Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1)[CH3:3].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(O)C.C(=O)([O-])[O-].[NH4+].[NH4+]>O>[CH3:3][CH:2]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1)[CH3:1]
Reactant: CCOC(=O)C1CCN(C(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)N1CCC(C(=O)O)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
Ethyl 1-(1-methylethyl)-4-piperidine carboxylate (3.6 g, 18 mmol, 1 eq) was combined with barium hydroxide octahydrate (10.4 g, 33 mmol, 1.8 eq) in a mixture of 70 mL of water with 44 mL of ethanol. The mixture was heated at 60° C. for 1.3 h. The reaction mixture was concentrated in vacuo and diluted with 70 mL of water. Ammonium carbonate (6.9 g, 87 mmol, 4.8 eq) was added portionwise and the reaction mixture was stirred at rt overnight. The mixture was filtered through diatomaceous earth, concentrated, and lyophilized to provide 3.1 g (100%) of 1-(1-methylethyl)-4-piperidine carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([C:21](O)=[O:22])[C:12]3[CH:13]=[N:14][N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=3[CH:17]=2)[CH2:5][CH2:4]1.[NH2:25][CH2:26][C:27]1[C:28](=[O:37])[NH:29][C:30]([CH3:36])=[CH:31][C:32]=1[CH2:33][CH2:34][CH3:35].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:24][N:2]([CH3:1])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[C:11]([C:21]([NH:25][CH2:26][C:27]3[C:28](=[O:37])[NH:29][C:30]([CH3:36])=[CH:31][C:32]=3[CH2:33][CH2:34][CH3:35])=[O:22])[C:12]3[CH:13]=[N:14][N:15]([CH:18]([CH3:19])[CH3:20])[C:16]=3[CH:17]=2)[CH2:7][CH2:8]1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CC(C)n1ncc2c(C(=O)O)cc(N3CCC(N(C)C)CC3)cc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(N2CCC(N(C)C)CC2)cc2c1cnn2C(C)C
Reaction time: 48 h
Yield: 67 %

Procedure:
To a solution of 6-[4-(dimethylamino)-1-piperidinyl]-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (34 mg, 0.103 mmol) in DMSO (1 mL) were added 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (29.0 mg, 0.134 mmol), N-methylmorpholine (0.045 mL, 0.412 mmol), 1-hydroxy-7-azabenzotriazole (28.0 mg, 0.206 mmol) and EDC (39.5 mg, 0.206 mmol), and the mixture was stirred for 48 h. The mixture was purified using reverse-phase HPLC to afford the title compound as a pale yellow solid (34 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.77-0.96 (m, 3H), 1.43 (d, J=6.57 Hz, 6H), 1.46-1.66 (m, 4H), 1.89 (m, 2H), 2.13 (s, 3H), 2.31 (s, 6H), 2.33 (m, 2H), 2.55 (s, 3H), 2.65-2.84 (m, 2H), 3.86 (m, 2H), 4.38 (m, 2H), 4.85-5.04 (m, 1H), 5.91 (s, 1H), 7.07 (s, 1H), 7.32 (m, 1H), 8.15 (m, 1H), 8.25 (br. s., 1H), 8.44 (t, J=4.93 Hz, 1H); LCMS: (M+H)+=493.2
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]([CH3:32])([CH3:31])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[O:29][CH3:30].CN(C)CCN(C)C.C(OC)(C)(C)C>CO.O.C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:16][C:17]([CH3:32])([CH3:31])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:12]2[CH:13]=[CH:14][C:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:10][C:11]2=[O:15])=[CH:22][C:21]=1[O:29][CH3:30]
Reactant: O=c1nc(C#Cc2ccccc2)cc[nH]1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Solvent: CO
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: COc1cc(-n2ccc(C#Cc3ccccc3)nc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 37 %

Procedure:
To a stirred mixture of 4-(phenylethynyl)pyrimidin-2(1H)-one Part B (20 mg, 0.1 mmol), 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D (48.9 mg, 0.2 mmol), and copper (II) acetate (18.5 mg, 0.1 mmol) in MeOH (2 mL) and H2O (0.5 mL) was added N1,N1,N2,N2-tetramethylethane-1,2-diamine (24 mg, 0.2 mmol) at RT. The reaction mixture was stirred at RT for 45 min under oxygen, diluted with CH2Cl2, washed sequentially with 5% aq. H2SO4 and sat. NaHCO3. The organic phase was dried (MgSO4), concentrated, and the residue was subjected to flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient) to afford impure product. Trituration with methyl t-butyl ether yielded the title compound B-1 (15 mg, 0.038 mmol, 37% yield) as a pure solid. LC/MS 391 (M+H)+, tR 0.82 min (method 5); 1H NMR (400 MHz, chloroform-D) δ 7.70 (1H, d, J=6.78 Hz), 7.51-7.66 (2H, m), 7.37-7.47 (3H, m), 6.95-7.12 (2H, m), 6.90 (1H, dd, J=8.53, 2.51 Hz), 6.54 (1H, d, J=6.78 Hz), 3.88 (3H, s), 3.85 (2H, s), 1.36 (6H, s).
Reaction SMILES: O[CH:2]([C:4]1[CH:21]=[CH:20][C:7]2/[C:8](=[CH:17]/[C:18]#[N:19])/[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)[CH3:3].B(Br)(Br)Br.[CH2:26]([C:29]1[NH:30][C:31]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1)[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH2:26]([C:29]1[N:33]([CH:2]([C:4]2[CH:21]=[CH:20][C:7]3/[C:8](=[CH:17]/[C:18]#[N:19])/[C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[CH2:11][CH2:12][C:6]=3[CH:5]=2)[CH3:3])[C:32]2[CH:34]=[CH:35][CH:36]=[C:37]([CH3:38])[C:31]=2[N:30]=1)[CH2:27][CH3:28]
Reactant: CC(O)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reactant: CCCc1nc2cccc(C)c2[nH]1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCCc1nc2c(C)cccc2n1C(C)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
[step 1] (E)-[2-(1-Hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (67 mg, 0.24 mmol) obtained in Example 83, step 2 was dissolved in dichloromethane (1 mL), boron tribromide (1.0 mol/L dichloromethane solution; 0.73 mL, 0.73 mmol) was added at 0° C., and the mixture was stirred for 20 min. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in DMA (0.5 mL), 2-propyl-4-methylbenzimidazole (63 mg, 0.36 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added, and the mixture was stirred at 70° C. for 4 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50) to give (E)-{2-[1-(2-propyl-4-methylbenzimidazol-1-yl)ethyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (46 mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[OH:11].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[OH:11]
Reactant: O=[N+]([O-])c1cccc(F)c1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cccc(F)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, a suspension of 2-fluoro-6-nitrophenol (5 g, 31.83 mmol), ammonium formate (6 g, 95.50 mmol) and Pd—C (10% w/w, 0.34 g, 3.2 mmol) in MeOH (100 ml) is stirred 0.5 h at room temperature. The reaction mixture is filtered through celite and concentrated in vacuo to give 2-amino-6-fluorophenol 1 (4 g) which is used in the next step without any further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]#[CH:4].Br[C:14]1[N:19]=[C:18]([CH2:20][C:21]2[O:26][C:25](=[O:27])[CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C>[OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]#[C:4][C:14]1[N:19]=[C:18]([CH2:20][C:21]2[O:26][C:25](=[O:27])[CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=c1cccc(Cc2cccc(Br)n2)o1
Reactant: C#CC(O)CCCCCCCC
Solvent: CCN(CC)CC
Product: CCCCCCCCC(O)C#Cc1cccc(Cc2cccc(=O)o2)n1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
3-Hydroxy-undec-1-yne (202 mg, 1.2 mmole) and 6-[1-[6-bromopyridine-2yl]methyl]pyran-2-one (270 mg, 1 mmole) are combined in 4 ml triethylamine in a 25 ml one-neck round bottom flask under argon. The mixture is treated with (bis)triphenylphosphine palladium dichloride (14 mg, 0.02 mmole), warmed to 55° C., and is treated with cuprous iodide (2 mg, 0.01 mmole). The reaction mixture is stirred one hour at 55° C., cooled to room temperature, and the volatiles are removed in vacuo. The residue is partitioned between 1×10 ml diethyl ether and 1×10 ml saturated sodium chloride/ammonium chloride (1:1). The aqueous layer is extracted with 3×10 ml diethyl ether. The combined organics are dried over magnesium sulfate and concentrated in vacuo to a brown oil.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=1.N1C=CC=NC=1C1C=C(C=CC=1)C(O)=O.Cl.CCOCC.[C:38]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:40])[CH3:39].[Li]>CO>[C:42]([O:41][C:38](=[O:40])[CH2:39][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:15]=2)[CH:5]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2ncccn2)c1
Agent: Cl
Agent: O=C(O)c1cccc(-c2ncccn2)c1
Agent: [Li]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1

Procedure:
The title compound was prepared from 3-pyrimidin-2-yl-benzoic acid methyl ester [prepared by the following procedure: 3-Pyrimidin-2-yl-benzoic acid (3.0 g) was esterified by heating in MeOH (160 ml)/4N HCl-Et2O (40 ml) for 16 h at 40° C.; white crystals (1.99 g).] (1.99 g, 9.3 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a light yellow oil (3.24 g, crude product).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([O:6][N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21])=[O:5]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72634728 %

Procedure:
A mixture of N-Boc-β-Ala-OH (1 g, 5.29 nmol), N-hydroxysuccinimide (0.9 g, 7.82 mmol) in DMF (10 mL) were added HOBt (0.7 g, 5.25 mmol) and EDCI.HCl (1 g, 5.23 mmol) at 5° C. The reaction mixture was warmed to RT and stirred for 16 h. The progress of the reaction was monitored by TLC. The reaction was quenched with water and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (3×100 mL), brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was triturated with ether (2×25 mL) to afford N-Boc-β-Ala-OSu (1.1 g, crude) as white solid. 1H NMR (500 MHz, CDCl3): δ 5.10 (bs, 1H), 3.52 (q, J=6.0 Hz, 2H), 2.85-2.82 (m, 6H), 1.31 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([OH:16])[C:7]=2[CH:17]=1)#[N:2].S(OC)(O[CH3:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([O:16][CH3:22])[C:7]=2[CH:17]=1)#[N:2]
Reactant: CCOC(=O)c1oc2ccc(C#N)cc2c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1oc2ccc(C#N)cc2c1OC
Yield: 90.9 %

Procedure:
Ethyl 5-cyano-3-hydroxy-2-benzofurancarboxylate (200 mg, 0.866 mmol), dimethyl sulfate (131 mg, 1.04 mmol) and potassium carbonate (132 mg, 0.953 mmol) were added to acetone (140 ml), and the mixture was refluxed under heating for 1.5 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and water (200 ml) was added to the residue, which was followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 193 mg of ethyl 5-cyano-3-methoxy-2-benzofurancarboxylate (91%). The obtained compound (170 mg, 0.694 mmol) was dissolved in methanol (5 ml) and potassium hydroxide (160 mg, 2.86 mmol) was added, which was followed by refluxing under heating for 45 minutes. Low boiling matters were distilled away from the reaction mixture under reduced pressure and IN hydrochloric acid was added to the residue to adjust the pH to 2-3. The resulting precipitate was collected by filtration to give 123 mg of 5-cyano-3-methoxy-2-benzofurancarboxylic acid as a colorless solid (82%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]1=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].[H-].[Na+].[O:30]=[S:31]1(=[O:47])[C:35]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:34]=2[C:33](=O)[N:32]1[CH2:42][CH2:43][CH2:44][CH2:45]Br>>[O:47]=[S:31]1(=[O:30])[C:35]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:34]=2[CH2:33][N:32]1[CH2:42][CH2:43][CH2:44][CH2:45][N:16]1[CH2:15][CH2:14][CH:13]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH2:3][C:2]([F:1])([F:20])[F:21])[C:5]2=[O:19])[CH2:18][CH2:17]1
Reactant: O=c1n(CC(F)(F)F)c2ccccc2n1C1CCNCC1
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Product: O=c1n(CC(F)(F)F)c2ccccc2n1C1CCN(CCCCN2Cc3cc(Cl)ccc3S2(=O)=O)CC1

Procedure:
From 4-(3-(2,2,2-trifluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine [prepared by a modification of Step 2 of Example 1 wherein cesium carbonate replaced the sodium hydride and the reaction was heated at 50° C. for 20 hours] and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one using the procedures described in Example 1 there was obtained a white solid upon formation of the HCl salt (from methanol and diethyl ether), melting point 237-239° C. Analysis calculated for C25H26ClF3N4O4S.HCl.0.4 H2O: C,48.85; H,4.56; N,9.12; found: C,48.83 ; H,4.53 ; N,9.04. The NMR was consistent with the structure.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[OH:27]>>[OH:27][C:21]1[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Cc1ccc(N)c(O)c1
Agent: [Na+]
Product: Cc1ccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c(O)c1
Yield: 78.1 %

Procedure:
The product is prepared according to the procedure described in Example 2, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 466 mg of 2-amino-5-methylphenol in place of the 2,4-difluoroaniline. 515 mg of N-(2-hydroxy-4-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a purplish solid, the characteristics of which are the following:
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:38][OH:39])[CH2:29][CH2:30][C:31]3[N:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[N:16][CH:17]=1>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([CH2:27][CH:28]([N:38]([OH:39])[CH:5]=[O:7])[CH2:29][CH2:30][C:31]3[N:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=3)(=[O:25])=[O:26])[CH2:22][CH2:23]2)=[N:16][CH:17]=1
Reactant: O=S(=O)(CC(CCc1ncc(F)cn1)NO)N1CCN(c2ccc(Cl)cn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CN(O)C(CCc1ncc(F)cn1)CS(=O)(=O)N1CCN(c2ccc(Cl)cn2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (0.51 ml) was added directly to formic acid (2.0 ml) which had been cooled to 0° C. and then added a solution of 2-[4-[4-(5-chloropyridin-2-yl)piperazino]sulfonyl-3-(hydroxyamino)butyl]-5-fluoropyrimidine (0.485 g) in tetrahydrofuran (11 ml). The solution was stirred at room temperature for 3 hours and then evaporated in vacuo, the resulting residue was azeotroped with toluene and then it was dissolved in methanol and heated to 40° C. for 30 minutes. The solution was evaporated to dryness and then added diethylether and stirred at room temperature for 10 minutes, solid filtered, dried in vacuo to give N-[1-([4-(5-chloropyridin-2-yl)piperazino]sulfonylmethyl)-3-(5-fluoropyrimidin-2-yl)propyl]-N-hydroxyformamide, (0218 g), mp 154-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[Cl:16].C(Cl)(=O)C([Cl:23])=O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:23])=[O:12])=[CH:9][C:8]=1[Cl:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of compound 27d (67 mg, 0.33 mmol) in THF (2 mL) was added oxalyl dichloride (43 pt, 0.50 mmol) dropwise at 0° C., followed by the addition of 2 drops of DMF. The resultant mixture was stirred at 0° C. for 3 h, and then was warmed up to room temperature over 18 h. The solvents were removed under reduced pressure. The resultant residue, crude compound 27e, was dried under reduced pressure for 2 h and used in the following step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[OH:17])[N:13]=[CH:12][CH:11]=[C:10]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:2][CH2:3][OH:4])[N:13]=[CH:12][CH:11]=[C:10]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: OCCBr
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
A solution of 2-bromo-ethanol (226 mg) in N,N-dimethylformamide (6 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (100 mg) and potassium carbonate (250 mg), and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (51.3 mg, yield 45%).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[Cl:30][C:31]1[CH:32]=[N+:33]([O-:56])[CH:34]=[C:35]([Cl:55])[C:36]=1[CH2:37][C@@H:38]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH:47]([F:49])[F:48])=[C:42]([O:50][CH2:51][CH:52]2[CH2:54][CH2:53]2)[CH:41]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:30][C:31]1[CH:32]=[N+:33]([O-:56])[CH:34]=[C:35]([Cl:55])[C:36]=1[CH2:37][C@@H:38]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH:47]([F:49])[F:48])=[C:42]([O:50][CH2:51][CH:52]2[CH2:54][CH2:53]2)[CH:41]=1)[O:24][C:23](=[O:25])[CH2:22][CH2:21][O:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a mixture of 3-(trityloxy)propanoic acid (0.5 g, 1.504 mmol) and EDC (0.865 g, 4.51 mmol) in dry DCM (20 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.632 g, 1.504 mmol) and DMAP (0.184 g, 1.504 mmol) were added, and the resulting solution was stirred at RT overnight. The solvent was evaporated and the residue was partitioned between EtOAc and a sat. sol. of NaHCO3. The organic layer was washed with aqueous 3% citric acid, with brine and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel column (DCM:MeOH: 32% aq. NH4OH=98:2:0.2) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(trityloxy)propanoyloxy)ethyl)pyridine 1-oxide (0.6 g, 0.817 mmol, 54.3% yield, MS/ESI+ 756.3 [MNa]+).
Reaction SMILES: N[CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.C(N(CC)CC)C.N[C@H](C)[CH2:32][OH:33]>CCO>[OH:33][CH2:32][C@H:3]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1)[CH3:2]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Reactant: C[C@@H](N)CO
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](CO)n1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 100 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethyl-1H-pyrimidine-2,4-dione (Intermediate A step 3) (200 mg 0.59 mmol), triethylamine (82 μl, 0.59 mmol) and (R)-2-aminopropan-1-ol (45 mg, 0.59 mmol) (commercial) were combined in EtOH (2 mL). The mixture was heated at 100° C. under microwave irradiation for 1 hour. The solvent was evaporated under reduced pressure. The solid residue dissolved in DCM and water and extracted (×3). The combined organic phases were washed with water, passed through a hydrophobic frit and evaporated under reduced pressure to afford the title compound as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:35]([NH:38][C:39](=[O:42])[CH2:40]Br)([CH3:37])[CH3:36].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:35]([NH:38][C:39](=[O:42])[CH2:40][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:37])[CH3:36]
Reactant: CC(C)NC(=O)CBr
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
A solution of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.3 g, 0.66 mmol), N-isopropylbromoacetamide (0.132 g, 0.726 mmole), and K2CO3 (0.183 g, 1.32 mmole) in DMF (3.6 mL) was heated overnight at 30° C. The crude product was poured onto ice-water (ca. 50 mL) and the suspension was stirred for approximately 0.5 h, filtered and dried (Na2SO4). The crude product was recrystallized from absolute EtOH (10 mL) to afford tert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.160 g, mmol, 45%).