Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][NH:17][C:18]1[C:19]2[N:31]([CH3:32])[N:30]=[C:29]([CH2:33][CH2:34][CH3:35])[C:20]=2[N:21]=[C:22]([CH2:24][CH2:25][C:26]([NH2:28])=O)[N:23]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][NH:17][C:18]1[C:19]2[N:31]([CH3:32])[N:30]=[C:29]([CH2:33][CH2:34][CH3:35])[C:20]=2[N:21]=[C:22]([CH2:24][CH2:25][C:26]#[N:28])[N:23]=1
Reactant: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(CCC(N)=O)nc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(CCC#N)nc12
Reaction time: 1 h

Procedure:
1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile at 0°. 1 equivalent of 3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionamide is then added. The mixture is stirred for one hour. After customary working up, 3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-yl]propionitrile is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>ClCCl>[N:23]1([CH2:22][CH2:21][O:18][C:14]2[CH:13]=[C:12]([C:10]3[CH:9]=[CH:8][C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[N:11]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ClCCN1CCCC1
Reactant: Nc1ncnc2ccc(-c3cccc(O)c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ncnc2ccc(-c3cccc(OCCN4CCCC4)c3)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
To a 4 mL screw-cap vial was added 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)phenol (100 mg; 0.32 mmol) followed by 1-(2-chloroethyl)pyrrolidine hydrochloride (CAS 7050-67-1) (1.1 equiv., 0.35 mmol, 59 mg) cesium carbonate (5 equiv., 1.57 mmol, 513 mg) and dimethylformamide (0.6 mL). The reaction was capped at shaken at 80° C. overnight. The reaction was cooled to room temperature, diluted with dichloromethane, and washed with water. Organic phase was concentrated, then purified by reverse phase HPLC yielding 16 mg of desired product. 1H NMR (400 MHz, DMSO) δ 8.48-8.39 (m, 2H), 8.15-8.08 (m, 2H), 8.00-7.89 (m, 3H), 7.47-7.40 (t, J=7.9 Hz, 1H), 7.12-7.03 (dd, J=8.1, 2.3 Hz, 1H), 4.27-4.18 (t, J=5.9 Hz, 2H), 2.90-2.81 (t, J=5.9 Hz, 2H), 2.59-2.53 (m, 4H), 1.76-1.66 (m, 4H). LCMS M/Z (M+H)=336.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.O>CC#N>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Ic1cnn(CCCOC2CCCCO2)c1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a mixture of 4-iodo-1H-pyrazole (2.0 g, 10.3 mmol) and Cs2CO3 (5.04 g, 15.5 mmol) in MeCN (28 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (1.84 mL, 10.8 mmol) and the mixture stirred overnight. The crude reaction mixture was poured into water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-80% EtOAc in cyclohexane, to give the title compound (2.95 g, 81%). 1H NMR (300 MHz, CDCl3): 150-1.58 (4H, m), 1.65-1.90 (2H, m), 2.12 (2H, qn, J=6.4 Hz), 3.35 (1H, dt, J=10.2, 5.9 Hz), 3.46-3.54 (1H, m), 3.73 (1H, dt, J=10.2, 5.9 Hz), 3.80-3.88 (1H, m), 4.26 (2H, td, J=6.9, 1.5 Hz), 4.54 (1H, dd, J=4.5, 3.1 Hz), 7.46 (1H, s), 7.50 (1H, s).
Reaction SMILES: [CH:1]([C:11]([O:13]C)=O)([C:7](OC)=[O:8])[CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl.[C:16]([NH2:19])(=[NH:18])[CH3:17].C[O-].[Na+]>CO>[OH:13][C:11]1[C:1]([CH2:2][C:3]([O:5][CH3:6])=[O:4])=[C:7]([OH:8])[N:19]=[C:16]([CH3:17])[N:18]=1
Reactant: COC(=O)CC(C(=O)OC)C(=O)OC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(O)nc(C)nc1O

Procedure:
Trimethyl ethane-1,1,2-tricarboxylate (204 g, 1 mol) and acetamidine hydrochloride (95 g, mol) are added to a solution of sodium methylate (108 g, 2 mol) in methanol (600 ml) with stirring. The mixture is stirred for 16 hours at room temperature. Acidification with concentrated hydrochloric acid, filtration, washing with cold water and drying gives the methyl 4,6-dihydroxy-2-methyl-pyrimidin-5-yl-acetate (or tautomeric forms thereof) as a colorless solid (210 g), m.p.>200° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH:11]2[CH2:13][CH2:12]2)=[O:7])=[CH:4][N:3]=1
Reactant: NC1CC1
Reactant: O=C(Cl)c1ccc(Br)nc1
Product: O=C(NC1CC1)c1ccc(Br)nc1

Procedure:
6-bromo-N-cyclopropylnicotinamide was prepared from 6-bromonicotinoyl chloride and cyclopropylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2].[Se](=O)=[O:23]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Yield: 58 %

Procedure:
6-Hydroxy-3-phenyl-1H-indene-2-carboxylate ethyl ester (1 g, 3.57 mmol) was dissolved in 1,4-dioxane (50 ml), and then selenium dioxide (5.49 g, 53.55 mmol) was added thereto. The mixture was refluxed for 12 hour with vigorous stirring. The resulting mixture was filtered and concentrated, and the concentrate was extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate, concentrated under a reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound (58%) as a rich red solid.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13].[CH2:20]([C:22]([CH2:29]C)([CH2:27]C)[C:23]([O-])([O-])[O-:24])C>C(#N)C>[CH3:3][NH:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:23](=[O:24])[C:22]([CH3:29])([CH3:27])[CH3:20]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CNC(Cc1ccccc1N)c1ccccc1
Agent: Cl
Solvent: CC#N
Product: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1ccccc1
Temperature: 70 °C
Yield: 82.6 %

Procedure:
A heterogeneous mixture of N-methyl-2-amino-α-phenylphen-ethylamine dihydrochloride (150g, 0.5 mol) in acetonitrile (500 ml) was treated with triethylorthoacetate (202 ml, 1.1 mol) and heated to 70° C. for 2 hours with stirring under a dry nitrogen atmosphere. The reaction mixture was filtered, concentrated in vacuo, and the residual solid recrystallized from 2-propanol at -10° C. to give 2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine hydrochloride (118g, 0.413 mol) in 83% yield. The product had a melting point of 239.5°-241° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[N+:19]([O-])([OH:21])=[O:20]>>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:9])[F:10]
Reactant: O=[N+]([O-])O
Reactant: Cn1nc(-c2ccc(Cl)cc2)c(Cl)c1OC(F)F
Product: Cn1nc(-c2ccc(Cl)c([N+](=O)[O-])c2)c(Cl)c1OC(F)F
Reaction time: 2 h

Procedure:
113.4 g (0.387 mol) of 4-chloro-3-(4-chlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole were added a little at a time at -40° C. to 500 ml of 98% strength nitric acid. The mixture was stirred at this temperature for 2 hours and then the solution was stirred into ice. The product was extracted from the aqueous phase with dichloromethane. The dichloromethane phase was subsequently washed a number of times with water and then with saturated sodium chloride solution. Drying over magnesium sulfate and removal of the dichloromethane gave 119.6 g of the target product.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:12]([NH:15][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[CH2:13][CH3:14]
Reactant: CCCN
Reactant: O=C1CCc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3,4-dihydro-1-H-naphthalen-2-one (5 g, 34 mmol) in 1,2-dichloroethane (250 mL), propyl amine (2.8 mL, 34 mmol) was added, followed by addition of sodium triacetoxyborohydride (22 g, 102 mmol). The reaction was stirred at ambient temperature under nitrogen for 24 hours, at which time it was concentrated in vacuo. The remaining solid was partitioned between 1M sodium hydroxide and ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was acidified with 1 M HCl in ether and 6.3 g of propyl-(1,2,3,4-tetrahydro-naphthalen-2-yl)-amine was collected as a pale pink precipitate.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[CH2:24][CH2:23]2)[C:10]1=[O:36])=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[CH2:26][CH2:27]2)[C:10]1=[O:36])([OH:5])=[O:3]
Reactant: CCOC(=O)CCCn1c(=O)n(CCN2CCN(c3ccccc3OC)CC2)c(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1N1CCN(CCn2c(=O)c3ccccc3n(CCCC(=O)O)c2=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
The 1-(3-ethoxycarbonylpropyl)3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione (4.53 g) obtained in Example 7-c) was dissolved in ethanol (40 ml). After adding 2N aqueous sodium hydroxide under cooling with ice, the resulting mixture was stirred at room temperature for 3 hours. The solvent was distilled off under vacuum and the residue was dissolved in water (20 ml). When the pH of the solution was adjusted to 7 with 10% aqueous hydrochloric acid, a crystal formed. It was filtered off and recrystallized from a mixture of ethanol and n-hexane to provide pale yellow needles of 1-(3-carboxypropyl)-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione (2.52 g) with a m.p. of 182° C. (decomposed).
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:25][CH2:26][S:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)(=O)=O)=CC=1.O>CN(C=O)C>[CH3:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[S:1][CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cn1ccnc1S
Reactant: Cc1ccc(S(=O)(=O)OCCSc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1SCCSc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
2-mercapto-1-methylimidazole (0.81 g) was dissolved in DMF (16.2 ml), potassium carbonate (1.37 g) was added to the mixture, 2-[(4-nitrophenyl)thio]ethyl 4-methylbenzene sulfonate (3.0 g) was added to the mixture, and the mixture was stirred for 12 hours at 60° C. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 1-methyl-2-[[2-[(4-nitrophenyl)thio]ethyl]thio]imidazole (1.3 g).
Reaction SMILES: [NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:38]1[CH:39]=[CH:40][C:41]2[O:45][C:44](=[O:46])[N:43]([CH3:47])[C:42]=2[CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:38]2[CH:39]=[CH:40][C:41]3[O:45][C:44](=[O:46])[N:43]([CH3:47])[C:42]=3[CH:48]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(N)=O
Reactant: Cn1c(=O)oc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)C(N)=O)cc3)cc21
Temperature: 75 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A mixture of (S)-tert-butyl 2-((S)-1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate (113 mg), 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (51.4 mg), [1,1′-bis[bis(1,1-dimethylethyl)phosphino-κP]ferrocene]dichloro palladium (7.34 mg) and potassium carbonate (93 mg) in acetonitrile (0.7 mL) and water (0.35 mL) was stirred at 75° C. for 2 h. The solvent was removed in vacuo and the residue was purified by flash silica chromatography eluting with 1:1 isohexane/acetone to give the subtitle compound (112 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C@H:10]2[C@@H:15]([CH3:16])[CH2:14][CH2:13][CH2:12][NH:11]2)=[N:6][CH:7]=1.C(NC(C)C)(C)C.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C@H:10]2[C@@H:15]([CH3:16])[CH2:14][CH2:13][CH2:12][N:11]2[C:29]([C:28]2[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=2[O:26][C:25]([F:24])([F:36])[F:37])=[O:30])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: C[C@H]1CCCN[C@H]1CNc1ncc(Cl)cn1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: C[C@H]1CCCN(C(=O)c2ccccc2OC(F)(F)F)[C@H]1CNc1ncc(Cl)cn1

Procedure:
To a solution of the forementioned rac-cis-5-chloro-N-((3-methylpiperidin-2-yl)methyl)pyrimidin-2-amine and diisopropylamine (3 eq) in DCM was added 2-(trifluoromethoxy)benzoyl chloride (1.2 eq) dropwise. The reaction was stirred at reflux for 3 h and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. (ESI) 429.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[NH3:11]>C(Cl)Cl>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: N#Cc1c(F)cccc1F
Solvent: ClCCl
Product: N#Cc1c(N)cccc1F
Yield: 98.1 %

Procedure:
50 parts of 2,6-difluorobenzonitrile and 40 parts by volume of ammonia are stirred for 10 hours at 100° C. in a closed vessel. The reaction mixture is taken up in methylene chloride, the solid is filtered off, the organic phase is extracted three times by shaking with water and is dried over sodium sulfate, the solvent is stripped off and the residue is dried under reduced pressure. 48 parts (98.1% of theory) of 2-amino-6-fluoro-benzonitrile, of solidification point 125°-128° C., are obtained.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].Br[CH:14]1[CH2:17][CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cccnc1S
Reactant: BrC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1SC1CCC1
Reaction time: 0.5 h

Procedure:
2-Mercapto-nicotinic acid (0.1 g, 0.64 mmol) was dissolved in DMF (2 mL), and the solution was cooled to 0˜5° C. NaH (0.13 g, 3.2 mmol) was added slowly thereto, and the mixture was stirred at 0˜5° C. for 30 minutes. Bromo-cyclobutane (0.12 mL, 1.28 mmol) was added thereto, and the mixture was stirred at 55˜65° C. for 3 hours, and then stirred at room temperature for 12 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure. The residue was diluted with water, and then 3N HCl was used to adjust the pH of the solution to 2˜3. The solution was extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C:13]([CH3:38])([CH3:37])[C:14]([N:16]([CH3:36])[C:17]2[CH:18]=[N:19][C:20]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>ClCCl>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([C:13]([CH3:38])([CH3:37])[C:14]([N:16]([C:17]2[CH:18]=[N:19][C:20]([N:30]3[CH2:35][CH2:34][N:33]([S:49]([CH3:48])(=[O:51])=[O:50])[CH2:32][CH2:31]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH3:36])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(N2CCNCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(N2CCN(S(C)(=O)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of 0.16 g (0.31 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide and 38 mg (0.38 mmol) triethylamine in 4 ml dichloromethane were added 38 mg (0.33 mmol) methanesulfonyl chloride at 0° C. After completed addition the reaction mixture was allowed to warm to room temperature. Conversion was monitored by thin layer chromatography. After complete consumption of the starting material the reaction mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.15 g (75%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=O)[CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:24]2[N:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=2)[CH:5]=[C:6]([C:7]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH:23]=1
Reactant: O=C(Nc1ccccc1Nc1ccccc1)c1cc(Br)cc(C(=O)Nc2ccccc2Nc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Brc1cc(-c2nc3ccccc3n2-c2ccccc2)cc(-c2nc3ccccc3n2-c2ccccc2)c1
Temperature: 100 °C
Yield: 67.1 %

Procedure:
To a suspension of Compound 6 (30 g, 52 mmol) in anhydrous 1,4-dioxane (300 mL), POCl3 (30.6 g, 18.6 mL, 200 mmol) was added slowly with water bath cooling. The resulting mixture was then maintained at 100° C. After cooling to room temperature, the mixture was poured into ice (ca. 300 g) and neutralized with Na2CO3, followed by extraction with CH2Cl2 (2×300 mL). The organic phase was then washed with brine, dried over Na2SO4 and concentrated in vacuo. To the mixture, acetonitrile (300 mL) was added and stirred, then filtered. The solid was collected and recrystallized in CH2Cl2/hexane to afford a white solid (18.9 g). The filtrant was purified by flash chromatography (SiO2, 100% hexanes to 9:1 to 4:1-hexanes/ethyl acetate). The main fraction was collected and concentrated to give additional product, white solid (5.17 g). Total amount is 24.1 g (86%): confirmed by LCMS (APCI): calculated for C32H21BrN4 (M+): 541; Found: 541.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]#[N:10])=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(O)C.O.[C].[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]#[N:10])=[CH:3][CH:2]=1
Reactant: N#CC=Cc1ccncc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#CCCc1ccncc1
Yield: 66.6 %

Procedure:
3-(4-Pyridyl)acrylonitrile (1.3 g, 10.0 mmol) was dissolved in ethanol (10 ml), and 10% palladium-carbon (0.13 g) and a solution of ammonium formate (2.5 g, 40.0 mmol) in water (3 ml) were added thereto. The reaction mixture was refluxed for 2.5 hrs. Palladium-carbon was filtered off, and the reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The reaction mixture was subjected to a silica gel (25 g) column chromatography. The fractions eluted with hexane-ethyl acetate (1:1, v/v) were collected and concentrated to give the titled compound (0.88 g, 67%)
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](SC)=[N:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:20])[CH2:3]1.[CH3:21][N:22](C)[CH:23]=O>C(N(CC)CC)C.CNC>[CH3:1][CH:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([N:22]([CH3:23])[CH3:21])=[N:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:20])[CH2:3]1
Reactant: CN(C)C=O
Reactant: CSc1ncnc2cc(C3=NNC(=O)CC3C)ccc12
Agent: CNC
Solvent: CCN(CC)CC
Product: CC1CC(=O)NN=C1c1ccc2c(N(C)C)ncnc2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
Compound 57 (0.6 g) obtained in Example 19 was dissolved in a mixture of 10 ml of dimethylformamide, 1 ml of triethylamine and 5ml of aqueous 50% dimethylamine solution. The resulting solution was stirred at 60° C. for 4 hours and then concentrated. Thereafter, water was added to the residue, and the crystals precipitated were collected by filtration and dried to give 0.3 g (51%) of 4,5-dihydro-5-methyl-6-(4-dimethylaminoquinazolin-7-yl)-3(2H)-pyridazinone (Compound 13).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([O:14]C)=O)[C:8]([S:16][CH3:17])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[N:19]1[CH:24]=[CH:23][C:22]([C:25](N)=[NH:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)=[N:26][C:12](=[O:14])[C:9]3=[C:8]([S:16][CH3:17])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N=C(N)c1ccncc1
Reactant: COC(=O)c1c(SC)nn(C2CCCC2)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CSc1[nH]n(C2CCCC2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 0 °C
Yield: 12.2 %

Procedure:
A mixture of methyl 1-cyclopentyl-3-methylthio-5-amino-1H-pyrazole-4-carboxylate (3.0 g, 0.012 mol), 4-pyridine carboxamidine hydrochloride (1.9 g, 0.012 mol), potassium carbonate (1.6 g, 0.012 mol) and DMF (25 ml) were refluxed for 4 hours. Additional 4-pyridinecarboxamidine hydrochloride (1.9 g) and potassium carbonate (1.6 g) were added and the reaction mixture was refluxed for 24 hours. The solution was poured into ice-water, neutralized with acetic acid and the resulting precipitate was collected by filtration and washed with water. Recrystallization of the solid from DMF afforded 0.48 g (12%) of 1-cyclopentyl-3-methylthio-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-one as a white powder, m.p. 272°-274° C. when dried at 110° C. for 16 hours in high vacuum.