Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][C:37]2[N:42]=[C:41]3[CH2:43][O:44][C:45](=O)[C:40]3=[CH:39][CH:38]=2)[CH2:30][CH2:29]1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[F: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=[C:45]1[C:40]2[C:41](=[N:42][C:37]([CH2:36][CH2:35][CH2:34][N:31]3[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][O:25][CH2:24][CH2:23][OH:22])[CH2:33][CH2:32]3)=[CH:38][CH:39]=2)[CH2:43][O:44]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1OCc2nc(CCCN3CCN(CCOCCO)CC3)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CCCN3CCN(CCOCCO)CC3)ccc21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 34.1 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (143 mg, 0.95 mmol) in THF (4 mL) at room temperature is treated with lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 2.2 mL, 2.2 mmol) and stirred for 10 min. A solution of 2-(3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-propyl)-7H-furo[3,4-b]pyridin-5-one (110 mg, 0.31 mmol) in anhydrous THF (2 mL) is added. The reaction mixture is stirred at room temperature for 2 h. The reaction mixture is poured into aqueous 2N HCl (10 mL) with stirring and is heated at 60° C. for 2.5 h. The mixture is then poured into 100 mL ice water, to which solid NaHCO3 is carefully added to adjust pH to 8. The aqueous layer is extracted with chloroform (3×). The combined organic layers are dried with anhydrous Na2SO4, and concentrated. The residue purified by column chromatography (MeOH-chloroform) to give the title compound as a yellow solid (51 mg, 34%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.CN(C)C=O.[C:32](Cl)(=[O:37])[O:33][CH:34]([CH3:36])[CH3:35].C(N(CC)CC)C>O>[O:23]=[C:21]1[NH:20][C:19]2[CH:24]=[CH:25][C:16]([NH:15][C:14]3[C:9]4[C:6]5[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:32](=[O:37])[O:33][CH:34]([CH3:36])[CH3:35])[CH2:4][C:5]=5[S:26][C:10]=4[N:11]=[CH:12][N:13]=3)=[CH:17][C:18]=2[S:22]1
Reactant: CC(C)OC(=O)Cl
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Yield: 40 %

Procedure:
A mixture comprising 50 mg (130 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20), 5 mL N,N-dimethylforamide, 130 μL isopropyl carbonochloridate (1M in toluene) and 18.2 μL N,N-diethylethanamine was stirred at 23° C. overnight. Water was added, the solvents were removed and the residue purified by chromatography to give 25 mg (40%) of the title compound.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH:11]([CH3:13])[O:10][CH:9]([CH3:14])[CH2:8]1.[H-].[Na+].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][C:23]#[N:24])=[CH:20][CH:19]=1>CN(C=O)C>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH:22]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[CH2:12][CH:11]([CH3:13])[O:10][CH:9]([CH3:14])[CH2:8]2)[C:23]#[N:24])=[CH:20][CH:19]=1
Reactant: CC1CN(CCCCCl)CC(C)O1
Reactant: N#CCc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CCCCC(C#N)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This intermediate (400 mg.) was prepared using the procedure described in Example 2a except using 1.0 g. (4.13 mmoles) of 4-(4-chlorobutyl)-2,6-dimethylmorpholine hydrochloride, 1.81 g. (0.021 mole) of sodium hydride, and 3.18 g. (0.021 mole) of 4-chlorobenzyl cyanide in 40 ml. of DMF.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([Mg]Br)[CH2:31][CH:32]=[CH2:33]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:33]([C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1)[CH2:32][CH:31]=[CH2:30]
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(I)c2)NC(=O)OC(C)(C)C)cc1
Reactant: C=CCC[Mg]Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: C=CCCc1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c2ccc(OC)cc2)c1
Yield: 62 %

Procedure:
To a solution of (5)-tert-butyl 3-(3-iodophenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (510 mg, 1.0 mmol), Pd(dppf)Cl2 (10 mol %) in THF (5 ml) was added but-3-enylmagnesium bromide (8 ml, 4 mmol, 0.5 M in THF). The solution was then heated at reflux overnight. The solution was cooled down and quenched with ammonia chloride (aq) and filtered through celite. The filtrate was extracted with EtOAc (2×25 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (20-40% EtOAc/hexanes) to provide the desired product (270 mg, 0.62 mmol), 62%. MS (m/z) 439 [M+H]+. Intermediate I-1A was used in the synthesis of Example 4.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([CH3:28])([CH3:27])[C:25]#[N:26])[CH2:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[CH:38][C:5]=2[N:4]=1)[CH3:2].[OH:39]S(O)(=O)=O.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([CH3:28])([CH3:27])[C:25]([NH2:26])=[O:39])[CH2:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[CH:38][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CCN(C(C)(C)C#N)CC3)n(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CCN(C(C)(C)C(N)=O)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-{4-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-1-yl}-2-methylpropionitrile (300 mg, 0.58 mmol) was added slowly to conc. H2SO4 (3.5 mL) The resulting mixture was allowed to stir at r.t. for 3 h then poured onto ice and basified with K2CO3. The resulting mixture was extracted with DCM and the combined organic phases dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 703 (177 mg, 57%). LCMS (method I): RT 2.45 min, [M+H]+ 532.3. 1H NMR (DMSO, 400 MHz): δ 8.01-7.97 (1 H, m), 7.63-7.62 (1 H, m), 7.23-7.22 (3 H, m), 6.93 (1 H, d, J=3.36 Hz), 4.26 (4 H, brd s), 3.79-3.74 (7 H, m), 3.26 (2 H, q, J=7.42 Hz), 3.07-2.97 (1 H, m), 2.88 (2 H, d, J=10.76 Hz), 2.32-2.21 (2 H, m), 1.93-1.91 (4 H, m), 1.33 (3 H, t, J=7.44 Hz), 1.12 (6 H, s)
Reaction SMILES: C[O:2][C:3]1[C:12]([NH:13][NH:14][C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=O)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:27])=[C:8]([C:23]([O:25][CH3:26])=[O:24])[CH:9]=2)[N:4]=1.O1CCCC1.S(Cl)(Cl)=O>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:27][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][C:8]=1[C:23]([O:25][CH3:26])=[O:24])[N:11]1[C:15]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:14][N:13]=[C:12]1[C:3](=[O:2])[NH:4]2
Reactant: COC(=O)c1cc2nc(NNC(=O)C3CCOCC3)c(OC)nc2cc1C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(cc1C)[nH]c(=O)c1nnc(C3CCOCC3)n12
Temperature: 70 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a mixed liquid of 4.83 g of methyl 2-methoxy-7-methyl-3-[2-(tetrahydro-2H-pyran-4-ylcarbonyl)hydrazino]quinoxaline-6-carboxylate and 96.6 mL of tetrahydrofuran were added 2 drops of N,N-dimethylformamide and 1.90 mL of thionyl chloride at room temperature, followed by stirring at 70° C. overnight. The reaction liquid was diluted with chloroform and added to ice-water portionwise, followed by stirring for 10 minutes. The obtained solid was collected by filtration and washed with diethyl ether to obtain 1.94 g of methyl 7-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:16])[CH:6]=[C:7]([CH3:15])[CH:8]=2)[N:3]=1.[NH2:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[C:26]([C@@H:18]([NH:17][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:16])[CH:6]=[C:7]([CH3:15])[CH:8]=2)[N:3]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:28])=[O:27]
Reactant: Cc1cc(C)c2nc(Cl)c(C(=O)O)cc2c1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CS(C)=O
Product: Cc1cc(C)c2nc(N[C@@H](Cc3ccccc3)C(=O)O)c(C(=O)O)cc2c1

Procedure:
In close analogy to the procedure described in Example 1, 2-chloro-6,8-dimethyl-quinoline-3-carboxylic acid is reacted with L-phenylalanine in DMSO to provide the title compound in good yield. LCMS m/z 364 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: [O-]B([O-])Oc1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4cccc(C(F)(F)F)c4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 3-trifluoromethylphenyl borate (131 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 10 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=4/1) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(3-trifluoromethylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 120) (148 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1>O1CCOCC1.[Ni]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([Cl:11])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cc(Cl)cnc1Cl
Reaction time: 22 h
Yield: 75.5 %

Procedure:
To a solution of 129.2 g (0.69 mol) of 2,5-dichloro-3-nitropyridine in 1300 ml of dioxane is added 26.0 g of Raney-nickel, that has previously been washed with ethanol. This mixture is then hydrogenated with hydrogen under normal pressure at 20°-35° C. After uptake of 20% of the theoretical amount of hydrogen, another 30 g of washed Raney-nickel catalyst are added. After hydrogenating for 22 hours, the catalyst is filtered off, the solvent is evaporated and the residue is crystallized from hexane/ethyl acetate. Thus, 84.9 g of 3-amino-2,5-dichloropyridine (78% of the theory) are obtained, which melts at 129°-132° C.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6])[CH3:2].[I-:15].[CH3:16][C:17]1[CH:22]=[CH:21][N+:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1>C(O)C>[I-:15].[CH2:1]([N:3]([C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[CH:16]/[C:17]2[CH:22]=[CH:21][N+:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6])[CH3:2]
Reactant: CCN(CCO)c1ccc(C=O)cc1
Reactant: Cc1cc[n+](CCO)cc1
Agent: [I-]
Solvent: CCO
Product: CCN(CCO)c1ccc(/C=C/c2cc[n+](CCO)cc2)cc1
Yield: 67 %

Procedure:
Following the procedure of Example 6, equimolar amounts of 4-(N-ethyl-N-hydroxyethylamino)benzaldehyde, prepared according to Example 2, and 4-methyl-N-(2-hydroxyethyl)pyridinium iodide, prepared according to Example 4, were reacted in ethanol at reflux, overnight. Upon cooling, dye3 precipitated as a red solid and was collected by filtration, washed, and dried. Yield: 67%. 1H-NMR (DMSO)-d6): δ1.0 (t, 3H), 3.3 (q, 2H), 3.40 (q, 2H), 3.50 (t, 2H), 3.80 (q, 2H), 4.40 (t, 2H), 4.70 (t, 1H), 5.2 (t, 1H), 6.7 (d, 2H), 7.1 (d, 1H), 7.80 (d, 2H), 7.90 (d, 1H), 8.10 (d, 2H), 8.70 (d, 2H) ppm. The elements analy. calcd. for C19H25IN2O2 : C, 51.8; H, 5.7; N, 6.4; Found: C, 51.5; H, 5.7; N, 7.1. Td 270° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:22]([O:24][CH3:25])=[O:23])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][O:24][C:22](=[O:23])[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[CH3:21]
Reactant: COC(=O)C(C)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)c1ccc(C2CCNCC2)cc1

Procedure:
The compound is prepared analogously to Example XI.1 using 4-[4-(1-methoxycarbonyl-ethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (VIII.1) as educt and TFA in DCM instead of HCl.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6](=[O:8])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(C(OC(C)=O)C(=O)O)cc1
Reactant: Nc1ccccn1
Product: COc1ccc(C(OC(C)=O)C(=O)Nc2ccccn2)cc1

Procedure:
was prepared from intermediate 79a and 2-aminopyridine following Method A. 1H NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 8.31–8.23 (m, 2H), 7.81–7.75 (m, 1H), 7.43 (d, 2H, J=8.59 Hz), 6.90 (d, 2H, J=8.59 Hz), 6.14 (s, 1H), 3.79 (s, 3H), 2.25 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 301, found 301.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:28][C@@:26]3([CH3:27])[C@@H:22]([CH2:23][C@H:24]4[CH2:29][C@:25]43[O:30][CH3:31])[C@H:21]3[C:12]2=[C:13]2[C@@:18](O)([CH2:19][CH2:20]3)[CH2:17][C:16]3(OCC[O:33]3)[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)C.O>C(O)(=O)C>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[CH2:28][C@@:26]3([CH3:27])[C@@H:22]([CH2:23][C@H:24]4[CH2:29][C@:25]43[O:30][CH3:31])[C@H:21]3[C:12]2=[C:13]2[C:18]([CH2:19][CH2:20]3)=[CH:17][C:16](=[O:33])[CH2:15][CH2:14]2)=[CH:9][CH:10]=1)=[O:3]
Reactant: CCOC(OCC)c1ccc([C@H]2C[C@@]3(C)[C@@H](C[C@H]4C[C@]43OC)[C@@H]3CC[C@@]4(O)CC5(CCC4=C32)OCCO5)cc1
Solvent: O
Solvent: CC(=O)O
Product: CO[C@@]12C[C@@H]1C[C@H]1[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(C=O)cc3)C[C@@]12C

Procedure:
0.6 g of 11beta-(4-(diethoxymethyl)-phenyl)-3,3-ethylenedioxy-17beta-methoxy-16alpha,17alpha-methylene-estr-9-en-5alpha-ol is dissolved in 10 ml of 70% aqueous acetic acid and heated on the water bath for about 2 hours at 70° C. Then, the steroid is precipitated by adding water and some ammonia. The isolated crude product is flash chromatographed with benzene/ethyl acetate (10:1) on neutral aluminum oxide. 0.41 g of the target compound, which can be crystallized from ether or acetonitrile, is obtained, melting point: 196° C. to 199.5° C., [α]D =315.9°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[NH:26]1[CH2:30][CH2:29][C@H:28]([O:31][NH2:32])[CH2:27]1>>[NH:26]1[CH2:30][CH2:29][C@H:28]([O:31]/[N:32]=[C:22](/[C:19]2[N:20]=[C:21]3[N:13]([CH2:12][C:3]4[CH:4]=[C:5]5[C:10](=[CH:11][C:2]=4[F:1])[N:9]=[CH:8][CH:7]=[CH:6]5)[N:14]=[N:15][C:16]3=[N:17][CH:18]=2)\[CH3:23])[CH2:27]1
Reactant: NO[C@H]1CCNC1
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Agent: Cl
Product: C/C(=N\O[C@H]1CCNC1)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 75.9 %

Procedure:
The title compound (37.0 mg, 70%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (40.0 mg, 0.12 mmol) and (S)—O-pyrrolidin-3-yl-hydroxylamine hydrochloride (30.0 mg, 0.17 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.30 (s, 1H), 8.92 (dd, 1H), 8.41 (dd, 1H), 8.18 (d, 1H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.23 (s, 2H), 4.95 (m, 1H), 3.16-2.87 (m, 3H), 2.77-2.71 (m, 1H), 2.25 (s, 3H), 2.01-1.87 (m, 2H). LCMS (method A): [MH]+=407, tR=3.09 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH3:29])=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31].C(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[O:28][CH3:29])[CH:5]=[CH:6][CH:7]=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (4.86 g, 11.4 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (10 mL). The reaction mixture was stirred at rt for 1 hr. The solvent was removed in vacuo to afford methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate as TFA salt (4.8 g, 100%), which was used for the next step directly without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:19][C:20]1[C:25]2=[N:26][S:27][N:28]=[C:24]2[C:23]([S:29](Cl)(=[O:31])=[O:30])=[CH:22][CH:21]=1>C(Cl)Cl>[F:19][C:20]1[C:25]2=[N:26][S:27][N:28]=[C:24]2[C:23]([S:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)(=[O:30])=[O:31])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(F)c2nsnc12
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc(F)c3nsnc23)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-aminobenzoate (412 mg, 2.5 mmol) in 20 mL of DCM was added pyridine (600 mg, 7.5 mmol) and 7-fluorobenzo[c][1,2,5]thiadiazole-4-sulfonyl chloride (39C) (633 mg, 2.5 mmol). The resulting mixture was stirred at 50° C. overnight. After removal of DCM, the residue was partitioned between water and EtOAc. The organic layer was washed with 2 N HCl, water and brine, dried over Na2SO4 and concentrated to give crude product 39D, which was confirmed by LCMS, and used in the next reaction without further purification. 1H NMR (CHLOROFORM-d) δ: 8.33 (dd, J=8.0, 4.6 Hz, 1H), 7.85 (d, J=8.7 Hz, 2H), 7.66 (s, 1H), 7.35-7.30 (m, 1H), 7.12 (d, J=8.7 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H). LC-MS: m/z 382.4 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14][CH2:13]2>>[Cl:1][CH2:2][C:3]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:18])[NH:16]2)=[O:4]
Reactant: COc1cccc2c1NC(=O)CC2
Reactant: O=C(Cl)CCl
Product: COc1ccc(C(=O)CCl)c2c1NC(=O)CC2

Procedure:
By using chloroacetyl chloride and 8-methoxy-3,4-dihydrocarbostyril, there was obtained 5-chloroacetyl-8-methoxy-3,4-dihydrocarbostyril as a white powder having a melting point of 187°-188° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[CH:7]=[CH:8][C@@H:9]([CH3:24])[C@H:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[CH3:4].[CH3:26]I.OS([O-])(=O)=O.[Na+]>C1COCC1.CN(C=O)C.CCOCC>[CH2:3]([O:5][C:6](=[O:25])[CH:7]=[CH:8][C@@H:9]([CH3:24])[C@H:10]([N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:26])[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[CH3:4]
Reactant: CCOC(=O)C=C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)c1ccco1
Reactant: CI
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C=C[C@@H](C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of NaH (0.707 g, 17.7 mmol) in THF (10.7 mL) at 0° C. was added 2.12b (1.14 g, 3.53 mmol) in DMF (1 mL), followed by MeI (1.33 mL, 21.2 mmol). After stirring at 0° C. for 1 hour, the reaction mixture was poured onto a ice cold mixture of 1.0 M aq. NaHSO4 solution and Et2O. The separated organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (0-50% EtOAc/heptane) to give 2.12c (1.08 g, 91% yield). MS m/z (M+23) 360.1
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH3:11])[CH:2]=C.C[OH:13]>C(Cl)Cl>[CH2:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH:2]=[O:13])[CH3:11]
Reactant: CO
Reactant: C=CCc1ccccc1CC
Solvent: ClCCl
Product: CCc1ccccc1CC=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 54.05 g of the crude 1-allyl-2-ethylbenzene in 500 mL of 1:1 CH2Cl2 --CH3OH was cooled to -78° C. A stream of O3 was bubbled through the solution for 3 h, until all of the starting material had disappeared. Then a stream of air was bubbled through the solution until the blue color had faded. A total of 25 mL of methyl sulfide was added and the solution was stirred at room temperature for 1 h. The solution was concentrated and dried under vacuum to afford (2-ethylphenyl) acetaldehyde as a colorless oil which was used directly in the next step.