Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH2:18][CH2:19][NH2:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:21]([NH:20][CH2:19][CH2:18][N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCN1Cc2ccccc2CC1Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: c1ccc(CNCCN2Cc3ccccc3CC2Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 70.1 %

Procedure:
26 mg of 2-[3-benzyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine was dissolved in 1 mL of toluene, and MS-4A (30 mg), 10.4 mg of benzaldehyde, 18 mg of sodium triacetoxyborohydride, and 0.01 mL of acetic acid were added thereto at room temperature, followed by stirring overnight. After completion of the reaction, to the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified using PLC (chloroform:methanol=20:1) to obtain 24.4 mg (yield 70%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[F:33])[CH2:23][CH2:22]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([C:27]4[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=4[F:33])[CH2:25][CH2:26]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCCC3)CC2)c1

Procedure:
Example 130 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.45–7.40 (m, 1H), 7.34–7.29 (m, 3H), 7.24–7.16 (m, 3H), 6.88 (t, 1H, J=8.7 Hz), 6.77–6.72 (m, 1H), 3.21 (q, 2H, J=5.6 Hz), 2.87–2.81 (m, 2H), 2.74–2.65 (m, 1H), 2.44 (septet, 1H, J=6.7 Hz), 2.28–2.21 (m, 4H), 1.92–1.76 (m, 4H), 1.69–1.69 (m, 4H), 1.56–1.47 (m, 8H), 1.18 (d, 6H, J=6.7 Hz); ESMS m/e: 542.2 (M+H)+; Anal. Calc. for C31H41ClFN3O2.HCl.0.20 CHCl3: C, 62.20; H, 7.06; N, 6.97. Found: C, 62.24; H, 7.03; N, 6.79.
Reaction SMILES: S([O-])(O)=O.[Na+].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:15]=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(OCC)(=O)C.[C-:30]#[N:31].[K+]>O>[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:15]([OH:16])[C:30]#[N:31])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(O)C#N
Reaction time: 8 h

Procedure:
A solution of sodium hydrogensulfite (0.92 g) in water (5 ml) is added to a suspension of (2S)-2-(tert-butoxycarbonyl)amino-3-phenylpropanal (2.00 g, Reference compound No. 2-1) in water (20 ml) under ice cooling, then the temperature is raised to room temperature, and the mixture is stirred overnight. Ethyl acetate (100 ml) is added to the mixture, and the whole is stirred for one hour. Then, a solution of potassium cyanide (0.58 g) in water (5 ml) is added thereto, and the whole is further stirred for four hours. The reaction mixture is extracted with ethyl acetate, and the extract is washed with saturated brine. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled reference compound (1.18 g).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O.CCN(C(C)C)C(C)C.[CH3:19][O:20][C:21]([NH:23][C@@H:24]([CH:35]([CH3:37])[CH3:36])[C:25](ON1C(=O)CCC1=O)=[O:26])=[O:22]>C(#N)C.CCCCCCC>[CH3:19][O:20][C:21]([NH:23][C@@H:24]([CH:35]([CH3:37])[CH3:36])[C:25]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:26])=[O:22]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COC(=O)N[C@H](C(=O)ON1C(=O)CCC1=O)C(C)C
Solvent: CCCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.8 %

Procedure:
To a mixture of L-proline (4.44 g, 38.6 mmol), water (20 ml), acetonitrile (20 ml) and DIEA (9.5 g, 73.5 mmol) was added a solution of (S)-2,5-dioxopyrrolidin-1-yl 2-(methoxycarbonylamino)-3-methylbutanoate (10 g, 36.7 mmol) in acetonitrile (20 mL) over 10 minutes. The reaction mixture was stirred overnight at room temperature. The solution was concentrated under vacuum to remove the acetonitrile. To the resulting clear water solution was added 6N HCl (9 ml) until pH˜2. The solution was transferred to a separatory funnel and 25% NaCl (10 ml) was added and the mixture was extracted with ethyl acetate (75 ml), and then again with ethyl acetate (6×20 ml), and the combined extracts were washed with 25% NaCl (2×10 ml). The solvent was evaporated to give a thick oil. Heptane was added and the solvent was evaporated to give a foam, which was dried under high vacuum. Diethyl ether was added and the solvent was evaporated to give a foam, which was dried under high vacuum to give (S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (10.67 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([O:15][CH2:16][CH3:17])=[C:4]([CH:18](Cl)[CH3:19])[CH:3]=1.[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[N:28][C:29]=2[NH2:31])[NH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([CH:18]([C:4]3[CH:3]=[C:2]([Cl:1])[C:7]([C:8]#[N:9])=[C:6]([N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)[C:5]=3[O:15][CH2:16][CH3:17])[CH3:19])[N:23]=[C:22]([CH3:21])[C:30]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1N1CCCC1
Temperature: 85 °C

Procedure:
The 6-chloro-4-(1-chloroethyl)-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile (0.048 g, 0.15 mmol, racemic mixture) was combined with 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.034 g, 0.23 mmol) and cesium carbonate (0.10 g, 0.31 mmol) in N,N-dimethylformamide (3.0 mL) and heated in an oil bath to 85° C. After heating for 18 hrs the reaction was complete. The crude reaction was purified with out work up by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compound as a white amorphous solid (0.012 g, 18%). The product was isolated as a racemic mixture. LCMS calculated for C21H25ClN7O (M+H)+: m/z=426.1; found 426.1. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 6.91 (s, 1H), 6.25 (q, J=7.1 Hz, 1H), 3.71 (dp, J=15.7, 8.1, 7.2 Hz, 4H), 3.49-3.35 (m, 2H), 2.55 (s, 3H), 2.00-1.76 (m, 4H), 1.70 (d, J=7.1 Hz, 3H), 1.34 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C([C@@](C([O-])=O)(O)[C@@](CC)(O)C([O-])=[O:27])C.C(N(C(C)C)CC)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+].C(OC(C)C)(=O)C.S(=O)(O)[O-].[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[CH3:1][C:2]1[C:3]([CH2:11][S@:12]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)=[O:27])=[N:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1c([N+](=O)[O-])ccnc1CSc1nc2ccccc2[nH]1
Reactant: CC[C@](O)(C(=O)[O-])[C@](O)(CC)C(=O)[O-]
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])ccnc1C[S@@](=O)c1nc2ccccc2[nH]1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 2-[[3-methyl-4-nitro-2-piridyl]methylthio]benzimidazole (10 g, 33 mmoles, containing 70 mg of water) and (+)-diethyl-L-tartrate (3.02 g, 14.6 mmoles), in THF (100 ml) is brought to reflux temperature and maintained under stirring for 30 minutes. Titanium isopropoxide (1.89 g, 6.66 mmoles) is added and the mixture is maintained under stirring at reflux temperature till the formation of a clear solution is achieved. The solution is then cooled and added with diisopropylethylamine (1.42 g, 10.9 mmoles). After having achieved the range temperature between −5° C. and 0° C., the solution is treated by slow cooling with cumene hydroperoxide 88% (17.3 g, 100 mmoles). The reaction mixture is maintained under stirring for 3 hours at about 0° C., then treated with a 30% sodium thiosulphate solution to decompose the residue of cumene hydroperoxide. After the separation of the phases the aqueous phase is washed with toluene, and the gathered up organic phases and concentrated under reduced pressure. The oily residue so obtained is taken up with water and treated with sodium hydroxide 30% till pH 12. The so obtained mixture is treated with isopropyl acetate and a solution of sodium bisulfite 25% till pH 9 is added. The precipitated solid is then filtered off and washed with isopropyl acetate and copious water. 9.2 g of product are recovered with a yield of 80% and a chemical and stereochemical purity (determined by HPLC and chiral HPLC) equal to or higher than 98%.
Reaction SMILES: [CH2:1]([N:3]1[C:12]([CH3:13])=[CH:11][C:10](=[O:14])[C:5]([C:6]([O:8]C)=[O:7])=[C:4]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([N:3]1[C:12]([CH3:13])=[CH:11][C:10](=[O:14])[C:5]([C:6]([OH:8])=[O:7])=[C:4]1[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCn1c(C)cc(=O)c(C(=O)OC)c1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(C)cc(=O)c(C(=O)O)c1-c1ccc(Cl)cc1
Yield: 95.5 %

Procedure:
46.1 g of crude methyl 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate is suspended in 600 ml of 5% aqueous NaOH solution and warmed to 80°-85°. After 1-11/2 hours at this temperature the reaction mixture is cooled and acidified with dilute HCl. The resulting solid precipitate is collected by filtration, yielding 42 g of 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinic acid, mp (methylene chloride/ether)=235°-237° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[C:4](=[O:7])[CH2:5]I)[CH3:2].[CH2:10]([NH:17][C:18]1[C:19]([F:28])=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:10]([N:17]([C:18]1[C:19]([F:28])=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21]2)[CH2:5][C:4]([N:3]([CH2:8][CH3:9])[CH2:1][CH3:2])=[O:7])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCc2c1ccc(NCc1ccccc1)c2F
Reactant: CCN(CC)C(=O)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN(CC)C(=O)CN(Cc1ccccc1)c1ccc2c(c1F)CCC2=O

Procedure:
As presented in the following reaction formula, N,N-diethyl-2-iodoacetamide (723 mg, 3 mmol) was added dropwise at room temperature to a mixture of 5-(benzylamino)-4-fluoro-2,3-dihydro-1H-inden-1-one (370 mg, 1.5 mmol) and cesium carbonate (Cs2CO3: 940 mg, 3 mmol) in acetonitrile (CH3CN; 20 mL). Then, the mixture was refluxed for 48 hours. The mixture was filtered and the filtrate was concentrated to give a crude product, which was purified by pre-TLC (product of Merck Co., Ltd.) to give 2-(benzyl(4-fluoro-1-oxo-2,3-dihydro-1H-inden-5-yl)amino)-N,N-diethylacetamide represented by Structural Formula (2) (5 mg, yield: 1%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([NH2:19])=[CH:4][C:3]=1Br.[C:21]1([O-:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([NH2:19])=[CH:4][C:3]=1[O:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cc(Br)c(O)c2c1C(=O)c1ccc(Cl)cc1C2=O
Reactant: [O-]c1ccccc1
Product: Nc1cc(Oc2ccccc2)c(O)c2c1C(=O)c1ccc(Cl)cc1C2=O

Procedure:
When 70.5 g of the 1-hydroxy-2-bromo-4-amino-7-chloroanthraquinone prepared above are subjected to a phenolate fusion as described in Example 467c, then 61 g, corresponding to 83% of theory, of 1-hydroxy-2-phenoxy-4-amino-7-chloro-anthraquinone are obtained, the colour shade of which on silica gel is a pink tinged with blue having the Indicator Number of 51 (Colour Index Hue Indication Chart).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Fc1cccc(C2CCCN2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1cccc(F)c1

Procedure:
The title compound, white solid, m.p. 126° C. and MS: m/e=339 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.Cl.[CH3:27][O:28][NH2:29].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:29][O:28][CH3:27])=[O:11])[CH:7]=1
Reactant: CON
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CONC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h
Yield: 3.5 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (430 mg, 1.19 mmol) and methoxyamine hydrochloride (125 mg, 1.78 mmol) in 10 mL of DMF was added PyBOP (926 mg, 1.78 mmol) and TEA (496 uL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a yellow solid (16.4 mg, yield 4%). Analytical data for title compound. MS calcd for (C16H18BN3O6S): 391.2. MS found (ESI negative): (M−H)−=390.0. 1H NMR (DMSO-d6) δ (ppm): 11.14 (s, 1H), 9.74 (s, 1H), 9.10 (bs, 1H), 7.36-7.40 (m, 2H), 7.16 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.36 (s, 1H), 6.31 (d, J=8.8 Hz, 1H), 4.80 (s, 2H), 3.58 (s, 2H), 3.56 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=1)[C@H:6]([OH:34])[CH2:7][NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=2)[N:12](C(OCC2C=CC=CC=2)=O)[CH2:11][CH2:10]1)(=[O:3])[CH3:2].Cl>CCO.[Pd]>[F:42][C:40]1[CH:41]=[C:36]([CH:37]=[C:38]([F:43])[CH:39]=1)[CH2:35][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C@H:6]([OH:34])[CH2:7][NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=2)[NH:12][CH2:11][CH2:10]1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1CCN(C(=O)OCc2ccccc2)c2ccc(CC(C)(C)C)cc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1CCNc2ccc(CC(C)(C)C)cc21
Reaction time: 4.5 h
Yield: 50.7 %

Procedure:
To a solution of benzyl 4-{[(2R,3S)-3-(acetylamino)-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-6-neopentyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.242 g) in EtOH (30 mL) was added 1N HCl (1.0 mL) and 10% palladium on carbon (0.030 g). The mixture was degassed with N2 for five minutes. The mixture was placed on a hydrogenation apparatus under 47 psi of H2 and was shaken for 4.5 hours. The palladium was filtered off using Celite and the solvent was concentrated under reduced pressure. The residue was then partitioned between water and ethyl acetate and the organic layers were washed with aqueous sodium bicarbonate, dried with magnesium sulfate, filtered, and concentrated. A silica gel column using 4% MeOH in dichloromethane with 0.25% NH4OH as the solvent solution gave 0.095 g of the title compound. MS (ESI+) for C26H35F2N3O2 m/z 460.27 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CN(C)CCCN.[C:15]([N:23]1[C:27]2[N:28]=[CH:29][C:30]3[C:31](OC4C=CC=CC=4)=[N:32][C:33]4[N:34]([N:36]=[CH:37][N:38]=4)[C:35]=3[C:26]=2[CH:25]=[N:24]1)(=O)[C:16]1C=CC=CC=1>>[CH2:15]([N:23]1[C:27]2[N:28]=[CH:29][C:30]3[C:31]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[N:32][C:33]4[N:34]([N:36]=[CH:37][N:38]=4)[C:35]=3[C:26]=2[CH:25]=[N:24]1)[CH3:16]
Reactant: CN1CCNCC1
Reactant: O=C(c1ccccc1)n1ncc2c1ncc1c(Oc3ccccc3)nc3ncnn3c12
Agent: CN(C)CCCN
Product: CCn1ncc2c1ncc1c(N3CCN(C)CC3)nc3ncnn3c12

Procedure:
By substituting 4-methylpiperazine for the 3-(dimethylamino)propylamine in the procedure of Example 1 (c), 8-ethyl-5-(4-methyl-1-piperazinyl)-8H-pyrazolo[4',3':5,6]-pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is formed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]3=[CH:19][CH:20]=[CH:21][N:8]3[CH2:7][C:6]=2[CH:22]=1.[Cl:23]N1C(=O)CCC1=O>O1CCCC1>[Cl:23][C:21]1[N:8]2[C:9]([CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[O:11][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[CH2:7]2)=[CH:19][CH:20]=1
Reactant: CN1CCC(C2Oc3ccc(Cl)cc3Cn3cccc32)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CN1CCC(C2Oc3ccc(Cl)cc3Cn3c(Cl)ccc32)CC1

Procedure:
A solution of 7-chloro-11-[(1-methyl)piperidin-4-yl]5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (4.0 g; 0.013 mole) and N-chlorosuccinimide (2.0 g; 0.015) mole in 150 ml of tetrahydrofuran was heated at reflux for 4.5 hours.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][C:18]([CH3:23])([CH2:21][Cl:22])[CH2:19][Cl:20])[C:14](F)=[O:15].C(N(CC)CC)C>O1CCOCC1.O.C(OC(=O)C)C>[CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][O:11][C:14](=[O:15])[N:13]([CH3:12])[S:17][C:18]([CH3:23])([CH2:19][Cl:20])[CH2:21][Cl:22]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: CN(SC(C)(CCl)CCl)C(=O)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(SC(C)(CCl)CCl)C(=O)ON=C1SC(C)(C)C(=O)N1C
Temperature: 30 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
To a solution of 3.28 g of 3,5,5-trimethyl-2-oximino-4-thiazolidinone and 5.0 g of N-methyl-N-(2-methyl-1,3-dichloro-2-propanesulfenyl)carbamoyl fluoride in 75 ml of dioxane, was added dropwise with stirring 2.18 g of triethylamine. The spontaneous exotherm raised the temperature to 30° C. After following the reaction mixture to stand at room temperature for 16 hours, the reaction mixture was diluted with 300 ml of water. The product was isolated in ethylacetate and purified by column chromatography over silica gel to yield 3.0 g of a white solid. m.p. 91°-92° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].C(Cl)Cl.[CH3:9][N:10]1[C:14]2[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([NH2:22])=[N:11]1>N1C=CC=CC=1>[CH3:9][N:10]1[C:14]2[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([NH:22][C:1](=[O:4])[CH2:2][CH3:3])=[N:11]1
Reactant: Cn1nc(N)c2sc3ccccc3c21
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1nn(C)c2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.8 g. of propionyl chloride in 10 ml. of methylene chloride was added to a stirred solution of 0.01 mole of the above-referred amine in 50 ml. of methylene chloride containing 2.0 ml. of pyridine. The resulting clear solution was stirred overnight at room temperature and then washed with water, 5% aqueous hydrochloric acid, water, 10% aqueous sodium bicarbonate and finally with water. The upper organic layer was dried over magnesium sulfate and concentrated in vacuo to give a solid residue. This residue was recrystallized from ethanol to give N-(1-methyl-1H-(1)-benzothieno[3,2-c]pyrazol-3-yl)propanamide, m.p. 88°-89° C.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])=[CH:17][CH:18]=1
Reactant: CCOC(=O)CNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CNC(=O)c1ccc(N)cc1
Yield: 96.4 %

Procedure:
17.6 g (0.07 mol) of ethyl 4-nitro-benzamidoacetate dissolved in 250 ml of ethanol are hydrogenated in the presence of a catalyst (2 g of palladium on charcoal); the catalyst is filtered off, the filtrate is evaporated to dryness in vacuo, the residue is taken up in 100 ml of diisopropyl ether and the product is filtered off. 15 g (87% yield) of the stated product are obtained. Melting point: 93°-94° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([N:32]5[CH2:37][CH2:36]N(C)[CH2:34][CH2:33]5)=[CH:31][C:24]=3[S:23]4)=[CH:16][CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1(C2C=CC3N=C(N)SC=3C=2)CC[O:42]CC1.CN1CCN(C2C=CC3N=C(N)SC=3C=2)CC1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([N:32]5[CH2:33][CH2:34][O:42][CH2:36][CH2:37]5)=[CH:31][C:24]=3[S:23]4)=[CH:18][CH:19]=2)=[O:12])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1nc2ccc(N3CCOCC3)cc2s1
Reactant: CN1CCN(c2ccc3c(c2)sc2nc(-c4ccc(NC(=O)Nc5cc(C(C)(C)C)on5)cc4)cn23)CC1
Agent: CN1CCN(c2ccc3nc(N)sc3c2)CC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(N5CCOCC5)ccc34)cc2)no1

Procedure:
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(4-methyl-piperazin-1-yl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea. was prepared in a manner similar to Steps A-D, except that in Step A, 6-morpholin-4-ylbenzothiazol-2-ylamine was substituted with 6-(4-methylpiperazin-1-yl)-1,3-benzothiazol-2-amine. 1H NMR (CDCl3) δ 9.3 (br, 1H), 7.84 (d and s, 3H), 7.59 (br, 1H), 7.56 (d, 2H), 7.49 (d, 1H), 7.20 (d, 1H), 7.05 (dd, 1H), 5.86 (s, 1H), 3.250 (t, 4H), 2.62 (t, 4H), 2.38 (s, 3H),1.36 (s, 9H). [Compound A7]
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:20][CH3:21])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C(OCC)(=O)C.CO>[CH3:24][N:25]([CH3:27])[CH:26]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:20][CH3:21])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CCN(c1cccc(C(C)=O)c1)S(=O)(=O)c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(=O)(=O)c1ccccc1
Yield: 96 %

Procedure:
1.05 g (3.46 mmol) of N-(3-acetyl-phenyl)-N-ethyl-benzenesulfonamide were dissolved in 10 ml of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 18 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was chromatographied over silica gel using a gradient of ethyl acetate/methanol as eluent. 1.2 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-benzenesulfonamide as a yellowish-white solid were obtained (yield 96%).