Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([CH:11]=[CH2:12])[C:3]([C:9]#[N:10])=[N:4][CH:5]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ncc(Cl)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=Cc1cc(Cl)cnc1C#N
Temperature: 100 °C
Yield: 67.9 %

Procedure:
A microwave vial was charged with 3-bromo-5-chloropicolinonitrile (1.40 g, 6.44 mmol) and dichlorobis(triphenyl-phosphine)palladium (II) (0.54 g, 0.77 mmol). The vial was evacuated and backfilled with nitrogen and 1,4-dioxane (10 mL) was added, followed by tri-n-butyl(vinyl)tin (2.45 mL, 7.73 mmol). The reaction mixture was heated at 100° C. for 1 h. The reaction mixture was diluted with water and EtOAc. The solvent was removed under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10% to 50% EtOAc in hexane, to provide 5-chloro-3-vinylpicolinonitrile (0.72 g, 4.37 mmol, 67.9% yield) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[CH:6]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:26](=[O:28])[CH3:27])[CH2:23][CH3:24])[CH:6]=1
Reactant: CC(=O)Cl
Reactant: CCNCc1cc(Br)ccc1Oc1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(Br)ccc1Oc1cc(CC(=O)OC)ccc1OC)C(C)=O

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: [3-(4-bromo-2-ethylaminomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12](=[CH2:15])[CH2:13][OH:14].[OH-].[K+].O>CS(C)=O>[CH3:15][C:12]([CH2:13][O:14][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5])=[CH2:11]
Reactant: N#Cc1c(Cl)cccc1Cl
Reactant: C=C(C)CO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=C(C)COc1cccc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
A solution of 30.0 grams (0.174 mole) of 2,6-dichlorobenzonitrile and 14.7 mL (0.174 mole) of 2-methyl-2-propen-1-ol in 200 mL of dimethyl sulfoxide was stirred, and 12.7 grams (0.191 mole) of 85% potassium hydroxide was added portionwise during a 5 minute period. During the addition, the reaction mixture temperature rose from 20° C. to about 35° C. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was poured into 600 mL of water. The mixture was filtered to collect a solid. The solid was washed with water and dried under vacuum, yielding 33.9 grams of 2-methyl-3-(3-chloro-2-cyanophenoxy)-1-propene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc(N3CCOCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 47.2 %

Procedure:
A mixture of 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide (0.1 mmol) and morpholine (0.087 ml, 1.0 mmol) in DMSO (0.5 ml) is heated at 80° C. for 6 h. The resulting mixture is diluted with CH2Cl2 (2 ml), washed with 0.01 N NaOH, and dried over sodium sulfate. After evaporation to dryness, the residue is purified by column chromatography on silica gel (50% EtOAc in hexane) to give 3-fluoro-5-morpholin-4-yl-N-{4-[(2-morpholin-4-ylpyrimidin-4-yl)oxy]-1-naphthyl}benzamide as a white solid (25 mg). Mp: 104-106° C.; 1H NMR (300 MHz, CDCl3) δ 3.26 (bs, 4H), 3.64 (bs, 8H), 3.87 (bs, 4H), 6.07 (d, J=4.5 Hz, 1H), 6.77 (d, J=11.7 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 7.32 (bs, 2H), 7.52-7.59 (m, 2H), 7.89-8.00 (m, 3H), 8.12-8.19 (m, 2H); MS: 530 (M+1).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]3[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]3)[CH:13]=2)[O:8]1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30]([CH2:33][NH2:34])[C:29]([CH3:35])=[N:28]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]3[CH2:23][CH2:22][CH:21]([NH:34][CH2:33][C:30]4[C:29]([CH3:35])=[N:28][N:27]([CH3:26])[C:31]=4[CH3:32])[CH2:20][CH2:19]3)[CH:13]=2)[O:8]1
Reactant: Cc1ccccc1C1CCc2cc(OC3CCC(=O)CC3)ccc2O1
Reactant: Cc1nn(C)c(C)c1CN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccccc1C1CCc2cc(OC3CCC(NCc4c(C)nn(C)c4C)CC3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 100 mg 4-(2-o-tolyl-chroman-6-yloxy)-cyclohexanone (0.30 mmol) in 2 ml of methanol and 0.15 ml of acetic acid at room temperature 124 mg (1,3,5-trimethyl-1H-pyrazol-4-yl-methyl)amine (0.89 mmol) and 56 mg of sodium cyanoborohydride (0.89 mmol) were added in one portion and stirring at room temperature was continued for 2 h. Volatile components were removed under reduced pressure and the resulting residue dissolved in dichloromethane. The organic layer was washed with aqueous 2N sodium hydroxide solution and saturated aqueous sodium chloride solution. The organic layer was dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by reversed phase HPLC. 132 mg of the title compound were isolated.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([O:40][C@@:6]2([OH:8])[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]2[CH:9]([CH3:11])[CH3:10])=[O:39])=[CH:41][CH:42]=1)([O-:33])=[O:32].[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:10])[CH3:11])[CH:6]([OH:8])[CH2:7]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@]1(O)OC(=O)c1ccc([N+](=O)[O-])cc1
Product: CC1CCC(C(C)C)C(O)C1
Reaction time: 17 h

Procedure:
After L-menthol (300 mg, 1.92 mmol), triphenylphosphine (605 mg, 2.30 mmol), 4-nitrobenzoic acid (385 mg, 2.30 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (540 mg, 2.30 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 17 hours. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (1S,2S,5R)-1-(4-nitrobenzoyloxy)-2-isopropyl-5-methyl cyclohexanol as a white solid substance (430 mg, yield: 73%/L-menthol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])=[CH:24][CH:25]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1cccc2cc(C(=O)Nc3ccc(C(C)(C)C)cc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and 4-t-butylaniline to give N-(4-t-butylphenyl)-7-methoxybenzofuran-2-carboxamide (Compound 389a). Successively, it was formylated to give N-(4-t-butylphenyl)-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 389b) then compound 389b was reacted with cyclobutylamine to give compound 389 as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:21][C:22]1([CH3:25])[CH2:24][O:23]1>C(Cl)Cl>[CH3:21][C:22]([OH:23])([CH3:25])[CH2:24][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 120 °C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.57 mmol), Cs2CO3 (840 mg, 2.57 mmol) and 2,2-dimethyloxirane (2 mL) was heated in a sealed vial at 120° C. for 3 minutes with stirring in a Smith Synthesizer microwave (at 300 W), then allowed to cool and diluted with CH2Cl2. The resulting suspension was filtered, the filtrate was concentrated to afford the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[C:14](=[O:27])[CH2:13]3)[NH:8][C:7]=2[CH:28]=1.[NH3:29]>CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH2:29])=[NH:24])=[CH:25][CH:26]=4)[C:14](=[O:27])[CH2:13]3)[NH:8][C:7]=2[CH:28]=1
Reactant: N
Reactant: N#Cc1ccc(CN2CCC(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1
Agent: Cl
Solvent: CO
Product: N=C(N)c1ccc(CN2CCC(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1
Temperature: 0 °C

Procedure:
Hydrochloric acid is bubbled into an ice cooled solution of 4-[4-(6-chloro-1H-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-1-ylmethyl]-benzonitrile (127 mg, 0.336 mmol) in 10 mL of methanol. The solution also contained 3Å molecular sieves. The reaction is stored at −30 for forty-eight hours. The methanol is condensed on the rotovap. Fresh methanol (15 mL) is added followed by a stream of ammonia gas. The reaction is heated to reflux for two and half hours. The reaction mixture is filtered at room temperature. Methanol is removed from the mother liquor. The resulting residue is purified by reverse phase HPLC (0-50% ACN/H2O). The product is isolated as a white solid with a melting point of 105-110° C. C21H22ClN5O MS m/z: 396,398. Anal. cald. for C21H22ClN5O.2C2HF3O2: C; 48.13; H, 3.88; N,11.22. Found: C, 45.05; H, 3.52; N, 9.89.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[CH:16][C:15](N)=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].[S-:23][C:24]#[N:25].[NH4+:26].C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.C(OCC)(=O)C.O>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[C:16]1[N:25]=[C:24]([NH2:26])[S:23][C:15]1=[CH:14][CH:13]=3)=[O:6])([CH3:2])[CH3:3]
Reactant: [NH4+]
Reactant: N#C[S-]
Reactant: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(N)cc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc4sc(N)nc4c3c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
297 mg of 6-amino-4-ethyl-β-carboline-3-carboxylic acid isopropyl ester is dissolved in 5 ml of acetic acid, mixed with 152 mg of ammonium thiocyanate and stirred for 1 hour at room temperature. Then, the reaction solution is cooled to 10° C. and mixed drop by drop with 0.05 ml of acetic bromine solution (0.5 ml of BR2 in 9.5 ml of acetic acid). It is stirred for 1 more hour at 10° C. and then heated to room temperature. The reaction mixture is taken up in ethyl acetate/water and neutralized with 10% K2CO3 solution. The organic phase is separated, dried and evaporated to dryness. The residue is triturated with ether. 214 mg of the title compound with a melting point of 160° C. (decomposition) is obtained.
Reaction SMILES: [C:1]([O:5]CC#C)(=[O:4])[CH:2]=[CH2:3].[CH:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1.C[SiH](C)Cl>>[CH:11]12[CH2:12][CH:13]([CH:9]=[CH:10]1)[CH2:3][CH:2]2[C:1]([OH:5])=[O:4]
Reactant: C1=CCC=C1
Reactant: C#CCOC(=O)C=C
Agent: C[SiH](C)Cl
Product: O=C(O)C1CC2C=CC1C2
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The propargyl ester of 2-norborn-5-ene carboxylic acid was prepared by Diels-Alder reaction of propargyl acrylate and cyclopentadiene at ambient temperature. Dimethylchlorosilane (56.4 g) was added portionwise to 100 grams of this norbornene carboxylate ester and 0.16 g Karstedt catalyst under nitrogen at 70° C. After exotherming to 80° C., the mixture was stirred for 3 hours at 70° C., stripped under light vacuum and then distilled. The product, ##STR12## (84% purity by GC), distilled at 100°-105° C. at 0.07 mm.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][CH3:22])[CH3:20]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Oc1ccccc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Phenol (28.5 g, 0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromobutyrate (0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=[O:6].O.P([O-])(O)(O)=[O:30].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.CC(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[C:5]([OH:30])=[O:6]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 72 h

Procedure:
To a slurry of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (3.80 g, 10.1 mmol) and sodium dihydrogenphosphate hydrate (7.00 g, 50.7 mmol) in 40 mL 1:1 water/t-BuOH under nitrogen was added 2-methylbut-2-ene (37.6 mL, 355 mmol) and sodium chlorite (4.59 g, 50.7 mmol). The reaction mixture was allowed to stir rapidly for 3 days. The thick reaction mixture was concentrated in vacuo to remove the 2-methyl-2-butene, and the slurry diluted with water and filtered, rinsing water and MeOH. The resulting solid was dried in vacuo to give 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid as an off-white solid which was used without further purification. MS (ESI) m/z: Calculated: 390.1; Observed: 391.1 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]1([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:34](=[O:35])[CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 64 h

Procedure:
A solution of 1.00 g (3.78 mmole) of (S)-4-(benzyloxycarbonyl)piperazine-2-carboxylic acid (from Example 7, Step A) in 10 ml of DMF at 25° C. was treated with 0.755 g. (7.46 mmole) of triethylamine. The solution was cooled to 0° C. and 0.95 g (4.12 mmole) of diphenylacetyl chloride was added in Portions over 2 hours. The solution was stirred at 25° C. for 64 hours, concentrated in vacuo and partitioned between 60 ml. of 1N HCl and 60 ml of ethyl acetate. The ethyl acetate was dried over sodium sulfate, concentrated in vacuo and chromatographed in two portions over an 85×2.5 cm LH-20 column with 11 ml fractions of methanol. Fractions 38-41 from both columns were combined and concentrated in vacuo to 785 mg (44%) of oil which was homogeneous by TLC (80:20:2 chloroform-methanol-ammonia water, Rf =0.40).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][C:9](=O)[C:8]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:29])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:29][C:9]1[C:8]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:19])([F:18])[F:20])[CH:15]=2)[N:10]=1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2c(-c2ccccc2)c1-c1nnn[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Temperature: 70 °C
Yield: 63.6 %

Procedure:
4-Phenyl-3-(1H-tetrazol-5-yl)-6-trifluoromethyl-1H-quinolin-2-one (160 mg, 448 μmol) was twice co-evaporated with toluene (5 ml). Then toluene (5 ml), phosphorus oxychloride (446 mg, 271 μl, 2.91 mmol) and N,N-diisopropylethylamine (72.3 mg, 97.8 μl, 560 μmol) were added and the mixture was heated to 70° C. for 5 h. Then all volatiles were removed and toluene (5 ml) was added and evaporated twice. Then ethanol (5 ml) was added and evaporated. Water and methanol were added to the remaining residue and the solid was filtered off and dried to obtain the title compound (107 mg, 64%) as brown solid. MS (ESI): 374.3 (M−H)−.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C@H:11]([OH:15])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20]O>>[O:1]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C@H:11]([OH:15])[C:12]([O:14][CH3:20])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Product: COC(=O)[C@@H](O)c1cccc(Oc2ccccc2)c1
Reaction time: 24 h

Procedure:
(S)-3-Phenoxymandelic acid (13.0 g) was added to a solution of dry hydrogen chloride (15.0 g) in methanol (100 ml) and the solution thus obtained kept at the ambient temperature for 24 hours after which period the volatile portion was evaporated yielding methyl (S)-3-phenoxymandelate as a residual oil. This was then added to liquid ammonia (20 ml) in a pressure vessel which was then sealed and temperature of the mixture allowed to rise to the ambient temperature over a period of 24 hours. The vessel was then opened and the excess of ammonia allowed to evaporate. The residual material was stirred with water and the solid collected by filtration, and recrystallised from benzene (70 ml) to yield impure (S)-3-phenoxymandelamide, m.p. 93° C. [α]D25 +25.4° (C, 2.0, methanol), (approximately 80% optically pure).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[O:5].[Si:15]([O:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Si:15]([O:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[O:5])=[O:36])([C:28]([CH3:30])([CH3:31])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)NCC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of 2-amino-1-(3-nitrophenyl)ethanone HCl salt (300 mg, 1.38 mmol) and 3-{[tert-butyl(diphenyl)silyl]oxy}-2,2-dimethylpropanoic acid (543 mg, 1.52 mmol) in DMF (1.3 mL) was added HATU (579 mg, 1.52 mmol) and the mixture was cooled to 0° C. Hunig's base (726 μL, 4.15 mmol) was added, and the mixture was stirred for two hours at this temperature. The mixture was diluted with ethyl acetate (30 mL), then washed with 1:1 water:saturated NaHCO3(aq) (30 mL) and 1:1 water:brine (2×30 mL). The aqueous fractions were further extracted with ethyl acetate (30 mL), then the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by chromatography on silica gel (100:0 to 50:50, hexanes:ethyl acetate) provided 680 mg of 3-{[tert-butyl(diphenyl)silyl]oxy}-2,2-dimethyl-N-[2-(3-nitrophenyl)-2-oxoethyl]propanamide (1.31 mmol, 95%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([CH2:18][O:19][C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[CH2:26]Br>>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[CH2:26][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Fc1cccc(F)c1CBr
Reactant: CC(=O)OCc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Product: CC(=O)OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 118.4 %

Procedure:
2-(2,6-Difluorophenyl)-4-acetoxymethylbenzimidazole (Example 101) (3.55 g, 11.74 mmol) and 2,6-difluorobenzylbromide (3.40 g, 16.4 mmol, 140 M %) were reacted. The crude product was purified using flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether, yielding white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetoxymethylbenzimidazole (5.94 g, 13.9 mmol, 76% yield). M.p. 126-127° C. 1HNMR (300 MHz, CD2Cl2): δ 7.54 (m, 1H, H4′), 7.48 (m, 1H, H6), 7.33-7.27 (m, 2H, H5,7), 7.25 (m, 1H, H4″), 7.08 (m, 2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.54 (s, 2H, CH2PhF2), 5.36 (s, 2H, CH2O), 2.08 (s, 3H, OAc).