo-1-heptanol (0.015 ml, 0.099 mmol, Aldrich). The reaction vessel was sealed and heated in a Biotage Initiator microwave to 100° C. for 15 min. After cooling the reaction was diluted with DMSO (0.5 ml) and purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a colourless gum (6.7 mg);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:15](OS(C)(=O)=O)[CH2:16][C:17]#[N:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](/[CH:15]=[CH:16]/[C:17]#[N:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(CC#N)OS(C)(=O)=O)CC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1(/C=C/C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 99.4 %

Procedure:
To 4-(2-cyano-1-hydroxyethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (4.24 g, 15.8 mmol) and pyridine (3.07 mL, 39.5 mmol) dissolved in dichloromethane (45 mL) at 0° C. is added methanesulfonyl chloride (3.45 mL, 42.6 mmol). After 1 hour, the reaction is not complete and is warmed to room temperature. After 18 hours at room temperature 1 equivalent of pyridine and 1 equivalent of methanesulfonyl chloride is added and stirred for 4 hours. The reaction mixture is diluted with EtOAc and washed several times with saturated NaHCO3. The organic layer is dried over Na2SO4, filtered and concentrated to give crude 4-(2-cyano-1-methanesulfonyloxy-ethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester. Assuming 100% yield, 4-(2-cyano-1-methanesulfonyloxyethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (5.47 g, 15.8 mmol) and triethylamine (11.0 mL, 79 mmol) are dissolved in MeOH (60 mL) and heated at 70° C. for 1 hour and concentrated. The residue is dissolved in EtOAc and washed with water, then concentrated and chromatographed using 100% dichloromethane to give cis/trans-4-(2-cyanovinyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (3.93 g, 99% yield) as a clear oil.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][CH2:17][CH:18]([CH2:28][CH3:29])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)[CH3:15]>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH:18]([CH2:28][CH3:29])[CH2:17][O:16][CH2:14][CH3:15])=[CH:27][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: CCOCC(CC)Oc1ccc(CBr)cc1
Product: CCOCC(CC)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Yield: 24.8 %

Procedure:
Procedures similar to those in Preparation Example 8 were carried out by using 2.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 3.1 g of 4-(2-ethoxy-1-ethylethoxy)-benzyl bromide to obtain 1.0 g of the aimed compound as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20](OCC)=[O:21]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti]>[C:1]1([CH2:7][CH2:8][N:9]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:20]=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)CC(NCCc2ccccc2)CC(C)(C)N1
Reactant: CCOC=O
Agent: [Ti]
Solvent: CCCCO
Product: CC1(C)CC(N(C=O)CCc2ccccc2)CC(C)(C)N1

Procedure:
114 g of 4-(N-phenylethylamino)-2,2,6,6-tetramethylpiperidine and 41.3 g of tetrabutyl orthotitanate in 220 ml of ethyl formate were refluxed for 14.5 hours. After the volatile constituents had been distilled off at 140° C./1 mmHg, the solidified residue was recrystallized from petroleum ether. 4-(N-phenylethyl-N-formylamino)-2,2,6,6-tetramethylpiperidine of melting point 86° C. was isolated.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[N:4][N:3]=[N:2]1.[CH2:14]=[C:15]([CH3:17])[CH3:16].CS(O)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:15]([N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[N:4]1)([CH3:17])([CH3:16])[CH3:14]
Reactant: C=C(C)C
Reactant: O=Cc1cccc(-c2nnn[nH]2)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)n1nnc(-c2cccc(C=O)c2)n1

Procedure:
In an autoclave, 3.2 g (18.4 mmol) of 3-(tetrazol-5-yl)-benzaldehyde (see Step 59.1) in 22 ml of toluene are heated at 110° C. for 1.5 hours with ≈1.5 g of isobutene and 0.216 ml of methanesulfonic acid. When cold the reaction mixture is diluted with 200 ml of ethyl acetate, washed four times with water and once with brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/ethyl acetate=3:1) and crystallization from diethyl ether/hexane (−15° C.) yield 3-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde; TLC: Rf=0.41 (hexane/ethyl acetate=3:1); FAB-MS: (M+H)+=231.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:35])[C:15]2[O:21][C:20]3[C:22]([Cl:31])=[CH:23][C:24]([NH:26][C:27](=[O:30])[CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:33])(=[O:32])[C:16]=2[CH:34]=1)=[O:11]>CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:35])[C:15]2[O:21][C:20]3[C:22]([Cl:31])=[CH:23][C:24]([NH:26][C:27](=[O:30])[CH2:28][NH:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:33])(=[O:32])[C:16]=2[CH:34]=1)=[O:11]
Reactant: NC1CCCCC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CNC3CCCCC3)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Cyclohexyl amine (0.3 ml, 2.7 mmol) was added to a solution of Example 133 (0.4 g, 0.9 mmol) in DMF (10 mL). The reaction mixture was stirred at 80° C. for 3 h, concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.365 g (80%); 1H NMR (CDCl3): δ 1.21 (q, 2H, CH2), 1.25 (q, 2H, CH2), 1.63 (bs, 2H, CH2), 1.73 (bs, 2H, CH2), 1.88 (bs, 2H, CH2), 2.44 (m, 1H, CH), 2.77 (s, 3H, CH3), 3.4 (s, 2H, CH2), 3.9 (s, 3H, OCH3), 4.7 (s, 2H, CH2), 7.57 (d, 1H, Ar), 7.83 (d, 1H, Ar), 8.1 (s, 1H, Ar), 8.4 (s, 1H, Ar), 9.72 (s, 1H, NH); MS m/e (ES+) 507 (M+1).
Reaction SMILES: O.[CH3:2][O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]2[CH:10]=[C:11]3[O:21][CH2:20][CH2:19][O:18][C:12]3=[CH:13][C:14]=2[C:15]=1[CH2:16][Cl:17])=[O:5].P(Cl)(Cl)([Cl:25])=O>>[CH3:2][O:3][C:4]([C:6]1[C:7]([Cl:25])=[N:8][C:9]2[CH:10]=[C:11]3[O:21][CH2:20][CH2:19][O:18][C:12]3=[CH:13][C:14]=2[C:15]=1[CH2:16][Cl:17])=[O:5]
Reactant: COC(=O)c1c(CCl)c2cc3c(cc2[nH]c1=O)OCCO3
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1c(Cl)nc2cc3c(cc2c1CCl)OCCO3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 4-necked 5-L round-bottom flask is equipped with a mechanical stirrer and water-cooled condenser. Under nitrogen, the flask is charged with 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester (Intermediate 5, 360 g, 1.16 mol), as a suspension in phosphorus oxychloride (1.8 kg). The mixture is heated to reflux Generating a black solution. After being heated at reflux for 20 h, the reaction mixture is allowed to cool to ambient temperature and transferred to a 25-L separatory funnel containing 18 L of ice water. After being stirred vigorously for 1.5 h, the precipitate is collected on a Buchner funnel, washed with water (3 L) and dried in vacuo at 50° C. yielding 7-chloro-9-chloromethyl-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxlic acid methyl ester as a dark crystalline solid: mp 130-132° C. 1H NMR (CDCl3, 200 MHz) d 4.05 (s, 3H), 4.42 (s, 4H), 4.81 (s, 2H), 7.50 (s, 2H). Elemental analysis: Calculated for C14H11Cl2NO4: C 51.24, H 3.38, N 4.27. Found: C 51.10, H 3.34, N 4.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:9][C:8](=[CH:10][CH2:11]C(O)=O)[C:7]=2[CH:15]=1.C([N:18](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:9][C:8](=[CH:10][CH2:11][NH2:18])[C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)C(=CCC(=O)O)C2
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=CCN)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.1 g (10 mmol) of 3-(5-methoxybenzocyclobuten-1-ylidene)propionic acid and 1.4 ml (10 mmol) of triethylamine are introduced under argon into 20 ml of toluene. 2.2 ml (10 mmol) of diphenylphosphorylazide are added thereto and the whole is heated, while stirring, at 80° for 30 minutes. The mixture is allowed to cool to room temperature, 2.9 ml (20 mmol) of 2-trimethyl- silylethanol are added thereto and the whole is heated at 80° for 7 hours. The reaction mixture is then concentrated to dryness in a rotary evaporator. The oily residue is taken up in diethyl ether, washed with water and 2N sodium hydroxide solution, dried over sodium sulphate and concentrated by evaporation. The crude product is purified by chromatography on a silica gel column, stirred at 50° for 2 hours with 10 ml (10 mmol) of a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran and then concentrated to dryness by evaporation. The residue is stirred vigorously with n-pentane/water (1:1). The n-pentane phase is separated off and discarded. The aqueous phase is adjusted to pH 8 with ammonium chloride, whereupon a crystalline product precipitates. The latter is filtered off with suction. The mother liquor is saturated with sodium chloride, whereupon more product crystallises out. The crystallisates are combined, taken up in trichloromethane/methanol (1:1), dried over sodium sulphate and concentrated by evaporation. The crystalline residue is stirred with diethyl ether and then filtered. 2-(5-methoxybenzocyclobuten-1-ylidene)ethylamine of m.p. 238°-240° is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH2:9]([Li])[CH:10]=[CH2:11].O>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:8])[CH2:11][CH:10]=[CH2:9])=[CH:3][CH:2]=1
Reactant: O=Cc1ccncc1
Reactant: [Li]CC=C
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(O)c1ccncc1
Temperature: 0 °C
Yield: 63 %

Procedure:
4.75 g (50 mmol) of pyridine-4-carboxaldehyde was dissolved in 50 ml THF and cooled to 0° C. Allyl lithium was then added with stirring until the mixture turned the dark color characteristic of the allyl lithium solution. After stirring for an additional 5 minutes, water was slowly added at 0° C. until two phases formed and all precipitate was dissolved. The THF layer was separated, dried over MgSO4, and evaporated in vacuo to an oil. Flash chromatography yielded 4.69 g (63%) of product as an oil. 1H NMR (CDCL3): 8.5 and 7.3 (4H, pyridyl), 5.8 and 5.15 (3H, vinyl), 4.75 (1H, CHOH), 3.6 (1H, OH), and 2.5 (2H, CH2) ppm.
Reaction SMILES: [CH:1]([NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([C:26]3[C:31]([CH3:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[S:23][C:22]=2[CH:34]=1)(=[O:17])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:44][CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]1>O1CCOCC1>[CH:1]([NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([C:26]3[C:31]([CH3:32])=[CH:30][N:29]=[C:28]([NH:44][CH2:45][CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]4)[N:27]=3)[S:23][C:22]=2[CH:34]=1)(=[O:17])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(S(=O)(=O)NC(c3ccccc3)c3ccccc3)cc2s1
Reactant: CN1CCN(CCCN)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(S(=O)(=O)NC(c3ccccc3)c3ccccc3)cc2s1
Temperature: 97 °C

Procedure:
To a stirred suspension of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-sulfonic acid benzhydrylamide (457 mg, 0.903 mmol) in dry 1,4-dioxane (4.5 mL) is added diisopropylethylamine (0.315 mL, 1.81 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (213 mg, 1.35 mmol). The mixture is heated at 97° C. for 1 day. After concentration and subsequent chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane: 0-10%, the title compound is obtained as a yellow solid (317 mg, 57% yield). ES+(m/z) 627 [M+H].
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]1[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]#[N:23])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:10]1[CH2:11][CH2:12]1)[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]#[N:23])[CH2:18][CH2:17]1)=[O:15])([CH3:1])([CH3:3])[CH3:4]
Reactant: N#CC1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
In a round-bottomed flask, Boc-D-cyclopropylglycine (1.80 g, 8.36 mmol) and piperidine-4-carbonitrile (1.2 g, 10.9 mmol) were dissolved in DMF (30 ml). HATU (3.5 g, 9.2 mmol) and N,N-diisopropylethylamine (2.3 ml, 13.2 mmol) were added and the yellow solution was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 2.72 g (95%) of [(R)-2-(4-cyanopiperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a light yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:29]I>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]([CH3:29])[N:19]=[N:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(-c3nnnn3C)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C
Yield: 45.6 %

Procedure:
Into a round bottom flask containing a solution of 4-cyano-5-ethyl-1-methyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0.116 g, 0.331 mmol, prepared in example E-242) in DMF (2 mL) cooled to 0° C. while stirring add NaH (0.015 g, 0.364 mmol, 60% in mineral oil). Let stir for 20 min, then add methyl iodide (0.022 mL, 0.364 mmol) and let stir for 3 h. Dilute the mixture with brine (20 mL) and extract the mixture with EtOAc (3×30 mL). Combine the organic layers and wash with brine (2×30 mL), aqueous NH4Cl (1×30 mL), aqueous NaHCO3 (1×30 mL) and water (1×30 mL). Dry the organic layer over anhydrous Na2SO4, filter and concentrate under reduced pressure. Separate the two regioisomeric products via silica gel chromatography (eluent: 20 to 98% EtOAc in hexanes) and concentrate under reduced pressure the purified fractions. Place the residue under vacuum to give the title compound as a white solid (0.055 g); mass spectrum (m/e): 365.07 (M+H)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]([OH:32])[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
23.8 ml of diisopropylamine were initially charged under argon in 250 ml of THF and cooled to 0° C., and 70 ml of n-butyllithium solution (2.5 M in toluene) were added. The mixture was stirred at 0° C. for 30 minutes, then cooled to −75° C., 16.2 ml of ethyl acetate were added slowly and the mixture was stirred for 30 minutes. Then, at −75° C., 30 g of p-benzyloxybenzaldehyde, dissolved in 250 ml of THF, were added dropwise (internal temp. max. −68° C.; 1 h). The mixture was stirred for a further 20 minutes and then the reaction mixture was quenched with 200 ml of sat. NH4Cl solution and 20 ml of 1 N HCl (internal temp. max. −50° C.). The mixture was allowed to thaw to room temperature, the phases were separated and the organic phase was washed three times with 100 ml each time of sat. NH4Cl solution and once with 100 ml of sat. NaCl solution. The solvent was removed under reduced pressure. The residue was extracted by stirring with n-heptane/2% THF and the precipitated solid was filtered off with suction and dried under reduced pressure at 40° C. This gave 41 g of ethyl 3-(4-benzyloxyphenyl)-3-hydroxypropionate as a colorless solid.
Reaction SMILES: F[B-](F)(F)F.[C:6]([N+:10]1[O:11][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([CH3:20])=[CH:15][C:14]=12)([CH3:9])([CH3:8])[CH3:7].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[C:6]([N:10]1[C:14]2[CH:15]=[C:16]([CH3:20])[C:17]([Cl:19])=[CH:18][C:13]=2[C:12]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:11]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: Cc1cc2c(cc1Cl)c(-c1ccccc1)o[n+]2C(C)(C)C
Reactant: C1COCCN1
Agent: F[B-](F)(F)F
Product: Cc1cc2c(cc1Cl)C(c1ccccc1)(N1CCOCC1)ON2C(C)(C)C

Procedure:
To a flask containing 6 g. of 1-tert.-butyl-5-chloro-6-methyl-3-phenyl-2,1-benzisoxazolium tetrafluoroborate is added 9 ml. of morpholine and the mixture heated at 80°C. for 1 hour. The reaction mixture is washed in diethyl ether and water and the ether layer separated, dried, evaporated in vacuo to dryness and the residue recrystallized from ether/methylene chloride to obtain 1-tert.-butyl-5-chloro-6-methyl-3-morpholino-3-phenyl-2,1-benzisoxazoline, m.p. 131°-133°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@H:4]([NH:25]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:24]=[CH:23][C:9]2[N:10]=[C:11]([CH3:22])[N:12]([S:13]([CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])(=[O:15])=[O:14])[C:8]=2[CH:7]=1.COC(=O)[C@H](NC(OCC1C=CC=CC=1)=O)CC1C=CC2N(S(CC[Si](C)(C)C)(=O)=O)C(C)=NC=2C=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:36])[C@H:4]([NH2:25])[CH2:5][C:6]1[CH:24]=[CH:23][C:9]2[N:10]=[C:11]([CH3:22])[N:12]([S:13]([CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])(=[O:14])=[O:15])[C:8]=2[CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)[C@@H](Cc1ccc2nc(C)n(S(=O)(=O)CC[Si](C)(C)C)c2c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: COC(=O)[C@@H](Cc1ccc2c(c1)nc(C)n2S(=O)(=O)CC[Si](C)(C)C)NC(=O)OCc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](N)Cc1ccc2nc(C)n(S(=O)(=O)CC[Si](C)(C)C)c2c1
Yield: 80 %

Procedure:
A methanol (50 mL) suspension of (R)-2-benzyloxycarbonylamino-3-[2-methyl-3-(2-trimethylsilanyl-ethanesulfonyl)-3H-benzoimidazol-5-yl]-propionic acid methyl ester and (R)-2-Benzyloxycarbonylamino-3-[2-methyl-1-(2-trimethylsilanyl-ethanesulfonyl)-1H-benzoimidazol-5-yl]-propionic acid methyl ester (1:1 mixture, 600 mg), and 10% palladium on charcoal (180 mg) was agitated on a Parr apparatus overnight under 40 psi of hydrogen at room temperature. After replacing the hydrogen atmosphere with nitrogen, the mixture was filtered through a pad of celite. Solvents were removed in vacuo to afford the title compound as a tan solid (80%). 1H-NMR (CD3OD, 500 MHz) δ 7.81 (d, J=8.5, 0.5 Hz, 0.5H), 7.70 (s, 0.5H), 7.58 (d, J=8.5 Hz, 0.5H), 7.49 (s, 0.5H), 7.25 (d, J=9.0 Hz, 1H), 3.89 (dd, J=14.0, 6.5 Hz, 1H), 3.75 (s, 1.5H), 3.72 (s, 1.5H), 3.55–3.51 (m, 2H), 3.18 (d, J=6.0 Hz, 1H), 3.22–3.18 (m, 0.5H), 3.14–3.09 (m, 0.5H), 2.81 (s, 1.5H), 2.80 (s, 1.5H), 0.92–0.88 (m, 2H), 0.02 (s, 4.5H), 0.01 (s, 4.5H); 13CNMR (CD3OD, 125 MHz) δ 174.3, 174.1, 153.5, 153.3, 141.7, 140.6, 133.9, 133.82, 133.78, 132.7, 126.5, 126.3, 119.7, 119.0, 114.1, 113.4, 55.6, 51.8, 51.7, 51.6, 40.2, 39.8, 15.83, 15.77, 9.9, −3.07, −3.11. Mass spec.: 398.20 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(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: C1COCCO1
Product: CCOC(=O)c1ccc(-c2ccncc2)cc1
Temperature: 80 °C
Yield: 35.2 %

Procedure:
The 4-bromo-benzoic acid ethyl ester (1.00 g, 4.37 mmol), pyridine-4-boronic acid (537 mg, 4.37 mmol), and tetrakis(triphenylphosphine)palladium(0) (757 mg, 0.655 mmol) were degassed under nitrogen. The solids were dissolved in 15 mL of 1,4-dioxane and 2.6 mL of 2M sodium carbonate solution. The mixture was heated to 80° C. overnight completion and allowed to cool to room temperature. The contents were partitioned between ethyl acetate and water, and the aqueous was extracted with ethyl acetate. The combined organic was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 1:1 hexanes:EtOAc, Rf=0.2) to afford the pure 4-pyridin-4-yl-benzoic acid ethyl ester as a pale yellow solid (350 mg, 35%). 1H NMR (CDCl3, 400 MHz) δ 8.71 (d, J=4.4 Hz, 2H), 8.16 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.53 (d, J=4.4 Hz, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H). LCMS (APCI+) m/z 228 [M+H]+; Rt=2.81 min.