Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC=CC=1C=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)(O)=O.C1N2C3CC4C=CC=CC=4C=3NC(=O)C2=NC=1.O=[CH:46][CH2:47][CH2:48][CH2:49][C:50]([O:52]CC)=[O:51].[H-].[Na+]>C(O)C.[OH-].[Na+].C(O)(=O)C.O.CS(C)=O>[OH:23][C:16]1[C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[C:19]2[C:7](=[CH:46][CH2:47][CH2:48][CH2:49][C:50]([OH:52])=[O:51])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[N:15]=1
Reactant: CCOC(=O)CCCC=O
Reactant: O=C(O)c1ccccc1C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Agent: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=C(O)CCCC=c1c2ccccc2c2nc(O)c3nccn3c12

Procedure:
The process is performed as in Example 3 for the preparation of 10-(2-carboxybenzylidene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one but starting with 3.3 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one, 66 ml of dimethyl sulphoxide, 2.35 g of ethyl 5-oxopentanoate and 1.06 g of sodium hydride. After treatment of the reaction mixture with water (66 ml) and with acetic acid (6.6 ml), the suspension obtained is filtered, the insoluble product is washed with water (50 ml), with methanol (25 ml) and then with ethyl ether (2×25 ml) and dried at 60° C. under reduced pressure. The solid obtained is suspended in a mixture of 70 ml of ethanol and 6 ml of 1ON sodium hydroxide, filtered off, washed with ethanol and purified by dissolution in 15 ml of water and precipitation with 15 ml of IN hydrochloric acid. The precipitate is filtered off, washed with water (2×10 ml), triturated at the reflux of methanol (200 ml), filtered off and dried. 0.4 g of 5-(4-hydroxyimidazo[1,2-a]indeno-[1,2-e]pyrazin-10-ylidene]pentanoic acid is obtained, which product is converted into the disodium salt of formula C18H13N3O3Na2 (Analysis, % calculated C: 59.18, H: 3.59, N: 11.50, O: 13.14, Na: 12.59, % found C 58.8, H: 3.4, N: 11.5).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Product: COC(=O)c1ccc2occ(-c3ccc(SC)cc3)c2c1
Yield: 92 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzofuran-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and 4-(methylthio)phenylboronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 92%) was obtained as colorless crystals.
Reaction SMILES: [OH-].[K+].C([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH:28]([CH3:30])[CH3:29])[CH2:17][CH2:16]2)[CH:11]=[CH:12][CH:13]=1)(=O)C>CO.C(O)(C)C>[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH:28]([CH3:30])[CH3:29])[CH2:17][CH2:16]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OCc1cccc(CN2CCN(c3ccccc3OC(C)C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Product: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CO)c2)CC1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 85% KOH (0.5 g, 7.57 mmol) in 50 mL of methanol was added compound 3 (2.50 g, 5.97 mmol). After overnight stirring, thin layer chromatography indicated very little reaction progress so the reaction mixture was refluxed under argon for several minutes. Chromatographic analysis still indicated little reaction progress so the reaction mixture was cooled. Additional KOH (0.53 g) was added and reflux was continued another 15 minutes. After this period of time, the starting material was completely consumed. The reaction mixture was concentrated, and the residue was partitioned between methylene chloride and water. The layers were separated, and the aqueous layer was further extracted with methylene chloride. The organic extracts were combined, washed with brine, and dried (MgSO4). The organic extract was concentrated to provide an oil which was dissolved in isopropanol and filtered through MgSO4. To the filtrate was added maleic acid (0.725 g), and the resulting mixture was concentrated in vacuo to provide an oil which was partitioned between 3N NaOH and methylene chloride. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic extracts were combined, washed with brine, and dried (MgSO4). The organic extract was concentrated, and the resulting oil was purified on TLC mesh silica (97:3 methylene chloride:methanol). The purified material was dissolved in ethyl ether and added to ethereal HCl. The resulting precipitate was collected by suction filtration and washed with ether. The sample was dried to provide 1.72 g (70%) of benzyl alcohol dihydrochloride 4, mp 201° C. (dec). The 1H NMR supported the desired structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([CH2:35][O:36]C(=O)C)=[O:34]>>[OH:36][CH2:35][C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:34]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A152) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.S(Br)([Br:12])=O>ClCCl>[Br:12][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: O=S(Br)Br
Solvent: ClCCl
Product: Clc1cc(CBr)ccn1
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloropyridine-4-methanol (1.02 g, 7.10 mmol) in 15 mL of dichloromethane was added thionyl bromide (1.77 g, 8.53 mmol) dropwise. After 15 min, the reaction was quenched with saturated aqueous ammonium chloride. The organic solution was washed 2× with water, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 4-(bromomethyl)-2-chloropyridine that gave a mass ion (ES+) of 208.0 for [M+H]+.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:24]([CH:31]4[CH2:33][CH2:32]4)[CH2:25][C:26]([O:28]CC)=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:13]=[CH:12][C:11]=2[C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=2[F:42])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO.C1COCC1>[C:1]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:24]([CH:31]4[CH2:33][CH2:32]4)[CH2:25][C:26]([OH:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:13]=[CH:12][C:11]=2[C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=2[F:42])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(C)(C)C)o3)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2-c2nnc(C(C)(C)C)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a solution of ethyl 3-(3-(((2-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)-3-cyclopropylpropanoate (115 mg) in methanol (1.0 mL) and THF (1.0 mL) was added 1N aqueous sodium hydroxide solution (0.60 mL), and the mixture was stirred at room temperature for 2 hr. Water and 1N hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (62 mg) as a colorless oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]([NH:24][C@H:25]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([OH:37])=[O:36])[C:28]=3[O:27][B:26]2[OH:38])=[O:23])[CH2:17][CH2:16]1)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O>O>[OH:38][B:26]1[C@@H:25]([NH:24][C:22](=[O:23])[CH2:21][C@H:18]2[CH2:19][CH2:20][C@H:15]([NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][OH:8])[CH2:16][CH2:17]2)[CH2:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([OH:37])=[O:36])[C:28]=2[O:27]1
Reactant: CC(C)(C)[Si](C)(C)OCCNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H]1CC[C@H](NCCNCCO)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the compound from step 1 was added a mixture of TFA (2 mL) and H2O (0.2 mL). The resultant reaction mixture was stirred at RT for 2 hr. The solvents were then removed in vacuo and the residue purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 434 (MH)+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][CH3:32])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.Cl[C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35]>CN1C(=O)CCC1.O>[CH2:31]([C:20]1[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:8][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH3:39])[C:18]=2[N:19]=1)[CH3:32]
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Reactant: CCCOC(=O)Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCCOC(=O)Nc1nc2ccccc2c2c1nc(CC)n2CCCCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 34.5 %

Procedure:
Triethylamine (1.93 mL, 5 eq) was added to a chilled (ice/water bath) suspension of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (1.0 g, 1 eq) in NMP (6.0 mL). Propyl chloroformate (1.02 g, 3 eq) was added dropwise. The reaction mixture was allowed to come to ambient temperature and stirred for 24 hours. The reaction mixture was diluted with cold water (25 mL) and then extracted with dichloromethane (50 mL). The organic layer was washed sequentially with water (2×50 mL), 4% sodium carbonate (50 mL), water (50 mL), and brine (50 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a linear gradient of 0-25% CMA in chloroform, 2000 mL) followed by recrystallization from acetonitrile to provide 0.427 g of propyl 2-ethyl-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-ylcarbamate as a white solid, mp 155-157° C. Anal calcd for C21H29N5O4S: C, 56.36; H, 6.53; N, 15.65. Found: C, 56.37; H, 6.37; N, 15.70.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[S:8][CH:9]=[C:10]([Br:13])[C:11]=1[Br:12])=[O:6])C.[OH-].[Na+].Cl>O>[Br:12][C:11]1[C:10]([Br:13])=[CH:9][S:8][C:7]=1[C:5](=[O:6])[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C(=O)c1scc(Br)c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)c1scc(Br)c1Br
Yield: 50.2 %

Procedure:
(3,4-Dibromothiophen-2-yl)-oxo-acetic acid ethyl ester (6.84 g, 20 mmol) was stirred in a mixture of 100 ml water and 10 N NaOH (10 ml, 100 mmol) at room temperature for 20 hours. The reaction mixture was then acidified with 3N HCl, and extracted with ethyl acetate (3×50 ml). The combined ethyl acetate extracts were dried over Na2SO4 and concentrated under vacuum to yield (3,4-dibromothiophen-2-yl)-oxo-acetic acid (3.15 g, 50%). MS (M−H)−: 312.74; 1H NMR (300 MHz, DMSO-d6) δ8.45 (1H, s).
Reaction SMILES: C(OC(N[C@H](C1C=CC=CC=1)C(O)=O)=O)C.Cl.C(OC(=O)[C@@H]1CCCN1)C1C=CC=CC=1.[CH2:33]([O:40][C:41]([C@@H:43]1[CH2:47][CH2:46][CH2:45][N:44]1[C:48](=[O:64])[C@H:49]([NH:56][C:57]([O:59][C:60](C)(C)[CH3:61])=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:40][C:41]([C@@H:43]1[CH2:47][CH2:46][CH2:45][N:44]1[C:48](=[O:64])[C@H:49]([NH:56][C:57]([O:59][CH2:60][CH3:61])=[O:58])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: CCOC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Agent: O=C(OCc1ccccc1)[C@@H]1CCCN1
Product: CCOC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1

Procedure:
Compound 42 was synthesized from compound 41 (2 mmol) and L-proline benzyl ester hydrochloride (2.2 mmol), following the procedure as described for compound 2a.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH2:14]([NH2:18])[C:15](=[CH2:17])[CH3:16]>>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:18][CH2:14][C:15]([CH3:17])=[CH2:16])[NH:7][C:6]=2[CH:8]=1
Reactant: C=C(C)CN
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Product: C=C(C)CNC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 64 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (128 mg, 0.5 mmol) in methallylamine (0.5 ml) was stirred for 48 h at 90° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (3 ml) followed by adjustment to pH 2 with 4M hydrochloric acid. The product was isolated by filtration and washed with water, to give 92 mg (64%) of the pure title compound; mp 224-226° C. (dec.); 1H-NMR (DMSO-d6): δ1.72 (s, 3H), 3.75 (d, 2H), 4.83 (s, 2H), 7.05 (s, 1H), 7.45 (br s, 1H), 11.0 (br s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:33])[CH:14]([C:16]2[C:17]([CH3:32])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:20][CH:21]=2)[CH3:15])=[CH:9][C:8]=1[CH2:34][CH2:35][CH2:36][O:37][CH3:38])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:38][O:37][CH2:36][CH2:35][CH2:34][C:8]1[CH:9]=[C:10]([N:13]([CH3:33])[CH:14]([C:16]2[C:17]([CH3:32])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)=[CH:20][CH:21]=2)[CH3:15])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)COc1ccc(N(C)C(C)c2ccc(-c3cccc(C(F)(F)F)c3)nc2C)cc1CCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCCc1cc(N(C)C(C)c2ccc(-c3cccc(C(F)(F)F)c3)nc2C)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
0.015 g (0.03 mmol) of the above prepared [rac]-[2-(3-methoxy-propyl)-4-(methyl-{1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-ethyl}-amino)-phenoxy]-acetic acid ethyl ester was dissolved in 0.2 ml of THF/EtOH=1/1, treated with 0.09 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 0.5 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the organic layer washed with water and brine, dried over sodium sulfate, and evaporated to dryness to leave 0.012 g of the title compound as light brown oil.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1Br)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:28]1[CH:29]=[C:24]([OH:23])[CH:25]=[CH:26][CH:27]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc2c(Br)c(Cc3ccccc3)nnc12
Reactant: OB(O)c1cccc(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Oc1cccc(-c2c(Cc3ccccc3)nnc3c(C(F)(F)F)cccc23)c1
Reaction time: 6 h
Yield: 74.3 %

Procedure:
A solution of 3-benzyl-4-bromo-8-trifluoromethyl-cinnoline (1.7 g, 4.6 mmol) and 3-hydroxyphenylboronic acid (0.84 g, 6.0 mmol) and Pd(PPh3)4 (300 mg) and K3PO4 (3.0 g) in dioxane (50 ml) was heated to reflux. After 6 hr, the reaction was cooled and poured into water and extracted with EtOAc. The organic layer was concentrated and the product purified by colum chromatography (eluent 10% EtOAc/Hexane) to give a solid 1.3 g. MS (ES) m/z 381.1.
Reaction SMILES: C(OC([N:8]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2)[CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[Cl:20])=O)(C)(C)C.C(OCC)(=O)C.[ClH:38]>>[ClH:16].[ClH:38].[Cl:20][C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][NH:8][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: Cc1ccc2cccc(N(Cc3c(Cl)ccc([N+](=O)[O-])c3Cl)C(=O)OC(C)(C)C)c2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc2cccc(NCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1

Procedure:
8-(N-tert-Butoxycarbonyl-N-(2,6-dichloro-3-nitrobenzyl)amino]-2-methylquinoline (100 mg) was treated with 4M hydrogen chloride-ethyl acetate (2 ml) at ambient temperature for 40 minutes. The precipitate was collected by vacuum filtration and washed with ethyl acetate to give 8-[(2,6-dichloro-3-nitrobenzyl)amino]-2-methylquinoline dihydrochloride (88 mg) as pale yellow crystals.
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.OC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1N>C(N(CC)CC)C>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
To a 250 ml round bottom flash, charged with 10.0 g (0.041 mole) of N ε-(tert-butoxy carbonyl) L-lysine 27, commercially available from BACHEM Bioscience Inc. (subsidiary of BACHEM Switzerland, 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia, Pa., 19406, USA), and 100 ml of methanol is added 10.0 g (0.07 mole) of ethyl trifluoroacetate followed by 20.0 ml (0.144 mole) of triethylamine. The mixture is stirred at 20-300° C. for 20 hours and then concentrated via rotary evaporation. The residue is diluted with 50 ml of diethyl ether and then filtered. The filtrate is then washed with 3×30 ml aliquots of 1N aqueous HCL, 20 ml of deionized water, and finally with 20 ml of deionized water. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is distilled under vacuum to yield product 28 in good yield. N ε-(tert-butoxy carbonyl) N1-α-trifluoroacetyl L-lysine is reacted with tri-o-acetyl tet-Gal-NAC 1-a-S-Pentylamine in the presence of a BOP reagent. The activated carboxylic acid reacts with the clustered galactosamine in DBIF and Triethylamine to afford galactose cluster lyEsine adduct 29 in good yield. The N a-trifluoroacetyl protection of the lysine is removed to afford Primary α-amino lysine-galactose cluster 29a in moderate yield.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].ClC1C=C(C=CC=1)C(OO)=[O:15]>ClCCl>[CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:7][O:15]1
Reactant: C=CCCCC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)CCCC1CO1

Procedure:
A solution of 6,6-dimethyl-1-heptene (5.33 g, 0.0423 mol) and m-chloroperoxybenzoic acid (9.5 g of 85%, 0.048 mol) in dichloromethane (100 ml) was stirred at room temperature for 16 hours. The resulting solution was washed and aqueous sodium hydroxide (3×50 ml of 2M) and dried over sodium sulfate. The solvent was distilled off at atmospheric pressure to yield (4,4-dimethylpentyl)oxirane as a residue, having the following structural characteristics:
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[CH:19]=1.C(Cl)Cl>C(Cl)Cl.CO>[CH3:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][CH:27]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:12][CH:11]=[CH:10][N:9]4[N:13]=3)[CH2:26][CH2:25]2)[CH:19]=1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Reactant: Nc1nc2c(N3CCOCC3)cccn2n1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N2CCC(Nc3nc4c(N5CCOCC5)cccn4n3)CC2)ncn1

Procedure:
Prepared in analogy to example 1h, starting from 8-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b). The title compound was obtained as a white solid (yield: 34%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[N:16]1([CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:28][CH2:27]1
Reactant: C1CCN(CCC2CCNCC2)C1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N1CCC(CCN2CCCC2)CC1
Yield: 49.1 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with 4-[2-(pyrrolidin-1-yl)ethyl]piperidine (230 mg, 1.3 mmol) to afford the desired product (190 mg, 47%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.74 (s, 1 H), 8.18 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 3.98-3.90 (m, 2H), 3.32-3.23 (m, 2H), 2.58-2.50 (m, 6H), 2.55 (s, 3H), 1.86-1.53 (m, 11H); ESI MS m/z 387 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:27][CH:28]=1)(=[O:39])=[O:38]
Reactant: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(O)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: -20 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
Methyl 2-({4-[2-(4-hydroxyphenoxy)ethyl]phenoxy}methyl)benzoate (0.547 g, 1.45 mmol) was dissolved in dichloromethane (10 ml) and the solution was cooled to −20° C. Triethylamine (0.22 g, 2.17 mmol) was added dropwise followed by the dropwise addition of methylsulfonyl chloride (0.18 g, 1.59 mmol). The ice bath was removed and the mixture was stirred overnight at room temperature. Excess of triethylamine was removed by addition of diethyl ether (5 ml) and filtering off the precipitate. The organic phase was washed with three portions of brine (10 ml) and dried (MgSO4). The solvent was removed by evaporation, the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 0.317 g of methyl 2-{[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]methyl}benzoate (yield 48%).