Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](C(Cl)=O)=[CH:3][CH:2]=1.C(O)CCCCCCCCC[OH:28].C(N(CC)CC)C>O1CCCC1>[C:1]1(=[O:28])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: OCCCCCCCCCCO
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C=CC=C2C1=Cc1ccccc12
Reaction time: 0.5 h

Procedure:
A 4.85 g quantity of 9-fluorenone-4-carbonyl chloride (0.02 mole, obtained from Aldrich Chemicals Co, Milwaukee, Wis. 53201, USA) and 100 ml of tetrahydrofuran (obtained from Aldrich) were added to a 250 ml, 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was stirred for about ½ hour, and then 1.74 g of 1,10-decanediol (0.01 mole, obtained from Aldrich) in 50 ml of tetrahydrofuran were added, followed by the addition of 2 g of triethylamine (0.02 mole, obtained from Aldrich). The solution was refluxed for 6 hours and filtered hot to remove triethylamine hydrochloride salt by-product, and the filtrate was evaporated to dryness. A liquid product was obtained, which solidified upon standing at room temperature for a couple of hours. The crude product was recrystallized from ethyl acetate with activated charcoal. The product was dried at 60° C. in a vacuum oven for 6 hours to yield a second dimeric fluorenone derivative, which was a yellow solid (2.5 g, 43% yield). The product had a melting point of 101–102° C. A 1H-NMR spectrum (300 MHz) in CDCl3 yielded chemical shifts (ppm) as follows: 1.15–1.61 (m, 12H); 1.71–1.92 (q, 4H); 4.34–4.47 (t, 4H); 7.32–7.37 (m, 4H); 7.50 (td, 2H); 7.70 (d, 2H); 7.82 (dd, 2H); 7.93 (dd, 2H); 8.28 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](Br)[CH3:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]([C:18](=[S:22])[O:19]CC)[NH2:17]>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:10])[S:22][C:18](=[O:19])[NH:16][N:17]=2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(=S)NN
Reactant: CC(Br)C(=O)c1ccc(N)c([N+](=O)[O-])c1
Solvent: CC#N
Product: CC1SC(=O)NN=C1c1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
36.5 g (134 mM) of 1-(4-amino-3-nitrophenyl)-2-bromopropan-1-one and 24.3 g (202.5 mM) of O-ethyl hydrazinecarbothioate dissolved in 190 ml of acetonitrile are refluxed for 4 hours with stirring. The reaction mixture is cooled and maintained at 0° C. for 16 hours. The crystalline solid is filtered off and washed with cold acetonitrile to give, after drying, 10.4 g of 5-(4-amino-3-nitrophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in the form of a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:21])[CH2:10][NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:5]=[N:6][C:7]=1Cl>C(O)(=O)C.O.[Br-].C[N+](C)(C)C.C(OCC)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:21])[CH2:10][NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Oc1ccc(CCNC[C@H](O)c2cnc(Cl)c(Cl)c2)cc1
Agent: C[N+](C)(C)C
Agent: [Br-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc(CCNC[C@H](O)c2cncc(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 10 h
Yield: 65.7 %

Procedure:
To a solution of 4-[2-[[(2R)-2-(5,6-dichloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]phenol (850 mg) in acetic acid (15 ml) and water (1.0 ml) were added tetramethylammonium bromide (5.2 mg) and zinc dust (509 mg), and the mixture was stirred at 50° C. for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 4-[2-[[(2R)-2-(5-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]phenol (500 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2C=C(C(O)=O)[N:12]=[C:11]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(OC1C=C(N2C=C(C(OCC)=O)N=C2C2C=CC(F)=CC=2)C=CC=1)C.[OH-].[Na+].Cl>O1CCCC1.O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-n2cc(C(=O)O)nc2-c2ccc(F)cc2)c1
Agent: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(F)cc2)n1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cccc(NC(=N)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide in 5.0 mL of tetrahydrofuran at ambient temperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and the resulting solution was stirred for 20 min. To this reaction mixture was slowly added a solution of 0.48 g (4.0 mmol) of 4-fluorobenzonitrile in 2.0 mL of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 5 hrs and then poured into brine (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as yellow solid which was used without further purification. LC/MS 259.2 (M+1). Step B: Ethyl 1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylate. To a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 30% ethyl acetate in hexanes gradient then 30% ethyl acetate in hexanes) gave the title compound as a viscous yellow oil. LC/MS 355.3 (M+1). Step C: 1-(3-Ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylic acid. To a solution of 0.67 g (1.9 mmol) of ethyl 1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylate in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 0.80 mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a pale yellow solid. LC/MS 327.2 (M+1).
Reaction SMILES: [C:1]([O-:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Zn+2:8].C([O-])(=O)C(C)(C)C.Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.[Mg]>>[C:1]([O-:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:24][C:23]([F:26])([F:25])[C:19]1[CH:18]=[C:17]([Zn+:8])[CH:22]=[CH:21][CH:20]=1
Reactant: [Zn+2]
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: CC(C)(C)C(=O)[O-]
Agent: [Mg]
Product: FC(F)(F)c1cccc([Zn+])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
2LiCl (2a prepared above; 2.64 g, 7.50 mmol) is placed in a 25 mL Schlenk-flask, dried for 5 min at 400° C. (heat gun) in high vacuum and then dissolved in dry THF (10.0 mL). 1-Bromo-3-(trifluoromethyl)benzene (3d; 1.13 g, 5.00 mmol) and magnesium-turnings (304 mg, 12.5 mmol) are added and the mixture was stirred for 2 h at 25° C. The solution is cannulated to a dry and argon-flushed 50 mL Schlenk-tube via syringe filter and the solvent is removed in vacuo. 3-(Trifluoromethyl)phenylzinc pivalate (1d) is obtained as a grey solid (3.72 g).
Reaction SMILES: [F:1][C:2]([F:23])([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:3](N(OC)C)=O.F[C:25](F)(C1C=CC(C2C=CC(OC)=CC=2)=CC=1)[C:26]([OH:28])=[O:27].C(Cl)(=O)C(Cl)=O.CN(C)C=O.Cl.CNOC.C(N(CC)CC)C>ClCCl.C(#N)C.C(O)(C)(C)C.C1COCC1.O>[F:23][C:2]([F:1])([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1)[CH2:3][CH2:25][C:26]([OH:28])=[O:27]
Reactant: COc1ccc(-c2ccc(C(F)(F)C(=O)O)cc2)cc1
Reactant: COc1ccc(-c2ccc(C(F)(F)C(=O)N(C)OC)cc2)cc1
Agent: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(-c2ccc(C(F)(F)CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2,2-Difluoro-N-methoxy-2-(4′-methoxy-biphenyl-4-yl)-N-methyl-acetamide. To a solution of difluoro-(4′-methoxy-biphenyl-4-yl)-acetic acid (3.74 g, 13.4 mmol) in dichloromethane (40 mL) and acetonitrile (40 mL) is added oxalyl chloride (2.40 mL, 27.5 mmol) followed by N,N-dimethylformamide (1.05 mL, 13.6 mmol). This mixture is stirred at room temperature for 45 min and added over 10 min to a solution of N,O-dimethylhydroxylamine hydrochloride (5.23 g, 53.6 mmol) and triethylamine (11.2 mL, 80.4 mmol) in t-butanol (40 mL), THF (80 mL), and water (30 mL) at 0° C. The resulting mixture is stirred for 4 hours while warming from 0° C. to room temperature. The reaction is diluted with water and the layers separated. The organic layer is washed in succession with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by column chromatography (silica gel, 20-30% EtOAc/hexanes) to give the desired product as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[NH2:25][C@H:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][OH:28].C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([NH:25][C@H:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][OH:28])[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Reactant: CC(C)[C@@H](N)CO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)[C@H](CO)Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Temperature: 120 °C

Procedure:
220 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 118.43 mg (R)-(−)-2-amino-3-methyl-butan-1-ol and 197.52 μl diisopropylethylamine are placed in 4 ml dioxane, and the mixture is heated to 120° C. in the microwave for 0.3 hours. Then the reaction mixture is mixed with water, the precipitate formed is suction filtered, washed and dried. The diastereomers are separated by preparative HPLC (method B). 25.5 mg of Diastereomer 1 (Example 54) and 40.5 mg of Diastereomer 2 (Example 57) are obtained as a powder. Analytical HPLC (method A): Diastereomer 1: RT=3.61 min; Diastereomer 2, RT=3.71 min.
Reaction SMILES: [Cl-].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1.[H-].[Na+]>N1C=CC=CC=1>[O:8]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: Brc1ccsc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: c1ccc(Oc2ccsc2)cc1
Yield: 73 %

Procedure:
Couprous chloride (3.08 g, 31.1 mmol) and phenol (8.78 g, 93.3 mmol) were sequentially added to a solution of 3-bromothiophene (5.06 g, 31.1 mmol) in pyridine (150 ml). Sodium hydride (3.73 g, 93.3 mmol, 60% dispersion in mineral oil) was then slowly added. The reaction was heated at reflux for 20 hours under Argon. The pyridine was removed under reduced pressure. The residue was diluted with EtO (200 ml) and washed with 1N NaOH (3×100 ml), 1N HCl (2×150 ml) and 1N NaOH (150 ml). The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was chromatographed using hexanes to give 3-phenoxy-thiophene as a clear oil (4.0 g, 74% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH2:13].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:9][C:10]1[CH:11]=[C:12]([NH:13][C:6]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)=[O:8])[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=C(O)c1ncc[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cc(F)cc(F)c1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of 1H-imidazole-2-carboxylic acid (2.50 g, 22.3 mmol) in DMF (30 mL) were added 3,5-difluoroaniline (2.23 mL, 22.3 mmol), EDCHCl (6.41 g, 33.46 mmol) and HOBt (4.52 g, 33.46 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuum and the crude was dissolved in dichloromethane. The solution was washed with a diluted aqueous solution of potassium carbonate, dried over sodium sulphate, filtered and concentrated. 2.75 g (55% yield) of the title compound were obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.[Mn]([O-])(=O)(=O)=O.[K+].Cl.C[C:23](C)=[O:24]>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:24][CH3:23])=[O:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1
Reactant: OCc1ccc(OCC2CC2)c(Cl)n1
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(OCC2CC2)c(Cl)n1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a solution of (6-chloro-5-(cyclopropylmethoxy)pyridin-2-yl)methanol (14.0 g) in acetone (100 mL) was added dropwise a solution of potassium permanganate (14.5 g) in water (100 mL) over 40 min at 0° C., and the mixture was stirred at the same temperature for 20 min. The reaction mixture was acidified with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in DMF (100 mL), potassium carbonate (9.06 g) and methyl iodide (4.10 mL) were added thereto, and the mixture was stirred with heating at 70° C. for 20 min. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.27 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][O:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][O:23][C:24]([CH3:33])([CH3:32])[C:25]([O:27]C(C)(C)C)=[O:26])[CH2:17]1>FC(F)(F)C(O)=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][O:23][C:24]([CH3:33])([CH3:32])[C:25]([OH:27])=[O:26])[CH2:17]1
Reactant: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](COC(C)(C)C(=O)OC(C)(C)C)C3)c(C)o2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](COC(C)(C)C(=O)O)C3)c(C)o2)cc1
Yield: 37.6 %

Procedure:
200 mg of tert-butyl 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclo-hexylmethoxy]-2-methylpropionate are stirred in 2 ml of trifluoroacetic acid for 1 h. The solution is concentrated completely and purified by flash chromatography (heptane/ethyl acetate 5/1) giving 66 mg of 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-2-methylpropionic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[Li]C1OC2C=CC=CC=2C=1.[C:25]([O:29][C:30](=[O:43])[NH:31][C@H:32]([C:37](=[O:42])N(OC)C)[C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([O:29][C:30](=[O:43])[NH:31][C@H:32]([C:37]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:42])[C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:28])([CH3:26])[CH3:27]
Reactant: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: c1ccc2occc2c1
Agent: [Li]CCCC
Agent: [Li]c1cc2ccccc2o1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)c1cc2ccccc2o1)C(C)(C)C
Temperature: -40 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
A solution of benzofuran (4.24 g, 36 mmol) in dry THF (20 mL) under argon was cooled to −78° C. n-Butyllithium (22.5 mL, 36 mmol, 1.6M in hexanes) was added dropwise such that an internal temperature below −65° C. was maintained. The reaction was allowed to stir at −78° C. for two hours during which time 2-lithiobenzofuran precipitated as a white solid. The suspension of 2-lithiobenzofuran was added dropwise to a cooled (−78° C.) solution of [1(S)-(Methoxy-methyl-carbamoyl)-2,2-dimethylpropyl]-carbamic acid-tert-butyl ester (3.34 g, 12 mmol) in THF (30 mL) via cannula such that an internal temperature of below −65° C. was maintained. The yellow solution was allowed to stir at −70° C. for 30 minutes and −40° C. for a further 3 hours. The reaction was quenched by addition of saturated ammonium chloride solution (200 mL). The aqueous phase was extracted with ethyl acetate (3×150 mL) and the combined organic extracts washed with brine (2×200 mL), dried over magnesium sulphate, filtered and the solvents removed in vacuo to give a crude yellow oil. Purification by column chromatography (SiO2, 10% ethyl acetate in hexanes) gave the title compound as a yellow solid (3.45 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH:18]=[CH:19][C:20](OCC)=[O:21].[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17](/[CH:18]=[CH:19]/[CH2:20][OH:21])[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C=Cc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(/C=C/CO)c1

Procedure:
According to the method described for Reference Example 23, ethyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate was subjected to reduction with diisobutylaluminum hydride to give (E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-propen-1-ol. Recrystallization from ethyl acetate gave colorless prisms, m.p.120°-121° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:37])[CH2:14][CH2:15][CH2:16][N:17]([C:24](=[O:36])[C@H:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:26])[CH2:18][CH:19](OC)OC)(C)(C)C.C([SiH](CC)CC)C.C(N(CC)CC)C>ClCCl>[Cl:35][C:30]1[CH:29]=[C:28]([N:27]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][C:13]([OH:12])=[O:37])[C:24](=[O:36])[C@H:25]2[CH3:26])[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: COC(CN(CCCC(=O)OC(C)(C)C)C(=O)[C@@H](C)Nc1ccc(Cl)c(Cl)c1)OC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@@H]1C(=O)N(CCCC(=O)O)CCN1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
0.69 ml (9.00 mmol) of trifluoroacetic acid was added to a cooled solution (0° C.) of 0.28 g (0.60 mmol) 4-[[(R)-2-(3,4-dichloro-phenylamino)-propionyl]-(2,2-dimethoxy-ethyl)-amino]-butyric acid tert-butyl ester (62% ee) in 6 ml of dichloromethane. After 30 min the ice bath was removed, then after 1 h, 0.49 ml (3.00 mmol) of triethylsilane was added. After 16 h the reaction mixture was cooled to 0° C. and treated with 1.25 ml (9.00 mmol) of triethylamine, then after 15 min partitioned between Et2O (3×)/aqueous 10% KHSO4, the organic phases were washed with aqueous 10% KHSO4 and aqueous 10% NaCl, dried over Na2SO4 and evaporated. The residue was precipitated (dichloromethane/n-pentane) to give 0.198 g (96%) of the titled compound as brown viscous oil. MS: 345.07 (MH+, 2Cl).
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH3:18][C:19]1[N:20]=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:22][C:23]=1[C:24](O)=[O:25].C(=O)([O-])O.[Na+]>O>[CH3:18][C:19]1[N:20]=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:22][C:23]=1[C:24]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:15])[F:16])=[O:25]
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)O
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1sc(-c2ccccc2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To 25 ml of N,N-dimethylformamide were dissolved 2.60 g (13 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 2.19 g (10 mmol) of 4-methyl-2-phenylthiazole-5-carboxylic acid, followed by the addition of 1.68 g (20 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate ether: hexane=1:9) to obtain 3.03 g (yield: 94%) of 4,4-difluoro-3-methyl-3-butenyl 4-methyl-2-phenylthiazole-5-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23]([OH:25])=O)[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][C:30]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)([OH:33])[CH2:29][CH2:28]1>>[OH:33][C:30]1([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)[CH2:31][CH2:32][CH:27]([NH:26][C:23]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[C:14]([O:13][CH2:12][C:9]2[C:8]4[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=4[O:11][CH:10]=2)[CH:22]=[CH:21][CH:20]=3)=[O:25])[CH2:28][CH2:29]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: COc1cccc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c12
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)c12

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (synthesis described in WO2005077932A2, cmpd 122) and amine 14.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=C(C)[N+:18]=1[O-])[CH2:9][CH2:10][CH3:11]>C(O)(=O)C>[C:5]([O:4][CH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:18]=1)(=[O:7])[CH3:6]
Reactant: CCCCOc1cccc(C)[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCOc1cccc(COC(C)=O)n1
Temperature: 135 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
An amount 60 ml of acetic anhydride was stirred at about 120° C., and a solution of 11.1 g of 6-butoxy-α-picoline N-oxide in 25 ml of glacial acetic acid was dropwise added thereto over about one hour. After the dropwise addition, the mixture was stirred at 135° C. for 4.5 hours, acetic acid and acetic anhydride were removed by concentration under a reduced pressure, the reaction mixture was dissolved in ether, and the remaining acetic acid was neutralized with an aqueous sodium hydrogen carbonate solution. The mixture was extracted with ether, concentrated under a reduced pressure, and separated by silica gel column chromatography (ethyl acetate:hexane=8:92) to obtain 4.89 g of the desired product (yield 35.9%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1>>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[S:10][C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(C)C(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC(C)C(=O)Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
The crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)isobutyramide (45 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 1.9 mg of 164. MS (Q1) 423 (M)+