Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:19]=2[C:20](O)=[O:21])=[CH:15][CH:14]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C.CO>[F:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:19]=2[C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)=[O:21])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CN1CCOCC1
Product: O=C(O)c1ccc(NC(=O)c2ccc(C(F)(F)F)cc2Oc2ccc(F)cc2)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
A solution of methyl 5-aminopicolinate (15.2 mg, 0.1 mmol), 2-(4-fluorophenoxy)-4-(trifluoromethyl)benzoic acid (33.0 mg, 0.12 mmol), N-methylmorpholine (22 μL, 0.2 mmol) and HATU (45.6 mg, 0.12 mmol) in DMF (0.4 mL) was stirred at 40° C. for 16 hours. Aqueous NaOH (166.7 μL, 3M) and methanol (0.2 mL) were added and the mixture was stirred at 40° C. for 1 hour. The reaction mixture was diluted with MeOH, filtered and purification by reverse phase HPLC using a gradient of ACN in Water (1-99%) and HCl as a modifier to give 5-(2-(4-fluorophenoxy)-4-(trifluoromethyl)benzamido)picolinic acid (56) (9.95 mg, 33%). ESI-MS m/z calc. 420.07. found 421.29 (M+1)+; Retention time: 1.60 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) δ 13.15-12.96 (m, 1H), 11.09 (s, 1H), 8.90 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.36-7.13 (m, 5H) ppm.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])#[CH:2].BrCCCCCC.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]CCCCCC>>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27])#[CH:2]
Reactant: C#Cc1c(CCCCCC)ccc2ccccc12
Reactant: CCCCCCCCCCCCCCCCCCBr
Solvent: CCCCCCBr
Product: C#Cc1c(CCCCCCCCCCCCCCCCCC)ccc2ccccc12

Procedure:
1-Ethynyl-2-n-octadecylnaphthalene was prepared in a similar manner to 1-ethynyl-2-hexylnaphthalene, except that bromohexane was replaced by bromo-n-octadecane.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O[SiH](OCC)OCC)C>C1COCC1.O.O.O.O.[Rh](Cl)(Cl)Cl.O.[N+]([O-])([O-])=O.[Cu+2].O.O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC#CCCCCCCO
Agent: Cl[Rh](Cl)Cl
Agent: [Cu+2]
Agent: CCO[SiH](OCC)OCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC/C=C\CCCCCCO
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a solution of rhodium(III) chloride trihydrate (1.3 mg, 0.005 mmol), copper(II) nitrate hemipentahydrate (5.8 mg, 0.025 mmol) in THF (2.5 mL) and water (0.5 mL) was added 7-dodecyn-1-ol (91 mg, 0.50 mmol). The solution was stirred for 5 minutes and then triethoxysilane (0.21 g, 0.23 mL, 1.25 mmol) was added. The solution was stirred at room temperature for 8 hours. The volatiles were removed in vacuo and a solution of hexane (5 mL) and ether (1 mL) was added. The solution was dried over magnesium sulfate and filtered through a one inch plug of silica gel. The substrate was diluted with hexane/ether (5:1). The solvent was removed in vacuo. The product was then added to a solution of 3N hydrochloric acid (3 mL) and stirred at room temperature for 1 hour. The aqueous layer was extracted with ether (3×10 mL). The combined organics were dried over magnesium sulfate and filtered. The solvent was removed in vacuo to afford 0.088 g (0.48 mmol, 96%) of Z-7-Dodecen-1-ol which was a 14:1 Z:E mixture by spectroscopic analysis. Spectral analysis of the Z-isomer: IR (neat) 3434.8, 2929.0, 2857.1, 1459.2, 1056.1 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 5.33 (m, 2 H), 3.62 (t, J=6.6 Hz, 2 H), 2.01 (br d, 4 H), 1.66 - 1.5 (m, 2H), 1.33 - 1.22 (m, 11 H), 0.88 (t, J=7 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 129.99, 129.67, 62.96, 32.74, 32.49, 31.93, 31.21, 29.69, 29.05, 28.58, 27.10, 26.90, 25.63, 22.32, 18.41, 13.99.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1([C@@H:28]2[CH2:30][C@H:29]2[C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:31]([C@@H:29]3[CH2:30][C@H:28]3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:32])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)cc1c23
Yield: 28 %

Procedure:
Preparation of example 61 from the title compound of Example 7 (198 mg, 0.72 mmol), (1R,2R)-2-phenylcyclopropanecarboxylic acid (175 mg, 1.08 mmol; as described by A. Thurkauf, et al., J. Med. Chem. 43, 3923-3932, (2000)), triethylamine (0.401 mL, 2.88 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (411 mg, 1.08 mmol) in N,N-dimethylformamide (10.0 mL) was carried out analogously to Example 11. Silica gel chromatography (3% methanol in CH2Cl2), also in an analogous manner, followed by collection on a frit and subsequent washing with diethyl ether afforded the title compound (86 mg, 0.20 mmol) as a yellow powder in 28% yield.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]=[C:7]([NH:15][CH2:16][CH:17]=[CH2:18])[C:8]2[S:13][CH:12]=[C:11](Br)[C:9]=2[N:10]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:22])[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH2:1]([NH:4][C:5]1[N:6]=[C:7]([NH:15][CH2:16][CH:17]=[CH2:18])[C:8]2[S:13][CH:12]=[C:11]([NH:22][CH2:19][CH:20]=[CH2:21])[C:9]=2[N:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(NCC=C)c2scc(Br)c2n1
Reactant: C=CCN
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCNc1nc(NCC=C)c2scc(NCC=C)c2n1
Yield: 72.6 %

Procedure:
120 mg (0.37 mmol) of 2,4-diallylamino-7-bromothieno[3,2-d]pyrimidine, 337 mg (5.9 mmol) of allylamine, 56 mg (0.41 mmol) of potassium carbonate and 1 mg of copper were heated in a sealed tube at 180° C. for 5 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by distilling off excess allylamine under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 81 mg (yield: 72.9%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>C(OCC)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:9][C:4]1[CH:3]=[C:2]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOCC
Product: Fc1cc(F)cc(N2CCOCC2)c1
Reaction time: 8 h

Procedure:
A sealed tube was charged with 1-bromo-3,5-difluorobenzene (1.79 ml, 15.5 mmol), Pd2(dba)3 (0.85 g, 0.93 mmol), X-PHOS (2.22 g, 4.66 mmol), and potassium carbonate (4.73 g, 34.2 mmol). The tube was evacuated and backfilled with argon 3×. Fully degassed tert-amyl alcohol (51 mL) was added followed immediately by the addition of morpholine (2.71 ml, 31.1 mmol). The tube was then sealed and placed in an oil bath at 100° C. and stirred overnight. The reaction mixture was taken up in diethyl ether and water. The aqueous layer was extracted twice with diethyl ether. The organics were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash chromatography (silica, 0-17% diethylether/hexanes) afforded the title compound as a light yellow solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[S:8][CH:7](Cl)[CH2:6]1)=[O:4].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br:1][CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[S:8][CH:7]([C:22]2[CH:23]=[CH:24][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)[CH2:6]1)=[O:4]
Reactant: COc1ccccc1
Reactant: COc1ccc2c(c1)CN(C(=O)CBr)CC(Cl)S2
Product: COc1ccc(C2CN(C(=O)CBr)Cc3cc(OC)ccc3S2)cc1
Yield: 74.3 %

Procedure:
The above-mentioned 4-bromoacetyl-2-chloro-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.19 g), anisole (0.07 g) end stannic chloride (0.17 g) were reacted in the same manner as in Experimental Example 13 to give 4-bromoacetyl-7-methoxy-2-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.17 g). This compound (0.1g), 4-benzyl piperidine (0.09 g) and potassium carbonate (0.11 g) were reacted in the same manner as in Experimental Example 6 to give 4-[1-(4-benzyl)piperidinyl]acetyl-7-methoxy-2-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.20 g).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:20]=[C:15]([C:16]([F:19])([F:18])[F:17])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>N1C=CC=CC=1>[C:21]([CH:6]([OH:7])[C@H:5]1[O:8][C@@H:1]([N:9]2[CH:20]=[C:15]([C:16]([F:18])([F:17])[F:19])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)C(O)[C@H]1O[C@@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To a stirring solution of 150 mg of trifluorothymidine in 5 mL of pyridine was added a solution of 90 mg of pivaloyl chloride in 1 mL of pyridine, with cooling. Stirring was continued at room temperature for 10 hours, then the reaction mixture was poured into 20 mL of ice water and extracted with 50 mL of ethyl acetate. The extract was washed with water and dried over sodium sulfate. The ethyl acetate was removed and the residue was purified by silica gel column chromatography using 20:1 chloroform/methanol as eluent. The title compound melted at 130°-132° C. after recrystallization from a mixture of ether and n-hexane.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:14]=[C:15]([CH2:16][CH3:17])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[CH2:16]([C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:25])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:14]=1)[CH3:17]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(CC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a solution of [4-ethyl-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.11 g, 0.32 mmol) in THF (4 mL) and H2O (2 mL) was added LiOH (0.040 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography to give [4-ethyl-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.080 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.20 (s, 1H), 8.56 (s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.27 (s, 1H), 7.16 (s, 1H), 5.56 (s, 1H), 3.05 (M, 1H), 2.65 (m, 2H), 2.19 (M, 1H), 1.20 (M, 3H). MS (ES) m/z: 315 (M+1)+. HPLC purity: 99.19% (220 nm), 98.31% (Maxplot).
Reaction SMILES: [CH2:1](Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[C:17]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[Na].O>C(O)C>[CH2:1]([CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]([O:25][CH2:26][CH3:27])=[O:24])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC=C(C)CCC=C(C)CCC=C(C)C)C(=O)OCC
Yield: 59 %

Procedure:
Then, 501 g of farnesyl bromide as mentioned above and 285 g of diethyl malonate in 1,500 ml of ethanol were subjected to a condensation reaction in the presence of 37.1 g of metallic sodium. The reaction mixture was poured into water and extracted with ether. The organic layer was dried over anhydrous sodium sulfate. After removing the solvent, the residue was fractionated in vacuo to give 378 g of diethyl farnesylmalonate, b.p. 155° - 160° C. (0.2 mmHg). This product was saponified and decarboxylated in 1,000 ml of ethanol with 204 g of potassium hydroxide. The reaction mixture was neutralized with hydrochloric acid and extracted with ether. After removing the solvent, the residue was fractionated in vacuo to give 218 g of farnesylacetic acid, b.p. 142° - 150° C. (0.2 mmHg). The gas chromatographic analysis using 5% of polyethylene glycol 20 M (PGE-20M. for short) on kieselguhr (60- 80 mesh) at 180° C. of the column temperature, indicated that the substance was a mixture of stereo-isomers, 16% of Δ4,8 -cis-isomer, 48% of Δ4 -cis-Δ 8 -trans- and Δ4 -trans-Δ 8 -cis-isomers, and 36% of Δ4 -trans-Δ 8 -trans-isomer. By further fractionation through a rectifying column with 40 theoretical plates, was obtained 56.5 g of Δ4,8 -trans-farnesylacetic acid, b.p. 147° - 149° C. (0.2 mmHg). This showed that the Δ4,8 -trans-isomer was recovered in a yield of 72% based on the amount contained in the mixture. Subsequently, 150 g of farnesylacetic acid, which was obtained as the first distillate, was isomerized by heating with 0.15 g of acetylacetonatoruthenium RU (AA)3 at 200° C. in a nitrogenous atmosphere. By gas chromatographic analysis, the ratio of Δ4,8 -cis-isomer, Δ4 -cis-Δ 8 -trans-isomer+ Δ4 -trans-Δ 8 -cis-isomer and Δ4,8 -trans-isomer was 23.3:69.7:7.0 in the starting farnesylacetic acid and was 17.7:52.9:29.4 after isomerization.
Reaction SMILES: CO[C:3]([C:5]1([N:14]([OH:27])[C:15](=[O:26])[CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:9][N:8]([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].Br[CH2:31][CH2:32][O:33][CH3:34].C[O-].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[CH3:12][N:11]([CH3:13])[N:8]1[CH2:7][CH2:6][C:5]2([N:14]([O:27][CH2:31][CH2:32][O:33][CH3:34])[C:15](=[O:26])[CH:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:3]2=[O:4])[CH2:10][CH2:9]1
Reactant: COCCBr
Reactant: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(C)cc2C)CCN(N(C)C)CC1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COCCON1C(=O)C(c2c(C)cc(C)cc2C)C(=O)C12CCN(N(C)C)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
420 mg 1-Dimethylamino-4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (from Step 4) is dissolved in 15 ml dimethylformamide, cooled to 0° C., then 43 mg sodium hydride is added. It is warmed to room temperature, and stirred for 30 minutes. Then, 186 mg 1-Bromo-2-methoxy-ethane is added slowly at ambient temperature. The mixture is stirred for an additional hour, cooled to 0° C., and 180 mg sodium methoxide is added. Stirring is continued for 2 hours at room temperature. Then the mixture is poured into 200 ml aqueous ammonium chloride and the pH is adjusted to 4.3 by the addition of hydrochloric acid. It is extracted three times with ethyl acetate, the organic layer is separated, dried over sodium sulfate, and the solvent is evaporated. The residue is purified by chromatography on silica gel with cyclohexane/acetone as a solvent, from 1:2 to pure acetone. Thus, 160 mg 8-Dimethylamino-1-(2-methoxy-ethoxy)-3-(2,4,6-trimethylphenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione is obtained as a solid, mp 108° C. 1H-NMR (d4-methanol): 6.84 ppm (s, 2H), 4.28 ppm (m, 2H), 3.68 ppm (m, 2H), 3.37 ppm (s, 3H), 2.70 ppm (s, 6H), 2.22 ppm (m, 5H), 2.10 ppm (m, 8H).
Reaction SMILES: C(Br)(C)(C)C.[C:6]([OH:11])(=[O:10])[CH:7]([CH3:9])[OH:8].C(=O)(O)[O-].[Na+].O.[CH3:18][S:19]([CH3:21])=O>>[CH3:18][S:19][CH2:21][O:10][C:6](=[O:11])[CH:7]([CH3:9])[OH:8]
Reactant: CC(O)C(=O)O
Reactant: CS(C)=O
Agent: CC(C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CSCOC(=O)C(C)O
Reaction time: 48 h

Procedure:
153 ml (1.1 mol) of tert.butyl bromide are slowly added dropwise to a suspension of 10 g (0.11 mol) of L (+)-lactic acid and 94.2 g (1.1 mol) of sodium bicarbonate in 200 ml of dimethyl sulphoxide. The mixture is stirred for 48 hours, then poured into 1 liter of water and extracted twice with 100 ml of ethyl acetate each time. The organic phase is back-washed three times with 200 ml of water each time and subsequently evaporated. The crude product is chromatographed on a 20-fold amount of silica gel with n-hexane/ethyl acetate (4:1) and the eluate is evaporated. There are obtained 5.7 g of L (-)-lactic acid [(methylthio)methyl] ester; [α]D20 =-39.27° (c=1.3% in chloroform).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH2:20][CH2:19]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][N:21]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)[CH2:20][CH2:19]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: O=[N+]([O-])c1cccc(CCBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(CCc1cccc([N+](=O)[O-])c1)CC2
Yield: 40.9 %

Procedure:
A mixture of 1-(2-bromoethyl)-3-nitrobenzene (2.3 g), 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride (2.3 g) and potassium carbonate (3 g) in DMF (50 ml) was heated at 50° for 12 h. The mixture was then filtered and the filtrate evaporated. The residue was then taken up in water, extracted with dichloromethane, dried, evaporated and purified by column chromatography eluting with dichloromethane/methanol (99:1) to give the title compound (1.4 g) as a yellow oil. NMR includes signals at d 3.6 (2H,s,N--CH2Ar), 3.75 (6H,s,OCH3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:5]=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[C:22](B(O)O)[N:23]2C(OC(C)(C)C)=O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[C:22]([C:2]3[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][N:9]4[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]4)[CH:3]=3)[NH:23]2)=[CH:19][CH:18]=1
Reactant: CN1CCN(Cc2cncc(Br)c2)CC1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Product: CN1CCN(Cc2cncc(-c3cc4ccc(Cl)cc4[nH]3)c2)CC1

Procedure:
1-(5-Bromo-pyridin-3-ylmethyl)-4-methyl-piperazine and 6-chloro-1-Boc-indole-2-boronic acid are processed according to the method described in Example 91 to give 6-chloro-2-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indole. (ESI) m/z 341.1 (M+H)+.
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C1NC(=O)c2c(CCCCCCCCN3CCCCC3)cccc21
Reactant: NN
Solvent: CO
Product: NCCCCCCCCN1CCCCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 8-piperidinyloctylphthalimide (274 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][N:13]=2)[C:5]1=[O:26])(=O)C.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[C:6]2[NH:7][C:8](=[O:10])[C:9](=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:4][C:5]2=[O:26])=[N:13][CH:14]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)N1CC(=O)NC(=Cc2ccc(OCc3ccccc3)cn2)C1=O
Reactant: O=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]c(=Cc2ccc(OCc3ccccc3)cn2)c(=O)[nH]c1=Cc1ccccc1
Temperature: 60 °C
Yield: 83 %

Procedure:
Compound A (3.51 g) was added to a 40 mL of dimethylformamide solution containing equal molar of benzaldehyde and 4 equivalents of triethylamine. The solution was refluxed at 60° C. for 16 hr and cooled at ice bath to produce a yellow precipitate. The precipitate was then collected and washed with ethyl acetate to give 3.3 g (83%) of the desired product 3-[(5-benzyloxypyridin-2-yl)methylidene]-6-phenylmethylidenepiperazine-2,5-dione (Compound 1) as a mixture of isomers. The mixture was predominately the ZZ and EZ isomers.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl.Cl.[N:36]1([CH:41]2[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:43]4[CH2:44][CH2:45][CH:41]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH2:42]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: C1CCN(C2CCNC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCC(N4CCCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and 3-pyrrolidinyl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 478 [M+H]
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.B.CSC.Cl>O1CCCC1>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:10][C:6]=1[CH2:7][OH:8]
Reactant: O=C(O)c1cc(I)ccc1O
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: OCc1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 5-iodosalicylic acid (25.0 g, 94.6 mmol) in tetrahydrofuran (500 mL) was cooled to 0° C. With vigorous mixing, borane-methyl sulfide complex (15.1 ml of M solution, 151.0 mmol) was added drop-wise over 0.25 hours. The solution was warmed to room temperature and then heated at reflux for 4 h. A white precipitate formed during the reflux. The solution was cooled to room temperature and 10% aqueous hydrochloric acid (100 mL) was added over 15 min and the solution stirred at room temperature for 2 h. The precipitate dissolved and the solvent was concentrated in vacuo to a volume of approximately 200 mL. The solution was poured into ethyl acetate (300 mL) and washed with water (2×200 mL), saturated sodium bicarbonate (2×200 mL), and saturated ammonium chloride (2×200 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The 2-hydroxy-5-iodobenzyl alcohol was isolated as a white solid (21.3 g, 85.2 mmol)from hexanes.(90% yield): mp 105-110° C. 1H NMR (CDCl3 /300 MHz) 8.21 (s, 1H), 7.30-7.33 (M, 2H), 6.57 (d, 1H, J=8.3 Hz), 4.97 (bs, 1H), 4.62 (s, 2H). EIHRMS m/z=249.9492 (M+, Calc'd 249.9491).