Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([NH:35][C:36](=[O:40])OCC)(=[O:34])=[O:33])=[CH:27][C:26]=3[F:41])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:42][CH3:43].[NH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:41])=[CH:27][C:28]([S:32]([NH:35][C:36](=[O:40])[NH:44][N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)(=[O:34])=[O:33])=[CH:29][C:30]=3[F:31])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:42][CH3:43]
Reactant: CCOC(=O)NS(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Reactant: NN1CCOCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NC(=O)NN4CCOCC4)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Yield: 46.9 %

Procedure:
Ethyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonylcarbamate (76 mg, 0.12 mmol, 1.0 eq) and 4-aminomorpholine (0.045 mL, 0.46 mmol, 4.0 eq) in toluene (2.5 mL, anhyd) were heated at reflux for 2.5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with water, followed by brine. After drying (MgSO4), the organics were concentrated and purified by chromatography (silica, 0 to 80% EtOAc/Hex, then 10% MeOH/DCM) to provide the title compound (40 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.41-7.16 (m, 4H), 7.03-6.90 (m, 3H), 6.57-6.43 (m, 4H), 4.02-3.98 (m, 2H), 3.71-3.65 (m, 3H), 3.57-3.50 (m, 3H), 3.48-3.38 (m, 1H), 3.31-3.25 (m, 1H), 2.69-2.58 (m, 3H), 1.46 (s, 6H); MS (EI) m/z 710.1 (MH+).
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[CH2:14][O:13]2)=[C:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]=1[OH:21])(=[O:5])[CH3:4].[OH:22][C:23]1[CH:40]=[CH:39][C:26]2[C:27](=[O:38])[CH:28]=[C:29]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[O:30][C:25]=2[C:24]=1[CH2:41][CH2:42][CH3:43]>C(O)C>[C:3]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]([OH:13])[CH2:14][O:22][C:23]2[CH:40]=[CH:39][C:26]3[C:27](=[O:38])[CH:28]=[C:29]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[O:30][C:25]=3[C:24]=2[CH2:41][CH2:42][CH3:43])=[C:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]=1[OH:21])(=[O:5])[CH3:4]
Reactant: CCCc1c(O)ccc2c(=O)cc(CCC(=O)OCC)oc12
Reactant: CCCCc1c(OCC2CO2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1c(OCC(O)COc2ccc3c(=O)cc(CCC(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O

Procedure:
To sodium hydroxide (0.6 g) in ethanol (200 ml) was added (4-acetyl-2-n-butyl-3-hydroxyphenoxy)methyloxiran (6 g) and ethyl 3-(7-hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2-yl)propionate (4.56 g). The mixture was refluxed for 6 hours, evaporated to 1/3 volume and acidified. Extraction with ethyl acetate and subsequent washing with 10% sodium hydroxide solution, and water, and evaporation gave a red oil which was chromatographed on silica with chloroform:ethyl acetate (12:1) mixture to yield a solid. Recrystallisation from ethyl acetate/cyclohexane mixture afforded the title ester as buff micro needles (2.3 g), mp 118°-118.5°.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[CH:37]=[CH:36][N:35]2[CH:38]=[N:39][N:40]=[C:34]2[CH:33]=1.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:32]3[CH:37]=[CH:36][N:35]4[CH:38]=[N:39][N:40]=[C:34]4[CH:33]=3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: Brc1ccn2cnnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ccn3cnnc3c2)c(F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a 20 mL vial were added N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide (45 mg, 0.10 mmol), 7-bromo-[1,2,4]triazolo[4,3-a]pyridine (21 mg, 0.10 mmol) K2CO3 (29 mg, 0.21 mmol), Pd(dppf)Cl2.CH2Cl2 (4 mg, 0.005 mmol), and a stir bar. The vial was sealed with a teflon lined cap and the vial sparged with N2. The vial was then charged with freshly sparged DMSO (2 mL) and stirred for 16 hours at 80° Celsius. The reaction mixture was then cooled to rt, filtered, and purified by HPLC to give the title compound (30 mg, 53%). MS (ESI): mass calcd. for C22H21FN4O2S, 424.14; m/z found, 425.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.40 (s, 1H), 8.79 (s, 1H), 8.20-8.11 (m, 2H), 7.77 (m, 1H), 7.70-7.57 (m, 3H), 7.47-7.38 (m, 3H), 1.10 (s, 9H).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:28]([C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1F
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-c1ccccc1F

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2′-fluoro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.34 min; [M+H]+=475.2.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]1)#[CH:20].F[B-](F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.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>[CH3:18][N:16]1[CH:17]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:20]#[C:19][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)[CH:14]=[N:15]1
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Reactant: Cn1cc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cn1
Temperature: 100 °C

Procedure:
To a degassed mixture of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine A74 (0.178 g, 0.640 mmol), 1-(2-ethynylphenyl)cyclopropanecarboxamide K6 (0.172 g, 0.928 mmol), PdCl2(PPh3)2 (0.005 g, 0.007 mmol), t-Bu3PH.BF4 (0.005 g, 0.02 mmol) and copper(I) iodide (0.003 g, 0.02 mmol) in DMF (8.0 mL) was added DIPEA (0.33 mL, 1.9 mmol). The mixture was heated in the microwave for 2×20 minutes at 100° C. before being concentrated under reduced pressure. Purification by silica gel column chromatography (Isolera, 0-100% EtOAc petroleum benzine 40-60° C. then 0-20% MeOH in EtOAc) gave the title compound A75 (0.120 g, 44%). LCMS-D: rt 3.30 min; m/z 427.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH3:20])=[CH:6]2.[H-].[Na+].F[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:20][C:7]1[C:8]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:9]([O:13][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 0 °C
Yield: 78.5 %

Procedure:
Compound 7 (428 mg, 1.62 mmol, 1 equiv) was dissolved in DMF (5 mL) and cooled to 0° C. under N2. Sodium hydride, 60% dispersion (71 mg, 1.78 mmol, 1.1 equiv), followed by 1-fluoro-4-nitrobenzene (457 mg, 3.24 mmol, 2 equiv) were added and the entire reaction mixture was heated to 70° C. for 18 h. The mixture was then partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel flash column chomatography (5% EtOAc in hexanes) to provide 28 (490 mg, 78%) as a clear oil. 1HNMR (400 MHz, DMSO-d6): δ 8.03 (m, 2H), 7.76 (s, 1H), 7.53 (m, 1H), 7.38-7.08 (m, 7H), 6.78 (m, 2H), 3.87 (s, 3H), 2.18 (s, 3H). MS m/z 473.3 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5]C=C[CH2:2]1.C[N+]1([O-])CCOCC1.[O:26]1[CH2:31][CH2:30][O:29]CC1.O>O=[Os](=O)(=O)=O>[OH:26][C@H:31]1[C@@H:30]([OH:29])[CH2:2][CH:1]([O:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5]1
Reactant: C1COCCO1
Reactant: O=C1c2ccccc2C(=O)N1OC1CC=CC1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OC1C[C@@H](O)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a solution of 2-(cyclopent-3-enyloxy)isoindoline-1,3-dione (736 mg, 3.2 mmol) in dioxane —H2O (5.0 mL, 4:1) was added NMO (421 mg, 3.60 mmol) and OsO4 (1.0 mL mg, 0.32 mmol, 2.5 wt % in H2O) and the reaction mixture was stirred for 24 h at rt. Quenched with 10% aqueous Na2S2O3 solution and extracted with ethyl acetate. The combined organic layers washed with brine and dried over anhydrous Na2SO4. Filtered and concentrated to provide yellow oil, which was purified by flash chromatography (80% EtOAc-hexane) to yield 2-((3R,4S)-3,4-dihydroxycyclopentyloxy)isoindoline-1,3-dione (650 mg, 77%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.94-2.12 (m, 2H) 2.14-2.35 (m, 2H) 4.22-4.88 (m, 2H) 4.75-5.11 (m, 1H) 7.67-7.78 (m, 2H) 7.79-7.86 (m, 2H). MS (ES) [M+H] calculated for C13H14NO5, 264.08. found 264.20.
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][CH2:50][NH2:51]>CC(N(C)C)=O>[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][CH2:50][NH:51][C:11]([C:13]1[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]2\[C:21](=[O:41])[NH:22][C:23]3[C:28]\2=[CH:27][C:26]([S:29]([CH2:32][C:33]2[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=2[Cl:39])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[NH:15][C:14]=1[CH3:42])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reactant: NCCc1ccccn1
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCc1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added 2-pyridin-2-yl-ethylamine (39 mg, 2 eq.). The mixture was stirred at rt for 3 days. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([O:33][CH2:34][O:35][CH3:36])=[C:29]([CH:32]=1)[CH:30]=[O:31]>C1COCC1>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([O:33][CH2:34][O:35][CH3:36])=[C:29]([CH:32]=1)[CH:30]([C:2]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:31]
Reactant: COCOc1ccc(Br)cc1C=O
Reactant: Brc1ncccc1C1OCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1ccc(Br)cc1C(O)c1ncccc1C1OCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To a solution of 2-bromo-3-(1,3-dioxolan-2-yl)pyridine (m.p. 35°-40° C.; 3.60 g) synthesized by a known method in THF (60 ml) was added, at -78° C. under argon atmosphere, a 1.6M n-butyl lithium hexane solution (10.8 ml). The mixture was stirred for 15 minutes at the same temperature, to which was then added a solution of 5-bromo-2-methoxymethoxybenzaldehyde (3.83 g) in THF (10 ml). The mixture was stirred for 15 minutes at the same temperature, then stirred for further 20 minutes while warming up to room temperature. The reaction mixture was poured into a saturated aqueous saline solution, which was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(5-bromo-α-hydroxy-2-methoxymethoxybenzyl)-3-(1,3-dioxolan-2-yl)pyridine (4.50 g) (Compound D-2). The physical properties and spectrum data are shown in Table 13 and Table 14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](=[O:20])[O:11][C:12]3[C:17]([C:18]=2[OH:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]Cl)[CH2:23][CH2:22]1>>[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:23][CH2:22]1
Reactant: COc1ccc(-c2c(O)c3ccccc3oc2=O)cc1
Reactant: ClCCN1CCOCC1
Product: COc1ccc(-c2c(OCCN3CCOCC3)c3ccccc3oc2=O)cc1
Yield: 82.5 %

Procedure:
Obtained according to the method of Example 8, from 12.1 g. (0.045 mol) of 3-(4'-methoxyphenyl)-4-hydroxy-coumarin and 8.7 g. (0.058 mol) of 2-morpholino-1-chlorethane. After recrystallisation from ethanol, there are obtained 14.7 g. of a beige product; M.P. 104° C. Yield 82.5% (theoretical yield 17.1 g.).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1)[C:2]#[CH:3].Br[C:13]1[C:14]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.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>[CH:22]1([N:21]2[C:14]3[N:15]=[C:16]([C:19]#[N:20])[N:17]=[CH:18][C:13]=3[CH:3]=[C:2]2[CH2:1][C:4]2[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: N#Cc1ncc(Br)c(NC2CCCCC2)n1
Reactant: C#CCc1ccc(CO)cc1
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: N#Cc1ncc2cc(Cc3ccc(CO)cc3)n(C3CCCCC3)c2n1
Temperature: 85 °C
Yield: 107.2 %

Procedure:
To a solution of (4-prop-2-ynyl-phenyl)-methanol (10 mmol) and 5-bromo-4-cyclohexylamino-pyrimidine-2-carbonitrile (7 mmol) in DMF (20 ml) are added triethylamine (21 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.35 mmol) and copper (I) iodide (0.7 mmol). The reaction mixture is heated at 85° C. ca. for 2 h. The reaction mixture is quenched with saturated ammonium chloride and extracted with AcOEt. The organic layer is washed with brine and then dried over sodium sulfate and concentrated under vacuum to give 2.6 g of crude product, which is purified by silica gel column chromatography. Yield 58%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][O:9][CH2:8][C:7]2=C.C[OH:14].C(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][O:9][CH2:8][C:7]2=[O:14]
Reactant: CO
Reactant: C=C1COCc2c(F)cccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1COCc2c(F)cccc21
Temperature: -78 °C

Procedure:
8-Fluoro-4-methylene-3,4-dihydro-1H-isochromene (400 mg) was dissolved in a solution of 1:1 MeOH/DCM (50 mL) and 1 mL of pyridine added. The mixture was chilled to −78° C. and ozone was bubbled through the mixture for 40 min. The reaction monitored by TLC. The mixture was purged with nitrogen at −78° C. for 10 min and then treated with PPh3. After concentration, the resulting residue was purified by preparative TLC to offer 300 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:8][C:7]=1[N+:28]([O-])=O)=[O:4].[H][H]>CN(C)C=O.[Pt](=O)=O>[NH2:28][C:7]1[CH:8]=[C:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:31])([CH3:1])[CH3:32]
Reactant: CC(C)(C)C(=O)Nc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1N
Temperature: 60 °C

Procedure:
Under nitrogen, the title compound of Example 28A (15.77 g, 35.0 mmol) was dissolved in 350 ml dimethylformamide. 500 mg platinum (IV) oxide were added, the mixture was heated to 60° C. and hydrogenated by monitoring with thin layer chromatography until the end of the reaction (1-5 days). The hydrogen was replaced with nitrogen, the catalyst was filtered off and the filtrate evaporated (all operations under nitrogen, otherwise the product has a deep blue color). The residue was triturated with degassed water to remove residual dimethylformamide. Yield after drying of title compound: 14.1 g (96%) m.p. 115° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.C1(C)C=CC(S(O[CH2:35][CH2:36][O:37][CH2:38][C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=2[F:46])(=O)=O)=CC=1>>[F:46][C:40]1[CH:41]=[CH:42][C:43]([F:45])=[CH:44][C:39]=1[CH2:38][O:37][CH2:36][CH2:35][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCc2cc(F)ccc2F)cc1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(OCCOCc3cc(F)ccc3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.665 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.824 g of 2-(2,5-difluorobenzyloxy)ethyl toluene-4-sulphonate are reacted. The title compound is obtained as a colourless oil. Rf=0.21 (1:1 EtOAc-heptane). Rt=5.01.
Reaction SMILES: CCOCC.N.[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1)[CH3:8].[Li]>C(O)C>[CH2:7]([C:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH:10]=1)[CH3:8]
Reactant: CCc1ccc(OC)cc1
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: CCOCC
Product: CCC1=CCC(=O)CC1
Reaction time: 0.25 h

Procedure:
To a stirred refluxing mixture of 600 ml. of dry ether and 1600 ml of liquid ammonia was added 136 g of p-ethylanisole. After 15 minutes, there was added portionwise, at -35° to -32° C., 26.4 g of lithium ribbon over 0.5-1 hour. After an additional 15 minutes, 193 g of dry ethanol was added dropwise at -35° to -32° C. Stirring was continued until the blue color disappeared, and the ammonia was allowed to evaporate on standing overnight. The residue was poured into 1 l of ice water and extracted twice with ether. The combined ether extracts concentrated to a volume of about 300 ml was stirred with 250 ml of water containing 46 g of oxalic acid overnight at ambient temperature. This mixture was diluted with 1 liter of water and extracted twice with ether. The combined ether extracts was washed with 5% sodium bicarbonate and then with water. After drying, the ether solution was vacuumconcentrated to a residue of 104.4 g of desired product; it was 94% pure by GLC analysis and used without distillation.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[OH:18][CH2:19][C@H:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22].[CH:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH2:27]>C1(C)C=CC=CC=1>[CH3:25][C@@H:20]([CH2:19][O:18][CH:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:27])[C:21]([O:23][CH3:24])=[O:22]
Reactant: C=COCC(C)C
Reactant: COC(=O)[C@@H](C)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)COC(C)OCC(C)C
Reaction time: 4 h

Procedure:
A catalytic amount of pyridinium para-toluenesulfonate was added to 5.9 g (0.05 mole) of methyl (S)-(+)-3-hydroxy-2-methylpropionate. Thereto was dropwise added 5.5 g (0.055 mole) of isobutyl vinyl ether at room temperature. Then, stirring was conducted at room temperature for 4 hours to give rise to a reaction. Thereto was added 100 ml of toluene. The resulting mixture was washed with 50 ml of a 0.1% aqueous sodium hydroxide solution and 20 ml of water in this order. The washed material was subjected to vacuum distillation to remove the solvent, whereby was obtained 10.5 g (yield: 97.0.%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[CH3:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>ClCCl>[C:2]([O:16][C:14](=[O:15])[C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:6]([CH3:5])[CH:7]=2)=[CH:18][CH:17]=1)([CH3:3])([CH3:1])[CH3:4]
Reactant: Cc1cc(Oc2ccc(C(=O)O)cc2)ccc1[N+](=O)[O-]
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Oc2ccc(C(=O)OC(C)(C)C)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of isobutylene (34 g) in dichloromethane (100 mL) was added compound 1 (5 g), at 5° C., followed by concentrated sulphuric acid (0.5 mL). The mixture was stirred at ambient temperature for 2 days and poured into saturated sodium bicarbonate solution (200 mL). The aqueous layer was extracted with dichloromethane and the combined organic extracts were dried and evaporated to give an an oil. The oil was chromatographed with 5% ethyl acetate in hexane to give 4-(3-methyl-4-nitro-phenoxy)-benzoic acid tert-butyl ester (compound 2), 2.5 g (42% yield; melting point=81-83° C.).
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: CC(C)(C)OC(=O)N[C@@H](CO)CCc1ccccc1
Reactant: Oc1ccc2ccccc2n1
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).