Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[CH3:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: CSc1ccccc1B(O)O
Reactant: O=Cc1c[nH]c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1ccccc1-c1cc(C=O)c[nH]1
Temperature: 105 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
5-Bromo-1H-pyrrole-3-carbaldehyde (174 mg), [2-(methylthio)phenyl]boronic acid (202 mg) and sodium carbonate (254 mg) were suspended in a mixed solvent of 1,2-dimethoxyethane (5 mL) and water (2 mL), and the mixture was sufficiently degassed under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium (58 mg) was added, and the mixture was further degassed and stirred at 105° C. for 16 hr. The reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as pale-yellow crystals (yield 150 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[C:22]([CH3:23])=[C:21]([O:24][CH2:25][C@@H:26]2[CH2:31][N:30]([CH3:32])[C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[O:27]2)[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15]([O:17]C)=[O:16])[CH:10]=[CH:11][C:12]=1[F:13])=[O:5].COCCOC.[OH-].[Na+].C(COC)(C)(C)C>CO>[CH3:1][C:2]1[C:22]([CH3:23])=[C:21]([O:24][CH2:25][C@@H:26]2[CH2:31][N:30]([CH3:32])[C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[O:27]2)[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15]([OH:17])=[O:16])[CH:10]=[CH:11][C:12]=1[F:13])=[O:5]
Reactant: COC(=O)Cc1ccc(F)c(NC(=O)c2ccc(OC[C@@H]3CN(C)c4ccccc4O3)c(C)c2C)c1
Agent: COCC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: Cc1c(OC[C@@H]2CN(C)c3ccccc3O2)ccc(C(=O)Nc2cc(CC(=O)O)ccc2F)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the compound (240 mg) prepared in Example 12, 1,2-dimethoxyethane (5.0 mL), and methanol (5.0 mL), 1N sodium hydroxide solution (3.0 mL) was added, and the mixture was stirred for 1 hour at room temperature. Methyl tert-butylmethyl ether was added to the reaction mixture, which was extracted by 1N sodium hydroxide solution. The water layer was neutralized by adding 5N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water and saturated brine solution, and was dried by anhydrous magnesium sulphate. The title compound (208 mg) having the following physical data was obtained by allowing the residue obtained by removing the solvent to recrystallize from a mixed solvent of n-hexane, ethyl acetate, and tetrahydrofuran.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].C1C=CC=CC=1.[Na].[Br:15][C:16]1[CH:34]=[CH:33][C:19]([O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])=[CH:23][CH:22]=2)=[C:18]([F:35])[CH:17]=1>CCOCC.O>[C:4]([CH:3]([C:27](=[O:28])[CH:26]([O:25][C:24]1[CH:31]=[CH:32][C:21]([O:20][C:19]2[CH:33]=[CH:34][C:16]([Br:15])=[CH:17][C:18]=2[F:35])=[CH:22][CH:23]=1)[CH3:30])[C:2](=[O:7])[CH3:1])(=[O:6])[CH3:5]
Reactant: CC(Oc1ccc(Oc2ccc(Br)cc2F)cc1)C(=O)Cl
Reactant: CC(=O)CC(C)=O
Agent: [Na]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)C(C(C)=O)C(=O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
A mixture of 1.7 g (17 mmol) of 2,4-pentanedione, 30 ml of benzene and 0.26 g (11.3 mmol) of sodium was warmed at reflux for 3 hours. The reaction mixture was cooled to room temperature and a solution of 10 mmol of 2-(4-(4-bromo-2-fluorophenoxy)phenoxy)propanoyl chloride was added dropwise. The resulting mixture was warmed at reflux for 2.5 hours, stirred at room temperature overnight and poured into water and ether. The organic layer was separated, dried over MgSO4 and evaporated to dryness. The residue was purified by prep LC, eluting with 4:1 hexane:acetone. The product was taken up in ether and extracted with two portions of 1% aqueous NaOH. The combined aqueous layers were made acidic with aqueous HCl and extracted with ether. The ether layer was evaporated to dryness and the residue again purified by prep LC, eluting with 85:15 hexane:acetone. This gave a yellow oil which was thoroughly dried to leave 0.70 g product. Calc for C20H18BrFO5 : C, 54.93, H, 4.15. Found: C, 54.13, H, 4.30.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:17]=[CH:16][C:15]=2[N+:25]([O-])=O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.O.Cl[Sn]Cl>CCO>[O:12]=[C:11]1[CH2:10][C:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[N:25][C:15]2[CH:16]=[CH:17][C:18]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)=[CH:19][C:14]=2[NH:13]1
Reactant: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cccc3)ccc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)c1

Procedure:
Alternatively, the title compound was also prepared from (3-(3-cyano-phenyl)-N-(2-nitro-5-pyrrol-1-yl-phenyl)-3-oxo-propionamide (Example M4) by reductive cyclization with SnCl2.2H2O in EtOH at 70° C. according to the general procedure J (method b). Obtained as an olive solid (161 mg).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[OH2:16]>C(Cl)Cl>[CH2-:9][C:6]([CH3:7])=[O:16].[O-:13][S:10]([C:9]([F:15])([F:14])[F:8])(=[O:12])=[O:11]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: O
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F
Product: [CH2-]C(C)=O
Reaction time: 1 h

Procedure:
To a solution of compound 1-1 (1.00 g) in methylene chloride (30 ml) were added under ice-cooling triethylamine (0.503 ml), anhydrous trifluoromethanesulfonic acid (0.607 ml), the mixture was stirred for 1 hr under ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2-1:4) to give acetonide deprotected compound with the protected phenolic hydroxyl group by a triflate (500 mg) as a colorless oil. Diisopropylamine (0.377 ml), heptanethiol (0.204 ml), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (31 mg) and tris(dibenzylideneacetone)palladium(0)-chloroform adduct (27 mg) were added to a solution of the colorless oil in dioxane (10 ml), and the mixture was stirred at 120° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2-1:3) to give the object product (390 mg) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([CH:23]=O)=[C:16]3[N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2].[NH:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[O:27].N1CCCCC1>CCO>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([CH:23]=[C:31]4[NH:25][C:26](=[O:27])[NH:28][C:29]4=[O:30])=[C:16]3[N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)Cc1cccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)c1
Temperature: 70 °C

Procedure:
To 5-(3-((diethylamino)methyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (10 mg, 0.031 mmol) in EtOH was added hydantoin (3 mg, 0.031 mmol) and piperidine (3 μL, 0.031 mmol). The mixture was heated at 70° C. overnight. The product was purified by HPLC to yield 5-((5-(3-((diethylamino)methyl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=406)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:18]=[C:17](Cl)[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21].[F-].[Cs+].O1CCOC[CH2:38]1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:38])[S:11]([C:14]2[CH:18]=[C:17]([CH:20]=[CH2:21])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(=O)(NCCc1ccc(F)cc1)c1csc(Cl)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C1COCCO1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: C=Cc1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Temperature: 25 °C

Procedure:
A solution of 5-chlorothiophene-3-sulfonic acid [2-(4-fluorophenyl)ethyl]amide (739 mg), vinyltributyltin (772 mg), cesium fluoride (740 mg), and bis(trit-butylphosphine)palladium (34 mg) in 1,4-dioxane (9 mL) was heated at 100° C. for 16 hours. After the reaction solution was cooled to room temperature, this solution was diluted with ethyl acetate, the resulting insoluble matter was removed by Celite filtration, and washed with ethyl. The residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (328 mg) was obtained as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH:21]([CH2:30][OH:31])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34].C[O-].[Na+:38]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH:21]([CH2:30][OH:31])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:38]
Reactant: O=C(NC(CO)Cc1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC(CO)Cc1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of 6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.087 g, 0.168 mmol) in methanol (2 ml) was added 0.5M sodium methanolate in methanol (0.354 ml, 0.177 mmol), and the reaction was stirred for 2 hours. It was concentrated, taken up in dichloromethane and hexanes, and concentrated again to yield 87 mg of the title compound (95.9% yield). MS (apci) m/z=515.9 (M-Na+2H).
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35].C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][CH:49]([NH2:52])[CH2:48][CH2:47]1>CN(C)C=O>[F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:52][CH:49]4[CH2:50][CH2:51][O:46][CH2:47][CH2:48]4)=[O:28])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Reactant: NC1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a mixture of 0.05 g (0.10 mmole) of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-281), 0.07 mL (0.40 mmole) of ethyldiisopropyl amine and 0.011 g (0.11 mmole) of tetrahydro-pyran-4-ylamine in 2.0 mL of dimethylformamide was added 0.048 g (0.11 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-95:5) gave 0.030 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-286) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:50]([Cl:51])=[CH:49][C:5]2[NH:6][C:7]([CH2:9][CH2:10][CH:11]3[CH2:14][CH:13]([N:15]([CH2:17][C@@H:18]4[C@H:22]5[O:23]C(C)(C)[O:25][C@H:21]5[C@H:20]([N:28]5[C:32]6[N:33]=[CH:34][N:35]=[C:36]([NH:37]CC7C=CC(OC)=CC=7OC)[C:31]=6[CH:30]=[CH:29]5)[CH2:19]4)[CH3:16])[CH2:12]3)=[N:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>FC(F)(F)C(O)=O.O>[NH2:37][C:36]1[C:31]2[CH:30]=[CH:29][N:28]([C@@H:20]3[CH2:19][C@H:18]([CH2:17][N:15]([CH:13]4[CH2:12][CH:11]([CH2:10][CH2:9][C:7]5[NH:8][C:4]6[CH:3]=[C:2]([Cl:1])[C:50]([Cl:51])=[CH:49][C:5]=6[N:6]=5)[CH2:14]4)[CH3:16])[C@@H:22]([OH:23])[C@H:21]3[OH:25])[C:32]=2[N:33]=[CH:34][N:35]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(Cl)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(Cl)c(Cl)cc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
7-((3aS,4R,6R,6aR)-6-(((3-(2-(5,6-Dichloro-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (377 mg, 0.513 mmol) was dissolved in a mixture of Trifluoroacetic Acid (7.1 ml) and Water (0.8 ml) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, then warmed to and stirring was continued for 3 h at RT. The suspension was concentrated and the residue was taken up in 15 ml MeOH and concentrated. This procedure was repeated twice and the residue placed on high vacuum. The material was taken up in 10 ml MeOH (gave a slurry) and was treated with 500 mg K2CO3 and 0.2 ml of water. The mixture was allowed to stir for 1.5 hr, during which time the pH of the solution was −9. The mixture was filtered through a fine frit, the solids were washed with 20 ml MeOH and the filtrate was concentrated to yield an off white solid. The material was left on high vacuum overnight and purified by flash chromatography (SiO2, eluting with 10-12% 7N NH3 in CH3OH/CH2Cl2) to give the desired product (227 mg). 1H NMR (400 MHz, MeOD) δH ppm 8.06 (s, 1 H), 7.63 (m, 2 H), 7.21 (dd, J=3.63, 2.38 Hz, 1 H), 6.59 (d, J=3.52 Hz, 1 H), 4.32 (m, 1 H), 3.88 (m, 1 H), 3.01 (m, 0.5 H), 2.84 (m, 2 H), 2.70 (m, 0.5 H), 2.51 (m, 1 H), 2.40 (m, 2 H), 2.26 (m, 2 H), 2.17 (d J=7.05 Hz, 3 H), 2.11 (m, 2 H), 2.02 (m, 1 H), 1.90 (m, 3 H), 1.62 (m, 1 H), 1.49 (m, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5]O)[OH:4].C(O)CO>O>[OH:1][CH2:2][C:3](=[O:4])[CH3:5].[CH2:2]([OH:1])[CH:3]([OH:4])[CH3:5]
Reactant: OCC(O)CO
Solvent: O
Solvent: OCCO
Product: CC(=O)CO
Product: CC(O)CO

Procedure:
20 wt % glycerol was dehydrated at nitrogen ambient pressure at 220° C. using 80 g of water as solvent. 1 g of 50% Cu+50% Mg catalyst of nano size catalyzed the reaction to give glycerol conversion of 24% with 79% selectivity to hydroxyacetone, 20% to 1,2-propylene glycol and 1% to ethylene glycol.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH2:13]1)C1C=CC=CC=1>[Pd].CO>[NH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH2:13]1
Reactant: Cc1ccc2c(N3CC[C@@H](CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Yield: 19.7 %

Procedure:
A solution of benzyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (0.19 g, 0.41 mmol) and MeOH (5 mL) was stirred with Pd/C (20 mg, 10% weight of Pd on carbon) under an H2 atmosphere at ambient pressure at ambient pressure overnight. Purification via silica gel chromatography using MeOH in CH2Cl2 (0-10%) gave 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (27 mg, 19%). LC/MS: m/z 335.5 (M+H)+ at 1.28 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[C:13]12([OH:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15](C3O)[CH2:14]1)[CH2:20]2.[OH:25][C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.Cl>ClCCl.N1C=CC=CC=1>[OH:24][C:13]12[CH2:14][CH:15]3[CH2:21][CH:19]([CH2:18][CH:17]([CH:7]3[O:6][C:5]([N:28]3[CH2:29][CH2:30][C@H:26]([OH:25])[CH2:27]3)=[O:11])[CH2:22]1)[CH2:20]2
Reactant: OC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O[C@H]1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OC1C2CC3CC1CC(O)(C3)C2)N1CC[C@H](O)C1
Temperature: -10 °C
Reaction time: 2.5 h

Procedure:
Triphosgene (0.58 g) dissolved in dichloromethane (10 mL) is added dropwise to a solution of adamantane-1,4-diol (1.00 g) and pyridine (10 mL) in dichloromethane (30 mL) cooled to −10° C. The solution is stirred at ca. 0° C. for 2.5 h and then (S)-3-hydroxy-pyrrolidine (0.50 mL) is added. The resulting solution is stirred overnight while warming to room temperature. The solution is then diluted with dichloromethane (50 mL) and chilled in an ice bath. 4 M hydrochloric acid (25 mL) is added and the resulting mixture is stirred for 5 min. The organic phase is separated and washed with 4 M hydrochloric acid and water. The organic phase is dried (MgSO4) and concentrated to give the title compound as a mixture of diastereomers (ca. 1:1). Yield: 0.98 g (59% of theory); Mass spectrum (ESI+): m/z=282 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[OH:12].[CH3:13][O:14][CH2:15]Br>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][CH2:13][O:14][CH3:15]
Reactant: COc1ccc(Br)c(O)c1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(OC)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 92410.5 %

Procedure:
1 -Bromo-4-metboxy-2-methoxymethoxybenzene. To a suspension of NaH (2.5 g, 0.06 mol) in dry DMF (100 mL) at 0° C. was added solution of 1-bromo-2-hydroxy-4-methoxybenzene (10.6 g, 0.05 mol). After stirring at 0° C. for 30 min. bromomethyl methyl ether (7.8 g, 0.06 mmol) were dropwise added. The mixture was warmed to room temperature over 20 min. and then stirred for 2 h, it was then quenched cautiously by the addition of cold dilute HCl and extracted with EtOAc. The EtOAc extract was washed successively with; H2O, 5% aqueous NaHCO3, H2O and finally brine. After drying (MgSO4) filtration and evaporation gave liquid. The product was purified by distillation (85° C., 0.2 mm Hg) to give the title compound as a colorless oil (13.7 g, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[CH:19]=[CH:20]C2N(O)N=[N:24][C:22]=2[CH:23]=1.N1CCCCC1.CCN(CC)CC>C(Cl)Cl>[CH3:16][C:10]1([CH3:17])[C@@H:11]([C:13]([N:24]2[CH2:20][CH2:19][CH2:18][CH2:23][CH2:22]2)=[O:15])[CH2:12][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCCCC2)C1(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.79 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.500 g, 2.057 mmol) in DCM (20 ml) EDCI (0.472 g, 2.469 mmol) and HOBt (0.378 g, 2.469 mmol) were added at 0° C. and after 10 minutes, piperidine (0.4 ml, 4.115 mmol) and Et3N (1.42 ml, 10.288 mmol) were added drop wise and the reaction mass was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, sat. NaHCO3 solution, water, 1N HCl, water, saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude residue was stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum to afford the title compound. Wt: 0.400 g; Yield: 62.79%; 1H NMR (300 MHz, CDCl3): δ 4.77 (d, 1H, J=8.4 Hz), 3.89-3.78 (m, 1H), 3.77-3.67 (m, 1H), 3.49-3.28 (m, 3H), 2.87-2.76 (m, 1H), 2.40-2.18 (m, 2H), 1.70-1.46 (m, 6H), 1.43 (s, 9H), 1.33 (s, 3H), 0.87 (s, 3H); Mass: [M+1]+ 311 (35%), [M+Na]+ 333 (100%); IR (KBr, cm−1): 3337, 2939, 1712, 1628, 1522, 1456, 1445, 1388, 1353, 1366, 1288, 1264, 1254, 1217, 1172, 1047, 1026, 1013, 976; M.R: 176.0° C.-178.0° C.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:10][C:11]([F:19])([F:18])[C:12]([O:14][CH2:15][CH2:16]Cl)=[O:13].[F:20][C:21]([F:25])=[C:22]([F:24])[F:23]>COCCOCCOC.O>[F:10][C:11]([F:19])([F:18])[C:12]1([C:22]([F:24])([F:23])[C:21]([F:25])([F:20])[O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:14][CH2:15][CH2:16][O:13]1
Reactant: O=C(OCCCl)C(F)(F)F
Reactant: FC(F)=C(F)F
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: FC(F)(F)C1(C(F)(F)C(F)(F)Oc2ccccc2)OCCO1
Yield: 73.3 %

Procedure:
A suspension of 12.0 g (0.25 mol) of 50% NaH in mineral oil in 100 mL of dry diglyme (diethylene glycol dimethyl ether) was stirred at 25° under nitrogen while a solution of 23.5 g (0.25 mol) of phenol in 50 mL of diglyme was added. The resulting mixture was stirred until evolution of gas ceased, then charged into a 400 mL metal tube along with 44.3 g (0.25 mol) of 2-chloroethyl trifluoroacetate and 40 g (0.70 mol) of tetrafluoroethylene. The resulting mixture was agitated for 6 h while the temperature rose to 34° and subsided. Next the mixture was heated at 50 ° for 6 h. The resulting reaction mixture was added to 1 L of water, thereby causing the formation of layers. The lower layer was separated, washed with water, dried over CaSO4, and distilled to give 61.2 g (73% yield) of 2-trifluoromethyl-2-(2-phenoxytetrafluoroethyl)-1,3-dioxolane, b.p. 64°-67° at 13 Pa (0.1 mm). The IR (CCl4) and NMR (CCl4) spectra of the product were consistent with the structure assignment. Anal.: Calcd. for C12H9F7O3 : C, 43.13; H, 2.71; F, 39.80. Found: C, 43.23; H, 2.75; F, 39.90.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH3:3].CN(CCN(C)C)C.C([Li])CCC.[CH2:25]([Sn:29](Cl)([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CCCCCC>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]([Sn:29]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:10][N:9]=[CH:8]1)[CH3:3]
Reactant: CN(C)CCCn1ccnc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cncn1CCCN(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
1-(N,N-Dimethylaminopropyl)-imidazole (3 g) was added to a mixture of TMEDA (7 ml) and n-butyl lithium (29.4 ml, 1.6 M) in n-hexane (25 ml) at −20° C. under nitrogen. After 30 minutes at −20° C. and 30 minutes at 20° C., the mixture was recooled to −20° C. and tri-n-butylstannyl chloride (13.05 ml) was added dropwise. The mixture was allowed to warm to 20° C. and stirred there for 20 hours. The mixture was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate and combined organic extracts were dried and concentrated. Purification by flash chromatography gave the title compound (2.10 g); δH CDCl3 7.70 (1H, s), 7.01 (1H, s), 3.98 (2H, t), 2.20(6H, s), 2.20 (2H, t), 1.90 (2H, m) 1.55 (6H, m), 1.37 (12H, m), 0.92 (9H, m).