Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[NH2:46][OH:47].O>C(Cl)Cl.CN(C=O)C.[NH4+].[Cl-]>[CH3:20][C:19]1[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]2[CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH:46][OH:47])=[O:28])=[CH:24][CH:23]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: NO
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(C(=O)NO)cc1
Reaction time: 0.25 h
Yield: 16.3 %

Procedure:
To a cold (0° C.) solution of 4-(3,3″-Dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid (0.124 g,0.31 mmol) in CH2Cl2 (3 mL) and DMF (5 drops) was added oxalyl chloride (0.11 mL, 1.26 mmol). After 15 minutes, the mixture was concentrated and provided a beige solid. The solid was dissolved in DMF (3 mL) and treated with DIPEA (0.50 mL, 2.87 mmol) followed by NH2OH.H2O (72 mg, 1.04 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was diluted with saturated aqueous NH4Cl (5 mL) and extracted with CH2Cl2 (5×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 5:1:1 CH2ClN—CH3OH—NH4OH) provided 21 mg (16%) of COMPOUND 72 as a white solid. 1H NMR (CDCl3) δ 1.48-1.67 (m, 3H), 1.88-2.13 (m, 3H), 2.31 (s, 6H), 3.46 (s, 2H), 3.94 (d, 2H, J=10.5 Hz), 6.54 (d, 2H, J=6.9 Hz), 6.93 (dd, 2H, J=7.5, 4.5 Hz), 7.26-7.39 (m, 4H), 8.28 (d, 2H, J=3.3 Hz); ES-MS m/z 417 (M+H).
Reaction SMILES: FC1C=CC(NCC2C(CO)=C(O)C(C([NH:18][OH:19])=O)=NC=2)=CC=1.[F:23][C:24]1[CH:46]=[CH:45][C:27]([CH2:28][CH2:29][NH:30][CH2:31][C:32]2[C:33]([CH2:43][OH:44])=[C:34]([OH:42])[C:35]([C:38](OC)=[O:39])=[N:36][CH:37]=2)=[CH:26][CH:25]=1>>[OH:19][NH:18][C:38]([C:35]1[C:34]([OH:42])=[C:33]([CH2:43][OH:44])[C:32]([CH2:31][NH:30][CH2:29][CH2:28][C:27]2[CH:45]=[CH:46][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:37][N:36]=1)=[O:39]
Reactant: O=C(NO)c1ncc(CNc2ccc(F)cc2)c(CO)c1O
Reactant: COC(=O)c1ncc(CNCCc2ccc(F)cc2)c(CO)c1O
Product: O=C(NO)c1ncc(CNCCc2ccc(F)cc2)c(CO)c1O

Procedure:
Product 22 was synthesized following a procedure similar to the one described above for the synthesis of 5-((4-fluorophenylamino)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide starting from methyl 5-((4-fluorophenethylamino)methyl)-3-hydroxy-4-(hydroxymethyl)picolinate (compound 22b). 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.08 (s, 1H), 7.24 (m, 2H), 7.09 (t, J=7.2 Hz, 2H), 4.58 (s, 2H), 3.92 (s, 2H), 2.80 (m, 2H), 2.76 (m, 2H). MS-ESI m/z 336 [MH]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH:13]([C:16]1[CH:35]=[CH:34][C:19]([CH2:20][O:21][C:22]2[C:29]([O:30][CH3:31])=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=2[O:32][CH3:33])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>CC(O)C>[CH:13]([C:16]1[CH:35]=[CH:34][C:19]([CH2:20][O:21][C:22]2[C:29]([O:30][CH3:31])=[CH:28][C:25]([CH:26]=[N:8][NH:7][C:5](=[O:6])[C:4]3[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([NH2:1])[CH:3]=3)=[CH:24][C:23]=2[O:32][CH3:33])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: COc1cc(C=O)cc(OC)c1OCc1ccc(C(C)C)cc1
Reactant: NNC(=O)c1ccc(O)c(N)c1
Solvent: CC(C)O
Product: COc1cc(C=NNC(=O)c2ccc(O)c(N)c2)cc(OC)c1OCc1ccc(C(C)C)cc1
Yield: 103.6 %

Procedure:
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above 4-(4-isopropylbenzyloxy)-3,5-dimethoxybenzaldehyde(93 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2×4 ml) and dried by suction to afford 144 mg (100%) of the title compound as a solid. M.p.: 174-175° C.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C@@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[C:15]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[CH2:19][CH:16]1[CH2:17][CH2:18][N:14]([C@H:11]2[CH2:10][CH2:9][C@@H:8]([CH2:7][OH:6])[CH2:13][CH2:12]2)[C:15]1=[O:28]
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@@H](N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Cl)cc2Cl)CCN1[C@H]1CC[C@@H](CO)CC1
Reaction time: 8 h

Procedure:
Dissolve 1-[cis-4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexyl]-3-(2,4-dichloro-benzyl)-pyrrolidin-2-one (Preparation 37) (0.12 g, 0.25 mmol) in THF (50 mL) and add TBAF (0.50 mL, 1.0 M in THF) at room temperature under nitrogen. Stir the solution overnight. Then add water (50 mL) and extract the aqueous layer with dichloromethane (3×100 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 50-80% EtOAc-Hexane) to give 0.085 g (95%) of the title compound as a white solid: Mass spectrum (ion spray): m/z=356.2, 358.2 (M+1).
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:31]/[C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[N:3]1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
(1H-indazol-3-ylmethyl)triphenylphosphonium iodide (3.20 g, 6.15 mmol) obtained in Step 4 was dissolved in methanol (60 mL), and the solution was added with methyl p-formylbenzoate (1.00 g, 6.09 mmol) and potassium carbonate (2.55 g, 18.5 mmol), followed by stirring at room temperature overnight. The reaction mixture was added with water, and was extracted with ethyl acetate, then the organic layer was washed with saturated brine, and was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin-layer chromatography (chloroform/methanol=15/1), was further triturated in mixed solvent of ethyl acetate/diisopropyl ether to obtain methyl (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoate (0.87 g, 51%).
Reaction SMILES: [CH:1]1([S:4]([N:7]2[C:11]3=[CH:12][C:13]4[S:17][N:16]=[N:15][C:14]=4[C:18]([F:19])=[C:10]3[N:9]([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])C2=O)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+]>C1COCC1>[F:19][C:18]1[C:14]2[N:15]=[N:16][S:17][C:13]=2[CH:12]=[C:11]([NH:7][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:5])=[O:6])[C:10]=1[NH:9][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27]
Reactant: O=c1n(-c2ccc(I)cc2F)c2c(F)c3nnsc3cc2n1S(=O)(=O)C1CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc2snnc2c(F)c1Nc1ccc(I)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of 7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (70 mg, 0.13 mmol) in THF (5 mL) was added potassium trimethylsilanolate (17 mg, 0.13 mmol). After stirring at room temperature for 1 h, the reaction was quenched with saturated NH4Cl (aq.). The aqueous layer was extracted with ethyl acetate (6 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the corresponding product (40 mg, 60.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H), 8.37 (s, 1H), 7.73 (s, 1H), 7.60 (dd, 1H), 7.30 (dd, 1H), 6.45 (m, 1H), 2.77 (m, 1H), 1.01-0.99 (m, 2H), 0.89-0.86 (m, 2H). MS APCI (+) m/z: 508.7, [M+H].
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[CH:15]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1.[CH3:20]COCC>CO>[O:5]=[C:6]1[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: CCOCC
Reactant: O=C(O)Cc1cc(=O)[nH]c2ccccc12
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(=O)[nH]c2ccccc12
Reaction time: 8 h
Yield: 80 %

Procedure:
95 g (0.8 mol) of thionyl chloride are added dropwise in the course of approximately 1 h to a stirred suspension of 60 g (0.295 mol) of 2-oxo-1,2-dihydro-4-quinolineacetic acid in 1 1 of methanol. The mixture is left overnight. The solvent is driven off and the residue obtained is dissolved in 300 ml of boiling methanol. After the mixture is cooled, 300 ml of ether are added. The solid is drained and then recrystallized in methanol. 51.5 g (80%) of methyl 2-oxo-1,2-dihydro-4-quinolineacetate, melting point 209°-210° C., are obtained
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16](OCC)=[O:17])[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O>[CH3:1][N:2]([CH3:21])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][OH:17])[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C1CCc2[nH]c3ccc(CO)cc3c2C1
Reaction time: 1 h

Procedure:
A solution of 12.8 g. of 3-(dimethylamino)-6-ethoxycarbonyl-1,2,3,4-tetrahydrocarbazole (Example 43) in 350 ml. of dry tetrahydrofuran was added dropwise to a refluxing solution of 3.5 g. of lithium aluminum hydride in 100 ml. of dry tetrahydrofuran and refluxing was continued for one hour after completion of the addition. Ethyl acetate was added followed by water, the mixture was filtered, and the filtrate was evaporated to dryness to give, after recrystallization from ethyl alcohol, 6.4 g. of 3-(dimethylamino)-6-hydroxymethyl-1,2,3,4-tetrahydrocarbazole, m.p. 195°-197° C.
Reaction SMILES: C(C1C=CC(C#C)=CC=1OC1C=CC(C)=CC=1)(C)(C)C.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][Si](C)(C)C)=[CH:27][C:26]=1[O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]#[CH:32])=[CH:27][C:26]=1[O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: CCc1ccc(Oc2cc(C#C[Si](C)(C)C)ccc2C(C)(C)C)cc1
Agent: C#Cc1ccc(C(C)(C)C)c(Oc2ccc(C)cc2)c1
Product: C#Cc1ccc(C(C)(C)C)c(Oc2ccc(CC)cc2)c1

Procedure:
Employing the same general procedure as for the preparation of 2-tert-butyl-5-ethynyl-1-[(4′-methyl)phenoxy]benzene (Compound W), 40 mg (0.1 mmol) 2-tert-butyl-5-trimethylsilanylethynyl-1-[(4′-ethyl)phenoxy]benzene (Compound V) was converted into the title compound using 4.3 mg (0.03 mmol) of potassium carbonate, 3 mL of methanol and 1 mL of dichloromethane. Purification by flash chromatography (silica, 100% hexane) gave the title compound as a clear, yellow oil.
Reaction SMILES: C[C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=CC=CC=1.[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([CH2:26][C:27](Cl)=O)=[CH:24][CH:23]=1.Cl>ClCCl>[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][CH2:27][C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:2][CH3:10])=[O:8])=[CH:30][CH:31]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccc(OCc2c(F)cccc2F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCc1ccc(OCc2c(F)cccc2F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Meldrum's acid (0.846 g, 5.8 mmol) in dichloromethane (5 ml) was added pyridine (2 ml) over a period of 10 minutes at 0° C. To this solution was added 4-(2,6-Difluorobenzyloxy)benzylcarbonyl chloride (Step D, 1.71 g, 5.7 mmol) in dichloromethane (5 ml), which resulted in an orange solution. The dark orange solution was stirred for 1 hour at 0° C., allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was diluted with dichloromethane and poured onto 2M HCl and ice. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed twice with 2M HCl and brine, dried over Na2SO4, filtered and concentrated to a solid. The solid was suspended in abs EtOH (15 ml) and refluxed for 2.5 hours. The solvent was removed in vacuo to give a dark oil. The residue was purified by flash chromatography on silica gel column (hex:ethyl acetate, 2:1) to provide the title compound as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:14][S:13][C@@H:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[S:11]1)(C(C)(C)C)(C)C>CO.C(Cl)(=O)C.[Cl-].[NH4+]>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])([C@H:12]1[S:11][C@@H:10]([CH2:9][OH:8])[CH2:14][S:13]1)=[O:16])[CH3:19]
Reactant: CCOP(=O)(OCC)[C@@H]1SC[C@H](CO[Si](C)(C)C(C)(C)C)S1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)Cl
Product: CCOP(=O)(OCC)[C@@H]1SC[C@H](CO)S1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of cis-4-(t-butyldimethylsilyloxymethyl)-2-(diethyloxyphosphinoyl)-1,3-dithiolane (example 49) (3.70 g, 9.56 mmol) in anhydrous methanol (50 mL) was added acetyl chloride (6 drops) at 0° C. The solution was stirred at 0° C. for 30 min and then at room temperature for 4.5 hrs. A saturated solution of ammonium chloride (3 drops) was added and the solution was stirred for 15 min followed by evaporation of solvents. The crude material was purified by flash chromatography with a mixture of dichloromethane and methanol (95:5) to give the compound (2.02 g) in 77% yield. 1H NMR (300 MHz, CDCl3) δ: 1.34 (t, 6H, J=7.0 Hz, CH3), 3.30 (dd, 1H, J=5.5 Hz, 12.0 Hz, H-5a), 3.42 (dd, 1H, J=6.0 Hz, 12.1 Hz, H-5b), 3.80 (m, 2H, CH2OH and 1H, OH), 4.05 (m, 1H, H-4) , 4.19 (m, 4H, CH2) , 4.35 (d, 1H, 2JHP =4.1 Hz, H-2).
Reaction SMILES: C(=O)=O.C(O)(C)C.[Si]([N:15]1[C:19](=[O:20])[CH2:18][S:17][CH2:16]1)(C(C)(C)C)(C)C.[Si](OC1CSCN=1)(C(C)(C)C)(C)C.Br[CH2:35][CH2:36][CH2:37][CH2:38]Br>C1COCC1.CCOC(C)=O.CCCCCC>[S:17]1[C:18]2([CH2:38][CH2:37][CH2:36][CH2:35]2)[C:19](=[O:20])[NH:15][CH2:16]1
Reactant: BrCCCCBr
Reactant: CC(C)(C)[Si](C)(C)N1CSCC1=O
Agent: CC(C)(C)[Si](C)(C)OC1=NCSC1
Agent: O=C=O
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1NCSC12CCCC2
Temperature: -75 °C
Reaction time: 1.17 h

Procedure:
To a -75° C. (CO2 /isopropanol bath) mixture of lithium bis(trtmethylsilyl)amide (0.151 mol) and THF (151 mL) under nitrogen was added a 0° C. solution prepared from 14.95 g of a 70:30 mixture between 3-t-butyldimethylsilyl-4-oxothiazolidine and 4-t-butyldimethylsilyloxy-3-thiazoline (prepared as in Example 1) and 1,4-dibromobutane (14.85 g) in THF (50 mL) over a period of 0.5 h. The resultant homogeneous solution was stirred at -75° C. for 70 min. TLC analysis (silica gel, 10% EtOAc/hexane) showed a major product, (Rf =0.48) and a minor product (Rf =0.31). The reaction mixture was removed from the cold bath and acidified with 2N HCl (200 mL). The aqueous mixture was stirred rapidly for 3.5 h at room temperature, placed in vacuo to remove the tetrahydrofuran, and extracted with dichloromethane (5×75 mL). The organic extracts were dried over Na2SO4 and concentrated in vacuo to yield 14.2 g of an oily solid. The crude oily product was chromatographed (Waters Prep 500, 2 silica gel columns, 20% hexane/ethyl acetate) to give 2.75 g of a white solid (Rf =0.45). Recrystallization from diethyletherhexane yielded 1.37 g of a crystalline solid, mp 92°-94° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.C([O:12][C:13]1[CH:38]=[CH:37][C:16]([C:17]([NH:19][C:20]2[CH:28]=[C:27]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[O:18])=[CH:15][CH:14]=1)(=O)C>O1CCCC1>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]2[CH:28]=[C:27]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[O:18])=[CH:37][CH:38]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2cc(CCc3ccccc3)ccc2C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(CCc2ccccc2)ccc1C(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10 mg of potassium carbonate were added to a mixed solution of 1.0 mL of methanol and 1.0 mL of tetrahydrofuran containing 20 mg of 2-(4-acetoxybenzamido)-4-phenethylbenzoic acid and stirred at room temperature for 3 hours. After insoluble were removed by filtration, 3.0 mL of 10% citric acid aqueous solution was added and a solid substance was separated by filtration to obtain 15 mg of 2-(4-hydroxybenzamido)-4-phenethylbenzoic acid as white solid.
Reaction SMILES: OC(CN(C)C)COC1C=CC(N[C:10]2[N:15]=[C:14]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17]3)[C:13](C)=[CH:12][N:11]=2)=CC=1.[OH:32][CH:33]([CH2:58][N:59]([CH3:61])[CH3:60])[CH2:34][O:35][C:36]1[CH:57]=[CH:56][C:39]([NH:40]C2N=C(N3C4C(=CC=CC=4)CC3)C=CN=2)=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[OH:32][CH:33]([CH2:58][N:59]([CH3:61])[CH3:60])[CH2:34][O:35][C:36]1[CH:57]=[CH:56][C:39]([NH:40][C:12]2[N:11]=[CH:10][N:15]=[C:14]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH:13]=2)=[CH:38][CH:37]=1
Reactant: CN(C)CC(O)COc1ccc(Nc2nccc(N3CCc4ccccc43)n2)cc1
Reactant: Cc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1-n1ccc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(C)CC(O)COc1ccc(Nc2cc(N3CCc4ccccc43)ncn2)cc1
Yield: 32.9 %

Procedure:
A solution of 4-chloro-6-(indolin-1-yl)pyrimidine (Method 15, 220 mg, 0.95 mmol) and 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 1, 229 mg, 0.81 mmol) in NMP (5 ml) was heated to 150° C. for 1 hour. Sodium bicarbonate solution (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The extracts were washed with water (2×10 ml) and dried. Silica (1 g) was added and volatile material removed by evaporation. The residue was purified by column chromatography, eluting with 0-8% 2.0M methanolic ammonia solution in DCM, to give the product as a colourless solid (108 mg). NMR: 2.18 (s, 6H), 2.32 (m, 2H), 3.17 (m, 2H), 3.86 (m, 5H), 4.78 (d, 1H), 5.96 (s, 1H), 6.85 (m, 3H), 7.16 (m, 2H), 7.44 (d, 2H), 8.26 (m, 2H), 9.02 (s, 1H); MS (MH+): 406.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:41])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([N:14]5[CH2:15][CH2:16][O:17][CH2:18][CH2:19]5)=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[O:39][N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCOCC4)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCOCC5)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M3) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (29 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]#[N:11])=[C:4]([CH3:12])[N:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:8]([C:7]1[C:2]([N:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[N:3][C:4]([CH3:12])=[C:5]([C:10]#[N:11])[CH:6]=1)#[N:9]
Reactant: COC(OC)N(C)C
Reactant: Cc1nc(N)c(C#N)cc1C#N
Solvent: Cc1ccccc1
Product: Cc1nc(N=CN(C)C)c(C#N)cc1C#N
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A solution of 2-Amino-6-methyl-pyridine-3,5-dicarbonitrile (0.158 g, 1.0 mmol) and N,N-Dimethylformamide dimethyl acetal (0.119 g, 1.0 mmol) in toluene (10 mL) was heated at reflux for 6 hours. After cooling to room temperature, the solution was concentrated under vacuum to provide the title compound as a brown solid (0.2 g, 94%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]([OH:26])([CH3:25])[CH3:24].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[C:23]([OH:26])([CH3:25])[CH3:24])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(O)c1ccncc1Br
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(O)c1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 18.8 %

Procedure:
Using the same reaction conditions as described in example 14, 1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 125 mg, 0.57 mmol) was reacted with 2-(3-bromo-pyridin-4-yl)-propan-2-ol (SM-156a: 122.7 mg, 0.57 mmol), 1,4-dioxane (5 mL), copper iodide (10.85 mg, 0.057 mmol), trans-1,2-diamino cyclohexane (19.57 mg, 0.171 mmol) and potassium phosphate (362.9 mg, 1.71 mmol) to afford the crude product. Purification by preparative HPLC afforded 38 mg of the product (19% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[CH:4][C:3]=1[C@@H:17]([CH3:27])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CI.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])([CH3:16])[O:9]2)[CH:5]=[CH:4][C:3]=1[C@@H:17]([CH3:27])[CH2:18][N:19]([CH3:30])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: [Na+]
Solvent: CI
Product: C[C@@H](CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Yield: 83.9 %

Procedure:
Following the procedure described for Example 647, (R)-tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (400 mg, 1 mmol) was reacted with methyl iodide (1M solution in toluene, 2 mL, 2 mmol) and NaHMDS (1 M solution, 2 mL, 2 mmol) to afford the desired product (330 mg, 82%) as viscous mass. ESI MS m/z 394 [C21H38BFNO4+H]+
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Cl[CH2:10][CH2:11][CH2:12][Si:13]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:15]>>[OH:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][C:1]=1[CH2:10][CH2:11][CH2:12][Si:13]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:15]
Reactant: Cc1ccc(O)cc1
Reactant: CO[Si](CCCCl)(OC)OC
Product: CO[Si](CCCc1cc(C)ccc1O)(OC)OC
Yield: 99 %

Procedure:
As shown in Scheme 2, a new 3-arylpropyl trimethoxysilane compound, 3-(2-hydroxy-5-methylphenyl)-propyltrimethoxysilane (abbreviated PholTMS) was synthesized. 60 g of p-cresol and 100 g of 3-chloropropyltrimethoxysilane were mixed under reflux for 24 hours. The product was confirmed by NMR spectrum, and the yield was more than 99%. 1H NMR of PholTMS (400 MHz, CD3OD): δ0.65 (t, 2H), 1.56 (p, 2H), 2.34 (s, 3H), 2.63 (t, 2H), 3.58 (s, 9H), 6.5-7 (m, 3H).