Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.Br[C:32]1[N:33]=[C:34]2[CH:40]=[C:39]([C:41]3[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=3)[N:38]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:35]2=[N:36][CH:37]=1.[NH:55]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[NH2:56].CC([O-])(C)C.[Na+]>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].O1CCOCC1>[CH3:46][N:44]1[CH:45]=[C:41]([C:39]2[N:38]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:35]3=[N:36][CH:37]=[C:32]([NH:56][NH:55][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[N:33]=[C:34]3[CH:40]=2)[CH:42]=[N:43]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cn1cc(-c2cc3nc(Br)cnc3n2COCC[Si](C)(C)C)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nc(NNC(=O)OC(C)(C)C)cnc3n2COCC[Si](C)(C)C)cn1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
To a flask was added Pd2 dba3 (0.309 g, 0.338 mmol), tert-Butyl X-Phos (0.287 g, 0.676 mmol) and 1,4-dioxane (25 mL). The mixture was heated to about 80° C. for about 10 min and then 2-bromo-6-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (1.38 g, 3.38 mmol, prepared using B from Preparation #A.1 and C), tert-butyl hydrazinecarboxylate (0.670 g, 5.07 mmol) and NaOt-Bu (0.487 g, 5.07 mmol) were then added and mixture was heated at about 80° C. for about 1 h. The mixture was cooled, filtered through Celite® and the filter pad was rinsed with EtOAc. The filtrate was concentrated in vacuo then purified by flash chromatography (40 g silica column eluting with 0 to 100% EtOAc/DCM to provide tert-butyl 2-(6-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (0.510 g, 33%): LC/MS (Table 2, Method c) Rt=1.59 min; MS m/z 460 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-])=O)=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[H][H]>O1CCCC1.[Pd]>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(C2=CCOCC2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C2=CCOCC2)cn1
Yield: 92.8 %

Procedure:
174 mg of 5-(3,6-dihydro-2H-pyran-4-yl)-2-nitropyridine are hydrogenated using 100 mg of 5% Pd/C and hydrogen in 10 ml of tetrahydrofuran. The mixture is filtered off and evaporated in a rotary evaporator, giving 138 mg of 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-ylamine crude product, which is reacted further above purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=O)=O.[NH2:31][CH2:32][CH:33]([C:35]1[CH:36]=[CH:37][C:38]([OH:44])=[C:39]([NH:41][CH:42]=[O:43])[CH:40]=1)[OH:34].O.C(OCC)(=O)C>CN(C)C=O>[CH:42]([NH:41][C:39]1[CH:40]=[C:35]([CH:33]([OH:34])[CH2:32][NH:31][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH:36]=[CH:37][C:38]=1[OH:44])=[O:43]
Reactant: NCC(O)c1ccc(O)c(NC=O)c1
Reactant: CS(=O)(=O)OCCOc1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=CNc1cc(C(O)CNCCOc2ccc(-c3ccc(C(=O)OCc4ccccc4)cc3)cc2)ccc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
A mixture of benzyl 4′-(2-methanesulfonyloxyethoxy)-biphenyl-4-carboxylate (0.117 g) and N-[5-(2-amino-1-hydroxyethyl)-2-hydroxyphenyl]formamide (0.054 g) in N,N-dimethylformamide (2 mL) was stirred at 80° C. overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=20/1-10/1) to afford benzyl 4′-{2-[2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]ethoxy}biphenyl-4-carboxylate (0.016 g).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([C@H:6](/[CH:20]=[CH:21]/[CH3:22])[C@@H:7]([C:16]([O:18]C)=[O:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:24]=[CH:23][C:5]([C@H:6](/[CH:20]=[CH:21]/[CH3:22])[C@@H:7]([C:16]([OH:18])=[O:17])[NH:8][C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: C/C=C/[C@@H](c1ccc(Br)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C/C=C/[C@@H](c1ccc(Br)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 25 g (62.8 mmol) of methyl (βS)-4-bromo-N-(tert-butoxycarbonyl)-β-[(1E)-prop-1-enyl]-L-phenylalaninate (Step D) in 600 mL of tetrahydrofuran (THF) was added in succession 200 mL of methanol and 200 mL (200 mmol) of 1N aqueous sodium hydroxide solution. The reaction mixture was stirred at ambient temperature for 3 h, and then the methanol and THF were removed under reduced pressure. To the aqueous mixture was added 250 mL of 1N hydrochloric acid and the mixture was extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with brine (300 mL) then dried over sodium sulfate, filtered, and concentrated in vacuo to afford the carboxylic acid, which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1>>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: ClCc1cccs1
Product: O=C1CCN(Cc2cccs2)CC1

Procedure:
1-(2-Thiopheneyl)methyl-4-piperidone is prepared from 4-piperidone and 2-(chloromethyl)thiophene essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[NH:19]1[CH2:23][CH2:22][CH2:21][C@@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:24][C@H:20]2[CH2:21][CH2:22][CH2:23][N:19]2[C:13]([C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)=[O:15])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: C1CN[C@@H](CN2CCCC2)C1
Product: CC1(C)OB(c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)OC1(C)C

Procedure:
[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl][4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone was prepared as described in Example 14 from 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid and (R)-(−)-1-(2-pyrrolidinylmethyl)pyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:34])[F:35])[CH:28]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 75.5 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted with 3-trifluoromethyl phenol (20 mg, 0.12 mmol) to give the title compound (42 mg, 82%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].[Cl-].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1cc2nc(-c3ccc(O)cc3)cn2cc1Br
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 96 h
Yield: 81.6 %

Procedure:
462 mg (corresponding to 1.52 mmol) of 6-bromo-2-(4′-hydroxyphenyl)-7-methylimidazo[1,2-a]pyridine was dissolved in 10 mL of dimethylformamide, and 630 mg (corresponding to 4.56 mmol) of potassium carbonate was added thereto. Then, 400 mg (corresponding to 1.67 mmol) of 1-bromo-2-(t-butyldimethylsiloxy)ethane was added thereto. After the reaction mixture was stirred at room temperature for 4 days, a saturated aqueous sodium chloride solution was added, and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate) to obtain 571 mg (corresponding to 1.24 mmol) of 6-bromo-2-[4′-(2″-t-butyldimethylsiloxyethoxy)phenyl]-7-methylimidazo[1,2-a]pyridine (FIG. 9, Step 4).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([N:13]3C(=O)C4=CC=CC=C4C3=O)[CH2:8]2)[CH:2]=1>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([NH2:13])[CH2:8]2)[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](c2cccnc2)C1
Solvent: CCO
Product: N[C@H]1CCC[C@H](c2cccnc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.6 %

Procedure:
A mixture of trans-N-[3-(3-pyridyl)cyclohexyl]phthalimide (3.00 g, 9.79 mmol) and hydrazinemonohydorate (0.95 mL, 19.6 mmol) in EtOH (40 mL) was stirred at room temperature for 1.5 h. The reaction mixture was filtered followed by the removal of solvent. The crude product was purified by column chromatography (NH, EtOAc) to yield trans-3-(3-pyridyl)cyclohexylamine (1.08 g, 60%) as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Product: O=C(NC1CCC(Nc2ccccc2)CC1)OCc1ccccc1

Procedure:
N-benzyloxycarbonyl-4-aminocyclohexanone and aniline were treated in the same manner as described in Reference example 51 to give N-benzyloxycarbonyl-N'-phenyl-1,4-diaminocyclohexane.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[O:17][CH3:18].[H-].[Na+].[C:21]([C:23]1[CH:34]=[CH:33][C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31]Cl)=[CH:25][CH:24]=1)#[N:22]>CN(C)C=O>[C:21]([C:23]1[CH:34]=[CH:33][C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]2[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH:9]([CH3:11])[CH3:10])[CH:12]([CH3:13])[CH3:14])=[O:7])=[CH:4][C:3]=2[O:17][CH3:18])=[CH:25][CH:24]=1)#[N:22]
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1O
Reactant: N#Cc1ccc(OCCCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCOc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 4-hydroxy-3-methoxy-N,N-bis(1-methylethyl)benzamide (1.0 g, 4.0 mmol) in 50 mL of N,N-dimethylformamide is treated with 60% sodium hydride (160 mg, 4.0 mmol). After stirring at 0° C. for 10 minutes, the reaction is treated with 4-(4-cyanophenoxy)butyl chloride (835 mg, 4.0 mmol) and stirred at 60° C. for 4 days. The reaction is partitioned between diethyl ether and water. The organic layer is washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting material is purified by chromatography on silica gel (30 g) with 60 % ethyl acetate/hexane as the eluent to afford 4-[4-(4-cyanophenoxy)butoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[CH2:17]([O:24][CH2:25][C:26](Cl)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:26](=[O:27])[CH2:25][O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of 4-amino-benzoic acid methyl ester 11 (10 grams, 66.15 mmol) and sodium bicarbonate (11 grams, 131.67 mmol) in ethyl acetate (150 mL) at 0° C. is added benzyloxy acetyl chloride (16.6 grams, 89.93 mmol) drop wise. The reaction mixture is stirred at room temperature for 10 hours. The solids are filtered off. The ethyl acetate layer is washed with 5% sodium bicarbonate solution (2×25 mL), water (2×25 mL), dried over sodium sulfate, and distilled to get crude 12, which can be purified in a suitable solvent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:36]=[CH:35][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH:33]=O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[N:37]1([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(O)(=O)C.C([BH3-])#N.[Na+].C1COCC1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][N:40]4[CH2:41][CH2:42][N:37]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:38][CH2:39]4)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:35][CH:36]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCC=O)c[nH]4)c3)cc2)c1
Reactant: CCOC(=O)CN1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(CCNC(=O)c2c[nH]c(-c3cc(Oc4ccc(NC(=O)Nc5cc(C)ccc5F)cc4)ccn3)c2)CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-oxoethyl)-1H-pyrrole-3-carboxamide (200 mg, 0.41 mmol) and ethyl piperazinoacetate (141 mg, 0.82 mmol) in anhydrous DMF (10 ml) was added acetic acid (10 mg, 0.17 mmol). The mixture was stirred under nitrogen for 30 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.8 ml, 0.8 mmol). The reaction mixture was stirred for another hour, and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water, and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 8˜12% methanol/chloroform solution to give ethyl [4-(2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)piperazin-1-yl]acetate as white solid. Yield: 90 mg, 34%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([CH2:18]O)=[C:16]3[C:11]([NH:12][C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[NH:15]3)=[CH:10][CH:9]=2)=[C:4]([O:23][CH3:24])[CH:3]=1.C(N(CC)CC)C.CS([Cl:36])(=O)=O.C(OCC)(=O)C>ClCCl.O1CCCC1.O>[Cl:36][CH2:18][C:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:23][CH3:24])=[CH:9][CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=[O:20])[C:13]([CH3:22])([CH3:21])[NH:12]2
Reactant: COc1cc(F)ccc1-c1ccc2c(c1CO)NC(=O)C(C)(C)N2
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1ccc2c(c1CCl)NC(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
7-(4-Fluoro-2-methoxyphenyl)-8-hydroxymethyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 3-2, 70.0 mg, 0.21 mmol) was dissolved in the mixed solvent of anhydrous dichloromethane (1 mL) and anhydrous tetrahydrofuran (1.5 mL), and triethylamine (35 μL, 0.25 mmol) and methanesulfonyl chloride (18 μL, 0.23 mmol) were added thereto successively. The reaction mixture was stirred at room temperature overnight. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction mixture and partitioned. The organic layer was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (49.5 mg) as a pale yellow solid. (Yield 68%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:31][CH2:32][CH2:33][CH2:34]Cl)=[CH:24][C:25]=2[O:27][CH:28]([CH3:30])[CH3:29])[N:20]=[CH:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][C:57]1=[O:62].[I-].[Na+]>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:31][CH2:32][CH2:33][CH2:34][N:59]3[CH2:60][CH2:61][N:56]([CH3:55])[C:57](=[O:62])[CH2:58]3)=[CH:24][C:25]=2[O:27][CH:28]([CH3:29])[CH3:30])[N:20]=[CH:19][N:18]=1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)cc(OC(C)C)c23)c2c1OCO2
Reactant: CN1CCNCC1=O
Agent: [I-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCO
Solvent: ClCCl
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)C(=O)C4)cc(OC(C)C)c23)c2c1OCO2
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-5-isopropoxyquinazolin-4-amine (0.320 g, as a 1:1.3 wt.:wt. mixture with triphenylphosphine) and 1-methylpiperazin-2-one (0.280 g) was dissolved in 2-methoxyethanol (7 ml), then sodium iodide (0.040 g) was added and the reaction mixture was then heated at 110° C. with stirring for 24 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (70 ml) and washed with water:brine (1:1) then water then brine and dried over magnesium sulfate before filtration and evaporation of solvents under reduced pressure. The residues so resulting were then purified by column chromatography on silica using increasingly polar mixtures of methanol in dichloromethane as eluent. There was thus obtained 4-(3-{4-[5-chloro-7-(3-methoxy-prop-1-ynyl)-benzo[1,3]dioxol-4-ylamino]-5-isopropoxy-quinazolin-7-yloxy}-propoxy)-1-methyl-piperazin-2-one (0.086 g) as a white foam; NMR Spectrum: (CDCl3) 1.53 (d, 6H), 2.02 (quin, 2H), 2.61 (t, 2H), 2.72 (t, 2H), 2.96 (s, 3H), 3.18 (s, 2H), 3.33 (t, 2H), 3.45 (s, 3H), 4.15 (t, 2H), 4.35 (s, 2H), 4.83 (sept, 1H), 6.10 (s, 2H), 6.49 (d, 1H), 6.82 (d, 1H), 7.05 (s, 1H), 8.51 (s, 1H), 9.41 (s, 1H); Mass Spectrum: M+H+ 596/598.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]=[N+]=[N-])[CH2:10][C@@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@@H]1CO
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](N)C[C@@H]1CO
Yield: 98.4 %

Procedure:
Hydrogenate a mixture of (2R,4R)-4-azido-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (225 g, 0.93 mol) and 10% palladium on carbon (22.5 g, pre-wetted with toluene) in methanol (2.3 L) at 15 psi of hydrogen at room temperature for 16 h. Filter off the catalyst and concentrate the filtrate to obtain the title compound as an oil (198 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 1.38 (s, 9H), 1.58 (m, 1H), 2.16 (m, 1H), 2.95 (m, 1H), 3.20-3.58 (m, 6H), 3.61 (m, 1H), 3.65 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[CH:17][C:18]2[O:22][CH2:21][CH2:20][C:19]=2[CH:23]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[O:22]1[C:18]2[CH:17]=[CH:16][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:23][C:19]=2[CH2:20][CH2:21]1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Brc1ccc2c(c1)CCO2
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)CCO3)C1=O
Yield: 80.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84 mmol) was reacted with 5-bromo-2,3-dihydro-benzofuran (167 mg, 0.84 mmol), 1,4-dioxane (10 mL), copper iodide (16 mg, 0.084 mmol), trans-1,2-diamino cyclohexane (28.8 mg, 0.25 mmol) and potassium phosphate (445 mg, 2.1 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 200 mg of the product (80.9% yield).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]1[CH:11]2[CH2:12][CH2:13][CH2:14][CH:10]2[CH2:9][N:8]1[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.[OH-:28].[K+]>C(O)C.O>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:9]1[CH:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:7][N:8]1[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:28])=[CH:22][CH:21]=1
Reactant: N#Cc1ccc(NCCCCN2CC3CCCC3C2)cc1
Reactant: [OH-]
Agent: O=C(O)C(=O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(NCCCCN2CC3CCCC3C2)cc1

Procedure:
436 mg of the compound of Example 18 are dissolved in 4 ml of ethanol. 86 mg of potassium hydroxide (1 eq.) are dissolved in 1.5 ml of water before being added to the alcohol solution. The mixture is heated at reflux for 1.5 hours and then evaporated to dryness. The residue is taken up in dichloromethane. The resulting solution is washed with water, dried over magnesium sulphate and then concentrated in vacuo. The product is crystallised in oxalate form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41]O)[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:41][CH:38]2[CH2:39][CH2:40][N:35]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:36][CH2:37]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
4-Fluorophenol (0.52 g, 4.64 mmol) and triphenylphosphine (1.22 g, 4.64 mmol) were added to a solution of N-boc-piperidine-4-methanol (500 mg, 2.32 mmol) in anhydrous THF (12 mL) under nitrogen. The reaction mixture was cooled to 0° C. and DEAD (670 μL, 3.69 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure then diluted with dichloromethane and filtered. The filtrate was washed three times with NaOH 0.2N, dried over Na2SO4 and concentrated. The residue was purified on column chromatography (eluent: pentane/EtOAc 95/5) to give the title compound (538 mg, 75%) as a yellow oil.