Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:16]([CH3:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[NH:30]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[CH2:31][C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][C:40](O)=[O:41])=[O:37])=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH:30]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[CH2:31][C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][C:40]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C@@H:16]([CH3:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:41])=[O:37])=[O:33]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
H-Glu(OtBu)-Thr(tBu)-OtBu (1.27 g, 3.05 mmol) and Z-Gly-Gly-Gly-OH (0.99 g, 3.05 mmol) were dissolved in DMF (20 ml). To the solution were added HOBT (453 mg, 3.35 mmol) and WSC (643 mg, 3.35 mmol). The mixture was stirred for 8 hours at 20° C. The reaction mixture was concentrated, which was suspended in 0.2M aqueous solution of citric acid (70 ml), followed by extraction with ethyl acetate (100 ml, 70 ml). The ethyl acetate layers were combined and washed with a 10% (w/v) aqueous solution of ammonium chloride, 5% (w/v) aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous saline solution, successively, which was dried over anhydrous sodium sulfate, followed by concentration. To the concentrate was added ether-hexane. Resulting precipitates were collected by filtration to afford Z-Gly-Gly-Gly-Glu(OtBu)-Thr(tBu)-OtBu (Z-P-2) as a while powdery product (1.87 g, 85%).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH:12]([CH3:16])C(O)=O)=O.[Br:17][C:18]1[C:19]([CH3:28])=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2.N1CCCCC1.[C:35]([OH:38])(=[O:37])C>C(O)C>[Br:17][C:18]1[C:19]([CH3:28])=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:1][C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:16][C:35]([OH:38])=[O:37]
Reactant: Cc1c(Br)ccc2c1CC(=O)N2
Reactant: CC(=O)O
Reactant: CC(C(=O)O)c1c(C=O)[nH]c2c1CCCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(Br)ccc2c1C(=Cc1[nH]c3c(c1CCC(=O)O)CCCC3)C(=O)N2
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of (2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 5.0 g of 5-bromo-4-methyl-2-oxindole and 2.7 g of piperidine in 25 mL of ethanol was refluxed for 4 hours. Acetic acid (8 mL) was slowly added and a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed in 30 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and vacuum dried to give 7.6 g (80%) of 3-[2-(5-bromo-4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as an red-orange solid.
Reaction SMILES: O[C:2]1[C:3](=O)[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7]C=C[CH:10]=1)[CH:5]=2.[OH-:16].[Na+].[C:18]([O:21][CH2:22][CH3:23])(=O)C>C(Cl)Cl.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>[CH3:18][O:21][C:22]1[CH:23]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][CH:2]=[CH:14][CH:13]=3)[C:5](=[O:16])[C:6]=2[CH:7]=1
Reactant: [OH-]
Reactant: CCOC(C)=O
Reactant: O=C1C(O)=CC=C2C1=Cc1ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A solution of 2-hydroxyfluorenone (5 g, 25 5 mmol) in 500 mL methylene chloride was charged with 100 mL solution of 1N NaOH (4 g, 100 mmol), a solution of p-methyl tosylate (9.5 g, 51 mmol) in 200 mL of water and tetrabutylammonium hydrogen sulfate (0.2 g, catalytic) at room temperature. The reaction was monitored by TLC (silica, 25% ethyl acetate in hexane). The reaction mixture was stirred overnight at room temperature, the layers were separated. The organic layer was dried over MgSO. and evaporated. Short path chromatography of the residual solid (silica, 5% ethyl acetate in hexane) afforded 3.8 g (71.0%) of the methylated product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[C:8]([CH3:22])[C:6]=2[N:7]=1.[CH3:29][S-:30].[Na+].CN(C=O)C>C1(C)C=CC=CC=1>[CH3:22][C:8]1[C:6]2[N:7]=[C:2]([S:30][CH3:29])[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1
Reactant: C[S-]
Reactant: Cc1c(CN2CCN(S(C)(=O)=O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)c(C)c2n1

Procedure:
2-Chloro-7-methyl-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (2.38 mM) was added to sodium thiomethoxide dissolved in 50 mL toluene under N2 and heated to reflux. The reaction was stirred at reflux 24 hours and there was very little product by LCMS. To this reaction mixture was added 50 mL DMF to dissolve the starting material and again heated to reflux for two hours. Complete product formation was confirmed by LCMS. The reaction was poured onto ice water, extracted with ether, dried over MgSO4, and concentrated in vacuo. This crude product waspurified by flash chromatography (MeOH/DCM) giving 7-methyl-2-(methylthio)-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidine. MS (Q1) 445 (M+)
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[CH:11]1[N:16]2[N:17]=[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[C:15]2[C:14](=[O:28])[NH:13][CH2:12]1>C(Cl)Cl>[F:7][CH:11]1[N:16]2[N:17]=[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[C:15]2[C:14](=[O:28])[NH:13][CH2:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1NCC(O)n2nc(COc3ccccc3)cc21
Solvent: ClCCl
Product: O=C1NCC(F)n2nc(COc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.7 %

Procedure:
DAST (0.035 mL, 0.29 mmol) was added to a solution of (rac)-7-hydroxy-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.19 mmol) in DCM (0.5 mL) at −10° C. The mixture was stirred at room temperature for 15 minutes. Then quenched with a 1N solution of HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield (rac)-7-fluoro-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (51 mg, quantitative) as light brown solid that was used without further purification.
Reaction SMILES: [C:1]1([C:11]2([CH2:16]OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C-:22]#[N:23].[Na+].C(OCC)(=O)C>CS(C)=O.CCCCCC>[C:1]1([C:11]2([CH2:16][C:22]#[N:23])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCC1(c2cccc3ccccc23)CCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: N#CCC1(c2cccc3ccccc23)CCCC1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
To a stirred solution of methanesulfonic acid 1-naphthalen-1-yl-cyclopentylmethyl ester (341) (2.1 g, 6.90 mmol) in dimethyl sulfoxide (10.0 mL) were added KI (115 mg, 0.69 mmol) and NaCN (507 mg, 10.35 mmol) and the reaction mixture was stirred at 140° C. for 2 h (silica TLC, 10% ethyl acetate in hexane; Rf=0.5). The reaction mass was cooled to room temperature, quenched with FeSO4 solution (15 mL) and diluted with water (100 mL). The resulting solid was separated through filtration and washed well with ethyl acetate. The biphasic layer was separated in a separating funnel. The organic part was washed with brine (2×50 mL), dried and concentrated in vacuo to get a crude mass which was purified by Combi-Flash using a mixture of ethyl acetate and hexane as gradient eluent to get pure (1-naphthalen-1-yl-cyclopentyl)-acetonitrile (342) (710 mg, 44%) as a yellow gummy liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=O.[C:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:7]([C:6]2[N:5]([CH3:12])[N:4]=[C:3]([CH3:13])[C:2]=2[Cl:1])=[O:9])=[CH:24][CH:25]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CCOC(=O)c1c(Cl)c(C)nn1C
Product: Cc1nn(C)c(C(=O)NCc2ccc(C(C)(C)C)cc2)c1Cl
Temperature: 200 °C
Yield: 69.9 %

Procedure:
A mixture of 2.03 g of ethyl 4-chloro-1,3-dimethylpyrazole-5-carboxylate and 2.45 g of 4-tertbutylbenzylamine was heated at 200° C. for 4 hours under stirring. After cooling to room temperature, the reaction product was purified by silica gel column chromatography to obtain 2.24 g of the compound (No. 36) described in Table 1.
Reaction SMILES: C[C:2]1[C:10]([CH3:12])(C)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CC1S[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.IC>>[CH:21]1[CH:20]=[CH:19][C:17]([N:18]=[CH:12][CH2:10][CH:2]=[N:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:22]=1
Reactant: Cc1nc2ccccc2s1
Reactant: CC1=Nc2ccccc2C1(C)C
Solvent: CI
Product: C(CC=Nc1ccccc1)=Nc1ccccc1

Procedure:
2,3,3-Trimethyl indolenine, methylbenzothiazole, iodomethane, and diidopropane were purchased from Aldrich and used without further purification. Malonaldehyde dianil was synthesized according to literature reports (Glauert, R. H. and Mann, F. G. J. Chem. Soc. (1952) 5012, by the method of Claisen Ber. (1903) 36, 3668). Dry nitrobenzene was freshly distilled from CaH2. Dry triethylamine was distilled from Na°. DMF was predried with MgSO4, fractionally distilled and stored over molecular sieves. All dry solvents were stored under N2. All reactions were run under anhydrous conditions under N2. Reactions were monitored by TLC (silica gel 60, A260, Fisher) and visualized with short and long wavelength UV irradiation. Flash column chromatography was performed on silica gel 60 (200-440 mesh Fluka).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH:1]([N:14]1[CH2:17][C:16]([O:18][S:21]([CH3:20])(=[O:23])=[O:22])([CH3:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: c1ccncc1
Product: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -20 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
10 g (0.0394 mol) of 1-benzhydryl-3-methylazetidin-3-ol (S. S. Chattergee and A. Shoeb, Synthesis 1973, p. 153-154) are dissolved in 100 ml of anhydrous pyridine, the mixture is cooled to -20° C. and 7.3 g (0.063 mol) of methanesulphonyl chloride are added dropwise. The temperature is kept below -10° C., stirring is carried out at this temperature for 1 hour and the reaction mixture is left between 0° C. and 3° C. for two days. It is poured into 600 ml of water/ice, the precipitate is recovered by filtration and is washed with water. After drying in the oven at 50° C. for 2 hours the product is taken up in isopropyl ether (100 ml), is filtered and is dried in the oven at 50° C. overnight to obtain approximately 10 g of 1-benzhydryl-3-methanesulphonyloxy-3-methylazetidine.
Reaction SMILES: [CH3:1][N:2]([CH3:55])[CH:3]([C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1)[CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35]C(C)(C)C)=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:55][N:2]([CH3:1])[CH:3]([C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1)[CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:27])([CH3:28])[C:16]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:40][CH:41]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCC(c3cccnc3)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCC(c3cccnc3)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 13.8 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)-2-(pyridin-3-yl)ethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (125 mg, 0.167 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 4.5 h then was concentrated under reduced pressure. The residue was dissolved in dioxane and MeOH and was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure. Impurities were still present so the residue was purified again by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give the title compound as an off-white solid (16 mg, 13.8%). LCMS: m/e 692.5 (M+H)+, 2.30 min (method 6). 1H NMR (500 MHz, Acetic Acid) δ ppm 8.83-8.98 (m, 2H), 8.27-8.42 (m, 1H), 7.99-8.11 (m, 2H), 7.71-7.84 (m, 1H), 7.27-7.35 (m, 2H), 5.33-5.42 (m, 1H), 5.22-5.30 (m, 1H), 4.79 (d, J=14.34 Hz, 1H), 4.67 (d, J=12.82 Hz, 1H), 4.21-4.38 (m, 2H), 3.34-3.52 (m, 1H), 2.97-3.15 (m, 1H), 2.83 (br. s., 3H), 2.82 (br. s., 3H), 2.43-2.58 (m, 1H), 0.88-2.23 (m, 40H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([O:11]CC)=[O:10])[CH2:3][CH2:2]1.C(O)(=O)C.Cl>O>[CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cnoc1C1CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnoc1C1CC1
Yield: 82.1 %

Procedure:
Ethyl 5-cyclopropylisoxazole-4-carboxylate (203.0 g, 1.12 mole) [prepared in Step B] was added to a solution of 405 ml of glacial acetic acid plus 505 ml of 6N HCl and the mixture was heated in an oil bath at 105°-110° C. for 3 h. After 18 h at ambient temperature the thick mixture was diluted with water, cooled in an ice bath and filtered to give 140.8 g (82%) of the title acid. Recrystallization of an aliquot from acetonitrile gave an analytical sample, mp 163°-165° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)O)c(C)c2)cc1
Yield: 89.2 %

Procedure:
4-Bromo-2-methyl-benzoic acid (2.15 g, 10 mmol), 4-methoxy-phenylboronic acid (1.52 g, 10 mmol) and sodium carbonate (3.24 g, 30 mmol) in a mixture of toluene, water and ethanol (15 mL:6 mL:3 mL) was sparged with nitrogen for 5 minutes. To this was added palladium acetate (0.014 g). The mixture was heated at reflux, under a static pressure of nitrogen, for 24 hours. The sample was diluted with water and ethyl acetate (50 mL each) and the pH was adjusted to 1. The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic extracts were combined and washed with water and brine. The sample was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate/hexanes to yield the title compound (2.16 g ) as a white solid, m.p 199-201° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O(CC)CC.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27](OCC)=O)[CH2:23][CH2:22]1>O>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[NH:20][CH:21]1[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1
Reactant: CCOC(=O)N1CCC(Nc2c(C)cccc2C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(C)c1NC1CCN(C)CC1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
To a stirred and refluxing suspension of 2 parts of lithium aluminiumhydride in 120 parts of 1,1'-oxybisethane is added dropwise a solution of 13 parts of ethyl 4-[N-(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate in 40 parts of 1,1'-oxybisethane. After the addition is complete, stirring and refluxing is continued for 20 hours. The reaction mixture is cooled to 5° C. and 7 parts of water are added. The formed precipitate is filtered off, washed on the filter with 1,1'-oxybisethane and the filtrate is evaporated. The oily residue is distilled, yielding 5.8 parts of N-(2,6-dimethylphenyl)-1-methyl-4-piperidinamine; bp. 90°-93° C. at 0.003 mm. pressure. On standing the distillate solidifies, to yield solid N-(2,6-dimethylphenyl)-1-methyl-4-piperidinamine with a melting point of 45° C.
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.[Br:49][C:50]1[CH:51]=[N:52][C:53](Cl)=[N:54][CH:55]=1.C(N(C(C)C)CC)(C)C.Cl>O1CCOCC1>[Br:49][C:50]1[CH:51]=[N:52][C:53]([N:33]2[CH2:34][CH2:35][CH:30]([C:10]3[C:9]([CH:36]([F:47])[C:37]4[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=4)=[C:8]([CH:5]4[CH2:6][CH2:7][C:2]([F:1])([F:48])[CH2:3][CH2:4]4)[C:17]4[CH:16]([O:18][CH2:19][C:20]5[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=4[N:11]=3)[CH2:31][CH2:32]2)=[N:54][CH:55]=1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
To a solution of 4.80 g (7.11 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, in 16 ml of 1,4-dioxane, 1.40 g (7.24 mmol) of 5-bromo-2-chloropyrimidine and 1.6 ml (9.4 mmol) of diisopropylethylamine were added, and the reaction solution was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into 40 ml of 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. n-Heptane was added to the obtained residue and the precipitate was obtained by filtration to provide 5.09 g of the title compound as a white solid (yield: 86%).
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:36]=[CH:35][C:23]3[N:24](COCC[Si](C)(C)C)[N:25]=[N:26][C:22]=3[CH:21]=2)[C:16]1=[O:37].CO>C(Cl)Cl>[ClH:1].[NH:24]1[C:23]2[CH:35]=[CH:36][C:20]([N:17]3[CH2:18][CH2:19][N:15]([C:10]4[CH:11]=[N:12][CH:13]=[CH:14][C:9]=4[CH3:8])[C:16]3=[O:37])=[CH:21][C:22]=2[N:26]=[N:25]1
Reactant: Cc1ccncc1N1CCN(c2ccc3c(c2)nnn3COCC[Si](C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc3[nH]nnc3c2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.4 %

Procedure:
Dioxane HCl (10 ml) was added to 1-(4-methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzotriazol-5-yl]-imidazolidin-2-one (I-141a: 350 mg, 0.78125 mmol) and the resulting mixture was stirred room temperature for 12 hours. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was concentrated and washed with ether. The solid formed was collected and dried under reduced pressure to afford 230 mg of the product (89.4% yield).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH2:14]Br)=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].[S-:22][C:23]#[N:24].[K+]>CC(C)=O>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH2:14][S:22][C:23]#[N:24])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: N#C[S-]
Reactant: CCCc1c(OCCCSCCBr)ccc(C(C)=O)c1O
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCSCCSC#N)ccc(C(C)=O)c1O

Procedure:
(2.8 mMole) S-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]-2-mercaptoethyl bromide and 5.0 g. potassium thiocyanate are heated to reflux for 2 hours in 25 ml. acetone. Subsequently, the precipitate is filtered off with suction, the solution is evaporated and the residue is stirred with diethyl ether. After evaporating the diethyl ether, there is obtained 0.7 g. (71% of theory) of the title compound in the form of an oil.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.NC(N)=[S:13].C(O)C.Cl.Cl[CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=1>O>[CH3:27][C:26]1[C:21]([CH2:20][S:13][C:2]2[NH:3][C:4]3[C:5]([N:10]=2)=[N:6][CH:7]=[CH:8][CH:9]=3)=[N:22][CH:23]=[C:24]([CH3:30])[C:25]=1[O:28][CH3:29]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: NC(N)=S
Reactant: Clc1nc2ncccc2[nH]1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1c(C)cnc(CSc2nc3ncccc3[nH]2)c1C

Procedure:
737 Milligrams of 2-chloro-imidazo[4,5-b]pyridine, 0.4 g of thiourea and 20 ml of ethanol were mixed together and this mixture was refluxed for 2 hours. Next, 666 mg of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride was added to the reaction mixture and refluxed for 5 hours. After the reaction was completed, ethanol was removed by evaporation, then to the residue thus obtained was added water and this solution was extracted with chloroform. The chloroform extract was dried with anhydrous magnesium sulfate and chloroform was removed by evaporation. The residue thus obtained was recrystallized from ethanol to obtain 450 mg of 2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]imidazo[4,5-b]pyridine in the form of white powdery crystals. Melting point: 186°-188° C.