Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[N:20]([CH3:31])[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23](SC)[N:22]=1.C(OCC)(=O)C.Cl.[NH2:39][NH2:40]>ClCCl.C(O)CC.O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[N:20]([CH3:31])[C:21]1[N:22]=[C:23]2[NH:39][N:40]=[C:25]([NH2:26])[C:24]2=[CH:27][CH:28]=1
Reactant: CSc1nc(N(C)c2ccc(F)cc2F)ccc1C#N
Reactant: NN
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: CCCO
Product: CN(c1ccc2c(N)n[nH]c2n1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
452 mg (1.84 mmol) of mCPBA is added under argon to a stirring solution of 486 mg (1.67 mmol) of 6-((2,4-difluorophenyl)(methyl)amino)-2-(methylthio)nicotinonitrile in 15 mL of dichloromethane. The reaction medium is stirred 30 min at room temperature before adding an ethyl acetate fraction. The organic phase is washed with a NaHCO3 saturated solution, dried on magnesium sulfate and dry evaporated. The crude reaction product is dissolved again in 6 mL of propanol and 164 μL (3.38 mmol) of hydrazine hydrochloride in water is added. The mixture is heated at 90° C. for 6 hours before being diluted in water and extracted with ethyl acetate. The organic phase is dried on magnesium sulfate and dry evaporated before being purified by silica gel chromatography to yield 328 mg of N6-(2,4-difluorophenyl)-N6-methyl-1H-pyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yellow-orange solid (70%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][C:21]([O:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[CH:22][CH:23]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Product: CN(C)CCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cn1
Yield: 20.3 %

Procedure:
Following general procedure D, (6-bromo-4-(6-(2-(dimethylamino)ethoxy)pyridin-3-ylamino)quinolin-3-yl)(cyclopropyl)methanone (100 mg, 0.22 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (95 mg, 0.33 mmol) to afford the desired product (24 mg, 20%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.25 (s, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.94 (s, 2H), 7.80 (s, 1H), 7.56 (dd, J=8.5, 2.8 Hz, 1H), 7.18 (s, 2H), 6.93 (d, J=8.5 Hz, 1H), 4.54 (t, J=5.5 Hz, 2H), 3.04 (t, J=5.5 Hz, 2H), 2.95-2.86 (m, 1H), 2.54 (s, 6H), 1.23-1.14 (m, 2H), 1.17-1.08 (m, 2H); ESI MS m/z 537 [C28H26Cl2N4O3+H]+; HPLC>99% (AUC), tR=11.42 min.
Reaction SMILES: O=[C:2]([CH3:15])[CH:3]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[C:4]([O:6][CH3:7])=[O:5].C([O-])(O)=O.[Na+]>P(Cl)(Cl)(Cl)=O>[C:10]([C:9]1[O:14][C:2]([CH3:15])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:8]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)C(NC(=O)C(C)(C)C)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1nc(C(C)(C)C)oc1C
Yield: 22.3 %

Procedure:
A solution of methyl 3-oxo-2-(pivalamido)butanoate (0.22 g, 1.0 mmol) in phosphorus oxychloride (1.5 mL) was heated at 110° C. for 30 min. The reaction was cooled in an ice bath, and saturated aqueous NaHCO3 was slowly added until the mixture was basic. The reaction was extracted with CH2Cl2, and the extracts were washed with saturated aqueous NaHCO3 and water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (0%-40% EtOAc-hexanes) to obtain methyl 2-tert-butyl-5-methyloxazole-4-carboxylate (44 mg, 22% yield). 1H NMR (400 MHz, CDCl3) δ 3.90 (s, 3H, 2.60 (s, 3H), 1.39 (s, 9H) ppm. LC/MS: m/z 198.3 (M+H)+ at 2.83 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.ON1C(=O)CCC1=O.C(Cl)(Cl)Cl.[CH:35]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(OCC)(=O)C.C(N(CC)CC)C>[CH:35]1([NH:41][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CCCCCCCCCCCC(=O)N[C@H](C(=O)O)C(C)C
Reactant: NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@H](C(=O)NC1CCCCC1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
61 mg (0.20 mmol) of N-lauroyl-L-valine and 39 mg (0.26 mmol) of N-hydroxysuccinimide monohydrate were dissolved into 3.0 mL of dried chloroform. 50 mg (0.26 mmol) of 1-ethyl-3-(3-dimethylpropyl)carbodiimide hydrochloride was added thereto under argon atmosphere and in the ice bath, and stirred at 0° C. for 3 hours. 35 μL of triethylamine and 35 μL of cyclohexylamine were added thereto and stirred at room temperature overnight. Then, 20 mL of ethyl acetate was added thereto and washed with 25 mL of 0.2N hydrochloric acid, 20 mL of water and 20 mL of a saturated aqueous solution of sodium hydrogen carbonate. The mixture was then dried with anhydrous sodium sulfate and condensed under reduced pressure. The residue was purified with a thin-layer chromatography (silica gel, chloroform:methanol=20:1) to obtain 34 mg of N-lauroyl-L-valine cyclohexylamide (0.089 mmol, yield 44%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:28])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[NH:26][CH:25]=[N:24][C:23]=3[Cl:27])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH:29]1([C:32]#[CH:33])[CH2:31][CH2:30]1>C1COCC1.[Cu]I>[Cl:27][C:23]1[N:24]=[CH:25][NH:26][C:22]=1[C:20]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:4]2[CH:3]=[C:2]([C:33]#[C:32][CH:29]3[CH2:31][CH2:30]3)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=2)[C:12]=1[F:28])=[O:21]
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Reactant: C#CC1CC1
Agent: [Cu]I
Solvent: C1CCOC1
Product: N#Cc1cc(C#CC2CC2)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 52 %

Procedure:
To a solution of N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (95.0 mg, 0.196 mmol), cyclopropylacetylene (25.9 mg, 0.392 mmol), copper(I) iodide (1.869 mg, 9.81 μmol) and Palladiumbischlorobistriphenylphosphine(II) (10.25 mg, 0.020 mmol) in THF (6 ml) was added TEA (0.137 ml, 0.981 mmol) and the reaction mixture was irradiated in a personal microwave reactor for 10 minutes at 120° C. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(cyclopropylethynyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (48 mg, 0.102 mmol, 52% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (br. s., 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.39-7.53 (m, 2H), 7.34 (t, 1H), 7.14 (s, 1H), 4.51 (d, 2H), 1.47-1.64 (m, 1H), 0.83-1.01 (m, 2H), 0.71-0.81 (m, 2H). LC-MS (ES+) m/z 469.09, [M+H].
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH2:16][C:17]1[S:18][C:19]([CH3:22])=[CH:20][CH:21]=1)S(C1C=CC(C)=CC=1)(=O)=O.Cl.[OH-].[Na+].O.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOCC>[CH3:22][C:19]1[S:18][C:17]2=[CH:16][N:5]=[CH:4][CH:3]=[C:21]2[CH:20]=1
Reactant: COC(CN(Cc1ccc(C)s1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: Cc1cc2ccncc2s1
Temperature: 107.5 °C
Yield: 58.2 %

Procedure:
76059-85: N-(2,2-Dimethoxy-ethyl)-4-methyl-N-(5-methyl-thiophen-2-ylmethyl)-benzenesulfonamide (2) (50.56 g crude) was dissolved in dioxane (250 mL) and conc. HCl (200 mL) was added cautiously. The dark red solution was heated at gentle reflux (105 to 110° C.) for 24 hours. The volume was reduced by approximately half, then diluted with ether (200 mL). The pH was adjusted to between 7 and 8 using 50% NaOH/H2O and sat NaHCO3 solution with cooling. More ether (400 mL) was added, the mixture was filtered to remove insoluble material and the phases separated. The organic phase was washed with water (2×350 mL), dried (MgSO4) and condensed to dark red-brown oil. Purification was accomplished using Kugelrohr distillation (120 to 130° C.) to give 11.89 g of title compound as a pale yellow liquid.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.CN(C=O)C>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCO
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCO)cc1
Reaction time: 2.5 h
Yield: 29.4 %

Procedure:
To a solution of 1,5-pentanediol (30 g, 0.29 mol) in dichloromethane/DMF (15/1, 320 ml) were added triethylamine (38.1 ml, 0.274 mol), dimethylaminopyridine (7.04 g, 57.6 mmol) and p-toluenesulfonic acid chloride (49.42 g, 0.259 mol) were in turn added at -30° C. and the mixture was stirred for 2.5 hours. To the reaction mixture was added purified water (200 ml) and the aqueous layer was extracted with chloroform (150 ml×3). The combined organic layer was washed succcessively with 5% aqueous hydrochloric acid (200 ml), saturated aqueous sodium hydrogen carbonate (200 ml) and saturated aqueous sodium chloride (200 ml), dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was chromatographed over silica gel and the fraction from ethyl acetate-hexane (1/1) gave 19.65 g of 5-hydroxypentyl p-toluenesulfonate. Yield=26%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13]OS(C)(=O)=O)=[CH:7][CH:6]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(O)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:9][CH:10]=1
Reactant: C1COCCN1
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCOS(C)(=O)=O)cc1
Solvent: CCO
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCN2CCOCC2)cc1
Yield: 95.1 %

Procedure:
To a stirred solution of (R)-tert-butoxycarbonylamino-[4-(2-methanesulfonyloxy-ethoxy)-phenyl]-acetic acid methyl ester (50 mg, 0.12 mmol) in ethanol (1 mL) was added morpholine (0.043 mL, 0.49 mmol) at room temperature. The reaction mixture was refluxed for 1 hour. The solvent was evaporated and the crude product was purified by chromatography over silica gel eluted with 1:1 v/v hexanes/ethyl acetate to give (R)-tert-butoxycarbonylamino-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetic acid methyl ester (45 mg, 92% yield) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[CH:7][S:8][CH:9]=1)[CH2:3][NH2:4].[C:10]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[CH3:24])=[CH:18][CH:17]=1)([O:12][CH3:13])=[O:11]>>[C:10]([CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH:23]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[CH:7][S:8][CH:9]=2)[CH3:24])=[CH:20][CH:21]=1)([O:12][CH3:13])=[O:11]
Reactant: NCC(O)c1cscn1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2cscn2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-hydroxy-2-(thiazol-4-yl)ethylamine with 1-(4-carbomethoxymethoxyphenyl)propan-2-one followed by purification of the base on a silica gel column using ethyl acetate/methanol=8:2 as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:10])[CH2:7][C:6]=2[CH:16]=1.[N+:17]([O-])([OH:19])=[O:18].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]2[O:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:10])[CH2:7][C:6]=2[CH:16]=1
Reactant: CCOC(=O)C1(C)Cc2cc(Cl)ccc2O1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C1(C)Cc2cc(Cl)cc([N+](=O)[O-])c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
Stirred concentrated sulfuric acid, 50 mL, was cooled in an ice-water bath, and 9.0 grams (0.037 mole) of 5-chloro-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran was added. To this solution was added dropwise a solution of 2.6 grams (0.041 mole) of 90% nitric acid in 2 mL of concentrated sulfuric acid, while maintaining the reaction mixture temperature at 10°-16° C. Upon completion of the addition, the reaction mixture was stirred at the ice-water bath temperature for 30 minutes, then allowed to warm to ambient temperature where it stirred for one hour. The reaction mixture was poured into ice and neutralized with sodium bicarbonate and extracted with three portions of methylene chloride. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel, with 3:7 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.0 grams of 5-chloro-2-ethoxycarbonyl-2,3-dihydro-2-methyl- 7-nitrobenzofuran, mp 69°-72.5° C. The NMR spectrum was consistent with the proposed structure. This reaction was repeated.
Reaction SMILES: [F:1][C:2]1([F:26])[O:7][C:6]2[CH:8]=[C:9]([F:21])[C:10]([NH:12]/[N:13]=[CH:14]/[C:15](=O)[C:16]([F:19])([F:18])[F:17])=[CH:11][C:5]=2[N:4]([CH2:22][C:23]#[CH:24])[C:3]1=[O:25].[C:27]([CH2:32][CH:33]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:28].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1([F:26])[C:3](=[O:25])[N:4]([CH2:22][C:23]#[CH:24])[C:5]2[CH:11]=[C:10]([N:12]3[C:27](=[O:28])[C:32]([CH3:33])=[C:15]([C:16]([F:19])([F:18])[F:17])[CH:14]=[N:13]3)[C:9]([F:21])=[CH:8][C:6]=2[O:7]1
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N/N=C/C(=O)C(F)(F)F)cc21
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(-n3ncc(C(F)(F)F)c(C)c3=O)cc21
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a stirred yellow suspension of (E)-2,2,7-trifluoro-4-(prop-2-ynyl)-6-(2-(3,3,3-trifluoro-2-oxopropylidene)hydrazinyl)-2H-benzo[b][1,4]oxazin-3-one (1399 mg, 3.69 mmol) in dry toluene (20 ml) was added (carbethoxyethylidene)triphenylphosphorane (1738 mg, 4.80 mmol), resulting in a clear orange/red solution. The reaction was continued overnight at reflux under Dean-Stark conditions, while conducting aezotropic dehydration. Thereupon the reaction mixture was concentrated in vacuo to yield 2.99 g of crude product containing ca. 50% triphenylphosphine oxide. The crude product was chromatographed over silica (9:1→1:1 heptane/ethyl acetate) to yield 1.08 g of product (ca. 89% purity). Recrystallisation from diisopropyl ether/heptane gave the title compound as a white powder (purity>99%).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=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][CH3:16].C(Cl)[Cl:30].[ClH:32]>COCCOC>[ClH:30].[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([Cl:32])=[O:25])=[CH:27][CH:28]=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][CH3:16]
Reactant: ClCCl
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)O)cc1
Agent: Cl
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)Cl)cc1

Procedure:
A solution of 37.6 g. of 4-hexadecylaminohydrocinnamic acid, prepared as described in Example 4, in 1200 ml. of methylene chloride and 300 ml. of 1,2-dimethoxyethane is stirred under reflux while hydrogen chloride gas is bubbled in for 1 hour. The mixture is then treated with 65.5 g. of thionyl chloride and stirred under reflux for another 1 hour. The dark solution is evaporated in vacuo to yield 4-(hexadecylamino)hydrocinnamoyl chloride hydrochloride.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.CN(C)CCCCCCN(C)C.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(#N)C.O>[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)CCCCCCN(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 8 h
Yield: 117 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (2.22 g, 10.0 mmol) was dissolved in acetonitrile (40 ml), to which triethylamine (2.74 ml, 19.7 mmol) and N,N,N′,N′-tetramethyl-1,6-diaminohexane (0.57 ml, 2.64 mmol) were added, and the mixture was cooled in an ice-bath. p-Toluenesulfonyl chloride (2.75 g, 14.4 mmol) was added to this mixture, which was allowed to return to room temperature and stirred overnight. Water was poured into the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (4.16 g, yield 89%) as a pale yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH3:21])[N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:6][CH:5]=1)([OH:3])=O.[C:22]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[C:22]1([S:28]([NH:31][C:1]([C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[C:9]([CH3:21])[N:10]3[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[CH:6][CH:5]=2)=[O:3])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Reactant: NS(=O)(=O)c1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: Cc1cc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an N,N-dimethylformamide (10 ml) solution of 6-carboxy-1-(2-chlorobenzyl)-2-methylindole (0.470 g), added is N,N′-carbonyldiimidazole (0.508 g), and stirred at room temperature for 1 hour. Next, benzenesulfonamide (0.493 g) and diazabicycloundecene (0.477 g) are added thereto, and stirred at 100° C. for 72 hours. The solvent is evaporated away under reduced pressure, and the residue is purified through silica gel column chromatography (eluent: chloroform) to obtain 6-(benzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylindole. This is dissolved in a small amount of ethyl acetate, to which is added hexane. The crystal formed is taken out through filtration, and dried to obtain 6-(benzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylindole (32) (0.440 g).
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:11][N:12]2[N:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[N:13]2)[O:9][CH:10]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH2:17])[CH:14]=[N:13]2)[O:9][CH:10]=1
Reactant: COCc1coc(Cn2ncc([N+](=O)[O-])n2)n1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COCc1coc(Cn2ncc(N)n2)n1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 4-(methoxymethyl)-2-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)oxazole (1.46 g, 6.10 mmol), iron powder (1.03 g, 18.31 mmol) and NH4Cl (1.65 g, 30.52 mmol) in a mixture of EtOH (30.0 mL) and water (15.0 mL) was stirred at 85° C. for 15 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (55 mL) was added followed by 1N NaOH (33 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (5×50 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.42 min; [M+H]+=210.09.
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[CH:4].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[C:4][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#CC(C)(O)CC(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(O)CC(C)C)c21

Procedure:
Using Method C above, 3,5-dimethyl-1-hexyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (146 mg, 0.4 mmol) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3,5-dimethyl-3-hydroxy-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 87 mg, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][OH:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][O:19][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)COc1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 32.2 %

Procedure:
N-tert-Butoxycarbonyl-D-homophenylalaninol (1.9 mmol), 2-hydroxyquinoline (2 mmol) and triphenylphosphine (2 mmol) were dissolved in dry THF (20 mL). The solution was cooled to 0° C. and diethyl azodicarboxylate (DEAD) (3.8 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 3 hr, then at room temperature for 16 hr at which time the solvent was evaporated under reduced pressure and the residue purified by chromatography on silica gel (100% CH2Cl2) to give the title compound (240 mg, 33%): 1H NMR (CDCl3) δ 1.46 (9H, s), 1.91-1.99 (2H, m), 2.76-2.81 (2H, m), 4.054.12 (1H, m), 4.51-4.53 (1H, m), 6.91-6.93 (1H, d), 7.19-7.30 (5H, m), 7.37-7.41 (1H, t), 7.61-7.65 (1H, t), 7.72-7.74 (1H, d), 7.82-7.84 (1H, d), 7.99-8.01 (1H, d); MS m/e 393 (100, M+1).