Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)=[O:2].CC(C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:18][C:19]1[N:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:27]([CH3:28])=[C:23]2[N:22]=[C:21]([CH3:36])[C:20]=1[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C1(C2ON2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:18][C:19]1[N:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:27]([CH3:28])=[C:23]2[N:22]=[C:21]([CH3:36])[C:20]=1[CH:37]([OH:2])[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)Cc1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Reactant: O=C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOC(=O)C(O)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Reaction time: 0.33 h
Yield: 51.9 %

Procedure:
To a cold (−78° C. dry ice/acetone) stirred solution of 0.91 M KHMDS in THF (32 ml, 29.1 mmol) in additional THF (100 ml) was added ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (8.3 g, 21.94 mmol) in THF (100 ml), by dropwise addition over 30 min. The mixture was stirred for 20 min, and then a solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (7.45 g, 28.5 mmol) in THF (50 ml) was added. The reaction was stirred for 2.5 hrs at −78° C. The orange reaction mixture was quenched with sat. NH4Cl (100 mL), diluted with EtOAc (300 mL), washed with water (200 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to give a yellow solid. The crude residue was loaded onto a flash silica gel column and eluted with 10%-30% EtOAc in hexanes. Product fractions were pooled and concentrated under reduced pressure, affording ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (5.4 g, 11.40 mmol, 51.9% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.89-7.84 (m, 1H), 7.74 (dt, J=7.2, 1.6 Hz, 1H), 7.44-7.36 (m, 2H), 5.73 (s, 1H), 4.32-4.26 (m, 2H), 3.65 (br. s., 1H), 2.63 (s, 3H), 2.51 (s, 3H), 1.24 (t, J=7.02 Hz, 3H). LCMS (M+H)=394.06.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[NH2:6].[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23]>CCOCC>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([NH:6][C:25]([NH:24][C:22](=[O:23])[C:21]2[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:20]=2[F:19])=[O:26])[CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:16])([F:15])[CH:12]([F:13])[F:14]
Reactant: Nc1ccc(OC(F)(F)C(F)F)c(C(F)(F)F)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CCOCC
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(OC(F)(F)C(F)F)c(C(F)(F)F)c1

Procedure:
5.4 g of 3-trifluoromethyl-4-(1,1,2,2-tetrafluoroethoxy)-aniline are placed into 20 ml of abs. ether, and 3.7 g of 2,6-difluorobenzoylisocyanate dissolved in 10 ml of abs. ether are subsequently added dropwise at room temperature. The solid which has precipitated is filtered off with suction after 1 hour; it is then washed with abs. ether and dried in air. Recrystallisation from toluene yields N-[3-trifluoromethyl-4-(1,1,2,2-tetrafluoroethoxy)-phenyl]-N'-(2,6-difluorobenzoyl)-urea having a melting point of 182°-185° C.
Reaction SMILES: [O:1]=[C:2]1[C:12]2[C:7](=[N+:8]([O-])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[O:1]=[C:2]1[C:12]2[CH:11]=[CH:10][C:9](=[O:19])[NH:8][C:7]=2[CH:6]=[CH:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2
Reactant: O=c1c2ccccc2ccc2c1ccc[n+]2[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1ccc2c(=O)c3ccccc3ccc2[nH]1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 2.23 grams (0.01 mole) of 5-oxo-benzo[4,5]cyclohepta[1,2-b]pyridine N-oxide intermediate and 2.29 grams (0.012 mole) of tosyl chloride in 100 milliliters of chloroform was added a solution of 1.76 grams of potassium carbonate in 25 milliliters of water and the resulting mixture stirred vigorously for 4 days at room temperature. During this period the desired 5-oxo-benzo[4,5]cyclohepta[1,2-b]pyrid-2(1H)one product formed in the reaction mixture as a solid. The solid was recovered by filtration, was washed successively with 10 percent sodium hydroxide solution, water and hot methanol, and was dried. The dried product was a TLC homogeneous 5-oxo-benzo-[4,5]cyclohepta[1,2-b]pyrid-2(1H)one.0.25 methanol solvate, m.p. 320° C. The elemental analyses were as follows:
Reaction SMILES: [NH:1]([C:3]([C:5]1[C:14]([C:15]([NH:17]N)=[O:16])=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([CH2:21][CH3:22])=[CH:10][C:11]=2[Br:20])[N:6]=1)=[O:4])N>C(O)(=O)C>[Br:20][C:11]1[C:12]2[C:13]([OH:19])=[C:14]3[C:15](=[O:16])[NH:17][NH:1][C:3](=[O:4])[C:5]3=[N:6][C:7]=2[CH:8]=[C:9]([CH2:21][CH3:22])[CH:10]=1
Reactant: CCc1cc(Br)c2c(O)c(C(=O)NN)c(C(=O)NN)nc2c1
Solvent: CC(=O)O
Product: CCc1cc(Br)c2c(O)c3c(=O)[nH][nH]c(=O)c3nc2c1
Temperature: 81 °C
Yield: 68.5 %

Procedure:
A stirred mixture of 2,3-bishydrazinocarbonyl-5-bromo-7-ethyl-4-hydroxyquinoline (0.40 g, 1.1 mM) in glacial acetic acid (12 mL) was heated at 81° C. for 1.5 hr. After cooling to room temperature, the reaction mixture was filtered and the collected solids washed with acetic acid and air dried to provide the title compound (0.25 g, 70%) as a light brown solid, mp >400° C.; MS(CI): 336 (M+H). Analysis for C13H10BrN3O3 ·0.13 CH3CO2H Calculated: C, 46.31; H, 3.08; N, 12.21 Found: C, 46.50; H, 3.32; N, 12.19
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1.[BH4-].[Na+].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.CO>[Br:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]([NH2:12])[CH3:1])[CH:6]=1
Reactant: N#Cc1cc(Br)ccn1
Reactant: C[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(N)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methylmagnesium bromide (3 M in THF) (63.4 mL, 190 mmol) in THF (100 mL) A solution of 4-bromopyridine-2-carbonitrile (11.6 g, 63.4 mmol; patent US 2009/0239876 A1, example 2) in THF (40 mL) was added drop-wise at room temperature over 40 min. Methanol (40 mL) was then added drop-wise followed by portion-wise addition of sodium borohydride (11.8 g, 312 mmol) in several batches. The resulting mixture was stirred at room temperature for 2 h, then diluted with ethyl acetate (200 mL). The pH of the mixture was adjusted to 9 with aqueous sodium hydroxide (1 M) and the solids were removed by filtration. The filtrate was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 10.3 g (crude) of the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrC1CCCC1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C3CCCC3)CC1)O2

Procedure:
Compound 138 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, bromocyclopentane and conditions outlined in procedure V. LCMS: 370 [M+H]; Rt=0.90 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]2[CH2:27][CH2:26][C:15]3([CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[ClH:28].CO>O1CCOCC1>[ClH:28].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]2[CH2:13][CH2:14][C:15]3([CH2:18][NH:17][CH2:16]3)[CH2:26][CH2:27]2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)N2CCC3(CC2)CN(C(=O)OC(C)(C)C)C3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(CC(=O)N2CCC3(CC2)CNC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 7-[(4-methoxyphenyl)acetyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (2.75 g, 11.2 mmol) in 15 mL of anhydrous dioxane was added 4N HCl in dioxane (3.8 mL). The reaction mixture was stirred at room temperature overnight. Methanol (3 mL) was added to dissolve the solids and the mixture was stirred at ambient temperature for another 2 hours. The reaction was concentrated to dryness and dried on high vacuum overnight to provide the product as a light yellow foam (2.31 g). MS (ES+) 275.4 (M+H)+. 1H NMR (D2O) δ 1.58 (t, 2H), 1.75 (t, 2H), 3.39 (t, 4H), 3.63 (s, 2H), 3.70 (s, 3H), 3.72-3.82 (m, 4H), 6.86 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:13])=[O:8])=[CH:3][CH:2]=1.[CH3:26][I:27]>CN(C=O)C>[I-:27].[CH3:26][N+:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:13])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cc1)c1ccncc1
Reactant: CI
Solvent: CN(C)C=O
Product: C[n+]1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cc2)cc1
Product: [I-]
Reaction time: 48 h
Yield: 59.3 %

Procedure:
To a stirring solution of 2-(4-pyridinecarbonyl)amino-N-(4-chlorophenyl)benzamide (500 mg, 1.42 mmol) in DMF (10 mL) was added methyl iodide (3 mL, 48 mmol). After 48 h, the precipitate was filtered, washed with diethyl ether and dried in vacuo to give 416 mg (59%) of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=O>C1COCC1>[CH3:7][C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9]1
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CNc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a 1M of LAH (30 mL) in THF was added 2b (630 mg, 3.88 mmol) in portion. The reaction mixture was stirred at rt for 2 h, then refluxed for 1 h. The reaction mixture was quench with 1 part of H2O (10 mL), one part of 15% NaOH (5 mL) and another part of H2O (5 mL). The aqueous layer was extracted with EtOAc. The EtOAc layer was dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure to afford 2c (320 mg, 56%) as an oil. MS (ES) m/z 150 [M+H]+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)CCC>>[S:26]1[CH:27]=[CH:28][N:29]=[C:25]1[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2nccs2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)thiazole. The title compound (19 mg) was obtained as a pale solid, m/z 332 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[CH3:22][C:23]1([CH3:38])[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[C:29]2[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][C:24]1=2.Cl>>[CH3:33][C:30]1([CH3:34])[CH2:31][CH2:32][C:23]([CH3:38])([CH3:22])[C:24]2[CH:25]=[C:26]([C:16]3[N:15]=[C:14]([N:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)[CH:19]=[CH:18][CH:17]=3)[CH:27]=[CH:28][C:29]1=2
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cccc(Br)n2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(N)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS 102 starting from (6′-bromo-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-4-yl)carbamic acid tert-butyl ester (preparation analogous to WO2005/26149) and 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylboronic acid. The protecting group is subsequently cleaved off in a corresponding manner to FS201. The product is in the form of the hydrochloride.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=2)=[CH:8][CH:7]=1.[CH3:28][C:29](C)([O-])C.[K+].ICC>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH2:28][CH3:29])[C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:13]=2)=[CH:10][CH:11]=1
Reactant: O=C(NCc1cccc(-c2ccc(C3OCCO3)cc2)c1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCN(Cc1cccc(-c2ccc(C3OCCO3)cc2)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
600 mg (1.7 mmol) of N-(4′-[1,3]dioxolan-2-ylbiphenyl-3-ylmethyl)benzamide, 5 ml of THF and 206 mg (1.85 mmol) of potassium tert-butoxide are introduced into a three-necked flask under nitrogen. 300 μl 15 (3.7 mmol) of iodoethane are added dropwise. The reaction mixture is stirred at room temperature for 3 hours, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (70/30). 400 mg (64%) of the desired product are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31](=[O:34])[CH2:32][OH:33])[NH:26][C:25](=[O:35])[CH2:24]2>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13](/[CH:16]=[C:24]3\[C:25](=[O:35])[NH:26][C:27]4[C:23]\3=[CH:22][C:21]([F:20])=[C:29]([NH:30][C:31](=[O:34])[CH2:32][OH:33])[CH:28]=4)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18]
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)CO)c(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 83.4 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide 27b as starting materials to obtain (Z)—N-{3-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide 27 (80 mg, yield 83.4%) as an orange solid.
Reaction SMILES: C(O[C:5]([O:7][C@@H:8]1[CH2:13][N:12]([C:14]([O:16][CH3:17])=[O:15])[C@H:11]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[C@@H:10]([C:32]([O:34][CH3:35])=[O:33])[CH2:9]1)=O)C=C.O1CC[CH2:38][CH2:37]1>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>[CH2:5]([O:7][C@@H:8]1[CH2:13][N:12]([C:14]([O:16][CH3:17])=[O:15])[C@H:11]([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[O:19])[C@@H:10]([C:32]([O:34][CH3:35])=[O:33])[CH2:9]1)[CH:37]=[CH2:38]
Reactant: C1CCOC1
Reactant: C=CCOC(=O)O[C@H]1C[C@H](C(=O)OC)[C@@H](C(=O)N2CCN(c3ccccc3)CC2)N(C(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCO[C@H]1C[C@H](C(=O)OC)[C@@H](C(=O)N2CCN(c3ccccc3)CC2)N(C(=O)OC)C1

Procedure:
A mixture of dimethyl (2S,3S,5S)-5-[(allyloxy)carbonyl]oxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (100 mg, 0.0002 mol) and tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.000020 mol) in tetrahydrofuran (5.00 mL, 0.0616 mol) was refluxed for 2 h. The mixture was concentrated to dry and used directly in next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=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.[F:51][C:52]1[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][C:53]=1[NH2:54]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:54][C:53]1[CH:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:52]=1[F:51])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(F)c(N)c1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
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: Cc1ccc(F)c(NC(=O)c2cccc(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-benzyloxy benzoic acid (1.00 g, 4.38 mmol) in 20 ml of anhydrous DMF were added HATU (1.83 g, 4.82 mmol) and DIPEA (1.7 ml, 9.6 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 2-fluoro-5-methylaniline (657 mg, 5.25 mmol). The mixture was heated at 66° C. for 16 hours, cooled to room temperature, and partitioned between EtOAc (100 ml) and 0.5M HCl (200 ml). The organic phase was washed with 0.5M HCl (2×50 ml), saturated NaHCO3 (50 ml) and brine (50 ml), dried over Na2SO4, and evaporated to dryness to afford 3-(benzyloxy)-N-(2-fluoro-5-methylphenyl)benzamide as light brown solid. Yield: 1.5 g, 100%.
Reaction SMILES: O=C(CCC([O-])=O)C([O-])=O.C(=O)=O.[C:14]([O-])(=O)[CH:15]([CH:17](CC([O-])=O)[C:18]([O-:20])=[O:19])[OH:16]>>[C:18]([O-:20])(=[O:19])[CH2:17][C:15]([CH3:14])=[O:16].[OH:16][CH:15]([CH3:14])[CH2:17][C:18]([O-:20])=[O:19]
Reactant: O=C([O-])CC(C(=O)[O-])C(O)C(=O)[O-]
Agent: O=C([O-])CCC(=O)C(=O)[O-]
Agent: O=C=O
Product: CC(=O)CC(=O)[O-]
Product: CC(O)CC(=O)[O-]

Procedure:
2-Oxoglutarate, CO2/isocitrate
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A solution of 4′-bromomethylbiphenyl-2-carboxylic acid t-butyl ester made as described in Preparation 2 (7.2 g, 20.8 mmol), N-(2-aminoethyl)(t-butoxy)carboxamide (10 g, 62.4 mmol), and potassium carbonate (4.3 g, 31.2 mmol) in THF (40 mL) was stirred at room temperature overnight. The mixture was concentrated then extracted with EtOAc (3×150 mL) and water (80 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford crude intermediate (3a) (98.4% yield), which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.S(=O)(=O)(O)O.[CH3:19]O>>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:19])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CO
Reactant: O=C(O)c1cccc2cnccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc2cnccc12
Temperature: 25 °C
Yield: 96 %

Procedure:
Isoquinoline-5-carboxylic acid (5.6 g, 32.36 mmol) obtained in Step (2) above and methanol (90 mL) were mixed and stirred. The reaction solution was slowly added with sulfuric acid (15 mL, 259 mmol) and refluxed for about 20 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled under reduced pressure. The concentrate was added with distilled water and adjusted to have a pH value in a range of 10˜11 by adding DIPEA. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (5.8 g, 96%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:28]=[CH:27][N:16]3[C:17](=[O:26])[C:18]([C:21]4[N:22]=[N:23][NH:24][N:25]=4)=[CH:19][N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)(C)(C)[CH3:2].CO[C:31]1C=CC(CN2N=NC(C3C(=O)N4C=CC(C(O)=O)=CC4=NC=3)=N2)=C[CH:32]=1.NC1SC2C=CC=CC=2N=1>>[S:8]1[C:9]2[CH:31]=[CH:32][CH:2]=[CH:1][C:5]=2[N:6]=[C:7]1[NH:10][C:11]([C:13]1[CH:28]=[CH:27][N:16]2[C:17](=[O:26])[C:18]([C:21]3[N:25]=[N:24][NH:23][N:22]=3)=[CH:19][N:20]=[C:15]2[CH:14]=1)=[O:12]
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(-c4nn[nH]n4)cnc3c2)n1
Reactant: COc1ccc(Cn2nnc(-c3cnc4cc(C(=O)O)ccn4c3=O)n2)cc1
Agent: Nc1nc2ccccc2s1
Product: O=C(Nc1nc2ccccc2s1)c1ccn2c(=O)c(-c3nn[nH]n3)cnc2c1

Procedure:
Reactions were performed in the same manner as in Example 10, (F) by using 3-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carboxylic acid (60 mg, 0.16 mmol) and 2-aminobenzothiazole (30 mg, 0.17 mmol) to obtain 2 mg (3% for the two steps) of an orange compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[N:47]=[C:20]2[CH:21]=[CH:22][C:23]([O:25][C:26]3[CH:27]=[C:28]([NH:33][C:34](=[O:46])[C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([C:44]#[N:45])([CH3:43])[CH3:42])[CH:36]=4)[CH:29]=[CH:30][C:31]=3[CH3:32])=[CH:24][N:19]2[N:18]=1.C(=O)([O-])O.[Na+]>O1CCCC1.N1C=CC=CC=1.CN(C)C=O>[C:44]([C:41]([C:37]1[CH:36]=[C:35]([C:34]([NH:33][C:28]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:26]([CH:27]=2)[O:25][C:23]2[CH:22]=[CH:21][C:20]3[N:19]([N:18]=[C:17]([NH:16][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[O:9])[N:47]=3)[CH:24]=2)=[O:46])[CH:40]=[CH:39][CH:38]=1)([CH3:43])[CH3:42])#[N:45]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Reactant: O=C(O)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)c3ccccn3)nn2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a solution of pyridine-2-carboxylic acid (234 mg, 1.90 mmol) in tetrahydrofuran (6 mL) were added oxalyl chloride (206 μL, 2.38 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue and N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (203 mg, 0.475 mmol) were dissolved in pyridine (7 mL), and the mixture was stirred at room temperature for 23 hr. A saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=40/60→20/80), and fractions containing the desired product were concentrated under reduced pressure. The crystals precipitated during concentration were collected by filtration and dried to give the title compound (146 mg, 58%) as colorless crystals.