Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].Cl>O1CCCC1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13]([C:4]3[CH:9]=[CH:8][C:7]([C:13]4[CH2:14][CH2:15][CH:10]([C@H:7]5[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]5)[CH2:11][CH:12]=4)=[CH:6][CH:5]=3)=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](C2CC=C(c3ccc(C4=CCC([C@H]5CC[C@H](CCC)CC5)CC4)cc3)CC2)CC1
Reaction time: 2 h

Procedure:
A solution of p-dibromobenzene (5.6 g, 0.024 mol) dissolved in tetrahydrofuran (200 ml) was dropwise added to sliced Mg (1.2 g, 0.049 mol) in nitrogen current so as to give soft reflux. After 7 hours, the reaction finished to yield its magnesium bromide, to which a solution of 4-(trans-4-propylcyclohexyl)-cyclohexanone (10.9 g, 0.049 mol) dissolved in tetrahydrofuran (100 ml) was rapidly dropwise added while the temperature was kept at 30° C. or lower. After the addition, the mixture was refluxed for 1.5 hour and 3N hydrochloric acid was added. The reaction liquid was extracted with toluene (100 ml×3), combined toluene layers were washed with water and the solvent was distilled off under reduced pressure. The remaining oily substance was 1,4-bis[4-(trans-4-propylcyclohexyl)-cyclohexan-1-ol]benzene, to which potassium hydrogen sulfate (2.5 g) was added, followed by dehydrating at 200° C. for 2 hours in nitrogen current, cooling, adding toluene (300 ml), filtering off potassium hydrogen sulfate, washing toluene layer with water, distilling off the solvent under reduced pressure and recrystallizing the residue from toluene to obtain an objective product, 1,4-bis[4-(trans-4-propylcyclohexyl)cyclohexen-1-yl]benzene (yield: 0.9 g) having a C-Sm point of 98.5° C. and a Sm-I point of 300° C. or higher.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:8][C:7]2[CH:9]=[CH:10][S:11][C:6]=2[C:5](=[O:12])[CH:4]=1.Cl.CNC.C=O.[C:19](=O)([O-])[O-:20].[K+].[K+]>>[OH:20][CH2:19][C:4]1[C:5](=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[S:8][C:3]=1[S:2][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: CSc1cc(=O)c2sccc2s1
Agent: C=O
Agent: CNC
Agent: Cl
Product: CSc1sc2ccsc2c(=O)c1CO
Yield: 76.5 %

Procedure:
5-Methylthio-7-oxo-7H-thieno-[3,2-b]thiopyran (1.77 g, 8.24 mmol) and dimethylamine hydrochloride (6.05 g, 74.2 mmol), paraformaldehyde (5.29 g) and potassium carbonate (2.28 g) were used to conduct the process similar to that shown in (1) of the Preparation 6, thus obtaining 1.54 g (yield: 77%) of 6-hydroxymethyl-5-methylthio-7-oxo-7H-thieno[3,2-b]thiopyran.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[NH:44][CH2:45][CH2:46][CH2:47][N:48]=3)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([N:30]3[CH2:35][CH2:34][CH:33]([CH2:36][C:37]4[CH:38]=[CH:39][C:40]([C:43]5[NH:48][CH2:47][CH2:46][CH2:45][N:44]=5)=[CH:41][CH:42]=4)[CH2:32][CH2:31]3)=[O:29])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: c1cc(C2=NCCCN2)ccc1CC1CCNCC1
Product: O=C(CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)N1CCC(Cc2ccc(C3=NCCCN3)cc2)CC1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 2c) and 2-(4-piperidin-4-ylmethyl-phenyl)-1,4,5,6-tetrahydro-pyrimidine (Reference Example 7) according to the method described in Example 1e. MS (EI) 688.3 (MH+).
Reaction SMILES: [Na].Cl[C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[CH:5][N:4]=1.[CH3:14][OH:15]>>[CH3:14][O:15][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[CH:5][N:4]=1
Reactant: CO
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
Agent: [Na]
Product: COc1cc([N+](=O)[O-])cnc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A round bottom flask was charged with methanol under nitrogen. Freshly cut sodium (91 mg, 3977 μmol) was added, and the mixture was stirred at RT under nitrogen until the sodium had dissolved. 2-Chloro-3-methoxy-5-nitropyridine (500 mg, 2652 μmol) was added and the reaction mixture was stirred under nitrogen at RT. After ˜15 min the mixture became heterogeneous and thick, and GC/MS analysis of a sample taken at 0.5 h indicated complete conversion to the desired product. The mixture was diluted with DCM and water and the layers were separated. The aqueous portion was extracted with additional DCM and the combined organics were dried, filtered and concentrated. The crude solid was passed through a silica plug using 5% MeOH/DCM. The filtrate was concentrated to provide 2,3-dimethoxy-5-nitropyridine as a light yellow solid. MS [M+H]=185.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Chloro-3-methylphenol (28.5 g., 0.2 mole) was dissolved in 400 ml. of acetone. Potassium carbonate (33.1 g., 0.24 mole) and then methyl iodide (34.1 g., 0.24 mole) were added and the mixture stirred for 16 hours at room temperature. The reaction mixture was filtered and the filtrate evaporated to an oil containing solids. This residue was distributed between methylene chloride and water. The organic layer was separated, washed in sequence with two portions of 1 N sodium hydroxide, two portions of water and one portion of brine, dried over anhydrous magnesium sulfate and concentrated to yield 4-chloro-3-methylanisole as an oil [24.6 g., 86%, pnmr/CDCl3 /delta 2.3 (s, 3H), 3.7 (s, 3H) 6.9 (m, 3H)].
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:7]2)[CH3:2].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([N:22]1[CH2:23][CH2:24][CH:19]([C:5]2[N:6]3[C:11]([C:10](=[O:12])[NH:9][C:8]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:7]3)=[C:3]([CH2:1][CH3:2])[N:4]=2)[CH2:20][CH2:21]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1nc(C2CCNCC2)n2nc(-c3ccccc3)[nH]c(=O)c12
Product: CCc1nc(C2CCN(C(=O)c3ccccc3)CC2)n2nc(-c3ccccc3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 103 Step (b), 30 mg (0.09 mmol) 5-ethyl-2-phenyl-7-(4-piperidinyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one, 14 mg (0.10 mmol) benzoyl chloride are stirred at room temperature overnight, proportionate amounts of the solvents are used.
Reaction SMILES: C([NH:7][CH2:8][CH2:9][N:10]([CH2:18][CH2:19][C:20]([NH:22][CH2:23][CH2:24][S:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:21])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(OCC=C)=O.C([O-])=O.C([NH+](CC)CC)C>C1COCC1.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>[NH2:7][CH2:8][CH2:9][N:10]([CH2:18][CH2:19][C:20]([NH:22][CH2:23][CH2:24][S:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:21])[C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12]
Reactant: C=CCOC(=O)NCCN(CCC(=O)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[NH+](CC)CC
Agent: O=C[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCN)CCC(=O)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Alloc-NH—(CH2)2—N(Boc)-(CH2)2—CONH—(CH2)2-STrt (48.3 mg, 0.078 mmol) was dissolved in THF, triethylammoniumformate (62 μl) and Pd(PPh3)4 (16 mg) were added. The solution was stirred for 12 h at RT and monitored by MS. After completion the solvent was removed in vacuo. The residue was dissolved in MeCN/H2O (50:50, with 0.1% TFA) and purified by RP-HPLC to give H2N—(CH2)2—N(Boc)-(CH2)2—CONH—(CH2)2-STrt (31).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([CH:14]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][NH:16][CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[CH3:13]>C(#N)C>[CH2:23]([CH:18]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][N:16]([CH2:15][CH:14]([CH2:12][CH3:13])[CH2:25][CH2:26][CH2:27][CH3:28])[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5])[CH3:24]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCC(CC)CNCC(CC)CCCC
Solvent: CC#N
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=O)c1ccccc1C(=O)O
Yield: 100.2 %

Procedure:
To 200 ml of acetonitrile were added 14.8 g of phthalic anhydride and 24.2 g of di(2-ethylhexyl)amine and the mixture was refluxed for 2 hours and then concentrated to provide 39.0 g of oily 2-{N,N-di(2-ethylhexyl)carbamoyl}-benzoic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[C:5]1(=O)[CH2:9][CH2:8][CH2:7][CH2:6]1>>[O:1]1[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:4][CH2:3][CH2:2]1
Reactant: NCCO
Reactant: O=C1CCCC1
Product: C1CCC2(C1)NCCO2

Procedure:
2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to afford 4-aza-1-oxaspiro[4.4]nonane. The oxazolidine was reduced according to method B4b, Step 2 to afford N-cyclopentyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to afford N-cyclopentyl-N-(2-chloroethyl)amine. The amine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1d to afford 2-(2-methyl-4-nitrophenylimino)-3-(cyclopentyl)-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.C(N(CC)CC)C.[Cl:29][CH2:30][CH2:31][CH2:32][C:33]#[CH:34]>C1(C)C=CC=CC=1.C(OCC)C.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:34]#[C:33][CH2:32][CH2:31][CH2:30][Cl:29])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: C#CCCCCl
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#CCCCCl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
Ethyl 6-chloro-8-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 73, Step 2) (1.50 g, 3.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.174 mmol), copper(I)iodide (0.066 g, 0.347 mmol), and triethylamine (1.05 g, 10.4 mmol) were dissolved in toluene (50 mL). 5-Chloro-1-pentyne (0.53 g, 5.20 mmol) was added via syringe and the mixture stirred for 18 hours at room temperature. The reaction was diluted with diethyl ether (50 mL), extracted with 0.5 N HCl (2×25 mL), and water (2×25 mL). The organic phase was dried over MgSO4, filtered, and evaporated to yield an orange oil. The crude material was purified by flash chromatography in 2% ethyl acetate in hexane. Recrystallization from hexane afforded the ester as a white solid (0.96 g, 68%): mp 84.8–85.9° C. 1H NMR (CDCl3/300 MHz) 7.61 (s, 1H), 7.33 (d, 1H, J=2.6 Hz), 7.14 (d, 1H, J=2.6 Hz), 5.79 (q, 1H, J=6.7 Hz), 4.37−4.29 (m, 2H), 3.75 (t, 2H, J=6.7 Hz), 2.67 (t, 2H, J=6.7 Hz), 2.11–2.03 (m, 2H,), 1.35 (t, 3H, J=7.2 Hz). FABLRMS m/z 424.1 (M+NH4+). ESHRMS m/z 424.0694 (M+NH4+, Calc'd. 424.0694). Anal. Calc'd. for C18H15Cl2F3O3: C, 53.09; H,3.71;, Cl,17.41. Found: C, 53.02; H, 3.90; Cl, 17.63.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]([C:21]3[NH:22][C:23]([CH3:27])=[C:24]([Cl:26])[CH:25]=3)=[O:20])[C@H:14]([O:28][CH3:29])[CH2:13]2)[N:3]=1.[CH3:30][OH:31].Cl>C[O-].[Na+]>[Cl:26][C:24]1[CH:25]=[C:21]([C:19]([NH:18][C@H:15]2[CH2:16][CH2:17][N:12]([C:4]3[N:3]=[C:2]([O:31][CH3:30])[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=3)[CH2:13][C@H:14]2[O:28][CH3:29])=[O:20])[NH:22][C:23]=1[CH3:27]
Reactant: CO
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)c3cc(Cl)c(C)[nH]3)[C@H](OC)C2)nc(Cl)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1nc(C(=O)O)cc(N2CC[C@H](NC(=O)c3cc(Cl)c(C)[nH]3)[C@H](OC)C2)n1
Temperature: 85 °C

Procedure:
Cis(±)methyl 2-chloro-6-(4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)pyrimidine-4-carboxylate (Example 23; 0.12 g, 0.27 mmol) was dissolved in 0.5 M sodium methoxide in MeOH (5.4 ml, 2.7 mmol) and heated in the microwave for 1.5 h at 85° C. The reaction mixture was acidified with 1N HCl and the product was extracted with EtOAc, dried with MgSO4 and concentrated to a solid which was purified by reverse phase chromatography (gradient elution from 20-50% CH3CN in water with 0.5% TFA). Freeze drying yielded product as a white solid. MS (ES) MH+: 424 for C18H22ClN5O5; NMR: 1.62 (s, 1H), 1.75 (s, 1H), 2.14 (s, 3H), 3.26 (s, 3H), 3.53 (m, 3H), 3.87 (s, 3H), 4.22 (s, 2H), 6.88 (d, J=2.64 Hz, 1H), 7.07 (s, 1H), 7.66 (d, J=7.91 Hz, 1H), 11.63 (s, 1H).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40].[CH2:42](I)[CH3:43]>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH2:42][CH3:43])[C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40]
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4C)c(Cl)c3)c2cc1OC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OCc1ccccc1C)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-methylbenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (62 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (84 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (53 mg, yield 79%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[CH3:12][N:13](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:12]#[N:13])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1cc(I)cc2nnsc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(Br)c2snnc2c1
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of 7-bromo-5-iodo-1,2,3-benzothiadiazole (22 mg, 0.0645 mmol), zinc cyanide (7.58 mg, 0.0645 mmol), Pd(PPh3)4 (7.46 mg, 0.00645 mmol) and DMF (2 mL) was heated to 60° C. for 4 h. The solution was extracted with EtOAc (50 mL), and the organic fraction was washed with saturated aqueous sodium bicarbonate solution (3×50 mL). The organic fraction was adsorbed onto silica gel and purified by ISCO chromatography (3 to 5% EtOAc:heptane) to afford 14 mg (90%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J=1.0 Hz, 1 H), 8.92 (d, J=1.3 Hz, 1 H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].F[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.[K+].[Br-]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CN1C(=O)N(C)CCC1.O>[CH3:1][N:2]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: O=Cc1ccc(F)cc1
Reactant: CNCCCCCCCCCCCO
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CN(CCCCCCCCCCCO)c1ccc(C=O)cc1
Temperature: 95 °C
Reaction time: 72 h

Procedure:
11.6 g of the N-methyl-N-(11-hydroxyundecyl)amine obtained according to Section 1, 8 g of potassium carbonate powder, 7.18 g of 4-fluorobenzaldehyde and 2 drops of the conventional and known phase transfer catalyst Aliquat® 336 (fatty quaternary ammonium chloride) in 50 ml of dimethylpropyleneurea were stirred for 72 hours at 95° C. Aliquat 336 is a commercial product and constitutes methyl-trioctylammonium chloride. It is a mixture of C8 - and C10 -chains, C8 being predominant. It is used as a phase transfer catalyst and liquid ion exchanger. The reaction mixture was then diluted with 700 ml of water and extracted with three times 50 ml of a solvent mixture of ether and ethyl acetate in a volume ratio of 1:1. The combined extracts were washed with three times 50 ml of water and then dried with sodium sulfate and, after the sodium sulfate had been separated off, were evaporated down. The resulting residue was freed from unconverted benzaldehyde by drying at 60° C. under reduced pressure from an oil pump, this procedure being monitored by thin layer chromatography. The dry product was purified by boiling with active carbon in acetone 12.45 g of 4-[N-methyl-N-(11-hydroxyundecyl)]-amino]-benzaldehyde were obtained, whose IR spectrum (KBr pellet) had bands at 3,400, 2,900, 2,850, 1,660, 1,580, 1,520, 1,460, 1,440, 1,380, 1,310, 1,240, 1,160, 1,050 and 820 cm-1.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:36][CH2:37][CH:38]([NH:61][CH2:62][C:63]1[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=1)[CH2:39][N:40]1[C:49]([C:50]#[N:51])=[C:48]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:58][CH3:59])[CH:46]=2)[C:41]1=[O:60])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[OH:36][CH2:37][CH:38]([NH:61][CH2:62][C:63]1[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=1)[CH2:39][N:40]1[C:49]([C:50]#[N:51])=[C:48]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:58][CH3:59])[CH:46]=2)[C:41]1=[O:60]
Reactant: COc1ccc2c(=O)n(CC(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)NCc3cccnc3)c(C#N)c(-c3ccccc3)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc2c(=O)n(CC(CO)NCc3cccnc3)c(C#N)c(-c3ccccc3)c2c1
Reaction time: 2 h

Procedure:
TBAF (1M in THF, 0.15 mL, 0.15 mmol) was added to a solution of silyl ether 101 in THF (2.5 mL). After stirring for 2 h, the reaction mixture was partitioned between EtOAc and NaHCO3. The organic phase was washed once with brine and then dried (Na2SO4) and concentrated. The product was purified by automated flash chromatography (0-8% MeOH(NH3)/EtOAc).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.C[Si](C)(C)[O-].[K+].Cl>C1COCC1.O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(Br)cc1
Yield: 101.1 %

Procedure:
Methyl 2-(4-bromophenyl)-2-methylpropanoate (3.75 g, 14.6 mmol, prepared according to J. Org. Chem., 59:2620-2622(1994)) in 150 mL of THF was allowed to react with potassium trimethylsilanolate (2.62 g, 20.4 mmol) at ambient temperature, for 60 hours, with continuous stirring. The reaction was then diluted with water and DCM. The pH of the aqueous phase was then adjusted to ca. 4, using 1M HCl. The aqueous layer was then extracted three times with additional DCM. The organic layers were pooled, dried over sodium sulfate, filtered and then concentrated to obtain 3.59 g of 2-(4-bromophenyl)-2-methylpropanoic acid, as a white solid, which gave LC/MS and proton NMR spectra consistent with theory.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH3:7][C:8]1([CH3:18])[C:12]([CH3:13])=[CH:11][CH2:10][CH:9]1[CH:14]([CH3:17])[CH:15]=[O:16].C(Cl)C(=C)C.O>CN(C=O)C>[CH3:17][C:14]([CH:9]1[CH2:10][CH:11]=[C:12]([CH3:13])[C:8]1([CH3:18])[CH3:7])([CH2:3][C:2]([CH3:5])=[CH2:1])[CH:15]=[O:16]
Reactant: CC1=CCC(C(C)C=O)C1(C)C
Reactant: CC(C)(C)[O-]
Agent: C=C(C)CCl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CC(C)(C=O)C1CC=C(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
A 4 neck 2 liter round bottomed flask was charged with 600 ml of DMF and 160 g of potassium t-butoxide (1.35 moles). Under nitrogen the flask was cooled to 0° C. and 200 g of 2-(2,2,3-trimethylcyclopent-3-en-1-yl)propanal (from Example 5) at 90% purity (1.08 moles) in 100 ml of DMF were added over 40 minutes at 0°-5° C. The reaction was stirred 30 minutes at 0° C. Then 140 g of methallyl chloride (1.54 moles) in 100 ml of DMF were added dropwise over 40 minutes at 5°-15° C. The batch was stirred 30 minutes at 10°-15° C. With good stirring the reaction mixture was poured onto 1 liter of water and extracted with 3×100 ml of hexane. The hexane extract was washed with 2×500 ml of water and 1 liter of brine. The extract was dried and concentrated in vacuo. The crude mixture of C- and O-alkylates, 261.4 g, was heated in a 500 ml 3 neck flask under nitrogen at 165° C. for 6.5 hours. Fractional distillation afforded 239.5 g of purified product (86.8% yield). BP 84° C./0.15 mmHg; 1H-NMR (300 MHz), δ 0.89 (3H, s), 1.03 (3H, s), 1.11 (3H, s), 1.55 (3H, s), 1.63 (3H, s), 2.20-2.27 (4H, m), 2.53 (1H, m), 4.67 (1H, s), 4.84 (1H, s), 5.27 (1H, s), 9.79 (1H, s); 13C-NMR (75 MHz), δ 12.34, 15.27, 22.25, 24.31, 28.11, 30.89, 46.11, 48.20, 52.83, 56.17, 115.57, 120.98, 141.43, 148.00, 207.01; m (Neat), 2980, 2700, 1725, 1645, 1450, 1380, 895 cm-1 ; MS (m/e), 220 (M+), 205, 191, 121, 108 (Base), 93, 55, 41;
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N+:17]([O-])=O)[C:8]1=[O:20])[C:4]([NH2:6])=[O:5].CO>[Pd]>[NH2:17][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[CH:16][N:7]([C@@H:3]([CH2:2][OH:1])[C:4]([NH2:6])=[O:5])[C:8]2=[O:20]
Reactant: NC(=O)[C@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@H](CO)n1ccc2c(N)cccc2c1=O

Procedure:
A round bottom flask (250 mL) was charged with (S)-3-hydroxy-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (0.2 g, 0.0007 mol) and methanol (20 mL, 0.5 mol) and palladium, 10% weight on charcoal (0.02 g, 0.0001 mol) was added and the flask was evacuated of air with the aid of vaccum and the reaction was stirred under an atmosphere of hydrogen (1 atm) with the aid of a balloon. The reaction was stirred for 45 minutes, in which time the reaction was complete. The reaction was filtered and the solvent removed under reduced pressure to yield the pure product as a light yellow solid. MS m/z=248.3 (M+H).