Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(OCC(CC)CC)[O:6][Sn:7]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[O:8][CH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])CCC>O>[CH2:19]([Sn:7]([CH2:15][CH2:16][CH2:17][CH3:18])([O:6][CH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[O:8][CH2:9][CH:10]([CH2:11][CH3:12])[CH2:13][CH3:14])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC[Sn](CCCC)(OCC(CC)CC)O[Sn](CCCC)(CCCC)OCC(CC)CC
Solvent: O
Product: CCCC[Sn](CCCC)(OCC(CC)CC)OCC(CC)CC
Reaction time: 0.53 h
Yield: 94 %

Procedure:
Nitrogen gas was fed from the gas supply line 7 at 0.04 NL/min, and a feed pump was used to start feeding from the supply line 4 a mixed solution of the starting material and the reactant prepared as described above at 20 g/Hr. The holding time in the reactor was about 32 minutes. Low boiling point substances, including water, began to be extracted in gaseous form from the extraction vent line 5 and high boiling point components began to flow out from the extraction line 6. Continuous feeding and continuous extraction operation was continued in this state for 2 hours. Analysis of the generated product extracted from the extraction line 6 showed that, using dibutyltin oxide as a reference, the generated product contained a dibutyltin alkoxide consisting of about a 94% yield of dibutyl-bis(2-ethyl-butyloxy)tin and about 6% of 1,1,3,3-tetrabutyl-1,3-bis(2-ethyl-butyloxy)-distannoxane. Tributyltin(2-ethyl-butyloxide) had a yield of 0.4%. Upon cooling of the gas phase extracted from the extraction vent line 5, a two-layer transparent liquid was obtained, in which moisture was present. The dehydration rate in the column reactor was 0.0033 mol/Hr, which was greater than the value 0.0005 mol/Hr calculated from expression (16).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[CH:10]=[C:11]([C:13]([O-:15])=O)[S:12][C:5]=12.[Li+]>>[CH3:1][NH:2][C:13]([C:11]1[S:12][C:5]2[C:6](=[N:7][CH:8]=[CH:9][C:4]=2[Cl:3])[CH:10]=1)=[O:15]
Reactant: CN
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: CNC(=O)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from methylamine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: n.d.; HPLC Rf: 3.70 min.; HPLC purity: 89%.
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.Cl[C:29]1[C:30]([O:43][CH2:44][CH:45]2[CH2:50][CH2:49][C:48]([F:52])([F:51])[CH2:47][CH2:46]2)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35]>>[CH:10]1([C:29]2[C:30]([O:43][CH2:44][CH:45]3[CH2:50][CH2:49][C:48]([F:52])([F:51])[CH2:47][CH2:46]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35])[CH2:1][CH2:2]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCC(F)(F)CC2)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 49 and making variation as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with 5-chloro-4-((4,4-difluorocyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.04 g, 13%): 1H NMR (300 MHz, CDCl3) δ 8.69 (d, J=15.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 6.55 (d, J=14.4 Hz, 1H), 3.88 (d, J=9.0 Hz, 2H), 3.39 (s, 3H), 2.25-2.11 (m, 2H), 2.04-1.66 (m, 6H), 1.54-1.41 (m, 2H), 0.97-0.89 (m, 2H), 0.67-0.61 (m, 2H); MS (ES−) m/z: 404.1 (M−1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[C:11]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:10]2=[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:8]=1[C:25]#[N:26])(=O)=O.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.P(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CCOC(C)=O.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>[CH2:16]([N:13]1[C:11]2=[N:12][C:7]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)=[C:8]([C:25]#[N:26])[C:9]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=3)=[C:10]2[CH:15]=[N:14]1)[CH3:17]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(C#N)c(OS(=O)(=O)C(F)(F)F)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=[PH]([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCn1ncc2c(-c3cncc(C)c3)c(C#N)c(-c3ccc(F)cc3)nc21
Yield: 79.6 %

Procedure:
To a mixture of 5-cyano-1-ethyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-6-yl trifluoromethanesulfonate (253 mg), 4-fluorobenzeneboronic acid (129 mg), powdered potassium phosphonate (195 mg) in 1,4-dioxane (4 ml) was added tetrakis(triphenylphosphine)palladium(0) (18 mg) at room temperature. The mixture was refluxed for 7 hours. Resulting mixture was diluted with EtOAc (10 ml), washed with water (×2) and brine and dried over MgSO4. The solvent was evaporated and the residue was purified with silica gel column chromatography to give 1-ethyl-6-(4-fluorophenyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (175 mg) as colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[S:10](=[O:14])(=[O:13])([OH:12])O.[OH:15][S:16](O)(=[O:18])=[O:17].O=S(=O)=O>>[CH2:1]([C:3]1[CH:4]=[C:5]([S:16]([OH:18])(=[O:17])=[O:15])[C:6](=[CH:8][C:9]=1[S:10]([OH:12])(=[O:14])=[O:13])[NH2:7])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCc1ccc(N)cc1
Agent: O=S(=O)=O
Product: CCc1cc(S(=O)(=O)O)c(N)cc1S(=O)(=O)O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
121 parts of 4-ethylaniline are added dropwise at 75°-83° C. to 183 parts of 100% sulfuric acid. The mixture is stirred for 15 minutes at 80° C., whereupon a clear solution forms. This sulfuric acid solution is added dropwise over 40 minutes to 320 parts of 66% oleum, while keeping the temperature at 60°-65° C. by cooling with an ice bath. After stirring for 15 minutes at 65° C., no more 4-ethylaniline can be detected. Stirring is continued for 4 hours at 150° C., then the sulfonation mixture is cooled to 80° C. and poured into 900 parts of ice/water. The monopotassium salt of 4-ethylaniline-2,5-disulfonic acid is precipitated by the dropwise addition of 370 parts of a 50% solution of potassium hydroxide and isolated by filtration, affording 350 parts of moist 53.0% 4-ethylaniline-2,5-disulfonic acid, corresponding to a yield of 66%, based on 4-ethylaniline. The purity is >99% (analysis by HPLC).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:22])([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:13][OH:14]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:22])([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:13][O:14][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(C)(CCCCBr)COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
Under N2 atmosphere, 3,4-dihydro-2H-pyran (6.39 g, 76.09 mmol) was added drop-wise to a stirred solution of 6-bromo-2-methyl-2-p-tolyl-hexan-1-ol (18.20 g, 63.86 mmol) and p-toluenesulfonic acid hydrate (0.43 g, 2.26 mmol) in dichloromethane (300 mL) at −5° C. The reaction mixture was allowed to warm to rt and stirred for 3 h. The solution was filtered through aluminum oxide (160 g), which was washed with CH2Cl2 (500 mL). The filtrate was concentrated in vacuo to furnish 2-(6-bromo-2-methyl-2-p-tolyl-hexyloxy)-tetrahydropyran (22 g, 93.4%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.25-7.05 (m, 4H), 4.60-4.48 (m, 1H), 3.82 (m, 2H), 3.48-3.37 (m, 2H), 3.35-3.26 (m, 2H), 2.30 (s, 3H), 1.90-1.40 (m, 11H), 1.40-1.33 (s, 3H), 1.40-1.08 (m, 1H), 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 142.78, 135.22, 128.81, 126.39, 99.09, 61.99, 41.67, 38.12, 37.87, 33.68, 30.99, 25.96, 23.08, 22.89, 21.12, 20.97, 19.41. HRMS (LSIMS, nba): Calcd. for C19H30O2Br (MH+): 369.1429, found: 369.1451.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH2:17])=[N:9]3)[CH:7]=1.[C:19](=[O:22])(O)[O-:20].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:19](=[O:22])[O:20][C:6]([CH3:8])([CH3:7])[CH3:5])=[N:9]3)[CH:7]=1
Reactant: NC1=N[C@@]2(c3cc(Br)ccc3F)OCC[C@H]2CS1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(Br)ccc3F)OCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of (4aR,7aR)-7a-(5-bromo-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-amine (4.8 g, 14.5015 mmol) in 1,4-Dioxane (40 mL) was added di-tert-butyl bicarbonate (6.19 mL, 29.003 mmol) followed by addition of saturated sodium bicarbonate (33.6 mL) and water (4.8 mL) at rt, and the reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3×100 mL), and the combined organics were dried over the sodium sulphate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluting with 30-40% ethyl acetate-hexanes (combiflash) to give the title compound as a white solid (3.5 g, 56% yield). 1H NMR (400 MHz, CDCl3) δ 7.67 (1H, dd, J=2.4, 6.8 Hz), 7.43 (1H, dt, J=1.2, 6.8 Hz), 6.96 (1H, dd, J=8.4, 11.2 Hz), 4.13 (1H, m), 4.03 (1H, m), 3.26 (1H, m), 2.86 (2H, m), 2.36 (1H, m), 2.21 (1H, m), and 1.47 (9H, s). MS (M+H)+:431.0, 435.0
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:43]([F:44])=[CH:42][CH:41]=[C:40]([O:45][CH3:46])[C:39]=4[F:47])[N:32]=3)=[O:30])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.CO.[OH-].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[NH2:20][C@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:13]2[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:43]([F:44])=[CH:42][CH:41]=[C:40]([O:45][CH3:46])[C:39]=4[F:47])[N:32]=3)=[O:30])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1
Reactant: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](N)C3)CCC4O)ccc2F)c1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3-({[6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (5.0 mg, 0.008 mmol), MeOH (90 μL), THF (45 μL) and 1.0 M aq. NaOH (50 μL, 0.050 mmol) was stirred at room temperature for 20 min. The solvents were removed under reduced pressure to give the crude intermediate, which was dissolved in DCM (0.08 mL), followed by the addition of TFA (0.078 mL, 1.0 mmol). The reaction mixture was stirred at room temperature for 20 min. After concentrating the solution under reduced pressure, the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give both diastereoisomers of the title compound as white powders.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH2:17])[C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>O.CCOCC>[NH:17]([C:24]([CH3:25])=[O:26])[C@H:5]([C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])[CH2:4][CH:2]([CH3:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Reaction time: 1 h
Yield: 74 %

Procedure:
Leu-Leu (1.0 g, 3.8 mmol) and potassium carbonate (7.0 g, 5 mmol) are dissolved in 100 ml of water. The solution is cooled with ice and 5.0 ml acetic anhydride in 50 ml of ether is added dropwise under vigorous stirring. Stirring is continued for one hour, then the ice-bath is removed and the stirring continued for further 2 hours. The water phase is separated, acidified with hydrochloric acid. The precipitate is stirred for one hour, filtered, washed with water and dried yielding 0.8 gram (74%) of Ac-Leu-Leu.
Reaction SMILES: [CH2:1]([C:3]1([CH2:14][CH3:15])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:4]1=2)[CH3:2].C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:13][C:10]1[CH:11]=[CH:12][C:4]2[C:3]([CH2:1][CH3:2])([CH2:14][CH3:15])[O:7][B:6]([OH:8])[C:5]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC1(CC)OB(O)c2cc(C)ccc21
Solvent: ClC(Cl)(Cl)Cl
Product: CCC1(CC)OB(O)c2cc(CBr)ccc21
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 3,3-diethyl-6-methylbenzo[c][1,2]oxaborol-1(3H)-ol (0.8 g, 3.92 mmol) in CCl4 (10 mL) under nitrogen was added NBS (698 mg, 3.92 mmol) and BPO (94 mg, 0.39 mmol). The mixture was refluxed for 2 h under the light from Sun lamp and then it was cooled to rt, washed with aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to provide the product (0.8 g, 72%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](F)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[F:13][C:14]([F:22])([F:21])[CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:17]2[CH2:18][CH2:19][CH2:20][CH:15]([C:14]([F:22])([F:21])[F:13])[CH2:16]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: FC(F)(F)C1CCCNC1
Reactant: CC#CCOc1cc(F)ncn1
Solvent: Cc1ccccc1
Product: CC#CCOc1cc(N2CCCC(C(F)(F)F)C2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.2 g of 4-(2-butynyloxy)-6-fluoropyrimidine and 0.15 g of 3-trifluoromethylpiperidine are added to 1 ml of toluene, then the mixture is stirred at room temperature for 30 minutes. Then the reaction mixture is subjected to silica gel column chromatography to obtain 4-(2-butynyloxy)-6-(3-trifluoromethylpyperidino)pyrimidine (referred as the present compound (10) hereinafter).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C:13]([CH3:34])([CH3:33])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:23][C:24]1[CH:25]=[C:26]([C:30](=O)[CH3:31])[CH:27]=[CH:28][CH:29]=1)[CH:20]([CH3:22])[CH3:21]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:13]([CH3:34])([CH3:33])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([CH3:1])=[CH2:31])[CH:25]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: [Li]CCCC
Reactant: CC(=O)c1cccc(CN(C/C=C/C#CC(C)(C)C)C(C)C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C(C)c1cccc(CN(C/C=C/C#CC(C)(C)C)C(C)C)c1
Yield: 90.4 %

Procedure:
The procedure described in Example 9 was repeated, except that methyl triphenylphosphonium bromide (2.88 g; 8.1 mmol), n-butyl lithium in n-hexane (1.56 M: 5.2 ml; 8.1 mmol), and Compound 40 (1.67 g; 5.4 mmol) were used, to thereby yield 1.50 g of the target compound (yield: 90.4%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:23][N:22]4[N:31]=[C:32]([C:34]([OH:36])=O)[N:33]=[C:21]4[N:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.C1C=CC2N(O)N=[N:45][C:43]=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][N:22]4[N:31]=[C:32]([C:34](=[O:36])[NH:45][CH3:43])[N:33]=[C:21]4[N:20]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(C(=O)O)nn4cc3-c3ccccc3)cc2)CCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1nc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cn2n1
Reaction time: 8 h

Procedure:
To a solution of 8-3 (243 mg, 0.5 mmol) in DMF (5 mL) was added Methanamine HC salt (50 mg, 0.75 mmol), HOBT (73 mg, 0.5 mmol), EDCI (192 mg, 1 mmol) and TEA (125 mg, 1.25 mmol) at room temperature and the mixture was stirred for overnight. The mixture was diluted with 15 mL of H2O, extracted with EA, the combined organic phase was washed with NaHCO3 aq. and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.HPLC to give 8-7.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17](O)=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[F:38][C:39]([F:49])([F:48])[O:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>C(#N)C>[F:38][C:39]([F:48])([F:49])[O:40][C:41]1[CH:42]=[CH:43][C:44]([NH:45][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[CH2:16][CH2:15]2)=[O:18])=[CH:46][CH:47]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(C(=O)O)CC2)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)N2CCC(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
1-[(4-Methylphenyl)sulfonyl]-4-piperidinecarboxylic acid (0.283 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in acetonitrile (40 ml) were treated at RT and under an argon atmosphere with N-methyl-morpholine (0.2 g) and the mixture was stirred for 2 h at RT. 4-trifluoromethoxy-aniline (0.176 g) was then added and stirring was continued for 20 h at RT until completion of the reaction. The reaction mixture was partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the organic layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 30%) to give 1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.298 g) as a white solid. MS (ESI): 443.1 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]1([C:22]2[C:31]([OH:32])=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:32][C:31]1[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: Oc1cc2ccccc2nc1-c1ccccc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3ccccc3)c2cc1OC
Temperature: 145 °C
Reaction time: 7 h
Yield: 67.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (222 mg), 2-phenylquinolin-3-ol (107 mg), and 4-dimethylaminopyridine (340 mg) were suspended in o-dichlorobenzene (11 ml), and the suspension was stirred at 145° C. for 7 hr. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (134 mg, yield 68%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])=[O:38]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:43]3[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(S(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 1-methanesulfonyl-piperazine in an analogous manner as described in example 25. LR-MS: 657.4 [(M+H)+]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:46](=[O:50])[CH:47]([CH3:49])[CH3:48].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:47]([CH3:49])([CH3:48])[CH:46]2[OH:50])=[O:19])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2cccnc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccnc1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a mixture of 4-[(pyridin-3-ylmethylene)-amino]-benzoic acid ethyl ester (51 g, 200 mmol) and Ytterbium(III) triflate hydrate (12.4 g, 20 mmol) in dry tetrahydrofuran (200 mL) at 25° C. was added isobutyraldehyde (18.2 mL, 200 mmol) and water (3.6 mL, 200 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-hydroxy-3,3-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (65.2 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H22N2O3 (M+H)+: 327.40, observed: 309.0.