Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][C:18](O)=[O:19])[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:34])=O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][C:18]([Cl:34])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)Cl)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3β-acetoxy-5-cholenic acid (50.0 g, 118 mmole) in dry dichloromethane (200 ml) was added dropwise oxalyl chloride (30 ml, 448 mmole). The solution was stirred at room temperature for one hour and then concentrated in vacuo to obtain 3β-acetoxy-5-cholenic acid chloride 331. 1H NMR (400 MHz, CDCl3) δ: 0.70 (3H, s, 18--CH3), 0.95 (3H, d, 21--CH3), 1.05 (3H, s, 19--CH3), 2.04 (3H, s, --OCOCH3), 4.60 (1H, m, 3α-H), 5.38 (1H, m, 6-H). Compound 331 was used in the following step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[OH-].[Na+].[CH3:12][C:13]([CH3:18])=[CH:14][C:15](Cl)=[O:16]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:15](=[O:16])[CH:14]=[C:13]([CH3:18])[CH3:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: CC(C)=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)=CC(=O)Nc1ccc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
To a biphasic mixture of 3-bromo-4-methylaniline (50 g, 0.269 mol), 10% NaOH (270 mL) and dichloromethane (160 mL) was added dropwise over a period of 2 hours 3,3-dimethylacryloyl chloride (36 mL, 0.322 mol) in dichloromethane (95 mL). The solution was stirred at room temperature for 48 hours then diluted with water (100 mL). The aqueous layer was further extracted with dichloromethane. The organic layers were combined and washed with water and brine, dried (MgSO4), filtered and evaporated. The white solid was triturated with hexane and collected to give 70 g (97%) of 3-Methyl-but-2-enoic acid (3-bromo-4-methyl-phenyl)-amide. 1H NMR (300 MHz; CDCl3): 1.89 (s, 3 H), 2.21 (s, 3 H), 2.33 (s, 3 H), 5.68 (s, 1 H), 7.14 (d, J=8.0 Hz, 1 H), 7.17 (br s, 1 H), 7.33 (d, J=8.0 Hz, 1 H), 7.79 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)[N:15]=3)[C:11]([OH:33])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:34]([O:38][C:39](=[O:58])[N:40]([S:46]([C:49]1[CH:54]=[C:53]([Cl:55])[C:52](F)=[CH:51][C:50]=1[F:57])(=[O:48])=[O:47])[C:41]1[N:42]=[CH:43][S:44][CH:45]=1)([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[C:34]([O:38][C:39]([N:40]([C:41]1[N:42]=[CH:43][S:44][CH:45]=1)[S:46]([C:49]1[C:50]([F:57])=[CH:51][C:52]([O:33][C:11]2[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][CH2:25]4)[N:15]=3)=[CH:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[C:53]([Cl:55])[CH:54]=1)(=[O:48])=[O:47])=[O:58])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(-c4cccc(F)c4)ncc3O)n2)CC1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(-c4cccc(F)c4)ncc3Oc3cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c4cscn4)cc3Cl)n2)CC1
Yield: 53.6 %

Procedure:
10.0 mg (1.0 eq) of the obtained tert-butyl 4-(4-(2-(3-fluorophenyl)-5-hydroxypyridin-4-yl)pyrimidin-2-yl)piperazin-1-carboxylate and 9.1 mg (1.0 eq) of the obtained tert-butyl((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate were dissolved in 0.2 mL of N,N-dimethylformamide 0.2 mL, then 21.6 mg (3.0 eq) of Cs2CO3 was added thereto. The mixture was reacted at room temperature for 16 hours. The solvent was removed by concentrating under reduced pressure. The residue was separated by PLC (developing solvent, hexane:ethyl acetate=2:1) to obtain 10 mg of tert-butyl 4-(4-(5-(4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-2-(3-fluorophenyl)pyridin-4-yl)pyrimidin-2-yl)piperazin-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:31])[N:15]([CH2:17][C:18]4[C:19]([C:28](Cl)=[O:29])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:4][CH:3]=1.CN.C[CH2:41][N:42](CC)CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:31])[N:15]([CH2:17][C:18]4[C:19]([C:28]([NH:42][CH3:41])=[O:29])=[N:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-6-(trifluoromethyl)picolinoyl chloride (36 mg, 0.066 mmol) in anhydrous THF (1 mL) at 0° C. was added 2 M methylamine solution in THF (0.33 mL, 0.66 mmol), followed by Et3N (0.046 mL, 0.33 mmol). The resulting mixture was stirred at 0° C. for 30 min, then at room temperature for 16 h. Analysis by HPLC/MS indicated the starting acid chloride had been consumed and the desired product had formed. The reaction mixture was diluted with water and extracted with EtOAc (15 mL×2). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 100% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 12 mg (34%) of the title compound as a pale yellow powder. HPLC/MS: retention time=2.83 min, [M+H]+=539.2.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[CH:29]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:30]=1.C(O)C>O1CCCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:29][CH3:30])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc(CN(Cc2ccc(F)cc2F)c2cccc([N+](=O)[O-])c2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 33A(39 mg, 0.1 mmole) and di-t-butylazo dicarboxylate (35 mg, 0.15 mmole) in tetrahydrofuran (1.5 ml) were added to PPh3 on resin (70 mg, 0.3 mmole: loading 3 mmole/g) followed by ethanol (5.7 mg, 0.125 mmole) in 50 microliter tetrahydrofuran. Reaction mixture was shaken at room temperature overnight. Filtered off and solvent removed. Solaris 530 organic synthesis system from PE Biosystems was used to do this reaction. The residue purified by HPLC (CH3CN:0.1 TFA in H2O) on a YMC ODS guardpak column.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+](C1C=CC([O:24][C:25]([N:27]2[C:36]3[C:31](=[CH:32][C:33]([C:37]([F:40])([F:39])[F:38])=[CH:34][CH:35]=3)[C@@H:30]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([N:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[CH:44][N:43]=3)[CH2:29][C@H:28]2[CH2:54][CH3:55])=O)=CC=1)([O-])=O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:7]([CH3:11])([CH3:10])[CH2:8][O:9][C:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([C:37]([F:40])([F:38])[F:39])=[CH:34][CH:35]=2)[C@@H:30]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:44][N:43]=2)[CH2:29][C@H:28]1[CH2:54][CH3:55])=[O:24])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)CO
Reactant: CC[C@@H]1C[C@H](Nc2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](Nc2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(C)(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
3-Hydroxy-2,2-dimethyl-propionic acid tert-butyl ester (137 mg) and sodium hydride (60%; 32 mg) were added to a solution of the compound obtained in Example 9 (1) (300 mg) dissolved in tetrahydrofuran (5 ml) and stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aq. solution and ethyl acetate were added and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=7:3→2:3) to give the titled compound (227 mg). MS (m/z):607 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([Br:12])=[CH:10][CH:11]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[Br:12][C:9]1[N:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:13])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C=Cc1ccc(Br)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C=Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
750 mg (3.1 mmol) of 3-(6-bromo-pyridin-3-yl)-acrylic acid methyl ester was dissolved in 30 ml of dioxane and 4.65 ml of a 2 N aqueous sodium hydroxide solution was added. The reaction mixture was stirred at room temperature for 2 h. The reaction solution was poured into water and acidified with concentrated hydrochloric acid, whereupon the product precipitated. The product was isolated by filtration and dried under reduced pressure. Yield: 673 mg.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1Cl>CN(C=O)C.O>[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[O:15][CH:13]1[CH2:12][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:14]1
Reactant: OC1CN(c2ccc3ccccc3n2)C1
Reactant: Clc1ccncc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnccc1OC1CN(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-ol (see PREPARATION P1.2, step 1; 320 mg, 1.60 mmol) in DMF (10 mL) was added Cs2CO3 (1.04 g, 3.2 mmol) and 3-bromo-4-chloropyridine (307 mg, 1.60 mmol). The mixture was stirred at 90° C. overnight and then diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in petroleum ether) to give the title product (350 mg, 0.98 mmol, 61% yield) as white solid. ESI-MS (M+1): 356 calc. for C17H14BrN3O 355.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)[O:16][CH:17]=1.Br[CH:30]([CH3:32])[CH3:31]>>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:30]([CH3:32])[CH3:31])[CH:19]=2)[O:16][CH:17]=1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OC(F)F)co2)cc1O
Reactant: CC(C)Br
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3OC(F)F)co2)cc1OC(C)C

Procedure:
Using the compound obtained in Example 270 and 2-bromopropane, white powdery 1-(2-difluoromethoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([CH3:27])[CH3:26]>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1
Reactant: CC(C)Br
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)-phenyl]-piperidine (0.02 g, 0.078 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 2-bromopropane (0.008 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 299 (M+, 3), 285 (15), 284 (bp), 205 (6) 133 (4).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[C:19]([CH3:31])[CH:18]=1)=[N:9][CH:10]=[N:11]2.[C:32]([OH:36])(=O)[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[OH:34][CH2:33][C:32]([N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[C:19]([CH3:31])[CH:18]=1)=[N:9][CH:10]=[N:11]2)=[O:36]
Reactant: O=C(O)CO
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(OCCN(C)C(=O)CO)c34)cc2C)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
5-[2-(Methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (32 mg, 0.077 mmol) and glycolic acid (6 mg, 0.085 mmol) were dissolved in DMA (10 ml). HATU (32 mg, 0.085 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated in vacuo, and the residue purified by reverse-phase HPLC, eluting with 5 to 50% acetonitrile in H2O containing 0.2% TFA. The appropriate fraction was evaporated, and the residue dissolved in methanol/DCM (1:1, 25 ml). The mixture was neutralised by stirring overnight with tetraalkylammonium carbonate, polymer bound. The mixture was filtered, and the filtrate was evaporated. Crystallisation from ethyl acetate/iso-hexane gave 2-hydroxy-N-methyl-N-(2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamide as a white crystalline solid (22 mg, 60%); NMR Spectrum (DMSO-d6, 400 MHz, 373K) 2.26 (s, 3H), 2.48 (s, 3H), 3.02 (s, 3H), 3.95 (t, 2H), 4.02-4.11 (m-3H), 4.55 (t, 2H), 6.96 (d, 1H), 7.20 (d, 1H), 7.23 (m, 2H), 7.38 (d, 1H), 7.65 (dd, 1H), 7.70 (d, 1H), 7.73 (dd, 1H), 8.20 (m, 1H), 8.49 (s, 1H), 9.77 (s, 1H); Mass spectrum MH+ 473.9
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][C:29]([CH3:34])=[CH:28]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:35][CH3:36])[CH2:7][CH2:6]1)=[O:4].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.[I-].[K+]>CN(C=O)C>[CH3:36][O:35][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:10][CH2:9]1)[N:21]=[CH:20][N:19]=[C:18]2[O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH3:34])=[CH:28]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCN(C(=O)CCl)CC1
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCN(C(=O)CN2CCCC2)CC1
Temperature: 80 °C

Procedure:
A mixture of 7-{2-[4-(chloroacetyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline (0.130 g), pyrrolidine (0.04 ml), potassium iodide (0.01 g) and DMF (3.5 ml) was stirred and heated to 80° C. for 1 hour. The mixture was cooled to ambient temperature, the solvent evaporated under vacuum and the residue was purified by column chromatography on silica using increasingly polar solvent mixtures, starting with dichloromethane and ending with dichloromethane/methanol saturated with ammonia (3.5M) (95/5). Evaporation of the solvents gave a foam, which was triturated under ether to give 6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-{2-[4-(pyrrolidin-1-ylacetyl)piperazin-1-yl]ethoxy}quinazoline (0.09 g) as a pale yellow solid which was collected by filtration and dried under vacuum.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C([Li])CCC.CN([CH:22]=[O:23])C.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[C:7]([CH:22]=[O:23])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCOc2c(I)cccc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCOc2c(C=O)cccc21
Reaction time: 0.5 h

Procedure:
14.40 g (50.0 mmol) of 4,4-dimethyl-8-iodochroman and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 22 ml (55.0 mmol) of n-butyllithium (2.5M in hexane) are added dropwise at -78° C., the reaction mixture is stirred for 30 minutes, then 4.2 ml (55.0 mmol) of DMF are added and the mixture is allowed to return to room temperature. The reaction mixture is poured onto an aqueous ammonium chloride solution and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. 10.40 g (100%) of the expected compound are collected in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[CH2:7][Br:18])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C(C)Oc1ccc(OC)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)Oc1ccc(OC)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A solution of 3-(4-methoxy-phenoxy)-but-2-enoic acid ethyl ester (0.98 g, 4.17 mmol) in carbon tetrachloride (23.2 mL) was treated with N-bromosuccinimide (0.81 g, 4.59 mmol) and benzoyl peroxide (81 mg, 0.33 mmol). The reaction was then heated to reflux for 5 h. At this time, the reaction was cooled to 25° C. and then was placed in the freezer over the weekend. At this time, the reaction was removed from the freezer and allowed to thaw. The resulting precipitate was removed by filtration and was rinsed with carbon tetrachloride (5 mL). The filtrate was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-4% ethyl acetate/hexanes) afforded impure 4-bromo-3-(4-methoxy-phenoxy)-but-2-enoic acid ethyl ester (1.03 g, 78%) as a pale, yellow oil. The material was used without further purification.
Reaction SMILES: COC([C:5]1([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)=O.CO.[OH-].[K+]>O.Cl>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(c2ncnc3cc(OC)c(OC)cc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Temperature: 100 °C
Yield: 66.7 %

Procedure:
A mixture of crude 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (33 g), as prepared in the previous step, MeOH (100 mL), and KOH pellets (26 g, 400 mmol assuming 87% w/w water) was stirred at reflux (100° C. oil bath) for 1 h, at which point the translucent reddish-amber solution was allowed to cool to rt and diluted with water (100 mL) and 6 M HCl (100 mL). The solution was stirred at 100° C. for 10 min (Caution: Initial vigorous bubbling), allowed to cool to rt, diluted with 2.5 M NaOH (90 mL) and extracted with DCM (1×150 mL; 1×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to afford the title compound as a beige powder (13.95g, 76% from 4-chloro-6,7-dimethoxyquinazoline). 1H-NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 3.98 (s, 3H), 3.96 (s, 3H)m 3.69 (m, 1H), 3.05 (m, 2H), 2.84-2.71 (m, 2H), 1.88-1.65 (m, 4H). LC/MS (ESI): calcd mass 273.2, found 274.2 (MH)+.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]1([CH2:18][NH2:19])[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH2:17])[CH:11]=1>C(O)(C)C.[Ni]>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:18][NH:19][CH2:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH:11]=1
Reactant: NCc1cccc(CN)c1
Reactant: O=Cc1ccccc1O
Agent: [Ni]
Solvent: CC(C)O
Product: Oc1ccccc1CNCc1cccc(CNCc2ccccc2O)c1
Yield: 3.2 %

Procedure:
34.4 g of a bisazomethine prepared from 2 mols of salicylaldehyde and 1 mol of m-xylylenediamine and having a melting point of 61°-63° C. are hydrogenated for 7 hours in 170 ml of isopropanol in an autoclave in the presence of 4 g of Raney nickel at 85° C. and under a pressure of 60 atmospheres. The catalyst is filtered off and the filtrate is concentrated in a rotary evaporator to give 35.8 g of crude product. 25.7 g are recrystallised from 77 ml of isopropanol and the bulk of the product separates out on cooling in a refrigerator. The precipitate is collected by filtration, washed off with cold isopropanol and dried in vacuo at 40° C., affording 11.0 g (41.8% of theory) of N,N'-bis-(2-hydroxybenzyl)-m-xylylenediamine with a melting point of 67°-68° C.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[C:21]#[N:22].[Na].[CH3:24][CH:25]([OH:30])[CH2:26][C:27]#[C:28][CH3:29]>>[CH3:24][CH:25]([O:30][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[C:21]#[N:22])[CH2:26][C:27]#[C:28][CH3:29]
Reactant: CC#CCC(C)O
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)F)[nH]c2c1Cl
Agent: [Na]
Product: CC#CCC(C)Oc1c(C#N)cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-5-cyano-2-pentafluoroethylbenzimidazole is reacted with the sodium derivative of 4-hexyn-2-ol to obtain 4-(1-methyl-3-pentyn-1-yloxy)-7-nitro-5-cyano-2-pentafluoroethylbenzimidazole, m.w., 402.3.