Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[C:4]2[C:21]([CH3:24])=[N:22][O:23][C:3]1=2.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[C:13]([C:12]1[CH:11]=[CH:10][C:9]([C:7]2[C:6]3[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=3[C:4]3[C:21]([CH3:24])=[N:22][O:23][C:3]=3[CH:2]([NH:1][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[N:8]=2)=[CH:16][CH:15]=1)#[N:14]
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(C#N)cc1)=NC2N
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1noc2c1-c1ccccc1C(c1ccc(C#N)cc1)=NC2NC(=O)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a round bottomed flask was added 4-(4-amino-1-methyl-4H-benzo[c] isoxazolo[4,5-e]azepin-6-yl)benzonitrile (69 mg, 0.22 mmol) and DMAP (2.7 mg, 0.022 mmol). The flask was purged with nitrogen, acetonitrile (5 mL) was added (5 mL), and the solution was cooled to 0° C. Isobutyryl chloride (55 μL, 0.53 mmol) and triethylamine (79 μL, 0.57 mmol) were added and the reaction was allowed to warm to ambient temperature and stirred for 2 h. The reaction was quenched with a 1:1 mixture of sat. aq. NaHCO3:brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated, and purified on a Biotage (isocratic elution 30% EtOAc: 70% Hexanes) to provide the title compound as white solid (66 mg). LC/MS m/z 385 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH2:31][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6])=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CC(=O)NCCN
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: CC(=O)NCCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from N-(2-amino-ethyl)-acetamide and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 142-155° C.; LC-MS: 457 (MH+); HPLC RT: 3.35 minutes.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6](=[O:17])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][CH3:16])[CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][CH:34]=1)=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][C:30](=[O:31])[N:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([O:8][CH2:7][C:6](=[O:17])[N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[CH3:18])[CH2:14][CH2:13]2)[CH3:16])=[CH:34][CH:35]=1
Reactant: CN[C@H]1CC[C@H](OCC(=O)N(C)CCN(C)C)CC1
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCN(C)C(=O)CO[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 150 mg (0.55 mmol) of trans-N-(2-dimethylamino-ethyl)-N-methyl-2-(4-methylamino-cyclohexyloxy)-acetamide in 4 mL of CH2Cl2 were added 0.14 mL (0.8 mmol, 1.5 eq) of N,N-diisopropylethylamine followed by 0.08 mL (0.58 mmol, 1.1 eq) of 4-bromophenyl chloroformate. The mixture was stirred at RT for 2 h, and the solution was added to a mixture of NaHCO3 solution and CH2Cl2. The phases were separated and the inorganic one was extracted with CH2Cl2. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Column chromatography on silica gel with CH2Cl2:MeOH 9:1 yielded 174 mg (67%) of trans-(4-{[(2-dimethylamino-ethyl)-methyl-carbamoyl]-methoxy}-cyclohexyl)-methyl-carbamic acid 4-bromo-phenyl ester as colorless oil, MS: 470 (MH+,1Br).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][S:20]([CH2:23][CH2:24][NH2:25])(=[O:22])=[O:21]>CO.C(O)C.[Pd]>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:25][CH2:24][CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CS(=O)(=O)CCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (277 mg) in methanol (10 mL) was added 2-methanesulfonyl-ethylamine (234 mg) and the reaction stirred at room temperature for 16 h. The solvent was reduced in vacuo and the residue redissolved in ethanol (50 mL). Palladium on carbon (20 mg) was added and the reaction stirred at room temperature under a hydrogen balloon for 48 h. The reaction was then filtered through Celite and the filtrate reduced in vacuo to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(2-methanesulfonyl-ethyl)-amine as a white solid.
Reaction SMILES: CN(C[CH:5]([C:10]1[N:11]=[CH:12][S:13][CH:14]=1)[S:6][CH2:7][CH2:8][NH2:9])C.[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[N:28]=[CH:29][N:30]([CH:32]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH:31]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:29][N:30]([CH2:32][C:12]1[S:13][CH:14]=[C:10]([CH2:5][S:6][CH2:7][CH2:8][NH:9][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[N:28]=[CH:29][N:30]([CH:32]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[CH:31]=3)=[CH:21][N:20]=2)[N:11]=1)[CH3:31]
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2cnc(Cc3cnc(N[N+](=O)[O-])[nH]c3=O)c2)cc1
Reactant: CN(C)CC(SCCN)c1cscn1
Solvent: CCO
Product: COc1ccc(C(c2ccc(OC)cc2)n2cnc(Cc3cnc(NCCSCc4csc(CN(C)C)n4)[nH]c3=O)c2)cc1
Yield: 50.7 %

Procedure:
A solution of 2-(dimethylaminomethyl-4-thiazolylmethylthio)ethylamine (2.3 g) and 2-nitroamino-5-[1-(4,4'-dimethoxybenzhydryl)imidazol-4-ylmethyl]-4-pyrimidone (4.62 g) in ethanol (11 ml) was refluxed for 22 hours. Ethanol was evaporated from the solution and the residue chromatographed using HPLC. The appropriate fractions were combined and freed of solvents to give about 1.6 g of 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-[1-(4,4'-dimethoxybenzhydryl)imidazol-4-ylmethyl]-4-pyrimidone as a glass.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[S:26][N:25]=[CH:24][N:23]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[OH:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[S:26][N:25]=[CH:24][N:23]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2ncns2)N1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C1N(O)[C@@H]2CC[C@@H](c3ncns3)N1C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
BCl3 (1 M in DCM, 3.0 mL, 3.0 mmol) was added dropwise to a solution of (2S,5R)-6-(benzyloxy)-2-(1,2,4-thiadiazol-5-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (190 mg, 0.60 mmol) in dry DCM (20 mL) at −78° C. The mixture was stirred at 0° C. for 6 hrs., then, MeOH (3 mL) was added slowly at −78° C. The solvents were evaporated under vacuum to give (2S,5R)-6-hydroxy-2-(1,2,4-thiadiazol-5-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (110 mg, 80%) as a yellow solid, which was directly used in the next step. ESI-MS (EI−, m/z): 227.1 [M−H]−.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[C:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.S([O-])([O-])(=O)=O.O[NH3+:28].O[NH3+]>O>[C:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:11]([C:14]#[N:28])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: [NH3+]O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
With stirring (20 rpm), a turbine dryer is charged at room temperature with 1007 parts by weight of anhydrous sodium sulfate, 222 parts by weight of biphenyl-4-carbaldehyde and 105 parts by weight of hydroxylammonium sulfate. Following evacuation to 13 mbar, the mixture is heated to 70° C. and stirred at this temperature for 3 hours. It is subsequently heated at 130° C., during which about 43 parts by weight of water are removed by distillation. After half an hour, the pressure is reduced to 4 mbar and the jacket temperature is raised successively to 170° C. over the course of 60-70 minutes, the product undergoing fractional distillation. 194 parts by weight of biphenyl-4-carbonitrile are obtained with an outstanding purity of ~98-99% (HPLC) and a melting point of 83°-85° C., along with 10 parts by weight of a less pure fraction.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2(OC)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Li]CCCC.C([O:27]B(OC(C)C)OC(C)C)(C)C.C(O)(=O)C.OO>C1COCC1.O>[C:11]1([C:6]2[C:7]3[C:3](=[C:2]([OH:27])[CH:10]=[CH:9][CH:8]=3)[CH2:4][CH:5]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC1(c2ccccc2)CCc2c(Br)cccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Oc1cccc2c1CC=C2c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, to a solution of 21.0 g (69.3 mmol) of 4-bromo-1-methoxy-1-phenylindane in 200 ml of THF, 27.7 ml of 2.5 M nBuLi (69.3 mmol) in hexanes was added with vigorous stirring for 1 hour at −78° C. Then, 24.0 ml (19.5 g, 104 mmol) of triisopropylborate was added at this temperature. The resulting mixture was slowly warmed to ambient temperature, and then 5.96 ml (6.25 g, 104 mmol) of glacial acetic acid was added. The resulting mixture was cooled to 0° C., and then 14.7 ml of 16% H2O2 was added. This mixture was stirred for ca. 30 min at room temperature, and then 300 ml of water was added. The product was extracted with 3×150 ml of CH2Cl2. The combined extract was dried over Na2SO4 and evaporated to dryness. The analytically pure product, 3-phenyl-1H-inden-7-ol, was obtained by flash chromatography on Silica Gel 60 (40-63 μm, d 50 mm, l 350 mm, eluant: hexanes-CH2Cl2=4:1). Yield, 9.68 g (67%).
Reaction SMILES: [ClH:1].[C:2]([CH2:5][CH2:6][N:7]1[CH:12]=[CH:11][C:10](=[O:13])[C:9]([OH:14])=[C:8]1[CH3:15])([OH:4])=[O:3].[CH3:16]O>Cl>[ClH:1].[OH:14][C:9]1[C:10](=[O:13])[CH:11]=[CH:12][N:7]([CH2:6][CH2:5][C:2]([O:4][CH3:16])=[O:3])[C:8]=1[CH3:15]
Reactant: Cc1c(O)c(=O)ccn1CCC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CCn1ccc(=O)c(O)c1C
Yield: 80 %

Procedure:
1-(2'-carboxyethyl)-3-hydroxy-2-methylpyrid-4-one hydrochloride (2 g) prepared as described under Example 17, is dissolved in methanol saturated with hydrogen chloride and the solution is refluxed for 3 hours. Rotary evaporation of the solution yields a white solid which on recrystallisation from methanol gives 3-hydroxy-1-(2'-methoxycarbonylethyl)-2-methylpyrid-4-one hydrochloride in 80% yield m.p. 140°-141° C., νmax 1545, 1595, 1645, 1730, 1750 cm-1, δ(d6DMSO), 2.45 (s, 3H), 2.85 (t, 2H), 3.5 (s, 3H), 4.45 (t, 2H), 7.30 (d, 1H), 8.15 (d, 1H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:33]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:28]3=[N:29][CH:30]=[CH:31][CH:32]=[C:27]3[CH:26]=2)=[CH:9]1>CN(C)C=O>[CH2:10]([O:2][C:1]([N:29]1[CH2:30][CH2:31][C:32]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH3:7])[CH:9]=[C:10]3[C:25]2[N:33]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:35])=[O:36])[C:28]3=[N:29][CH:30]=[CH:31][CH:32]=[C:27]3[CH:26]=2)=[CH:27][CH2:28]1)=[O:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(OS(=O)(=O)C(F)(F)F)cc34)cc3cccnc32)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C5=CCN(C(=O)OCc6ccccc6)CC5)cc34)cc3cccnc32)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl 1-[3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl](2H)pyridinecarboxylate (2 g, prepared according to the procedure described by P. Eastwood, Tetrahedron Letters, 2000, 41, pages 3705-3708), dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium[II] (0.25 g,) and potassium carbonate (2.42 g), under nitrogen, was treated with a solution of trifluoro-methanesulfonic acid 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yl ester [1.6 g, Reference Example 18(a)] in dimethylformamide(76 mL). The mixture was heated at 80° C. for 4 hours (TLC indicated that starting material was still present), then treated with a further quantity of trifluoro-methanesulfonic acid 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yl ester (0.15 g), then heated at reflux temperature for 4 hours and then left at room temperature overnight. A further quantity of trifluoro-methanesulfonic acid 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol -5-yl ester [0.15 g, Reference Example 18(a)] was added and the mixture was heated at reflux temperature for a further 4 hours then evaporated. The residue was partitioned between ethyl acetate and water, and the aqueous layer was extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with brine, then dried overmagnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give the title compound as a light brown viscous liquid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=1.C1(S)C=CC=CC=1.[H-].[Na+].O>CN(C)C=O>[OH:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:7]=1
Reactant: COc1cc(CCCC(=O)O)c([N+](=O)[O-])cc1OC
Agent: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(CCCC(=O)O)cc1O
Temperature: 145 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(4,5-dimethoxy-2-nitrophenyl)butanoic acid (4.75 g) and thiophenol (2 g) in N,N-dimethylformamide (40 ml) was added NaH dispersion (1.1 g, 80% NaH in mineral oil). The mixture was stirred under nitrogen at 140-150° C. for three hours, poured into cold water and acidified. The solid was filtered, washed with water and dried under vacuum. Finally, the product was triturated with diethyl ether. Yield: 3.37 g.
Reaction SMILES: C1[O:14][C:4]([CH3:13])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)OC1.[O-]CC.[Na+].Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[CH:21]=1.Cl>C(O)C.CO>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:14])[CH3:13])=[CH:11][CH:10]=2)[CH:21]=1
Reactant: CC1(Cc2ccc(O)cc2)OCCO1
Reactant: ClCc1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(=O)Cc1ccc(OCc2cccnc2)cc1

Procedure:
A solution of (4-hydroxyphenyl)propan-2-one ethylene ketal (5 g) in ethanol (20 ml) was added to a stirred solution of sodium ethoxide in ethanol (1.26 g sodium in 50 ml). A suspension of 3-picolyl chloride hydrochloride (4.5 g) in ethanol (40 ml) was added, the mixture boiled for 41/2 hr, cooled and filtered. After evaporation of the solvent the residue was chromatographed on alumina. Elution with 10% methanol in dichloromethane gave a dark oil which was dissolved in methanol (50 ml) and boiled with 2M hydrochloric acid (40 ml) for 3 hours. Neutralisation with 2M sodium hydroxide solution followed by extraction into dichloromethane yielded an oil which was purified by bulb to bulb distillation at 70° C./0.4 mm to give [4-(3-pyridylmethyloxy)phenyl]propan-2-one.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[C:10](I)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[C:10]([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:32][CH:33]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1nccc2c1c(I)nn2Cc1ccccc1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2Cc1ccccc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a mixture of 1-benzyl-3-iodo-4-methoxy-1H-pyrazolo[4,3-c]pyridine (0.75 g), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (0.60 g) and sodium carbonate (0.44 g) in DME/water (6 mL/3 mL) was added dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) (73 mg) under nitrogen atmosphere. The reaction mixture was stirred overnight at 85° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (0.72 g).
Reaction SMILES: [F:1][CH:2]([F:47])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:22]([N:24]([CH:41]([CH3:43])[CH3:42])[C@H:25]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:28]([CH2:38][CH2:39][OH:40])[CH2:27][CH2:26]3)=[O:23])[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]=2[O:11][C:10]([CH3:45])([CH3:44])[C:9]1=[O:46])=[O:4].C[N+]1([O-])CCOCC1>C(Cl)Cl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:47][CH:2]([F:1])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:22]([N:24]([CH:41]([CH3:42])[CH3:43])[C@H:25]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[C@@H:28]([CH2:38][CH:39]=[O:40])[CH2:27][CH2:26]3)=[O:23])[C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=2[O:11][C:10]([CH3:45])([CH3:44])[C:9]1=[O:46])=[O:4]
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)C(F)F)[C@@H]1CC[C@H](CCO)N(C(=O)OC(C)(C)C)C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)C(F)F)[C@@H]1CC[C@H](CC=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 69 %

Procedure:
Under the nitrogen atmosphere, to a solution of tert-butyl (2R,5R)-5-[{[4-{2-[(difluoroacetyl)-amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]-2-(2-hydroxyethyl)piperidine-1-carboxylate (1.1 g) in methylene chloride -acetonitrile (5 ml, 5 ml) were added N-methylmorpholine oxide (283 mg) and molecular sieve 4 Å (750 mg), and the mixture was stirred at room temperature for a while. Then, tetrapropylammonium perruthenate (56 mg) was added thereto, and the mixture was stirred at room temperature for 3 hours. Then, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone=2/1) to give the title compound (757 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8](=[O:12])[CH2:7]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].CC#N>[Na+].[I-].CO>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10](=[O:11])[CH2:9][S:8](=[O:12])[CH2:7]2)[CH2:23][CH2:22]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1CS(=O)CN1CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: COc1ccccc1N1CCN(CCCCN2CS(=O)CC2=O)CC1
Temperature: 95 °C
Yield: 99.7 %

Procedure:
A mixture of 3-(4-bromobutyl)-1,4-dioxothiazolidine (3.37 g), 1-(2-methoxyphenyl)piperazine (2.80 g), K2CO3 (4.60 g), NaI (190 mg) and CH3CN (150 ml) was heated at reflux (bath temperature 95° C.) for 24 h. TLC analysis (silica gel, 20% MeOH/CH2 Cl2) showed the consumption of the starting sulfoxide and the presence of one major product with Rf =0.43. The mixture was cooled to room temperature, EtOAc (100 m) was added and the mixture was filtered. The filtrate was concentrated in vacuo to an oil which was filtered through silica gel using 20% MeOH/CH2Cl2 as the eluent. The fractions containing the material with Rf 0.43 were concentrated in vacuo to yield 4.83 g of a foam, which was dissolved in MeOH/CH2 Cl2 and flash chromatographed (silica gel) to yield 3.28 g of a crude product. Rechromatography over silica gel using 50% MeOH/toluene as eluent yielded 2.98 g of an oil which solidified on standing. The solid was dissolved in 50% MeOH/EtOAc and filtered through silica gel. The filtrate containing the product was concentrated to approximately 5 ml and the oily liquid was seeded and left standing, yielding 0.91 g of a white solid, mp, 111°-113° C. The mother liquor was concentrated in vacuo to a solid which was recrystallized from CH2Cl2 /Et2O, yielding an additional 0.79 g of fine needles, mp, 111°-113° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[N:15][OH:16])[CH:10]([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(O)C(=O)c1ccc(F)c(F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(O)C(=NO)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a well stirred solution of 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one (5.5 g, 29.6 mmol) in MeOH (200 mL) was added hydroxylamine hydrochloride (2.6 g, 38.4 mmol) and sodium acetate (8.1 g, 59.2 mmol) and the turbid solution was stirred overnight at room temperature. The solvent was evaporated and the residue was extracted with CH2Cl2. The organic layer was washed with sat. NaHCO3, separated, dried over Na2SO4 and then filtered. The solvent was removed in vacuo to obtain 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one-oxime as an orangish yellow oil (5.8 g, 97%). It was used in the next step without purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][C:3]1([CH3:18])[CH3:17].[Br:19][C:20]1[CH:21]=[C:22]2[C:27](Cl)=[C:26]([C:29]([NH2:31])=[O:30])[CH:25]=[N:24][N:23]2[CH:32]=1>>[Br:19][C:20]1[CH:21]=[C:22]2[C:27]([NH:1][C@@H:2]3[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:8])[CH2:4][C:3]3([CH3:18])[CH3:17])=[C:26]([C:29](=[O:30])[NH2:31])[CH:25]=[N:24][N:23]2[CH:32]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CC1N
Product: CC1(C)CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12

Procedure:
According to the procedure described for Step 1 of Example 294, the title compound was prepared by coupling enantiopure Intermediate 11 with Intermediate 2.