Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].CO.[S:5]1[CH:9]=[CH:8][C:7]2[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=[C:26]([C:34]([O:36]CC)=[O:35])[CH:25]=4)[CH2:16][CH2:15]3)=[CH:11][CH:12]=[CH:13][C:6]1=2.[ClH:39]>O>[ClH:39].[S:5]1[CH:9]=[CH:8][C:7]2[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=[C:26]([C:34]([OH:36])=[O:35])[CH:25]=4)[CH2:16][CH2:15]3)=[CH:11][CH:12]=[CH:13][C:6]1=2
Reactant: CCOC(=O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)c2ccccc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
An aqueous solution of 4N lithium hydroxide (3 ml) was added to a methanol solution (7 ml) of ethyl 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-quinolin-2-carboxylate (1.5 g), followed by stirring at room temperature overnight. Then, water (10 ml) and aqueous solution (3 ml) of 4N lithium hydroxide were further added, followed by stirring at 50° C. for 11 hours. The reaction mixture was cooled in an ice-bath, and an aqueous solution (4 ml) of 6N-HCl was added thereto. Then, crystals precipitated were filtered out, washed with water and dried to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolin-2-carboxylic acid hydrochloride (1.43 g, yield: 98%) as white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[CH2:16](Cl)[O:17][CH3:18].CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[O:10][CH2:16][O:17][CH3:18])[CH:5]=[O:6]
Reactant: COCCl
Reactant: CCOc1cc(C=O)cc(Br)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(C=O)cc(Br)c1OCOC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
A solution of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (1.0 g, 4.1 mmol) in DMF (10 mL) was cooled at 0° C., NaH (180 mg, 4.5 mmol) was added, and the mixture was stirred for 15 minutes. MOM-Cl (360 mg, 4.5 mmol) was added, and the mixture was warmed to room temperature in two hours. TLC (PE:EtOAc=5:1) indicated that the starting material was consumed. Ice water was added to quench the reaction, and aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography to give 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (0.7 g, yield: 59.3%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1nc(-c2ccccc2)c(CCO)c2ncnn12
Product: CC(C)(C)C(=O)OCCc1c(-c2ccccc2)nc(N)n2ncnc12

Procedure:
The title compound, m.p. 160°, was prepared by the method of Example 2 using 2.5 g (0.01 mole) of the product compound of Example 1 and 1.3 g (0.01 mole) of trimethylacetyl chloride, except that the reaction mixture was poured into 150 ml of water, giving a solid precipitate. Recrystallization from ethyl acetate/diethyl ether, rather than chromatography, afforded the title product.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=1.[Li+].[OH-:18]>>[OH:18][C:7]1[CH:2]=[C:3]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: O=C(O)Cc1csc(-c2ccccc2O)n1
Agent: [Li+]
Product: O=C(O)Cc1csc(-c2cccc(O)c2)n1
Yield: 99 %

Procedure:
The procedure used for the preparation of 5a was repeated with 4d (1.84 g, 7.00 mmol) and 2N LiOH (14.0 mL) to provide 5d (1.63 g, 99%) as a white solid, which was recrystallized from EtOAc/toluene. mp 172.0°-174.0° C.; IR (KBr) 3500-2400 (br), 3336 (br), 1689, 1442, 1276, 1231 cm-1 1H NMR (DMSO-d6) δ3.72 (2H, s, CH2), 6.81 (1H, d, J=7.4 Hz, Ar), 7.19-7.30 (3H m, Ar), 7.43 (1H, s), 9.67 (1H), br, s, OH), 12.40 (1H, br, s, CO2H); FDMS m/z 236 M+ +1); Anal. Calcd for C11H9NO3S: C, 56.14; H, 3.86; N, 5.95. Found: C, 56.11; H, 3.73; N, 5.80.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].FC(F)(F)C(O)=O.C([BH3-])#N.[Na+].O>CO>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1cc(/C=N/OCCO)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(NOCCO)c1cc(CNOCCO)c(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
To a solution of (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyimino)-methyl]-benzamide (3.62 g, 6.70 mmol) obtained in Step B in methanol (100 ml) were added portionwise trifluoroacetic acid (6.5 ml) and sodium cyanoborohydride (3.78 g, 60.2 mmol) over 2 days while monitoring the progression of the reaction by TLC. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH (15:1)), and the resultant crude compound was crystallized from methylene chloride to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamino)-methyl]-benzamide (1.66 g, 46%, as a total of first and second crystals).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[NH:13]([CH2:20][CH2:21][C:22]#[N:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>CS(C)=O.CO.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:21](=[CH:20][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:22]#[N:23]
Reactant: N#CCCNc1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: N#CC(=CNc1ccccc1)Cc1ccc2ccccc2c1

Procedure:
To a mixture of 2-naphthaldehyde (4.69 g, 30 mmol) and beta-anilinopropionitrile (4.82 g, 33 mmol) in dimethyl sulfoxide (35 ml) was added potassium t-butoxide (3.70 g, 33 mmol). The solution immediately turned a dark red. It was heated at 100° for 30 minutes, cooled, and diluted with methanol (15 ml) and water (25 ml). A copious yellow precipitate formed, which was chilled and isolated. The precipitate, 2-(2-naphthylmethyl)-3-anilinoacrylonitrile, was washed with dilute methanol and hexane; yield, 7.65 g. A portion was recrystallized from absolute ethanol; m.p. 148°-153° C. Anal. Calcd. for C20H16H2 : C, 84.48; H, 5.67; N, 9.85. Found: 84.38; H, 5.69; N, 9.82.
Reaction SMILES: [Mg].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](O)=[C:14](Br)[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH2:28][CH3:29])=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)=[CH:13][CH:14]=2)([OH:30])[CH2:28][CH3:29])=[CH:25][CH:26]=1
Reactant: Oc1ccc(OCCCN2CCCCC2)cc1Br
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(Cl)cc1)c1ccc(OCCCN2CCCCC2)cc1

Procedure:
To a Grignard reactant prepared from 1.82 g. of magnesium turnings and 22.3 g. of 4-[3-(piperidin-1-yl)-propoxy]-bromophenol in 100 ml. of dry tetrahydrofuran a solution of 8.4 g. of p-chloropropiophenone in 30 ml. of tetrahydrofuran is added dropwise, under slight reflux. The reaction mixture is slightly boiled for an additional hour, whereupon it is cooled and decomposed with a saturated aqueous ammonium chloride solution. The aqueous phase is extracted with tetrahydrofuran, the tetrahydrofuran phase is washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. Crystallization of the residue from a mixture of n-hexane and ethyl acetate yields 12.2 g. of the named compound, melting at 104° to 105° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][CH2:14][CH2:15][C:16]1[CH:20]=[CH:19][NH:18][N:17]=1.O>O1CCOCC1.C(OCC)(=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][CH2:14][CH2:15][C:16]1[CH:20]=[CH:19][NH:18][N:17]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCc1cc[nH]n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccccc1C(=O)NCCc1cc[nH]n1
Temperature: 25 °C

Procedure:
A slurry containing 17.7 g (O.109 mol) of isatoic anhydride in 80 ml of dioxane was slowly added to a cold (0° C.) solution of 12.1 g (O.109 mol) of 3-(2-aminoethyl)pyrazole in 150 ml of dioxane, under nitrogen. The reaction solution was gradually warmed to room temperature and allowed to react overnight. When the reaction was complete, as indicated by thin layer chromatography, water was added and the solution was reduced to dryness under reduced pressure. The resultant residue was dissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated and the organic layer was washed with water and reduced to dryness to provide an oil. This oil was purified by crystallization from dichloromethane, followed by recrystallization from an ethyl acetate/diethyl ether solution, to provide 12.8 g of the desired subtitled intermediate (m.p. 97°-99° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.C(=O)([O-])[O-].[K+].[K+].[C:36]([O:39][CH2:40][CH3:41])(=[O:38])[CH3:37]>C(O)C>[CH2:40]([O:39][C:36](=[O:38])[CH:37]=[CH:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C:12]([N:14]1[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:16][C@H:15]1[CH3:29])=[O:13])[CH3:41]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=O
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C=Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (0.50 g, 1.19 mmol) in ethanol (10 mL) at 0° C. was added potassium carbonate (0.4 mL, 2.4 mmol, 6 M solution in water) and triethyl phosphonoacetate (0.47 mL, 2.4 mmol). The reaction was stirred at 0° C. for 2 hours, then at ambient temperature 12 hours. The reaction was diluted with ethyl acetate and filtered through a pad of celite. The filtrate was then washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give the title compound (0.51 g)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[N:2]1.[NH:9]1[CH:13]=[C:12]([CH2:14][CH2:15][OH:16])[CH:11]=[N:10]1.C(N(CC)CC)C.[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.O>[C:25]1([C:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:1]2[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[N:2]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1.[C:25]1([C:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:9]2[CH:13]=[C:12]([CH2:14][CH2:15][OH:16])[CH:11]=[N:10]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OCCc1cn[nH]c1
Reactant: OCCc1cc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: OCCc1ccn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: OCCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 1 h

Procedure:
A mixture of 2-(3-pyrazolyl)ethanol and 2-(4-pyrazolyl)ethanol (2.4:1) (2.50 g) was dissolved in DMF (30 ml). To the solution were added, while stirring, triethylamine (2.26 g) and trityl chloride (6.22 g). The mixture was stirred at 25° C. for one hour, then at 40° C. for one hour. The reaction mixture was diluted with water, which was subjected to extraction with ethyl acetate. The organic layer was washed with an aqueous saline solution, which was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was purified by means of a column chromatography (carrier: silica gel, 300 g, developing solvent: ethyl acetate-hexane, 1:1) to afford 2-(1-triphenylmethyl-3-pyrazolyl)ethanol (3.75 g) and 2-(1-triphenylmethyl-4-pyrazolyl)ethanol (1.42 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32]C)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17][N:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([OH:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17][N:16]=1
Reactant: COC(=O)Cc1cccc(OCc2ccnc(OCc3nc(-c4ccccc4)oc3C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2cccc(CC(=O)O)c2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl 2-[3-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-4-pyridylmethoxy]phenyl]acetate (0.596 g), tetrahydrofuran (6.0 mL) and methanol (6.0 mL) was added a 1N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (3.0 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 2-[3-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-4-pyridylmethoxy]phenyl]acetic acid. Recrystallization from ethanol-hexane gave colorless prism crystals (0.566 g, 98%). melting point: 148-149° C.
Reaction SMILES: C(OC([NH:11][NH:12][C:13](=[O:32])[C@@H:14]([CH2:20][NH:21][C:22](OCC1C=CC=CC=1)=[O:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=O)C1C=CC=CC=1.CC[OH:35]>[Pd]>[NH:12]([C:13]([C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][N:21]([OH:35])[CH:22]=[O:23])=[O:32])[NH2:11]
Reactant: CCO
Reactant: CCCCC[C@H](CNC(=O)OCc1ccccc1)C(=O)NNC(=O)OCc1ccccc1
Agent: [Pd]
Product: CCCCC[C@H](CN(O)C=O)C(=O)NN
Reaction time: 5 h

Procedure:
To a solution of N′-{(R)-2-[(Benzyloxyformylamino)methyl]heptanoyl]-hydrazinecarboxylic acid benzyl ester (1 mmol) in EtOH (10 mL) was added 10% Pd/C (50 mg). The mixture was subjected to hydrogenation for 5 hours at room temperature and then filtered through Celite. The filtrate was evaporated and purified by hplc to afford N-[(R)-2-(Hydrazinocarbonyl)-heptyl]-N-hydroxy-formamide as a glass. MH+218.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:24](O)(=O)[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.[OH-].[Na+]>[NH:1]1[C:10](=[O:14])[CH2:11][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]1=2.[N:1]1([CH:20]2[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH2:19]2)[CH2:25][CH2:24][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]1=2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)O
Reactant: c1ccc2c(c1)CCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCCCc3ccccc32)CC1
Product: O=C1CCCc2ccccc2N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 127 %

Procedure:
A mixture of compound 1 (1 g, 6.793 mmol), N-tert-Butoxycarbonyl-4-piperidone (1.35 g, 6.793 mmol) and acetic acid (0.44 mL, 6.793 mmol) in 25 mL of 1,2-dichloroethane was cooled to 0° C. and treated with NaBH(OAc)3 (2.16 g, 10.19 mmol). The reaction was brought to room temperature and was stirred for 2 days. The solution was diluted with 3N NaOH solution (125 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4) and was concentrated. The crude product was subject to flash chromatography on silica gel using 5% ethyl acetate/hexanes. The sample was concentrated and dried resulting in a colourless viscous liquid, compound 2 (2.12 g, 94%). 1H NMR (CDCl3) δ 7.12-7.08 (m, 2H), 6.93 (d, J=7.8 Hz, 1H), 6.83 (t, J=14.7 Hz, 1H), 4.16-4.13 (m, 2H), 3.42 (tt, J=7.2, 22.2 Hz, 1H), 2.98 (brs, 2H), 2.85-2.75 (m, 4H), 1.88 (d, J=12.0 Hz, 2H), 1.73-1.60 (m, 6H), 1.47 (s, 9H); MS-ESI (m/z, %): 331 (MH+, 17), 275 (100).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH2:40][C:39](=[O:41])[NH:38][N:37]=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[NH:37][N:38]=[C:39]([O:41][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]5[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:40]=2)=[CH:34][CH:35]=1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(Oc3ncnc4cc(OCC5CCN(CCS(C)(=O)=O)CC5)c(OC)cc34)n[nH]2)cc1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)quinazoline (115 mg, 0.28 mol) and 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (65 mg, 0.33 mol), (prepared as described for the starting material in Example 10), in DMF (1.5 ml) containing potassium carbonate (60 mg, 0.42 mol) was heated at 100° C. for 30 minutes. After cooling, water was added. The precipitate was collected by filtration, washed with water and dried under vacuum. The solid was dissolved in methylene chloride/methanol and pentane was added. The precipitate was collected by filtration, washed with pentane and dried under vacuum to give 4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)-6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)quinazoline (120 mg, 75%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[C:15]([O:21][CH2:22][N:23]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][C:28]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:29][C:30]=2O)[N:25]=[CH:24]1)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>ClCCl>[CH2:36]([O:35][C:28]1[CH:27]=[C:26]2[C:31]([C:32](=[O:33])[N:23]([CH2:22][O:21][C:15](=[O:20])[C:16]([CH3:17])([CH3:18])[CH3:19])[CH:24]=[N:25]2)=[C:30]([O:1][CH2:2][C@H:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:29]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: CC(C)(C)C(=O)OCn1cnc2cc(OCc3ccccc3)cc(O)c2c1=O
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.70 g, 8.6 mmol) was added to a solution of [7-(benzyloxy)-5-hydroxy-4-oxoquinazolin-3(4H)-yl]methyl pivalate (see WO01/094341, 3.0 g, 7.8 mmol) and PS-triphenylphosphine (1.5 mmol/g, 7.2 g, 4.2 mmol) in dichloromethane (120 ml). The reaction mixture was cooled to 0° C. and then a solution of di-tert-butylazodicarboxylate (2.1 g, 9.3 mmol) in dichloromethane (15 ml) was added dropwise over 30 minutes. The mixture was allowed to warn to room temperature and then stirred for 2 hours. The mixture was evaporated under reduced pressure and the residue was purified by silica gel chromatography eluting with a 0 to 10% mixture methanol in dichloromethane to give tert-butyl (2R)-2-{[(7-(benzyloxy)-3-{[(2,2-dimethylpropanoyl)oxy]methyl}-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (1.58 g, 36% yield):
Reaction SMILES: [C:1]([N:4]1[CH2:18][CH2:17][CH:7]([C:8]([O:10]C2C=CC=CC=2)=O)[CH2:6][CH2:5]1)(=O)[CH3:2].[C:19](N1CCC(C(Cl)=O)CC1)(=[O:21])C.[C:31]1([OH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(CC)CC>C1COCC1.CCOC(C)=O>[OH:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:8]([CH:7]1[CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH2:19][OH:21])[CH2:18][CH2:17]1)=[O:10]
Reactant: CC(=O)N1CCC(C(=O)Oc2ccccc2)CC1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1O)C1CCN(CCCO)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
Phenyl N-acetylisonipecotate. To a suspension of N-acetylisonipecotoyl chloride (3.70 g, 19.50 mmol) in THF (60 mL) were added phenol (2.70 g, 27 mmol) and Et3N (5.0 mL, 36 mmol). The resulting heterogeneous mixture was stirred at 25° C. for 20 h, diluted with EtOAc (50 mL) and was washed with a saturated solution of NH4Cl (50 mL). The crude compound was purified by filtration on silica gel using EtOAc/n-hexane as eluant to afford the title compound as a colorless solid (3.45 g, 80%): mp 96-98 C; 1H NMR (CDCl3) d 1.60-1.95 (m, 2H), 2.00-2.2 (m, 5H), 2.70-3.00 (m, 2H), 3.10-3.30 (m, 1H), 3.75-3.90 (m, 1H), 4.40-4.60 (m, 1H), 7.06 (d, J=7.5 Hz, 2H), 7.22 (d, J=7.5 Hz, 1H), 7.38 (t, J=7.5 Hz, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[N:7]1([CH2:13][C:14]2[CH:28]=[CH:27][C:17]3[NH:18][C:19]([C:21]4[C:25]([NH2:26])=[CH:24][NH:23][N:22]=4)=[N:20][C:16]=3[CH:15]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:1]([CH2:3][C:4]([NH:26][C:25]1[C:21]([C:19]2[NH:18][C:17]3[CH:27]=[CH:28][C:14]([CH2:13][N:7]4[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[CH:15][C:16]=3[N:20]=2)=[N:22][NH:23][CH:24]=1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: N#CCC(=O)Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A mixture of cyano-acetic acid (23 mg, 0.28 mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (70%, 100 mg, 0.23 mmol), TBTU (89 mg, 0.28 mmol) and DMF (2 ml) was stirred at 25° C. overnight. The mixture was then evaporated in vacuo. Flash chromatography, eluting with DCM-6% MeOH/DCM afforded 2-cyano-N-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide as a yellow solid (65 mg, 77%). (LC/MS (acidic method/final compound): Rt 4.61, [M+H]+ 366).