Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23]CC)=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:44]=[CH:43][C:37]2[C:38](=[O:42])[CH2:39][CH2:40][O:41][C:36]=2[C:35]=1[CH2:45][CH2:46][CH3:47])C.O.[OH-].[Li+].S(=O)(=O)(O)O.C(OCC)(=O)C>C1COCC1.O>[C:21]([C:17]1[CH:16]=[C:15]([C:13]([C:11]2[CH:10]=[CH:9][C:8]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]3[CH:44]=[CH:43][C:37]4[C:38](=[O:42])[CH2:39][CH2:40][O:41][C:36]=4[C:35]=3[CH2:45][CH2:46][CH3:47])=[C:7]([CH2:6][CH2:5][C:4]([OH:48])=[O:3])[CH:12]=2)=[O:14])[CH:20]=[CH:19][CH:18]=1)([OH:23])=[O:22]
Reactant: CCCc1c(OCCCCCCOc2ccc(C(=O)c3cccc(C(=O)OCC)c3)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 25.5 h

Procedure:
A mixture of 0.144 g (0.70 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 0.371 g (0.70 mmol) of 2-[(6-bromohexyl)oxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, 0.479 g (3.47 mmol) of anhydrous granular potassium carbonate and 13.1 mL of 2-butanone was stirred and refluxed for 18 hr. The resulting slurry was filtered with suction and the solids washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the residue was purified by flash chromatography on 75 g of silica gel, eluting with 3:1 hexane-ethyl acetate, giving 0.37 g (80.6%) of 2-[6-[(2,3-dihydro-4-oxo-8-propyl-4H-1-benzopyran-7-yl)oxy]hexyloxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester as a white solid, mp 58°-59.5° C. A mixture of 0.331 g (0.50 mmol) of this ester in 6 mL of THF and 6 mL of water was treated with 64.7 mg (1.54 mmol) of lithium hydroxide monohydrate and the resulting mixture was stirred for 25.5 hr at room temperature, before being acidified with 17 mL of 3N aqueous sulfuric acid. Work-up with ethyl acetate in the usual manner gave a crude product which was recrystallized from hexane-ethyl acetate affording 0.242 g (79.7%) of the title compound as a white solid, mp 169°-172° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:20])[C:5]([C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].ICCC[Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].O.[CH2:33]1C[O:36][CH2:35][CH2:34]1>>[Si:25]([O:36][CH2:35][CH2:34][CH2:33][O:12][C@H:10]1[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C@H:7]([C:5]([N:4]([CH3:20])[CH3:3])=[O:6])[CH2:11]1)([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:26])[CH3:27]
Reactant: C1CCOC1
Reactant: CN(C)C(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C)C(=O)[C@@H]1C[C@@H](OCCCO[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, to a suspension of 1.55 g of NaH in THF (100 ml) was added 10.0 g of tert-butyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-hydroxypyrrolidine-1-carboxylate and the reaction mixture was stirred at 50° C. for one hour. Thereafter, at the same temperature, solution of 23.2 g of (3-iodopropyl)-tert-butyl-dimethyl silane in THF (10 ml) was added, and the solution was refluxed for two hours. The solution was poured into water and the resulting mixture was extracted with EtOAc; the organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: n-hexane/EtOAc=1/1 to 0/1; v/v) to obtain 2.10 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)[C:5]([O:7]C)=[O:6].C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)CCC.[Cl-].[Li+].CN(C)C=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:14])=[O:15])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N(C)S(C)(=O)=O)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(c1cc(C(=O)O)cc(-c2ccco2)c1)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 7 h
Yield: 71 %

Procedure:
A mixture of methyl 3-bromo-5-[methyl(methylsulfonyl)amino]benzoate obtained in Reference Example 15 166 mg (0.5.0 mmol), tri-n-butyl(2-furyl)stannane 0.18 mL (0.55 mmol), lithium chloride 42 mg (0.10 mmol), tetrakistriphenylphosphine palladium(0) 29 mg (0.025 mmol) and N,N-dimethylformamide (1.5 mL) was stirred at 100° C. under argon atmosphere for 7 hours. The mixture was diluted with a mixed solvent of ethyl acetate/toluene=1:1 and washed twice with water. After drying of the mixture on magnesium sulfate, the mixture was concentrated and the residual oil was purified by a column chromatography on silica gel (eluted with hexane/ethyl acetate=2:1→1:1). The resulting solid was dissolved in a mixture of 2N aqueous sodium hydroxide solution (2 mL), methanol (2 mL) and tetrahydrofuran (2 mL) and the mixture was stirred at room temperature for 15 hours. The solvent was concentrated and thereto added water and the mixture was washed with a mixed solvent of hexane/ethyl acetate=1:1. The aqueous layer was adjusted by adding 1N hydrochloric acid to pH=3 and the mixture was extracted with ethyl acetate. After drying of the mixture on magnesium sulfate, the solvent was evaporated to give 105 mg (0.355 mmol) of the title compound (yield: 71%).
Reaction SMILES: [I:1][C:2]1[C:10]2[CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6][C:5]=2[NH:4][N:3]=1.[CH3:13]C(C)([O-])C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6][C:5]=2[N:4]([CH3:13])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)CCc2[nH]nc(I)c2C1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2c1CCC(C)(C)C2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 73.5 %

Procedure:
In a round-bottomed flask, 3-iodo-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole (642 mg, 2.33 mmol) was dissolved in THF (8.5 ml). The solution was cooled to 0° C. and potassium tert-butoxide (365 mg, 3.26 mmol) was added. The reaction mixture was stirred at 0° C. for 40 min then methyl iodide (0.18 ml, 2.88 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1.5 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/Hexanes (gradient 0-15% EtOAc) to provide 497 mg (74%) of 3-iodo-1,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indazole as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.76 (s, 3H), 2.53 (t, J=6.4 Hz, 2H), 2.11 (s, 2H), 1.58 (t, J=6.6 Hz, 2H), 0.99 (s, 6H).
Reaction SMILES: C(OC([NH:8][C:9](=[CH2:14])[C:10]([O:12][CH3:13])=[O:11])=O)CCC.[SH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(Cl)(Cl)[Cl:24]>CO>[ClH:24].[NH2:8][CH:9]([CH2:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: Oc1ccc(S)cc1
Reactant: ClC(Cl)Cl
Reactant: C=C(NC(=O)OCCCC)C(=O)OC
Solvent: CO
Product: COC(=O)C(N)CSc1ccc(O)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
20 g (100 mmol; 120 ml) methyl 2-(butoxycarbonylamino)-propenoate in chloroform was dissolved in 180 ml of methanol. 13.88 g (110 mmol) 4-mercaptophenol was added and the mixture was then stirred at room temperature under nitrogen for 24 hours. Solvents were removed in vacuo until foaming occurred, then the mixture was taken up in 700 ml dry ether. HCl gas was bubbled through the solution, quickly forming a white precipitate. Bubbling was continued for 1 hour with cooling, then the solution was cooled to 5° C. and filtered to yield the title compound in 80.8% yield.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18](O)=O)[CH2:7]1)[CH:2]=[CH2:3].[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C(Cl)=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:37]1([NH2:44])[C:38]([NH2:43])=[CH:39][CH:40]=[CH:41][CH:42]=1>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:7][C@@H:8]([C:18]2[NH:44][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[N:43]=2)[N:9]([C:11](=[O:13])[CH:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccccc1N
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: C=CCON=C1C[C@@H](c2nc3ccccc3[nH]2)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 1,2-benzenediamine the title compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=451.4.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].COC[CH2:14][CH2:15][NH2:16].[C:17](=[O:20])([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:16][CH2:15][CH2:14][O:20][CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: O=C([O-])[O-]
Reactant: COCCCN
Reactant: N#Cc1c(F)cccc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCNc1cccc(F)c1C#N
Yield: 71.6 %

Procedure:
A solution of 2,6 difluorobenzonitrile (3.5 g, 25.16 mmol) in dimethylformamide (50 mL) was treated with 3-methoxypropylamine (2.24 g, 25.16 mmol) and potassium carbonate (6.94 g, 50.32 mmol). The reaction mixture was stirred over night under a nitrogen atmosphere. Water (100 mL) was added to the reaction solution. The layers were partitioned, and the aqueous layer was extracted with ethyl acetate (1.2 L). The combined organic layers were washed with water (1.5 L), dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 7:1 heptane:ethyl acetate as the eluent. The column afforded 3.5 g (68%) of 2-fluoro-6-[(2-methoxyethyl)amino]benzonitrile. 1H NMR (DMSO-d6, 400 MHz) δ 7.48-7.39 (m, 1H), 6.64-6.48 (m, 2H), 3.45-3.31 (m, 2H), 3.30-3.20 (m, 5H), 1.85-1.75 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 6.57 min (97%).
Reaction SMILES: [NH:1]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:2]([C:30]([OH:32])=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:29])[N:8]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O[N:41]1[C:46](=[O:47])[CH2:45][CH2:44][C:42]1=[O:43].CCN(C(C)C)C(C)C.C(Cl)CCl>C(Cl)Cl>[NH:1]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:2]([C:30]([O:32][N:41]1[C:46](=[O:47])[CH2:45][CH2:44][C:42]1=[O:43])=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:29])[N:8]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Reactant: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reaction time: 48 h
Yield: 86.9 %

Procedure:
To a solution of Boc-(D)-Arg(Cbz2)—OH (1 g, 1.8 mmol) in CH2Cl2 (10 mL) was added HOSu (466 mg, 4.06 mmol), DIEA (1 mL) and EDC (846 mg, 4.4 mmol). The solution was stirred for 48 h. The solvent was evaporated and residue was dissolved in EtOAc (50 mL) and water (10 mL). The separated organic layer was washed with sat. NaHCO3 (10 mL), water (10 mL), 1 M HCl (10 mL) and sat. NaCl (3×10 mL). The organic layer was dried over MgSO4, filtered and evaporated. The oily residue was either used directly in Example 4 without further purification or purified by flash column over silica gel (50% EtOAc in hexane) to give Boc-(D)-Arg(Cbz2)-OSu (1 g, 85% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[CH2:16][CH2:17][CH:18]([OH:27])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C(O)CCC>[O:20]([CH2:19][CH:18]([OH:27])[CH2:17][CH2:16][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: OC(CCCl)COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(C)O
Product: COc1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
This compound was prepared according to the procedure of Example 6. A mixture of 4.8 g (0.025 mole) of 1-(4-methoxyphenyl)piperazine, 5.0 g (0.025 mole) of 4-chloro1-phenoxy-2-butanol and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 6.4 g (72%) of tan towder., m.p. 95°-97° C. Recrystallizing solvent used was isopropyl alcohol.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH3:34])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>C(#N)C>[CH2:33]([O:32][CH2:31][C@@:13]12[CH2:12][N:11]([S:8]([C:5]3[CH:6]=[N:7][C:2]([N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:20][CH2:19][C:18]1=[CH:17][C:16]1[N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:22]=[CH:23][C:15]=1[CH2:14]2)[CH3:34]
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: C1CCNC1
Solvent: CC#N
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCCC3)nc1)C2

Procedure:
A solution of (R)-6-(6-chloropyridine-3-sulfonyl)-4a-ethoxymethyl-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene (0.013 g) and pyrrolidine (0.025 mL) in acetonitrile was heated at 100° C. in a microwave reactor for 10 minutes. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (5:1 by volume), to afford the title compound as a clear gum (0.0080 g). LCMS (Method B): 538 (M+H)+, Retention time 4.0 minutes.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]2([CH2:18][CH2:17][NH:16][CH2:15]2)[O:11]1)=O)(C)(C)C.C([O:21][C:22]([C:24]1[CH2:25][N:26]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([F:34])=[C:29]([Cl:35])[N:28]=2)=[O:23])C.C(N(CC)CC)C>N1C=CC=CC=1>[ClH:35].[ClH:35].[NH2:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]2([CH2:18][CH2:17][N:16]([C:29]3[N:28]=[C:27]4[C:32]([CH:33]=[C:24]([C:22]([OH:23])=[O:21])[CH2:25][N:26]4[C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=4[F:43])=[CH:31][C:30]=3[F:34])[CH2:15]2)[O:11]1
Reactant: CC(C)(C)OC(=O)NCC1COC2(CCNC2)O1
Reactant: CCOC(=O)C1=Cc2cc(F)c(Cl)nc2N(c2ccc(F)cc2F)C1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cl
Product: NCC1COC2(CCN(c3nc4c(cc3F)C=C(C(=O)O)CN4c3ccc(F)cc3F)C2)O1
Temperature: 45 °C
Reaction time: 6 h
Yield: 232.8 %

Procedure:
In a reaction similar to that of Step 1 Example 387, into oven-dried glassware maintained under dry N2 were placed 0.733 g (2.8 mmol) of 2-t-butoxycarbonylaminomethyl-1,4-dioxa-7-azaspiro[4.4]nonane, from Step 5 Example 159, 0.725 g (1.9 mmol) of 1-(2,4-difluorophenyl)-7-chloro-6-fluoro-1,8-naphthyridine-3-carboxylic acid ethyl ester dissolved in 20 mL of pyridine and 1.06 mL (7.6 mmol) of triethylamine. The reaction was stirred at 45° C. for 6 hours, then the solvent was removed in a rotary evaporator after toluene was added to azeotrope the pyridine. The residue was dissolved in 60 mL of methylene chloride, washed with 2×50 mL of water and dried over anhydrous sodium sulfate and filtered. The solvent was removed by evaporation and the product was washed with hexane and dried to afford 1.184 g of the title compound, MS (DCl) M/Z 605 (M+H). NMR (CDCl3) d 1.40 (t, 3H, J=6 Hz), 1.47 (s, 9H), 2.03 (m, 2H), 3.16 (m, 2H), 3.51 (m, 4H), 3.69 (m, 1H), 4.04 (m, 1H), 4.22 (m, 1H), 4.38 (q, 2H, J=6 Hz), 4.81 (m, 1H), 7.05 (m, 2H), 7.38 (m, 1H), 8.09 (dd, 1H, J=12, 1.5 Hz), 8.39 (d, 1H, J=1.5 Hz).
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][CH2:4][C:3]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH2:6]2)[CH2:2]1.C(N(CC)CC)C.[CH3:28][Si:29]([CH3:44])([CH3:43])[CH2:30][CH2:31][O:32][C:33](ON1C(=O)CCC1=O)=[O:34]>C(Cl)Cl.O>[N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][CH2:4][C:3]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:33]([O:32][CH2:31][CH2:30][Si:29]([CH3:44])([CH3:43])[CH3:28])=[O:34])[CH2:6]2)[CH2:2]1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CNc3ccccc32)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccccc12
Temperature: 25 °C
Reaction time: 22 h
Yield: 105.7 %

Procedure:
t-Butyl spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (10.0 g, 36.4 mmol) was dissolved in methylene chloride (73 mL). Thereafter, triethylamine (15.2 mL, 109 mmol) and N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (14.2 g, 54.8 mmol) were added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at room temperature for 22 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (16.1 g, quant.) in the form of a light yellow oily product.
Reaction SMILES: C([Li])CCC.C(OCC)C.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[B:18](OC)([O:21]C)[O:19]C>CCCCCC>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([B:18]([OH:21])[OH:19])[CH:13]=1
Reactant: COB(OC)OC
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of n-butyllithium (16 mL of a 2.5M solution in hexane=50 mL dry diethyl ether) at -78° C. was added a solution of 3-bromopyridine (6 g in 15 mL diethyl ether) and the mixture stirred for 25 minutes. At this time trimethyl borate (4.3 mL) was added and the mixture allowed to warm to room temperature. After 1 hour the reaction was quenched by the addition of 10 mL glacial acetic acid and 60 mL water and the mixture stirred for 18 hours at room temperature. The pH of the mixture was adjusted to pH12 by the addition of 2M sodium hydroxide and extracted with diethyl ether. The aqueous layer was acidified to pH 6 by the dropwise addition of 1N hydrochloric acid and extracted with methylene chloride. The combined organics were dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with 20 mL acetonitrile:water (1:1) and filtered to give the title compound (1.0 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([NH:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:11])[CH3:10].C([O-])(=O)C.[Na+].O>C(OC(=O)C)(=O)C.CC(C)=O>[C:9]([NH:12][C:13](=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:14]([OH:16])=[O:15])(=[O:11])[CH3:10]
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1cccnc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CC(=O)NC(=Cc1cccnc1)C(=O)O
Reaction time: 0.17 h
Yield: 23.1 %

Procedure:
Pyridine-3-carboxaldehyde (92.6 g), N-acetylglycine (86.0 g) and sodium acetate (35.3 g) were heated together under reflux in acetic anhydride (150 ml) for 1 hour. After cooling, water (250 ml) was added and the mixture was filtered to give the crude azlactone (50.9 g) m.p. 55°-60°. Partial hydrolysis of the azlactone (50 g) was achieved by heating under reflux in acetone (450 ml) and water (75 ml) for four hours. After this time the bulk of the acetone was distilled off and more water (300 ml) added. The resulting deep red solution was boiled with charcoal for 10 minutes and filtered through celite. The filtrate was evaporated to dryness and the residue was triturated and washed with acetone to give 2-acetamido-3-(3-pyridyl)acrylic acid (35 g) m.p. 191°-92° which was not further purified.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)=[O:25].O>ClCCl>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:24]([C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)=[O:25])[CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a stirred solution of 4-(4-chlorophenoxy)piperidine hydrochloride (250 mg, 1.01 mmol), and triethylamine (0.56 mL, 4.03 mmol) in dichloromethane (10 mL) was added methyl 4-(chlorocarbonyl)benzoate (220 mg, 1.11 mmol) at room temperature. After stirring at room temperature for 2 hours, the mixture was poured into water (30 mL). This was extracted with dichloromethane (30 mL) and washed with water (30 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (eluting with n-hexane/ethyl acetate=3/1) to give 329 mg (87% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.[I:13]Cl>C(Cl)(Cl)Cl>[I:13][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([NH2:12])=[C:5]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:6]=1
Reactant: Cc1ccc(S(N)(=O)=O)c(N)c1
Reactant: ClI
Solvent: ClC(Cl)Cl
Product: Cc1cc(N)c(S(N)(=O)=O)cc1I
Temperature: 0 °C
Yield: 62.1 %

Procedure:
A stirred suspension of 4-methyl-2-aminobenzenesulfonamide (620 mg; 3.3 mmol) in CHCl3 (7 ml) at 0° C. was added a solution of iodine monochloride (1.6 g; 9.9 mmol) in CHCl3 (7 ml). The reaction mixture was stirred at 0° C. until H-NMR indicated full conversion of starting material. The reaction mixture was filtered and the isolated solid washed with small volumes of CHCl3, NaHCO3 (sat. aq.), H2O and air dried to give 640 mg (62%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:14])=[O:13])[C:9]([O:25]C)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.B(Br)(Br)[Br:28]>>[BrH:28].[Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:13])=[O:14])[C:9]([OH:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: BrB(Br)Br
Reactant: COc1c(S(=O)(=O)NCCCc2ccccc2)cc(Cl)c2cccnc12
Product: Br
Product: O=S(=O)(NCCCc1ccccc1)c1cc(Cl)c2cccnc2c1O

Procedure:
The title compound is prepared from 5-chloro-8-methoxy-N-(3-phenylpropyl)-7-quinolinesulfonamide, which is the title compound of Preparation 11, and 6 equivalents of BBr3 according to the procedure described in Example 18. Crystallization from CHCl3/acetone/EtOH affords 0.063 g of the title compound as a red-brown solid.