Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([Cl:26])=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([Cl:26])=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3nc(Cl)c4ccccc43)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-n3nc(Cl)c4ccccc43)nc12
Reaction time: 15 h
Yield: 38 %

Procedure:
To a stirred solution of N-tert-butyl-2-(3-chloro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.1 g, 200 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(3-Chloro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (28 mg, 38%). MS (M−H)−=367; 1H NMR (DMSO-d6) δ: 8.96 (s, 1H), 8.62 (d, J=8.8 Hz, 1H), 8.44 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.70 (ddd, J=8.4, 7.2, 1.0 Hz, 1H), 7.61 (s, 1H), 7.47-7.54 (m, 1H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:13]I>C1(C)C=CC=CC=1.[Ag]=O>[CH3:13][O:12][C:3]1[C:2]([CH3:1])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1nc2ccccc2[nH]c1=O
Reactant: CI
Agent: O=[Ag]
Solvent: Cc1ccccc1
Product: COc1nc2ccccc2nc1C
Temperature: 100 °C
Yield: 60.6 %

Procedure:
A suspension of 3-methylquinoxalin-2(1H)-one (3.2 g, 20 mmol), silver oxide (5.56 g, 24 mmol), and methyl iodide (5.68 g, 40 mmol) in toluene (100 mL) was heated to 100° C. for 16 h. After cooling to room temperature, the reaction mixture was filtered, concentrated, and purified by column chromatography to afford the title compound as an orange solid (2.11 g). MS (ESI): m/z 175 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH2:18][CH:17]2[CH:13]([CH2:14][CH2:15][C:16]2=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=1[F:74].CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH2:18][CH:17]2[CH:13]([CH2:14][CH:15]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=3[F:74])[C:16]2=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2CN(C(=O)OCc3ccccc3)CCC12
Reactant: Fc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1C(c2ccccc2F)CC2CN(C(=O)OCc3ccccc3)CCC12
Reaction time: 0.25 h
Yield: 51.8 %

Procedure:
After adding 191 mg of 3-benzyloxycarbonyl-7-oxo-3-azabicyclo[4.3.0]nonane, 16 mg of palladium acetate and 104 mg of BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) to 3 ml of toluene under a nitrogen atmosphere, the mixture was stirred for 15 minutes, and then 245 mg of o-bromofluorobenzene, 134 mg of sodium tert-butoxide and 6 ml of toluene were added and the mixture was stirred overnight at 100° C. Saturated aqueous ammonium chloride solution was added to the reaction solution and extraction was performed with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain 133 mg of 3-benzyloxycarbonyl-8-(2-fluorophenyl)-7-oxo-3-azabicyclo[4.3.0]nonane.
Reaction SMILES: [O-]C1C=CC=CC=1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([CH2:21][O:22]S(C)(=O)=O)[O:18]C2=O)=[CH:12][CH:11]=1)#[N:9].NC1C=CC(C#N)=CC=1.O1CC1CO>CN(C)C=O>[OH:18][CH:19]([CH2:21][OH:22])[CH2:20][NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OCC1CN(c2ccc(C#N)cc2)C(=O)O1
Agent: N#Cc1ccc(N)cc1
Agent: OCC1CO1
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(NCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 Equivalent of NaH is added to a solution of 1.7 g of Na p-methoxycarbonylmethylphenoxide (obtainable by converting p-hydroxybenzyl cyanide into the corresponding carboxylic acid, esterifying with methanol to give p-methoxycarbonylmethylphenol and subsequently converting the latter into the phenoxide) in 20 ml of dimethylformamide (DMF), and the mixture is stirred at room temperature for 30 min. After that, 3.0 g of 3-p-cyanophenyl-5-methanesulfonyloxymethyloxazolidin-2-one ("A") (obtainable by reacting p-aminobenzonitrile with 2,3-epoxypropan-1-ol to give p-(N-2,3-dihydroxypropylamino)benzonitrile, reacting the latter with diethyl carbonate in the presence of K tert-butoxide to give 3-p-cyanophenyl-5-hydroxymethyloxazolidin-2-one and subsequently esterifying the latter with methanesulfone chloride), dissolved in 10 ml of DMF, are added and the mixture is once again stirred at room temperature for 15 min. Following removal of the solvent, and the customary working-up, 3-p-cyanophenyl-5-(p-methoxycarbonylmethylphenoxymethyl)oxazolidin-2-one is obtained, M.p. 114°-115°.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[C].[Pd]>[C:1]([C:5]1[N:6]=[C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(C=Cc2cccc(C(=O)O)c2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(CCc2cccc(C(=O)O)c2)n1
Yield: 92.6 %

Procedure:
3-[2-(4-tert-Butyl-2-thiazolyl)vinyl]benzoic acid (1.20 g, 4.18 mmol) was dissolved in tetrahydrofuran (24 ml), 10% palladium-carbon powder (0.2 g) was added to the solution, and the mixture was stirred at room temperature for 3 hours in an atmosphere of hydrogen. The reaction solution was filtered and the resulting filtrate was concentrated under reduced pressure. By crystallizing the resulting residue from diethyl ether-hexane, 3-[2-(4-tert-butyl-thiazolyl)ethyl]benzoic acid (1.12 g, 93%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[C:11]([N+:23]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1.[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[NH2:23][C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=2)[CH:14]=[CH:13][C:12]=1[S:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1
Reactant: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c([N+](=O)[O-])c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Yield: 101.5 %

Procedure:
A solution of the product of Example 10D (1.06 g, 2.76 mmol), iron powder (0.63 g, 11.04 mmol) and ammonium chloride (0.18 g, 3.31 mmol) in a methanol (18 mL), tetrahydrofuran (18 mL), and water (6 mL) solution was heated to reflux for 3 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.99 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[C:25](=O)[CH2:24][CH2:23][CH2:22]2.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl.C(O)(=O)C.O>[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH2:24][CH2:23][CH2:22]2
Reactant: O=C1CCCc2cccc(Br)c21
Reactant: Cc1ccccc1N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1NC1CCCc2cccc(Br)c21
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 57.1 g (533 mmol) of 2-methylaniline in 300 ml of toluene 25.3 g (133 mmol) of TiCl4 was added dropwise for 30 min at room temperature in argon atmosphere. The resulting mixture was stirred for 30 min at 90° C. followed by an addition of 30.0 g (133.0 mmol) 8-bromo-3,4-dihydronaphthalen-1(2H)-one. This mixture was stirred for 10 min at 90° C., poured into 500 ml of water, and the product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The residue was re-crystallized from 50 ml of ethyl acetate. The obtained solid was dissolved in 600 ml of methanol, 15.4 g (244 mmol) of NaBH3CN and 5 ml of acetic acid were added in argon atmosphere. The resulting mixture was refluxed for 3 h, then cooled to room temperature, and evaporated to dryness. The residue was diluted with 500 ml of water, and crude product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The residue was re-crystallized from 400 ml of methanol. Yield 33.2 g (79%) of a yellow crystalline powder. Anal. Calc. for C17H18BrN: C, 64.57; H, 5.74; N, 4.43. Found: C, 64.69; H, 5.82; N, 4.55. 1H NMR (CDCl3): δ 7.45 (m, 1H, 7-H in tetrahydronaphtalene); 7.19 (m, 1H, 6-H in tetrahydronaphtalene); 7.08-7.14 (m, 3H, 5-H in tetrahydronaphtalene and 3,5-H in 2-methylphenyl); 6.86 (m, 1H, 6-H in 2-methylphenyl); 6.68 (m, 1H, 4-H in 2-methylphenyl); 4.78 (m, 1H, 4-H in 2-methylphenyl); 3.51 (br.s, 1H, NH); 2.86-2.92 (m, 1H, 4- or 4′-H in tetrahydronaphtalene); 2.72-2.81 (m, 1H, 4′- or 4-H in tetrahydronaphtalene); 2.30-2.34 (m, 1H, 3- or 3′-H in tetrahydronaphtalene); 2.06 (s, 3H, CH3 in 2-methylphenyl); 1.85-1.97 (m, 1H, 3′- or 3-H in tetrahydronaphtalene); 1.77-1.81 (m, 1H, 2- or 2′-H in tetrahydronaphtalene); 1.59-1.67 (m, 1H, 2′- or 2-H in tetrahydronaphtalene).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)N(C)CCC2
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCCc2ccc(CO)cc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of methyl 1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (320 mg, 1.559 mmol) in THF (25 mL) was added a solution of DIBAL-H in THF (6.24 ml, 6.24 mmol). The reaction mixture was stirred for 3 hr at 0° C. The reaction mixture was treated with 30 mL of 10% aqueous sodium potassium tartrate and stirred for 2 h at 20° C. The mixture was extracted with AcOEt. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound. MS (Method A) [M+H]+=178.0
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1.C([Li])CCC.[C:19](OCC)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].[BH4-].[Na+].C(=O)(O)[O-].[K+]>O1CCCC1.CCCCCC.C(O)C.O.C(O)(=O)C>[CH3:10][C:7]1([CH3:11])[O:6][C:5]2[CH:12]=[CH:13][C:2]([CH:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][C:4]=2[CH2:9][O:8]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC1(C)OCc2cc(Br)ccc2O1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(O)c1ccc2c(c1)COC(C)(C)O2
Temperature: -80 °C
Yield: 76.4 %

Procedure:
6-Bromo-2,2-dimethylbenzo[1,2-d]-1,3-dioxane (30.0 g) was dissolved in 610 ml of tetrahydrofuran, 136 ml of 1.56 M n-butyl lithium in hexane was added to the solution with stirring at -80° C., and the mixture was subjected to 15 minutes of reaction. With stirring at -80° C., the reaction solution was added to a solution of 21.6 g of diethyl oxalate in 200 ml of tetrahydrofuran, and the mixture was subjected to 1 hour of reaction. Then, 100 ml of ethanol and a solution of 1.40 g of sodium borohydride in 100 ml of ethanol were added in that order. The reaction solution was stirred at -30° C. for 30 minutes, 8.26 ml of acetic acid was added, and the mixture was stirred for 5 minutes. Then, a solution of 14.8 g of potassium bicarbonate in 50 ml of water was added, and the reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane/ethyl acetate=5/1) to give 25.1 g of ethyl 2-(2,2-dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)2-hydroxyacetate in an oily form.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cn1
Reactant: Brc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccn2)cn1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
In a 300 mL inner volume flask replaced by nitrogen, tetrahydrofuran solution of isopropylmagnesium chloride (19.5% by weight, 30.3 g, 57.5 mmol) was charged, and cooled at 10° C., and then tetrahydrofuran solution (20 g) of 5-bromo-2-methoxypyridine (9.4 g, 50.0 mmol) was added dropwise in the range of 10 to 20° C. for 1.0 hour. After adding dropwise, the reaction mixture was stirred in the range of 10 to 20° C. for 1.5 hours, and then added dropwise to the tetrahydrofuran solution (20 g) containing 2-bromopyridine (7.9 g, 50.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.14 g, 0.25 mmol) in the range of 10 to 20° C. for 2.0 hours. After adding dropwise, the reaction mixture was stirred in the range of 10 to 20° C. for 4.0 hours, however, 6-methoxy-3,2′-bipyridine could not be obtained.
Reaction SMILES: C(NC(=O)C(C)=CC1C=C(OC)C(OC)=CC=1N)CC1C=CC=CC=1.C([O:28][C:29](=[O:44])[C:30]([CH3:43])=[CH:31][C:32]1[CH:37]=[C:36]2[CH:38]=[CH:39][C:40]([NH2:42])=[CH:41][C:35]2=[CH:34][CH:33]=1)C.[OH-].[Na+].Cl>O1CCCC1>[NH2:42][C:40]1[CH:39]=[CH:38][C:36]2[C:35]([CH:41]=1)=[CH:34][CH:33]=[C:32]([CH:31]=[C:30]([CH3:43])[C:29]([OH:44])=[O:28])[CH:37]=2
Reactant: CCOC(=O)C(C)=Cc1ccc2cc(N)ccc2c1
Agent: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=Cc1ccc2cc(N)ccc2c1)C(=O)O
Yield: 98 %

Procedure:
Into 10 ml of tetrahydrofuran (THF), 0.65 g of (E) 3-(2-amino-benzo[d]phenyl)-2-methyl-2-propenoic acid ethyl ester was dissolved; and, with 10 ml of a 1-N aqueous sodium hydroxide solution being added thereto, the mixture was reacted for 4 hours at 40° C. After the completion of the reaction, the reaction liquid was cooled with 10 ml of a 1-N aqueous hydrochloric acid solution being added thereto, and the precipitated crystal was filtered out, whereby 0.57 g of the aimed compound was obtained (yield: 98%).
Reaction SMILES: O[C:2]1[C:10]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[N:16]1[CH:15]=[CH:14][C:13]([C:12]2[O:19][C:2]3[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]=3[N:11]=2)=[CH:18][CH:17]=1
Reactant: O=C(Nc1cccc(C(=O)O)c1O)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc2nc(-c3ccncc3)oc12
Yield: 86.4 %

Procedure:
A mixture of methyl ester of 2-hydroxy-3-isonicotinoylamino-benzoic acid (500 mg, 1.84 mmol), p-toluenesulfonic acid mono-hydrate (349 mg, 1.84 mmol) and xylene (20 ml) was heated under reflux for 14 hrs. and then p-toluenesulfonic acid mono-hydrate (349 mg, 1.84 mmol) was further added and refluxed under heating for 2 hrs. The reaction mixture was cooled with ice, and ethyl acetate and 10% aqueous potassium carbonate solution were added thereto. The organic phase was separated, washed with water and brine in turn and then dried. The solvent was distilled off under reduced pressure, and the residue was triturated with a mixture of n-hexane/diisopropyl ether (4/1), filtered and dried to give methyl ester of [2-(4-pyridyl)-benzoxazol-7-yl]carboxylic acid (382 mg, 82%) as pale yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2CC(C)(C)C([O-])=O)[N:10]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:35]CC1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:18]=[CH:17][C:16]2[C:15]([OH:35])=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: C1CCOC1
Reactant: CC(C)(Cc1cccc2nc(C#Cc3ccccn3)ccc12)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Oc1cccc2nc(C#Cc3ccccn3)ccc12
Yield: 9 %

Procedure:
2-(Pyridine-2-ylethynyl)quinoline-5-ol (3.7 mg, 9%) was prepared as yellow solid according to the same method as described in Example 16 except that 2-(pyridine-2-ylethynyl)quinoline-5-ylpivalate (56.8 mg, 0.17 mmol), LiAlH4 (0.43 mL, 1.0 M in THF), and THF (2.8 mL) were used.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C([O-])([O-])=O.[K+].[K+].[CH2:36](I)[CH3:37]>CN(C=O)C.Cl>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:36][CH3:37])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2CO3 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added EtI (82 mg, 0.52 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCl (50 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with 10% aq. NaHCO3 (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 88 mg (82%) of the title compound as an off white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][C:12]=1[Cl:24])[C:6](=O)[CH2:7][CH3:8])C.[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([NH2:39])[CH:33]=1)[CH3:30]>>[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]2[C:33]=1[C:4](=[O:3])[C:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][C:12]=1[Cl:24])=[C:6]([CH2:7][CH3:8])[NH:39]2)[CH3:30]
Reactant: COC(=O)[C@H](C)Oc1ccc(F)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1Cl)C(=O)CC
Product: CCc1[nH]c2c(F)ccc(O[C@@H](C)C(=O)OC)c2c(=O)c1Cc1ccc(C(=O)N2CCCC2)cc1Cl

Procedure:
The title compound was prepared by the method of Preparation 65c using 2-[2-chloro-4-(pyrrolidine-1-carbonyl)benzyl]-3-oxopentanoic acid ethyl ester and (S)-2-(3-amino-4-fluorophenoxy)propionic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:13][NH2:14].[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25](OCC)=[O:26])[N:24]=2)[CH:21]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25]([NH:14][CH2:13][C:3]3[CH:4]=[C:5]([O:8][C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:7][C:2]=3[F:1])=[O:26])[N:24]=2)[CH:21]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1cc(OC(F)(F)F)ccc1F
Product: O=C(NCc1cc(OC(F)(F)F)ccc1F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2-fluoro-5-(trifluoromethoxy)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: C(N(CC)CC)C.[F:8][CH2:9][C@H:10]1[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:12](=[O:23])[C@@H:11]1O.CS(Cl)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>O.C(Cl)Cl>[N:30]([C@H:11]1[C@@H:10]([CH2:9][F:8])[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:12]1=[O:23])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](c1ccccc1)N1C[C@H](CF)[C@@H](O)C1=O
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1C[C@H](CF)[C@H](N=[N+]=[N-])C1=O
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
Triethylamine (3.07 ml, 22.02 mmol) was added to a methylene chloride (40 ml) solution of 4-(S)-fluoromethyl-3-(R)-hydroxy-N-[1-(R)-phenylethyl]-2-pyrrolidone (2.61 g, 11.00 mmol), methanesulfonyl chloride (1.28 ml, 16.54 mmol) was added dropwise to the thus prepared solution at −10° C. and then the resulting mixture was stirred for 30 minutes at the same temperature. The reaction solution was washed with 10% citric acid aqueous solution and dried over sodium sulfate and then the solvent was evaporated. The thus obtained residue was dissolved in N,N-dimethylformamide (80 ml), mixed with sodium azide (2.86 g, 44.00 mmol) and then stirred overnight at 100° C. The reaction solution was mixed with water, extracted with ethyl acetate (200 ml×3) and then the resulting organic layers were combined and dried over sodium sulfate, subsequently evaporating the solvent. The thus obtained residue was subjected to a silica gel chromatography to give 1.81 g (63%) of the title compound from the eluate of ethyl acetate:hexane=1:3 in the form of a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([O-:18])=[O:17])[CH:11]=1.CS(C)=O>O>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[CH:7]=[O:8])(=[O:18])=[O:17])[CH:11]=1
Reactant: O=Cc1sccc1Cl
Reactant: O=S([O-])c1cccnc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1sccc1S(=O)(=O)c1cccnc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
A mixture of 3-chlorothiophene-2-carbaldehyde (0.16 g), pyridine-3-sulfinic acid sodium salt (0.30 g) and dimethyl sulfoxide (2.0 mL) was heated at 80° C. for 3 hours and then at 90° C. for 3 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined organic extract was dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as a grey solid (0.079 g).