Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(Cl)Cl.[CH:22](N(CC)C(C)C)(C)[CH3:23].C1N=CN([C:36]([N:38]2[CH:42]=N[CH:40]=[CH:39]2)=[O:37])C=1.N1CCCCC1>>[CH:2]1([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:36]([N:38]4[CH2:39][CH2:40][CH2:23][CH2:22][CH2:42]4)=[O:37])[CH2:13]3)[C:9]2=[O:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C1N(C2CCCCC2)CCC12CCCNC2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C(N1CCCCC1)N1CCCC2(CCN(C3CCCCC3)C2=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one hydrochloride (20 mg, 0.00007 mol) in methylene chloride (0.5 mL, 0.008 mol) was added N,N-diisopropylethylamine (14.0 μL, 0.0000806 mol) and the solution was stirred at rt for 5 min. prior to the addition of N,N-carbonyldiimidazole (24 mg, 0.00015 mol). After stirring the reaction mixture at rt for 3 h, piperidine (6.2 mg, 0.00007 mol) was added and stirring was continued for 12 h. To drive the reaction to completion the mixture was heated at 170° C. under microwave irradiation for 1 h. The crude mixture was purified by prep.-HPLC to afford the desired product. LC-MS: 348.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.C([Li])CCC.Cl[Si](C)(C)C.[CH3:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21]>C1COCC1>[NH2:1][C:2]1[S:3][C:4]([C:19]([OH:22])([CH2:20][CH3:21])[CH2:18][CH3:17])=[N:5][N:6]=1
Reactant: CCC(=O)CC
Reactant: Nc1nncs1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)(CC)c1nnc(N)s1
Temperature: -20 °C

Procedure:
To a −78° C. solution of 2-amino-1,3,4-thiadiazole (commercially available) (2.5 g, 24.72 mmol) in THF (200 mL, 0.1M) was added first n-butyllithium 1.6M hexanes (30.9 mL, 49.4 mmol) followed 15 min later by chlorotrimethylsilane (6.27 mL, 49.4 mmol). The temperature raised to −20° C. for 15 min and cooled back to −78° C. More n-butyllithium 1.6M hexanes (15.45 mL, 24.72 mmol) was added followed 15 min later by 3-pentanone (2.62 mL, 24.72 mmol). The solution was then warmed to rt (overnight). The reaction mixture was quenched with a saturated NH4Cl solution and THF was removed under vacuum. The aqueous phase was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over MgSO4 and concentrated. The crude residue obtained was purified by column chromatography (100% EtOAc) to yield the title compound. 1H NMR (400 MHz, acetone-d6): δ 6.3 (bs, 2H), 4.4 (bs, 1H), 2.0-1.7 (m, 4H), 0.9 (t, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.[I:28]I>CCO.CCOC(C)=O.S([O-])([O-])(=O)=O.[Ag+2]>[OH:1][C:2]1[C:7]([I:28])=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1
Reactant: II
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(I)c3O)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of the title compound from Example 1 Step B (2.00 g, 5.30 mmol) and silver sulfate (1.653 g, 5.30 mmol) in EtOH (53 mL) was added iodine (1.35 g, 5.30 mmol). The resulting suspension was stirred vigorously at ambient temperature. After 4 h, the reaction mixture was diluted with EtOAc, and the organic phase was washed successively with water, sat. aq. sodium bisulfate, and sat. aq. NaHCO3. The organic phase was then concentrated in vacuo. The title compound was separated from the para-iodo isomer upon purification by flash chromatography on silica gel (0 to 15% EtOAc in hexanes, then 15% EtOAc in hexanes, then 15 to 100% EtOAc in hexanes; the title compound is the later eluting isomer): LCMS m/z 504.5 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 13.08 (s, 1H), 8.17 (s, 1H), 8.10 (t, J=8.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.86 (dd, J=7.5, 1.5 Hz, 1H), 7.82 (dd, J=8.0, 1.5 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 6.75 (t, J=8.0 Hz, 1H), 4.33 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[F:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=1[N+:19]([O-])=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>>[ClH:22].[NH2:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[N:7]=[CH:6][N:5]2[C:16]1[CH:15]=[CH:14][C:13]([NH:19][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([C:32]([F:34])([F:33])[F:35])[CH:25]=2)=[O:31])=[C:12]([F:11])[CH:17]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: Cl
Product: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound can be synthesized from adenine, 2,4-difluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by the same method as in Examples 29 and 30.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl.[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCCCC(=O)Cl
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Triethylamine (23.1 ml) and hexanoyl chloride (11.4 ml) were added dropwise to a methylene chloride solution (300 ml) of L-proline benzylester hydrochloride (20.00 g) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was successively washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate, and brine, dried over magnesium sulfate, and concentrated to obtain 26.20 g of N-hexanoyl-L-proline benzyl ester.
Reaction SMILES: [CH2:1]([C:3]1[S:25][C:6]2=[N:7][C:8]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[N:5]2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO>[CH2:1]([C:3]1[S:25][C:6]2=[N:7][C:8]([N:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)=[CH:9][C:10](=[O:11])[N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2c(=O)cc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCc1nn2c(=O)cc(N3CCNCC3)nc2s1
Reaction time: 18 h
Yield: 83.4 %

Procedure:
To a solution of tert-butyl 4-(2-ethyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (3.39 g, 9.28 mmol, 1.0 equiv) in 40 mL of dichloromethane is added trifluoroacetic acid (10 ml, 130 mmol, 14 equiv). The mixture stirred for 18 h, after which it is concentrated in vacuo and azeotroped with dichloroethane to give a yellow solid. The crude residue is dissolved in MeOH and purified by HPLC to give 2-ethyl-7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (2.053 g, 83% yield) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 5.30 (s, 1H), 3.37-3.44 (m, 4H), 2.94 (q, J=7.56 Hz, 2H), 2.64-2.73 (m, 4H), 1.25 (t, 3H); LCMS: (electrospray+ve), m/z 266.0 (MH)+; HPLC: tR=2.71 min, UV254=100%. HRMS (ESI): m/z calcd for C11H16N5OS [M+H]+266.1069. found 266.1073.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1.[CH3:13][OH:14]>>[CH3:13][O:14][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1
Reactant: CO
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Na]
Product: COc1cc(C)c([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a stirred solution of sodium (2.30 g, 100 mmol, 3.8 eq) in absolute methanol (75 ml) at 0° C., a solution of 2-chloro-4-methyl-5-nitropyridine (4.50 g, 26.07 mmol) in absolute methanol (15 ml) was added dropwise rapidly. The resulting dark colored solution was stirred at room temperature for 30 minutes, and then it was concentrted to a solid via evaporation under reduced pressure. This solid was placed in water (25 ml), the pH of which was ad]usted to 6 with concentrated HCl, and this aqueous mixture was extracted with ethyl acetate (2×25 ml). These extracts were combined, dried (MgSO4), and evaporated under reduced pressure to yield 2-methoxy-4-methyl-5-nitropyridine (4.30 g, 25.57 mmol, 98%) as an orange solid: mp, 70°-72° C.; 1H NMR (DMSO-d6) δ 8.94 (s, 1H), 6.97 (s, 1H), 3.99 (s, 3H), 2.58 (s, 3H); LRMS (m/z relative intensity) 168 (M+, 98), 167 (100), 151 (34), 138 (24), 80 (17).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:2]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[N:28]=[C:29]([NH2:32])[S:30][CH:31]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[N:28]=[C:29]([NH:32][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([S:8](=[O:9])(=[O:10])[NH:7][C:3]3[CH:2]=[C:1]([CH3:20])[CH:6]=[CH:5][CH:4]=3)=[CH:19][CH:18]=2)[S:30][CH:31]=1
Reactant: Cc1cccc(NS(=O)(=O)c2ccc(C(=O)O)cc2)c1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: Cc1cccc(NS(=O)(=O)c2ccc(C(=O)Nc3nc(-c4ccccn4)cs3)cc2)c1

Procedure:
4-(N-m-tolylsulfamoyl)benzoic acid (14) (99 mg, 0.34 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 75-100% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(4-(pyridin-2-yl)thiazol-2-yl)-4-(N-m-tolylsulfamoyl)benzamide as an off white solid. Yield: 24 mg (19%). 1H-NMR: 8.64-8.62 (m, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.95-7.89 (m, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.36 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 6.98-6.96 (m, 1H), 6.88 (d, J=8.0 Hz, 1H), 3.18 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:25])[CH:3]=1.[ClH:26]>ClCCl.CO.O1CCOCC1>[ClH:26].[F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:25])[CH:3]=1
Reactant: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-(4-fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (˜12.3 mmol, 4.3 g) (D4a) was dissolved in dichloromethane/methanol (50 ml/20 ml) and was treated with HCl (10 eq., 0.123 mol, ˜30 ml of a 4M solution in 1,4-dioxane) at room temperature; the mixture was stirred at room temperature for one overnight. Solvent was evaporated and the solid obtained was triturated with diethyl ether to afford the title compound (3.5 g, about 12.3 mmol brown solid) as the mono hydrochloride salt, M++H=250.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:30][NH:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][C:38]=1[NH:39][C:40]1[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=1)=[O:33].C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[CH3:30][NH:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][C:38]=1[NH:39][C:40]1[C:45]([Cl:46])=[CH:44][N:43]=[C:42]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)[N:41]=1)=[O:33]
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCCOc2ccc(N)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCN1CCCOc2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21
Yield: 48.7 %

Procedure:
9-Ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamine (57 mg, 0.30 mmol), 10-Camphorsulfonic acid (72.3 mg, 0.311 mmol) and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide (9.0E1 mg, 0.30 mmol) in Isopropyl alcohol (2.0 mL) was irradiated in a CEM microwave (120° C., 30 min). The mixture was diluted with satd. sodium bicarbonate (1 mL) and water (6 mL). The flocculent solids were separated from an oily residue on the sides of the vial, filtered and washed with water. Drying in vacuo of the solids furnished 3-[5-Chloro-2-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide (67 mg, 49%). MP=153-155° C.; LCMS: 459 (M+H); 1H-NMR (CDCl3): 11.27 (s, 1H), 8.31 (d, 1H, J=5.1 Hz), 8.08 (s, 1H), 6.92 (s, 1H), 6.88 (m, 2H), 6.71 (s, 1H), 5.67 (s, 1H), 4.14 (m, 2H), 3.29 (m, 2H), 3.27 (m, 2H), 3.02 (d, 3H, J=4.8 Hz), 2.03 (m, 2H), 1.18 (t, 3H, J=6.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([CH2:16][CH2:17]Cl)(=[O:15])=[O:14])=[O:11])[N:3]=1.[OH-].[Na+]>C(O)C.O>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH:9][C:10]([NH:12][S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14])=[O:11])[N:5]=1
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)CCCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CS(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 40 °C

Procedure:
14.6 g (0.05 mole) of N-(4,6-dimethyl-pyrimidin-2-yl)-N'-(2-chloro-eth-1-yl-sulfonyl)-urea (cf. Example 12) were dissolved in 150 ml of ethanol, and 4 g (0.1 mole) of sodium hydroxide, dissolved in 10 ml of water, were added at room temperature. The reaction mixture was then warmed to 40° C. for 4 hours, concentrated in vacuo and taken up in 150 ml of water. After acidification with 2 N HCl (pH 5), the mixture was extracted with ethyl acetate, and the extracts were then dried and concentrated. After the addition of n-hexane, 8.9 g (69.5% of theory) of N-(4,6-dimethyl-pyrimidin-2-yl)-N'-(vinylsulfonyl)-urea of melting point 131°-3° C. were obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]=[C:10]=[O:11])[CH:4]=1)[CH3:2].[C:12]([NH:15][C:16]1[NH:17][CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:20]=1[C:21]([NH2:23])=[O:22])(=[O:14])[CH3:13]>O1CCCC1>[C:12]([NH:15][C:16]1[NH:17][CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=3)=[O:11])=[CH:26][CH:25]=2)[C:20]=1[C:21]([NH2:23])=[O:22])(=[O:14])[CH3:13]
Reactant: CCc1cccc(N=C=O)c1
Reactant: CC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Solvent: C1CCOC1
Product: CCc1cccc(NC(=O)Nc2ccc(-c3c[nH]c(NC(C)=O)c3C(N)=O)cc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.061 cm3 (0.426 mmol) of 1-ethyl-3-isocyanatobenzene is added at room temperature to a suspension of 100 mg (0.387 mmol) of 2-acetylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide in 5 cm3 of anhydrous tetrahydrofuran. The reaction medium is stirred at room temperature for 24 hours and then evaporated to dryness under reduced pressure. The crude product is purified by flash chromatography [eluent; dichloromethane/methanol (97/3 by volume)]. After concentrating under reduced pressure the fractions containing the expected product, 107 mg of 2-acetylamino-4-{4-[3-(3-ethylphenyl)ureido]phenyl}-1H-pyrrole-3-carboxamide are obtained in the form of a brown solid.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][NH:27]2)=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCCl>[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][N:27]2[C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([N:13]4[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]4)[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:23][CH:22]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: CN1CCN(c2ccc3ncnc(Cl)c3c2)CC1
Agent: Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CN1CCN(c2ccc3ncnc(N4CCc5ccc(Cl)cc54)c3c2)CC1

Procedure:
4-Chloro-6-(4-methylpiperazin-1-yl)-quinazoline hydrochloride (537 mg, 1.80 mmol) and 6-chloroindoline (169 mg, 1.10 mmol) were refluxed in 10 mL of 1,2-dichloroethane and pyridine (350 mg, 4.40 mmol) for 48 hours. The product was isolated as the (58%); using the analogous method of Example 120; 267 mg (58%); M.P. 289°-290° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=O)[OH:25])[CH2:19][CH2:18]3)[CH2:7][C:6]2=1.[O:27]=[C:28]1[CH2:33][S:32][C:31]2[CH:34]=[CH:35][C:36](C(O)=O)=[N:37][C:30]=2[NH:29]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([C:36]4[CH:35]=[CH:34][C:31]5[S:32][CH2:33][C:28](=[O:27])[NH:29][C:30]=5[N:37]=4)=[O:25])[CH2:19][CH2:18]3)[CH2:7][C:6]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)O)CC1)CO3
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Product: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)c2ccc4c(n2)NC(=O)CS4)CC1)CO3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 6 and in analogy to Example 1 using [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid text-butyl ester and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[BrH:12].CS(C)=O.[OH-].[Na+]>C(O)(=O)C>[Br:12][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1
Reactant: CC(C)(C)c1ccccc1N
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Br)ccc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
25 g (168 mmol) of 2-tert-butylaniline are placed in 300 ml of acetic acid. 450 ml of aqueous HBr at 48% are added and the mixture is then cooled to 0° C. 150 ml of DMSO are added dropwise, the mixture having been brought back to ambient temperature is stirred for 2 hours and it is then poured into ice-cold water and basified to pH 10 with 5N NaOH. It is extracted with diethyl ether and the organic phase is then dried and concentrated to dryness. The residue is column-purified (95/5 heptane/EtOAc). 25.2 g of 4-bromo-2-tert-butylphenylamine are obtained in the form of a yellow oil (yield=65%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[C:15]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[CH2:26][CH2:27]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: c1ccc2c(C3CCNCC3)cccc2c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2c(C3CCN(CCCCn4nnc5ccccc54)CC3)cccc2c1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-naphthyl)piperidine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.9 g compound (I-156) with a yield of 60.1%. ESI-MS [M+H]+: m/z 385.3.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:12])[CH2:5][P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8].C(NC1C=CC(S([N:26]=[N+:27]=[N-])(=O)=O)=CC=1)(=O)C>C1C=CC=CC=1.C1COCC1>[N+:26](=[C:5]([P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8])[C:4](=[O:3])[CH3:12])=[N-:27]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a suspension of 4.1 g of NaH (washed with hexane) in 110 mL of benzene and 25 mL of THF at 5° C., was added 15.5 g of dimethyl 2-oxopropylphosphonate (Formula 13) in 15 mL of benzene. The resulting solution was stirred at 5-10° C. for 1 hour. A solution of 24.7 g of 4-acetamidobenzenesulfonyl azide (Formula 14) in 25 mL of benzene and 50 mL of THF was then added and the mixture was stirred at room temperature for 2 hours. The yellow suspension was filtered through celite and washed with ethyl ether. The filtrate was concentrated to give 18 g of dimethyl 1-diazo-2-oxopropylphosphonate (Formula 15) as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH3:2].[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[NH:41][CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[N:41]([C:6]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C#Cc1ccc(OC)cc1
Product: CCOC(=O)C=C(c1ccc(OC)cc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 88 %

Procedure:
The title compound was synthesized from (4-methoxy-phenyl)-propynoic acid ethyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in a 88% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.32 (m, 2H), 7.21 (m, 1H), 7.11-6.85 (m, 6H), 6.70 (m, 1H), 6.50 (m, 1H), 6.13 (s, 0.5H), 6.03 (s, 0.5H), 4.40 (m, 2H) 4.10 (q, 2H, J=7.2 Hz), 3.86 (s, 1.5H), 3.83 (s, 1H), 3.76 (t, 2H, J=5.2 Hz), 3.70 (t, 2H, J=6.0 Hz), 3.20 (t, 2H, J=6.8 Hz), 2.70 (t, 2H, J=6.8 Hz, J=6.8 Hz), 1.90 (m, 2H), 1.49 (s, 9H), 1.23 (t, 1.5H, J=7.2 Hz), 1.18 (t, 1.5H, J=7.2 Hz). Mass Spectrum (LCMS, ESI) calculated for C30H32N3O4 498.2 (M-Boc+H); found 498.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:10]=[C:5]2[NH:4][CH2:3]1.[Br:20]Br>C(O)(=O)C>[BrH:20].[Br:20][C:8]1[C:7](=[O:17])[N:6]2[CH2:18][C:2]([CH3:19])([CH3:1])[CH2:3][NH:4][C:5]2=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: BrBr
Reactant: CC1(C)CNc2nc(-c3ccncc3)cc(=O)n2C1
Solvent: CC(=O)O
Product: Br
Product: CC1(C)CNc2nc(-c3ccncc3)c(Br)c(=O)n2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.0 g (11.7 mmol) of 7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 75 ml of acetic acid was added dropwise 0.6 ml (11.7 mmol) of bromine. The mixture was allowed to stir at room temperature for 2 h.