Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=1)=[O:5].C(N(CC)CC)C.Cl.OC(C)(C)CN1C=CC(NC(=O)[C@@H](N2[CH2:51][C:50]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([Cl:59])[C:54]=3[Cl:60])=[CH:49][C:48]2=[O:61])CC(C)C)=N1>CO>[Cl:60][C:54]1[C:55]([Cl:59])=[CH:56][CH:57]=[CH:58][C:53]=1[O:52][C:50]1[CH2:51][N:2]([C@@H:3]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[N:8]=2)=[O:5])[C:48](=[O:61])[CH:49]=1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@@H](N)CC2CCCCO2)n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCO2)N2CC(Oc3cccc(Cl)c3Cl)=CC2=O)n1
Yield: 3.7 %

Procedure:
(S)-2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydropyran-2-yl)-propionamide hydrochloride (118 mg, 0.30 mmol) was dissolved in methanol (2 mL) and triethylamine (0.2 mL) was added. The mixture was evaporated to dryness. The residue was dissolved in acetonitrile (5 mL). To this solution was added (E)-4-bromo-3-(2,3-dichloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 77, 109 mg, 0.30 mmol). The mixture was refluxed for 40 h. The mixture was evaporated and the residue was treated with ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate and concentrated to give a crude product (180 mg). One part of the crude product (30 mg) was purified through reverse phase preparative HPLC (acetonitrile in water, 25% to 100% linear gradient) to afford (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-2-yl)-propionamide as a white powder (6 mg): LR-ES-MS m/z calculated for C25H30Cl2N4O5 [M]+ 536, observed [M+H]+ 537; 1H-NMR (CDCl3) δ ppm 1.16 (s, 6H), 1.25-1.73 (m, 5H), 1.73-2.00 (m, 2H), 2.17-2.34 (m, 1H), 3.29-3.49 (m, 2H), 3.88-4.06 (m, 3H), 4.24 (d, J=17.8 Hz, 1H), 4.42 (d, J=17.8 Hz, 1H), 4.89 (s, 1H), 5.02-5.16 (m, 1H), 6.70 (br s, 1H), 7.14-7.23 (m, 1H), 7.28-7.37 (m, 3H), 7.42 (d, J=8.2 Hz, 1H), 8.76 (br s, 1H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:44])[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:43])=[C:31]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:32]=1>>[CH2:18]([S:15]([NH:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@H:24]([OH:44])[CH2:25][O:26][C:27]3[CH:28]=[CH:29][C:30]([OH:43])=[C:31]([NH:33][S:34]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)(=[O:35])=[O:36])[CH:32]=3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1)(=[O:17])=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: NC[C@H](O)COc1ccc(O)c(NS(=O)(=O)c2ccccc2)c1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)c(NS(=O)(=O)c4ccccc4)c3)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 228) and N-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-benzenesulfonamide (which was obtained in Example 21) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3 H), 1.20–1.40 (m, 4 H), 1.55–1.70 (m, 2 H), 1.80–1.95 (m, 2 H), 2.50–2.80 (m, 5 H), 2.92 (t, J=7.6 Hz, 2 H), 3.50–3.90 (m, 5 H), 6.39 (d, J=8.7, 2.9 Hz, 1 H), 6.57 (d, J=8.7 Hz, 1 H), 6.72 (d, J=2.9 Hz, 1 H), 6.90 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 2 H), 7.40–7.60 (m, 3 H), 7.74 (d, J=7.7 Hz, 2 H); MS (ES) m/z: 633.1 (MH+); HRMS Calcd. for C30H41N4O7S2 (MH+): 633.2411. Found: 633.2409.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([C:18]#[CH:19])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].Cl>CN(C=O)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:30][O:29][C:27]([C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=4)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=3)[N:22]=[N:21]2)=[CH:32][CH:31]=1)=[O:28]
Reactant: COC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: C#Cc1nn(C(=O)OC(C)(C)C)c2ccc(C)cc12
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(C)cc34)nn2)cc1
Temperature: 80 °C

Procedure:
Copper sulfate pentahydrate (0.08 g; 0.33 mmol; 0.06 eq.) was added to a solution of tert-butyl-3-ethynyl-5-methyl-1H-indazole-1-carboxylate (1.55 g; 6.03 mmol; 1.0 eq.), methyl 4-azidobenzoate (prepared as described in JOC (2006), 71(15), 5822-5825; 1.20 g; 6.77 mmol; 1.1 eq.) and D-(−)-isoascorbic acid sodium salt (0.24 g; 1.22 mmol; 0.20 eq.) in DMF (15 mL) and water (0.50 mL). The reaction suspension was heated in MW at 80° C. for 45 min then poured into HCl (0.1 N solution) and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (n-heptane/EtOAc, gradient from 90:10 to 60:40) to give the title compound as a yellow solid. 1H NMR (300 MHz, DMSO) δ 9.66 (s, 1H), 8.35-8.25 (m, 3H), 8.20 (d, J=8.8 Hz, 2H), 8.05 (d, J=8.7 Hz, 1H), 7.54 (dd, J=1.5, 8.7 Hz, 1H), 3.91 (s, 3H), 2.53 (s, 3H), 1.69 (s, 9H). HPLC (Condition A): Rt 5.07 min (purity 96.8%). MS (ESI+): 434.4.
Reaction SMILES: FC1C=CC(CN)=CC=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccncc1
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccncc1
Yield: 49 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 4-(aminomethyl)pyridine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 49% yield: mp 96-97° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=4.8 Hz, 2H), 7.31-7.19 (m, 7H), 6.52 (t, J=5.7 Hz, 1H), 4.53 (d, J=5.7 Hz, 2H), 4.35 (s, 2H), 4.02 (t, J=7.5 Hz, 2H), 3.41 (t, J=7.5 Hz, 2H), 2.56 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.8, 157.5, 155.3, 153.7, 149.7, 147.7, 135.4, 128.9, 128.2, 128.0, 122.3, 116.7, 47.9, 42.6, 42.0, 41.6, 17.3: MS (ES+) m/z 408.3 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH3:12])=[N:6][CH:5]=1.O.[OH-].[Li+]>O1CCOCC1.O>[C:16]([O:15][C:13]([N:10]([CH2:11][CH3:12])[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][N:6]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)OC)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The crude 6-(tert-butoxycarbonyl-ethyl-amino)-nicotinic acid methyl ester is taken up in 100 mL dioxane and a solution of lithium hydroxide monohydrate (13.5 g, 0.32 mol) in 100 mL water is added and the reaction mixture is stirred at RT for 4 h. The dioxane is removed from the reaction mixture under reduced pressure, water is added and the reaction mixture is acidified to pH 6 with a solution of 10% citric acid in water. The formed precipitate is filtered off and dried in vacuo. Yield: 36 g. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 8.8 (s, 1H), 8.2 (d, 1H), 7.8 (d, 1H), 4.0 (quart, 2H), 1.5 (s, 9H), 1.2 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:6]=[N:7][CH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11].[BH4-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9]([O:10][CH3:11])[O:12][CH3:13]
Reactant: COc1ccc(C=NCC(OC)OC)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CNCC(OC)OC)cc1OC
Yield: 91.7 %

Procedure:
Imine 11a (13.90 g, 0.055 mol) was dissolved in ethanol (50 mL) and NaBH4 (4.2 g) was added over 1 h while stirring the reaction mixture at reflux. The reaction was diluted with water (250 mL). The amine was extracted into chloroform (300 mL) washed with water (2×200 mL), brine (200 mL), dried Na2SO4 and concentrated to provide a yellow liquid (12.88 g, 91.7%). 1H NMR (300 MHz CDCl3) 6.81 (s, 1H), 6.78 (d, J=8.1 Hz, 1H), 6.74 (d, J=8.1, 1H), 4.41 (t, J=5.4 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.67 (s, 2H), 3.29 (s, 6H), 2.67 (d, J=5.4 Hz, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:23]=[CH:22][C:11]2[C:12](=[O:21])[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[O:15][C:10]=2[CH:9]=1.[C:24](=[O:27])([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[O:21]=[C:12]1[C:11]2[CH:22]=[CH:23][C:24]([O:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:23]=[CH:22][C:11]4[C:12](=[O:21])[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[O:15][C:10]=4[CH:9]=3)=[CH:9][C:10]=2[O:15][CH:14]=[CH:13]1
Reactant: CCOC(=O)c1cc(=O)c2ccc(OCCCCCBr)cc2o1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1cc(=O)c2ccc(OCCCCCOc3ccc4c(=O)ccoc4c3)cc2o1

Procedure:
A mixture of 4.6 parts of 7-(5-bromopentyloxy)4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, 2 parts of ethyl 7-hydroxychromone-2-carboxylate,1.8 parts of potassium carbonate, a few potassium iodide crystals and 80 parts by volume of dry acetone was refluxed on a steam bath for 20 hr. The cooled mixture was filtered and the filtrate evaporated down to give an oil which when treated with petroleum ether (40-60° ), solidified to give 4.0 parts of crude product. Crystallisation from ethanol gave 2.9 parts of 7-[5-(4-oxo-4H-1-benzopyran-7-yloxy)pentyloxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid; ethyl ester, m.p. 113°-116° .
Reaction SMILES: Cl.C(OC([NH:9][CH:10]([CH:16]([OH:30])[C:17]1[S:18][C:19]([CH2:22][CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)=[CH:20][CH:21]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C>C(O)C>[NH3:9].[NH2:9][CH:10]([CH:16]([OH:30])[C:17]1[S:18][C:19]([CH2:22][CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)=[CH:20][CH:21]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(O)c1ccc(CC2CCCCCN2)s1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)C(O)c1ccc(CC2CCCCCN2)s1
Product: N
Yield: 184.6 %

Procedure:
A mixed solution of concentrated hydrochloric acid:ethanol=1:5 (60 ml) was added to 12.6 g of ethyl 2-tert-butoxycarbonylamino-3-hydroxy-3-[5-(1-hexahydroazepinylmethyl)-2-thienyl]propionate, and the mixture was immediately concentrated under reduced pressure, mixed with 60 ml of the above mixed solution and again concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography and elution was carried out with mixed solutions of chloroform:ethanol=60:1, chloroform:methanol=20:1 and 10:1 and chloroform:methanol:concentrated aqueous ammonia=100:10:1 in that order to obtain 8.9 g of ethyl 2-amino-3-hydroxy-3-[5-(1-hexahydroazepinylmethyl)-2-thienyl]propionate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]1([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][C:35]([F:38])([F:37])[F:36])[C:24]=2[CH2:39]O)[CH2:22][CH2:21]1.C(Br)(Br)(Br)[Br:42]>ClCCl>[Br:42][CH2:39][C:24]1[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][C:35]([F:38])([F:37])[F:36])=[N:26][O:27][C:23]=1[CH:20]1[CH2:22][CH2:21]1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1c(-c2ccccc2OC(F)(F)F)noc1C1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1CBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 88 %

Procedure:
Triphenylphosphine (1.1 equiv., 51.5 mmoles, 13.5 g) is added in small portions to a 0° C. solution of [5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-yl]-methanol and carbon tetrabromide (1.1 equiv, 51.5 mmoles, 17.1 g) in dichloromethane (187.1 mL). The reaction mixture is stirred at ambient temperature for 15 h and concentrated under reduced pressure. The crude residue is purified via silica gel chromatography eluting with 5:1 hexanes/ethyl acetate) to afford the title compound (15 g, 88%) as a white powder.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-])=O)[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1>C(O)C.CN(C=O)C.[H][H].[C].[Pd]>[NH2:18][C:9]1[C:10]([F:17])=[C:11]([F:16])[C:12]([O:14][CH3:15])=[C:13]2[C:8]=1[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: COc1c(F)c(F)c([N+](=O)[O-])c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 62.3 %

Procedure:
To a solution of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxo-3-quinolinecarboxylic acid (322 mg) in ethanol-DMF (4:1) was added 10% palladium-carbon (25 mg) and the mixture was stirred in hydrogen gas atomosphere for 6 hours at room temperature. The catalyst was filtered off and washed with a solution of chloroform-methanol-concentrated aqueous ammonia (10:10:3). The filtrate and washings were combined and concentrated. The residue was recrystallized from a solution of chloroform-methanol-concentrated aqueous ammonia (20:6:1) to give the title compound (183 mg) as yellow prisms, mp 291°-291.5° C. (decompd.).
Reaction SMILES: CN(CCN(C)C)C.[F:9][S:10]([F:23])([F:22])([F:21])([F:20])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl.O>C1COCC1.[Li]C(CC)C.C1CCCCC1>[Cl:24][C:13]1[CH:12]=[C:11]([S:10]([F:20])([F:21])([F:22])([F:23])[F:9])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1Cl
Temperature: -90 °C
Reaction time: 2 h

Procedure:
20.0 ml of TMEDA were dissolved in 150 ml of THF (anhydrous) and, at a temperature between −80° C. and −90° C., 93.0 ml of a 1.25M solution of sec-BuLi in cyclohexane were added. Then, at a temperature between −87° C. and −93° C., a solution of 4-pentafluorosulfanylbenzoic acid (example 2a) in 50 ml of THF (anhydrous) was added dropwise over the course of 35 minutes, After stirring at −90° C. for 2 hours, 38.2 g of 1,1,1,2,2,2-hexachloroethane in 60 ml of THF (anhydrous) were added dropwise at −90° C. The mixture was allowed to warm to −70° C., and then 100 ml of water were added dropwise. The solvent was removed in vacuo, and the residue was chromatographed on silica gel with DIP/2% HOAc. 5.0 g of the desired product were obtained as a partly crystallizing oil.
Reaction SMILES: [OH-:1].[Na+:2].Cl[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])(=[O:6])=[O:5]>>[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O-:12])=[O:11])([OH:1])(=[O:6])=[O:5].[Na+:2]
Reactant: [OH-]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: [Na+]
Product: O=C([O-])c1cccc(S(=O)(=O)O)c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 96.5 %

Procedure:
The pH of 345 g of mother liquor from Example 1 is adjusted to 4 with about 60 g of sodium hydroxide. 300 ml of this solution are introduced together with 264.5 g of 3-(chlorosulfonyl)benzoic acid (water content: 25.7%) (corresponding to 196.5 g (0.89 mol) of 100% 3-(chlorosulfonyl)benzoic acid). The reaction mixture is heated to 100° C. and stirred for a further 45 minutes at this temperature. The mixture is then allowed to cool over about 1 hour to 40° C. Subsequently it is cooled with an ice bath to <5° C. and stirred for a further 30 minutes at this temperature. The precipitated product is filtered off with suction and washed with 256 g of 5% strength sodium chloride solution, prepared from 13.8 g of sodium chloride and 243.2 g of water and cooled to 5° C., in two portions. The filter cake is dried at 100° C./100 torr (13.16 kPa). 192.6 g of sodium 3-sulfobenzoate are obtained with a purity of 96% and a sodium chloride content of 3.2% (corresponding to 184.9 g (0.83 mol) of 100% sodium 3-sulfobenzoate). The yield is 92.6% of theoretical.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[C:18]([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH:25]([CH3:18])[CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCC(C)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 86.8 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 20 mmol), K2CO3 (5.2 g), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (5.0 g, 1022 mmol), and dimethylformamide (90 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and concentrated to afford 7.4 g of a yellow solid. The solid was chromatographed on a Waters Prep LC 500 utilizing dichloromethane/methanol (4%) as eluent, and subsequent concentration of the appropriate fraction afforded 4.0 g of a yellow solid. The solid was recrystallized from ethyl alcohol to yield 3.1 g (38%) of 1-[4-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone, as slightly yellow flakes, m.p.=132-134° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:22]=2[N:23]=1.[H-].[Na+]>CN(C=O)C.[Cu]I>[CH3:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][C:25]([O:28][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[CH:5]=[CH:4][N:3]=3)=[CH:24][C:22]=2[N:23]=1
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Reactant: Cc1nc2cc(O)ccc2s1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ccn3)ccc2s1

Procedure:
This material was prepared according to the method described in Example 413 using 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 0.16 g, 0.6 mmol), 2-methyl-5-benzothiazolol (0.12 g, 0.7 mmol), sodium hydride (38 mg, 1.0 mmol) and copper (I) iodide (12 mg, 0.06 mmol) in DMF (3 mL). Purification on a Biotage 40S column (3:1 hexanes: EtOAc), provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 367 (M+1). Mp: 160.5-163.5° C. Anal. Calcd for C20H13F3N2OS. 0.25 H2O: C, 61.45; H, 3.48; N, 7.17; S, 8.20.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([B:13]2[O:17][C:16]([CH3:19])(C)C(C)(C)[O:14]2)=[C:6]([C:9]([F:12])=[CH:10][CH:11]=1)C=O)[CH3:2].[OH-].[Na+].[N+:24](C)([O-:26])=[O:25].Cl>O>[CH2:1]([O:3][C:4]1[C:5]2[B:13]([OH:14])[O:17][CH:16]([CH2:19][N+:24]([O-:26])=[O:25])[C:6]=2[C:9]([F:12])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(C=O)c1B1OC(C)(C)C(C)(C)O1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(F)c2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 118.8 %

Procedure:
3-Ethoxy-6-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (1.65 g, 5.61 mmol) was added to a solution of NaOH (225 mg, 5.60 mmol) in H2O (10 mL) and stirred for 10 min at RT. Added nitromethane (1.03 g, 16.83 mmol) dropwise and stirred for 4 h at RT. The reaction mixture was acidified with 4N HCl and extracted with ethyl acetate. Organic layer was washed with water, brine and dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography with 10 to 40% EtOAc/hexanes afforded 1.7 g of a mixture of compounds by 1H NMR spectrum. This mixture was used in next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.13 (t, J=8.8 Hz, 1H), 6.79 (dd, J=8.8, 2.5 Hz, 1H), 5.95 (d, J=9.0 Hz, 1H), 5.14 (s, 1H), 5.01 (dd, J=13.3, 2.3 Hz, 1H), 4.44 (dd, J=13.3, 9.0 Hz, 1H), 4.10 (q, J=6.8 Hz, 2H), 1.45 (t, J=6.8 Hz, 3H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −131.00-−130.97 (m, 1F).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.[H-].[Na+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:27])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (440 mg, 2.00 mmol) in anhydrous THF (40 mL) was added NaH (160 mg, 4.00 mmol). The reaction was stirred for 10 minutes at room temperature. Then, tert-butyl-bromoacetate was added and the mixture was stirred for 18 h at room temperature. Then, extracted with ethyl acetate (4×20 mL) and the organic layers were washed with an aqueous saturated solution of NaCl (3×20 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. Flash chromatography of the residue on silica gel (SiO2, hexane:ethyl acetate, 9:1) afforded 96.3 mg of tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate as a white solid (74% yield). RMN1H (CDCl3, 400 MHz): δ: 7.86-7.59; (m, 2H), 6.95-6.78; (m, 2H), 4.53; (s, 2H), 1.33; (s, 12H) ppm.