Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)=[C:13]([CH3:26])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C([O-])([O-])=[O:30].[K+].[K+]>CS(C)=O>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]([NH2:21])=[O:30])=[CH:18][N:17]=2)=[C:13]([CH3:26])[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(CCNCc2ccccc2)ccc1Oc1ccc(C#N)cn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(CCNCc2ccccc2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 96.8 %

Procedure:
Combine nitrile, 6-[4-(2-benzylamino-ethyl)-2-methyl-phenoxy]-nicotinonitrile (compound of example 219, step 3) (13 mg, 0.04 mmol), H2O2 (5 μL) and K2CO3 (3 mg, 0.02 mmol) in DMSO (0.2 mL), and stir the mixture at room temperature overnight. Add water and extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4 and eliminate the solvent. Purify by flash chromatography (eluent: CHCl3/0.5% EtOH/0.05% NH4OH) to give the title compound (7 mg, 52%). Electrospray MS M+1 ion=362. 1H-NMR (methanol-d4, 300 MHz): 8.59 (d, 1H, J=2.5 Hz), 8.24 (dd, 1H, J=2.5 and 8.0 Hz), 7.33-7.21 (m, 5H), 7.15-7.07 (m, 2H), 6.98-6.93 (m, 2H), 3.78 (s, 2H), 2.83 (s, 4H), 2.09 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:16]=1[CH:17]=[CH:18][C:19](O)=O>>[CH3:13][O:14][C:15]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:16]=1/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: COc1cccc(C=CC(=O)O)c1OC
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Product: COc1cccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c1OC
Yield: 20.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (14.7 mmol) of 5,6-diamino-1,3-dimethyluracil and 3.37 g (16.2 mmol) of 2,3-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 1.03 g (yield 41%) of Compound 88 as pale yellow needles.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:12](Cl)(=[O:14])=[O:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[CH3:16][NH2:17]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([S:12]([NH:17][CH3:16])(=[O:14])=[O:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CN
Reactant: N#Cc1cc([N+](=O)[O-])cc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: CNS(=O)(=O)c1cc(C#N)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a solution of Intermediate 71B (150 mg, 0.61 mmol) in DCM (4 mL) was added methylamine (2.0 M solution in THF, 1.5 mL, 3.0 mmol) and TEA (0.424 mL, 3.04 mmol). The reaction mixture was stirred at room temperature for 1 hour, diluted with DCM, washed with water, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (flash chromatography, 12 g, EtOAC/hexane=0-100%) to give Intermediate 71C (45 mg, 31%) as a white solid. HPLC: Rt=1.112 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). 1H NMR (500 MHz, CDCl3) δ ppm 8.90 (1H, s), 8.71 (1H, s), 8.46 (1H, s), 4.76 (1H, br. s.), 2.81 (3H, d, J=4.95 Hz).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1>>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([S:1][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OCc1cccc(S)c1
Product: N#Cc1ccc(Sc2cccc(CO)c2)nc1
Yield: 75.8 %

Procedure:
Using the method of Preparation 155 using (3-mercaptophenyl)methanol (10.0 g, 71.3 mmol) and 6-chloronicotinonitrile (19.8 g, 142.7 mmol) affords the title compound (13.1 g, 76%): 243 (M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](O)(C)[CH2:16][C:17](O)=O.[C:22]([O:25]C(=O)C)(=[O:24])C>>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]=[CH:17][C:22]([OH:25])=[O:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)(CC(=O)O)c1ccccc1-c1ccc(Br)cc1Br
Product: O=C(O)C=CCc1ccccc1-c1ccc(Br)cc1Br

Procedure:
1 g. of 3-(2',4'-dibromobiphenylyl)-3-hydroxybutyric acid and 10 ml. of acetic anhydride are heated under reflux for 2 hours and the mixture is poured onto ice and worked up in the customary manner to give 3-(2',4'-dibromo-4-biphenylyl-2-butenoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)NC=C2.[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:21])=[CH:15]2>>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:2]1[CH:3]=[CH:4][CH:8]=[CH:9][CH:10]=1)[C:16]([CH3:21])=[CH:15]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Product: Cc1cc2cc(Br)ccc2n1-c1ccccc1

Procedure:
The same reaction was performed as in Reference Example 1 except for using, instead of the 5-bromoindole, 5-bromo-2-methylindole to afford the above-identified compound (4.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][N:20]2C(=O)C4C(=CC=CC=4)C2=O)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.NN>O1CCCC1.C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH2:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN)c1
Temperature: 25 °C

Procedure:
To a solution of 2-{2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]-ethyl}-isoindole-1,3-dione (87 mg in a mixture of 4 mL tetrahydrofuran and 4 mL ethanol) was added 0.6 mL of 95% aqueous hydrazine and the reaction stirred at room temperature. After 18 hours the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 9:6:1) to provide the title compound (54 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[CH3:17][O:18][CH2:19][CH2:20][NH2:21].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:17][O:18][CH2:19][CH2:20][NH:21][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: COCCN
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCCNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 635.5 %

Procedure:
To a stirred solution of 3-nitro-5-(trifluoromethyl)benzoic acid (1.00 g, 0.42 mmol) in DCM (20 mL), were added 2-methoxyethanamine (0.41 mL, 0.47 mmol), DMAP (620 mg, 0.51 mmol) and EDCI (900 mg, 0.47 mmol). The reaction mixture was allowed to stir at rt overnight and then concentrated. The residue was diluted with EtOAc and washed with water. The organic solution was dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, MeOH/DCM) to yield the title compound as a white solid (780 mg, 63%). LCMS: (FA) ES+ 293.2 (M+1), ES− 291.2 (M−1).
Reaction SMILES: CO[C:3](=[O:21])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]1=[O:20].C(O)(=O)C.C(OCC)(=O)C.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[O:20]=[C:6]1[CH:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]1[CH2:4][C:3]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:21]
Reactant: C1COCCN1
Reactant: COC(=O)CN1C(=O)C(c2ccccc2)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CN1C(=O)C(c2ccccc2)c2ccccc21)N1CCOCC1

Procedure:
11 g of methyl(2,3-dihydro-2-oxo-3-phenyl-1-indolyl)-acetate were dissolved in 50 ml of morpholine and the mixture was heated under nitrogen on a steam bath for 9 hours and then poured into a mixture of glacial acetic acid and ethyl acetate; the aqueous phase was extracted with methylene chloride and the organic phase was dried and concentrated. The crude product was recrystallized from isopropanol. Melting point 153°-154° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH2:14]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C(C)(C)C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a stirred solution of o-(t-butyl)-phenol (11.3 g; 75 mmol) in acetone (150 ml) is added allyl bromide (10.9 g, 1.2 equiv.) and anhydrous K2CO3. After stirring 18 hr at reflux, the reaction is added to water (200 ml) and extracted with 3×150 ml portions of petroleum ether. The combined organic layers are dried (MgSO4), filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel (sg) chromatography (hexane elution) to yield 1-prop-2-enyloxy-2-t-butylbenzene (11.6 g; 81% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:8][C:9]=1[N:10]([C@@H:20]([CH3:24])[CH2:21][CH2:22][NH2:23])[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N+](C1C=CC([O:40][C:41](=O)[O:42][CH:43]2[CH:50]3[CH:46]([O:47][CH2:48][CH2:49]3)[O:45][CH2:44]2)=CC=1)([O-])=O.C(N(C(C)C)CC)(C)C>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:25]#[C:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]([C@@H:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:41]([O:42][CH:43]1[CH:50]2[CH:46]([O:47][CH2:48][CH2:49]2)[O:45][CH2:44]1)=[O:40])[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC2OCCC12
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@@H](C)CCN
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@@H](C)CCNC(=O)OC1COC2OCCC12
Reaction time: 1 h

Procedure:
A mixture of crude 3-[[3-Amino-1-(S)-methyl-propyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester in ACN (3.0 mL) was treated with carbonic acid hexahydro-furo[2,3-b]furan-3-yl ester 4-nitro-phenyl ester (0.11 g, 0.375 mmol) followed by diisopropylethyl amine (0.1 mL, 0.625 mmol) and DMAP (cat). The reaction was stirred for 1 h and quenched with CH3OH (1 mL). Solvent was removed under reduced pressure and the crude material was partitioned between EtOAc, and ½ sat NaHCO3(aq). The organics were dried over Na2SO4, solids filtered and solvent removed under reduced pressure. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[3-(hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-1-(S)-methyl-propyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was isolated by reverse phase HPLC and carried forward wet to the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C@H:7]([NH:17][C:18]([C:20]2[NH:29][C:23]3=[CH:24][N:25]=[C:26]([Cl:28])[CH:27]=[C:22]3[CH:21]=2)=[O:19])[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[H-].[Na+]>CN(C=O)C>[CH2:32]([O:16][CH:13]1[CH2:12][CH2:11][N:10]([C:8](=[O:9])[C@@H:7]([NH:17][C:18]([C:20]2[NH:29][C:23]3=[CH:24][N:25]=[C:26]([Cl:28])[CH:27]=[C:22]3[CH:21]=2)=[O:19])[CH2:6][C:5]2[CH:30]=[CH:31][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ncc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(OCc2ccccc2)CC1)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 16 h

Procedure:
To 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [1-(S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]amide (EXAMPLE 5, 50 mg, 0.11 mmol) in anhydrous DMF (3 mL) under argon was added benzylbromide (16 μl, 0.13 mmol) followed by sodium hydride (6.3 mg, 0.16 mmol) and the reaction stirred for 16 h. Solvent was removed in vacuo and the residue partitioned between ethyl acetate (2×20 mL) and water (20 mL). The organic fractions were washed with 1M HCl (20 mL), NaHCO3 (2×20 mL) then brine (2×20 mL), dried (MgSO4) and the solvent removed in vacuo. Crude material was purified by chromatography on silica gel with dichloromethane/methanol (9:1) as the eluent to give the title compound as an off-white powder. m/z (ES+)=535.33 [M+H]+; RT=3.44 min.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:10]([O:12][CH3:13])=[O:11])[C:6]([O:8][CH3:9])=[O:7])=[CH2:2].C(O)[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1>>[CH:1]([CH:3]1[CH2:5][C:4]1([C:10]([O:12][CH2:13][C:18]1[O:19][CH:15]=[CH:16][CH:17]=1)=[O:11])[C:6]([O:8][CH3:9])=[O:7])=[CH2:2]
Reactant: OCc1ccco1
Reactant: C=CC1CC1(C(=O)OC)C(=O)OC
Product: C=CC1CC1(C(=O)OC)C(=O)OCc1ccco1
Yield: 34.6 %

Procedure:
A transalcoholysis reaction was carried out in a manner similar to that described for Example II using dimethyl 2-vinylcyclopropane-1,1-dicarboxylate (92 g; 0.5 mol) and furfuryl alcohol (24.5 g; 0.25 mol). When essentially all of the furfuryl alcohol was consumed, the reaction mixture was dissolved in ethyl ether and washed with aqueous potassium hydroxide (5%). The ether portion was dried over MgSO4, filtered and vacuum distilled to obtain 21.63 g crude methyl (2-furyl)methyl 2-vinylcyclopropane-1,1-dicarboxylate. B.p. 91°-97° C. at 0.015 mm Hg. The distilled product (M.p. 58°-64° C.) was first recrystallized from methanol and then from a mixture of petroleum ether and methanol to obtain high purity methyl (2-furyl)methyl 2-vinylcyclopropane-1,1-dicarboxylate (translucent crystals melting at 67.5°-68.5° C.). The infrared spectra and nuclear magnetic resonance spectra were consistent with the desired product. Similar results are obtained when (5-methyl-2-furyl)carbinol, (5-allyl-3-furyl)carbinol and 5-hydroxymethyl-2,2'-difuryl methane are substituted for the furfuryl alcohol in the above reaction and all of these products are useful in insecticidal formulations.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].I[CH2:14][CH2:15][F:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:14][CH2:15][F:16])[C:8](=[O:11])[C:7]2=[O:12]
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C(=O)N(CCF)c2c(F)cccc21

Procedure:
7-Fluoro-1H-indole-2,3-dione (prepared according to the method of Gassman as described in U.S. Pat. No. 4,188,325 (2.00 g, 12.1 mmol), 1-iodo-2-fluoroethane (4.21 g, 24.2 mmol) and potassium carbonate (3.30 g, 24.2 mmol) in DMF (20 ml) are stirred at room temperature for 20 hours. The reaction mixture is diluted with cold water and the resulting precipitate filtered and dried to give the title compound as an orange solid. HPLC r.t. 4.18 min; MS for C10H7F2NO2 m/z 212.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].N>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Agent: N
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: Cc1ccc(CCOc2ccc(N)cc2)cc1
Yield: 94.6 %

Procedure:
4-[2-(4-Methylphenyl)ethoxy]nitrobenzene (VI) (5.14 g, 0.02 mole) and sodium sulfide nonahydrate (9.6 g, 0.04 mole) were added to a mixture of 95% aqueous ethanol (50 ml) and 29% aqueous ammonia (50 ml), followed by heating under reflux for 20 hours. Sulfur deposited was filtered while hot, and the filtrate was cooled, extracted with ether and treated in the same manner as in Example 17 to obtain 4.3 g of 4-[2-(4-methylphenyl)ethoxy]aniline (V) (yield, 95%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH:12]1[CH:17]2[CH:13]1[CH2:14][N:15]([C:18]1[N:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][N:19]=1)[CH2:16]2.O>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH:12]1[CH:13]2[CH:17]1[CH2:16][N:15]([C:18]1[N:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:19]=1)[CH2:14]2
Reactant: CCOC(=O)c1cnc(N2CC3C(C2)C3Nc2ccc3ccccc3n2)nc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(N2CC3C(C2)C3Nc2ccc3ccccc3n2)nc1
Yield: 30.3 %

Procedure:
Ethyl 2-[6-(quinolin-2-ylamino)-3-azabicyclo[3.1.0]hex-3-yl]pyrimidine-5-carboxylate (0.98 mmol) was stirred in THF (10 ml) and H2O (10 ml) at r.t. for 64 h. The reaction was then acidified to pH˜3 and the solvent removed in vacuo to give a brown solid. The solid was collected and washed with a little H2O to give the title compound as a brown solid (103 mg, 30% over 3 steps). LCMS purity 90%, m/z 348 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[C:24]([C:26]([OH:28])=O)[CH:23]=[CH:22][C:20]=3[N:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.[CH3:38][NH:39][CH3:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:38][N:39]([CH3:40])[C:26]([C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:32])([CH3:31])[CH3:1])=[C:7]([CH3:29])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[O:18][C:19]=2[CH:25]=1)=[O:28]
Reactant: CNC
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2ccc(C(=O)O)cc2o1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2ccc(C(=O)N(C)C)cc2o1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzooxazole-6-carboxylic acid (150 mg, 0.343 mmol) in CH2Cl2 (5.0 mL) is treated with DMAP (125 mg, 1.03 mmol) and EDC (99 mg, 0.514 mmol). The mixture is stirred for 15 m at RT, and dimethylamine hydrochloride (42 mg, 0.514 mmol) is added. The reaction is stirred for 18 h and quenched with aqueous NH4Cl (5.0 mL). The organic layer is loaded onto a silica gel column and purified with 50% EtOAc/Hex to afford the title compound (125 mg, 79%). MS (ES) m/e: 465.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:23][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCI
Reactant: COC1(c2ccc(F)c(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN1CCC(OC)(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.6 %

Procedure:
To a solution of 3-(3,4-difluorophenyl)-3-methoxypyrrolidine (0.19 g, 0.89 mmol) in acetonitrile (5 ml), potassium carbonate (0.17 g, 1.25 mmol) and iodoethane (0.075 ml, 0.94 mmol) was added and the mixture was stirred at ambient temperature for 5 h. Aqueous sodiumcarbonate (10%, 50 ml) and ethyl acetate (50 ml) was added and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phase was washed with Brine, dried (Na2SO4) and evaporated to give the crude product. Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) followed by flash column chromatography on silica gel (EtOAc/MeOH 4:1) gave the title compound (0.10 g, 46%). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 135-136° C. MS m/z (rel. intensity, 70 eV) 241 (4), 226 (27), 211(17), 141 (26), 71 (bp).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=[CH:10][C:5]2=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>CN1C(=O)CCC1>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH:27][CH2:26][CH2:24][OH:25])[N:7]=[C:6]2[N:8]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=[CH:10][C:5]=12
Reactant: NCCO
Reactant: Clc1nc(-c2ccco2)c2cnn(CCc3ccccc3)c2n1
Solvent: CN1CCCC1=O
Product: OCCNc1nc(-c2ccco2)c2cnn(CCc3ccccc3)c2n1
Temperature: 100 °C
Yield: 57.2 %

Procedure:
A solution of 6-chloro-4-(2-furyl)-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidine (162 mg, 0.5 mmol) in NMP (1 mL) was treated with ethanolamine (60 μL, 1 mmol), heated at 100° C. for 16 h, cooled and purified by chromatography (EtOAc:Heptane, 2:1). The resulting colourless oil was crystallised (MeOH/water) and filtered to give the title compound (100 mg, 57%) as a white solid.
Reaction SMILES: [I-:1].[K+].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[CH:22]=[C:21](/[CH:23]=[CH:24]/[CH:25]([C:30]2[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=2)[C:26]([F:29])([F:28])[F:27])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>O1CCOCC1.[Cu]I>[I:1][C:14]1[CH:22]=[C:21](/[CH:23]=[CH:24]/[CH:25]([C:30]2[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=2)[C:26]([F:29])([F:28])[F:27])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1I
Temperature: 100 °C

Procedure:
Per Buchwald, et al.; JACS, 2002, 124, 14844-14845, potassium iodide (KI, 273 mg, 1.64 mmol), CuI (31 mg, 0.16 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (catalytic amount) were added to a solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (400 mg, 0.82 mmol) in 1,4-dioxane (8 mL). The mixture in an Ace pressure tube was heated at 100° C. for 3 h. The reaction mixture was brought to ambient temperature and filtered through a Celite® pad. The filtrate was concentrated and residue was diluted with EtOAc and washed with 1N HCl followed by brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica eluting with 25% EtOAc in petroleum ether to afford the title compound as brown semi solid (240 mg, 55%): 1H NMR (400 MHz, DMSO-d6) δ 13.3 (bs, 1H), 8.21 (s, 1H), 7.91 (s, 2H), 7.71-7.64 (m, 2H), 7.01 (dd, J=15.6, 9.2 Hz, 1H), 6.75 (d, J=15.6 Hz, 1H), 4.85-4.81 (m, 1H); ESIMS m/z 532.8 ([M−H]−); IR (thinfilm) 3436, 1699, 1113, 750 cm−1.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.NC1C=CC(F)=C2C=1C=CC(=O)N2.[NH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[C:39]([F:47])[CH:40]=[CH:41][C:42]=2[NH2:46])[N:37]=1>[Ti](Cl)(Cl)(Cl)Cl>[NH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[C:39]([F:47])[CH:40]=[CH:41][C:42]=2[NH:46][CH:11]2[C:5]3[C:4](=[C:3]([O:20][CH3:21])[C:2]([F:1])=[CH:7][CH:6]=3)[C:8]([CH3:19])([CH3:18])[CH2:9][C:10]2([OH:17])[C:13]([F:16])([F:14])[F:15])[N:37]=1
Reactant: Nc1ccc2c(N)ccc(F)c2n1
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Nc1ccc(F)c2[nH]c(=O)ccc12
Product: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1ccc(F)c2nc(N)ccc12

Procedure:
Analogously to Example 10, a mixture of the corresponding imines is produced starting from 237 g of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 137 mg of a mixture that consists of 5-amino-8-fluoroquinolin-2(1H)-one and 2,5-diamino-8-fluoroquinoline. Analogously to Example 3, the mixture of imines with 2.5 ml of titanium tetrachloride solution (1 M in dichloromethane) is reacted, and the two title compounds are obtained after chromatography on silica gel.