Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].C[N+](C)(C)C.[OH-].[C:22]([O-])(=[O:24])[CH3:23]>>[C:4]1(=[O:6])[N:5]([CH2:23][CH2:22][OH:24])[C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: CC(=O)[O-]
Reactant: O=C1C=CC(=O)N1
Agent: C[N+](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1C=CC(=O)N1CCO

Procedure:
In addition, the maleimide-based monomer of formula (2) according to the present invention may be prepared in accordance with any one of the following steps (h) to (n): (h) adding K2CO3, NaOH or TMAH aqueous solution to 2-maleimidethyl acetate of the step (a) to produce 2-maleimidyl ethanol; or (i) adding K2CO3, NaOH or TMAH aqueous solution to 3-maleimidepropyl acetate of the step (b) to produce 3-maleimidyl propanol; or (j) adding K2CO3, NaOH or TMAH aqueous solution to 1-maleimideisopropyl acetate of the step (c) to produce 1-maleimidyl isopropanol; or (k) adding K2CO3, NaOH or TMAH aqueous solution to 2-maleimidepropyl acetate of the step (d) to produce 2-maleimidyl propanol; or (1) adding K2CO3, NaOH or TMAH aqueous solution to 2-maleimidebutyl acetate of the step (e) to produce 2-maleimidyl-1-butanol; or (m) adding K2CO3, NaOH or TMAH aqueous solution to 4-maleimidebutyl acetate of the step (f) to produce 4-maleimidyl-1-butanol; or (n) adding K2CO3, NaOH or TMAH aqueous solution to 2-maleimide-2-methylpropyl acetate of the step (g) to produce 2-maleimidyl-2-methyl- 1-propanol.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52](=[O:64])[C@H:53]([OH:63])[C@H:54]([NH2:62])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:50]>C(Cl)Cl>[CH2:55]([C@@H:54]([NH:62][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[C@H:53]([C:52]([O:51][CH2:49][CH3:50])=[O:64])[OH:63])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)CCCc1ccccc1C(=O)O
Reaction time: 1 h
Yield: 8.6 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (69.9 mg, 336 μmol, 1.0 eq.) was combined with DIPEA (187 μL, 3.2 eq.) and HATU (128 mg, 336 μmol, 1.0 eq.) in DCM (7 mL). (2R,3R)-3-Amino-2-hydroxy-4-phenyl-butyric acid ethyl ester (75 mg, 340 μmol, 1.0 eq.) was added and the resulting mixture was stirred for 1 hour. The reaction was quenched by adding saturated NH4Cl and the product was extracted with DCM, dried, and evaporated. One third of the crude product (was dissolved in AcOH (1 mL) and purified by preparative HPLC to yield the title compound (12 mg, 95% purity). MS m/z [M+H]+ calc'd for C23H27NO6, 414.18. found 414.2.
Reaction SMILES: C1OC1C.[I-].[CH3:6][S+:7]([CH3:9])[CH3:8].[Cl:10][C:11]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([CH:22]=1)[C:19]([OH:21])=[O:20]>O1CCCC1>[Cl:10][C:11]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([CH:22]=1)[C:19]([O-:21])=[O:20].[CH3:6][S+:7]([CH3:9])[CH3:8]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: CC1CO1
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Product: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
Trimethyl sulfonium 5-(2-chloro-4-trifluoro-methylphenoxy)-2-nitrobenzoate was prepared by adding an excess of propylene oxide to a solution of trimethyl sulfonium iodide and one equivalent of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitro benzoic acid in aqueous tetrahydrofuran at 35° C. After 2 hours, the volatile organic compounds were removed under reduced pressure. The remaining aqueous phase was shaken with ether, separated and the water was then removed under reduced pressure to yield trimethyl sulfonium 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate. It was also prepared by regenerating Amberlite 200 cation exchange resin with about 10 equivalents of trimethylsulfonium iodide (Amberlite 200 is a macroreticular, high capacity, strongly acidic cation exchange resin having sulfonic acid functionality, prepared from a styrene divinylbenzene copolymer). Thereafter the column containing the regenerated resin was washed with deionized water and a solution of sodium-5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate was then passed down the column to yield trimethylsulfonium 5-(2-chloro-4-trifluoromethyl-phenoxy)-2-nitrobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[CH2:11][CH2:10][C:9]2([CH3:24])[CH3:23])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[CH2:11][CH2:10][C:9]2([CH3:24])[CH3:23])=[CH:4][CH:3]=1
Reactant: CC1(C)CCc2sc(-c3ccncc3)cc2C1(O)c1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCc2sc(-c3ccncc3)cc2C1c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
In a 100 mL round bottomed flask was placed 4-(4-chlorophenyl)-5,5-dimethyl-2-pyridin-4-yl-4,5,6,7-tetrahydro-1-benzothiophene-4-ol (240 mg, 0.65 mmol) and 1,2-dichloroethane (10 mL). To the solution were added trifluoroacetic acid (1 mL, 10 mmol) and triethylsilane (1 mL, 6 mmol). The resulting yellow solution was stirred for 16 hr at 90° C. The mixture was allowed to cool to rt then was concentrated under reduced pressure. The residue was diluted with EtOAc, then was washed with a saturated aqueous solution of NaHCO3 (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (24 g RediSep column, gradient 30% EA in hexane to 100% EA in hexane) to give the product (215 mg, 94%) as a colorless syrup: 1H NMR (400 MHz, CDCl3) δ: 8.49 (dd, 2H), 7.31 (dd, 2H), 7.25-7.27 (m, 2H), 7.03 (br d, 2H), 6.84 (s, 1H), 3.67 (s, 1H), 1.77-1.83 (m, 1H), 1.63-1.70 (m, 1H), 1.03 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH2:13][CH3:14])[CH2:9][CH:8]([NH:15][CH2:16][CH:17]([C:19]1[C:28]([CH3:29])=[CH:27][C:26]([O:30]COC)=[C:25]3[C:20]=1[CH:21]=[CH:22][C:23](=[O:34])[NH:24]3)[OH:18])[CH2:7]2)[CH3:3]>C(O)(C)C.O1CCCC1>[CH2:13]([C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[CH2:2][CH3:3])[CH2:7][CH:8]([NH:15][CH2:16][CH:17]([C:19]1[C:28]([CH3:29])=[CH:27][C:26]([OH:30])=[C:25]3[C:20]=1[CH:21]=[CH:22][C:23](=[O:34])[NH:24]3)[OH:18])[CH2:9]2)[CH3:14]
Reactant: CCc1cc2c(cc1CC)CC(NCC(O)c1c(C)cc(OCOC)c3[nH]c(=O)ccc13)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCc1cc2c(cc1CC)CC(NCC(O)c1c(C)cc(O)c3[nH]c(=O)ccc13)C2
Temperature: 40 °C

Procedure:
3N Hydrochloric acid (1 mL) is added to a solution of 5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-methoxymethoxy-6-methyl-1H-quinolin-2-one (12 mg) in isopropanol (1 mL) and tetrahydrofuran (1 mL) at room temperature and the reaction mixture heated for 18 hours at 40° C. The solvent is removed in vacuo, and the product purified by preparative scale HPLC on a C8 column, eluting with a water/acetonitrile/trifluoroacetic acid gradient.
Reaction SMILES: C1CO[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:17])[CH2:9][CH2:10][CH2:11][C:12]([O:15][CH3:16])([CH3:14])[CH3:13])([CH3:4])[O:2]1.Cl>CO.O>[CH3:16][O:15][C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]([CH3:17])=[CH:7][CH2:6][CH2:5][C:3](=[O:2])[CH3:4]
Reactant: COC(C)(C)CCCC(C)=CCCC1(C)OCCO1
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(C)(C)CCCC(C)=CCCC(C)=O
Yield: 97.7 %

Procedure:
This and the next reaction could be effected with the E and Z isomers or mixtures thereof. A solution of 1.1 g of 2,2-ethylenedioxy-10-methoxy-6,10-dimethyl-5-undecene in 22 ml of methanol containing 11 ml of 0.5N aqueous hydrochloric acid was stirred for 20 hours at room temperature and was then diluted with water and extracted with petroleum ether (b.p.= 40°-75° C.). The extracts were washed with an aqueous sodium bicarbonate solution, then with water and evaporated to dryness to obtain 900 mg of 10-methoxy-6,10-dimethyl-5-undecene-2-one in the form of a colorless oil which was used as is for the next step.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f24) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:15]=[N:16][N:17]([CH2:19][C:20]([O:22]CC)=O)[CH:18]=1.[CH3:25][NH2:26]>CO>[CH3:25][NH:26][C:20](=[O:22])[CH2:19][N:17]1[CH:18]=[C:14]([C:3]2[N:4]=[C:5]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[S:6][C:2]=2[CH3:1])[CH:15]=[N:16]1
Reactant: CCOC(=O)Cn1cc(-c2nc(Nc3ccccn3)sc2C)cn1
Reactant: CN
Solvent: CO
Product: CNC(=O)Cn1cc(-c2nc(Nc3ccccn3)sc2C)cn1
Yield: 46 %

Procedure:
According to Scheme 18 Step 2: A solution of ethyl 2-(4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazol-1-yl)acetate (87 μmol, 30 mg) and methylamine (0.26 mmol, 8.1 mg) in MeOH (4 mL) was heated at 60° C. for 4 hours. After evaporation, the crude product was purified by flash chromatography over silica gel using DCM/MeOH (100:0 to 90:10) as eluent to afford N-methyl-2-(4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazol-1-yl)acetamide (40 μmol, 13 mg, 45%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2([NH:32]C(=O)C)[CH2:29][O:28]C(C)(C)[O:26][CH2:25]2)=[CH:18][CH:17]=1.Cl>C(O)C>[NH2:32][C:24]([CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:3]2[CH:4]=[CH:5][C:6]([S:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=3)=[CH:7][C:2]=2[F:1])=[CH:21][CH:20]=1)([CH2:29][OH:28])[CH2:25][OH:26]
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Sc4ccc(C)cc4)cc3F)cc2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(Sc2ccc(-c3ccc(CCC(N)(CO)CO)cc3)c(F)c2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 49.6 %

Procedure:
N-(5-{2-[2′-Fluoro-4′-(4-methylphenylthio)biphenyl-4-yl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)acetamide (1.187 g) was dissolved in ethanol (20 mL), concentrated hydrochloric acid (10 mL) was added, and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was concentrated, aqueous potassium carbonate solution was added to the residue, and the precipitated crystals were collected by filtration. The crude crystals were purified by preparative HPLC to give the title compound (491 mg) as white crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C@H:22]([C@@H:24]([C@@H:26]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=1)[OH:25])[OH:23])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[Na+]>CO.[Pd]>[CH2:1]([O:8][CH2:9][C@H:10]([C@H:22]([C@@H:24]([C@@H:26]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([NH2:35])=[CH:33][CH:34]=1)[OH:25])[OH:23])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CO[C@H](COCc2ccccc2)[C@@H](O)[C@H](O)[C@@H](COCc2ccccc2)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: Nc1ccc(CO[C@H](COCc2ccccc2)[C@@H](O)[C@H](O)[C@@H](COCc2ccccc2)OCc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,6-di-O-benzyl-2,5-di-O-(4-nitrobenzyl)-D-mannitol (64 mg, 0.1 mmol) prepared in example 74 in MeOH was added 5% palladium on charcoal (40 mg) and sodium borohydride (114 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 2 h. Saturated sodium chloride (2 mL) was added and stirring was continued for 5 h. The mixture was extracted with EtOAc, dried over magnesium sulfate and concentrated in vacuo to yield (44 mg, 85%) after purification by flash chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([F:13])[F:12])=[CH:6][C:5]=1[NH2:14].[CH:16]([N:19]1[C:23]([Sn](CCCC)(CCCC)CCCC)=[CH:22][CH:21]=[N:20]1)([CH3:18])[CH3:17]>O1CCOCC1.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]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:23]2[N:19]([CH:16]([CH3:18])[CH3:17])[N:20]=[CH:21][CH:22]=2)[C:7]([CH:11]([F:13])[F:12])=[CH:6][C:5]=1[NH2:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C(C)C
Reactant: COC(=O)c1cc(I)c(C(F)F)cc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C(C)C)c(C(F)F)cc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
To a solution of 2-amino-4-difluoromethyl-5-iodo-benzoic acid methyl ester (750 mg, 2.29 mmol) in dioxane (30 mL) were added 1-isopropyl-5-tributylstannanyl-1H-pyrazole (1.1 g, 1.2 equiv) and Pd(dppf)2Cl2 (187 mg, 0.1 equiv) and the resulting mixture was stirred at 90° C. for 18 h. Another portion of catalyst (0.1 equiv) was added and the mixture was stirred at 90° C. for an additional 6 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:100 to 30:70)) to provide the title compound as an off-white solid (380 mg, 54%). ES-MS: m/z 310.3 [M+H]+, rt 5.54 min.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: Cc1cccc(Br)n1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: Cc1cccc(N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)n1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-6-methyl-pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1>C(#N)C.[Cu]I>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH2:7][C:8]2=[O:12])=[CH:28][CH:27]=1
Reactant: Fc1ccc(I)cc1
Reactant: COc1ccc2c(c1)NC(=O)C2
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COc1ccc2c(c1)N(c1ccc(F)cc1)C(=O)C2
Temperature: 120 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
To a mixture of 6-methoxy-1,3-dihydro-indol-2-one (500 mg, 3.06 mmol), copper(I) iodide (58.3 mg, 306 μmol), N,N′-dimethylethylenediamine (65.3 μl, 613 μmol) and potassium carbonate (932 mg, 6.74 mmol) in ACN (7 ml) was added 4-fluoroiodobenzene (474 μl, 3.68 mmol). The reaction mixture was stirred for 3 h at 120° C. in a microwave reactor. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (EA/HEP 1:4). 510 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[OH:17])[C:9]([O:11]CC)=[O:10])[C:3]([CH3:5])=[CH2:4].[OH-].[K+]>CO.O>[CH3:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[OH:17])[C:9]([OH:11])=[O:10])[C:3]([CH3:5])=[CH2:4]
Reactant: C=C(C)C(C)c1cc(C(=O)OCC)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C(C)C(C)c1cc(C(=O)O)ccc1O
Yield: 51.1 %

Procedure:
Ethyl 3-(1,2-dimethyl-allyl)-4-hydroxy-benzoate (600 mg, 2.56 mmol) was dissolved in methanol (20 ml), a solution of potassium hydroxide (560 mg, 10.0 mmol) in water (10 ml) was added and the mixture was stirred and held at reflux for 16 hours. Upon cooling the methanol was removed in vacuo and the solution acidified to pH 2 or below by the addition of 2M hydrochloric acid. The solution was extracted with dichloromethane, the organic layer was separated and the solvent was removed in vacuo to afford 3-(1,2-dimethyl-allyl)-4-hydroxy-benzoic acid (270 mg, 51%) as a colourless gum. 1H NMR (DMSO-d6) 12.38 (1H, br s), 10.22 (1H, br s), 7.63 (2H, m), 6.88 (1H, d), 4.90 (1H, s), 4.87 (1H, s), 3.75 (1H, q), 1.60 (3H, s), 1.28 (3H, d). MS: [M−H]+ 205.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@H:9]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[F:18])[N:5]2[CH:6]=[N:7][CH:8]=[C:4]2[C:3]1=[O:19].[F:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1.CCOCC>C1COCC1>[F:18][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=1[C@@H:9]1[N:5]2[CH:6]=[N:7][CH:8]=[C:4]2[C@:3]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)([OH:19])[C:2]1([CH3:20])[CH3:1])[C:14]#[N:15]
Reactant: CC1(C)C(=O)c2cncn2[C@H]1c1ccc(C#N)cc1F
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)[C@H](c2ccc(C#N)cc2F)n2cncc2[C@@]1(O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-((R)-6,6-dimethyl-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile (157 mg, 0.45 mmol) in THF cooled to −78° C. was added a 2 M solution of 4-fluoro-phenyl-magnesium bromide in ether (0.39 mL, 0.78 mmol). The crude was allowed to warm to room temperature overnight. The crude was quenched with H2O and diluted in EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was purified via flash chromatography first with EtOAc/heptane system followed by MeOH/CH2Cl2 to give 160 mg of the entitled product. MS 366.2 (M+H); LCMS condition B, retention time 1.14 min. 1H NMR (400 MHz, CDCl3) δ ppm 0.88 (s, 3H), 1.00 (s, 3H), 5.45 (s, 1H), 6.92 (t, 1H), 7.04 (s, 1H), 7.05-7.13 (m, 2H), 7.32-7.44 (m, 2H), 7.49 (s, 1H), 7.50-7.58 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][C:6]1[CH:10]=[CH:9][O:8][CH:7]=1.C([Li])CCC.[OH-].[Na+]>O1CCCC1.CCCCCC>[C:17]1([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:4]2[CH2:3][CH2:2][C:7]3[O:8][CH:9]=[CH:10][C:6]=3[CH2:5]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCN(CCCCCCc1ccccc1)Cc1ccoc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(CCCCCCN2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1.533 g (4.793 mmol) of N-(2-chloroethyl)-N-(3-furylmethyl)-6-phenylhexylamine in 100 ml of tetrahydrofuran, 8.99 ml (14.4 mmol) of 1.6 M n-butyl lithium in hexane was added under ice-cooling, followed by stirring at room temperature for 4 hours. This reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to yield the desired product.
Reaction SMILES: Cl[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[OH:4].C1(C)C=CC=CC=1.[OH-].[Na+]>O>[F:12][C:7]1[CH:6]=[C:5]([C@H:3]2[CH2:2][O:4]2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: O[C@H](CCl)c1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc([C@H]2CO2)cc1F
Temperature: 40 °C
Yield: 96 %

Procedure:
A mixture of (1S)-2-chloro-1-(3,4-difluorophenyl)-1-ethanol (net 11.47 g, 59.5 mmol), toluene (25.23 g), sodium hydroxide (2.53 g, 1.06 molar equivalents) and water (24.25 g) was stirred and heated at 40° C. for 1 hour. The organic layer was separated, washed with water, and concentrated under reduced pressure. (2S)-2-(3,4-difluorophenyl)oxirane was obtained as resultant concentrate (net 8.94 g, yield: 96%).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][N:11]([C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23](=[O:26])[NH:24][N:25]=1)[CH2:12][C:13]([O:15]C)=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-].O>C1COCC1>[C:1]([NH:8][CH2:9][CH2:10][N:11]([C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23](=[O:26])[NH:24][N:25]=1)[CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCc1ccc(=O)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCN(CC(=O)O)C(=O)CCc1ccc(=O)[nH]n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a solution of methyl N-(2-Bocaminoethyl)-N-[3-oxo-2,3,-dihydropyridazin-6-yl-propionyl]glycinate (1.00 mmol, 382 mg) in THF (12.5 mL) was added LiOH (2M, aqueous, 2.0 mL). The solution was stirred at rt. for 15 minutes, additional water (10 mL) was added and the THF was removed in vacuo. The pH of the aqueous phase was adjusted to 3.0 by addition of HCl (2M, aqueous). The product was isolated by continuous extraction with dichloromethane (DCM) followed by evaporation in vacuo to give the desired product (215 mg, 80%) as a colorless powder (UVmax 287 nm). 1H NMR (DMSO-d6): δ 12.73 (s br and s vbr, 2H, NH and COOH), 7.38 (7.35) (d, J=9.7 Hz, 1H, arom.), 6.78 (d, J=9.7 Hz, 1H, arom.), 6.83 (6.70) (t, 1H, NH), 3.92 (4.11) (s, 2H, CH2), 3.39-3.27 (m, 2H, CH2), 3.08 (3.00) (q, 2H, CH2), 2.73-2.66 (m, 2H, CH2), 2.69-2.52 (m, 2H, CH2), 1.33 (1.36) (s, 9H, Boc). 13C NMR (DMSO-d6): δ 171.50 (171.93), 171.04 (171.38), 160.39, 155.73, 146.88 (146.92), 134.41, 129.53, 77.99 (77.76), 47.44 (49.98), 47.61 (46.64), 38.31 (37.97), 30.05 (30.40), 29.31 (29.12), 28.24. FAB+ MS: 369.14 (M+H+, calc. for C16H24N4O6+H+ 369.1774).