Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][CH2:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)C(C)(C)CCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCOc1ccc(C=O)cc1
Temperature: 65 °C
Reaction time: 0.75 h

Procedure:
A solution of 48.9 g (0.4 mol) of 4-hydroxybenzaldehyde in 600 ml of dimethylformamide was stirred under a nitrogen atmosphere. Sodium hydride (31.2 g; 0.44 mol) was added to the stirring solution over 45 minutes. The temperature of the reaction mixture was maintained at 35°-40° during the addition, and stirring was continued for an additional 45 minutes at room temperature. Methyl 5-bromo-2,2-dimethylpentanoate (98.1 g; 0.44 mol), was added dropwise over 20 minutes. The reaction temperature was maintained at 40° during the addition. After addition was complete, the temperature was raised to 65° C. and stirring was continued at 65° C. for 31/2 hours. After standing overnight, the dimethylformamide was removed on a rotary evaporator and the residue was taken up in water and ether. The aqueous layer was extracted a second time with ether and the combined extracts were washed, dried, and concentrated under reduced pressure. The residue was triturated two times with n-heptane. The heptane insoluble oil was distilled via a short path apparatus to give methyl 5-[4-formylphenoxy)-2,2-dimethyl-pentanoate: bp 143°-144° C. at 0.03 mm of Hg; yield 39.4 g (37%). Additional analytically pure product was obtained from the heptane extract: 32.3 g (31%). Anal. Calcd. for C15H20O4 :
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].B(F)(F)F.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:30])=[C:14]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:20][CH:19]=2)=O)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:30])=[C:14]([C:16]2([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:22][CH:23]=3)[S:4][CH2:1][CH2:2][S:3]2)[CH:15]=1
Reactant: SCCS
Reactant: O=C(c1ccc(OCC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)COc1ccc(C2(c3cc(Br)ccc3Cl)SCCS2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At 0° C., ethane-1,2-dithiol (3 mL) and BF3.2HOAc (4.8 mL) were added into a solution of (5-bromo-2-chlorophenyl)(4-(2,2,2-trifluoroethoxy)phenyl)methanone (5.0 g) in dry DCM. The mixture was stirred at room temperature for 12 hours. The mixture was added with saturated Na2CO3 aqueous solution and then extracted with DCM. The organic phases were combined, dried over Na2SO4, and concentrated to obtain the crude product, then the crude product was purified by silica-gel column chromatography (PE/EA=200/1) to obtain 4 g of 2-(5-bromo-2-chlorophenyl)-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1,3-dithiolane.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][CH2:32][CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCCO)ccc21
Yield: 86 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (3-hydroxy-propyl)-amide (98 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 3-amino-1-propanol (20 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 466.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.78-7.60 (m, 2H), 7.45 (d, 1H), 7.34 (d, 1H), 4.48 (s, 1H), 3.63 (bs, 3H), 3.48 (q, 2H), 3.38-3.30 (m, 2H), 1.76-1.64 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][C:13]([N:15]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][C:13]([N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=C(CCl)N(c1ccccc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CSc1ccc(F)cc1)N(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-fluorothiophenol (0.13 mL, 1.2 mmol) in tetrahydrofuran (4 ml) was added aqueous 15% sodium hydroxide. 2-Chloro-N-cyclohexyl-N-phenylacetamide (320 mg, 1.3 mmol) was added, and the solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue purified on a preparatory plate using 20% ethyl acetate/hexanes to furnish 2-(4-fluorophenylthio)-N-cyclohexyl-N-phenylacetamide as a white solid. (M+1)=343.9
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([N:8]2[C:17](=[O:18])[CH:11]3[CH2:12][CH:13](O)[CH2:14][CH2:15][N:10]3[C:9]2=[O:19])=[N:6][CH:7]=1.C(N(S(F)(F)[F:27])CC)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([N:8]2[C:17](=[O:18])[CH:11]3[CH2:12][CH:13]([F:27])[CH2:14][CH2:15][N:10]3[C:9]2=[O:19])=[N:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1C2CC(O)CCN2C(=O)N1c1ncc(Cl)cc1F
Solvent: O
Product: O=C1C2CC(F)CCN2C(=O)N1c1ncc(Cl)cc1F
Reaction time: 1 h

Procedure:
2.6 g of 2-(5-Chloro-3-fluoro-pyridine-2-yl)-7-hydroxi-tetrahydroimidazo-(1.5-a)-pyridine-1,3-dione (isomer B) in 80 ml dichlorromethane is treated at −55° C.-−65° C. with 1.9 ml of diethylaminosulfur trifluoride (DAST) and stirred at the same temperature for 1 hr. The vessel is then allowed to stirr at room temperature over night. The resulting brownish solution is treated with ice and water and extracted with ethyl acetate. The extracts are washed with water, dried, filtered through a small siligcagel column and evaporated to give the desired product with m.p. 154-157° C.
Reaction SMILES: [CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([OH:40])=O)=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3].[N:41]1([CH2:47][CH2:48][O:49][CH2:50][CH2:51][OH:52])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[OH:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][N:41]1[CH2:46][CH2:45][N:44]([C:38](=[O:40])[CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([S:2]([CH3:1])(=[O:3])=[N:4][C:5](=[O:6])[C:7]3[CH:12]=[C:11]([C:13]#[C:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]5[O:25][CH:26]=[CH:27][C:28]=5[CH3:29])=[O:23])[CH:16]=4)[CH:10]=[N:9][CH:8]=3)=[CH:31][CH:32]=2)[CH2:43][CH2:42]1
Reactant: OCCOCCN1CCNCC1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)O)cc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)N4CCN(CCOCCO)CC4)cc3)c2)c1
Yield: 46.8 %

Procedure:
In a manner similar to that described in Example 485, 3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)-phenyl]propanoic acid (0.050 g, 0.090 mmol) and 2-(2-piperazin-1-yl-ethoxy)-ethanol (0.030 mL, 0.180 mmol) were reacted to give the title compound (0.030 g, 47%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:32])[C:13]([C:23]([NH:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:24])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CCO>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:32])[C:13]([C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC(=O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CNC(=O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 25 h
Yield: 93.4 %

Procedure:
300 mg of the compound of Example 1 was suspended in 5.0 ml of EtOH, to which 0.8 ml of aqueous 1M NaOH was added under ice cooling, for stirring at ambient temperature for 25 hours. Water was added to the reaction mixture, which was neutralized with aqueous 1M HCl. The resulting solid was filtered and washed with EtOH, to obtain 263 mg of ({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetic acid.
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][C:5](=O)[CH2:6][C:7](=O)[CH3:8].[CH3:28][O:29][C:30]([CH2:32][C:33]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:34])=[O:31].C[O-].[Na+].[Na]>CO>[OH:34][C:33]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:7]([CH3:8])[CH:6]=[C:5]([CH2:4][CH2:3][C:2]([OH:1])([CH3:27])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[C:32]=1[C:30]([O:29][CH3:28])=[O:31]
Reactant: CC(=O)CC(=O)CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1c(C)cc(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c(C(=O)OC)c1O
Temperature: 25 °C
Reaction time: 44 h
Yield: 103.5 %

Procedure:
To a solution of 7-hydroxy-7,11,15,19-tetramethyleicosane-2,4-dione (72.5 g) and dimethyl acetonedicarboxylate (29.6 g) in methanol (190 ml) at 0° was added a solution of sodium methoxide in methanol from 2.44 g of sodium and 90 ml of methanol). The solution as stirred at room temperature for 44 hr and was concentrated on a rotary evaporator to remove approx. 100 ml of methanol. The residual solution was poured onto ice (500 g) and 20% (v/v) aqueous hydrochloric acid (45 ml). The mixture was extracted with ether (3 × 300 ml) and the combined extracts were washed with brine and dried over anhydrous sodium sulfate and were concentrated on a rotary evaporator to give 91.65 g of crude dimethyl 2-hydroxy-4-methyl-6(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate as an orange oil. A 90.2 g portion of the oil was dissolved in ether (400 ml) and was washed with 20% by weight aqueous potassium carbonate (to remove the unreacted dimethyl acetonedicarboxylate), brine and was dried over anhydrous sodium sulfate. The solution was concentrated on a rotary evaporator to give 83.13 g of partially purified diester dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate. The total material was chromatographed on 2.45 kg of silica gel eluting with 20-30% by volume ether in hexane to give 30.83 g of dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][OH:9].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH:8]=[O:9]
Reactant: OCCCc1ccco1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCCc1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
The product from Example 50A (2.0 g, 15.9 mmol) in CH2Cl2 (50 mL) was treated with Dess-Martin periodinane (8.1 g, 19.2 mmol) in portions. The mixture was stirred at rt for 2 hrs, quenched with saturated NaS2O3, and the mixture was extracted with CH2Cl2. The CH2Cl2 layer was washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated. The resulting residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 1.44 g (73%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 2.80 (t, J=8.24, 6.41 Hz, 2 H) 2.98 (t, J=7.32 Hz, 2 H) 6.02 (d, J=3.97 Hz, 1 H) 6.19-6.36 (m, 1 H) 7.28-7.33 (m, 1 H) 9.82 (s, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20].[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23].C(Cl)(Cl)Cl>O>[CH2:21]([N:24]([CH2:25][CH2:26][CH3:27])[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20])[CH2:22][CH3:23]
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2Cl)c(F)c1
Reactant: CCCNCCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)c1c(-c2c(F)cc(F)cc2F)c(Cl)nc2nccn12
Temperature: 80 °C
Yield: 83.1 %

Procedure:
A mixture of 0.095 g of 5,7-dichloro-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine and 0.12 g of di-n-propylamine was heated at 80° C. for one hour. The reaction mixture was allowed to cool, and chloroform and water were added thereto. The separated organic layer was dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 0.095 g of 5-(di-n-propylamino)-6-(2,4,6-trifluorophenyl)-7-chloroimidazo[1,2-a]pyrimidine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][C:22](Cl)=[O:23]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:22](=[O:23])[CH2:21][C:17]4[S:16][CH:20]=[CH:19][CH:18]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)Cc1cccs1
Product: O=C(Cc1cccs1)Nc1nc2cccc(-c3ccoc3)n2n1

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 2-thiopheneacetyl chloride (80 mg; 0.50 mmol; 2.0 eq.) as a white powder (30.9 mg, 38%). HPLC, Rt: 3.28 min. (purity 96.6%). LC/MS, M+(ESI): 357.2, M−(ESI): 355.2.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([CH2:13][C:14](=[O:33])[N:15]3[C:23]4[C:18](=[C:19](C5CCCN(CCC)C5)[CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[NH:10][C:9](=[O:34])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.CN(C)[CH2:38][CH2:39][CH2:40]N=C=NCC.N1(C2N=C(CC([O-])=O)NC(=O)C=2)CCOCC1.[Na+]>CN(C)C=O.N1C=CC=CC=1>[N:1]1([C:7]2[N:12]=[C:11]([CH2:13][C:14](=[O:33])[N:15]3[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH:17]4[CH2:38][CH2:39][CH2:40][CH:16]34)[NH:10][C:9](=[O:34])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCN1CCCC(c2cccc3c2CCN3C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)C1
Agent: Cl
Agent: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1c2ccccc2C2CCCC21
Temperature: 25 °C
Reaction time: 72 h
Yield: 143.4 %

Procedure:
320 mg of 1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole [reference example 7d] and 424 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 525 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2d of example 1d) in 4 ml of N,N-dimethylformamide and 4 ml of pyridine. The reaction mixture is stirred at ambient temperature for 72 hours and then concentrated under reduced pressure. The residue is taken up in a mixture of water and ethyl acetate and the organic phase is washed successively with water, a 1M hydrochloric acid solution and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is triturated from methanol, filtered and washed with diisopropyl ether, so as to give 375 mg of 6-(morpholin-4-yl)-2-[2-oxo-2-(2,3,3a,8b-tetrahydrocyclopenta[b]indol-4(1H)-yl)ethyl]pyrimidin-4(3H)-one, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2([CH3:17])[CH3:16])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][C:12]1([CH3:17])[CH2:13][CH2:14][CH2:15][N:11]1[C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1
Reactant: CC1(C)CCCN1c1cc(Cl)nn2ccnc12
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CCCN1c1cc(-c2ccccc2)nn2ccnc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
A mixture of 6-chloro-8-(2,2-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine (140 mg, 0.56 mmol), phenylboronic acid (103 mg, 0.84 mmol), Pd2(dba)3 (34 mg, 0.06 mmol), X-phos (114 mg, 0.24 mmol) and K2CO3 (235 mg, 1.70 mmol) in dioxane (10 mL) and water (1 mL) was heated to 100° C. with stirring for 4 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=200:1) to give 8-(2,2-dimethylpyrrolidin-1-yl)-6-phenylimidazo[1,2-b]pyridazine (65 mg, 40%) as a light yellow solid. 1H NMR (300 MHz, DMSO): δ 7.91-7.87 (m, 3H), 7.53-7.49 (m, 4 h), 6.54 (s, 1H), 4.43-4.40 (m, 1H), 2.08-2.06 (m, 4 h), 1.70 (s, 6H). LC-MS: [M+H]+, 293, tR=1.76 min, HPLC: 95% at 214 nm, 95.55% at 254 nm, tR=3.943 min.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=2)[N:4]=1.ONC(=N)CC1C=CC([I:26])=CC=1>>[Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([I:26])=[CH:11][CH:10]=2)[N:4]=1
Reactant: ClCc1nc(Cc2cccc(I)c2)no1
Reactant: N=C(Cc1ccc(I)cc1)NO
Product: ClCc1nc(Cc2ccc(I)cc2)no1

Procedure:
The title compound is prepared essentially as described for 5-chloromethyl-3-(3-iodo-benzyl)-[1,2,4]oxadiazole, employing N-hydroxy-2-(4-iodo-phenyl)-acetamidine. LC-MS (m/e): 335 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:4][CH:5]([O:11][CH2:12][CH3:13])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3].[CH2:14]([O:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.CCOCC>[CH2:12]([O:11][CH:5]([O:4][CH2:2][CH3:3])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:26](=[O:27])[C@@H:25]1[CH2:29][CH2:30][CH2:31][N:24]1[C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23])[CH3:13]
Reactant: CCOC(OCC)[C@@H]1CCCN1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(OCC)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of L-prolinal diethyl acetal hydrochloride (898 mg) and benzyloxycarbonyl-L-proline (1.2 g, 4.82 mmol) in dichloromethane (15 ml) are added successively, under ice-cooling and agitation, 1-hydroxy-benzotriazole (645 mg), triethylamine (0.68 ml, 4.88 mmol) and N,N-dicyclohexylcarbodiimide (1.0 g, 4.90 mmol). After the addition, stirring is further continued for 2 hours under ice-cooling, and then for 45 minutes at room temperature. Ether (40 ml) is added to the reaction mixture and the mixture is filtered for removal of insolubles. The filtrate is washed successively with water (10 ml), a saturated aqueous solution of sodium hydrogen carbonate (10 ml) and a saturated aqueous solution of edible salt (10 ml), dried over magnesium sulfate and filtered. The filtrate is concentrated to dryness under reduced pressure. The residue is purified by column chromatography on silica gel (benzene-ether-ethanol, 20:20:1) to give 1.125 g (69%) of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCc1ccncc1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
A mixture of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (112 mg, 0.35 mmol), potassium carbonate (138 mg, 1 mmol) and 4-(chloromethyl)pyridine hydrochloride (59 mg, 0.36 mmol) in DMF (2 ml) was heated at 80° C. for 1 hour. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline (115 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15](Cl)=O.C(NC1C=CC2N=C(C3C(F)=CC=CC=3F)OC(=O)C=2C=1)(=O)C>C(N(CC)CC)C.C1(C)C=CC=CC=1>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15]1[O:5][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cccc(N)c1C(=O)O
Agent: CC(=O)Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc2nc(-c3c(F)cccc3F)oc(=O)c12

Procedure:
2-Amino-6-methylbenzoic acid (0.498 g), 2,6-difluorobenzoyl chloride (0.93 mL) and triethyl amine/toluene (1/1) (20 mL) were reacted as described under (10).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:6]2[N:5]=1)=O.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[OH:19])[N:6]4[N:5]=3)=[CH:29][CH:28]=2)[CH2:25][CH2:26]1
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3O)n2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5O)n4n3)cc2)CC1
Yield: 51.7 %

Procedure:
Into a microwave vial, 2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenol (0.165 g, 0.604 mmol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.254 g, 1.33 mmol), 1-Methoxy-2-propanol (1.20 mL) and N,N-Diisopropylethylamine (0.231 mL, 1.33 mmol) were added. The reaction was microwaved on 300 watts, 180° C. for 2 hours. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded 2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenol as a yellow solid (125 mg, 51%). LCMS (E/I+) 401.10 (M+H). NMR 1H (DMSO-d6)-9.73 (s, 1H), 9.13 (s, 1H), 8.88 (s, 1H), 7.92 (d, 1H, J=7.74 Hz), 7.61 (d, 2H, J=8.23 Hz), 7.25 (t, 1H, J=7.26 Hz), 6.93-7.08 (m, 3H), 6.88 (d, 1H, J=4.35 Hz), 6.81 (d, 2H, J=8.23 Hz), 3.03 (bs, 4H), 2.44 (bs, 3H), 2.21 (s, 3H).