Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([Cl:18])[CH:12]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]#[CH:27]>O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([N:5]1[C:9](=[O:10])[N:8]([CH2:27][C:26]#[CH:25])[C:7]([C:11]2[CH:12]=[C:13]([Cl:18])[N:14]=[C:15]([Cl:17])[CH:16]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)n1nc(-c2cc(Cl)nc(Cl)c2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C#CCn1c(-c2cc(Cl)nc(Cl)c2)nn(C(C)(C)C)c1=O
Reaction time: 2.5 h

Procedure:
To 2.06 g (7.2 mmol) of crude 2-(t-butyl)-5-(2,6-dichloro-4-pyridyl)-1,2,4-triazolin-3-one were added 30 mL of ethyl acetate, 1 drop of water, and 1.00 g (7.30 mmol) of powdered K2CO3. The mixture was heated to reflux and after 15 min 1.10 g (7.4 mmol) of an 80% by weight solution of propargyl bromide in toluene was added. Refluxing was continued for 2.5 hours. The mixture was cooled, diluted with 175 mL of ethyl acetate, washed with 25 mL of water, and dried over MgSO4. Reomoval of the solvent left 2.18 g of crude product as a reddish solid. The crude product was combined with 0.69 g of material from another run and purified by flash chromatography first on a silica gel column and then on a neutral alumina column eluted portionwise in both cases with ether hexane mixtures containing successively greater percentages of ether to afford 0.97 g of 2-(t-butyl)-5-(2,6-dichloro-4-pyridyl)-4-propargyl-1,2,4-triazolin-3-one (Compound 1) as a white solid, m.p. 107°-109° C. 1H-NMR (CDCl3)∂1.6 (9H,s), 2.45 (1H,t), 4.6 (2H,d), 7.75 (2H,s).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:34][C:35]#[N:36]>CN(C)C=O>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:34][C:35]#[N:36])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC#N)CC1
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), sodium hydride and bromoacetonitrile in N,N-dimethylformamide, to give the desired product as a yellow oil (54%).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[OH:10].O.O=O>Cl[Pd]Cl.Cl[Cu].CCCCCC>[C:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:10])[CH3:1]
Reactant: CO
Reactant: C=Cc1ccccc1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: O
Solvent: CCCCCC
Product: CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Wacker-Tsuji oxidation of styrene in a PDMS thimble. A PDMS thimble containing PdCl2 (0.025 g, 0.141 mmol) and CuCl (0.282 g, 2.82 mmol) was placed in a 2-necked Schlenk flask with a stir bar. MeOH (1.98 mL) and H2O (0.28 mL) were added to the inside of the PDMS thimble and the flask was capped with a rubber septum. A balloon filled with O2 was affixed to the septum and the reaction mixture was stirred at room temperature for 1 hour. Styrene (0.323 mL, 2.82 mmol) was added to the reaction mixture and allowed to stir under an O2 atmosphere for 24 hours. The PDMS thimble was swelled with hexane (2×25 mL) for 12 hours with a stir bar on the exterior of the PDMS thimble. The hexane extracts were combined and the solvent was removed in vacuo. A 1H NMR spectrograph was recorded in CDCl3 to determine quantitative conversion of the styrene to the following products: 89% ketone, 1% aldehyde, 8% acetal, and 2% ketal. Acetophenone (0.249 g, 73% yield) was isolated as a clear liquid by column chromatography using hexanes/EtOAc (95/5). NMR spectra matched those reported in the literature.13 1H NMR (300 MHz, CDCl3, δ): 7.94 (m, 2H), 7.54 (m, 1H), 7.45 (m, 2H), 2.58 (s, 3H). 13C NMR (75.48 MHz; CDCl3, δ): 197.9, 137.0, 132.9, 128.4, 128.1 and 26.4.
Reaction SMILES: [CH2:1]([C:5]1C=CC=[C:7]([OH:8])[C:6]=1O)CCC.C([O-])([O-])=O.[Na+].[Na+].[NH2:19][C:20]1[CH:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].C(CC(Cl)=O)=C>CC(C)=O>[C:7]([NH:19][C:20]1[CH:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:8])[CH:6]=[CH:5][CH3:1]
Reactant: CCCCc1cccc(O)c1O
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: C=CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC=CC(=O)Nc1cc(C(=O)OC)ccc1C(=O)OC

Procedure:
110 mg of butylpyrocatechol (as a polymerization inhibitor) and 180 g of dry Na2CO3 (anhydrous) are added to 167.4 g (0.8 mol) of dimethyl aminoterephthalate in 3 1 of acetone. 89 g (0.85 mol) of vinylacetyl chloride are added dropwise to this mixture at 35°-40 ° C. in the course of 20 minutes and the mixture is then boiled under reflux for 4 hours. The filtered solution is concentrated to 1 1 and the concentrate is crystallized in the cold. The crystals of dimethyl N-butenoylaminoterephthalate isolated are recrystallized once from 1.2 1 of methanol and then from a mixture of 426 ml of ethyl acetate and 344 ml of methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([CH:10]([Mg]Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])C.[CH2:18](OCC)C>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([CH:13]([CH2:12][CH2:11][CH2:10][CH3:8])[CH2:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15]
Reactant: Brc1ccccc1
Reactant: CCCCCC(CC)[Mg]Br
Reactant: CCOCC
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Product: CCCCC(CC)Cc1ccccc1
Temperature: 0 °C
Yield: 70 %

Procedure:
A dry 250-mL three-neck round bottom flask, equipped with a condenser and an addition funnel, was purged with N2 and charged with bromobenzene (15 g, 0.10 mol), [1,3-bis(diphenylphosphino)propane]dichloronickel(II) (Ni(dppp)Cl2) (0.27 g, 0.50 mol %). The reaction flask was cooled down to 0° C., whereupon (ethylhexyl)magnesium bromide 1 M solution in diethyl ether (100 mL) was added dropwise from the addition funnel over a 30-minute time period. The reaction was slightly exothermic, and a dark-brown color developed within minutes. The ice bath was replaced with an oil bath, and the solution was heated up to gentle reflux and maintained at that temperature for 12 hours, then cooled in an ice bath, and quenched with cold HCl (100 mL, 1.0 N). The aqueous layer was separated and extracted with diethyl ether (3×100 mL). The combined organic phase was collected and dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was distilled under vacuum to yield 3.3 g (70%) of colorless oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14](=[O:29])[N:13]2C)=[O:11])=[CH:5][CH:4]=1.[CH3:33]N1C(=O)C(C2C=CC=CC=2)C(C2C=CC=CC=2)N1.FC(F)(F)C1C=CC(N=C=O)=CC=1>>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:14]([O:29][CH3:33])=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CN1NC(c2ccccc2)C(c2ccccc2)C1=O
Reactant: CN1C(=O)C(c2ccccc2)C(c2ccccc2)N1C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COC1=NN(C(=O)Nc2ccc(C(F)(F)F)cc2)C(c2ccccc2)C1c1ccccc1

Procedure:
Also isolated was 1-[(4-trifluoromethylphenyl)-aminocarbonyl]-2-methyl-4,5-diphenyl-3-pyrazolidinone, corresponding to a product prepared, according to the method of Example 1, from 2-methyl-4,5-diphenyl-3-pyrazolidinone and 4-trifluoromethylphenylisocyanate.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH:16](Cl)Cl>O1CCCC1.[Cl-].[Na+]>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH:16]([P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])[P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CCOP([O-])OCC
Reactant: COCCOC(Cl)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(OCCOC)P(=O)(OCC)OCC
Reaction time: 0.25 h

Procedure:
Diethyl phosphite (18.0 ml) was added dropwise at 20° C. to a stirred suspension of 55% sodium hydride (5.45 g) in dry tetrahydrofuran (100 ml). After stirring for a further 15 minutes, the mixture was cooled in ice, and dichloromethyl 2-methoxyethyl ether (7.15 g) was added during 15 minutes. The mixture was stirred at room temperature for 1 hour, diluted with saturated aqueous sodium chloride and extracted with chloroform. The organic phase was dried and evaporated to leave an oil which was purified by chromatography on silica gel. The pure title compound was isolated as a colourless oil.
Reaction SMILES: [C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[C:13]([C:16]#[N:17])([CH3:15])[CH3:14].[N+:21]([O-])([O-:23])=[O:22].[K+].[OH:26]S(O)(=O)=O>C(Cl)Cl>[C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:21]([O-:23])=[O:22])[C:6]([C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:5][C:4]=1[C:13]([CH3:14])([CH3:15])[C:16]([NH2:17])=[O:26]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Oc1ccc(C(C)(C)C)cc1C(C)(C)C#N
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1C(C)(C)C(N)=O
Temperature: 30 °C
Reaction time: 96 h

Procedure:
To a stirred mixture of compound 16 (10.0 g, 36.3 mmol) and KNO3 (5.51 g, 54.5 mmol) in DCM (1000 mL) was added dropwise 98% H2SO4 (145.4 g, 1.45 mol) at 0° C. The mixture was stirred at 30° C. for 4 days. The H2SO4 layer was then separated and poured into ice-water (50 g) and then extracted with DCM (100 mL×3). The combined organic layers were washed with water, aqueous NaHCO3 solution and brine, then dried over MgSO4 and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Petroleum ether/EtOAc 20:1→10:1→5:1→3:1) to give compound 17 as a yellow solid. 1H NMR (CDCl3; 400 MHz) δ 8.05 (s), δ 7.74 (s), δ 7.61 (s), δ 7.32 (s), δ 5.32 (s), δ 3.91 (s), δ 3.92 (s), δ 1.62 (s), δ 1.59 (s), δ 1.42 (s), δ 1.38 (s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[CH3:26][O:27][N:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][C:31](=[O:36])[CH2:30][C:29]1([CH3:38])[CH3:37]>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:31]3([OH:36])[CH2:32][C:33]([CH3:34])([CH3:35])[N:28]([O:27][CH3:26])[C:29]([CH3:38])([CH3:37])[CH2:30]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CON1C(C)(C)CC(=O)CC1(C)C
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: CON1C(C)(C)CC(O)(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1(C)C

Procedure:
The title compound was prepared as described in Example 1 step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 1-methoxy-2,2,6,6-tetramethyl-piperidin-4-one (WO 9854174). 1H-NMR (CD3OD; 400 MHz): δ 8.21 (d, 1H, J=8.4 Hz), 8.01 (s, 1H), 7.45 (dd, 1H, J=8.4, 2.0 Hz), 7.37 (d, 1H, J=2.0 Hz), 5.75 (br s, 1H), 4.08 (s, 3H), 2.35 (m, 4H), 2.09 (m, 4H), 1.72 (s, 6H), 1.61 (m, 2H), 1.50 (s, 6H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C29H39N5O3, 506.3 (M+H). found 506.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Br.Br.[NH:13]1[CH:17]=[C:16]([CH2:18][CH2:19][S:20]C(=N)N)[N:15]=[CH:14]1.[OH-].[Na+]>C(O)C.O>[NH:13]1[CH:17]=[C:16]([CH2:18][CH2:19][S:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[N:15]=[CH:14]1
Reactant: N=C(N)SCCc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(SCCc2c[nH]cn2)nc1

Procedure:
A hot solution of 0.2 g (1.3 mmol) of 2-chloro-5-nitropyridine in 5 ml of ethanol is added to a solution of 0.2 g (1.1 mmol) of S-{2-[1H-imidazol-4-yl]ethyl}isothiourea dihydrobromide in 2 ml of water. The resulting suspension is stirred under nitrogen. The reaction mixture is cooled to 0°-5° C. and a solution of 4 molar equivalents of sodium hydroxide (0.16 g) in 2 ml of water is added dropwise under N2. The reaction mixture is stirred for 1 h at the same temperature and for 3 h at 21° C. The reaction mixture is evaporated to dryness and the residue is subjected to column chromatography (silica gel) eluted with a gradient mixture of chloroform and methanol (1-10%) to provide the title compound which is then crystallized from 2-propanol, M.p.: 147°-148° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].O.[C:14]1(C)C=CC(S(O)(=O)=O)=C[CH:15]=1>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH2:14][CH3:15])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(OC)c(O)c1

Procedure:
A solution of 3-Hydroxy-4-methoxybenzoic acid (25 g, 148.67 mmol) and p-Toluenesulfonic acid monohydrate (3.17 g, 16.66 mmol) in abs ethanol (300 ml) was refluxed for 6 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with EtOAc (60 ml) and washed with water (20 ml). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.[C:18](=[S:20])=[S:19].[CH3:21]I>C1COCC1>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:18](=[S:20])[S:19][CH3:21])=[CH:4][C:3]=2[O:2]1
Reactant: CI
Reactant: Nc1ccc2c(c1)OCO2
Reactant: S=C=S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSC(=S)Nc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
3,4-Methylenedioxyaniline (7.0 g) was dissolved in 100 ml of THF, to which 5.7 g of triethylamine and 5.8 g of carbon disulfide were added. The resulting mixture was stirred for 1 hour at room temperature. Then, 10.8 g of methyl iodide were added, followed by overnight stirring. The reaction mixture was washed with water and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, 8.3 g or reddish brown crystals were obtained. The crystals were recrystallized from ethyl acetate, whereby 7.2 g of methyl N-(3,4-methylenedioxyphenyl)dithiocarbamate were obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15]COC(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:19](=O)(O)[O-:20].[Na+].C[OH:25]>>[CH2:1]([O:8][CH2:9][CH:10]([CH2:15][OH:25])[CH2:19][OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCCC(COCc2ccccc2)O1
Reactant: CO
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: OCC(CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Benzyloxymethyl-2,2-dimethyl-[1,3]dioxane (5.54 g, 23.44 mmol) was dissolved in methanol (20 ml) and then 3N hydrochloric acid (3 ml) was added. The reaction was stirred at 25° C. for 30 min. After this point the pH was adjusted to 8 with solid sodium bicarbonate and evaporated. The residue was dissolved in ethyl acetate, filtered through a short silica gel pad, washed with ethyl acetate and concentrated in vacuo to afford 2-benzyloxymethyl-propane-1,3-diol (4.39 g, 95%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ ppm 1.99-2.07 (m, 1H, CH), 2.74 (s, 2H, 2×OH), 3.60 (d, J=5.7 Hz, 2 H, OCH2), 3.78 (d, J=5.4 Hz, 4H, 2×OCH2), 4.50 (s, 2H, OCH2Ar), 7.25-7.38 (m, 5H, Ar).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]([N:19]1[CH2:23][CH2:22][CH:21](O)[CH2:20]1)([CH3:18])[CH3:17].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:21]1[CH2:22][CH2:23][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: CC(C)N1CCC(O)C1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)C3)ccc2[nH]1

Procedure:
A mixture of 3.08 g (15 mmol) 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester, 2.51 g (20 mmol) 1-isopropyl-3-pyrrolidinol and 8.7 ml (30 mmol) tri-N-butyl phosphine in 75 ml was treated at room temperature with 7.57 g (30 mmol) 1,1′-(azodicarbonyl)-dipiperidine in 75 ml THF. The mixture was allowed to stir for a prolonged period of time and subsequently evaporated to dryness. The residue was suspended in 40 ml DCM/n-heptane 1/1, filtered and again washed with 40 ml DCM/n-heptane 1/1. The filtrate was evaporated and purified on silica eluting with a gradient of DCM/2N NH3 in methanol 99/1 to DCM/2N NH3 in methanol 93/7. The product fractions were evaporated and the residue was titurated with diethyl ether to yield after filtration, washing and drying of the residue at 50° C. under vacuum 2.1 g (44%) of the title compound as off-white solid. MS (m/e): 317.1 (MH+, 100%).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[N:32]=1>CN(C)C=O>[F:37][C:33]1[N:32]=[C:31]([CH2:30][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: Fc1cccc(CCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cccc(F)n4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 14.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (40 mg, 0.14 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (28.3 μL, 0.14 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a suspension of this solid in N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-6-fluoro-pyridine (52.7 mg, 0.36 mmol) described in manufacturing Example 45-1-1, which was stirred for 14 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (7.8 mg, 11%) as a trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:26])=O>CN(C=O)C>[Cl:26][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCN(C)CC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(C)CC1
Yield: 23 %

Procedure:
A mixture of 6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (500 mg, 1.57 mmol), thionyl chloride (20 ml) and DMF (3 drops) was heated at reflux for 3 hours and allowed to cool. The excess thionyl chloride was removed by evaporation, and the residue was azeotroped with toluene. The residue was treated with aqueous sodium hydrogen carbonate and the product was extracted with methylene chloride. The combined extracts were washed with brine, passed through phase separating paper and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline (120 mg, 23%).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][C:8]=2[CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:33](Cl)=[O:34].C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[C:23]([O:22][C:20]([NH:19][CH2:18][C:8]1[CH:9]=[C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([Cl:39])=[C:30]([Cl:29])[CH:31]=2)=[CH:28][CH:27]=1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)Cc1ccc(Oc2ccc(N)cc2)c(CNC(=O)OC(C)(C)C)c1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNC(=O)OC(C)(C)C)c1
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Methyl 2-(4-(4-aminophenoxy)-3-((tert-butoxycarbonyl)aminomethyl)phenyl)acetate (100 mg, 0.259 mmol) was diluted with methylene chloride (3 mL) followed by the addition of 3,4-dichlorobenzoyl chloride (81.3 mg, 0.388 mmol) and N,N-diisopropylethyl amine (0.0451 mL, 0.259 mmol). The reaction was stirred for 3 hours. The reaction mixture was diluted with methylene chloride and water. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 12i eluting with hexanes:ethyl acetate (3:1) to yield 130 mg of methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)acetate.
Reaction SMILES: [N:1]1[CH:6]=CC=[CH:3][CH:2]=1.[CH:7]1([C:13]([Cl:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(OCC)(=[O:18])C>CN(C)C1C=CN=CC=1>[ClH:15].[CH:7]1([C:13]([O:14][CH2:3][CH2:2][NH:1][CH3:6])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: c1ccncc1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Product: CNCCOC(=O)C1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl (methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL) were added pyridine (0.97 mL), and 4-dimethylaminopyridine (catalytic amount), and cyclohexanecarbonyl chloride (1.60 mL) was dropwise added. After stirring at room temperature for 2 hrs., pyridine (0.65 mL) and cyclohexanecarbonyl chloride (0.58 mL) were added, and the mixture was stirred overnight at room temperature. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), a 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hrs., diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. The solid was dried under reduced pressure to give the title compound (1.88 g) as a white solid. 1H-NMR (DMSO-d6): 1.10-1.45 (5H, m), 1.54-1.73 (3H, m), 1.83-1.93 (2H, m), 2.29-2.42 (1H, m), 2.54 (3H, s), 3.12-3.18 (2H, m), 4.23-4.29 (2H, m), 9.23 (2H, br).