Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[CH3:34][NH:35][CH2:36][CH:37]([C:39]1[S:40][CH:41]=[CH:42][N:43]=1)[OH:38].O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:35]([CH2:36][CH:37]([OH:38])[C:39]4[S:40][CH:41]=[CH:42][N:43]=4)[CH3:34])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: CNCC(O)c1nccs1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1nccs1
Temperature: 90 °C
Yield: 36 %

Procedure:
N,N-Diisopropylethylamine (0.24 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.250 g) were added to a solution of rac-2-(methylamino)-1-(1,3-thiazol-2-yl)ethanol (Preparation 53, 0.217 g) in DMF (15 mL). The reaction mixture was heated to 90° C. for 2 h. The mixture was allowed to cool to room temperature, poured into water (30 mL), and was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 98/2, 95/5) followed by recrystallization from ethyl acetate to yield 0.120 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 114-116° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.55, 7.70, 7.61, 7.41-7.32, 6.86, 6.13, 5.034.98, 4.55, 3.91, 3.77, 2.89-2.84, 2.74-2.69, 2.35; MS (ESI+) m/z 487 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[N:27]=1)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:28]3[N:27]=[C:26]([CH:24]([CH3:25])[CH3:23])[O:30][N:29]=3)=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: CC(C)c1nc(CN)no1
Product: CC(C)c1nc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 5-(1-methylethyl)-1,2,4-oxadiazole-3-methanamine, (CAN 936940-30-6) as starting materials; LC-MS (UV peak area/ESI) 100%, 455.1092 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].Cl.Cl.[NH:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH2:8].[C:15](OCC)(=[O:23])/[CH:16]=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19].N(C1C=NC=CC=1)N>C(O)C>[O:23]=[C:15]1[NH:8][N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16]1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CC(=O)NN1c1cccnc1

Procedure:
In a preferred reaction, sodium ethoxide in an anhydrous ethanol are introduced into a reaction vessel and 3-hydrazinopyridine.dihydrochloride is added. The mixture is stirred and diethyl maleate is added. The mixture is heated at about 60° C. until most of the 3-hydrazinopyridine has reacted. The mixture is allowed to cool and the excess base is neutralized with acid. The crude ethyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a) is conveniently isolated and purified by standard techniques.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:18])([C:13]#[C:14][CH:15]([CH3:17])[CH3:16])[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:19])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:27][C:28](Br)=[O:29].[H-].[Na+]>CCOCC>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:28](=[O:29])[CH2:27][O:18][C:8]([C:13]#[C:14][CH:15]([CH3:16])[CH3:17])([C:9]([F:10])([F:11])[F:12])[C:7]=2[CH:6]=1
Reactant: O=C(Br)CBr
Reactant: CC(C)C#CC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)C#CC1(C(F)(F)F)OCC(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a stirred ice-cooled solution of 4.37 g (15 mmol) of 6-amino-3-chloro-α-(isopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 200 mL of dry ether was added 2.4 mL of dry pyridine and, quickly dropwise, 1.40 mL (16 mmol) of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 150 mL of dry DMF and was treated at 0° with 400 mg of 100% sodium hydride (16.7 mmol) for 20 min. The cooling bath was removed, and the reaction was allowed to proceed at ambient temperature for 1.5 h. The reaction mixture was poured onto a mixture of 1.2 L of water and 300 mL of saturated aqueous sodium chloride and this was extracted 3 times with ether. The combined extracts were washed with brine, dried, and evaporated to a solid which was crystallized by dissolving in hot ethyl acetate and adding hexanes. This material was recrystallized from ethyl acetate/hexane to afford 3.125 g of pure title compound as a crystalline solid: mp 183-183.5°; HRMS Calcd. for C15H14NO2ClF3 (M+H)+: 332.066516. Found: 332.065892.
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=NC=1.[NH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:51]=[C:50]3[C:46]([CH2:47][N:48]([C@@H:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])[C:49]3=[O:52])=[CH:45][CH:44]=2)=[N:41][CH:42]=1.[CH3:61][C:62]1[CH:63]=[C:64]([N:69]=[C:70]=[O:71])[CH:65]=[CH:66][C:67]=1[CH3:68]>>[CH3:61][C:62]1[CH:63]=[C:64]([NH:69][C:70](=[O:71])[NH:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]3[CH:51]=[C:50]4[C:46]([CH2:47][N:48]([C@@H:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])[C:49]4=[O:52])=[CH:45][CH:44]=3)=[N:41][CH:42]=2)[CH:65]=[CH:66][C:67]=1[CH3:68]
Reactant: Cc1ccc(N=C=O)cc1C
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C)c(C)c4)cn3)cc2C1=O

Procedure:
The compound of example 397 was prepared analogous to the compound of example 393 by reaction of the compound of example 392 with 3,4-dimethyl phenyl isocyanate. The compound of example 397 was used directly for the preparation of compound of example 398 without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C>[CH3:15][C:16]1[C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]=[C:11]([CH3:13])[O:10][N:9]=3)=[CH:4][C:3]=2[CH3:14])=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc(-c2ccc(Br)c(C)c2)no1
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)c(C)c2)no1

Procedure:
Example 30 was prepared using 3-(4-bromo-3-methylphenyl)-5-methyl-[1,2,4]oxadiazole and N-[4-methyl-3-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 25) using DMF as the solvent.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][O:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[ClH:25].[CH3:26][O:27][NH2:28].C(O)C.Cl>C(OCC)C>[ClH:25].[CH3:26][O:27][N:28]=[C:18]([CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:21][O:22][CH2:23][CH3:24])[CH3:19]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=O
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=NOC

Procedure:
By the general method described in Part F of Example 30, 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one was reacted with O-methylhydroxylamine hydrochloride. The product was dissolved a mixture of ethanol and diethyl ether, and a solution of hydrogen chloride (1 equivalent of a 1.0 M solution in diethyl ether) was added. A precipitate formed, and the solvents were removed under reduced pressure. The resulting solid was recrystallized from a mixture of ethanol and diethyl ether to provide 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-methyloxime hydrochloride in about a 6.4 to 1 mixture of E and Z isomers as a white solid, mp 189-192° C.
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[C:4](=[O:12])[NH:3][C:2]1=[O:13].C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+]>CO>[NH2:20][CH:8]1[CH2:9][CH2:10][C:5]2([NH:1][C:2](=[O:13])[NH:3][C:4]2=[O:12])[CH2:6][CH2:7]1
Reactant: O=C1CCC2(CC1)NC(=O)NC2=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCC2(CC1)NC(=O)NC2=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a suspension of 1,3-diazaspiro[4.5]decane-2,4,8-trione (5.00 g, 27.4 mmol) in MeOH (91 mL) was added ammonium acetate (6.35 g, 82 mmol), and the mixture was stirred at RT for 25 minutes. To the suspension was added sodium cyanoborohydride (5.17 g, 82 mmol), and the mixture was stirred at RT. After 90 minutes, the flask was cooled, and the contents were quenched by careful addition of aqueous concentrated HCl, adjusting the pH to 7 with solid NaHCO3. The mixture was filtered through a pad of Celite® brand filter aid and concentrated in vacuo. The material was used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][NH:10][C:11](=O)[C@H:12]([NH:16][C:17]2[C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:20]([C:26]#[N:27])=[CH:19][CH:18]=2)[C@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:8][C:11]([C@H:12]([NH:16][C:17]3[C:25]4[CH:24]=[CH:23][S:22][C:21]=4[C:20]([C:26]#[N:27])=[CH:19][CH:18]=3)[C@H:13]([OH:15])[CH3:14])=[N:10][N:9]=2)=[CH:29][CH:30]=1)#[N:2]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
To a solution of 4-cyano-N′-((2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (0.95 g, 2.26 mmol) in THF (150 mL) was added PS-BEMP (3.1 g, 6.82 mmol, ˜2.2 mmol/g) and p-TsCl (470 mg, 2.46 mmol) at room temperature. The mixture was stirred at room temperature for 2 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH (400 mL). The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2R)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (401 mg, 44%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.14 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.83 (d, J=5.6 Hz, 1H), 7.68 (d, J=5.6 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 5.18 (dd, J=6.5, 8.8 Hz, 1H), 4.72 (b, 1H), 4.61 (m, 1H), 1.50 (d, J=6.2 Hz, 3H).
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:15]([O-])([O-])=[O:16].[Cs+].[Cs+].I[C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][OH:25]>[Cu]I.CO>[CH3:15][O:16][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][OH:25]
Reactant: O=C([O-])[O-]
Reactant: OCc1ccccc1I
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1ccccc1CO
Temperature: 80 °C
Reaction time: 24 h
Yield: 88.3 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 10 mol %), 1,10-phenanthroline (36 mg, 0.20 mmol, 20 mol %), Cs2CO3 (456 mg, 1.4 mmol), 2-iodobenzylalcohol (234 mg, 1.0 mmol) and methanol (1.0 mL). The test tube was sealed and the reaction mixture was stirred at 80° C. for 24 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with diethyl ether. The filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2×20 cm; pentane/diethyl ether 2:1) provided 122 mg (88% yield) of the title compound as a colorless oil.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[C:30]3[C:29](=O)[CH2:28][CH2:27][CH2:26][C:25]=3[NH:24][C:23]=2[CH3:32])=[CH:17][CH:16]=1.Cl.[NH2:34][OH:35]>C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[C:30]3[C:29](=[N:34][OH:35])[CH2:28][CH2:27][CH2:26][C:25]=3[NH:24][C:23]=2[CH3:32])=[CH:17][CH:16]=1
Reactant: NO
Reactant: Cc1[nH]c2c(c1Sc1ccc(Cl)cc1)C(=O)CCC2
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: CCO
Product: Cc1[nH]c2c(c1Sc1ccc(Cl)cc1)C(=NO)CCC2
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Tributylamine (6.6 mL 28 mmol) was added to a stirred suspension of 3-(4-chlorophenylsulfanyl)-2-methyl-4,5,6,7-tetrahydro-1H-indol-4-one (8.0 g, 27 mmol) and hydroxylamine hydrochloride (1.9 g, 27 mmol) in ethanol (40 mL). The mixture was heated to 65° C. and maintained at this temperature for 4 h then allowed to cool to r.t. and left overnight. Additional hydroxylamine hydrochloride (0.15 g, 2.2 mmol) and tributylamine (1.0 mL, 4.2 mmol) were added and the mixture was re-heated to 65° C. for a further 2 h. After cooling to r.t., the solid product was collected by filtration, washed with ethanol (2×10 mL) then dried in a vacuum oven at 40° C. to give the title compound as an off-white solid; 5.71 g (68%); purity: 96.3 area % by HPLC; m/z: 307/309 (MH+); 1H-NMR: 11.26 (1H, s), 10.20 (1H, s), 7.23 (2H, m), 6.92 (2H, m), 2.62-2.58 (2H, m), 2.56-2.52 (2H, m), 2.12 (3H, s), 2.83-1.76 (2H, m).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:30][CH:31]([CH3:33])[CH3:32])[C@@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]1)=[O:11].Br[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:32][CH:31]([CH3:33])[CH2:30][N:12]([C:10]([C:2]1[N:3]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)=[O:11])[C@@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]1
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3[nH]2)CN(C(=O)OC(C)(C)C)C1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
To a solution of 1-tert-butyl 3-methyl(3R,5S)-5-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (1.38 g) and (2-bromoethyl)benzene (810 μl) in N,N-dimethylacetamide (30 ml) was added cesium carbonate (2.93 g), and the mixture was stirred at 65° C. for 15 hr. (2-Bromoethyl)benzene (810 μl) was added to the reaction mixture, and the mixture was further stirred at 65° C. for 5 hr. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object product (1.40 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH2:12].Cl[CH2:14][C:15](=O)[CH3:16].C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[CH:14]=[C:15]([CH3:16])[N:12]=[C:7]12
Reactant: Nc1nccc2c(Cl)cccc12
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cn2ccc3c(Cl)cccc3c2n1
Temperature: 60 °C
Yield: 82.4 %

Procedure:
A mixture of 5-chloro-1-aminoisoquinoline (2.8 g), chloroacetone (5.4 g) and sodium bicarbonate (7.6 g) in anhydrous ethanol (35 ml) was heated at 60° C. for 16 hours and filtered by suction. The filtrate was evaporated in vacuo and the residual solid was washed with ethanol to give 7-chloro-2-methylimidazo[2,1-a]isoquinoline (2.8 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH3:16])[C:6]=2[CH:5]=1)[CH3:2].F[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=1.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH3:16])[C:6]=2[CH:5]=1)[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=1)[CH3:2]
Reactant: O=C(O)c1ccc(F)nc1
Reactant: CCNc1ccc2c(c1)C(C)=CCC2(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(c1ccc2c(c1)C(C)=CCC2(C)C)c1ccc(C(=O)O)cn1
Temperature: 125 °C
Yield: 12 %

Procedure:
To a mixture of 1.78 g (8.3 mmol) of ethyl-(5,5,8-trimethyl-5,6-dihydro-naphthalen-2-yl)-amine (Compound 166) and 0.55 g (3.9 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. The product was purified by flash chromatography (silica, 50% ethyl acetate in hexanes) followed by recrystallization using ethyl acetate:hexane (1:1) to give the title compound as white crystals (158 mg).
Reaction SMILES: N1(C(C[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:11]2=[O:19])=O)CCNCC1.N(OCCC(C)C)=O>C(Cl)(Cl)Cl>[S:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:10][C:11]1=[O:19]
Reactant: O=C(Cn1c(=O)sc2ccccc21)N1CCNCC1
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ccccc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 155.3 %

Procedure:
To a solution of 3-[(1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (3.0 g) in chloroform (50 ml) was added dropwise isoamyl nitrite (7.3 ml), for a period of 10 minutes below 20° C. The mixture was stirred for 18 hours at ambient temperature. Then, the reaction mixture was extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and evaporated to give a crystalline product, which was recrystallized from a mixture of ethyl acetate and ethanol to give 3-[4-nitroso-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (2.54 g) as needles.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:15]=2)[CH2:10][CH:9]1[C:32](=[O:44])[NH:33][C:34]1([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][CH:35]1[CH:37]=[CH2:38])=[O:7])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>>[C:26]1([C:16]2[N:15]=[C:14]([O:13][CH:11]3[CH2:12][CH:8]([C:6]([OH:7])=[O:5])[CH:9]([C:32](=[O:44])[NH:33][C:34]4([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][CH:35]4[CH:37]=[CH2:38])[CH2:10]3)[CH:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1C(=O)O)C(=O)OCC
Yield: 110.8 %

Procedure:
Compound 17b (1.2 g, 2 mmol) was treated with triethylsilane (0.58 g, 5.0 mmol) and TFA (25 ml) according to the procedure described in Example 13 step b, which gave the crude title compound, (1.2 g), (M+H)+542.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:11][C:12]1[CH:13]=[C:14]2[C:24]([CH2:25][CH:26]=1)=[C:17]1[NH:18][C:19](=[O:23])[C:20](=[O:22])[NH:21][C:16]1=[CH:15]2.C(N(CC)CC)C>CN(C)C=O>[C:1]1([NH:7][C:8](=[O:9])[NH:11][C:12]2[CH:13]=[C:14]3[C:24]([CH2:25][CH:26]=2)=[C:17]2[NH:18][C:19](=[O:23])[C:20](=[O:22])[NH:21][C:16]2=[CH:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1=CCC2=c3[nH]c(=O)c(=O)[nH]c3=CC2=C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1=CCC2=c3[nH]c(=O)c(=O)[nH]c3=CC2=C1)Nc1ccccc1
Reaction time: 8 h

Procedure:
1.92 ml of phenyl isocyanate are added at a temperature in the region of 20° C. to a solution of 1.5 g of 7-amino-1,4-dihydro-5H-indeno [1,2-b]pyrazine-2,3-dione hydrochloride and 2.48 ml of triethylamine in 20 ml of dimethylformamide. After overnight stirring at the same temperature, the precipitate formed is filtered off, washed with water and dried under a partial vacuum (1 mm Hg; 0.13 kPa) at 40° C. to yield 1.4 g of 7-(3-phenylureido)-1,4-dihydro-5H-indeno[1,2-b]pyrazine-2,3-dione in the form of a greenish solid, the melting point of which is above 260° C. (Analysis C18H14N4O3 ; 4.0 H2O; % calculated C: 64.66; H: 4.22; N: 16.76; % found C: 64.4; H: 4.5; N: 16.8; 1H NMR spectrum [250 MHz, (CD3)2SO-d6, δ in ppm]: 3.58 (s, 2H CH2 9); 7.00 (t, J=7.5 Hz, 1H: aromatic H of the phenyl at para with respect to the ureido); 7.30 (t, J=7.5 Hz, 2H: aromatic H of the phenyl at meta with respect to the ureido); 7.50 (d, J=7.5 Hz, 2H: aromatic H of the phenyl at ortho with respect to the ureido); from 7.20 to 7.60 (mt, 2H: H 5 and H 6); 7.72 (s broad, 1H: H 8); 8.80 (s broad, 2H: ArNHCONH); 12.00 and 12.28 (2 unres. comp. 1H each: NHCOCONH).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C([Si](C)(C)[O:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:29])(C)(C)C.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([C:24]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:4]=2)=[CH:22][C:21]=1[CH3:29]
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Reactant: NC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccccc3c(=O)[nH]2)cc(C)c1OCCO
Temperature: 150 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A mixture of anthranilamide (0.15 g, 1.10 mmol), 4-[2(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.340 g, 1.101 mmol), sodium hydrogensulfite (0.126 g, 1.101 mmol) and p-toluenesulfonic acid (20 mg) in N,N-dimethyl acetamide (5 mL) was stirred at 150° C. for 3 h under nitrogen. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The solid was collected by filtration, washed with water (10 mL×3) and dried under high vacuum to provide desired compound (328 mg, 70%), as a white solid. A solution of the above described compound (0.316 g, 0.745 mmol) in THF (3 mL) was cooled to 0° C. under nitrogen and TBAF (1.5 mL, 1.49 mmol) was added, followed by stirring at room temperature for 1 h. The reaction mixture was diluted with cold water (30 mL), the white precipitate was filtered off, washed with water (15 mL×3) and MeOH (20 mL×3) and dried under high vacuum, to afford 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (150 mg, 65%), as a white solid. Selected data: MS (ES) m/z: 311.04; MP 260-261° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>CN(C)C=O>[Cl:9][CH2:10][C:11]([NH:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)nn1
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1ccc(Cl)nn1

Procedure:
3-Amino-6-chloropyridazine (10.4 g) was dissolved in N,N-dimethylformamide (200 mL). Chloroacetyl chloride (7.48 mL) was added thereto, and the resultant mixture was stirred at room temperature for 1 hour. The solvent was distilled away under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the residue. The precipitated solid was recoverd by filtration, followed by washing with ethyl acetate and water, to thereby give the title compound (9.39 g).