Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12].[NH2:13][CH2:14][CH2:15][CH2:16][Si:17](OCC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[NH2:13][CH2:14][CH2:15][CH2:16][Si:17]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[O:8][C:7]1[C:2]([Cl:1])=[C:3]([Cl:12])[C:4]([Cl:11])=[C:5]([Cl:10])[C:6]=1[Cl:9]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCO[Si](CCCN)(OCC)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reaction time: 0.17 h

Procedure:
In a 250 ml three-necked flask equipped with magnetic stirrer, reflux condenser and dropping funnel, 26.6 g of pentachlorophenol is placed for dissolving in 70 ml of chloroform and 50 ml of triethylamine. Over a period of 10 minutes, 22.1 g of 3-aminopropyltriethoxysilane is added, drop by drop, with refluxing and stirring. After three hours of boiling and stirring, the clear solution is concentrated by distilling out the chloroform, the ethanol that is formed, and most of the triethylamine, and the product is carefully precipitated with 130 ml of pentane, with stirring. It is washed thrice with pentane and decanted, then dried in a high vacuum at about 60° C. 41 g of a finely divided 3-aminopropyldiethoxypentachlorophenoxysilane is obtained having a melting point of 122° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([P:8]([O-:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([CH:18]=[CH:19][C:20]#[N:21])=[CH:16][CH:15]=1.[H-].[Na+].C(O)(=O)C>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]([P:8]([CH:4]([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])(=[O:12])[O:9][CH2:10][CH3:11])[CH2:19][C:20]#[N:21])=[CH:22][CH:23]=1
Reactant: N#CC=Cc1ccc(Cl)cc1
Reactant: CCOC(OCC)P([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(CC#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 25.8 g of ethyl (diethoxymethyl)phosphonite and 18.0 g of 4-chlorocinnamonitrile in 100 ml of ethanol is added to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 1-(4-chlorophenyl)-2-cyanoethyl(diethoxymethyl)phosphinate, b.p. 180°-200° C./0.02 mbar, 31P=+37.9 and +37.8 ppm (CDCl3).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:34])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+]>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:34])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:20][CH:21]=1)=[O:15]
Reactant: COC(=O)CCCCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.8 %

Procedure:
Into a suspension of methyl 8-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-8-oxooctanoate (420 mg, 0.73 mmol) in THF/H2O (2/1) (15 mL) was added NaOH (1.0 N, 3.6 mL). The resulting solution was stirred at rt for 2.5 hr and quenched with HCl (5 N, 2 mL). A yellow solid precipitated out. Filtration, washing with water (4×5 mL) and drying under vacuo at 70° C. for 20 hrs gave the title compound as a yellow powder (340 mg, 82%) in 99.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([OH:14])=[O:13])=[O:4].N1(O)C2C=CC=CC=2N=N1.[N:31]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[C@@H:33](O)[CH2:32]2.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[O:13]=[C:12]([O:14][C@@H:33]1[CH:34]2[CH2:37][CH2:38][N:31]([CH2:36][CH2:35]2)[CH2:32]1)[CH:11]([NH:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1sccc1NC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
A mixture of 2-(2-(methoxycarbonyl)thiophen-3-ylamino)-2-phenylacetic acid (I10) (700 mg, 2.40 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (487 mg, 3.60 mmol), (R)-quinuclidin-3-ol (458 mg, 3.60 mmol), and DCC (744 mg, 3.60 mmol) in dry THF (20 ml) was stirred at room temperature overnight. THF was evaporated, the crude product was partitioned between DCM and 2M K2CO3. The organic phase was collected, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash-chromatography (DCM/MeOH=95/5) to obtain methyl 3-(2-oxo-1-phenyl-2-((R)-quinuclidin-3-yloxy)ethylamino)thiophene-2-carboxylate (302 mg, 31.4% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]#[CH:14]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:18]([O:17][C:16](=[O:22])[NH:15][CH2:12][C:13]#[C:14][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ncc(C#CCNC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 79.3 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitropyridine (2.81 g, 12.9 mmol) in TEA (25 mL) was added tert-butyl prop-2-yn-1-ylcarbamate (2.58 g, 16.6 mmol). The solution was degassed with argon. To the reaction mixture were added bis(triphenylphosphine)palladium(II)chloride (0.18 g, 0.26 mmol) and copper(I)iodide (0.098 g, 0.52 mmol). The reaction mixture was allowed to stir at 70° C. for 2.5 h and was then concentrated and diluted with EtOAc (100 mL). The mixture was filtered over a pad of Celite® and the resulting filtrate was washed with sat. aq. NaHCO3 (100 mL). The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl[3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-yl]carbamate (2.98 g, 79%) as a yellow solid. LCMS (FA): Rt=1.81 min, m/z=292.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH:24]3[CH2:26][CH2:25]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH:24]1([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:30]=[N:29][C:28]([NH2:27])=[CH:33][CH:32]=4)[CH:7]=3)[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=2)[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(-c3ccnc(Cl)c3)nc(C3CC3)c2)cc1
Product: Nc1ccc(-c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C4CC4)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2′-chloro-6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.29) (0.300 g, 0.80 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.229 g, 1.17 mmol) according to the general procedure VI. Obtained as a white solid (0.060 g, 17%). MS (ISP) 433.1 [(M+H)+]; mp 172-174° C.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16](=[N:18][OH:19])[NH2:17])=[N:13][N:12]=2)[CH2:7][CH2:6]1.[C:25]([OH:33])(=[O:32])[C@H:26]([CH2:28][C:29](O)=O)[OH:27]>>[Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:17]=[C:29]([CH2:28][C@H:26]([OH:27])[C:25]([OH:33])=[O:32])[O:19][N:18]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: NC(=NO)c1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1
Reactant: O=C(O)C[C@H](O)C(=O)O
Product: O=C(O)[C@@H](O)Cc1nc(-c2nnc(N3CCC(Oc4cc(F)ccc4Br)CC3)s2)no1

Procedure:
The title compound was prepared in a similar manner as described for Example 16 from 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-N′-hydroxy-1,3,4-thiadiazole-2-carboximidamide and (S)-(−)-malic acid.
Reaction SMILES: ClC1C=[C:4]([N:8]2[C:16]3[C:11](=CC=CC=3)[CH2:10][C:9]2=O)C=CC=1.[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][C:24](=[O:34])[N:25]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][CH:20]=1.CN1CCCC1=O>>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23](=[C:9]3[CH2:10][CH2:11][CH2:16][N:8]3[CH3:4])[C:24](=[O:34])[N:25]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][CH:20]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1c1ccccc1
Reactant: O=C1Cc2ccccc2N1c1cccc(Cl)c1
Solvent: CN1CCCC1=O
Product: CN1CCCC1=C1C(=O)N(c2ccccc2)c2cc(Cl)ccc21

Procedure:
By the procedure of Example B1 a mixture of 1-(3-chlorophenyl)-2(1H,3H)-indolone and 6-chloro-1-phenyl-2(1H,3H)-indolone (1.36 g, 5.56 mmoles) and N-methyl-2-pyrrolidone (0.9 ml, 9.34 mmoles) were converted to a crude mixture of title products, as an oil. The isomers were separated, purified and isolated as solid products by silica gel chromatography, using the same eluant. The 3-chlorophenyl isomer was the faster moving, yield 0.72 g, m.p. 134°-137°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cccc(Br)n1
Product: Brc1cccc(-c2ccccc2)n1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 2,6-dibromo-pyridine and phenylboronic acid. After purification the product still contained some 2,6-dibromo-pyridine starting material. The mixture was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:27][NH2:28]>O1CCOCC1>[NH:27]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:28]
Reactant: COc1cc(C(=O)N2CCc3nnc(Cl)cc3C2)cc(OC)c1OC
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(=O)N2CCc3nnc(NN)cc3C2)cc(OC)c1OC

Procedure:
12.8 g of 3-chloro-5,6,7,8-tetrahydro-6-(3,4,5-trimethoxybenzoyl)pyrido[4,3-c]pyridazine and 40 cc of hydrazine hydrate in 40 cc of dioxane are stirred at a bath temperature of 100° for 41/2 hours. The title compound has a M.P. of 194°- 197° (decomp., from absolute ethanol/methanol 2:1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[O:21]1[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][C:30]2[N:31]=[C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[S:33][CH:34]=2)[CH2:23][CH2:22]1.[CH3:43][C:44]([CH3:46])=[O:45]>O1CCCC1>[OH:45][C:44]([C:34]1[S:33][C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[N:31][C:30]=1[CH2:29][CH2:28][O:27][CH:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)([CH3:46])[CH3:43]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1nc(CCOC2CCOCC2)cs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)Nc1nc(CCOC2CCOCC2)c(C(C)(C)O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a solution of diisopropylamine (9.5 mL, 67.2 mmol) in tetrahydrofuran (100 ml) was added butyllithium (42 mL, 1.6M in hexanes, 67.2 mmol) drop wise at −78° C. and stirred for 30 min. Thus obtained lithium diisopropylamide solution was immediately added by cannulation to a solution of Example 3C (7.36 g, 22.4 mmol) in tetrahydrofuran (100 ml) at −78° C. and stirred for 30 min at the same temperature. Then, dry acetone (8.2 ml, 112 mmol, Acros) was added slowly and the reaction mixture was removed from the cold bath and allowed to warm to room temperature with continued stirring overnight. The reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® IT280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 4.6 g (53%) of the title compound. MS (ESI+) m/z 387 (M+H)+
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](Cl)=[N:11][N:10]=1)[CH3:7]>CO>[CH2:6]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12]([S:5][CH2:2][CH:3]=[CH2:4])=[N:11][N:10]=1)[CH3:7]
Reactant: C=CCS
Reactant: CCOc1nnc(Cl)c2c1CCCC2
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(OCC)c2c1CCCC2

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 100 ml of absolute methanol and then mixed with 0.93 ml (0.01 mol) of allylmercaptan. To this mixture was added 2.13 g(0.01 mol) of 1-ethoxy-4-chloro-5,6,7,8-tetrahydro-phthalazine obtained from Preparation 9. The reaction solution was refluxed for 3 hours and then treated according to the same manner as Example 1 to obtain the title compound as a freezing white crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>C(OCC)C.Cl.[NH4+].O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]([OH:12])([CH2:13][C:14]2[CH:21]=[CH:20][C:17]([CH3:18])=[CH:16][CH:15]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(CBr)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)N1CCC(O)(Cc2ccc(C)cc2)CC1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A solution of 1-ethoxycarbonyl-4-piperidone (39 ml, 0.26 mol) in diethylether (150 ml) was added dropwise at room temperature to a solution prepared from 4-methyl-benzylbromide (237 g, 1.28 mol) and Mg (31.2 g, 1.28 mol) in diethylether (300 ml). Room temperature was maintained for 45 min with stirring and the mixture was then refluxed for 5 h. It was cooled to 0° C., diluted with diethylether (700 ml) and hydrolyzed with saturated ammoniumhydrochloride solution (200 ml) and water (350 ml). Insoluble material was removed by filtration over Celite", the residue washed twice with diethylether (2×500 ml) and the organic phase was separated. The water layer was extracted with diethylether, the organic phases were pooled and dried with MgSO4 and the solvent evaporated. The residue was chromatographed over silica gel (hexane-ethyl acetate, 2:1) to give 4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-carboxylic acid ethylester (70.5 g, 99%) as a yellowish oil, MS: m/e=278 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([CH:14]([O:16]C(=O)C)[CH3:15])=[O:13])[NH:7][C:6](=[O:20])[CH2:5]2.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12](=[O:13])[C@@H:14]([OH:16])[CH3:15])[NH:7][C:6](=[O:20])[CH2:5]2
Reactant: CC(=O)OC(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
The stirred mixture of acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester (750 mg, 2.67 mmol) in methanol (5 ml) and water (5 ml) was added with sodium hydroxide (240 mg, 60 mmol). The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was extracted with ethyl acetate (100×3) and water (100×3). The organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (S)—N-(5-Fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide (270 mg, 42%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](I)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=1)(=[O:25])=[O:24].[CH3:36][C:37]1[CH:42]=[C:41](B(O)O)[CH:40]=[CH:39][N:38]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:41]4[CH:40]=[CH:39][N:38]=[C:37]([CH3:36])[CH:42]=4)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=1)(=[O:25])=[O:24]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1I
Reactant: Cc1cc(B(O)O)ccn1
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1-c1ccnc(C)c1

Procedure:
Following the procedure described in Example 44 (Step 5) N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (114.0 mg, 180 μmol) was combined with 2-methylpyridin-4-ylboronic acid (30 mg, 216 μmol) to afford the title compound, N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-(2-methylpyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide as a yellow solid. LCMS (ESI positive ion) m/z: 600.0 (M+1); 1H NMR (400 MHz, MeOH) δ ppm 2.21 (s, 3H), 2.67 (s, 3H), 6.80 (t, J=73.11 Hz, 1H), 7.35 (dd, J=8.22, 1.96 Hz, 1H), 7.47 (t, J=8.07 Hz, 1H), 7.54 (s, 1H), 7.57-7.64 (m, 1H), 7.80-7.85 (m, 1H), 7.86-7.96 (m, 2H), 8.14 (d, J=9.49 Hz, 1H), 8.57 (d, J=5.38 Hz, 1H), 8.74 (dd, J=22.45, 2.20 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:19]=[N:20][C:21]=3F)[N:10]=2)=[CH:5][CH:4]=1.[F:48][C:49]1[CH:50]=[C:51]([NH2:57])[CH:52]=[N:53][C:54]=1[O:55][CH3:56].O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:19]=[N:20][C:21]=3[NH:57][C:51]3[CH:52]=[N:53][C:54]([O:55][CH3:56])=[C:49]([F:48])[CH:50]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Yield: 90.2 %

Procedure:
A solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (25 g, 38.8 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem LLC, Monmouth N.J.) (8.28 g, 58.3 mmol) in tetrahydrofuran (400 mL, 38.8 mmol) contained in an oven dried 1 L 3-neck round-bottomed flask equipped with N2 inlet was stirred at a temperature between −5° C. and −10° C. and treated dropwise with a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (117 mL, 117 mmol). The dark pink solution was stirred between −5° C. and −10° C. for 1 h. The reaction was quenched with water (100 mL) and NH4Cl (100 mL) and diluted with EtOAc (350 mL). The separated aqueous layer was extracted with EtOAc (2×300 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product which was adsorbed onto silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (Teledyne ISCO, Lincoln, Nebr.) (330 g) eluting with a gradient of 10% to 50% EtOAc in hexane to give tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (26.8 g, 35.0 mmol, 90% yield). m/z (ESI, positive ion) m/z 766 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:10][CH:11]1[NH:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(NCc2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1NCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a mixture of 5-benzylamino-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (10.2 g, 28.9 mmol) in toluene (110 mL) was added NaBH(OAc)3 (30 g, 141.5 mmol) and freshly activated 4A0 powder molecular sieve (24 g) with vigorous stirring. The reaction mixture was cooled to 0° C., then acetic acid (32.5 mL, 566 mmol) was added drop-wise in such a way that reaction mixture temperature remained below 5° C. After the addition of acetic acid was complete, the mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was filtered and concentrated to remove most of the acetic acid. The crude residue was dissolved in ethyl acetate (125 mL) and saturated aqueous NaHCO3 solution (100 mL) was slowly added to neutralize the residual acid under stirring. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure (11.25 g, crude). The residue was purified (FCC, SiO2, ethyl acetate/hexanes, gradient 0-40%) to yield the title compound (4.59 g, 45%). MS (ESI) mass calcd. for C20H30N2O2, 362.46; m/z found, 363.3 [M+H]+. 1H NMR (DMSO-d6): 7.53-6.76 (m, 5H), 4.10-3.96 (m, 3H), 3.89-3.87 (m, 1H), 3.66 3.54 (m, 1H), 3.05-2.60 (m, 4H), 1.80-1.65 (m, 2H), 1.60-1.45 (m, 1H), 1.40 (s, 9H), 1.14 (t, J=7.1, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][C:3]1([CH3:27])[CH3:26].[C-:28]#[N:29].[K+]>CN(C)C=O>[C:28]([C:2]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][C:3]1([CH3:27])[CH3:26])#[N:29]
Reactant: [C-]#N
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)(C)C3)c(F)c2)C(=O)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C#N)C(C)(C)C3)c(F)c2)C(=O)O1
Yield: 78 %

Procedure:
By reacting (S)—N-{3-[4-(4-oxo-3,3-dimethyl-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.40 mmol) and potassium cyanide (2.6 mmol) in dimethylformamide (10 ml) followed by silica gel chromatographic separation of diastereomer the compound was obtained in 78% yield. M.P. 65-68° C. and MS (M+1)=405 (MH+, 100%) for M.F.=C20H25FN4O4.