Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[CH2:15](C([Sn])=C(CCCC)CCCC)[CH2:16]CC>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:15]=[CH2:16])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1ccc(C(=O)OC)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 102.8 %

Procedure:
To a solution of 4-bromo-2-nitro-benzoic acid methyl ester (1 g, 3.85 mmol) in dioxane (5 mL) were added tributylvinyltin (1.7 mL, 5.76 mmol) and Pd(Ph3P)2Cl2 (275.4 mg, 0.385 mmol). The reaction mixture was stirred at 80° C. for 18 h, was cooled to r.t. and was diluted with EtOAc. After removal of the precipitate by filtration, the solution was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexanes 1:1 hexanes:EtOAc) to provide the title compound (820 mg, 100%, 97% purity by HPLC) as a yellow oil. ESI-MS: m/z 208.2 [M+H]+, rt 5.14 min.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([F:27])=[C:22]([CH2:28][NH2:29])[CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:29][CH2:28][C:22]1[CH:21]=[C:20]([C:19]([O:18][CH3:17])=[O:30])[CH:25]=[C:24]([Cl:26])[C:23]=1[F:27])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: COC(=O)c1cc(Cl)c(F)c(CN)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Cl)c(F)c(CNC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-boc-trans-4-fluoro-L-proline (143 mg, 0.61 mmol), 3-aminomethyl-5-chloro-4-fluoro-benzoic acid methyl ester (prepared as described in Part C, 275 mg, 0.61 mmol) and HATU (0.35 g, 0.92 mmol) in DMF (4 mL) was added DIPEA (430 μl, 2.45 mmol) and the resulting solution was stirred overnight at ambient temperature. The reaction mixture was splitted in two batches and the crude product was purified without aqueous workup by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 ml/min) to give the title compound. MS (LC-MS): 333.0 [M−100]+; tR (HPLC conditions c): 5.05 min.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:27])[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[CH2:14][C:13]([CH3:26])([CH3:25])[NH:12]1>C1(C)C(C)=CC=CC=1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:12]2[C:13]([CH3:25])([CH3:26])[CH2:14][CH:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[CH2:16][C:11]2([CH3:27])[CH3:10])[N:7]=1
Reactant: CC(=O)CCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: Cc1ccccc1C
Product: CC(=O)CCCCNC1CC(C)(C)N(c2nc(Cl)nc(Cl)n2)C(C)(C)C1

Procedure:
9.2 g of cyanuric chloride and 26.7 g of 2,2,6,6-tetramethyl-4-(N-acetylbutylamino)-piperidine are reacted in 100 ml of xylene as described in Example 1 and worked up. 2,4-Dichloro-6-[2,2,6,6-tetramethyl-4-(N-acetylbutylamino)-piperidin-1-yl)-1,3,5-triazine is obtained as colorless crystals having a melting point of 131°-133°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.CCCCCCC.C(OCC)(=O)C>S(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1)[C:12]([NH:41][C:38]1[CH:39]=[CH:40][N:36]([CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)[N:37]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccn(Cc2ccccn2)n1
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(Cc3ccccn3)n2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
1.4 3-Benzyloxy-5-isopropoxy-benzoic acid (0.86 mmol) is dissolved in thionyl chloride (1.6 ml) and heated to 70° C. for one hour. After cooling to RT, the solvent is removed in vacuo. The residue is dissolved in dichloromethane and triethylamine (1.5 eq.) and 1-pyridine-2-ylmethyl-1H-pyrazole-3-ylamine (1.2 eq.) are added. The reaction is stirred 16 hours at RT. 3-Benzyloxy-5-isopropoxy-N-(1-pyridine-2-ylmethyl-1H-pyrazole-3-yl)-benzamide is obtained after column chromatography (heptane/ethyl acetate) as a colorless powder in a yield of 43%; HPLC (Method B): 3.21 min; LC-MS: 2.285 min, 443.15 (M+H+);
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:11][C:10]=1[C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=O)[C:22]=2[CH:21]=[CH:20][CH:19]=1>C(O)C.O>[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:11][C:10]=1[C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[N:2][OH:3])[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: NO
Reactant: O=C1c2ccccc2-c2c1cccc2-c1nc2ccncc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
In a 500-ml three-necked flask, dissolve 20 g of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-one, obtained in Example 1, in 328 ml of ethanol, then add successively 14.02 g of hydroxylamine hydrochloride and 27.59 g of dry sodium acetate. After stirring overnight at room temperature, dilute with 328 ml of water. The precipitate that formed is drained, washed with water and dried in the stove at 500. In this way we obtain 18.6 g of equimolecular mixture of the Z and E oximes of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-one, in the form of a pale yellow powder, witH-NMR purity over 95%, with the following characteristics:
Reaction SMILES: C1C=CC(/C=C/C[O:10][C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H](O)[C@H:13](O)[C@H:12]2O)=CC=1.[C:22]([O-])(=O)C(C)=C.CC(C1C=C2CC[C@H]3[C@@](C(O)=O)(C)CCC[C@]3(C)[C@H]2CC=1)C>S(Cl)(Cl)=O>[C:11]([O:16][CH2:15][CH2:17][OH:18])(=[O:10])[C:12]([CH3:13])=[CH2:22]
Reactant: OC[C@H]1O[C@@H](OC/C=C/c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C=C(C)C(=O)[O-]
Agent: CC(C)C1=CC[C@H]2C(=C1)CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(=O)O
Solvent: O=S(Cl)Cl
Product: C=C(C)C(=O)OCCO

Procedure:
This example is to prepare quaternary ammonium-containing rosin-derived methacrylate polymers, according to the exemplary method shown in FIG. 2. The method involves the synthesis of methacrylate monomers containing Diels-Alder adduct (anhydride) by esterification, and homopolymer by free radical polymerization. Following the amidation and quaternization reactions, the quaternary ammonium group is introduced. A typical procedure for the synthesis is described as follows: levopimaric acid is dissolved in thionyl chloride and refluxed for 12 h. Thionyl chloride is removed by reduced pressure distillation. The methacrylate monomer containing Diels-Alder adduct (anhydride) 3 is obtained by the addition of excess 2-hydroxyethyl methacrylate (2-HEMA) and using triethylamine as catalyst. The homopolymer is prepared by the radical polymerization of monomer 3 in the presence of the toluene and azoisobutyronitrile (AIBN). The homopolymer is dissolved in ethanol and then added with the dimethylethylenediamine. The mixture is stirred at 85° C. for 5 h and precipitated in diethyl ether to obtain the rosin-derived tertiary ammonium homopolymer. The quaternary ammonium unit 4 is then introduced by the reaction between the rosin-derived tertiary ammonium homopolymer and alkyl halide (e.g. bromoethane, bromohexane, bromooctane and bromododecane) in tetrahydrofuran at 40° C. for 48 h.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[C:12]1([C:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][C:2]#[N:1])[CH2:7][CH:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCCCN1CC=C(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCCCN1CC=C(c2ccccc2)CC1
Reaction time: 8 h

Procedure:
N-(4-Aminobutyl)-4-phenyl-1,2,3,6-tetrahydropyridine (C) 1.8 g of lithium aluminium hydride are suspended in small portions (exothermic dissolution) in 50 ml of anhydrous THF (freshly distilled over sodium). 4.5 g of 4-(4-phenyl-1,2,3,6-tetrahydropyridinyl)butyronitrile, in solution in THF, are added dropwise at 0° C. and then reaction is allowed to take place at 0° C. for 3 hours with good stirring. The mixture is hydrolysed with a mixture of 5 ml of water in solution in 50 ml of THF and the combined mixture is allowed to stand overnight in order to agglomerate the precipitate. The precipitate is filtered on celite and the filtrate is dried over anhydrous sodium sulphate and concentrated. The residue is distilled under pump vacuum. A colourless oil is obtained. Y=86%. 1H NMR (CDCl3):1.26 (bs, 2H, --NH2), 1.43-1.66 (m, 4H, --H2C--CH2 --), 2.44-2.51 (t, 2H, --CH2 --) 2.59 (b s, 2H, --CH2 --), 2.68-2.76 (m, 4H, --CH2 --CH2 --) 3.15-3.19 (d, 2H, --CH2 --), 3.72-3.78 (q, 2H, --CH2 --), 6.06 (q, 1H, --CH=), 7.22-7.41 (m, 5H, phe). 13C NMR (CDCl3):24.6 (--CH2 --CH2 --CH2 --NH2), 28.1 (--CH2 --CH2 --NH2), 31.9 (--CH2 --CH2 --N<, pyrid), 42.2 (--CH2 --NH2), 50.4 (--CH2 --CH2 --N<, pyrid), 53.3 (=CH--CH2 --N<), 58.3 (>N--CH2 --), 121.9 (>CH--), 124.9 (>CH)2 --), 126.9 (>(CH)2 --), 128.2 (<C=CH--, pyrid), 135.0 (>C=CH--, pyrid), 140.9 (>C<).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)=[O:19]>CN(C)C=O>[CH2:1]([S:8][C:16]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccnc1C(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1C(=O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
Benzylmercaptan (4.3 g) and potassium carbonate (4.8 g) were added to a solution of 2-(2'-chloro-3'-nitro-benzoyl)-1-methyl-imidazole (9.2 g) in 150 ml of N,N-dimethylformamide. The reaction mixture was stirred at 80° C. for 5 hours. Then, the reaction mixture was poured onto ice water, and the resulting mixture was extracted twice with ethyl acetate. The combined organic phases were washed with water and then dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and the remaining residue was purified by silica gel column chromatography (eluting solvent:hexane/ethyl acetate=95:5 v/v). 2-(2'-Benzylthio-3'-nitrobenzoyl)-1-methylimidazole (8.7 g) was obtained in this manner.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24])(=[O:19])=[O:18]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:23](=[O:24])[C:22]4[CH:26]=[CH:27][CH:28]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:21]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: CS(=O)(=O)c1cccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)c1

Procedure:
The title compound was prepared following procedure described for example 2, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 3-methylsulphonylbenzoic acid (60 mg, 0.3 mmol, 1.2 eq.) as an off-white solid (9 mg, 9%). HPLC, Rt: 2.79 min. (purity 96.5%). LC/MS, M+(ESI): 383.0, M−(ESI): 381.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:9]([OH:12])[CH2:10]Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:25])[CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:9]([OH:12])[CH2:10][NH:25][CH2:21][CH:22]([CH3:24])[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Reactant: CC(C)CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 62.5 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
The mixture of [(1S,2S)-3-chloro-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid tert-butyl ester (5, 100 g), isobutyl amine (294 g), sodium carbonate (31.3 g) and water was heated to 60-65° C. and maintained for 3 hours. After completion of reaction water (200 mL) was added and distilled out excess isobutyl amine under vacuum at below 75° C. Water (800 mL) was added to the distillate, cooled to 25-35° C. and stirred for 2 hours. The obtained solid was filtered and washed with water to get title compound 4 (yield 105 g).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][C@@H:37]2[CH3:42])[CH3:35])=[CH:4][N:3]=1.CCN(CC)CC.[CH3:50][S:51](Cl)(=[O:53])=[O:52].[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][N:39]([S:51]([CH3:50])(=[O:53])=[O:52])[CH2:38][C@@H:37]2[CH3:42])[CH3:35])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCNC[C@@H]4C)cnc3F)nc(C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)nc(C)n2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A solution of 6-(2-fluoro-5-((1R)-1-((2S)-2-methyl-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.200 g, 0.350 mmol) in CH2Cl2 (3 mL) at −20° C. was treated with NEt3 (0.488 mL, 3.50 mmol) followed by methanesulfonyl chloride (0.083 mL, 1.051 mmol). The mixture stirred at −20° C. for 30 minutes. 1 M NaOH (aq.) and CH2Cl2 were then added. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 60% to 100% EtOAc in hexane, to provide 6-(2-fluoro-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.130 g, 0.200 mmol, 57.2% yield) as a white foam. m/z (ESI, +ve) 649.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.42 (dd, J=9.29, 2.45 Hz, 1H); 8.14 (d, J=1.17 Hz, 1H); 7.18 (d, J=7.82 Hz, 4H); 6.81-6.89 (m, 5H); 4.74 (br. s., 4H); 4.04 (q, J=6.78 Hz, 1H); 3.79 (s, 6H); 3.28-3.37 (m, 1H); 3.16-3.24 (m, 1H); 3.12 (dd, J=10.95, 2.93 Hz, 1H); 2.85-3.01 (m, 2H); 2.77 (s, 3H); 2.63-2.70 (m, 2H); 2.62 (s, 3H); 1.44 (d, J=6.85 Hz, 3H); 1.10 (d, J=6.26 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:14]Br.CCCCC>CN(C=O)C.C(Cl)Cl>[Br:14][C:11]1[O:10][C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=1
Reactant: BrBr
Reactant: Fc1ccc(Cc2ccco2)cc1
Solvent: CCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1ccc(Cc2ccc(Br)o2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a -30° C. solution of 2-(4-fluorophenylmethyl)furan, prepared as in step 1 (32.0 g, 0.18 mol) in anhydrous DMF (60 mL) was added a solution of bromine (28.9 g, 0.18 mol) in CH2Cl2 (250 mL). The mixture was stirred for 0.5 hours at -10° C. and poured into pentane (1600 mL). The penlane was then decanted from the dark colored insoluble layer. Evaporation of the pentane gave the crude product which was purified by flash-chromatography on silica gel eluting with penlane to provide 2-Bromo-5-(4-fluorophenylmethyl)furan as a cream colored solid in a yield of 8.87 g (19.2%).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.O>C1(C)C=CC=CC=1.Cl.[Fe]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]2[S:4][N:3]=[C:2]([Cl:1])[C:6]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Agent: [Fe]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc2snc(Cl)c2c1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-5-nitro-1,2-benzisothiazole (2.00 g) in toluene is treated with iron powder (8.40 g, 325 mesh) and concentrated hydrochloric acid (8 drops), heated to reflux, treated dropwise with water (8.00 mL), refluxed for 35 minutes, cooled to room temperature, and filtered through diatomaceous earth. The resultant filtrate is concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (1:1) gives the title product.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:31]([Cl:34])(=[O:33])[CH3:32]>CN(C=O)C>[ClH:34].[C:31]([NH:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.12 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride are initially charged in 0.3 ml of DMF, and 18.7 mg (0.18 mmol) of triethylamine and 11.6 mg (0.15 mmol) of acetyl chloride are added. After 16 h of stirring at RT, a further 18.7 mg (0.18 mmol) of triethylamine and 11.6 mg (0.15 mmol) of acetyl chloride are added. After a further 12 h of stirring at RT, the supernatant solution of the reaction mixture is purified by preparative HPLC. The product fractions are concentrated and the residue is dissolved in a mixture of methanol and 4M HCl in dioxane, then reconcentrated and dried under high vacuum. 8 mg (17.1% of theory) of the title compound are obtained.
Reaction SMILES: C([O:3][C:4](=[O:21])[C@H:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:6][CH2:7][CH2:8][CH2:9][S:10]([OH:13])(=[O:12])=[O:11])C>[OH-].[Na+]>[C:15]1([CH2:14][C@H:5]([NH:6][CH2:7][CH2:8][CH2:9][S:10]([OH:13])(=[O:11])=[O:12])[C:4]([OH:21])=[O:3])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NCCCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H](Cc1ccccc1)NCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
The N-(3-sulfo-propyl)-phenylalanine ethyl ester (DM-258-069, 860 mg, 2.7 mmol) was dissolved in 2N NaOH (1.2 g of NaOH and 15 mL of water). The reaction was stirred at room temperature overnight. Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure and lyophilized, affording the title compound (654 mg, 84%). 1H NMR (D2O, 500 MHz) δ ppm 7.20 (m, 5H), 3.96 (t, 1H, J=6.3 Hz), 3.11 (m, 4H), 2.80 (t, 2H, J=7.3 Hz), 1.95 (m, 2H). 13C (D2O, 125 MHz) δ ppm 171.46, 134.03, 129.50, 129.28, 128.10, 62.02, 47.97, 45.64, 35.23, 21.39. [α]D=+14.9° (c=0.0013 in water), ES-MS 286 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]#[C:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][OH:17])=[C:11](/[CH:30]=[CH:31]/[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:10]=[C:9]1[C:37]([O:39]CC1C=CC=CC=1)=[O:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.CO>O.[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:16][OH:17])=[C:11]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:10]=[C:9]1[C:37]([OH:39])=[O:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cc(C(=O)OCc2ccccc2)n(Cc2ccccc2)c1C#CC(CO)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCOC(=O)CCc1cc(C(=O)O)n(Cc2ccccc2)c1CCC(CO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
A 25-mL flask was charged with 6 (21 mg, 0.03 mmol), 20% Pd(OH)2 on carbon (nominally 50% in water, 7 mg), and 1 mL each of EtOAc and MeOH. The suspension was stirred under a hydrogen balloon at room temperature for 5-17 hours. The catalyst was filtered off (Celite), the residue concentrated to give 20 mg (quantitative) of a pale yellow foam, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.30-7.15 (m, 13H), 6.95 (s, 1H), 6.90 (m, 2H), 5.45 (ABq, J=16.4 Hz, 2H), 4.21 (td, J=8.5, 2.1 Hz, 1H), 4.09 (q, J=7.0H, 2H), 3.75 (d, J=8.6 Hz, 1H), 2.72-2.58 (m, 4H), 2.46 (t, J=7.4 Hz, 2H), 1.06-1.51 (m, 2H), 1.48-1.44 (m, 2H), and 1.22 (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.45, 165.67, 142.18, 141.36, 139.65, 138.95, 129.11, 128.99, 128.88, 128.72, 128.30, 127.20, 127.15, 126.94, 126.01, 120.86, 120.09, 119.67, 73.09, 60.66, 58.67, 48.23, 35.37, 34.81, 21.23, 20.70, and 14.50; IR (KBr) 3428, 3027, 2933, 1732, 1663, and 1450 cm−1; LRMS-El m/z 481 ([M−CO2+], 64%), 167 ([Ph2CH3+], 75%), and 91 ([PhCH2+], 100%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1.S(=O)(=O)(O)O.[CH2:34](O)CC>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH2:25][CH3:34])=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1
Reactant: CCCO
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Agent: O=S(=O)(O)O
Product: CCCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1

Procedure:
A mixture of ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.04 g), n-propanol and a trace of concentrated sulfuric acid was heated under reflux for 4 hours. The mixture was concentrated and then partitioned between dichloromethane and water. The dichloromethane layer was washed with water, dried over MgSO4 and evaporated to give n-propyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (0.72 g) as a yellow oil.