Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]([NH:23][NH2:24])=O)[C:17]=3[O:19][CH3:20])[NH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:26](=[NH:30])(OC)[CH3:27].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[NH:23][N:24]=[C:26]([CH3:27])[N:30]=4)[C:17]=3[O:19][CH3:20])[NH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C(=O)NN)ccc2[nH]nc(/C=C/c3cccc(F)c3)c12
Reactant: COC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1c(-c2nc(C)n[nH]2)ccc2[nH]nc(/C=C/c3cccc(F)c3)c12
Temperature: 150 °C
Reaction time: 17.5 h
Yield: 5.8 %

Procedure:
To a suspension of 19 mg of 3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic acid hydrazide in 4 mL of ethanol were added 50 mg of O-methyl acetimidate hydrochloride and 0.19 mL of triethylamine, and stirred in a sealed tube at 150° C. for 17.5 hours. The reaction solution was allowed to cool to room temperature, the solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography, and further purified and separated by LC-MS, to afford 1.17 mg of the title compound as a yellow amorphous.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH3:4][CH2:5][C@H:6]([C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])[CH3:7].O>>[C:16]([O:15][C:13]([NH:12][C@@H:8]([C:9]([O:11][CH2:1][CH3:2])=[O:10])[C@@H:6]([CH2:5][CH3:4])[CH3:7])=[O:14])([CH3:17])([CH3:19])[CH3:18]
Reactant: CC[C@@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCI
Solvent: O
Product: CCOC(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](C)CC

Procedure:
The title compound was prepared by the method of Example 8 using ethyl iodide (0.4 mL, 5 mmol) instead of methyl iodide and BOC--D--Ile--OH--0.5 H2O (1.0 g, 4 mmol) instead of the title product of Example 1. Concentration afforded the title compound (1.2 g) as a water white liquid and the structure verified by NMR.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:22]=[CH:21][C:11]3[NH:12][C:13](=[O:20])[C:14]4[CH:15]=[CH:16][CH:17]=[N:18][C:19]=4[C:10]=3[CH:9]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH3:32]>C(#N)C>[CH2:30]([N:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:22]=[CH:21][C:11]3[NH:12][C:13](=[O:20])[C:14]4[CH:15]=[CH:16][CH:17]=[N:18][C:19]=4[C:10]=3[CH:9]=2)[CH2:5][CH2:6]1)[CH2:31][CH3:32]
Reactant: CCCBr
Reactant: O=c1[nH]c2ccc(OC3CCNCC3)cc2c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(Oc2ccc3[nH]c(=O)c4cccnc4c3c2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
Compound (55 mg, 0.17 mmol) prepared in step 4 and potassium carbonate (70 mg, 0.50 mmol) were dissolved in acetonitrile (10 ml), added with 1-bromopropane (53 μl, 0.058 mol) at room temperature. The resulting mixture was stirred overnight at 60° C. and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (chloroform:methanol=5:1) to obtain the title compound (34 mg, yield: 61%, white solid).
Reaction SMILES: [CH2:1]([S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[C:13]1([S:10]([C:1](=[CH:24][C:23]2[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=2)[C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:3])(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CS(=O)(=O)c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Product: O=C(C(=Cc1ccc(F)cc1)S(=O)(=O)c1ccccc1)c1ccccc1
Yield: 62 %

Procedure:
A solution of phenacylphenyl sulfone (0.01 mol) and 4-fluorobenzaldehyde (0.01 mol) was subjected to Method 1 of Procedure 4. The title compound, melting point 142-143° C., was obtained in 62% yield.
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][CH3:26])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:25]([C@H:2]1[NH:1][C:28](=[O:30])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]([CH:22]([CH3:23])[CH3:24])=[N:20][O:21][C:17]=4[CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3onc(C(C)C)c23)nc1
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc4onc(C(C)C)c34)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R)-2-amino-N-(6-{[3-(1-methylethyl)-1,2-benzisoxazol-4-yl]oxy}-3-pyridinyl)butanamide (Intermediate 44) was dissolved in dichloromethane (1.0 ml) and TEA (3 μL, 0.022 mmol) was added. The reaction mixture was cooled down to 0° C. and triphosgene (0.6 mg, 1.98 μmol) was added and the mixture was stirred at that temperature for 30 minutes. The reaction mixture was quenched with water and water was removed by addition of sodium sulphate. The organic phase was pipetted off and evaporated and the residue obtained was charged on a silica gel column (Biotage SP1 system) and eluted with Cyhexane/EtOAc (from all 1/0 to 7/3, then 7/3, then from 7/3 to 1/1, then 1/1, then 0/1) to afford the title compound (1 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH3:20])[C:18]([C:21]34[CH2:28][CH2:27][C:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([CH2:25][CH2:26]3)[CH2:23][CH2:22]4)=[N:17][N:16]=2)=[C:11]([C:35]([F:38])([F:37])[F:36])[CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[CH3:20][N:19]1[C:18]([C:21]23[CH2:22][CH2:23][C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([CH2:25][CH2:26]2)[CH2:27][CH2:28]3)=[N:17][N:16]=[C:15]1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[C:35]([F:37])([F:36])[F:38]
Reactant: Cn1c(-c2ccc(OCc3ccccc3)cc2C(F)(F)F)nnc1C12CCC(c3ccccc3)(CC1)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1c(-c2ccc(O)cc2C(F)(F)F)nnc1C12CCC(c3ccccc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 3-[4-(Benzyloxy)-2-(trifluoromethyl)phenyl]-4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)4H-1,2,4-triazole (8-E) (27 mg, 0.05 mmol) was dissolved in ethyl acetate/methanol (1:1, 4 mL) to which 10% palladium-on-carbon (4 mg) was added. The reaction was then placed under hydrogen atmosphere and stirred for 3 h at room temperature and pressure. After appropriate evacuation of the hydrogen atmosphere, the palladium was filtered through a filter aid with methanol (40 mL). The filtrate was collected and the solvent removed in vacuo to afford 4-[4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazol-3-yl]-3-(trifluoromethyl)phenol (8-F). MS: m/z 428 (M+1); 1H NMR (500 MHz, CDCl3): δ 1.92 (6H, m), 2.11 (6H, m), 3.41 (3H, s), 7.17 (2H, m), 7.24 (1H, m), 7.31 (2H, m), 7.38 (3H, m) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]([C:20]1[S:21][C:22]([S:35][CH3:36])=[C:23]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=2)(=[O:27])=[O:26])[CH:24]=1)=[NH:19])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]([C:20]1[S:21][C:22]([S:35][CH3:36])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=3)[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)=[NH:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccc(N)c2)c1

Procedure:
Following the same procedure as in Example 1, step c, reaction of 3-amino-phenyl boronic acid (27 mg, 0.2 mmol), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (50 mg, 0.1 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosine)palladium(0) (29 mg, 0.025 mmol, Strem Chemicals Inc, Newburyport, Mass.), Na2CO3 (400 μL, 2M), and toluene/EtOH mixture (2:1, 1.2 mL) afforded 35 mg (70%) after purification (SiO2, flash elution: 30% EtOAc in hexanes) of the title compound as a white foam. ESI-MS (m/z): Calcd. for C23H25N3O4S3: 503.6; found: 503.9, 404.1 (M−Boc).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]([O:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[CH:12]([O:15][C:16]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:17]=1[C:18]([NH:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:19])([CH3:14])[CH3:13]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: CC(C)Oc1cc(C(F)(F)F)ccc1C(=O)O
Product: CC(C)Oc1cc(C(F)(F)F)ccc1C(=O)NC1CCCC1N1CCCC1

Procedure:
The title compound, light brown oil, MS: m/e=385.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-isopropoxy-4-trifluoromethyl-benzoic acid (intermediate AF).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:46][CH2:47][C:48]1[C:57](=[O:58])[C:56]2[C:51](=[CH:52][C:53]([Cl:59])=[CH:54][CH:55]=2)[N:50]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:49]=1>C(Cl)Cl>[Cl:59][C:53]1[CH:52]=[C:51]2[C:56]([C:57](=[O:58])[C:48]([CH2:47][NH:46][C:7]([C:4]3[S:3][C:2]([Br:1])=[N:6][CH:5]=3)=[O:9])=[CH:49][N:50]2[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:55][CH:54]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1cnc(Br)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
To a stirred solution of 2-bromothiazole-5-carboxylic acid (241 mg, 1.16 mmol) and N,N-diisopropylethylamine (409 mg, 552 μL, 3.16 mmol) in methylene chloride was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (559 mg, 1.26 mmol). After 15 min., 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (300 mg, 1.05 mmol) was added. The reaction mixture was stirred at room temperature. The mixture was diluted with CH2Cl2 and washed with water followed by 1N aqueous HCl and finally saturated aqueous sodium carbonate solution. The organic layer was dried (Na2SO4), filtered and concentrated. The product 2-bromo-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide (464 mg, 93%) was obtained without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH:12]=[O:13])[CH:5]=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[C:23]([NH:11][S:8]([C:6]1[CH:7]=[C:2]([Br:1])[C:3]([O:14][CH3:15])=[C:4]([CH:12]=[O:13])[CH:5]=1)(=[O:10])=[O:9])(=[O:25])[CH3:24]
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(S(=O)(=O)NC(C)=O)cc1C=O
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A 100 mL round-bottom flask was charged with 5-bromo-3-formyl-4-methoxy-benzenesulfonamide (586 mg, 2.0 mmol) dissolved in dichloromethane (40 mL) and the solution was stirred vigorously while triethylamine (252 mg, 2.50 mmol) was added, followed by acetic anhydride (224 mg, 2.2 mmol) and a catalytic amount of N,N-dimethylaminopyridine. The mixture was stirred for 1 hour and then concentrated by evaporation. The residue was partitioned between 5% citric acid and ethyl acetate. The organic layer was separated, washed with water and brine and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give N-acetyl-5-bromo-3-formyl-4-methoxybenzenesulfonamide (616 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.I[CH2:13][CH3:14].[BH4-].[Na+]>>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:13][CH3:14])[CH2:7]2
Reactant: CCI
Reactant: Nc1cccc2cnccc12
Agent: [BH4-]
Agent: [Na+]
Product: CCN1CCc2c(N)cccc2C1

Procedure:
The title compound was prepared by treatment of 5-aminoisoquinoline with iodoethane followed by reduction with sodium borohydride using procedures analogous to those described in Preparation 1 and Preparation 2.
Reaction SMILES: [Br:1][CH:2]1[CH2:6][S:5](=[O:8])(=[O:7])[CH:4]([CH2:9][O:10]CC2C=CC=CC=2)[CH2:3]1.B(Cl)(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[S:5](=[O:8])(=[O:7])[CH:6]=1
Reactant: O=S1(=O)CC(Br)CC1COCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: O=S1(=O)C=C(Br)C=C1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a -78° C. solution, under argon, of 4.23 g of product from Example 175 in 28 ml of dry methylene chloride is added, dropwise, 17.2 ml of 1M boron trichloride. The reaction mixture is warmed to 0° C. and stirred for 1 hour. The reaction is quenched with methyl alcohol, concentrated in vacuo and chromatographed (silica gel: 0-30% ethyl acetate/hexane) to give 2.57 g of the desired product (1:1 mixture of isomers).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].Cl[C:7]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH3:16])[CH:10]=[C:9]([Cl:17])[N:8]=1>C1COCC1>[Cl:17][C:9]1[N:8]=[C:7]([S:5][CH2:3][CH3:4])[C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH3:16])[CH:10]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1nc(Cl)cc(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
6.1 g (153 mmol, 60% w/w in mineral oil) NaH were dissolved in THF (90 ml) at 0° C. At this temperature 3.4 g (54.7 mmol) ethane thiol were added. After stirring for 15 min at 0° C., 12.4 g (60.2 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid were added portionwise. The RM was allowed to warm to RT and stirring was continued at RT for 16 h. Then the reaction was quenched with a 2M aq. HCl and diluted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Crystallisation (DCM/hexane) of the residue yielded 12.0 g (51.7 mmol, 95%) 6-chloro-2-ethylsulfanyl-4-methyl-pyridine-3-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]([OH:22])(=[O:21])[CH2:19][SH:20]>N1C=CC=CC=1>[C:12]1([C:4]2[CH:3]=[C:2]([S:20][CH2:19][C:18]([OH:22])=[O:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CS
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Solvent: c1ccncc1
Product: O=C(O)CSc1cc(-c2ccccc2)nc2ccccc12
Yield: 86.6 %

Procedure:
4-Chloro-2-phenylquinoline (3 g) and thioglycolic acid (1.38 g) in pyridine (40 cc) are heated under reflux for 4 hours. After evaporation of the pyridine under reduced pressure, the residue is taken up with water (125 cc) and normal aqueous sodium hydroxide solution (40 cc). The aqueous phase is washed with ethyl ether (2×50 cc), acidified to pH 5 with glacial acetic acid and extracted with ethyl ether (3×50 cc). The ether phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. [(2-Phenyl-4-quinolyl)thio]acetic acid (3.2 g), m.p. 138° C., is thereby obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[NH2:12][C:13]1[C:22](Br)=[N:21][C:20]([Br:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:12][C:13]1[C:22]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=2)=[N:21][C:20]([Br:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: OCc1cccc(B(O)O)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: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2cccc(CO)c2)c1N
Yield: 72.5 %

Procedure:
A flask containing a mixture of 3-(hydroxymethyl)phenylboronic acid (0.88 g, 5.79 mmol), methyl 3-amino-2,6-dibromoisonicotinate (1.5 g, 4 8 mmol), tetrakistriphenylphosphine Pd(0) (0.335 g, 0.290 mmol), sodium carbonate (1.23 g, 11.6 mmol) was flushed with nitrogen and toluene (12 mL), and MeOH (4 mL) were added. The reaction was heated at reflux under nitrogen for 48 hr. It was partitioned between EtOAc and water and the organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed. Chromatography (step gradient elution with DCM containing 0 to 15% EtOAc) afforded methyl 3-amino-6-bromo-2-(3-(hydroxymethyl)phenyl)isonicotinate (1.4 g, 4.2 mmol, 86% yield) as a yellow solid. MS (ESI) m/z 339.02 (M+H). 1H NMR (400 MHz, chloroform-d) δ ppm 7.80 (1H, s), 7.58 (1H, s), 7.40-7.55 (3H, m), 5.94 (2H, br. s.), 4.74 (2H, d, J=5.79 Hz), 3.92 (3H, s), 1.77 (1H, t, J=5.92 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([O:19][CH3:20])[CH:3]=1.[Cl-].[Li+].CS(C)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1OC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ccc(Br)cc1OC
Temperature: 120 °C
Reaction time: 20 h
Yield: 42.4 %

Procedure:
A mixture of diethyl 2-(4-bromo-2-methoxyphenyl)malonate (1213 mg, 3.500 mmol), lithium chloride (620 mg, 14.6 mmol), and DMSO (6 ml) was stirred at 120° C. for 20 hours, then at 150° C. for 4 hours, and again at 120° C. for 20 hours. The reaction was cooled to room temperature, diluted with 25 mL of water, and extracted with ethyl acetate-heptane mixture (1:1). The extract was washed with brine (2 times), dried over magnesium sulfate, and loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 0% to 30% of ethyl acetate in heptane gave the title compound (405 mg, 42% yield over two steps). GCMS (ES+) 272 (M+).
Reaction SMILES: [C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+].C(OCC)(=O)C.C(O)C.N>C(O)C>[ClH:36].[C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:41])[NH2:28])=[CH:25][CH:26]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 84 %

Procedure:
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbonylmethyl-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 84% of theory, C27H28N6O3 (484.56) Rf value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5) EKA mass spectrum: (M+H)+ =485
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14](=O)[CH:13]([C:18]([O:20]CC)=O)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC[O-].[Na+].CCO>CCO.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3[NH:30][N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18](=[O:20])[C:13]=3[CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc(C)cc2)CCC1=O
Reactant: NNc1ccccc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCc3[nH]n(-c4ccccc4)c(=O)c3C2)cc1
Temperature: 25 °C
Yield: 25 %

Procedure:
In a three-necked flask, under a N2 atmosphere, 0.300 g (0.92 mmol) of ethyl 1-[(4-methyl phenyl)sulfonyl]-4-oxopiperidine-3-carboxylate and 0.099 g (0.92 mmol) of phenyl hydrazine were stirred in 3 mL of EtOH for 1 h at 50° C. HPLC and UPLC-MS analysis revealed the formation of the hydrazone intermediate. After having cooled to room temperature, a solution of EtONa/EtOH—prepared by dissolution of 42 mg (1.84 mmol) of Na in 2 mL of EtOH—was added to the reaction mixture and it was stirred for 1 additional hour at room temperature (reaction monitored by HPLC and UPLC-MS). The reaction mixture was diluted with brine (10 mL) and extracted with ethylacetate (50 mL×3). The combined organic phases were dried over Na2SO4 and evaporated. The crude (400 mg) was purified by silica flash chromatography using ethylacetate/petroleum ether (80/20, gradient to 100% ethylacetate) yielding 84 mg of a white solid as the desired 5-[(4-methylphenyl)sulfonyl]-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one (25% yield). 1HNMR (500 MHz, DMSO-d6): 3.95 (s, 3H); 2.64 (t, J=5.5 Hz, 2H); 3.17 (d, J=5 Hz, 2H); 3.30 (m, 2H, hidden by H2O); 7.20 (t, J=7.25 Hz, 1H); 7.40-7.45 (m, 4H); 7.65-7.7 (m, 4H); 11.36 (bs, NH); 370.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]2[N:15]([CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:39]>ClCCl>[CH2:1]([S:8]([C:9]1[N:14]=[C:13]2[N:15]([CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CCN1C(=O)N(c2ccccc2Cl)Cc2cnc(SCc3ccccc3)nc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCN(CC)CCN1C(=O)N(c2ccccc2Cl)Cc2cnc(S(=O)Cc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxidation of the 7-benzylthio-3-(2-chlorophenyl)-1-(2-diethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one was accomplished using 3-chloroperoxybenzoic acid (0.339 g, 1.96 mmol) in dichloromethane with stirring at room temperature for 1 hour. The reaction was quenched with 10% sodium sulfite solution (aq, 5 mL), poured into saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried with magnesium sulfate and concentrated in vacuo to provide 7-benzylsulfinyl-3-(2-chlorophenyl)-1-(2-diethylamino-ethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one, which was used without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([OH:20])=[C:9]([O:16][C:17](=O)[CH3:18])[C:10](=[O:15])[N:11]2[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:21](Br)C=C.CI>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([OH:20])=[C:9]([O:16][CH2:17][CH:18]=[CH2:21])[C:10](=[O:15])[N:11]2[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=CCBr
Reactant: CC(=O)Oc1c(O)c2ccc([N+](=O)[O-])cc2n(C)c1=O
Solvent: CI
Product: C=CCOc1c(O)c2ccc([N+](=O)[O-])cc2n(C)c1=O

Procedure:
In accordance with EXAMPLE 15, using 7-nitro-3-acetoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, allyl bromide was used as an alkylating agent instead of methyl iodide, 7-nitro-3-(2-propenyloxy)-4-hydroxy-1-methyl-2(1H)-quinolinone was provided. In the following, the spectrum data was shown.