Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)(=[O:41])=[O:40]>C1COCC1>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:48][CH:45]3[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]3)[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3sc(N4CCOCC4)nc3-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)n2)CC1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.2 g, 0.352 mmol) and 1-(methylsulfonyl)-4-piperidinamine (0.314 g, 1.76 mmol) in THF (1 mL) the title compound was obtained as a white solid (0.14 g, 0.197 mmol, 56.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75 (s, 1H), 7.90 (d, J=5.2 Hz, 1H), 7.68-7.71 (m, 1H), 7.45-7.63 (m, 3H), 7.36-7.45 (m, 1H), 7.21-7.35 (m, 2H), 7.05-7.20 (m, 1H), 3.38-3.78 (m, 5H), 3.32 (s, 3H), 2.56-3.18 (m, 4H), 1.38-2.43 (m, 8H). MS (ESI): 710 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[N:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:37][CH:36]=1>ClCCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([N:12]([CH3:13])[CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([N:46]2[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][C:38]3[CH:37]=[CH:36][N:35]=[CH:40][CH:39]=3)[CH2:44][CH2:45]2)=[O:21])[CH:16]=1)(=[O:10])=[O:11]
Reactant: c1cc(CCN2CCNCC2)ccn1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CN(Cc1cc(C(=O)N2CCN(CCc3ccncc3)CC2)co1)S(=O)(=O)c1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
5-({[(2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (465 mg, 1.3 mmol) was dissolved in DCE (40 mL) and CDI (422 mg, 2.6 mmol) was added. The reaction was stirred for 1 h. 4 mL of activated acid solution in DCE was added to a vial containing 1-[2-(pyridin-4-yl)ethyl]piperazine (50 mg, 0.261 mmol). The reaction was stirred at ambient temperature for 3 days, then washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and shaken with PL-MIA and Ambersep resins, then filtered. The solvent was removed in vacuo and a portion of the crude product purified using prep method B.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH:9]=[C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[CH3:21])=[O:12])[C:4]=2[N:3]=1.Cl.[NH:36]1[CH2:39][CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>CCO>[N:36]1([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:32])([F:33])[F:34])=[O:24])[CH:9]=[C:10]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=4[CH3:21])=[O:12])[C:4]=3[N:3]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: C1CNC1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(Cl)nc12
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(N3CCC3)nc12
Yield: 32.4 %

Procedure:
A solution of 2-chloro-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (80 mg, Example 135), azetidine hydrochloride (60 mg) and N,N-diisopropylethylamine (208 μL) in EtOH (1.8 mL) was reacted at 120° C. for 20 minutes in a microwave reactor (Biotage, Initiator). The reaction mixture was concentrated under reduced pressure, and the residue was purified on column chromatography to obtain 2-(azetidin-1-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (27 mg). This was dissolved in MeOH (1 mL), 2N hydrogen chloride/MeOH solution (1 Eq) was added, and it was stirred and concentrated. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (21 mg) as white powder.
Reaction SMILES: [N:1]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:14]CCC.CI.[NH4+].[Cl-]>C1COCC1>[CH3:14][N:6]1[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: [Li]CCCC
Reactant: O=C1CCCc2ncccc2N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)CCCc2ncccc21
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A solution of 1.0 eq of 96 in 30 mL of dry THF was cooled to −78° C. While stirring, 1.1 eq of n-BuLi (2.5 M in hexanes) was added dropwise. The reaction solution was warmed to 0° C. and stirred for 1 hr. The solution was then cooled to −78° C. and 1.2 eq of methyl iodide was slowly added. The mixture was stirred, as the solution warmed to rt. After 17 hrs, 50 mL of saturated NH4Cl was added and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and dried under vacuum to afford a dark orange colored solid as 97.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[CH3:12][CH:13]([CH3:17])[C:14](=O)[CH3:15]>C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:10]=[C:14]([CH3:15])[C:13]2([CH3:17])[CH3:12]
Reactant: CC(=O)C(C)C
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(C)(C)C(C)=N2
Temperature: 100 °C

Procedure:
To 4-methoxyphenyl hydrazine hydrochloride (4.84 g) was added 3-methyl-2-butanone (6.4 ml) and acetic acid (45 ml). The mixture was heated to 100° C. for 2.5 hours after which time the solvent was removed by rotary evaporation. Flash column chromatography gave the product (4.66 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[NH:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](O)=[O:24]>>[NH:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:24]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc[nH]4)cc23)CC1
Yield: 88.8 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.1 mg (0.131 mMol) pyrrole-2-carboxylic acid, 12.6 mg (78%) of the title compound were recovered.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1([C@@H:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C@@H:31]([NH:33][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:23])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: C[C@H](N)c1ccccc1
Product: C[C@H](NC(=O)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1)c1ccccc1

Procedure:
The product from Example 33B and (S)-1-phenylethanamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 437 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=[O:2].[OH-:21].[Na+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:18][C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]2[S:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])[CH3:19]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)s2)CC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)s2)CC1
Temperature: 65 °C
Yield: 70.8 %

Procedure:
A solution of tert-butyl 4-(5-formylthien-2-yl)piperazine-1-carboxylate (2.5 1 g, 8.50 mmol) in ethanol (85 ml) was added in one portion to a solution of silver (I) nitrate (10.0 g, 58.8 mmol) and sodium hydroxide (4.83 g, 120.6 mmol) in water (85 ml). This mixture was stirred and heated at 65° C. for 22 h. The mixture was cooled by the addition of ice and then filtered to remove silver salts. The filtrate was carefully evaporated to remove the ethanol and the resulting aqueous solution was filtered again through a glass-fibre pad to remove tarry material. The filtrate was then diluted with water to a total volume of 400 ml and then acidified to pH 5 with acetic acid. The precipitate was filtered off, washed with water and then dried in a vacuum oven at 45° C. overnight to give 5-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]thiophene-2-carboxylic acid (1.88 g, 71%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]#[C:6][C:7](=O)[C:8]([F:11])([F:10])[F:9])[CH3:2].Br.[CH2:17]([S:23][C:24](=[NH:26])[NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[N:26]=[C:24]([S:23][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:25]=1)[CH3:2]
Reactant: CCOC(C#CC(=O)C(F)(F)F)OCC
Reactant: CCCCCCSC(=N)N
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCSc1nc(C(OCC)OCC)cc(C(F)(F)F)n1
Temperature: 20 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
5,5-Diethoxy-1,1,1-trifluoro-pent-3-yn-2-one (2 g, 8.9 mmol) and 2-hexyl-isothiourea hydrobromide (2.4 g, 9.8 mmol) were dissolved under nitrogen in THF (20 mL). Then triethylamine (2.7 mL, 19.6 mmol) was added slowly. The reaction was exothermic (40° C.). The suspension was stirred for 4 h at 20° C. The product was extracted with AcOEt, sat. NH4Cl solution, dried and concentrated. The residue was purified by silica gel chromatography in heptane/AcOEt 20:1. One obtained 2.5 g (76%) of a colorless oil. MS: m/z=367 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:5]([CH2:15][CH3:16])[C:6]([NH:8][C:9]1[O:10][CH:11]=[C:12]([CH3:14])[N:13]=1)=[O:7])[CH3:4].[CH2:17](I)[CH3:18]>CN(C)C=O>[CH2:17]([N:8]([C:9]1[O:10][CH:11]=[C:12]([CH3:14])[N:13]=1)[C:6](=[O:7])[CH:5]([CH2:3][CH3:4])[CH2:15][CH3:16])[CH3:18]
Reactant: CCC(CC)C(=O)Nc1nc(C)co1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)C(=O)N(CC)c1nc(C)co1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
Sodium hydride (2.8 g. of a 50% dispersion in oil, 0.058 mol) was added in small portions to a stirred solution of 2-(2-ethylbutyramido)-4-methyloxazole (8.0 g., 0.041 mol) in dimethylformamide (100 ml.) at -5° to 0° C. The mixture was stirred for 2 hours at room temperature and then ethyl iodide (4.7 ml. 0.058 mol) was added. The mixture was stirred for a further 2 hours at room temperature and then poured onto ice-water (250 ml.) and extracted with ether (3 × 100 ml.). The extract was washed with dilute hydrochloric acid, then with sodium chloride solution, dried over sodium sulphate and evaporated. The residue was distilled under vacuum to give the product 4.7 g. (51%) b.p. 71°-72° C/0.3 mm.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[C:19]2[CH:25]=[C:24]([N+:26]([O-])=O)[C:22]([NH2:23])=[CH:21][C:20]=2[C:29]#[C:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+]>O1CCOCC1.O>[C:31]1([C:30]#[C:29][C:20]2[CH:21]=[C:22]([NH2:23])[C:24]([NH2:26])=[CH:25][C:19]=2[C:10]2[CH:11]=[C:12]([NH2:16])[C:13]([NH2:15])=[CH:14][C:9]=2[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nc1cc(C#Cc2ccccc2)c(-c2cc([N+](=O)[O-])c(N)cc2C#Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(C#Cc2ccccc2)c(-c2cc(N)c(N)cc2C#Cc2ccccc2)cc1N
Reaction time: 0.08 h
Yield: 75.5 %

Procedure:
A solution of 2,2'-bis(phenylethynyl)-5,5'-dinitrobenzidine (0.474 g, 0.00100 mol) in dioxane (50 ml), freshly distilled from FeSO4 (3.65 g, 0.024 mol), was added to a boiling solution of FeSO4 (3.65 g, 0.024 mol) in water (50 ml.) which was stirred under nitrogen. After 5 minutes, ammonium hydroxide (20 ml, 30%) was added slowly followed by 20 ml. more of dioxane. The resultant dark suspension was stirred and refluxed for 30 minutes at which point additional ammonium hydroxide (20 ml) was added. Refluxing was continued for 30 minutes and then the reaction mixture was cooled and extracted three times with 100 ml. of chloroform. The combined chloroform extracts were concentrated to dryness on a rotary evaporator. The residue was dissolved in methylene chloride (20 ml.) and filtered after which the filtrate was poured with stirring into 20 ml. of hexane. The resultant precipitate was filtered, washed with hexane, and dried at 23° C in a vacuum oven at 1 mm of Hg for 24 hours to give 0.313 g (76% yield) of 2,2'-bis(phenylethynyl)-5,5'-diaminobenzidine which softened above 100° C to a viscous melt.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([OH:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])(=[O:17])=[O:16])[NH2:14]>C(O)(=O)C>[OH:27][C:21]1[CH:20]=[CH:19][C:18]([S:15]([NH:13][N:14]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])(=[O:16])=[O:17])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]
Reactant: NNS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Temperature: 100 °C
Yield: 59 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 5-(hydrazinosulfonyl)-2-hydroxybenzoic acid. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 108 mg of the title compound (59%) as a yellow solid in 92.8% purity by HPLC (Rt: 4.85, gradient of 10 min, MaxPlot detection between 230 and 400 mn).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]([OH:22])[CH2:20][CH3:21]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:22][CH:19]([CH2:20][CH3:21])[CH3:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CCC(C)O
Product: CCC(C)OC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-butanol there is obtained 2-butyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resinous product, 1H-NMR(CDCl3): 1.02 (t, CH2CH3), 1.35 (d, CH--CH3), 1.4-2.0 (m, 2H), 4.23 (s, 4H), 4.83 (m, 1H), 7.3-7.7 (8H);
Reaction SMILES: C([NH:4][C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH3:17])[C:10](=[O:18])[N:9]([CH2:19][CH2:20][CH2:21][CH3:22])[C:8]=2[NH:7][N:6]=1)(=O)C.[OH-].[Na+].Cl>C(O)C.O>[NH2:4][C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH3:17])[C:10](=[O:18])[N:9]([CH2:19][CH2:20][CH2:21][CH3:22])[C:8]=2[NH:7][N:6]=1
Reactant: CCCCn1c(=O)n(CCC)c(=O)c2c(NC(C)=O)n[nH]c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCn1c(=O)n(CCC)c(=O)c2c(N)n[nH]c21
Yield: 92.7 %

Procedure:
3-Acetylamino-7-butyl-5-propylpyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(10 g) was heated under reflux for 5 hours in 80% ethanol(100 ml) containing sodium hydroxide (2 g). The reaction mixture was concentrated to give crystals. The crystals were suspended in water(100 ml), to which was added 6N-HCl to make it weakly acid to afford colorless crystals(8 g,93%),m.p. 209°-211° C.
Reaction SMILES: [C:1]([CH:6]1[CH2:15][CH2:14][C:13]2[NH:12][C:11](=[O:16])[N:10]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])[N:19]=[C:9]3[C:8]=2[CH2:7]1)([O:3]CC)=O.O>O1CCCC1>[C:6]1([C:1]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:3])[CH:6]2[CH2:15][CH2:14][C:13]3[NH:12][C:11](=[O:16])[N:10]4[CH:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[F:26])[N:19]=[C:9]4[C:8]=3[CH2:7]2)[CH:15]=[CH:14][CH:13]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CC(C(O)(c1ccccc1)c1ccccc1)CC2
Reaction time: 0.25 h

Procedure:
To a solution of 9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (110 mg) in 15 mL of anhydrous tetrahydrofuran was added 2 mL of 1.8M phenylithium. The reaction was allowed to stand for 15 minutes and then quenched with 1 mL of 10% acetic acid. The solvent was removed in vacuo and the crude reaction mixture triterated with water. The solid was then collected and dried to yield 9-(Diphenylhydroxymethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 46), m.p. 315°-318° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:24][CH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[C:28](=[O:44])[N:29]([CH:36]1[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:37]1=[O:43])[C:30]2=[O:35].C(N(CC)CC)C>CN(C=O)C>[O:43]=[C:37]1[CH:36]([N:29]2[C:28](=[O:44])[C:27]3[C:31](=[CH:32][CH:33]=[CH:34][C:26]=3[CH2:25][NH:24][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)=[O:10])[C:30]2=[O:35])[CH2:41][CH2:40][C:39](=[O:42])[NH:38]1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccc(Br)n4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A mixture of 6-bromopicolinic acid (0.40 g, 2.0 mmol) and CDI (0.39 g, 2.4 mmol) in DMF (25 mL) was stirred at ambient temperature under nitrogen for 2 hours. 4-Aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) were added, and the mixture was allowed to stir for 16 hours. The solvent was evaporated under vacuum, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting the product with 97:3 methylene chloride-methanol. This material was further purified by preparative HPLC, eluting with 1:1 acetonitrile-water, providing 0.50 g of the purified product in 53% yield: mp 181-183° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H), 2.52-2.65 (m, 2H), 2.84-2.93 (m, 1H), 4.96 (d, J=6.3 Hz, 2H), 5.17 (dd, J=12.6 Hz, d=5.4 Hz, 1H), 7.67-7.72 (m, 1H), 7.80-7.82 (m, 2H), 7.90 (dd, J=7.8 Hz, J=1.0 Hz, 1H), 7.97 (t, J=7.6 Hz, 1H), 8.07 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 9.39 (t, J=6.3 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.5, 48.9, 121.7, 121.9, 127.1, 131.2, 131.6, 133.0, 134.8, 138.9, 140.3, 141.0, 151.0, 163.1, 167.0, 167.6, 169.8, 172.8; Anal. calcd for C20H15BrN4O5.0.5H2O: C, 50.01; H, 3.35; N, 11.66. Found: C, 49.97; H, 3.21; N, 11.56.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>CC(O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[CH:4][C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Cl
Reactant: Nc1cccc(Br)c1
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Nc1cccc(Br)c1
Yield: 40.5 %

Procedure:
The reaction mixture of 200.0 mg (0.74 mmol) of 4-chloro-3-ethoxycarbonyl-5,8-difluoroquinoline and 155.1 mg (0.88 mmol) of 3-bromoaniline in 4.0 mL of 2-propanol was refluxed for 2 h and cooled down. The yellow precipitate was filtered, washed with cold 2-propanol, and dried in oven at 30° C. overnight to give 122.0 mg (40%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S([O-])([O-])(=O)=O.[Mg+2].[OH:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]2[N:28]=[N:27][C:26]([O:29][CH3:30])=[C:25]([C:31](=O)[CH2:32][CH3:33])[CH:24]=2)=[CH:18][C:17]=1[CH3:35].C(O)(=O)C>CC(N(C)C)=O>[CH3:30][O:29][C:26]1[N:27]=[N:28][C:23]([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([OH:15])=[C:17]([CH3:35])[CH:18]=2)=[CH:24][C:25]=1[C:31]1[NH:4][C:3]2[C:2]([C:32]=1[CH3:33])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCC(=O)c1cc(-c2cc(C)c(O)c(C)c2)nnc1OC
Reactant: Nc1ccccc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1[nH]c2ccccc2c1C
Temperature: 140 °C

Procedure:
73.4 μl of 2-chloroaniline and 21 mg of anhydrous magnesium sulfate are suspended in 3 ml dimethylacetamide. 100 mg of 1-[6-(4-hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-propan-1-one and 31.4 mg acetic acid are added and the reaction is degassed with argon. 96 mg of tripotassium phosphate and 35.7 mg of bis(tri-tert-butylphosphine) palladium (0) are added and the reaction is degassed with argon. The reaction is heated to 140° C. for 16 h. The solution is filtered. The product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 35 mg.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[C:7](Cl)(=O)[C:8]([CH3:11])([CH3:10])[CH3:9]>ClCCl.C(N(CC)CC)C>[CH3:9][C:8]([C:7]1[N:2]([CH3:1])[C:3](=[S:6])[NH:4][N:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CNC(=S)NN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(C(C)(C)C)n[nH]c1=S
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-methyl-3-thiosemicarbazide (0.53 g) in dichloromethane (10 mL) and triethylamine (0.73 mL) was added slowly via syringe pivaloyl chloride (5 mmol). Formation of a precipitate was observed. The mixture was kept overnight. Volatiles were evaporated in vacuo, the residue heated to 80° C. in aqueous NaOH (1 M, 25 mL) for 3 h. Aqueous HCl (2 M) was then added at 25° C. until pH ca. 6. The mixture was concentrated to dryness, water (10 mL) was added and the product collected by filtration, washing with saturated aqueous NaHCO3 (2.5 mL) and then water (10 mL) to give, after drying, the title compound (0.23 g) of ca. 90% purity by NMR as a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[C:8]([O:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CCCCCCCCBr
Product: CCCCCCCCOc1cc(OCCCCCCCC)cc(C(=O)OC)c1

Procedure:
200 ml of ethyl alcohol and then 2.3 g of purified sodium are introduced into a 500 ml Erlenmeyer flask. A reflux condenser is fitted to the Erlenmeyer flask and the reaction medium is stirred with a magnetized bar. When the sodium ethylate is formed, 8.4 g of methyl-3,5-dihydroxybenzoate is added, accompanied by stirring. As soon as the medium has become homogeneous, 20.26 g of distilled octyl bromide are added dropwise. Heating under refluxing takes place for 20 hours.