Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.C([N-]C(C)C)(C)C.[Li+].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([I:33])[CH:26]=1.O>C1COCC1.CCOC(C)=O>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:6]2([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]([C:2]([F:14])([F:15])[F:1])[CH2:8][CH2:7]2)=[C:27]([I:33])[CH:26]=1
Reactant: BrCc1ccc(Br)cc1I
Reactant: CCOC(=O)C1CCC(C(F)(F)F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccc(Br)cc2I)CCC(C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Ethyl 4-(trifluoromethyl)cyclohexanecarboxylate (Intermediate 76, 1.492 g, 6.65 mmol) was dissolved in THF (25 mL). The atmosphere was exchanged to argon, and the solution was cooled to −78° C. Lithium diisopropylamide (1.8 M in THF/heptane/ethylbenzene) (4.07 mL, 7.32 mmol) was added, while the temperature was kept at −78° C. The solution was stirred for 30 min at −78° C. 4-Bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239., 2.50 g, 6.65 mmol) in THF (25 mL) was added via a syringe. The mixture was allowed to reach r.t., while stirred for 2 h. Water (10 mL) was added to the reaction mixture, followed by EtOAc (40 mL). The phases were separated. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (eluent: heptane/EtOAc 95/5) to give the title compound (2.41 g, 69% yield): 1H NMR (400 MHz, CDCl3) δ ppm 1.22-1.27 (m, 3 H) 1.29-1.43 (m, 4 H) 1.82-1.90 (m, 2 H) 1.82-1.90 (m, 3 H) 1.97 (br. s., 2 H) 2.28-2.36 (m, 3 H) 3.01 (s, 3 H) 4.18 (q, 3 H) 6.91 (m, 1 H) 7.38 (m, 1 H) 7.99 (m, 1 H); MS (ES+) m/z 520 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O-]CC.[Na+].[Na].Cl[C@@H:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[S:28][CH2:29][C:30]([OH:32])=[O:31].Cl>O.C(O)C>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][C@@H:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[S:28][CH2:29][C:30]([OH:32])=[O:31])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C(O)CS[C@@H]1CCC[C@H]1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 1.5 h

Procedure:
2.6-bis(1.1-Dimethylethyl)-4-mercaptophenol (0.73 g, 0.0031 mole) was added to freshly prepared sodium ethoxide [sodium (0.16 g, 0.007 mole)]in ethanol (10 ml). Once dissolved, the product of Example 4 (0.50 g, 0.0026 mole) was added and the reaction mixture was stirred for 90 minutes and poured into water (50 ml) containing 1N hydrochloric acid (25 ml). The mixture was extracted three times with 20 ml of diethyl ether, and the combined extracts were washed with water (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography. The structure was supported by NMR and elemental analysis.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]([O:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=[O:8])[CH3:7].CN([CH:22]=[O:23])C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[C:6]([O:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[S:15][C:16]([CH:22]=[O:23])=[CH:17][CH:18]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)OCCCSc1cccs1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCCCSc1ccc(C=O)s1
Temperature: 0 °C
Yield: 80.1 %

Procedure:
POCl3 (3.4 mL, 0.036 mol) was added dropwise to a solution of 61 (4.9 g, 0.023 mol) and dry DMF (3.5 mL, 0.045 mol) in 1,2-dichloroethane (100 mL) at 0° C. The resultant mixture was refluxed for 2 hours, poured into ice water and neutralized by addition of 6 M sodium carbonate. The reaction mixture was extracted with methylene chloride (3×100 mL). The combined extracts were washed with saturated brine, dried (MgSO4). After filtration, methylene chloride was removed using a rotary evaporator. The residue was purified by column chromatography over silica gel, eluting with 10% ethyl acetate in methylene chloride. The product was obtained as orange liquid (4.5 g, 82%). 1H NMR δ: 2 (m, 2 H, CH2—CH2—OCOCH3), 2.03 (s, 3 H, CH3), 3.04 (t, 2 H, J=7.2 Hz, S—CH2), 4.15 (t, 2 H, J=6.2 Hz, CH2—OCOCH3), 7.04 (d, 1 H, J=3.9 Hz, aromatic H), 7.59 (d, 1 H, J=3.9 Hz, aromatic H), 9.75 (s, 1 H, CHO); λmax/nm (εmax/dm3 mol−1cm−1) 339 (14,200); HRMS (EI+) calc. for C10H12O3S2: 244.0231. found 244.0228. The product was used without further purification in preparation of 63.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C(C1C=CC(N)=CC=1)(C)(C)C>>[F:20][C:21]([F:30])([F:31])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:12]2[C:11]3[CH:18]=[CH:19][C:8]([C:3]4[C:2]([C:21]([F:31])([F:30])[F:20])=[CH:7][CH:6]=[CH:5][N:4]=4)=[CH:9][C:10]=3[S:14](=[O:16])(=[O:15])[N:13]=2)=[CH:25][CH:24]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Agent: CC(C)(C)c1ccc(N)cc1
Product: O=S1(=O)N=C(Nc2ccc(OC(F)(F)F)cc2)c2ccc(-c3ncccc3C(F)(F)F)cc21

Procedure:
The title compound was prepared using the procedure as described in Example 1C, substituting the product of Example 7B for the product of Example 1B, and substituting 4-trifluoromethoxy aniline for 4-tert-butylaniline. MS (DCI+) m/z 488 (M+H)+ (50%), m/z 309 (M-177)+ (100%); 1H NMR (DMSO-d6) δ 7.53 (d, J 8.5, 2H), 7.78 (dd, J 5.1, 7.2, 1H), 8.01 (m, 3H), 8.15 (s, 1H), 8.42 (d, J 8.1, 1H), 8.57 (d, J 7.1, 1H), 8.99 (d, J 4.7, 1H), 11.11 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:13]([C:14]#[N:15])=[C:12]([N:16]=[CH:17][N:18](C)C)[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)N.C([O-])(O)=O.[Na+].C(OCC)(=O)C>CO>[CH2:1]([NH:8][C:9]1[C:13]2[C:12](=[N:16][CH:17]=[N:18][C:14]=2[NH:15][C:28]2[CH:27]=[CH:25][CH:24]=[C:23]([Cl:22])[CH:29]=2)[NH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CN(C)C=Nc1[nH]nc(NCc2ccccc2)c1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Clc1cccc(Nc2ncnc3[nH]nc(NCc4ccccc4)c23)c1
Temperature: 50 °C

Procedure:
With the exclusion of moisture, 79.2 g (295 mmol) of N'-(3-benzylamino-4-cyano-1H-pyrazol-5-yl)-N,N-dimethylformamidine are suspended in 700 ml of methanol; 60.6 g (369 mmol) of 3-chloro-aniline hydrochloride are added and the reaction mixture is boiled under reflux for 22 hours. The resulting yellow reaction solution is cooled to ≈50° C. and poured onto 2 liters of ice-water, 200 ml of saturated NaHCO3 solution and 1 liter of ethyl acetate. The aqueous phase is separated off and extracted twice with ethyl acetate. The organic phases are washed twice with water, saturated NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation to a residual volume of ≈1.5 liters. Inoculation and dilution with 300 ml of diethyl ether yield crystalline 3-benzylamino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 214-217° C.; TLC: Rf =0.29 (ethyl acetate:hexane=1:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:45][C:46]1[CH:51]=[CH:50][C:49]([NH:52][S:53]([C:56]2[CH:61]=[CH:60][C:59](B(O)O)=[CH:58][CH:57]=2)(=[O:55])=[O:54])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:59]2[CH:58]=[CH:57][C:56]([S:53](=[O:54])(=[O:55])[NH:52][C:49]3[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=3)=[CH:61][CH:60]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: O=S(=O)(Nc1ccc(F)cc1)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(F)cc3)cc2)c1C
Temperature: 25 °C
Yield: 8.5 %

Procedure:
A stirred solution of (6-chloro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.15 g, 0.38 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Triphenylphosphine (0.016 g, 0.06 mmol), palladium(II) acetate (0.009 g, 0.038 mmol), 4-(N-(4-fluorophenyl)sulfamoyl)-phenylboronic acid (0.15 g, 0.51 mmol) and a 2 M aqueous solution of sodium carbonate (0.6 mL, 1.2 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and then brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to give {6-chloro-4-[4-(4-fluoro-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.016 g, 8%) as a solid. MS calcd. for C26H20ClFNO4S [(M−H)−] 496, obsd. 496.2.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CNS(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
4-Methoxy-N-methylbenzenesulfonamide (1.02 g, 4.82 mmol) was dissolved in dichloromethane (50 ml). A solution of boron tribromide (1M in dichloromethane, 14.5 mL, 14.5 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 650 mg (68% yield) of the title compound. Purity 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:31][C@@H:29]([C:26]4[CH:25]=[N:24][C:23]([O:22][CH3:21])=[N:28][CH:27]=4)[CH3:30])[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Reactant: COc1ncc([C@@H](C)N)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc([C@@H](C)Nc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (130 mg, 0.41 mmol) and (R)-1-(2-methoxypyrimidin-5-yl)ethanamine (85 mg, 0.55 mmol) (prepared similarly according to the method for Intermediate 16) in acetonitrile (3 mL) and N,N-diisopropylethylamine (140 μL, 0.83 mmol) was subjected to microwave irradiation at 180° C. for 3 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to yield a white solid.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:47][C:48]1[CH:53]=[C:52]([NH:54][NH2:55])[CH:51]=[CH:50][N:49]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:54]([C:52]3[CH:51]=[CH:50][N:49]=[C:48]([Cl:47])[CH:53]=3)[N:55]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: NNc1ccnc(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccnc(Cl)c2)n1

Procedure:
690 mg (1.77 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 350 mg (1.94 mmol) of 2-chloropyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 475 mg (58% of theory) of the title compound is obtained.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:27]1([CH:33](O)[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.O>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:11])[CH2:3]2
Reactant: OC(Cc1ccccc1)c1ccccc1
Reactant: O=C(O)C1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: O=C(OC(Cc1ccccc1)c1ccccc1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (160 mg, 0.83 mmol), EDC (290 mg, 1.51 mmol), and HOBT (232 mg, 1.51 mmol) were dissolved in dry DMF (8 ml). 1,2-Diphenylethanol (150 mg, 0.76 mmol) and TEA (0.32 ml, 2.27 mmol) were added, and the resulting mixture was stirred at room temperature overnight. Then quinuclidine-3-carboxylic acid hydrochloride (72.5 mg, 0.38 mmol), EDC (87 mg, 0.45 mmol), and HOBT (57.9 mg, 0.38 mmol) were added followed by TEA (0.16 ml, 1.13 mmol), and the mixture was stirred for additional 32 hours. The mixture was diluted with water and extracted three times with Et2O. The organic phases were collected, washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The crude residue was purified by flash chromatography (DCM/MeOH=9/1) to obtain 1,2-diphenylethyl quinuclidine-3-carboxylate (136 mg, racemic mixture).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[BH4-].[Na+].[C:37](O)(=O)[CH3:38]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH2:37][CH3:38])[CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CC(=O)O
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CCN(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(Method B) 4-(6-Chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-piperazinone (14 g) was dissolved in acetic acid (160 ml) and the reaction mixture was treated portionwise with sodium borohydride (11.36 g) while keeping the temperature at 20° C., and then stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue was made alkaline by adding an aqueous solution of sodium hydroxide, extracted with dichloromethane, dried and concentrated. The residue obtained was crystallized from ethanol to obtain the title compound (12.96 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>>[CH3:17][Si:18]([CH3:20])([CH3:19])[CH:7]1[C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: Cc1ccnc2c1CCCC2
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Product: Cc1ccnc2c1CCCC2[Si](C)(C)C
Yield: 95 %

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 5,6,7,8-tetrahydro-4-methylquinoline (0.1 M), butyl lithium (0.11 M) and trimethylsilyl chloride (0.2 M) in 95% yield b.p. 80°/0.1 mm (Found: C71.1; H,9.3; N,6.0 C13N21NSi requires: C71.2; H,9.6; N,6.4%).
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[C:6]2[C:7]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:8][C:9]([F:11])=[CH:10][N:5]2[N:4]=1)[CH3:2].[H-].[Na+].Cl.Cl[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>CN(C=O)C>[CH2:1]([C:3]1[CH:20]=[C:6]2[C:7]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:18])[N:16]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[N:17]=3)=[CH:8][C:9]([F:11])=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1cc2c(C3=NNC(=O)CC3C)cc(F)cn2n1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c(C3=NN(Cc4cccnc4)C(=O)CC3C)cc(F)cn2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
The compound of Example 199 (100 mg) was dissolved in DMF (3.6 mL) and 60% sodium hydride (32 mg) was added at 0° C. The mixture was stirred at room temperature for 30 min. Subsequently, 3-(chloromethyl)pyridine-hydrochloride (65.8 mg) was added and the mixture was stirred at 60° C. for 6 hours. The reaction was terminated by adding a saturated aqueous ammonium chloride solution and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (hexane:ethyl acetate=1:4) afforded the title compound as a yellow powder (98.5 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20]O)([CH3:4])([CH3:3])[CH3:2].C(O)C.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][Br:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCBr
Reaction time: 8 h
Yield: 47.5 %

Procedure:
Alternatively, 1.61 g (5.03 mmol) of 9a was co-evaporated successively with 100% ethanol and toluene, then dried over anhydrous sodium sulfate and 4A molecular sieves in dichloromethane. The mixture was filtered and concentrated. To the dried compound (1.42 g) in 20 ml of dichloromethane was added 2.48 g of carbontetrabromide (CBr4, 7.47 mmol) and 1.50 g of triphenylphosphine (PPh3, 5.71 mmol). After stirring under an atmosphere of argon overnight, the reaction mixture was filtered through a silica gel bed, then concentrated and purified by silica gel chromatography. (EtOAc/Hexane Gradient starting at a ratio of 1:2 and changing to a ratio of 2:3) to yield 0.92 g of the 10a. (62%). Rf=0.64 (EtOAc); 1H NMR (CDCl3) 3.785 (t, 2H, J=6.3+6.3 Hz), 3.68 (t, 2H, J=6.5+6.5 Hz), 3.650 (m, 8H), 3.615 (m, 4H), 3.462 (t, 2H, J=6.3+6.4 Hz), 2.491 (t, 2H, J=6.5+6.5 Hz), 1.434 (s, 9H); 13C NMR 171.063, 80.656, 71.368, 70.831, 70.764, 70.706, 70.678, 70.545, 67.061, 36.431, 30.474, 28.263; MS m/z 408.74 (M+Na)+, 406.70, 405.70, 404.73.
Reaction SMILES: C([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(OC(C)(C)C)=O.ON1C2C=CC=CC=2N=N1.[ClH:33].CN(C)CCCN=C=NCC.[F:45][C:46]([F:60])([F:59])[C:47]1[CH:48]=[C:49]([CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1)[CH2:50][NH2:51]>CN(C)C=O.ClCCl.Cl>[ClH:33].[F:45][C:46]([F:59])([F:60])[C:47]1[CH:48]=[C:49]([CH:52]=[C:53]([C:55]([F:58])([F:56])[F:57])[CH:54]=1)[CH2:50][NH:51][C:20](=[O:22])[C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
To a stirred solution of N-Boc-L-tryptophan (5 g) and 1-hydroxybenzotriazole (2.48 g) in dimethyl formamide (85 ml) was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (3.15 g) at 0° C. After 30 minutes 3,5-bistrifluoromethylbenzylamine (4.43 g) was added and stirring continued for 16 hours at 25° C. The reaction mixture was diluted with dichloromethane and washed with sodium bicarbonate solution, water and dried (Na2SO4). The solvents were evaporated in vacuo to give a white solid which was dissolved in methanolic hydrogen chloride and allowed to stand for 16 hours. Concentration under reduced pressure afforded the title compound as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Cl)=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([OH:22])=[O:21])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:26])[CH2:24][NH2:25].O.C(O)(=O)C>CN1CCCC1=O>[NH2:25][CH2:24][CH2:23][NH:26][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]2=[O:19]
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccc(Cl)cc2c1=O
Reactant: NCCN
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: NCCNc1ccc2c(c1)c(=O)c(C(=O)O)cn2Cc1ccccc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 24.8 %

Procedure:
To a solution of 1-Benzyl-6-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (300 mg) in 1-methyl-2-pyrrolidinone (6 mL) was added ethylenediamine (170 mg) under argon atmosphere. The mixture was heated at 120° C. for 18 h and then at 145° C. for 4 h. The reaction mixture was cooled and poured into water (12 mL). The pH value was adjusted with acetic acid to 7.0–7.5. The reaction mixture was extracted with DCM (5×30 mnL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica SPE-column (eluent: from DCM 100% to DCM/MeOH/NH4OH 85/13/2) giving the title compound (80 mg).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:15]=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:17])=[O:18])[CH:15]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1onc(C)c1Br
Yield: 61 %

Procedure:
5-Bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 5-bromo-2-methoxybenzenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 192°-195° C., yield 61%.