Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:21]([O:25][C:26]([N:28]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])[CH3:29])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[C:30]([N:28]([C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[CH3:29])[CH:31]=3)[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(C(=O)O)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(C(=O)Nc2ncn(Cc3ccc(C(C)(C)C)cc3)c2C(N)=O)c1
Yield: 65 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 17, using 4.31 g (14.0 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazolecarboxamide which was prepared in the same manner as in Example 57 and 3-(N-t-butyloxycarbonyl-N-methylamino)benzoic acid instead of 3-pyridylacetic acid hydrochloride to obtain 4.59 g of 1-(4-t-butylbenzyl)-4-(3-(N-t-butyloxycarbonyl-N-methylamino)benzoylamino)-5-imidazolecarboxamide (yield 65%).
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=O)=[C:8]([O:18][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:24]([C:26]1[C:27](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[O:28][C:29]([CH3:36])([C:32]([F:35])([F:34])[F:33])[C:30]=1[CH3:31])#[N:25]>C(O)C>[CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:31][C:30]2[C:29]([CH3:36])([C:32]([F:35])([F:33])[F:34])[O:28][C:27](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[C:26]=2[C:24]#[N:25])=[C:8]([O:18][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=CC=CC=O)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=CC=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C(F)(F)F)c(OC)c1
Temperature: 50 °C
Yield: 82.8 %

Procedure:
To 5 ml of ethanol were added 130 mg (0.41 mmol) of 5-(4-dibutylamino-2-methoxyphenyl)-2,4-pentadienal and 115 mg (0.45 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene) propanedinitrile, and the mixture was stirred with heating at 50° C. for 2 hours. The precipitate was separated by filtration and purified by silica gel column chromatography to give 187 mg of a greenish brown crystal (yield: 82.5%; mp: 168-172° C.)
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[C:8]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:7]=1)(=[O:4])=[O:3].[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].C([O-])(=O)C.[Na+]>ClCCl>[CH3:27][S:24]([O:23][C:8]1[CH:7]=[C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:11]=[CH:10][C:9]=1[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[C:32]2[S:28][C:29](=[O:34])[NH:30][C:31]2=[O:33])=[CH:19][CH:20]=1)(=[O:25])=[O:26]
Reactant: O=C1CSC(=O)N1
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)c(OS(C)(=O)=O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)c(OS(C)(=O)=O)c1
Temperature: 175 °C
Reaction time: 0.33 h
Yield: 69.2 %

Procedure:
0.887 g (2.14 mmole) 4-[2-(4-formylphenoxy)ethyl]-3-(methylsulfonyloxy)phenyl methanesulfonate was dissolved in 8 ml dichloromethane. 0.314 g (2.68 mmole) 2,4-thiazolidinedione and 0.439 g (5.35 mmole) sodium acetate were added and everything was mixed together. The solvent was evaporated in vacuo and the mixture was heated under vacuum to 175° C. and kept at this temperature for 20 minutes (the mixture melted at ca. 100° C.). After cooling the reaction mixture was stirred in water and acetone. Acetic acid was added and the precipitate was collected by filtration, washed with acetone/water, pure water and dried to give 0.76 g (yield 69%) of 5-(4-[2-(2,4-dimethanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[Cl:25]>N1C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([NH:1][C:2]2[C:3]([C:9](=[O:10])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccccc1Cl
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: O=C(c1ccccc1Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (3-amino-5-chloro-pyridin-2-yl)-(2-chloro-phenyl)-methanone (26.8 mg, 0.10 mmol) and 3,4-dichloro-benzenesulfonyl chloride (24.5 mg, 0.10 mmol) in anhydrous pyridine (1 mL) were stirred overnight at 60° C. Reaction mixture was concentrated and the residue was treated with 1 M NaOH (5 mL) and THF (5 mL) to hydrolyze bis-sulfonamide. The resultant solution was neutralized to pH 6 and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The was purified by preparative HPLC (20→90% gradient of MeCN-water) and pure product fractions were lyophilized to provide 3,4-dichloro-N-[5-chloro-2-(2-chloro-benzoyl)-pyridin-3-yl]-benzenesulfonamide as a solid. MS m/z: 498.0 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:14]1([C:13]2[NH:12][C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(N)c1NC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cccc2nc(-c3ccccc3)[nH]c12
Temperature: 0 °C
Yield: 71.4 %

Procedure:
A solution of 810 mg (3.0 mmol) of methyl 3-amino-2-benzoylamino-benzoate 9y in 15 ml acetic acid was heated to 125° C. for 1.5 h. The reaction was cooled and poured into ice/water. The aqueous layer was made basic with NaHCO3 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and evaporated to give 540 mg (71%) of methyl 2-phenyl-1H-benzo[d]imidazole-7-carboxylate, 9z. MS m/z (M+H+) 253.2
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[CH3:18][C:19]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[N:34][O:35][CH3:36])[C:30](OC)=[O:31].ClCCl>CO>[CH3:18][C:19]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[N:34][O:35][CH3:36])[CH:30]=[O:31]
Reactant: CON=C(C(=O)OC)c1ccccc1COc1cc(C)ccc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: CON=C(C=O)c1ccccc1COc1cc(C)ccc1C
Reaction time: 3 h

Procedure:
1M diisobutylaluminum hydride/toluene solution (5.5 ml, 5.5 mmol) was added dropwise to a mixture of methyl 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetate (1.64 g, 5 mmol) and dichloromethane (15 ml) at −70° C. over 0.5 hours, and then the mixture was stirred at −70° C. to room temperature for 3 hours. Methanol (3 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated insoluble materials were removed, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetaldehyde (0.54 g, 36.3%) as a colorless oil.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:16]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2cccc3ccccc23)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
Under an argon gas atmosphere, 200.0 g (1.163 mol) of 1-naphthaleneboronic acid, 329.0 g (1.163 mol) of 4-bromoiodobenzene, 26.9 g (23.3 mmol) of tetrakis(triphenylphosphine) palladium(0), 3.7 L of toluene and 1.74 L of 2M sodium carbonate solution were mixed, and stirred for 24 hours at 90 degrees C. After the reaction in the mixture was over, the mixture experienced filtration, through which aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, toluene was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 268 g of 1-(4-bromophenyl)naphthalene was obtained with an yield of 81%.
Reaction SMILES: Cl.F[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)[CH:6]=[CH:5][N:4]=1.C([O-])(O)=[O:23].[Na+]>>[O:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:11]2[N:10]=[C:9]([C:7]3[CH:6]=[CH:5][NH:4][C:3](=[O:23])[CH:8]=3)[CH:14]=[CH:13][N:12]=2)[CH2:17][CH2:18]1
Reactant: O=C([O-])O
Reactant: Fc1cc(-c2ccnc(NC3CCOCC3)n2)ccn1
Agent: Cl
Agent: [Na+]
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)cc[nH]1
Yield: 94 %

Procedure:
1M HCl (35 mL) was added to 4-(2-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (0.32 g, 1.2 mmol). The mixture was heated at reflux overnight. The cooled reaction mixture was neutralized with solid NaHCO3. The resulting solid was collected by vacuum filtration, washed into a flask with EtOAc/MeOH, evaporated and dried to afford 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.30 g, 1.1 mmol, 94% yield). 1H NMR (400 MHz, (CD3)2SO) δ 11.74 (br s, 1H), 8.40 (d, 1H), 7.48 (d, 1H), 7.33 (d, 1H), 7.11 (d, 1H), 6.99 (br s, 1H), 6.85-6.76 (m, 1H), 4.04-3.92 (m, 1H), 3.92-3.85 (m, 2H), 3.45-3.36 (m, 2H), 1.90-1.81 (m, 2H), 1.59-1.48 (m, 2H); m/z (APCI-pos) M+1=273.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@H:5]2[O:7][C@H:8]([C:10](=[O:14])[CH2:11][O:12][CH3:13])[CH2:9][C@H:4]2[O:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH3:15])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([OH:14])[CH2:11][O:12][CH3:13])[CH2:9][C@H:4]2[O:3]1
Reactant: COCC(=O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCC(O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a stirred solution of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-methoxy-ethanone (compound 21c, 1.4 g, 6.5 mmol) in methanol (50 mL) was added sodium borohydride (494 mg, 13 mmol). After being stirred at room temperature for 2 hours, the resulting solution was quenched by saturated NH4Cl solution and concentrated in vacuo. The residue was suspended in EtOAc and then filtered. The filtrate was concentrated in vacuo to afford 1.24 g of crude product of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-methoxy-ethanol (compound 21d) as a colorless oil. MS obsd. (ESI+) [(M+NH4)+]: 236.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1>N1C=CC=CC=1.CC(=O)OCC>[CH3:1][S:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CS(=O)(=O)Oc2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(CS(=O)(=O)Oc2ccccc2)cc1
Reaction time: 20 h

Procedure:
Methanesulphonyl chloride (1.12 ml) was added to a cooled stirred solution of phenyl 4-aminobenzenemethanesulphonate, hydrochloride (3.0 g) in pyridine (9 ml). The resulting mixture was allowed to warm up to 20° and then stirred for 20 h. The reaction mixture was diluted with EA (150 ml) and washed with 8% NaHCO3 (400 ml), H2O (250 ml) and brine (250 ml). The organic extract was dried (MgSO4) and evaporated to leave a brown gum which was crystallised from toluene (100 ml) to give the crude title compound (as an off-white solid which was recrystallised from toluene (100 ml) to give the title compound (1.25 g) as a white solid m.p. 128°-129°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[CH:7]1)[CH3:2].C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH2:1]([O:3][C:4](=[O:15])[C:5]([N:6]1[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[N:8]=[CH:7]1)=[CH:19][N:20]([CH3:22])[CH3:21])[CH3:2]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cn1cnc(C(F)(F)F)c1
Product: CCOC(=O)C(=CN(C)C)n1cnc(C(F)(F)F)c1

Procedure:
38.0 g (170.8 mmol) of the compound from Example 32A and 58.5 ml (50.3 g, 341.6 mmol) dimethylformamide diethyl acetal are stirred at a bath temperature of 100° C. for 16 h. For working up, the cooled reaction solution is concentrated on a rotary evaporator and the residue is dried in vacuo.
Reaction SMILES: O1CCCC1.C([O:8][C:9]([C:11]1[NH:37][C:14]2[N:15]=[CH:16][N:17]=[C:18]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[O:28])=[CH:22][CH:21]=3)[C:13]=2[CH:12]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]3[C:13]4[CH:12]=[C:11]([CH2:9][OH:8])[NH:37][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:25][CH:24]=2)=[O:28])=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(CO)cc23)cc1
Reaction time: 48 h
Yield: 70.4 %

Procedure:
After adding 9 ml of tetrahydrofuran to 55 mg of the 4-{4-[3-(4-fluorophenyl)ureido]phenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester synthesized in Example 163 and stirring the mixture, 25 mg of lithium aluminum hydride was added at room temperature and the mixture was stirred for 2 days. Water was then added, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran mixed solvent, and the organic layer was filtered with celite and concentrated to dryness to obtain 35 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[CH:24]1([CH2:23][O:22][C:14]2[CH:15]=[C:16]([CH2:17][OH:18])[CH:20]=[CH:21][C:13]=2[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1ccc(CO)cc1OCC1CC1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a stirred solution of 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoic acid (for reference procedure see Example 18, WO 2010/089107, which is incorporated herein by reference in its entirety) (0.500 g, 1.297 mmol) in anhydrous THF (10 ml), BH3*THF complex (1M solution in THF, 2.59 ml, 2.59 mmol) was added drop wise at RT under nitrogen atmosphere. After 4 hours, the reaction was cooled to 0° C. and quenched with aqueous NH4Cl. The mixture was extracted with EtOAc and the organic phase was dried over Na2SO4 and evaporated under reduced pressure affording tert-butyl 2-(cyclopropylmethoxy)-4-(hydroxymethyl)phenyl(methylsulfonyl)carbamate as a colorless oil (0.430 g, 1.158 mmol, 89% yield, MS/ESI+ 394.2 [MNa]+). This product was used without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(CCCNCCCc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCCNCCCc2ccc(N)cc2)cc1
Reaction time: 4 h

Procedure:
A solution of N,N-bis-(4-nitrophenethyl)methylamine (1.2 g, 3.6 mmol) in ethanol (50 ml) containing 5% Pd/C (0.15 g) was stirred under a hydrogen atmosphere (50 p.s.i.) for 4 hours. The reaction mixture was filtered and the solvent evaporated to give the title compound as an oil, yield 1.0 g, which was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25]Cl)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:27]#[N:28])=[C:4]([F:29])[CH:3]=1.[I-].[Na+].[CH3:32][NH:33][CH3:34]>O1CCCC1>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:33]([CH3:34])[CH3:32])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:27]#[N:28])=[C:4]([F:29])[CH:3]=1
Reactant: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCCl
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCN(C)C
Temperature: 125 °C

Procedure:
A mixture of 0.8 g (1.83 mmol) of 4-(4-chloro-2-fluoro-5-hydroxy-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile and 0.055 g of sodium iodide in 15.6 ml of 2M dimethylamine in tetrahydrofuran was placed in a sealed tube and heated to 125° C. for 2.5 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and the residue was treated with with ethyl acetate-ether depositing a solid and giving 0.51 g of the title compound as a off-white solid: mass spectrum (electrospray, m/e) M+H 445.0; (M+2H)+2 243.4.
Reaction SMILES: [C:1]([N:8](C(OC(C)(C)C)=O)[C:9]1[S:10][C:11]([C:15](=[O:21])/[CH:16]=[CH:17]/[N:18]([CH3:20])[CH3:19])=[C:12]([CH3:14])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+].[OH-].[Na+].Cl>CO>[C:1]([NH:8][C:9]1[S:10][C:11]([C:15](=[O:21])/[CH:16]=[CH:17]/[N:18]([CH3:19])[CH3:20])=[C:12]([CH3:14])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Cc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1C(=O)/C=C/N(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)/C=C/N(C)C
Temperature: 25 °C
Yield: 110.8 %

Procedure:
A solution of enamino ketone 337 (859 mg, 2.09 mmol) in methanol (12 mL) was treated with NaOMe solution (25% ww, 1.9 ml). The reaction mixture refluxed for 24 hours, treated with NaOH solution (1M, 3 ml), cooled to the room temperature, carefully neutralized (pH 7.5-8) with 1M HCl and extracted with EtOAc. Extract was dried over MgSO4, filtered and evaporated to provide a residue corresponding to the title compound (721 mg, more than quantitative yield), which was used for the next step without further purification. MS (m/z): 311.40 (calc) 312.1 (MH+) (found).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=[N:18][C:17]2[N:20]([OH:23])N=N[C:16]=2[CH:15]=1.NC1C=CON=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[NH:18][C:17]1[CH:16]=[CH:15][O:23][N:20]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: Nc1ccon1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccon1
Reaction time: 8 h

Procedure:
A mixture comprising BOC-β-alanine (1 g, 5.29 mmol), WSCD (0.985 g, 6.34 mmol) and HOAT (0.216 g, 1.59 mmol) in DCM is treated with 3-aminoisoxazole (0.43 ml, 5.81 mmol) and left stirring overnight. The resulting mixture is washed with water, brine, dried (MgSO4) and concentrated in vacuo. The crude product is purified by chromatography on silica eluting with EtOAc to afford the title compound as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[S:22][C:21]([C:23]([NH:25][NH:26]C(OC(C)(C)C)=O)=[O:24])=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[S:22][C:21]([C:23]([NH:25][NH2:26])=[O:24])=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(C(=O)NNC(=O)OC(C)(C)C)s3)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(C(=O)NN)s3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of tert-butyl 2-[(5-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophen-2-yl)carbonyl]hydrazinecarboxylate (300.0 mg) in anhydrous dichloromethane (15 ml) was added trifluoroacetic acid (0.91 ml, 12.3 mmol) at 0° C. After stirring at room temperature for 1 hr, the mixture was cooled again to 0° C., and trifluoroacetic acid (0.91 ml, 12.3 mmol) was added. After stirring at room temperature for 12.5 hrs, the reaction mixture was concentrated under reduced pressure. Ethyl acetate (30 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. This operation was repeated 3 times to remove trifluoroacetic acid azeotropically. The residue was purified by aminopropylated silica gel column chromatography (2-propanol:dichloromethane=1:9). The fraction containing the target product was concentrated to about 20 ml under reduced pressure, and hexane (50 ml) was added. This operation was repeated 3 times to crystallize the target product. Hexane (100 ml) was added to the mixture, and the precipitate was filtered, washed with a mixed solvent of diethyl ether-hexane (1:1), and dried under reduced pressure to give the title compound (173.2 mg, yield 75.7%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:29]1[CH2:31][CH:30]1[CH2:32][O:33][C:34]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][CH:40]=[CH:39]2)=[O:35]>C(O)(C)C>[OH:29][CH:30]([CH2:31][N:25]1[CH2:26][CH2:27][CH2:28][CH:23]([C:21](=[O:22])[NH:20][CH:10]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:24]1)[CH2:32][O:33][C:34]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][CH:40]=[CH:39]2)=[O:35]
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCNC1
Reactant: O=C(OCC1CO1)c1ccc2ncccc2c1
Solvent: CC(C)O
Product: O=C(OCC(O)CN1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1)c1ccc2ncccc2c1
Temperature: 70 °C
Yield: 83.7 %

Procedure:
Piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (13) (150 mg; 0.4 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. Quinoline-6-carboxylic acid oxiranylmethyl ester (17) (90.8 mg; 0.4 mmol) is added, then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (1%→20% methanol in methylene chloride) affording the desired product (203.4 mg) as an oil. ESMS: MH+ 608.4 (base).