Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:13][C:14]1[CH:30]=[CH:29][C:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:21][CH2:22][C:16]=2[C:15]=1[NH:31][CH2:32][C:33]([CH3:43])([CH3:42])[CH2:34][O:35]C1CCCCO1>CO>[Cl:13][C:14]1[CH:30]=[CH:29][C:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:28])[C:24]([F:26])([F:25])[F:27])[CH2:21][CH2:22][C:16]=2[C:15]=1[NH:31][CH2:32][C:33]([CH3:43])([CH3:42])[CH2:34][OH:35]
Reactant: CC(C)(CNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(CO)CNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 77 %

Procedure:
Add p-toluensulfonic acid monohydrate (538 mg, 2.83 mmol) to a solution of 7-chloro-6-[2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.190 g, 2.57 mmol) in methanol (80 mL). Stir the reaction at RT for 16 hr, concentrate, redissolve in EtOAc, wash with saturated aqueous sodium bicarbonate solution, brine, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:4 EtOAc:hexanes) to give the title compound (750 mg, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[C:11]([O:15][C:16](=O)[O:17]C(C)(C)C)([CH3:14])([CH3:13])[CH3:12].CC#N>CN(C)C1C=CN=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
5-Bromoindoline (3.96 g, 20 mmol), di-t-butylcarbonate (4.37 g, 20 mmol), 4-dimethylaminopyridine (2.69 g, 22 mmol) and CH3CN (50 mL) were mixed and stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (300 mL) and the organic solution was washed successively with water (50 mL), a 1 N HCl solution (50 mL), a saturated NaHCO3 solution (2×50 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford a solid. Trituration with hexane and drying in vacuo provided a white solid (2.26 g, 38% yield): 1H NMR (DMSO-d6, 300 MHz): 7.36 (s, 1H), 7.29 (d, 2H, J=7), 3.86 (t, 2H, J=7), 3.04 (t, 2H, J=7), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>[Ti](Cl)(Cl)(Cl)Cl.C1(OC)C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:2]2[N:1]=[C:14]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[C:6]3[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]=2[CH:19]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Nc2cc(Cl)ccc2N)sc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccc(Cl)cc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-5-chloroanilino)benzo[b]thiophene-3-carboxylate (2.6 g), 1-methylpiperazine (15 ml), anisole (50 ml) and titanium tetrachloride (2.3 ml), 8-chloro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (363 mg) was obtained.
Reaction SMILES: C(N(CC)[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5])C.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=1.Br>>[BrH:15].[Br:22][C:18]1[N:17]=[C:16]([C:4]([CH:6]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)=[O:5])[CH:21]=[CH:20][CH:19]=1
Reactant: CCN(CC)C(=O)C1CCN(C)CC1
Reactant: Brc1cccc(Br)n1
Agent: Br
Product: CN1CCC(C(=O)c2cccc(Br)n2)CC1

Procedure:
reacting N,N-diethyl-1-methylpiperidine-4-carboxamide with a solution of 2,6-dibromopyridine and Grignard reagent followed by hydrobromic acid to yield (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone hydrobromide;
Reaction SMILES: [NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([N:25]([CH3:41])[C@H:26]([C:34]([NH:36][NH:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.OO.CC[O:53]CC.CN(C=O)C>C(O)(=O)C>[NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([N:25]([CH3:41])[C@H:26]([C:34]([NH:36][NH:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])=[O:20])[CH2:15][CH2:16][S:17]([CH3:18])=[O:53])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCOCC
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N(C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Agent: OO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN(C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reaction time: 0.17 h

Procedure:
In 3 ml of acetic acid is dissolved 0.35 g of BOC-Tyr-(D)-Met-Gly-MePhe-NHNHCONH2 followed by addition of 0.082 ml of 30% aqueous H2O2. The solution is stirred for 10 minutes, treated with 100 ml of ether and filtered to obtain a powder. Yield 0.35 g (88%); m.p. 110°-115° C.; [α]D24 -35.1° (c=1.04, DMF); Rf1 0.05.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:24])[CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[Cl:24][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:25])=[O:2])[CH:17]=[CH:16][C:15]=1[N:18]1[C:22]([CH3:23])=[N:21][N:20]=[N:19]1
Reactant: COC(=O)C(CC1CCCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(C(CC2CCCCC2)C(=O)O)cc1Cl
Temperature: 47.5 °C
Yield: 85.2 %

Procedure:
A solution of 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid methyl ester (278 mg, 0.76 mmol) in ethanol (6 mL) was treated with a 1N aqueous sodium hydroxide solution (1.5 mL). The solution was heated at 45-50° C. for 5 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (20 mL) and extracted with diethyl ether (1×40 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid (226 mg, 85%) as an amorphous solid: EI-HRMS m/e calcd for C17H21ClN4O2 (M+) 348.1353, found 348.1354.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][C@H:8]([C:10]([O:12]CC)=[O:11])[C@H:7]([CH2:15][CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>Cl>[C:1]([NH:4][C@@H:5]1[CH2:9][C@H:8]([C:10]([OH:12])=[O:11])[C@H:7]([CH2:15][CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H](NC(C)=O)C[C@H]1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC[C@@H]1C[C@H](NC(C)=O)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.7 %

Procedure:
To a flask containing (1S,2R,4S)-ethyl 4-acetamido-2-ethylcyclopentanecarboxylate (9.44 g, 41.5 mmol) was added NaOH (2 N aqueous, 141 mL, 282 mmol). After stirring at ambient temperature for about 12 h, the reaction was acidified to about pH 1 by the addition of 6 N aqueous HCl (50 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give crude (1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylic acid (7.25 g, 88%): LC/MS (Table 1, Method a) Rt=1.51 min; MS m/z: 200 (M−H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].CN([CH:19]=[O:20])C>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:19]=[O:20])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)cn1
Temperature: 0 °C
Yield: 57.2 %

Procedure:
To a solution of 2-bromo-5-chloropyridine (14.8 g, 77 mmol) in THF (38.5 mL) was added dropwise a solution of i-PrMgCl.LiCl (14% in THF, 81 mL, 85 mmol) at 0-5° C. and the resulting mixture stirred at 0° C. for 1 h. Then DMF (7.7 mL, 100 mmol) was added dropwise at −5° C. and the temperature maintained at 0° C. for 2 h. The reaction mixture was then poured into ice cold saturated brine (500 mL) and then extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with saturated sodiumhydrogencarbonate solution, brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:0 to 9:1) afforded the title compound (6.24 g, 57%) which was obtained as a brown solid. MS: m/e=141.0 [M]+.
Reaction SMILES: [O-:1][S:2]([O-:4])=[O:3].[Na+].[Na+].Cl[CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>O>[S:2]([CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([OH:4])(=[O:1])=[O:3]
Reactant: O=S([O-])[O-]
Reactant: ClCCc1cccnc1
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)CCc1cccnc1

Procedure:
A mixture of Na2SO3 (2.7 g., 21 m.moles) and (3-(2-chloroethyl)pyridine (1.2 g., 8.5 m.moles) in water (10 ml.) was heated under reflux overnight with stirring and column chromatographed on IR-120 resin (H+, 100 ml.) by eluting with water. The eluate containing the desired product was collected and concentrated to give colorless plates (1.1 g., 69%), melting at 275°-278° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:20].[Na+].II>CN.C(O)C.O>[OH:19][C:16]1[C:17]([I:20])=[CH:18][C:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Agent: CN
Agent: II
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(O)c(I)cc2CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 7-hydroxy-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (5.2 g, 20 mmol) in 33% methylamine in ethanol (30 ml) was stirred at 0° C. A solution of sodium iodide (4.6 g, 30 mmol) and iodine (5.2 g, 20 mmol) in water (30 ml) was added below the surface of the reaction mixture. After stirring at 0° C. for 1 hour the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was separated, washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound (D41); (7.0 g, 90%), 1H NMR (d6-DMSO) 10.0 (1H, br s), 7.41 (1H, s), 6.65 (1H, s), 3.40 (4H, m), 2.70 (4H, m), 1.40 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].ClC(Cl)(Cl)C(O)=O.[N-:19]=[N+]=[N-].[Na+]>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:19][C:6]2=[O:11]
Reactant: Cc1cccc2c1CCC2=O
Reactant: [N-]=[N+]=[N-]
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [Na+]
Product: Cc1cccc2c1CCNC2=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A mixture of 4.7 g (32.2 mmol) of 2,3-dihydro-4-methyl-1H-inden-1-one and 53 g of trichloroacetic acid was heated to 65°. To the resulting solution was added 4.2 g (64.4 mmol) of sodium azide and the mixture was kept at 65° for 18 hours. An additional 1.0 g of sodium azide was then added and heating continued for another four hours. The mixture was diluted with 200 ml of ice water and extracted with ether. The ether extracts were washed with water, saturated sodium hydrogen carbonate, dried (MgSO4), and concentrated. The residue was chromatographed (SiO2, ether to ether/methanol 95/5). The resulting product was recrystallized from toluene to give 2.45 g (47%) of product; mp 141°-143°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH2:34][C:35]([F:38])([F:37])[F:36])[C@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]4[CH2:31][CH2:32][CH2:33][C@H:28]([N:27]([CH3:26])[CH2:34][C:35]([F:36])([F:38])[F:37])[CH2:29]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CN(CC(F)(F)F)[C@H]1CCCNC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@H](N(C)CC(F)(F)F)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N-methyl-N-(2,2,2-trifluoroethyl)piperidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.92 (m, 4 H) 2.26-2.41 (m, 4 H) 2.59-2.80 (m, 2 H) 2.93-3.36 (m, 3 H) 3.55 (br. s., 1 H) 3.75-4.19 (m, 2 H) 4.36-4.54 (m, 1 H) 7.55-7.68 (m, 1 H) 7.71-7.78 (m, 1 H) 8.53 (s, 4 H). ESI-MS m/z [M+H]+ 517.3.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:26](=[O:28])[CH3:27])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.75 g, 2.0 mmol) and acetic anhydride (0.19 mL, 2.0 mmol) in acetonitrile (20 mL), was added triethylamine (0.56 mL, 4.0 mmol) at room temperature under nitrogen. After 1 h, the solids were isolated by filtration. The crude product was triturated in water (20 mL) for 1.0 h, then isolated by filtration and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-acetamide as a white solid (0.47 g, 75% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 3.28 min (96.26%); mp: 183-185° C.; 1H NMR (DMSO-d6) δ 1.89 (s, 3H, CH3), 1.93-2.07 (m, 1H, CHH), 2.26-2.48 (m, 1H, CHH), 2.54-2.70 (m, 1H, CHH), 2.77-3.04 (m, 1H, CHH), 4.22-4.51 (m, 4H, CH2, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 7.39 (d, J=7.9 Hz, 1H, Ar), 7.47 (s, 1H, Ar), 7.68 (d, J=7.9 Hz, 1H, Ar), 8.45 (t, J=5.8 Hz, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 22.56, 31.21, 42.14, 47.10, 51.59, 122.08, 122.90, 127.05, 130.32, 142.36, 143.95, 167.93, 169.25, 171.00, 172.86; LCMS: MH=316; Anal Calcd for C16H17N3O4: C, 60.94; H, 5.43; N, 13.33. Found: C, 60.61; H, 5.31; N, 13.30.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C=O.Cl.NCCC[Si](OCC)(OCC)[O:20]CC.C[Si](C)(C)Cl.[N+](C1C=CC=CC=1)([O-])=O>C(N(CC)CC)C>[OH:20][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:2][CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Oc1cccc2cccnc12
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: C=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1ccc2ccccc2n1

Procedure:
Preferably, Route A can be used. A chloromethylated ligand can be prepared, for example, by reacting 8-hydroxyquinoline with formaldehyde and hydrochloric acid. That derivative is further reacted with γ-aminopropyltriethoxysilane in the presence of trimethylchlorosilane and triethylamine and nitrobenzene. Next, the prepared organosilicon derivative is reacted with the support to obtain hydroxyquinoline modified silica gel. A sample of this sequence of reactions is described in further detail in Example 2 below.
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31]C)[CH:27]=2)[CH2:22]1)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH2:1]([N:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:9][CH:10]=1)[C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=2[CH2:22]1)[CH3:2]
Reactant: ClCCN1CCOCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCOCC2)cc1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Yield: 77.3 %

Procedure:
Synthesized from N-ethyl-4-hydroxy-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (250 mg) and 4-(2-chloroethyl)morpholine hydrochloride (140 mg) according to an analogous synthetic method to Example 368, the title compound (225 mg) was obtained.
Reaction SMILES: [CH3:1][S:2][CH:3]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)[C:4]([O:6]C(C)(C)C)=[O:5].[OH-].[Na+]>CO.O>[CH3:1][S:2][CH:3]([O:11][C:12]1[CH:13]=[C:14]([Cl:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1)[C:4]([OH:6])=[O:5]
Reactant: CSC(Oc1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSC(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To the product of Step 1 (0.2 g) in methanol (3 ml) at ambient temperature was added a solution of sodium hydroxide (0.050 g) in water (1 ml). The reaction was stirred for 2 hours, the solvent evaporated then water and ethyl acetate were added. The aqueous phase was separated, acidified with dilute aqueous hydrochloric acid then extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulphate, filtered and evaporated to give 2-methylthio-2-(3,5-dichlorophenoxy)acetic acid as a pale yellow gum (0.153 g) that was used in the next step without further purification.
Reaction SMILES: C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.[N+:23]([C:26]1[N:27]=[CH:28][N:29]([CH:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:32]([OH:34])=[O:33])[CH:30]=1)([O-:25])=[O:24].C(N(CC)CC)C>O.C(O)C>[N+:23]([C:26]1[N:27]=[CH:28][N:29]([C@H:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:32]([OH:34])=[O:33])[CH:30]=1)([O-:25])=[O:24]
Reactant: CCCCCCC(C(=O)O)n1cnc([N+](=O)[O-])c1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCCCCC[C@H](C(=O)O)n1cnc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 35.9 %

Procedure:
To a solution of (-)-cinchonidine (48.0 g, 163 mmol) in 880 mL of distilled H2O at room temperature was added 2-(4-nitro-1H-imidazol-1-yl)-octanoic acid (83.0 g, 326 mmol) as a solution in 440 mL of ethanol. To this mixture was added triethylamine (11.7 mL). The mixture was then heated to 80° C., and the pH was maintained between 6.9 and 7.1 by the dropwise addition of triethylamine (5-10 mL). After the pH stabilized at 7.01, the solution was allowed to cool to room temperature, and let stand overnight whereupon crystallization of the (R)-2-(4-nitro-1H-imidazol-1-yl)-octanoic acid-cinchonidine salt occurred. The crystalline salt was collected by filtration. The salt was then suspended in 200 mL ea. of ethyl acetate/H2O. To this suspension was added in HCl (750 mL). The layers were separated, and the aqueous was extracted with ethyl acetate (2×500 mL). The organic was combined, dried (Na2SO4 ), and concentrated in vacuo to provide 29.9 g (72%) of (R)-2-(4-nitro-1H-imidazol-1-yl)-octanoic acid as an off-white solid. M.pt. 116°-118° C. Calculated for C11H17N3O4 : C, 51.76; H, 6.71; N, 16.46. Found: C, 51.89; H, 6.76; N, 16.20. [a]D -29.9 (c 1.00, ethanol).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:15][CH2:14]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 120 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (2.5 g, 14 mmol), 1-methylpiperizine (3.2 mL, 30 mmol), and potassium carbonate (K2CO3) (2.0 g, 14 mmol) in dimethylformamide (DMF) (20 mL) was stirred at 120° C. for 18 h. The reaction mixture was cooled to room temperature and poured into water (150 mL). The precipitated crude product was collected by filtration, dried in vacuo, and purified by recrystallization from ethyl acetate (EtOAc) (75 mL) to yield yellow-green crystals (1.8 g, 54%). See, J. Med. Chem., 39:997 (1996).
Reaction SMILES: O.[OH-].[Na+].O.Cl.[NH2:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9].Cl[C:14](OC1C=CC=CC=1)=[O:15]>C1(C)C=CC=CC=1>[O:15]=[C:14]1[NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][S:9]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1N[C@H](C(=O)O)CS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A aqueous solution comprising 0.88 liter of water and 184.0 g of sodium hydroxide was dissolved 175.6 g of L-cysteine monohydrochloride monohydrate under ice-cooling, 0.35 liter of a toluene solution containing 313.2 g of phenyl chloroformate was added to the above solution within a range not exceeding 30° C. After stirring the mixture at room temperature for 2 hours, it was allowed to stand and the liquids were separated. The aqueous layer was washed with 0.35 liter of toluene, the layers were separated, and the aqueous layer was concentrated to give 139.84 g of (4R)-2-oxothiazolidin-4-carboxylic acid as colorless crystal.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:14])=[CH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12)=[O:5])C.[OH-].[Na+]>CCO.O>[CH3:14][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[N:9]([CH:8]=1)[CH:13]=[CH:12][S:11]2
Reactant: CCOC(=O)c1c(C)cn2ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cn2ccsc2c1C(=O)O
Temperature: 75 °C

Procedure:
A mixture of 6-methyl-pyrrolo[2,1-b]thiazole-7-carboxylic acid ethyl ester (7.29 mmol) and NaOH (10.9 mmol) in EtOH (11.8 mL) and water (11.8 mL) is heated to 75° C. for 3 d. The mixture is concentrated in vacuo and made acidic by addition of hydrochloric acid (1.0 M). The obtained precipitate is filtered off and dried in vacuo to give the desired product. LC-MS: tR=0.73 min; [M+H]+=182.0.