Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:15]=1[CH2:16][CH:17]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl.O>[CH2:1]([O:8][C:9]([N:21]1[CH2:20][CH2:19][NH:18][CH:17]([CH2:16][C:15]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:14]=2[O:13][CH3:12])[CH2:22]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(CC2CNCCN2)c1OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cccc(CC2CN(C(=O)OCc3ccccc3)CCN2)c1OC
Reaction time: 0.25 h
Yield: 53.1 %

Procedure:
A solution of benzyloxycarbonyl chloride (0.59 g) in dichloromethane (3.0 ml) was added dropwise to a solution of 2-(2,3-dimethoxybenzyl)piperazine (0.91 g) and triethylamine (0.64 ml) in dichloromethane (18 ml) below 5° C. over 5 minutes under ice-cooling, and the reaction mixture was stirred at the same temperature for 15 minutes. After 2 hours of stirring at room temperature, the mixture was poured into a mixed solvent of water (40 ml) and dichloromethane (25 ml) and the whole was adjusted to pH 9 with aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (20 g) using a mixed solvent of dichloromethane and methanol (40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give colorless oil of 1-(benzyloxycarbonyl)-3-(2,3-dimethoxybenzyl)piperazine (0.68 g).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:5].Cl.[N:20]([O-])=O.[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[Br:18][C:15]1[CH:16]=[CH:17][C:2]2[N:1]=[N:20][N:6]([CH2:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:4](=[O:5])[C:3]=2[CH:14]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Br)cc1C(=O)NCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1c2cc(Br)ccc2nnn1Cc1cccnc1
Yield: 84.1 %

Procedure:
To a mixture of 29.4 g of 2-amino-5-bromo-N-(3-pyridylmethyl)benzamide, 32 ml of conc. hydrochloric acid and 400 ml of water was dropwise added a solution of 6.83 g and 400 ml of water was dropwise added a solution of 6.83 g of sodium nitrite and 48 ml of water at 0° to 2° C. The resultant mixture was stirred at 0° to 2° C. for 45 minutes, neutralized with 1N aqueous sodium hydroxide and shaken with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 25.6 g of the titled compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: OC1CCNCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: CCO
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Reaction time: 1 h
Yield: 76.7 %

Procedure:
2-chloro-5-nitrobenzonitrile (36 g) and 4-hydroxypiperidine (50 g) were added to ethanol (300 ml), and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give 5-nitro-2-(4-hydroxypiperidin-1-yl)benzonitrile (37.4 g), melting point: 114–115° C.
Reaction SMILES: C1(C)CCC(C(C)C)[CH:3]([C:10]([CH:20]2C(C(C)C)CCC(C)C2)([CH3:19])[C:11](=[O:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)C1.[Br:31]Br>>[Br:31][CH:12]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C:11](=[O:18])[C:10]([CH3:20])([CH3:19])[CH3:3]
Reactant: BrBr
Reactant: CC1CCC(C(C)C)C(C(C)(C(=O)Cn2cncn2)C2CC(C)CCC2C(C)C)C1
Product: CC(C)(C)C(=O)C(Br)n1cncn1

Procedure:
Thus, for example, 3,3-dimethyl-1-(4-methoximinomethyl-phenoxy)-1-(1,2,4-triazol-1-yl)-butan-2-one of the formula ##STR11## can be prepared by reacting 3,3-dimenthyl-1-(1,2,4-triazol-1-yl)-butan-2-one initially with bromine to form 1-bromo-(1,2,4-triazol-1-yl)-3,3-dimethyl-butan-2-one, and subsequently reaching this with 4-hydroxybenzaldehyde O-methyl oxime ether in the presence of a base. This synthesis can be illustrated by means of formulae as follows:
Reaction SMILES: [N:1]([C@H:4]([C@H:34]([O:50][C:51](=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:5][O:6][C@@H:7]1[O:23][C@H:22]([CH2:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:12]([O:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:10]([OH:11])[C@H:8]1[OH:9])=[N+]=[N-].[C:59](Cl)(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.[CH3:68][OH:69]>N1C=CC=CC=1.C(Cl)Cl>[C:51]([O:50][C@H:34](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@H:4]([NH:1][C:68](=[O:69])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:4][CH3:5])[CH2:5][O:6][C@@H:7]1[O:23][C@H:22]([CH2:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:12]([O:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:10]([O:11][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@H:8]1[OH:9])(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CO
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](OC(=O)c1ccccc1)[C@H](CO[C@@H]1O[C@H](COCC(=O)OC(C)(C)C)[C@H](OCC(=O)OC(C)(C)C)[C@H](O)[C@H]1O)N=[N+]=[N-]
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCC/C=C/[C@@H](OC(=O)c1ccccc1)[C@H](CO[C@@H]1O[C@H](COCC(=O)OC(C)(C)C)[C@H](OCC(=O)OC(C)(C)C)[C@H](OC(=O)c2ccccc2)[C@H]1O)NC(=O)CCCCCCCCCCCCCCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of (2S,3R,4E)-2-azido-3-benzoyloxy-1-(4,6-di-O-tert-butyloxycarbonylmethyl-β-D-galactopyranosyloxy)-4-octadecene described in Example 15-A (1.34 g 1.63 mmol) in a mixture of pyridine/methylene chloride (1:1, 70 mL) was treated with benzoyl chloride (210 μL, 1.81 mmol) at -78° C. The mixture was stirred at -78° C. for 1 hour, then methanol (10 mL) was added and the resulting mixture was stirred at 22° C. for 20 more hours. The solvents were evaporated and the residue was dissolved in ethyl acetate (200 mL). This solution was washed with water (4×75 mL), saturated aqueous sodium bicarbonate (2×100 mL) and brine (2×100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (150 g, 5 to 50 % ethyl acetate/hexane) and gave the title compound (0.275 g, 20%), along with the starting material (0.839 g, 63%), the 2-benzoate (0.124 g, 8%) and the bis-benzoate (0.030 g, 2%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[N:13]1([C:19]2[N:20]=[N:21][CH:22]=[CH:23][N:24]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:16]1[CH2:15][CH2:14][N:13]([C:19]2[N:20]=[N:21][CH:22]=[CH:23][N:24]=2)[CH2:18][CH2:17]1.[C:3]1([CH3:2])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1cnc(N2CCNCC2)nn1
Reactant: FC(F)(F)c1ccccc1CBr
Product: Cc1ccccc1
Product: FC(F)(F)c1ccccc1CN1CCN(c2nccnn2)CC1
Yield: 33 %

Procedure:
Compound 5 is prepared from 1-bromomethyl-2-trifluoromethyl-benzene and intermediate 5a according to synthesis method 2 in refluxing toluene (33% yield).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].O[CH2:11][NH:12][C:13](=[O:16])[CH2:14]Cl.[C:17](=O)([O-])[OH:18].[Cs+]>CN1C(=O)CCC1>[C:4]([O:6][CH2:14][C:13](=[O:16])[N:12]([O:18][CH3:17])[CH3:11])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: O=C([O-])O
Reactant: O=C(CCl)NCO
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCC(=O)N(C)OC
Yield: 60.8 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N-methyl, N-hydroxymethyl chloroacetamide (0.63 g, 4.61 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol). The crude material precipitated out from a concentrated ethyl acetate (EtOAc) solution. The solid was filtered off and dried in vacuum to provide 0.54 g (61% yield) of the title compound (10) as a white solid. 1H NMR (CD3OD, 400 MHz): δ 6.92-6.89 (m, 2H), 5.01 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 3.20 (s, 3H). MS (ESI): m/z 232.06 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([F:40])=[C:34]([CH:39]=3)[C:35]([O:37]C)=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].O.Cl>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([N:22]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([F:40])=[C:34]([CH:39]=3)[C:35]([OH:37])=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN(Cc1ccc(F)c(C(=O)O)c1)S(=O)(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 100 °C
Reaction time: 0.69 h
Yield: 86.4 %

Procedure:
To a solution of methyl 5-{[({4-[(4-butylphenyl)ethynyl]phenyl}sulfonyl)(hexyl)amino]methyl}-2-fluorobenzoate (66 mg; 0.12 mmol) in THF (4 mL) were added lithium hydroxide monohydrate (49 mg; 1.17 mmol) and water (1 mL). The reaction mixture was stirred at 100° C. for 2500 s under MW. The mixture was poured into HCl 1N (10 mL) and extracted with EtOAc (2×75 mL). Combined organic layers were washed with brine (125 mL), dried over magnesium sulfate and filtrated. The solvent was removed under reduced pressure to give 57 mg (88.6%) of the title compound as a white powder. HPLC: Rt=5.71 min (purity=98.9%), LC/MS: M−(ESI): 548.3.1H NMR (MeOD) δ: 7.87 (d, J=8.6 Hz, 3H), 7.72 (d, J=8.6 Hz, 2H), 7.69 (m, 1H), 7.48 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 7.18 (s, 1H), 4.39 (s, 2H), 3.75 (m, 1H), 3.55 (t, J=4.3 Hz, 1H), 3.16 (t, J=7.3 Hz, 2H), 2.68 (t, J=7.7 Hz, 2H), 1.63 (q, J=7.5 Hz, 3H), 1.35 (m, 4H), 1.15 (m, 4H), 0.95 (t, J=7.3 Hz, 3H), 0.82 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:17][CH:16]3[CH:18]([OH:19])[CH:13]2[CH2:14][CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1.ClC1C=CC(S(N(CC2C=CC(C#N)=CC=2)[C@@H]2CCC[C@H]2CO)(=O)=O)=CC=1>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:11]([CH:12]2[CH2:17][CH:16]3[CH:18]([OH:19])[CH:13]2[CH2:14][CH2:15]3)[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:29][CH:28]=1
Reactant: O=S(=O)(NC1CC2CCC1C2O)c1ccc(Cl)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: N#Cc1ccc(CN([C@@H]2CCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(Br)cc1)C1CC2CCC1C2O
Yield: 72.4 %

Procedure:
The title compound was synthesized from 2-(4-chlorophenylsulfonamido)bicyclo[2.2.1]heptan-7-ol (302 mg, 1.0 mmol), cesium carbonate (652 mg, 2.0 mmol), and 1-bromo-4-(bromomethyl)benzene (300 mg, 1.2 mmol) according to the procedure described for 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (Example 2) to give N-(4-bromobenzyl)-N-(7-hydroxybicyclo[2.2.1]heptan-2-yl)-4-chlorobenzenesulfonamide (341 mg, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 7.65-7.72 (2H, m), 7.40-7.46 (2H, m), 7.37 (2H, d, J=8.56 Hz), 7.18 (2H, d, J=8.56 Hz), 4.68 (2H, dd, J=38.27, 17.12 Hz), 3.97 (1H, t, J=7.30 Hz), 3.77 (1H, s), 1.94 (1H, hr. s.), 1.79-1.88 (3H, m), 1.36-1.62 (3H, m), 1.00-1.12 (2H, m). LC/MS R.T.=2.33 min; [M+H]+=470.03. HRMS [M+H]+ calc'd 470.0192, found 470.0202.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(OCC)C>N1C=CC=CC=1>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NS(C)(=O)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) and triethylamine (0.50 mL, 3.6 mmol) in pyridine (15 mL) was added dropwise methanesulfonyl chloride (62 μL, 0.54 mmol). After the addition the reaction was allowed to stir at ambient temperature for 1 h. The solvent was evaporated in vacuo and the residue was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent. This gave, after crystalization from diethyl ether, 100 mg (63% yield) of the title compound as white crystals: mp 135-137° C.; [α]21D +22° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 323 (59, M+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].Cl.[NH2:13][CH:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([S:29][CH:30]([F:32])[F:31])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[CH2:15][OH:16].C(=O)(O)[O-].[Na+]>ClCCl.O>[F:32][CH:30]([F:31])[S:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([CH:14]([NH:13][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])[CH2:15][OH:16])=[CH:18][CH:19]=2)=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NC(CO)c1ccc(-c2ccc(SC(F)F)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(NC(CO)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of 0.137 g (0.776 mmol) of 2,6-difluorobenzoyl chloride in 1 mL of dichloromethane was added dropwise to a mixture of 0.23 g (0.693 mmol) of β-amino-4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-ethanol hydrochloride salt, 1.5 mL of dichloromethane, and 1.5 mL of sodium bicarbonate (saturated aqueous solution). The mixture was stirred for 2 h, and was diluted with 10 mL of water. The mixture was extracted with 3×20 mL of dichloromethane, 35 mL of dichloromethane and the organic phase separated. The combined extracts were dried and evaporated. Chromatography on silica gel (eluted with ethyl acetate/hexane (1:1)) gave the product 0.28 g (93% yield) as a white solid m.p. 156.5-157° C. IR(Nujol): 3294, 1649, 1624, 1589, 1535, 1309, 1233, 1071, 1004, 819 cm-1. 1H-NMR(CDCl3): δ2.15 (t, J=5.75 Hz, 1H), 4.03-4.06 (m, 2H), 5.33-5.37 (m, 1H), 6.81 (d, J=7.2 Hz, 1H), 6.86 (t, J=57 Hz, 1H), 6.94-6.99 (m, 2H), 7.35-7.43 (m, 1H), 7.48 (d, J=8 Hz, 2H), 7.50-7.65 (m, 6H).
Reaction SMILES: C(=O)(O)N.[N:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](OC)=O)[CH:6]=1.[CH:18]([Sn](CCCC)(CCCC)CCCC)=[CH2:19]>C1(C)C=CC=CC=1.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>[CH3:10][N:9]1[C:8]2[C:7](=[CH:14][CH:11]=[CH:12][CH:13]=2)[C:6]([CH:18]=[CH2:19])=[N:5]1
Reactant: COC(=O)c1cnn2ccccc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: NC(=O)O
Solvent: Cc1ccccc1
Product: C=Cc1nn(C)c2ccccc12

Procedure:
A solution of compound 1 (1.6 g, 8 mmol) and vinyl tributyl tin (2.6 mL, 11 mmol) in toluene (10 mL) was treated with Pd(PPh3)4 (0.92 g, 0.8 mmol) and heated to reflux overnight. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 20% EtOAc in hexanes) to afford the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C([O-])([O-])=O.[K+].[K+]>O=S(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([O:19][CH3:18])[CH:21]=1)=[O:6]
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Reactant: COc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (500 mg, 2.10 mmol, 1.0 eq) in SOCl2 (5 mL) was heated at 65° C. under N2 for 1 h. The solution was then evaporated in vacuo and the remaining residue dissolved in CH2Cl2 and added dropwise to a mixture of 3-methoxyaniline (220 mg. 1.9 mmol, 0.9 eq) and K2CO3 (1.4 g, 10.1 mmol, 5.0 eq) in THF (10 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the solution extracted with EtOAc. The combined organic extracts were washed with aqueous Na2CO3 and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a colourless oil (580 mg, 96%).
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH3:27])[CH:17](C2C=NC=CN=2)[C:18](=[O:20])[NH2:19])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br-].[OH:36][C@@H:37]1[CH2:41][CH2:40][N+:39](C)(C(C2C=NC=CN=2)C(=O)N)C1.[Br-].O[C@@H]1CC[N+](CC(=O)NC2C=CON=2)(C)C1>>[Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH2:17][C:18](=[O:20])[NH:19][C:40]2[CH:41]=[CH:37][O:36][N:39]=2)[CH3:27])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[N+]1(C(C(N)=O)c2cnccn2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reactant: C[N+]1(C(C(N)=O)c2cnccn2)CC[C@@H](O)C1
Agent: C[N+]1(CC(=O)Nc2ccon2)CC[C@@H](O)C1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-((R/S)-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide (Example 1) by replacing (1R/S,3R)-3-hydroxy-1-methyl-1-(pyrazin-2-yl-carbamoylmethyl)-pyrrolidinium bromide (Intermediate B) with (1R/S,3R)-3-hydroxy-1-(isoxazol-3-ylcarbamoyl-methyl)-1-methyl-pyrrolidinium bromide (Intermediate D).
Reaction SMILES: C=CC1C=CC=CC=1.[C:9]([O:14]C)(=[O:13])[C:10]([CH3:12])=[CH2:11].[C:16](OCCCC)(=[O:19])C=C.C(N)(=[O:29])C(C)=C.C(OCCO)(=O)C=C.C(OC)(=O)C(C)=C.C(O)(=O)C(C)=C.N>O>[OH:19][CH2:16][CH2:12][C:10](=[CH2:11])[C:9]([O:14][OH:29])=[O:13]
Reactant: C=CC(=O)OCCCC
Reactant: C=C(C)C(=O)OC
Reactant: C=C(C)C(N)=O
Agent: C=C(C)C(=O)O
Agent: C=CC(=O)OCCO
Agent: N
Solvent: C=Cc1ccccc1
Solvent: O
Product: C=C(CCO)C(=O)OO

Procedure:
This example illustrates a graft copolymer according to the present invention comprising 94% backbone made from styrene/methyl methacrylate/n-butyl acrylate/methacrylamide/2-hydroxyethyl acrylate (in the weight ratio of 27/14.5/46/4/2.5) and 6% macromonomer (from Example 1) made from methyl methacrylate/methacrylic acid (in the weight ratio of 3.6/2.4). This graft copolymer copolymerized after dispersion in water using ammonia to form a high molecular weight binder with both hydroxy (2-hydroxyethyl acrylate) and amide (methacrylamide) functionalities. The following components were used in the preparation:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](/[N:11]=[C:12](/[NH:25][C:26](=[O:35])[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[NH:19][C@@H:18]2[C:22]([OH:24])=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9](/[N:11]=[C:12](/[NH:25][C:26](=[O:35])[CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[NH:19][C@@H:18]2[C:22]([O:24][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N[C@@H]1C(=O)O)NC(=O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccccc1)NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 148 (74 mg, 1.0 eq.) in DMF (1.5 mL) was added benzyl alcohol (19 uL, 1.2 eq.), EDC-HCl (35 mg, 1.2 eq.), HOBt (24 mg, 1.2 eq.) and DIEA (60 μL eq.). The reaction was stirred at room temperature for 16 hours and then diluted with ethyl acetate and washed with 1N HCl. The aqueous layer was then washed with ethyl acetate (2×10 mL). The combined organics were then washed with saturated NaHCO3 (2×10 mL), water (10 mL), dried over magnesium sulfate and concentrated in vacuo to give the crude product (55 mg) as a colorless oil. The product was purified by silica gel chromatography using a gradient elution from 20% EtOAc in hexanes to 50% EtOAc in hexanes to yield 149 (50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:31]([O:33]C)=[O:32])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:35]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:31]([OH:33])=[O:32])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:35]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(Cl)ccc4o3)c(N3CCCc4cc(F)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3cc4cc(Cl)ccc4o3)c(N3CCCc4cc(F)ccc43)nc2c1
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of methyl 2-(5-chloro-1-benzofuran-2-yl)-3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (53 mg, 0.11 mmol) in methanol (25 mL) and water (1 mL) was added sodium hydroxide (12.0 mg, 0.30 mmol) with stifling overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (10 mL), adjusted pH to 5 with hydrogen chloride (3 N) to give the precipitation, which was collected by filtration to afford 2-(5-chloro-1-benzofuran-2-yl)-3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylic acid (37.5 mg, 73%).
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=[C:4](F)[CH:3]=1.BrCC1C=CC([C:42]#[N:43])=CC=1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([C:11]1[N:12]=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:42]#[N:43])=[CH:34][CH:33]=2)=[CH:9][CH:10]=1)([F:32])[F:31]
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(COc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cc1

Procedure:
Compound 9 was prepared in a similar manner to compound 1 from 4-(bromomethyl)benzonitrile to afford a white solid (80 mg, 33%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.24 (s, 1H), 7.72 (d, J=7.5 Hz, 2H), 7.75-7.52 (m, 3H), 7.43 (br s, 1H), 7.39-7.35 (m, 1H), 7.31-7.29 (m, 1H), 6.78-6.74 (m, 1H), 6.70-6.67 (m, 1H), 5.51 (d, J=14.0 Hz, 1H), 5.18 (s, 2H), 5.13 (d, J=14.0 Hz, 1H). MS(ESI): m/z 485 [M++1]. HPLC: 97.12%.