Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:24][N:23]=[CH:22][CH:21]=1)=[CH:16][CH:15]=3.[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35]Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:21]=[CH:22][N:23]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[N:24]=1)=[CH:16][CH:15]=3
Reactant: COCCOCCl
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Product: COCCOCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 10 above, with the compound from Example 39 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-5-yl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and methoxyethoxymethyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[C:5](NN)=[N:4][N:3]=1>C1C=CC=CC=1.C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[CH:5]=[N:4][N:3]=1
Reactant: NNc1nnc(Cl)c2c(-c3ccccc3)noc12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCO
Product: Clc1nncc2onc(-c3ccccc3)c12
Temperature: 0 °C
Yield: 65 %

Procedure:
The compound prepared in Example 81 (4.40 g) was dissolved in benzene (500 mL)-ethanol (50 mL) and 1 mol/L aqueous sodium hydroxide (67.0 mL) was added. This mixture was cooled to 0° C. Oxygen was bubbled through the vigorously stirred mixture for 30 minutes. The mixture was separated and the aqueous portion was extracted with dichloromethane. The combined organics were washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the title compound (2.53 g) having the following physical data.
Reaction SMILES: [Mg].II.Cl[CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7].[S:15](Cl)([Cl:18])(=[O:17])=[O:16].P([O-])([O-])([O-])=O>C1COCC1>[CH3:7][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH2:5][S:15]([Cl:18])(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(CCl)c1ccccc1
Agent: II
Agent: O=P([O-])([O-])[O-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(CS(=O)(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
In a flask under argon were placed magnesium turnings (0.8 g, 0.036 mol), dry THF (10 mL) and a iodine crystal. Then, 1-chloro-2-methyl-2-phenylpropane (5 mL, 0.031 mol) in THF (15 mL) was added slowly and the reaction mixture was refluxed for 30 min. It was then allowed to cool to room temperature and finally it was cooled to -70° C. and sulfuryl chloride (2.5 mL, 0.031 mol) in THF (10 mL) was added dropwise. The reaction was allowed to warm up to room temperature and was stirred at this temperature overnight. The resulting solution was poured into diluted phosphate buffer and extracted with EtOAc (3×). Evaporation of the solvent afforded the title compound (4.6 g, 65%).
Reaction SMILES: Cl.[F:2][C:3]1[C:11]2[O:10][CH:9]([C:12]3([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([Br:26])C(=O)C1>CO.C(Cl)Cl>[Br:26][C:5]1[CH:4]=[C:3]([F:2])[C:11]2[O:10][CH:9]([C:12]3([OH:18])[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH2:8][C:7]=2[CH:6]=1
Reactant: OC1(C2Cc3cccc(F)c3O2)CCNCC1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: OC1(C2Cc3cc(Br)cc(F)c3O2)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.3 %

Procedure:
To a solution of 4-(7-fluoro-2,3-dihydrobenzofuran-2-yl)piperidin-4-ol hydrochloride (380 mg, 1.388 mmol) in MeOH (11.1 mL) at 0° C. was added NBS (235 mg, 1.319 mmol) in one portion. Upon completion of addition, the reaction mixture was stirred at room temperature for 3 hours, and then quenched with aqueous Na2H2S2O5 (10%, 5 mL). The solvent was removed under reduced pressure to yield a residue. The residue was diluted with CH2Cl2 (5 mL), washed with aqueous NaOH (1 N, 3 mL) and brine (3 mL). The organic layer was separated, dried (K2CO3), filtered, and concentrated to afford Compound 1G as a white solid (0.168 g, 38% yield). LC/MS (m/z)=317 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH2:31][CH3:32].ClCCl>N1C=CC=CC=1>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][CH2:30][CH2:31][CH3:32])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:8])=[O:7])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
2-Thiophenesulfonyl chloride (0.3 g in 10 ml dichloromethane, 1.6 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (0.5 g, 1.6 mmol), dichloromethane (40 ml), and pyridine (0.8 ml). The reaction was maintained at room temperature for a few hours and then an additional portion of 2-thiophenesulfonyl chloride (0.1 g, 0.6 mmol) was added. The reaction was maintained overnight and then concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol) and the fractions containing product were washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered, and concentrated to provide 0.2 g of N2-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-thiophenesulfonamide as an off white powder, m.p. 137.5–141.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, J=8.0 Hz, 1H), 7.89 (dd, J=5.0, 1.3 Hz, 1H), 7.83 (broad s, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.54 (dd, J=3.7, 1.3 Hz, 1H), 7.42 (t, J=7.2 Hz, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 6.44 (broad s, 2H), 4.47 (t, J=7.4 Hz, 2H), 2.87 (m, 4H), 1.80 (m, 4H), 1.58–1.38 (m, 4H), 0.96 (t, J=7.4 Hz, 3H); IR (KBr) 3467, 3361, 3167, 3091, 2957, 2933, 2870, 1644, 1617, 1585, 1533, 1478, 1405, 1336, 1154, 1095, 1014, 854, 761, 733 cm−1; MS (EI) m/e 457.1606 (457.1606 calcd for C22H27N5O2S2); Anal calcd for C22H27N5O2S2: C, 57.74; H, 5.95; N, 15.30. Found: C, 57.50; H, 5.98; N, 15.15.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10](Cl)(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]>C(OCC)C>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: CCCCC(=O)Cl
Solvent: CCOCC
Product: CCCCC(=O)N(CCCC)CCCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
a round-bottom flask containing a magnetic stirring bar, diethyl ether (400 mL) and N,N-dibutylamine (37 mL, 0.22 mol, 2.2 equiv.) was cooled in ice for 30 minutes. Valeroyl chloride (12.0 mL, 0.099 mol, 1.0 equiv.) was combined with diethyl ether (75 mL) and added dropwise over 30 minutes to the stirring dibutylamine solution on ice. A white precipitate, likely the amine's chloride salt, was observed. The flask was removed from ice and stirred at room temperature for 3 h. Two 500 mL extractions were performed with dilute HCl (10 mL conc. HCl per 500 mL extraction) to remove the excess amine and ammonium chloride byproduct. The diethyl ether layer was retained and dried with MgSO4. Diethyl ether was removed under rotary evaporation and high vacuum, leaving crude N,N-dibutylpentanamide.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([CH2:10][N:11]([CH3:13])[CH3:12])=[O:9])=[N:4][N:3]=1.[CH3:14]C(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.O>[CH3:14][CH2:1][C:2]1[S:6][C:5]([NH:7][C:8]([CH2:10][N:11]([CH3:12])[CH3:13])=[O:9])=[N:4][N:3]=1
Reactant: Cc1nnc(NC(=O)CN(C)C)s1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCc1nnc(NC(=O)CN(C)C)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of AK-1 (2.00 g, 13.1 mmol) in THF (25 mL) is added Boc2O (3.45 mL, 15.0 mmol) and TEA (3.64 mL, 26.1 mmol). The reaction mixture is stirred at rt for 18 h and then diluted with H2O and extracted with EtOAc. The organic layers are concentrated to yield AK-2.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.C(#N)C.[F-].[K+].F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=1>C(OCC)C>[Cl:23][C:17]1[CH:16]=[C:15]([O:7][CH:3]2[CH2:4][CH2:5][CH2:6][CH:1]([OH:8])[CH2:2]2)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: OC1CCCC(O)C1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: N#Cc1ccc(OC2CCCC(O)C2)cc1Cl
Yield: 8.7 %

Procedure:
1,3-Cyclohexanediol (116 mg, 1.0 mmole) was added to a flame dried round bottom flask under nitrogen. The flask was then charged with 5 mL of dry acetonitrile, 26 mg of potassium fluoride on alumina (0.1 mmol), and 4-fluoro-2-chloro-benzonitrile (155 mg, 1.0 mmole) and heated at reflux for 16 h. Diethyl ether (15 ml) was added to the reaction mixture, which was then extracted with water (2×), dried (MgSO4) and concentrated. Purification using a chromatotron, eluting with 10% EtOAc/hex (ethylacetate and hexane) provided 22 mg of the title compound. GC/MS: 251 (M/Z for C13H14ClNO2).
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:12][CH2:13][C:14](=[O:18])[N:15]([CH3:17])[N:16]=1.C1(O)C=CC=CC=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>CO>[OH:1][CH:2]([CH2:19][NH:30][CH:27]([CH3:29])[CH3:28])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:12][CH2:13][C:14](=[O:18])[N:15]([CH3:17])[N:16]=1
Reactant: CN1N=C(c2ccccc2OCC2CO2)CCC1=O
Reactant: CC(C)N
Solvent: Oc1ccccc1
Solvent: CO
Product: CC(C)NCC(O)COc1ccccc1C1=NN(C)C(=O)CC1
Yield: 75 %

Procedure:
A mixture of 6-[2-(2,3-epoxypropoxy)phenyl]-2-methyl-4,5-dihydro-3(2H)-pyridazinone (1.05 g, 0.004 mole; prepared from the corresponding phenol by the method of Example 1(b)(i), methanol (15 ml) and isopropylamine (2.1 ml, 0.024 mole) was heated under reflux for 90 minutes. The solution was evaporated under reduced pressure to give a viscous oil (1.43 g.), which was purified on a silica column by elution with a mixture of chloroform and methanol to give 6-[2-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-2-methyl-4,5-dihydro-3(2H)-pyridazinone (0.97 g, 75%, m.p. 82°-84°C). The hydrochloride crystallised from 2-propanol, had m.p. 170°-171°C.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1COc1ccccc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
A mixture of methyl 2-(bromoethyl)-5-chlorobenzoate (100 mg, 0.38 mmol), 2-chlorophenol (43 μL, 0.42 mmol) and potassium carbonate (105 mg, 0.76 mmol) in N,N-dimethylforamide (2 mL) was stirred at room temperature for 3 h and at 50° C. for 4 hours. Water (5 mL) was added and the mixture was extracted with diethyl ether (15 mL×2). The combined organic extracts were washed with brine (15 mL) and dried (sodium sulfate). After removal of solvent, the residue was purified by pTLC eluting with hexane/ethyl acetate (9/1) to afford 103 mg (87%) of the title compound:
Reaction SMILES: ClS(O)(=O)=[O:3].[CH2:6]([P:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].Cl>>[CH2:15]([P:10](=[O:3])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCP(CCCC)CCCC
Reactant: O=S(=O)(O)Cl
Agent: Cl
Product: CCCCP(=O)(CCCC)CCCC
Yield: 120.5 %

Procedure:
116.5 g (1 mol) chlorosulfonic acid was placed in an apparatus as described in Example 4 and reacted therein within 60 minutes with 208 g (1 mol) tributylphosphane at 18°-20° C. while cooling with ice. Towards the end of the reaction when cooling was stopped, the reaction temperature rose to 34° C. The whole was stripped at 70° C. under a pressure of 0.5 millibar. This was accompanied by a violent exothermal reaction. The temperature rose up to 140° C. The material was stripped once again at 80° C. under a pressure of 1 millibar. 263 g tributylphosphane oxide was obtained in the form of a HCl-adduct (determined by elementary analysis and 31P -NMR-spectroscopy). 90% P was in the form of a tributylphosphane oxide HCl-adduct.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH2:11].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([C:26]2[S:27][C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22](=[O:35])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:32]([C:28]1[S:27][C:26]([N:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][C:22]2=[O:35])=[N:30][C:29]=1[CH3:31])=[O:33]
Reactant: NCc1nc2ccccc2o1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1nc2ccccc2o1
Yield: 44 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use benzo[d]oxazol-2-ylmethanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 44% yield: 1H NMR (300 MHz, DMSO-d6) δ 9.01 (t, J=5.5 Hz, 1H), 8.62 (d, J=8.1 Hz, 1H), 7.72-7.64 (m, 2H), 7.45-7.31 (m, 7H), 6.40 (dd, J=8.1, 2.7 Hz, 1H), 6.24 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.68 (d, J=5.5 Hz, 2H), 2.57 (s, 3H); MS (ES+) m/z 473.1 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([NH:12][C:13](=[NH:16])SC)[CH2:7][CH2:6]2.[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][NH2:22])[CH3:18]>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([NH:12][C:13]([NH:22][CH2:21][CH:20]([O:23][CH2:24][CH3:25])[O:19][CH2:17][CH3:18])=[NH:16])[CH2:7][CH2:6]2
Reactant: CCOC(CN)OCC
Reactant: CSC(=N)NN1CCc2cc(Cl)ccc21
Agent: Cl
Product: CCOC(CNC(=N)NN1CCc2cc(Cl)ccc21)OCC

Procedure:
6 g of 1-(5-chlorindolin-1yl)-2-methylisothiourea hydrochloride and 10 ml of aminoacetaldehyde diethyl acetal were heated to a bath temperature of 120° for 1 hour. The excess aminoacetaldehyde diethyl acetal was removed by evaporation in a vacuum and the evaporation residue was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The organic phase was dried over magnesium sulphate and was evaporated to dryness. The 1-(5-chloroindolin-1-yl)-3-(2,2-diethoxyethyl)guanidine obtained as the evaporation residue was crystallized as the naphthalene-1,5-disulphonate having a M.Pt. of 163° -165° (from ethanol/ether).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([NH2:20])[C:9]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[C:21]([CH2:25][C:26](Cl)=O)([CH3:24])([CH3:23])[CH3:22]>C(OCC)(=O)C>[CH3:22][C:21]([CH3:24])([CH3:23])[CH2:25][C:26]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][C:8]=2[N:20]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCS(=O)(=O)c1ccc(NCC2CCOCC2)c(N)c1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CCOCC1
Reaction time: 2 h
Yield: 34 %

Procedure:
To a solution of 4-(ethylsulfonyl)-N′-(tetrahydro-2H-pyran-4-ylmethyl)benzene-1,2-diamine (Step B) in ethyl acetate (16 mL) was added tert-butylacetyl chloride (0.1 mL, 0.8 mmol) at room temperature. After stirring for 2 h, the mixture was quenched with water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in ethanol and 2N sodium hydroxide solution. The mixture was microwaved for 30 min at 130° C. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by amine coated silica gel column chromatography (hexane:ethyl acetate=2:1 as eluent) to afford the title compound (103 mg, 34%) as a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:13]=[C:14]([S:17](Cl)(=[O:19])=[O:18])[S:15][CH:16]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH3:21]>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:13]=[C:14]([S:17]([NH2:21])(=[O:19])=[O:18])[S:15][CH:16]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)c2ccc(CBr)cc2)cs1
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)c1cc(S(=O)(=O)c2ccc(CBr)cc2)cs1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 22.0 g (0.053 mole) of product from Step A dissolved in 150 ml CHCl3 was added gaseous NH3 at 0°-10° C. for 5 minutes. The reaction mixture was then stirred at room temperature for 2.5 hours. The solvent was then removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 4% methanol/CHCl3 to give pure title compound, as an oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10]C(C)(C)C)=[O:9])=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]1[CH:16]=[CH:15][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(c1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
A mixture of tert-butyl 4-(methoxy(phenyl)methyl)benzoate (200 mg, 0.67 mmol), 2,2,2-trifluoroacetic acid (1 mL) and dichloromethane (4 mL) were stirred at 20° C. for 4 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 4-(methoxy(phenyl)methyl)benzoic acid as a white solid (162 mg, 100%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[O:16])[O:7][C:8]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH:5]1[C:6](=[O:16])[O:7][CH:8]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(OC(C)=O)c(=O)o1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCC1CCC(OC(C)=O)C(=O)O1
Temperature: 75 °C

Procedure:
3-Acetoxy-6-acetoxymethyl-pyran-2-one (2.2) (4.80 g, 21.2 mmol) was dissolved in ethyl acetate (50 mL) and added to the Parr reactor, followed by Pd/C (5%, 0.2 g). The mixture was stirred under hydrogen (5×106 Pa) and heated to 75° C. for 4 hours. The product was filtered through celite and the solvent removed under vacuum. A colourless syrup was obtained (4.83 g, 21.0 mmol, 99%). 1H NMR (400 MHz, CDCl3) δ 5.45 (1H, dd, 3JH—H=17.08 Hz, 3JH—H=8.55 Hz, H-2), 4.65 (1H, m, H-5), 4.26 (1 H, dd, 2JH—H=12.13 Hz, 3JH—H=3.54 Hz, H-6), 4.18 (1 H, dd, 2JH—H=12.16, 3JH—H=6.32 Hz, H-6′), 2.36 (1H, m, H-3), 2.19 (3H, s, COCH3), 2.11 (3H, s, COCH3), 2.07-1.88 (3H, m, H-3′, H-4, H-4′) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 170.6, 169.8, 168.6 (2×COCH3, C-1), 74.9 (C-5), 65.9 (C-2), 64.9 (C-6), 22.7, 22.4 (C-3, C-4), 20.7 (2×COCH3) ppm. CI (NH4+): 248 (100%), 306 (30%), 478 (20%). m/z (CI-ammonia gas): 248 [M+NH4+]. [α]D=0° (CHCl3, 10 mg/mL). Anal. Calcd for C10H14O6: C, 52.17; H, 6.13. Found: C, 52.11; H, 6.17.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=1.[CH3:30][C:31]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([N:12]([CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:39]2[C:31]([CH3:30])=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=[O:34])[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=1)[CH3:14]
Reactant: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 150 °C
Yield: 109.2 %

Procedure:
To the compound 4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (176 mg, 0.418 mmol) in dioxane (4.5 mL) and water (1.5 mL) was added 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (173 mg, 0.626 mol), potassium carbonate (289 mg, 2.09 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.2 mg, 0.0259 mmol). The mixture was heated with microwave at about 150° C. for about 15 min. The mixture was filtered. Separation by HPLC with TFA afforded the title compound (238 mg, 99%). LC-MS m/z 522 (M+H)+.
Reaction SMILES: O[CH2:2][N:3]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]1=[O:16].C(N(CC)CC)C.S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[Cl:26][CH2:2][N:3]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]1=[O:16]
Reactant: O=S(Cl)Cl
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1CCl
Temperature: 25 °C

Procedure:
To a suspension of 4-hydroxymethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (22.42 g) in chloroform (50 ml) is added a catalytic amount of triethylamine. The mixture is stirred at ambient temperature, treated dropwise with thionyl chloride, and stirred at 60° C. for 6 hours. The reaction mixture is made free form insoluble materials by filtration and the filtrate is poured into water. The separated chloroform layer is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution successively, dried, and evaporated to obtain 4-chloromethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (17.23 g).
Reaction SMILES: [CH3:1]OC(OC)N(C)C.[CH3:9][C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]2[C:18]=1[CH:17]=[N:16][NH:15][C:14]2=[O:19]>C1C=CC=CC=1>[CH3:1][N:15]1[C:14](=[O:19])[N:13]2[C:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:11][C:10]([CH3:9])=[C:18]2[CH:17]=[N:16]1
Reactant: COC(OC)N(C)C
Reactant: Cc1nc(-c2ccccc2)n2c(=O)[nH]ncc12
Solvent: c1ccccc1
Product: Cc1nc(-c2ccccc2)n2c(=O)n(C)ncc12
Yield: 100 %

Procedure:
Dimethylformamide dimethyl acetal (0.73 ml; α=0.897, 0.005 mole) is added slowly to a slurry of 8-methyl-6-phenylimidazo[1,5-d]-as-triazin-4(3H)-one (1.13 g, 0.005 mole in benzene (25 ml). The reaction mixture is stirred, refluxed for 24 hours, cooled and filtered. The filtrate is evaporated to yield 1.4 g (100%) product. Recrystallization from methyl cyclohexane yields yellow crystals, found to be identical (ir:nmr) to the product obtained by Method A.