Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH:7]([OH:10])[S:6][C:5]1=[N:11][N:12]=[C:13]1[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][S:14]1)[CH:2]=[CH2:3].Cl[P:21]1(=[O:27])[N:25]([CH3:26])[CH2:24][CH2:23][O:22]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]1[C:8](=[O:9])[CH:7]([O:10][P:21]2(=[O:27])[N:25]([CH3:26])[CH2:24][CH2:23][O:22]2)[S:6][C:5]1=[N:11][N:12]=[C:13]1[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][S:14]1)[CH:2]=[CH2:3]
Reactant: CN1CCOP1(=O)Cl
Reactant: C=CCN1C(=O)C(O)SC1=NN=C1SCC(=O)N1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN1C(=O)C(OP2(=O)OCCN2C)SC1=NN=C1SCC(=O)N1C

Procedure:
In a manner analogous to that described in Example 24 starting from 7.5 g (0.025 mol) of 3-allyl-5-hydroxy-2-[[3-methyl-4-oxo-2-thiazolidinylidene]-hydrazono]-4-thiazolidinone, 7.8 g (0.05 mol) of 2-chloro-3-methyl-1,3,2-oxazaphospholidine-2-oxide and 4.53 ml (0.0325 mol) of triethylamine in 50 ml of methylene chloride there is obtained 2-[3-allyl-2-[[3-methyl-4-oxo-2-thiazolidinylidene]-hydrazono]-4-oxo-5-thiazol-idinoxy]-3-methyl-2-oxo-1,3,2-oxazaphospholidine having a melting point of 184°-185°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[C@H:21]([NH2:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[C:32]([CH3:33])=[C:31](I)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C[C@H](N(C)C)C1[CH-]C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[C@H:21]([NH:23][C:31]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:24])[C:32]=1[CH3:33])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(I)ccc(C#N)c1Cl
Reactant: C[C@@H](N)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: C[C@@H](c1[cH-]ccc1P(c1ccccc1)c1ccccc1)N(C)C
Solvent: Cc1ccccc1
Product: Cc1c(N[C@H](C)[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Temperature: 140 °C
Yield: 18.2 %

Procedure:
To a solution of 80D (137 mg, 0.40 mmol) in nitrogen degassed toluene (3 mL) at rt was added 2-chloro-4-iodo-3-methyl-benzonitrile (122 mg, 0.44 mmol), Cs2CO3 (260 mg, 0.80 mmol) and Pd2(dba)3 (7.3 mg, 0.008 mmol) and (S)—N,N-dimethyl-1-[(R)-2-(diphenyphosphino)ferrocenyl]ethylamine (11 mg, 0.024 mmol). The reaction was degassed with nitrogen for 30 min, sealed and heated at 140° C. for 2 h under microwave conditions. The mixture was cool to rt, diluted with hexane and filtered through a layer of celite. The filtrate was evaporated to give the crude product. Purification by flash chromatography (10 g ISCO silica gel cartridge, 0-20% EtOAc in hexane gradient) gave the title compound 80E (36 mg): MS (ES) m/z 345 [M+H]+; HRMS calcd for C25H41N3O3ClSi 494.2606, found 494.2606.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>COCCOC>[OH:11][C:8]([C:5]1[CH:4]=[CH:3][C:2]2[N:7]([CH:13]=[C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[N:1]=2)[CH:6]=1)([CH3:9])[CH3:10]
Reactant: CC(C)(O)c1ccc(N)nc1
Reactant: O=C(CBr)C(=O)Nc1ccccc1
Solvent: COCCOC
Product: CC(C)(O)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.5 %

Procedure:
A solution of 100 mg of 2-(6-aminopyridin-3-yl)propan-2-ol in 10 ml of 1,2-dimethoxyethane is treated with 190 mg of 3-bromo-2-oxo-N-phenylpropionamide, then stirred at 25° C. for 15 hours and brought to reflux for 3 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is taken up in 40 ml of ethyl acetate and 40 ml of a saturated sodium carbonate solution. The aqueous phase is washed twice with 40 ml of ethyl acetate. The combined organic phases are dried and concentrated to dryness under reduced pressure. The residue is chromatographed on a cartridge of 40 g of silica, elution being carried out with dichloromethane and then with mixtures of dichloromethane and methanol, 97/3 and then 95/5. The fractions comprising the expected product are combined and concentrated to dryness to give 63 mg of 6-(1-hydroxy-1-methylethyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28]O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(S(F)(F)[F:36])CC)C>C(Cl)Cl>[F:36][CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][N:9]1[CH:10]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:11][CH2:12][CH2:13][CH:8]1[C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1CO
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1CF
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
To a cold (0° C.) solution of [2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-phenyl]-methanol (0.107 g,0.28 mmol) in CH2Cl2 (3 mL) was added (diethylamino)sulfur trifluoride (80 μL, 0.61 mmol). After 15 minutes, the cooling bath was removed and the reaction mixture was warmed to room temperature. After an additional 3 hours, the reaction mixture was treated with saturated aqueous NaHCO3 (5 mL) and extracted with CH2Cl2 (4×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.032 g (29%) of COMPOUND 62 as a white solid. 1H NMR (CDCl3) δ 1.60-1.74 (m, 3H), 2.02-2.10 (m, 1H), 2.26-2.41 (m, 8H), 3.56 (s, 2H), 4.13 (d, 2H, J=11.1 Hz), 5.06 (d, 2H, JC-F=48 Hz), 6.81-6.88 (m, 5H), 7.14-7.16 (m, 3H), 8.31 (d, 2H, J=3.6 Hz). 13C NMR (CDCl3) δ 19.24, 25.64, 28.65, 50.09, 67.20, 82.93 (d, JC-F=648 Hz), 122.29, 125.94, 127.47, 127.62, 129.79, 132.36, 133.66 (d, JC-F=62 Hz), 138.14, 139.34, 146.63, 159.99; ES-MS m/z 390 (M+H). Anal. Calcd. For C25H28N3F.0.1H2O: C, 76.73; H, 7.26; N, 10.74. Found: C, 76.66; H, 7.23; N, 10.70.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[O:10][CH:11]=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[C:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[C:18]([Cl:23])[CH:17]=1)(=[O:15])[NH2:14]>>[C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[CH:11][O:10][C:6]2=3)=[C:18]([Cl:23])[CH:17]=1)(=[O:15])[NH2:14]
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Reactant: CCN1Cc2ccoc2C(O)C1
Product: CCN1Cc2ccoc2C(Oc2ccc(C(N)=O)cc2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 34) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH2:24][CH:25]=[O:26])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=CCCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a 0° C. solution of 4-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)butan-1-ol (150 mg, 0.426 mmol) in DCM (3 mL) was added Dess-Martin periodinane (217 mg, 0.511 mmol) over 5 min. The reaction mixture was slowly warmed up to rt and stirred for 2 h. An aq. solution of saturated NaHCO3-Na2S2O3 was added, and the mixture was stirred at rt for 5 min. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2; gradient from 0 to 40% EtOAc:hexanes) to afford the title compound as a white solid (120 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 9.77 (t, J=1.5 Hz, 1H), 7.35-7.27 (m, 2H), 7.24 (s, 1H), 7.16-7.03 (m, 3H), 7.01-6.94 (m, 2H), 6.84 (ddd, J=8.0, 2.4, 1.0 Hz, 1H), 3.80 (s, 2H), 2.42 (td, J=7.3, 1.5 Hz, 2H), 2.07-1.96 (m, 4H), 1.76-1.55 (m, 6H), 1.23-1.10 (m, 2H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Na].Br[CH2:7][CH2:8][CH2:9]Br>>[CH2:1]([OH:4])[CH2:2][O:3][CH2:7][CH2:8][CH2:9][O:3][CH2:2][CH2:1][OH:4]
Reactant: OCCO
Reactant: BrCCCBr
Agent: [Na]
Product: OCCOCCCOCCO
Temperature: 25 °C
Yield: 17.9 %

Procedure:
To 280 ml (5.0 mol) of ethylene glycol is added 17.25 g (0.75 mol) of sodium metal in small pieces, in order to control the exothermic reaction. The reaction mixture is cooled to room temperature and 80.89 g (0.393 mol) of 1,3-dibromopropane (available from Aldrich Chem. Co., catalog no. 12,590-3) is added dropwise. The reaction is heated to 100° C. for 6 hours. Excess ethylene glycol then is removed by simple distillation under aspirator pressure and 3,7-dioxanonane-1,9-diol is obtained in 17.9% yield from the reaction mixture by fractional distillation at 108°-112° C. and 0.025 mm Hg. A solution of 11.47 g (0.072 mol) of the diol and 17.4 ml (0.215 mole) pyridine in 100 ml of methylene chloride is added to a stirred solution of 26.68 g of tosyl chloride (0.15 mol) in 140 ml methylene chloride. Following addition, the reaction is allowed to stand stirred at 0° C. for 24 hours. The mixture then is washed with water, 10% HCl, and once again with water. The mixture is dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to give 33.51 g of a clear oil. Kugelrohr distillation (80° C., 0.005 mm Hg) removes unreacted tosyl chloride, leaving 29.43 g of 3,7-dioxanonane-1,9-diol ditosylate as a slightly brown oil.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:12][C:13]([C:15]1[N:16]=[C:17]([N:20]2[CH2:23][CH:22]([S:24][C:25]3[C@H:26]([CH3:49])[C@@H:27]4[C@@H:44]([C@H:45]([OH:47])[CH3:46])[C:43](=[O:48])[N:28]4[C:29]=3[C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:31])[CH2:21]2)[S:18][CH:19]=1)=[O:14])[CH3:11])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C@@H:10]([NH:12][C:13]([C:15]1[N:16]=[C:17]([N:20]2[CH2:21][CH:22]([S:24][C:25]3[C@H:26]([CH3:49])[C@@H:27]4[C@@H:44]([C@H:45]([OH:47])[CH3:46])[C:43](=[O:48])[N:28]4[C:29]=3[C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:31])[CH2:23]2)[S:18][CH:19]=1)=[O:14])[CH3:11]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](CO)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Yield: 58.4 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(1S)-2-(t-butyldimethylsilyloxy)-1-methyl-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (940 mg, 1.28 mmol) (obtained as described in Example 40(1)) in tetrahydrofuran (47 ml) were added acetic acid (221 μl, 3.85 mmol) and a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (3.85 ml, 3.85 mmol) in an ice bath and the mixture was stirred for 3 days at room temperature. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate: methanol (99:1 and 9:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-((1S)-2-hydroxy-1-methylethylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (462 mg, yield 58%) as a pale yellow solid.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:8][O:9]C=O>>[N:2]1([NH:1][CH:8]=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NN1CCCCC1
Reactant: COC=O
Product: O=CNN1CCCCC1
Yield: 77.6 %

Procedure:
A solution of N-aminopiperidine (2.0 ml, 18.5 mmol) and methylformate (2.3 ml, 37 mmol) was stirred for four days in a sealed tube at 40° C. The mixture was concentrated in vacuo, suspended in ether (100 ml) and filtered to give 1.84 g of N-(piperidin-1-yl)formamide as a white powder.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C@H:13]([C:18]([OH:20])=O)[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][CH2:23][C:24]#[N:25].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:23]([CH2:24][NH:25][C:18](=[O:20])[C@H:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[NH:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][N:10]=1)#[N:22]
Reactant: N#CCN
Reactant: CC(C)C[C@H](Nc1nnnn1-c1ccccc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](Nc1nnnn1-c1ccccc1)C(=O)NCC#N
Reaction time: 36 h
Yield: 55 %

Procedure:
To a solution of N-(1-phenyl-1H-tetraazol-5-yl)-L-leucine (100 mg, 0.36 mmol), aminoacetonitrile hydrochloride (62 mg, 0.68 mmol) and PyBOP (230 mg, 0.44 mmol) in DMF (3 mL) was added triethylamine (0.2 mL, 1.4 mmol). The solution was stirred 36 h, then partitioned between ethyl acetate and pH 3 phosphate buffer. The organic phase was washed with brine and concentrated. Purification by flash chromatography (60% to 90% ethyl acetate/hexanes) gave 62 mg of N1-(cyanomethyl)-N2-(1-phenyl-1H-tetraazol-5-yl)-L-leucinamide. MS (+APCI): 313.9 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([O:9][C:10]2[C:15]([NH:16]C(=O)C3C=CC(OC)=C(C(F)(F)F)C=3)=[CH:14][C:13]([O:31][CH3:32])=[CH:12][C:11]=2[Br:33])=O)=[CH:5][C:4]=1[C:36]([F:39])([F:38])[F:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:33][C:11]1[C:10]2[O:9][C:7]([C:6]3[CH:34]=[CH:35][C:3]([O:2][CH3:1])=[C:4]([C:36]([F:37])([F:39])[F:38])[CH:5]=3)=[N:16][C:15]=2[CH:14]=[C:13]([O:31][CH3:32])[CH:12]=1
Reactant: COc1cc(Br)c(OC(=O)c2ccc(OC)c(C(F)(F)F)c2)c(NC(=O)c2ccc(OC)c(C(F)(F)F)c2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1cc(Br)c2oc(-c3ccc(OC)c(C(F)(F)F)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 20, Step d (Route a), from 2-bromo-4-methoxy-6-{[4-methoxy-3-(trifluoromethyl)benzoyl]amino}phenyl 4-methoxy-3-(trifluoromethyl)benzoate and p-toluenesulfonic acid monohydrate. The product was obtained as an off-white solid, m.p. 183-185° C.; MS m/e 402 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([CH2:10][C:11]([OH:13])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH:14][C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O.C(OCC)(=O)C>[OH:14][C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[CH2:20][CH2:19][N:18]([C:11](=[O:13])[CH2:10][C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)[CH2:17][CH2:16]1
Reactant: O=C(O)Cc1ccc2nc[nH]c2c1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc2[nH]cnc2c1)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.46 g (0.0083 mol) of 1H-benzimidazol-6-ylacetic acid from preparation 3, 2.0 g (0.0081 mol) of 4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidine, 3.6 g of BOP and 3.4 ml of triethylamine in 40 ml of dimethylformamide is stirred at ambient temperature overnight. A mixture of ethyl acetate and of water is added, the two phases are separated, the organic phase is dried over sodium sulfate and the solvent is evaporated. The crude product is purified by chromatography on a column of silica gel, elution being carried out with an ethyl acetate/methanol=9/1 mixture, and the title compound is thus obtained.
Reaction SMILES: ClC(OCC(C)C)=O.[O:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]#[C:17][C:18]([OH:20])=O)[CH2:11][CH2:10]1.CN1CCOCC1.N#N.[NH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][C:35]([C:41]#[N:42])=[C:34]2[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Br:50])[CH:45]=1>N1C=CC=CC=1>[Br:50][C:46]1[CH:45]=[C:44]([NH:43][C:34]2[C:33]3[C:38](=[CH:39][CH:40]=[C:31]([NH:30][C:18](=[O:20])[C:17]#[C:16][CH2:15][N:12]4[CH2:11][CH2:10][O:9][CH2:14][CH2:13]4)[CH:32]=3)[N:37]=[CH:36][C:35]=2[C:41]#[N:42])[CH:49]=[CH:48][CH:47]=1
Reactant: O=C(O)C#CCN1CCOCC1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: N#Cc1cnc2ccc(NC(=O)C#CCN3CCOCC3)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
Isobutyl chloroformate (0.161 g, 1.18 mmol) was dropwise added into an ice cold solution of 4-morpholino-2-butynoic acid (0.25 g, 1.48 mmol) and N-methylmorpholine (0.15 g, 1.48 mmol) in 8 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 025 g (0.74 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 6 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.096 g (27%) of yellow solid; :mass spectrum (electrospray, m/e,) 490.1, 492.1 (M+H+); mp 145-148° C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:39])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:39][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:36])[F:37])[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2C(F)(F)F)n1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)n(-c2ccccc2C(F)(F)F)n1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(2-trifluoromethyl-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 519.05 [M+H]+; tR=3.08 min (System 3).
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:20])[NH:14][O:15][CH2:16][C:17]([OH:19])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:21][C@@H:22]([CH3:46])[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH2:43]([O:42][CH:38]([O:39][CH2:40][CH3:41])[C@@H:37]([N:25]([CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[C:23](=[O:24])[C@@H:22]([NH:21][C:17](=[O:19])[CH2:16][O:15][NH:14][C:13]([NH:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:20])[CH3:46])[CH3:45])[CH3:44]
Reactant: O=C(O)CONC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(naphthalen-1-ylmethyl)ureidooxy)acetic acid (Compound VI-12) 115 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)-propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(-c2nc3c(O)cccc3s2)cc1
Product: COC(=O)c1ccc(-c2nc3c(OC(C)=O)cccc3s2)cc1

Procedure:
The methyl 4-(4-hydroxybenzothiazol-2-yl)benzoate (2.5 g) obtained in Example 4 was added to 30 ml of acetic anhydride, and the mixture was refluxed for 2 hours. After the reaction, the reaction mixture was dried under reduced pressure. The residue was washed with a small amount of cyclohexane, and recrystallized from cyclohexane and ethyl acetate to give 2.3 g of methyl 4-(4-acetoxybenzothiazol-2-yl)benzoate.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9]C>N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(CCC(=O)O)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)CCc1ccc(O)c(F)c1
Temperature: 190 °C
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
A pyridine/hydrochloric acid complex prepared by mixing pyridine (30 ml) and concentrated hydrochloric acid (30 ml) and heating the mixture at 190° C. for 1 hour was added with Intermediate 9 (2.40 g) and stirred at 190° C. for 1.5 hours. The reaction mixture was poured into 1 N hydrochloric acid (100 ml) cooled with ice, and extracted with ethyl acetate (200 ml). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 10, 1.98 g).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.F[C:20]1[N:25]=[C:24]([C:26]2[C:34]3[C:29](=[CH:30][N:31]=[C:32]([C:35]4[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=4)[CH:33]=3)[N:28]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[N:27]=2)[CH:23]=[CH:22][CH:21]=1>>[CH3:40][N:38]1[CH:39]=[C:35]([C:32]2[CH:33]=[C:34]3[C:26]([C:24]4[N:25]=[C:20]([N:1]5[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]6[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=6)[CH2:3][CH2:2]5)[CH:21]=[CH:22][CH:23]=4)=[N:27][N:28]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[C:29]3=[CH:30][N:31]=2)[CH:36]=[N:37]1
Reactant: O=C(N[C@H]1CCCNCC1)OCc1ccccc1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@H](NC(=O)OCc6ccccc6)CC5)n4)nn(C4CCCCO4)c3cn2)cn1
Yield: 73.4 %

Procedure:
Following the procedure of Example 189, (S)-benzyl azepan-4-ylcarbamate and 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted to give benzyl (4S)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate as a solid (73.4%). LC/MS: m/z 607.3 [M+1].