Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([C:16]#[CH:17])=[CH:10][CH:11]=3)[C:6]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[C:5]=2[CH:4]=1)#[CH:2].I[C:27]1[S:31][C:30]([CH:32]=[O:33])=[C:29]2[O:34][CH2:35][CH2:36][O:37][C:28]=12>C1(C)C=CC=CC=1.CCN(CC)CC.[Cu]I.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>[CH2:22]([C:6]1([CH2:18][CH2:19][CH2:20][CH3:21])[C:7]2[CH:8]=[C:9]([C:16]#[C:17][C:27]3[S:31][C:30]([CH:32]=[O:33])=[C:29]4[O:34][CH2:35][CH2:36][O:37][C:28]=34)[CH:10]=[CH:11][C:12]=2[C:13]2[C:5]1=[CH:4][C:3]([C:1]#[C:2][C:27]1[S:31][C:30]([CH:32]=[O:33])=[C:29]3[O:34][CH2:35][CH2:36][O:37][C:28]=13)=[CH:15][CH:14]=2)[CH2:23][CH2:24][CH3:25]
Reactant: O=Cc1sc(I)c2c1OCCO2
Reactant: C#Cc1ccc2c(c1)C(CCCC)(CCCC)c1cc(C#C)ccc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC1(CCCC)c2cc(C#Cc3sc(C=O)c4c3OCCO4)ccc2-c2ccc(C#Cc3sc(C=O)c4c3OCCO4)cc21
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
Air was removed from a solution of 2,7-diethynyl-9,9-dibutyl-9H-fluorene and 5-iodo-3,4-ethylenedioxythiophene-2-carboxaldehyde (Jessing, M.; Brandt, M.; Jensen, K. J.; Christensen, J. B.; Boas, U. J. Org. Chem. 2006, 71, 6734) (2.3 equiv) in toluene/Et3N (4/1) by blowing argon for 20 min. Then CuI (2×4 mol %) and Pd(PPh3)2Cl2 (2×4 mol %) were added, and deaeration was continued for 10 min. Thereafter the mixture was stirred at 40° C. for 16 h. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (heptane/CH2Cl2 50:50 then 40:60) to yield 5,5′-(9,9-dibutyl-9H-fluorene-2,7-diyldi-2,1-ethynediyl)bis(3,4-ethylenedioxy-2-thiophenecarboxaldehyde).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][CH2:5][CH:4]([C:7]2[C:11]([CH2:12][OH:13])=[C:10]([C:14]([F:17])([F:16])[F:15])[S:9][N:8]=2)[CH2:3]1.[F:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH:23]=[C:24]([F:27])[C:25]=1O>>[F:18][C:2]1([F:1])[CH2:6][CH2:5][CH:4]([C:7]2[C:11]([CH2:12][O:13][C:25]3[C:24]([F:27])=[CH:23][C:22]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:21][C:20]=3[F:19])=[C:10]([C:14]([F:16])([F:17])[F:15])[S:9][N:8]=2)[CH2:3]1
Reactant: OCc1c(C2CCC(F)(F)C2)nsc1C(F)(F)F
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: O=C(O)CCc1cc(F)c(OCc2c(C3CCC(F)(F)C3)nsc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling [3-(3,3-difluorocyclopentyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 6.90-6.98 (m, 2H), 5.22 (s, 2H), 3.88-3.94 (m, 1H), 2.89 (t, J=7.5 Hz, 2H), 2.50-2.64 (m, 4H), 2.20-2.41 (m, 4H). 19F NMR (300 MHz, CD3OD) δ−56.37, −90.10, −90.91, −130.13. Mass spectrum (ESI, m/z): Calcd. for C19H16F7NO3S, 470.1 (M−H). found 470.1.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]([O:34]CC)=[CH2:33])CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([C:32](=[O:34])[CH3:33])=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1cnc2ccc(Cc3cnc4ccc(-c5cnn(C)c5)nn34)cn12
Temperature: 150 °C

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 100 mg, 0.245 mmol) was dissolved in dioxane (0.98 mL) in a microwave reactor. Then tributyl(1-ethoxyvinyl)tin (85 μL, 0.245 mmol) and tetrakis(triphenylphosphine)palladium (2.8 mg, 0.002 mmol) were introduced. The RM was heated at 150° C. for 1 h under microwave irradiations. The solvent was removed and the residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated and the residue was triturated with Et2O. The precipitate was filtered off and dried to afford the title compound as a white solid (tR 0.7 min (conditions 2), MH+=372).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([N:20]2[CH2:24][C@@H:23]([OH:25])[CH2:22][C@H:21]2[C:26](=[O:32])[NH:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([CH3:33])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[CH:28]1([NH:27][C:26]([C@@H:21]2[CH2:22][C@H:23]([OH:25])[CH2:24][N:20]2[C:18](=[O:19])[CH2:17][O:16][C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH3:33])=[CH:11][CH:12]=3)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=2)=[O:32])[CH2:29][CH2:30][CH2:31]1
Reactant: CCOC(=O)c1cc(OCC(=O)N2C[C@@H](O)C[C@H]2C(=O)NC2CCC2)c2ccc(C)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2c(OCC(=O)N3C[C@@H](O)C[C@H]3C(=O)NC3CCC3)cc(C(=O)O)nc2c1
Reaction time: 4 h

Procedure:
To a solution of 109 mg 4-[2-((2S,4S)-2-Cyclobutylcarbamoyl-4-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid ethyl ester in 1 ml THF were added 0.24 ml aqueous NaOH (1 M) at 0° C. After 4 h the mixture was brought to pH 4 by adding 1 N HCl and the reaction mixture was concentrated to give the crude product. Yield: 147 mg.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCCC2=O)cc1
Yield: 37.5 %

Procedure:
A mixture of pyrrolidin-2-one (500 mg, 5.9 mmol), 4-bromo benzoic acid methyl ester (1.5 g, 6.97 mmol), Pd2(dba)3 (135 mg, 0.14 mmol), xantphos (256 mg, 0.44 mmol) and cesium carbonate (2.7 g, 8.28 mmol) in dioxane (2 mL) in a sealed tube was subjected to reaction in a microwave reactor (time: 20 min, temp: 105° C., power: zero). The reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to afford the residue. The residue obtained was purified by column chromatography (using 60-120 silica gel and 50% ethyl acetate in hexane as eluent) to afford 485 mg (37.89% Yield) of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester. NaOH (295 mg, 7.4 mmol) was added to a stirred mixture of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (485 mg, 2.2 mmol) in a mixture of MeOH (5 mL) and H2O (5 mL), stirring was continued at 60° C. for 1 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the residue, which was acidified with 10% aqueous HCl solution, the precipitate was collected to afford 300 mg (66% Yield) of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(Cl)cc1C(C)=O
Temperature: 85 °C
Yield: 79.1 %

Procedure:
Dissolve 5′-chloro-2′-hydroxyacetophenone (15.3594 g, 90.03 mmol) in 100 mL of anhydrous acetonitrile in a pressure vessel. Add K2CO3 (13.7541 g, 99.52 mmol) and MeI (25.56 mL, 180.06 mmol) to the vessel. Seal the vessel and heat the reaction mixture to 85° C. for 18 hours. Cool the reaction and concentrate it in vacuo. Partition the residue between Et2O and H2O. Wash the organic layers with 2N NaOH (2×). Dry the combined organic layers with MgSO4. Filter off the drying agent and concentrate in vacuo to afford 13.15 g of 1-(5-chloro-2-methoxy-phenyl)-ethanone (79%).
Reaction SMILES: C[C:2]1([C:19]([O-:21])=[O:20])[CH:11]=[C:10]2[C:5](=[C:6]([C:13]3[N:14]=[C:15]([CH3:18])[S:16][CH:17]=3)[CH2:7][C:8](=[O:12])[O:9]2)[CH:4]=[CH:3]1.[OH-].[Li+].Cl>C1COCC1>[CH3:18][C:15]1[S:16][CH:17]=[C:13]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([C:19]([OH:21])=[O:20])=[CH:3][CH:4]=3)[O:9][C:8](=[O:12])[CH:7]=2)[N:14]=1
Reactant: Cc1nc(C2=C3C=CC(C)(C(=O)[O-])C=C3OC(=O)C2)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(=O)oc3cc(C(=O)O)ccc23)cs1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of 7-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-oxo-2H-chromene-7-carboxylate (840 mg, 2.79 mmol) in THF (40 mL) a solution of lithium hydroxide (14 mL, 14.0 mmol) was added. The solution was then heated at 65° C. for 1.5 hours. After cooling, THF was removed under reduced pressure and 2N HCl (8.6 mL, 17.2 mmol) was added. After 1 h stirring, the solid formed was collected by filtration to afford the title compound. 1H NMR (400 MHz, DSMO-d6): 13.6 (bs, 1H), 8.40 (d, 1H), 8.32 (s, 1H), 7.91 (d, 1H), 7.89 (s, 1H), 6.86 (s, 1H), 2.82 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:5][CH:4]=1.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:49]([O:53][C:54]([CH2:56][O:57][C:58]1[CH:59]=[C:60]([CH:68]=[C:69]([O:71][CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH:70]=1)[CH2:61][NH:62][CH2:63][CH2:64][C:65]([OH:67])=[O:66])=[O:55])([CH3:52])([CH3:51])[CH3:50]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:26])[N:62]([CH2:61][C:60]2[CH:59]=[C:58]([O:57][CH2:56][C:54]([O:53][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:55])[CH:70]=[C:69]([O:71][CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH:68]=2)[CH2:63][CH2:64][C:65]([OH:67])=[O:66])=[CH:28][CH:29]=1
Reactant: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)COc1cc(CNCCC(=O)O)cc(OCC(=O)OC(C)(C)C)c1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)O)Cc2cc(OCC(=O)OC(C)(C)C)cc(OCC(=O)OC(C)(C)C)c2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Hexadecanedioic acid mono-(4-methoxy-benzyl)ester (0.4 g, 0.98 mmol) was dissolved in ethyl acetate (10 mL). N-Ethyl-N-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.187 g, 0.98 mmol) and 1-hydroxy-7-azabenzotriazole (0.134 g, 0.98 mmol) was added and the mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, diisopropylethylamin (0.50 mL, 2.95 mmol) was added followed by 3-(3,5-Bis-tert-butoxycarbonylmethoxybenzylamino)propionic acid (0.432 g, 0.98 mmol). The mixture was stirred overnight under nitrogen at room temperature. The mixture was separated between ethyl acetate (200 mL) and water (2×100 mL). The organic phase was dried (Na2SO4), solvent removed in vacuo. The crude product was purified by RP-HPLC on C18-column, buffer A: 0.1% TFA, buffer B: MeCN+0.1% TFA; gradient 80-100% B to yield the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.C(OC(C)C)(C)C>O>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1cccs1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)OC(C)C
Product: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Reaction time: 70 h
Yield: 0.1 %

Procedure:
8.32 kg (65 moles) of the 2-(2-thienyl)-ethanol obtained in 1. above are mixed with 12.68 kg (66.6 moles) paratoluene sulfonyl chloride and 6.8 kg (67.2 moles) triethylamine and with 63 liters diisopropyl ether at room temperature. After stirring during 70 hours, the reaction mixture is poured over 40 liters water. The organic phase is washed with carbonated water and then with pure water until neutral, after which it is dried over sodium sulfate. Evaporation of the solvent gives 16.62 g (Yield: 90.60%) 2-(2-thienyl)-ethyl paratoluene sulfonate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([N+:20]([O-])=O)[CH:12]=2)=[N:7][CH:8]=1)#[N:2].C(O)(=O)C>C(O)C.[Fe]>[NH2:20][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[NH2:17])[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1)=[O:23]
Reactant: N#Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)nc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: N#Cc1ccc(NC(=O)c2ccc(N)c(N)c2)nc1

Procedure:
Prepared analogously to example 91a from N-(5-cyano-pyridin-2-yl)-3,4-dinitro-benzamide, iron powder and glacial acetic acid in ethanol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:7][OH:8].[N:25]1([C:31]([NH:33][C@@H:34]([CH2:38][C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=2)[C:35]([OH:37])=[O:36])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1C=C2C(C=C(C[C@H](N)C(O)=O)C=C2)=CC=1.[N:65]1([C:71]([NH:73][C@@H:74]([CH2:78][C:79]2[C:88]3[C:83](=[CH:84][CH:85]=[CH:86][CH:87]=3)[CH:82]=[CH:81][CH:80]=2)[C:75]([OH:77])=O)=[O:72])[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>>[N:25]1([C:31]([NH:33][C@@H:34]([CH2:38][C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=2)[C:35]([OH:37])=[O:36])=[O:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1.[OH:8][CH2:7][C@@H:6]([N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:75]([C@@H:74]([NH:73][C:71]([N:65]1[CH2:66][CH2:67][O:68][CH2:69][CH2:70]1)=[O:72])[CH2:78][C:79]1[CH:80]=[CH:81][C:82]2[C:87](=[CH:86][CH:85]=[CH:84][CH:83]=2)[CH:88]=1)=[O:77]
Reactant: COc1ccc(S(=O)(=O)N(CC(C)C)[C@H](CO)CCCCN)cc1
Reactant: O=C(O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C(O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N1CCOCC1
Product: COc1ccc(S(=O)(=O)N(CC(C)C)[C@H](CO)CCCCNC(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)N2CCOCC2)cc1

Procedure:
This derivative was prepared from (1S)-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-4-methoxy-benzenesulfonamide (XII) (this example, step B) as described in general procedure B using (2S)-2-[(morpholine4-carbonyl)-amino]-3-naphthalen-2-yl-propionic acid. The (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-2-yl-propionic acid derivative was prepared from L-2-naphthylalanine as described for the preparation of (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid (example 32, step A). The final product was obtained in 46% yield (47 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:31][C:30]=1[F:29]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a white solid. MS (m/e, ISP neg. ion)=566.2 [M−H+]
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCC1>CO>[CH:12](=[C:6]1/[C:7](=[O:11])[NH:8][C:9]2[C:5]/1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccccc1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccccc1

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (1.0 g, 5.7 mmol) was reacted with benzaldehyde (0.6 g, 5.7 mmol) (Aldrich) and pyrrolidine (0.4 g, 5.7 mmol) in methanol to give a mixture of E- and Z-3-benzylidene-6-chloro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.5 g, 100%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.[C:18](=[O:20])=[O:19].CCOCC>O1CCCC1.O>[CH3:10][O:9][C:5]1[C:4]([C:18]([OH:20])=[O:19])=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(C(F)(F)F)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(F)(F)F)c1C(=O)O
Reaction time: 3 h

Procedure:
A solution of 3-trifluoromethylanisol (50.0 g, 0.28 mole) in tetrahydrofuran was cooled to -78° C. under nitrogen atmosphere with stirring. To this solution was added n-butyl lithium (114 ml of 2.5M, 0.28 mole), dropwise at such a rate that the temperature did not exceed -65° C. When the addition was complete, the mixture was stirred at -78° l C. for three hours. The mixture was then poured over a slurry of dry ice/ether and allowed to come to room temperature. The solvent was removed under reduced pressure to give a white solid. This solid was dissolved in a minimum amount of water, extracted with diethyl ether (2×100 ml) and the aqueous phase was acidified to pH 2 with dilute hydrochloric acid. An oil formed and was extracted with diethyl ether, washed several times with water and dried over magnesium sulfate. The solvent was removed to give 45.6 g (74 percent of theory) of the title compound as a white solid of m.p. 129°- 130° C.
Reaction SMILES: [CH:1]([S:3]([OH:6])(=[O:5])=[O:4])=[CH2:2].ClCCS(Cl)(=O)=O.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>>[CH:1]([S:3]([O:6][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])=[O:4])=[CH2:2]
Reactant: C=CS(=O)(=O)O
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=S(=O)(Cl)CCCl
Product: C=CS(=O)(=O)Oc1ccccc1

Procedure:
The aryl ester of vinylsulfonic acid can be prepared by several available techniques. U.S. Pat. No. 3,121,730 teaches reacting a beta-chloroethanesulfonyl chloride with phenol in an aqueous medium at a pH of between 7.5 and 11.5. The reaction proceeds with a loss of 2 mols of hydrogen chloride to yield phenyl vinylsulfonate. U.S. Pat. No. 3,133,948 teaches reacting carbyl sulfate with an aromatic hydroxy compound in an aqueous alkaline medium at a pH between 7.5 and 11.5 to yield a aryl vinylsulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:16][CH:15]=3)[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:31]N1C(=O)CCC1=O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:28]([CH3:29])[CH3:30])[CH:25]([CH3:27])[CH3:26])=[CH:18][CH:19]=3)[C:10]=2[Br:31])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(c2cc(-c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3)no2)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2onc(-c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3)c2Br)CC1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
A solution of 1-[3-(4-triisopropylsilanyloxy-phenyl)-isoxazol-5-yl]-cyclopropanecarboxylic acid ethyl ester (288 g) in 3 L DMF was cooled to 5° C. under an atmosphere of N2. The reaction solution was treated with N-bromosuccinimide (131.5 g) and allowed to slowly warm to room temperature over 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2 L), cooled to −15° C., and quenched with 10% sodium metabisulfite solution (150 mL) with stirring. The organic layer was separated, washed with sat. NaHCO3 (250 mL) and brine (250 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (0 to 20% ethyl acetate in hexanes) to afford 1-[4-bromo-3-(4-triisopropylsilanyloxy-phenyl)-isoxazol-5-yl]-cyclopropanecarboxylic acid ethyl ester (285 g) as a light-brown thick liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:40][C:41]1[C:42]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[N:43][O:44][C:45]=1[CH:46]1[CH2:48][CH2:47]1>C1COCC1.[Cl-].[Na+].O.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:40][C:41]2[C:42]([C:49]3[C:50]([Cl:56])=[CH:51][CH:52]=[CH:53][C:54]=3[Cl:55])=[N:43][O:44][C:45]=2[CH:46]2[CH2:48][CH2:47]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)CC1
Reaction time: 2 h

Procedure:
Cool a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (352 g, 1.75 mol) and 18-crown-6 (463 g, 1.75 mol) in THF to between 0° C. and 5° C. Add potassium tert-butoxide (268 g, 2.39 mol) while maintaining the temperature between 0° C. and 10° C. Cool the resulting mixture to −10° C. to −5° C. Add a 40 wt % solution of 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole in THF (1.38 kg, 1.59 mol) while maintaining the temperature between −5° C. and 0° C. Allow the mixture to warm to 15° C. to 25° C. and stir for 2 h. Cool to 0° C. to 5° C., and add water dropwise while maintaining the temperature between 0° C. and 10° C. Add ethyl acetate (3.5 L) and brine (5.5 L). Separate the phases and extract the aqueous phase with ethyl acetate (2×2.5 L). Wash the combined organic phases with brine (3×5.5 L). Concentrate the organic phase under vacuum to approximately 1.5 L total volume to afford a solution of crude 4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester. Add additional ethyl acetate (3.0 L). Cool the solution to 0° C. to 5° C. Add HCl (gaseous) (319 g, 8.75 mol) while maintaining the temperature between 0° C. and 5° C. Allow to warm to 15° C. to 25° C. and stir for 4 h. Concentrate the mixture under vacuum to approximately 1.2 L total volume. Filter the resulting solid and wash with cold ethyl acetate (2×0.6 L). Dry to afford 506 g (79%) of the title compound as an off-white solid. mp 200-202° C. (by differential scanning calorimetry).