Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[OH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1>C(N(CC)CC)C.C1COCC1>[C:31]([C:30]1[CH:34]=[CH:35][C:27]([O:26][C:18]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)/[C:9](=[CH:8]/[C:3]3[NH:4][C:5]([CH3:7])=[CH:6][C:2]=3[CH3:1])/[C:10]2=[O:25])=[O:19])=[CH:28][CH:29]=1)([OH:33])=[O:32]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Oc3ccc(C(=O)O)cc3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indol-2-one (332 mg, 1.0 mmol), 4-hydroxybenzoic acid (138 mg, 1.0 mmol), and 2 drops of triethylamine in 3.0 mL of THF was stirred at room temperature overnight and concentrated. The residue was then purified on a silica gel column eluting with ethyl acetate-hexane (1:3) and 0.5% of acetic acid in ethyl acetate-dichloromethane (2:1) to afford 150 mg (37%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 4-carboxy-phenyl ester. 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, vbr, 1H, COOH), 12.60 (s, br, 1H, NH-1′), 8.12 (d, J=7.39 Hz, 2H), 7.86–7.88 (m, 1H), 7.64 (s, vbr, 1H), 7.51 (s, 1H, H-vinyl), 7.43 (d, J=7.39 Hz, 2H), 7.21–7.23 (m, 2H), 6.09 (s, br, 1H, H-4′), 2.40 (s, 3H, CH3), and 2.38 (s, 3H, CH3).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([I:12])=[CH:14][CH:15]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(I)cc1

Procedure:
Prepared by a method analogous to that described for the preparation of Intermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 4-iodobenzoic acid; the compound was purified by solid phase extraction on silica gel using ammoniated methanol/chloroform mixtures as the eluent followed by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were evaporated, the residue was dissolved in methanol, excess hydrogen chloride solution (4M in 1,4-dioxane) was added and the solution was evaporated to give the hydrochloride salt of the title compound as a colourless solid; MS (ES+) 357 (MH+).
Reaction SMILES: [CH2:1]([N:19]([CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])[C:20]([CH2:22][CH2:23][CH:24]([CH:26]1[C:42]2([CH3:43])[CH:29]([CH:30]3[CH:39]([CH2:40][CH2:41]2)[C:38]2([CH3:44])[CH:33]([CH2:34][CH:35]([O:45][C:46](=[O:86])[NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53]([N:55]4[CH2:59][CH:58]([OH:60])[CH2:57][CH:56]4[CH:61]([C:80]4[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=4)[O:62][CH:63]([C:72]4[CH:77]=[CH:76][C:75]([O:78][CH3:79])=[CH:74][CH:73]=4)[C:64]4[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][CH:65]=4)=[O:54])[CH2:36][CH2:37]2)[CH2:32][CH2:31]3)[CH2:28][CH2:27]1)[CH3:25])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:105]1(=[O:111])[O:110][C:108](=[O:109])[CH2:107][CH2:106]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:71][O:70][C:67]1[CH:68]=[CH:69][C:64]([CH:63]([C:72]2[CH:77]=[CH:76][C:75]([O:78][CH3:79])=[CH:74][CH:73]=2)[O:62][CH:61]([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)[CH:56]2[N:55]([C:53](=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][NH:47][C:46]([O:45][CH:35]3[CH2:34][CH:33]4[C:38]([CH3:44])([CH:39]5[CH:30]([CH2:31][CH2:32]4)[CH:29]4[C:42]([CH3:43])([CH:26]([CH:24]([CH3:25])[CH2:23][CH2:22][C:20](=[O:21])[N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])[CH2:27][CH2:28]4)[CH2:41][CH2:40]5)[CH2:37][CH2:36]3)=[O:86])[CH2:59][CH:58]([O:60][C:105](=[O:111])[CH2:106][CH2:107][C:108]([OH:110])=[O:109])[CH2:57]2)=[CH:65][CH:66]=1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(OC(=O)NCCCCCC(=O)N5CC(O)CC5C(OC(c5ccc(OC)cc5)c5ccc(OC)cc5)c5ccccc5)CCC4(C)C3CCC12C
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(OC(=O)NCCCCCC(=O)N5CC(OC(=O)CCC(=O)O)CC5C(OC(c5ccc(OC)cc5)c5ccc(OC)cc5)c5ccccc5)CCC4(C)C3CCC12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
Referring to scheme 21, Compound 84 (1.44 g, 1 mmol) was mixed with succinic anhydride (0.15 g, 1.5 mmol) and DMAP (0.0122 g, 0.1 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.101 g, 0.14 mL, 1 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 16 h. It was then diluted with dichloromethane (50 mL) and washed with ice cold aqueous citric acid (5% wt., 25 mL) and water (2×25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to afford compound 86 as white solid (1.1 g, 71% yield; Rf=0.5 in 10% MeOH/CHCl3).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[IH:10].[CH3:11][NH:12][C:13](=[N:16][CH3:17])SC.CS>C(O)C>[IH:10].[CH3:11][NH:12][C:13]([NH:16][CH3:17])=[N:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: CN=C(NC)SC
Agent: CS
Agent: I
Solvent: CCO
Product: CNC(=NCCc1ccccc1)NC

Procedure:
2-phenylethylamine (2.4 g.), N,N',S-trimethylisothiourea hydriodide (4.92 g.) and ethanol (70 ml.), were boiled together under reflux for eight hours; methyl mercaptan was evolved. The resulting solution was evaporated to dryness and the residue recrystallised from methanol/ether mixture to yield N,N'-dimethyl-N"-2-phenylethylguanidine hydriodide, melting point 156°-160°C.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]1.O>C(O)C>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH2:19][CH2:20][O:21][CH:22]2[CH2:23][C:24]([CH3:31])([CH3:30])[NH:25][C:26]([CH3:28])([CH3:29])[CH2:27]2)=[CH:8][CH:7]=1
Reactant: CC1(C)CC(OCCBr)CC(C)(C)N1
Reactant: Oc1ccc(-c2nc3ccccc3o2)cc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(OCCOc2ccc(-c3nc4ccccc4o3)cc2)CC(C)(C)N1

Procedure:
Equal molar quantities of p-hydroxybenzaldehyde and o-aminophenol in excess nitrobenzene was refluxed for five hours. The nitrobenzene was removed and the residue was washed with hot xylene. 2-(4-Hydroxyphenyl)benzoxazole was obtained by crystallization from ethanol in 64% yield (m.p. 253°). A mixture of the sodium salt of 2-(4-hydroxyphenyl)benzoxazole (0.01 mole) and 4-(2-bromoethoxy)-2,2,6,6-tetramethylpiperidine (0.01 mole) in 250 ml of ethanol was refluxed for 20 hours. The reaction mixture was cooled, 200 ml. of water was added and the product, I, was filtered out.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+].C(OCC)C.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[O:26]=[C:17]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)CCc1ccccc1)C(=O)O
Yield: 84.6 %

Procedure:
L-Leucine (7.87 g, 60 mmol) was dissolved in a solution of sodium hydroxide (4.8 g, 120 mmol) in water (40 ml, 1.5M). Diethyl ether (40 ml) was added. The mixture was cooled in an ice bath and while stirring rapidly, hydrocinnamoyl chloride (10.1 g, 8.92 ml, 60 mmol) was added dropwise over a period of 30 minutes. The ice bath was removed and the mixture was stirred at room temperature 2 hours, maintaining a slightly basic pH by periodic addition of small amounts of 1N sodium hydroxide solution. The layers were separated. The ether layer was reextracted with 1N sodium hydroxide solution. The combined aqueous layers were washed once with ether and then acidified with concentrated hydrochloric acid. The product was extracted into chloroform, dried over magnesium sulfate, and freed of solvent in vacuo leaving a white solid (13.36 g). This material was recrystallized from ethyl acetate (65 ml) to give 8.37 g of the title B compound (53%), m.p. 129°-130° C. [α]D =-41.3° (c=1.3, MeOH).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2.[CH3:18][NH:19][CH3:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:18][N:19]([CH3:20])[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2CCCCl
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C)CCCN1CCSc2cc([N+](=O)[O-])ccc21
Yield: 41.5 %

Procedure:
A solution of 4-(3-chloropropyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.7 g, 2.57 mmol), dimethylamine (2M solution in THF) (2.57 mL, 5.13 mmol), potassium iodide (0.426 g, 2.57 mmol), and potassium carbonate (1.773 g, 12.83 mmol) in dry acetonitrile (20 mL) was stirred at 80° C. for 6 hours in a sealed tube. The reaction was then brought to room temperature and diluted with water (60 mL), and the product was extracted into ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (1:9 (2 M NH3 in MeOH):CH2Cl2) on silica gel to obtain the title product (0.3 g, 42%) as a thick syrup. 1H NMR (DMSO-d6) δ 7.85-7.80 (m, 2H), 6.85 (d, 1H, J=8.7 Hz), 3.77 (t, 2H, J=5.1 Hz), 3.47 (t, 2H, J=7.2 Hz), 3.06 (t, 2H, J=5.1 Hz), 2.24 (t, 2H, J=6.6 Hz), 2.14 (s, 6H), 1.75-1.65 (m, 2H); ESI-MS (m/z, %): 282 (MH+, 100).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=4[C:18]([O:20]CC)=[O:19])=[N:11][N:10]3[CH:27]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCCC1>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=4[C:18]([OH:20])=[O:19])=[N:11][N:10]3[CH:27]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccccc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of ethyl 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoate (200 mg, 0.54 mmol) in tetrahydrofuran (10 mL) was added 4N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at room temperature for 3 hr. 6N Hydrochloric acid (1.5 mL) and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (130 mg, 73%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.Cl.[NH2:17][OH:18]>CCO.O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)/[C:5](=[N:17]/[OH:18])/[C:4]=2[CH:3]=1
Reactant: NO
Reactant: O=C1c2ccccc2-c2ccc(Br)cc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: O/N=C1/c2ccccc2-c2ccc(Br)cc21

Procedure:
To a solution of 2-bromo-9H-fluoren-9-one (100 mg, 0.39 mmol) in EtOH (10 mL) and water (3 mL) was added hydroxylamine hydrochloride (54 mg, 0.77 mmol). The mixture was then heated to reflux for 1 h. The solvent was then removed in vacuo, and to the residue was added aqueous NaHCO3. The solid was then filtered and dried to give the title product. LRMS (M+H)+ 274.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)OCC)cc1

Procedure:
A solution of 8.2 g. of p-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hrs. The solution is concentrated to ca. 50 ml. by distillation of the solvent and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate, dried and evaporated to yield ethyl p-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of 1-bromohexadecane, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated to 80° C. for 7 hours. The mixture is then cooled, diluted with water and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from a mixture of chloroform and hexane, yielding ethyl (4-hexadecylaminophenyl)acetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[C:4]([OH:16])[CH:3]=1.O1CCCC1.O[Li].O.Cl>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([OH:16])[CH:3]=1
Reactant: CCOC(=O)CNc1cc(Cl)c(Cl)cc1O
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Reaction time: 0.5 h
Yield: 111.5 %

Procedure:
To a solution of ethyl 2-((4,5-dichloro-2-hydroxyphenyl)amino)acetate (2 g, 7.6 mmol) in of 4:1 mixture of tetrahydrofuran and water (30 mL) at room temperature, LiOH.H2O (3.2 g, 76 mmol) were added and the resulting mixture was stirred for 30 min and then acidified with aqueous HCl (1N) to adjust the pH to 3-5. The mixture was extracted with ethyl acetate (40 mL×3). The combined organic layer was washed with brine (40 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product (2 g) which was used directly in the next step without further purification.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]([O:19][C:20](=[O:36])[NH:21][C@H:22]([C@@H:30]1[CH2:34][CH2:33][C:32](=[O:35])[O:31]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:18])([CH3:17])[CH3:16].Br[CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41]>C(=O)=O.CC(C)=O.O1CCCC1>[C:15]([O:19][C:20](=[O:36])[NH:21][C@H:22]([C@@H:30]1[CH2:34][C@@H:33]([CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41])[C:32](=[O:35])[O:31]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)=CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)=CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
To a flame dried round bottom flask under a nitrogen atmosphere was added tetrahydrofuran (40 mL) followed by 1,1,1,3,3,3-hexamethyldisilazane (8 mL, 37.8 mmol). The mixture was cooled to 0° C. and n-butyl lithium (14.5 mL of a 2.5 M solution in hexanes, 36.0 mmol) was added. The mixture was stirred for 15 minutes, then cooled to −78° C. in dry ice/acetone bath. {1(S)-[5-Oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (5 g, 16.4 mmol) (prepared by the method of Fray, J. Org. Chem., (51) 4828 (1986)) dissolved in tetrahydrofuran (50 mL) was added dropwise via syringe and stirring continued for 30 minutes. A solution of 4-bromo-2-methyl-2-butene (2.07 mL, 18.0 mmol) in 40 mL of THF was added dropwise via syringe. Stirring was continued for 3 hours during which time the temperature rose to −60° C. The mixture was quenched by slow addition of saturated, aqueous ammonium chloride (25 mL). Upon warming to room temperature, the solution was diluted with ether (300 mL) and transferred to a separatory funnel. The organic phase was washed with saturated aqueous citric acid (2×100 mL), saturated aqueous sodium bicarbonate (NaHCO3)(2×100 mL), and 100 mL brine. The organic layer was dried over magnesium sulfate (MgSO4) and the solvent removed under reduced pressure. Thin layer chromatography in 1:2 hexane/diethyl ether (Et2O) revealed product with an Rf of 0.8. The resulting crude oil was chromatographed on silica gel (225 g) eluting with 2:1 hexanes/diethyl ether to provide 4.73 g (77%) of the title compound. TLC: 1:2 Hexanes/Et2O Rf: 0.8. 1H NMR (400 MHz, CDCl3): δ7.27 ppm (5H, m), 5.02 (1H, b), 4.52 (1H, d, J=9.3 Hz), 4.42 (1H, t, J=7.1 Hz), 3.98 (1H, dt, J=8.5, 7.8 Hz), 2.93 (2H, m), 2.88 (1H, b), 2.68 (1H, m), 2.41 (1H, m), 2.24 (1H, m), 1.92 (1H, m), 1.65 (3H,s), 1.58 (3H,s), 1.37 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([NH:12][C:13](=[O:16])[CH:14]=[CH2:15])O.CC(C)=O>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:1][C:2]1[C:3]([OH:9])=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:10][NH:12][C:13](=[O:16])[CH:14]=[CH2:15]
Reactant: Cc1ccc(O)c(C)c1
Reactant: C=CC(=O)NCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: C=CC(=O)NCc1cc(C)cc(C)c1O
Yield: 84.9 %

Procedure:
A flask equipped with a condenser and a stirrer was charged with 122 g of 2,4-dimethylphenol, 101 g of N-methylolacrylamide, 1.80 g of p-toluenesulfonic acid and 100 ml of acetone, and the mixture was reacted at 60° C. for 60 minutes with stirring. The obtained reaction mixture was poured into excess water to separate an organic layer. The organic layer was dissolved in 200 ml of methylene chloride, which was washed with three 100 ml portions of water to give 174 g of N-(3,5-dimethyl-2-hydroxybenzyl)acrylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])=[S:38])=[CH:18][C:17]=1[F:23]
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (55 mg, yield 70%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([CH2:33][OH:34])=[CH:30][C:29]=2[CH:35]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:67][C:68]([F:72])([F:71])[CH2:69]O>C1C=CC=CC=1>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([CH2:33][O:34][CH2:69][C:68]([F:72])([F:71])[F:67])=[CH:30][C:29]=2[CH:35]=1
Reactant: Cc1c(COc2ccc3oc(CO)cc3c2)oc2cccc(OCCCNCc3cccnc3)c12
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: Cc1c(COc2ccc3oc(COCC(F)(F)F)cc3c2)oc2cccc(OCCCNCc3cccnc3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound of Example 40 (60 mg) and 1,1′-(azodicarbonyl)dipiperidine (64 mg) were suspended in dry benzene (2 ml). To the suspension was added tributylphosphine (63 μl) at room temperature. The mixture was stirred at room temperature for 15 minutes. To the mixture was added 2,2,2-trifluoroethanol (74 μl). The mixture was stirred at room temperature overnight. After removing the solvent the reaction mixture was separated by silica gel column chromatography developed by the solvent mixture of dichloromethane and methanol. The title compound (57 mg) was obtained as a colorless oil. ESI-MS: m/z 555 (MH+); 1H-NMR (CDCl3): δ 2.05 (2H, quintet, J=6.5 Hz), 2.33 (3H, s), 2.87 (2H, t, J=7 Hz), 3.83 (2H, s), 3.91 (2H, q, 8.5 Hz), 4.14 (2H, t, J=6 Hz), 4.74 (2H, s), 5.10 (2H, s), 6.60 (1H, d, J=7 Hz), 6.71 (1H,s), 6.95-7.25 (5H, m), 7.38 (1H, d, J=9 Hz), 7.66 (1H, dt, J=7.5 Hz, 2 Hz), 8.48 (1H, dd, J=1.5 Hz, 4.5 Hz), 8.56 (1H, d, J=1.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](Cl)=[O:7].C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:26][N:27]1[CH2:31][CH2:30][C@@H:29]([NH2:32])[CH2:28]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([NH:32][C@@H:29]1[CH2:30][CH2:31][N:27]([CH3:26])[CH2:28]1)=[O:7]
Reactant: CN1CC[C@@H](N)C1
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
3-methoxy-4-nitro-benzoyl chloride (Intermediate 189; 374 mg, 1.73 mmol) was dissolved in DCM (20 mL) and N,N-diisopropylethylamine (0.96 mL, 5.54 mmol) added. The mixture was cooled in an ice/water bath and (3R)-1-methylpyrrolidin-3-amine dihydrochloride (Intermediate 184; 300 mg, 1.73 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hour. The mixture was washed with brine, 2N NaOH(aq), dried with MgSO4 and evaporated to yield the title compound as a brown solid (227 mg, 46.9%).