Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16]C(OC(C)(C)C)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(NC(=O)OC(C)(C)C)c2c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCOC(=O)c1oc2cccc(N)c2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-tert-butoxycarbonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (624 mg, 1.95 mmol, prepared according to Example 59, Step 1) was added 1,2-dichloroethane (12 mL) and trifluoroacetic acid (TFA, 6 mL). The reaction was stirred at room temperature for 2 hours. Solvent was removed in vacuo to provide 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.7 (s, 3 H) 4.3 (q, J=7.1 Hz, 2 H) 6.5 (dd, J=7.8, 0.8 Hz, 1 H) 6.8 (d, J=8.3 Hz, 1 H) 7.2 (t, J=8.1 Hz, 1 H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]=[CH:9][CH:10]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]1.C[SiH](C)O[SiH](C)C.[CH:23]1([CH2:29][CH2:30][Si:31]([CH3:37])([CH3:36])[O:32][SiH:33]([CH3:35])[CH3:34])[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1>C(O)(CC)(C)C.C(C(C)=O)C>[CH:10]1([CH2:9][CH2:8][Si:33]([CH3:34])([CH3:35])[O:32][Si:31]([CH2:30][CH2:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]2)([CH3:37])[CH3:36])[CH2:11][CH2:12][CH2:13][CH:14]=[CH:15]1
Reactant: C[SiH](C)O[Si](C)(C)CCC1C=CCCC1
Reactant: C=CC1CC=CCC1
Agent: C[SiH](C)O[SiH](C)C
Solvent: CCC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Product: C[Si](C)(CCC1C=CCCC1)O[Si](C)(C)CCC1C=CCCC1

Procedure:
To a 20 ml toluene solution of 51.93 g (0.48 mole) of 4-vinylcyclohexene-1 and 0.37 g of 5% H2PtCl6 in t-amyl alcohol is added 33.6 (0.23 mole, 90% purity) of 1,1,3,3-tetramethyldisiloxane at 45° C. to 50° C. for 1 hour and 30 minutes. The reaction is complete after maintaining the reaction at 55° C. for 5 hours. To this mixture is added 250 ml methyl ethyl ketone. After washing successively with four 100 ml portions of H2O, 78 g (>95% purity by GC) of 1,3-bis-((2-cyclohexenyl)-ethyl)-1,1,3,3-tetramethyldisiloxane having a light yellowish color is obtained after stripping off solvent at 120° C. and <10 mm Hg. The structure of the product, 1,3-bis-((2-cyclohexenyl)ethyl-1,1,3,3-tetramethyldisiloxane, is confirmed by IR and 1H NMR as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.[Na].O>C(O)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]([CH3:13])([CH3:12])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:9])[CH2:10][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[CH:16][CH:17]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCCO
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 48 h
Yield: 18.4 %

Procedure:
A solution of 30 g (0.093 mol) of 2-(4-chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane in 40 ml of n-propanol is added dropwise to a solution of 7.6 g (0.107 mol) of sodium 1,2,4-triazole in 60 ml of n-propanol at room temperature. The reaction mixture is subsequently stirred at the reflux temperature for 48 hours and is cooled, water is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography. 6.7 g (18.4% of theory) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-2-butanol are obtained. This product is stirred with 20 ml of saturated hydrogen chloride/ether solution at room temperature. The precipitate which has separated out is filtered off with suction, rinsed with a little ether and dried at 40° C. in vacuo. 6.5 g (89% of theory, based on the base employed) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-2-butanol hydrochloride of melting point 135° C. are obtained.
Reaction SMILES: C([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)C.Br.[OH-].[Na+].[ClH:25]>O.O1CCOCC1.CO>[ClH:25].[OH:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: OCCn1c(N2CCCNCC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (5.10 g, 1.8 mmol) and 48% hydrobromic acid (25 mL). Heat to reflux. After 18 hours, dilute with water and adjust the pH to 12 using aqueous 5 M sodium hydroxide solution. Extract three times with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Combine the residue and methanol (50 mL). Add a solution of hydrochloric acid (5.0 mL, 4 M, 20 mmol) in dioxane. Evaporate in vacuo to give a residue. Triturate the residue with diethyl ether to give a solid. Collect the solid by filtration and dry to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH2:15][CH2:14]1)=[O:12].[H-].[Na+].I[CH3:31]>CN(C)C=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH3:31])[CH2:15][CH2:14]1)=[O:12]
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cnccc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
A solution of 0.12 g (0.30 mmol) [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 3) in 1 mL N,N-dimethylformamide was treated with 0.014 g (0.32 mmol) sodium hydride (60% suspension in mineral oil) upon which gas evolution set in and a colour change occurred. After stirring for 30 min., 0.022 mL (0.36 mmol) iodomethane were added. After stirring for 7 hours at room temperature, the reaction mixture was poured onto water and was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) to give the desired compound as an orange solid (32 mg, 26%). MS (ESI): m/z=414.077 [M+H]+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([OH:23])[CH:17]=1.[CH3:24][C:25]([CH3:30])=[CH:26][C:27](O)=[O:28]>CS(O)(=O)=O>[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]2[C:17]=1[C:27](=[O:28])[CH2:26][C:25]([CH3:30])([CH3:24])[O:23]2
Reactant: Oc1cc(O)cc(O)c1
Reactant: CC(C)=CC(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1(C)CC(=O)c2c(O)cc(O)cc2O1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
40 ml of methanesulfonic acid was added to 1.99 g of diphosphorus pentoxide under nitrogen atmosphere. Thereafter, a mixture consisting of 3.15 g of 1,3,5-trihydroxybenzene and 3,3-dimethylacrylic acid was added to the reaction solution at 70° C. The reaction solution was stirred at 70° C. for 30 minutes and then cooled to a room temperature. The reaction solution was added to ice water, followed by extraction with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 2.81 g of the subject compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:14](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:5]([O:10][CH3:14])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC(C)c1cc(Br)cc(C=O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1c(C=O)cc(Br)cc1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
5-bromo-2-hydroxy-3-isopropylbenzaldehyde (25.88 g) was dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (27.64 g) and dimethylsulfuric acid (9.5 mL) were added to the solution under water cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (26.76 g) as a brown oily substance.
Reaction SMILES: Br[CH:2]([C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[S:22])=[CH:19][CH:18]=1>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:23]=[C:21]([C:20]3[CH:24]=[CH:25][C:17]([OH:16])=[CH:18][CH:19]=3)[S:22][C:2]=2[CH2:3][C:4]([OH:6])=[O:5])=[CH:9][CH:10]=1
Reactant: O=C(O)CC(Br)C(=O)c1ccc(Cl)cc1
Reactant: NC(=S)c1ccc(O)cc1
Solvent: CN(C)C=O
Product: O=C(O)Cc1sc(-c2ccc(O)cc2)nc1-c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 98.7 %

Procedure:
3-Bromo-3-(4-chlorobenzoyl)propionic acid (27 g), and 4-hydroxy-thiobenzamide (14.6 g) were heated to 80° in dimethylformamide (50 ml). The reactants were kept at this temperature for 1 hour, cooled and poured onto ice. The resulting gum solidified, and was filtered, and washed with water, to give 31.6 g of powder, m.p. 184°-194° C. (decomp.). This was recrystallised from aqueous isopropanol affording 25.4 g of the title compound, hemihydrate, m.p. 192°-194° (d).
Reaction SMILES: [C:1]([OH:9])(=O)[CH:2]([CH2:4][C:5](O)=[O:6])[OH:3].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH2:10]([N:17]1[C:1](=[O:9])[CH:2]([OH:3])[CH2:4][C:5]1=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CC(O)C(=O)O
Reactant: NCc1ccccc1
Solvent: CCO
Product: O=C1CC(O)C(=O)N1Cc1ccccc1

Procedure:
Heating malic acid with benzylamine in ethanol at 170° C. to give N-benzyl-3-hydroxysuccinimide and reducing with lithium aluminum hydride to give N-benzyl-3-pyrrolidinol.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][CH:26]([CH3:29])[CH2:27]Br>CN(C=O)C>[CH3:25][CH:26]([CH3:29])[CH2:27][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: CC(C)CBr
Reactant: Clc1ccc(OCc2nc3ccccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(COc2ccc(Cl)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.3 %

Procedure:
To a solution of 52 (5.17 g, 0.02 mol) in DMF (50 mL) was added K2CO3 (5.53 g, 0.04 mol) followed by addition of 2-methylpropyl bromide (5.2 g, 0.038 mol) under Ar. The resulting mixture was stirred at rt for 48 hr. HPLC analysis showed that the reaction was not complete. The reaction mixture was further heated at 90° C. for 8 hr, at which point HPLC analysis showed the reaction was complete. The reaction mixture was cooled to rt and filtered. The filter cake was washed with EtOAc (100 mL). The filtrate was washed with H2O (2×75 mL) and brine (100 mL), filtered through phase separation filter paper, and concentrated in vacuo to give an oil (6 g) which solidified. The solid was triturated with hexanes (50 mL), filtered, washed with hexanes (25 mL), and dried to give 4.25 g (80%) of Compound #4. HPLC analysis showed a purity of 100%. 1H NMR (300 MHz, CDCl3): δ 7.85 (m, 1H), 7.45-7.25 (m, 5H), 7.05 (m. 2H), 5.4 (s, 2H), 4.1 (d, 2H), 2.35 (m, 1H), 1.0 (d, 6H) ppm.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:10]([OH:13])[CH2:11][OH:12])=O)(C)(C)C.C(OC(N[C@@H](CC1C=CC=CC=1)[C@H](O)CO)=O)C1C=CC=CC=1>>[OH:12][CH2:11][C@H:10]1[O:13][C:6](=[O:5])[NH:8][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CO
Agent: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CO)OCc1ccccc1
Product: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Yield: 69.8 %

Procedure:
The reaction procedure of Example 9 was repeated except that 434 mg (1.27 mmols) of (2S,3S)-3-(t-butoxycarbonylamino) -4-phenylbutane-1,2-diol was used in lieu of 400 mg (1.27 mmols) of (2S,3S)-3-(benzyloxycarbonylamino)-4-phenylbutane-1,2-diol and the reaction product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to provide 183 mg (0.887 mmol, yield 70%) of (4S,5S)-5-hydroxymethyl-4-phenylmethyloxazolidinone as crystals.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].[Li].[CH2:35]([CH2:37][NH2:38])[OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH:38][CH2:37][CH2:35][OH:36])=[O:22])=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: NCCO
Reactant: CC(=O)N1c2ccc(-c3ccc(CC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccc(-c3ccc(CC(=O)NCCO)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
To a solution of 2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)acetic acid, lithium salt (Intermediate 9)(166 mg, 0.377 mmol) and ethanolamine (0.034 mL, 0.565 mmol) in DMF (3 mL) were added HATU (287 mg, 0.754 mmol) and DIPEA (0.197 mL, 1.131 mmol). The resulting mixture was stirred at room temperature for 1 h, the reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was dissolved in 1:1 MeOH/DMSO and was purified by MDAP (formate). The appropriate fractions were combined and concentrated in vacuo to give 2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-N-(2-hydroxyethyl)acetamide (21 mg, 11%) as a colourless oil. LCMS (Formate, 2 min), Rt=0.76 min, MH+=484.
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][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[O:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:36]=[C:35]([NH:37][C:38](=O)[O:39]C3C=CC=CC=3)[O:34][N:33]=2)[CH2:28][CH2:27]1.COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[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][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([NH:22][C:38]([NH:37][C:35]2[O:34][N:33]=[C:32]([CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[CH:36]=2)=[O:39])[CH:23]=[CH:24][CH:25]=1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C2CCOCC2)no1)Oc1ccccc1
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CCOCC5)no4)c3)c2cc1OC
Yield: 20.2 %

Procedure:
Prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (60 mg, 0.176 mmol) and phenyl 3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-ylcarbamate from Example 123A (56 mg, 0.194 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-yl)urea as a colorless solid (19 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ 10.70 (brs, 1H), 9.38 (brs, 1H), 8.55 (s, 1H), 7.57 (s, 2H), 7.38-7.42 (m, 2H), 7.32 (m, 1H), 6.98 (m, 1H), 6.00 (s, 1H), 4.34-4.35 (m, 2H), 3.99 (s, 3H), 3.87-3.90 (m, 2H), 3.77-3.78 (m, 2H), 3.42-3.46 (m, 2H), 3.35 (s, 3H), 2.88 (m, 1H), 1.76-1.81 (m, 2H), 1.60-1.65 (m, 2H); LC-MS (ESI) m/z 536 (M+H)+.
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:14]1[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:17]([NH:23][C:24](=[O:36])[C@H:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[NH2:26])[C@H:15]1[OH:16].[C:37]([O:41][C:42]([NH:44][C@H:45]([C:55](O)=[O:56])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[NH2:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:14]1[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:17]([NH:23][C:24](=[O:36])[C@H:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[NH:26][C:55](=[O:56])[C@H:45]([CH2:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=2)[NH:44][C:42]([O:41][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:43])[C@H:15]1[OH:16]
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OC)cc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Yield: 28.3 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-3-[N-(N-tert-butoxycarbonyl-O-methyl-L-tyrosyl)-O-methyl-L-tyrosylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (125 mg) was prepared by reacting 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-(O-methyl-L-tyrosylamino)-β-D-ribofuranuronic acid dihydrochloride monohydrate (330 mg) prepared in Example 4 with N-hydroxysuccinimide ester of N-tert-butoxycarbonyl-O-methyl-L-tyrosine (255 mg) according to a similar manner to that of Example 5, mp. 178°-180° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([CH2:28][S:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])(=[O:31])=[O:30])[CH:25]=[CH:24][CH:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH2:28][S:29]([CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])(=[O:31])=[O:30])[N:27]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)CS(=O)(=O)Cc1cccc(Br)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)CS(=O)(=O)Cc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared using the procedure described in Example 1 with 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.097 g, 0.33 mmol) and 1-{[(6-bromopyridin-2-yl)methyl]sulfonyl}-2-methylpropan-2-ol (0.10 g, 0.32 mmol) as starting materials.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[CH3:20][N:21](/[CH:23]=[N:1]/[C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH3:22]
Reactant: COC(=O)c1cc2ccc(OC)cc2cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1cc2ccc(OC)cc2cc1/N=C/N(C)C
Yield: 64.6 %

Procedure:
According to the procedure of example 97, the reaction mixture of 1.05 g (4.54 mmol) of methyl 3-amino-6-methoxy-2-naphthoate in 20 mL of dimethylformamide dimethylacetal is refluxed for 2.5 hours to give 840.5 mg (64.6%) of methyl 3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate as a beige solid, mp 122-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: Oc1ccnc2ccc(Cl)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2nccc(Cl)c2c1

Procedure:
From 93.6 g of 6-chloro-4-hydoxyquinoline and 200 ml of phosphorus oxychloride reacted in a manner similar to that described in Example 2(b) there was obtained 63.6 g of the above named compound as white needles, mp 101°-104°.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:28]=[CH:27][C:26]2C(=CN(C)[N:25]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31].IC>O1CCCC1.[Cl-].[NH4+]>[Br:19][C:20]1[CH:28]=[CH:27][C:26]2[C:6](=[C:5]([CH3:7])[N:4]([CH3:1])[N:25]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)c1c(Br)ccc2nn(C)cc12
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1c(Br)ccc2nn(C)c(C)c12
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a solution of diisopropylamine (1.38 mL, 9.73 mmol) in tetrahydrofuran (25 mL) was added 1.6M butyllithium/hexane solution (5.62 mL, 8.99 mmol) at −78° C., and the mixture was stirred for 30 min. A solution of methyl 5-bromo-2-methyl-2H-indazole-4-carboxylate (2.00 g, 7.49 mmol) in tetrahydrofuran (50 mL) was added and, after stirring for 30 min, iodomethane (933 μL, 15.0 mmol) was added. After stirring for 30 min, the reaction solution was diluted with saturated aqueous ammonium chloride solution. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→50/50) to give the title compound (1.10 g, yield 52%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([SH:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C>[OH:10][C:3]1[C:2]([CH3:1])=[C:7]([S:8][CH2:18][C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:6]=[C:5]([CH3:9])[CH:4]=1
Reactant: Cc1cc(O)c(C)c(S)c1
Reactant: COC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CSc1cc(C)cc(O)c1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of 2,5-dimethyl-3-sulfanylphenol (126 mg) and DMF (dry) (8.0 mL) were added K2CO3 (124 mg) and methyl 4-chloro-3-oxobutanoate (0.096 mL) at 0° C. The mixture was stirred at 0° C. for 3 h. The mixture was quenched with water at 0° C. and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (179 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[CH2:12](O)[CH2:13][OH:14].B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH3:2][C:1]1([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])[O:14][CH2:13][CH2:12][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1cccc(C#N)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1(c2cccc(C#N)c2)OCCO1
Temperature: 100 °C
Yield: 99.7 %

Procedure:
A suspension of 3-acetylbenzonitrile (50.0 g), ethylene glycol (34.0 g) and boron trifluoride etherate (1 ml) in benzene (200 ml) was heated at 100° C. by means of a Dean-Stark apparatus for 5 hours. After cooling, a saturated aqueous sodium hydrogencarbonate solution (200 ml) was added. The benzene layer was collected and then dried with sodium sulfate. The solvent was removed under reduced pressure to afford 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile (65.0 g) (oil).