Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nccs1)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid (204.5 mg, 0.70 mmol), 2-aminothiazole (71 mg, 0.70 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (314 mg, 0.70 mmol) in N,N-dimethylformamide (3.55 mL) was treated with N,N-diisopropylethylamine (260 μL, 1.49 mmol). The mixture was stirred under nitrogen at 25° C. for 18 h. At this time, the reaction was diluted with water (50 mL). This solution was extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-N-thiazol-2-yl-propionamide (232.2 mg, 88.4%) as a white solid: mp 69–71° C.; EI-HRMS m/e calcd for C16H16Cl2N2O2S (M+) 370.0309, found 370.0309.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:13])[CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:13][C:4]1[CH:3]=[C:2]([Br:1])[C:11]([CH3:12])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(C)c(Br)cc1O
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c(Br)cc1OC(C)=O
Reaction time: 1 h

Procedure:
To a solution of methyl 4-bromo-2-hydroxy-5-methylbenzoate (may be prepared as described in Description 14; 1.2 g, 4.90 mmol) in pyridine (10 ml) was added acetic anhydride (2.08 ml, 22.03 mmol). The solution was stirred for one hour, then the solvent was removed in vacuo and purified by column chromatography (SiO2, 6:1 cyclohexane/ethyl acetate) to yield the title compound as a white solid. 1.28 g.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:15]([O:17]CC)=[O:16])[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:15]([OH:17])=[O:16])[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:21]
Reactant: CCOC(=O)c1cc2ccc(N(CC)CC)cc2oc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)c1ccc2cc(C(=O)O)c(=O)oc2c1
Yield: 89.9 %

Procedure:
--A solution of the ester 1 (11.6g, 40 mmol) in MeOH (100 ml) was heated under reflux and 0.5 M aq. NaOH (100 ml) was added rapidly. A yellow solid precipitated within 5 min and the mixture was cooled and acidified with 2 M aq. HCl to give an orange solid which was filtered and washed with 2 M aq. HCl, then with water until neutral and finally with MeOH (50 ml), and dried in vacuo to give the acid 2 (9.4 g) A sample recrystallised from MeOH-diisopropyl ether as orange laths, m.p. 231-232° C. (lit. m.p. 227-229° C. see U.S. Pat. No. 4,317,774).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[C:12]3[C:8]=2[C:9]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:10]([C:22]([O:24]CC)=[O:23])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.[OH-].[Li+]>O1CCCC1.O>[C:29]([CH2:28][CH2:27][C:9]1[C:8]2[C:12](=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:11][C:10]=1[C:22]([OH:24])=[O:23])([OH:31])=[O:30]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(-c3ccccc3)cc(-c3ccccc3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1c(C(=O)O)[nH]c2cc(-c3ccccc3)cc(-c3ccccc3)c12
Temperature: 25 °C
Yield: 95 %

Procedure:
Ethyl 4,6-diphenyl-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (4.42 g, 10 mmol) was dissolved in 25 ml tetrahydrofurane (THF) with stirring at rt. Then a solution of 1.26 g of lithium hydroxide trihydrate (3 equiv.) in 25 ml water was added and the resulting mixture was let to stir at rt for 24 h. After completion of the reaction THF was removed under reduced pressure and the pH was adjusted to 4-5, and the product was extracted with diethyl ether (3×25 ml). The organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield a light-beige-colored solid in 95-100% yield. mp. 243-245° C. 1H-NMR (DMSO-d6) δ 2.07 (m, 2H, 2′-H); 2.83 (m, 2H, 1′-H); 7.09 (d, 1H, 2J=1.6 Hz, 7-H); 7.34 (t, 1H, 3J=7.4 Hz, ph-ring), 7.44 (m, 7H, Ph-ring), 7.66 (d, 2H, 2J=0.9 Hz, 5-H); 7.68 (d, 1H, 1.6 Hz, Ph-ring); 11.72 (s, 1H, NH); 12.33 (b, 2H, 2CO2H). 13C-NMR (DMSO-d6) δ 20.3 (C-2′); 34.9 (C-1′); 109.5 (C-4); 120.9 (C-6); 121.7 (C-3); 123.8 (C-2); 125.5 (C-3a); 127.0 (C-2″, C-6″); 127.3 (C-4″′); 127.5 (C-4″); 128.0 (C-3″′, C-5″′); 129.0 (C-3″, C-5″); 129.1 (C-2″′, C-6″′); 135.4 (C-7a); 137.3 (C-4), 137.4 (C-6); 140.8 (C-1″); 141.0 (C-1″′); 163.1 (2′-CO2H); 173.4 (2-CO2H). LC-MS (m/z): 386 [M-NH4+]+, 366 [M]+, 384 [M]−. Purity (LC-MS): 95%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=Cc1cc(O)cc(OCc2ccccc2)c1

Procedure:
Preparation takes place in analogy to Example 3H from 5.0 g (36.2 mmol) of 3,5-dihydroxybenzaldehyde, 6.81 g (39.8 mmol) of benzyl bromide and 11.8 g (36.2 mmol) of cesium carbonate.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22]Cl)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][N:24]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C1CNCCNC1
Reactant: CC(C)c1ccc(S(=O)(=O)n2cc(CCl)c3ccccc32)cc1
Product: CC(C)c1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3ccccc32)cc1

Procedure:
Using essentially the same procedure as described in example 127, 1-(4-isopropylbenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:10]=1)=[O:8])([O-])=O.CO>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:10]=1)=[O:8]
Reactant: O=C(O)CCCn1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2ccccc21
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cccc(C(=O)c2cn(CCCC(=O)O)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.4 %

Procedure:
A mixture of 4-[3-(3-nitrobenzoyl)indol-1-yl]butyric acid (1.20 g), 10% palladium on carbon (300 mg), methanol (12 ml) and 1,4-dioxane (12 ml) was stirred under hydrogen atmosphere (3 atm) at 25° C. for 45 minutes. The mixture was filtered and the filtrate was evaporated to give 4-[3-(3-aminobenzoyl)indol-1-yl]butyric acid (982 mg) as yellow oil.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[S:24][CH:25]=[C:26]([CH3:28])[N:27]=3)[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.C1COCC1.Cl>O>[CH3:28][C:26]1[N:27]=[C:23]([NH:22][C:18]2[CH:17]=[C:16]([S:15][C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=3)[CH:21]=[CH:20][N:19]=2)[S:24][CH:25]=1
Reactant: Cc1csc(Nc2cc(Sc3cccc(O[Si](C)(C)C(C)(C)C)c3)ccn2)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Sc3cccc(O)c3)ccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A 3 dram vial was charged with 4-(3-(tert-butyldimethylsilyloxy)phenylthio)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.470 g, 1.09 mmol and THF (2 mL) and 6M HCl (1 mL) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give desired product (0.309 g, 89.6% yield) as yellow solid. 1H NMR (DMSO) δ 11.07 (s, 1H), 9.84 (s, 1H), 8.08 (d, 1H), 7.32 (t, 1H), 6.98 (m, 1H), 6.92 (m, 2H), 6.76 (d, 1H), 6.59 (dd, 1H), 6.51 (d, 1H), 2.20 (d, 3H); Mass spectrum (esi) m/z=316 (100) (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].Cl[CH2:12][C:13]([O:15][CH3:16])=[O:14].C[O-].[Na+].CO>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:6][CH:12]2[C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1OC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-dichlorobenzaldehyde (51.0 g) and methyl chloroacetate (51 mL) in methanol (500 mL) was added 28% sodium methoxide/methanol (68 mL) solution under ice-cooling, and the mixture was stirred at room temperature overnight. The resultant product was collected by filtration, and washed with distilled water to give the title compound (90.9 g).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[C:23]1([CH2:29][CH2:30][CH2:31]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH4+].[Cl-]>CN(C=O)C>[C:23]1([CH2:29][CH2:30][CH2:31][O:3][CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[C:10]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCn1ccc2c(OCc3ccccc3)cccc21
Reactant: BrCCCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1ccc(CCCOCCn2ccc3c(OCc4ccccc4)cccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Under argon atmosphere, sodium hydride (40 mg) was added to 1-(2-hydroxyethyl)-4-benzyloxyindole (52 mg) in DMF (3 ml) and the mixture was stirred at room temperature for 15 minutes. To the mixture, 3-phenyl-1-bromopropane (0.15 ml) was added and the resultant was stirred at room temperature for another 18 hours. The reaction mixture was added to saturated aqueous NH4Cl solution (5 ml) to stop the reaction, and the resultant was extracted with ethyl acetate (3×10 ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (72 mg, yield: 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[NH:4][C:5]([CH3:9])([CH3:8])[C:6]#[CH:7].[F:11][C:12]1[C:13](I)=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])/[C:15]/2=[CH:22]\[C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:10])[NH:4][C:5]([CH3:9])([CH3:8])[C:6]#[C:7][C:13]1[C:12]([F:11])=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:22]/[C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])/[C:16](=[O:21])[NH:17]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC(C)(C)NC(=O)OC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C)(C)C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, (1,1-dimethyl-2-propynyl)-carbamic acid methyl ester (47.7 mg, 0.34 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give (Z)-[3-[2,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-1,1-dimethyl-2-propynyl]carbamic acid methyl ester. (Yield 40 mg, 77%).
Reaction SMILES: [CH3:1][O:2][C:3](=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].C1COCC1>CO.[Pd]>[CH3:1][O:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(Cc1ccc(N)cc1)C(=O)O
Reaction time: 0.72 h
Yield: 87.1 %

Procedure:
2-Methoxy-3-(4-nitrophenyl)acrylic acid (6.7 g, 30 mmol) was taken up in methanol (700 ml) and THF (300 ml) and 10% Pd on C (wet basis) (0.67 g) was added. The mixture was hydrogenated at 45 psi for 43 mins, followed by repeated refills to 45-48 psi every hour for 3 hr and finally 48 psi for 18 hr. The resulting suspension was filtered through GF/F filter paper and the filter residue washed with MeOH (200 ml). The filtrates were concentrated to an off-white solid. The solid was slurried in IMS (75 ml) at 20° C. for 1.5 hr, filtered, and washed with IMS/heptane (1:2) (20 ml) and dried on the filter for 1 hr to afford (±)-2-methoxy-3-(4′-aminophenyl)-propionic acid as an off-white solid (5.1 g, 88% yield)
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([OH:29])[CH:23]=1)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])(C)(C)C.C(O)(=O)/[CH:31]=[CH:32]/[C:33]1[CH:40]=[CH:39][C:37]([OH:38])=[C:35]([OH:36])[CH:34]=1>>[C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([OH:29])[CH:23]=1)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)(=[O:7])/[CH:31]=[CH:32]/[C:33]1[CH:40]=[CH:39][C:37]([OH:38])=[C:35]([OH:36])[CH:34]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCc1ccc(O)c(O)c1
Product: O=C(/C=C/c1ccc(O)c(O)c1)N[C@@H](Cc1ccc(O)cc1)C(=O)NCc1ccc(O)c(O)c1
Reaction time: 2 h
Yield: 51.2 %

Procedure:
The title compound was prepared from N-(N-tert-butoxycarbonyl-L-tyrosyl)-3,4-dihydroxybenzylamine (example 56, step A) (1.4 g, 3.3 mmol) according to the indications of example 3, for 2 h. The crude intermediate was coupled with caffeic acid (978 mg, 5.4 mmol) according to the indications of example 4. The crude product was purified by flash chromatography using 40-80% AcOEt/CH2Cl2 containing 1% AcOH to yield the title product as yellow crystals (784 mg, 47%).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[N:26][C:27]([CH:30]([NH2:32])[CH3:31])=[N:28][CH:29]=2)=[CH:20][C:19]=1[CH3:33].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[N:28][C:27]([CH:30]([NH:32][C:2]3[N:7]=[C:6]([N:8]4[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]4=[O:16])[CH:5]=[CH:4][N:3]=3)[CH3:31])=[N:26][CH:25]=2)=[CH:20][C:19]=1[CH3:33]
Reactant: Cc1cc(-c2cnc(C(C)N)nc2)ccc1F
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(-c2cnc(C(C)Nc3nccc(N4C(=O)OC[C@@H]4C(C)C)n3)nc2)ccc1F
Yield: 27.4 %

Procedure:
A solution of (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (1055 mg, 4.68 mmol), 1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethanamine (1300 mg, 5.62 mmol, 1.2 equiv) and diisopropylethylamine (908 mg, 7.03 mmol, 1.5 equiv) in DMSO (20 mL) was heated at 110° C. for 1 h. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (2×50 mL). Combined organics were washed with water (40 mL), brine (40 mL), dried over Na2SO4, filtered and concentrated directly onto silica gel. Silica gel chromatography provided the mixed distereomers of (S)-3-(2-(1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethylamino) pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (560 mg). Chiral separation was carried out with SFC (ID, 5 μm, 20×250 mm) using 35% MeOH in CO2 to give (S)-3-(2-((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one and (S)-3-(2-((R)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:26][CH2:27][CH2:28][N:29]([CH3:52])[CH2:30][CH2:31][C@:32]3([O:46][C:47](=[O:51])[CH:48]([CH3:50])[CH3:49])[CH2:37][C@H:36]4[CH2:38][CH2:39][C@@H:33]3[CH:34]=[C:35]4[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:10](COCC[Si](C)(C)C)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)Cl>[C:12]1([C:11]2[N:10]=[C:9]([CH2:26][CH2:27][CH2:28][N:29]([CH3:52])[CH2:30][CH2:31][C@:32]3([O:46][C:47](=[O:51])[CH:48]([CH3:50])[CH3:49])[CH2:37][C@H:36]4[CH2:38][CH2:39][C@@H:33]3[CH:34]=[C:35]4[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)C(=O)O[C@@]1(CCN(C)CCCc2nc(-c3ccccc3)c(-c3ccccc3)n2COCC[Si](C)(C)C)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)O[C@@]1(CCN(C)CCCc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Yield: 57 %

Procedure:
To a solution of 30 mg of rac-isobutyric acid (1R*,2R*,4R*)-2-[2-({3-[4,5-diphenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-propyl}-methyl-amino)-ethyl]-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester in 0.5 mL of anh. THF was added dropwise 0.2 mL of a 1M solution of TBAF in THF. The reaction mixture was refluxed for 6 h, diluted with DCM and washed with sat.-NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using EtOAc/MeOH/NEt3 from 100/0/1 to 90/10/1 as eluant to yield 14 mg of rac-isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(4,5-diphenyl-1H-imidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as a yellowish solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].B(O)(O)[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C

Procedure:
To a mixture of dimethyl 5-bromoisophthalate (2.50 g, 9.15 mmol), p-tolylboronic acid (1.37 g, 10.1 mmol), toluene (50 mL), ethanol (10 mL), cesium carbonate (3.28 g, 10.1 mmol), and water (5 mL) under argon was added tetrakis(triphenylphosphine)-palladium(0) (529 mg, 0.458 mmol). The mixture was heated to reflux for 6 h, and then cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified by silica gel column (0-50% EtOAc/hexane) to yield a white solid. 1H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 8.45 (s, 2H), 7.57 (d, 2H, J=8.0 Hz), 7.29 (d, 2H, J=8.0 Hz), 3.98 (s, 6H), 2.42 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:33])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O1CCCC1.CO.O>C(O)(=O)C>[CH2:3]([NH:10][C:11](=[O:33])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C=CC(=O)OCC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C=CC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
1.6 g (40 mmol, 10 eq) of sodium hydroxide are added to a solution of 1.69 g (4.0 mmol, 1 eq) of ethyl 3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in 30 ml of 9/1 tetrahydrofuran/methanol. The reaction mixture is stirred for one hour at room temperature. The reaction is stopped by addition of 20 mL of water and 5 mL of acetic acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). The oil obtained is crystallized from Heptane/ethyl acetate. 1.29 g of 3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylic acid in the form of white crystals are obtained. (m.p.=125-126° C.) Yield=82%
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[CH3:23][O:24][C:25]([C:27]1(OC)[CH2:31][CH2:30][CH:29](OC)O1)=[O:26]>C(O)(=O)C>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([N+:20]([O-:22])=[O:21])=[C:2]([N:1]4[CH:29]=[CH:30][CH:31]=[C:27]4[C:25]([O:24][CH3:23])=[O:26])[CH:11]=3)[NH:6][C:7](=[O:19])[C:8]2=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2C1CCCCC1
Reactant: COC(=O)C1(OC)CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)c1cccn1-c1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2C1CCCCC1
Temperature: 0 °C
Yield: 78.6 %

Procedure:
4.5 g (14.8 mmol) of 7-amino-1-cyclohexyl-6-nitro-2,3(1H,4H)-quinoxalinedione (product 37b) and 3.5 g (14.8 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran in 75 ml of acetic acid were refluxed for 2 h. The mixture was poured into ice-water, and the precipitate was filtered off with suction to yield 4.8 g (78%) of the product. Melting point 293° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[N:26][CH:27]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1)[O:17][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=2)=[N:26][CH:27]=1
Reactant: FC(F)(F)c1cccc(-c2ccc(CCl)cn2)c1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3cccc(C(F)(F)F)c3)nc2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A solution of 100 mg (0.43 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 18 mg (0.45 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 117 mg (0.43 mmol) 5-Chloromethyl-2-(3-trifluoromethyl-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1 and diisopropylether. The residue was dried at 40° C. to give 160 mg (79%) of the title compound as white powder.