Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:13]([I:14])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH2:15][CH3:16])[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[C:13]([I:14])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH2:15][CH3:16])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CCc1cc(C2CC2)c(I)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(C2CC2)c(I)cc1C(=O)O
Temperature: 60 °C
Reaction time: 15 h
Yield: 91.9 %

Procedure:
To a solution of methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate (compound 226.4, 2.50 g, 7.57 mmol, 1.00 equiv) in methanol (40 mL) was added aqueous sodium hydroxide (3.10 g, 77.5 mmol, 10.0 equiv, in 10 mL water). The resulting mixture was stirred for 15 h at 60° C. in an oil bath. After cooling to ambient temperature, the organic solvent was removed under reduced pressure and pH of the remaining aqueous layer was adjusted to 4 with hydrogen chloride (aq, 1 M). The solids were collected by filtration and dried in an oven under reduced pressure to yield 2.20 g (92%) of 4-cyclopropyl-2-ethyl-5-iodobenzoic acid as a white solid.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:19]=[CH:18][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2].C(O)(=O)C.[B-].[Na+].O>CS(C)=O.C(OCC)C.C(OCC)(=O)C>[N+:1]([CH2:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Agent: [B-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 49 %

Procedure:
To a solution of 2-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine described in Manufacturing Example 230-1-3 (30.8 g, 120 mmol) and acetic acid (7.4 mL) in dimethyl sulfoxide (150 mL) was added sodium borohydrate (2.45 g, 64.8 mmol) at 30° C. or below. The reaction solution was stirred for 40 minutes at room temperature. Water, ethyl acetate and diethyl ether were added to the reaction solution at 30° C. or below, which was partitioned into aqueous and organic layers. The aqueous layer was extracted with ethyl acetate. The previously obtained organic layer and the ethyl acetate layer were combined, washed with water (3 times) and aqueous sodium chloride (once), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (15.2 g, 49%).
Reaction SMILES: C(#N)C.[S:4]([NH2:14])(=[O:13])([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O>[C:22]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([S:4]([NH2:14])(=[O:13])=[O:5])=[CH:11][CH:10]=1)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a mixture of 200 ml of acetonitrile, 50 g of sulfanilamide, and 30 g of triethylamine was added dropwise 35 g of pivaloyl chloride at 50° C. They were then stirred for 30 minutes and the resulting suspension was poured into 1.5 l of water. The thus formed crystals were separated by filtration to yield 68 g of p-pivaloylaminobenzenesulfonamide (m.p., 219°-220° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C1NCCCCC1NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 62.8 %

Procedure:
4-Chloro-N-(2-oxo-azepan-3-yl)-benzenesulfonamide (1.21 g, 4.00 mmol), 4-(bromomethyl)-benzonitrile (0.79 g, 4.00 mmol), potassium carbonate (5.58 g, 40.0 mmol) and potassium iodide (0.13 g, 0.80 mmol) in 200 ml dimethylformamide were stirred at 65° C. for 16 hours. Extraction with water/ethylacetate and chromatography on silicagel with ethylacetate yielded 1.05 g (63%) 4-chloro-N-(4-cyano-benzyl)-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=418.1 (MH+, 100).
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)=[O:28])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[OH-].[Li+]>C(O)C.O>[CH:23]1([C:21]([N:18]2[CH2:17][CH2:16][CH:15]([CH:14]([NH:26][C:27]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:40])([F:38])[F:39])=[CH:34][CH:35]=3)=[O:28])[C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:42])=[O:2])=[O:41])=[CH:9][CH:10]=3)[CH2:20][CH2:19]2)=[O:22])[CH2:24][CH2:25]1
Reactant: COC(=O)CCNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCN(C(=O)C3CC3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCN(C(=O)C3CC3)CC2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The above 3-{4-[1-(1-cyclopropanecarbonylpiperidin-4-yl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic acid methyl ester (0.17 g, 0.28 mmol) was dissolved in 10 mL ethanol and hydrolysed by adding lithium hydroxide (14 mg, 0.56 mmol) dissolved in water (1 mL). The mixture was stirred at 50° C. for 2 hours. The solvent was evaporated and water (25 mL) was added to the mixture followed by HCl (1 N) adjusting pH to 3-4 allowing the title compound to be isolated as a precipitate.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[C:18]([O:20]CC)=[O:19].CO.[OH-].[Li+]>C1COCC1.O>[C:14]([O:13][C:11]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:23])([CH3:1])[CH:3]1[C:18]([OH:20])=[O:19])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)C1N(C(=O)OC(C)(C)C)c2ccccc2C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1c2ccccc2C(C)(C)C1C(=O)O
Temperature: 50 °C
Yield: 96.4 %

Procedure:
To a solution of 1-tert-butyl 2-ethyl 3,3-dimethylindoline-1,2-dicarboxylate (0.25 g, 783 μmol, Eq: 1.00) in THF (3.2 mL)/MeOH (1.8 mL) was added lithium hydroxide (126 mg, 5.26 mmol, Eq: 6.72) dissolved in water (1 mL) and the resulting suspension was heated at 50° C. for 36 h. The reaction mixture was concentrated in vacuo and then the residue was taken up in water and washed with diethyl ether. The aqueous layer was then carefully acidified to pH˜3 with 1 M aqueous HCl and extracted with EtOAc. The combined organic layers were concentrated in vacuo to give 1-(tert-butoxycarbonyl)-3,3-dimethylindoline-2-carboxylic acid as a white foam (220 mg), m/z=292 (M+H).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:28])=O>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:28])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature suspension of 15 g of product from Example 2, 160 ml methylene chloride and 5 drops dimethylformamide is added 5.87 ml oxalyl chloride. The reaction mixture is stirred at room temperature for 18 hours, concentrated in vacuo, dissolved in 300 ml of diethyl ether, filtered through diatomaceous earth and the filtrate concentrated in vacuo to give 15.5 g of the desired product.
Reaction SMILES: C1(OC([N:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=3[F:25])[CH2:14][C:13](=[O:26])[CH:12]=[C:11]2[C:27]([O:29][CH3:30])=[O:28])=O)C=CC=CC=1.C[O-].[Na+]>CO>[CH3:30][O:29][C:27]([C:11]1[NH:10][CH:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[CH2:14][C:13](=[O:26])[CH:12]=1)=[O:28]
Reactant: COC(=O)C1=CC(=O)CC(c2ccc(Cl)c(OC)c2F)N1C(=O)Oc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=CC(=O)CC(c2ccc(Cl)c(OC)c2F)N1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
6-(4-Chloro-2-fluoro-3-methoxyphenyl)-4-oxo-5,6-dihydro-4H-pyridine-1,2-dicarboxylic acid 2-methyl ester 1-phenyl ester (15; 7.213 g, 0.0166 mol) was slurried in MeOH (80 mL). The suspension was cooled in an ice bath, and solid sodium methoxide (NaOMe; 1.08 g, 0.02 mol) was added. After 1 h, the reaction was quenched with saturated aqueous NH4Cl solution (80 mL) and H2O (50 mL) and then cooled in ice. The precipitate was filtered, washed with H2O followed by cold MeOH and dried in air to give 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (16; 4.93 g, 94%) as a white powder: mp 164.9-166.2° C.; 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, JF-H=1.8 Hz, JH-H=8.7 Hz, 1H, aromatic), 7.10 (dd, JF-H=6.9 Hz, JH-H=8.7 Hz, 1H, aromatic), 5.84 (d, J=0.9 Hz, 1H, H3), 5.68 (br s, 1H, NH), 5.10 (t, J=9.3 Hz, 1H, H6), 3.98 (d, JF-H=1.5 Hz, 3H, OMe), 3.91 (s, 3H, CO2Me), 2.71 (d, J=9 Hz, 2H, H5); 13C{1H} NMR (75.4 MHz, CDCl3) δ 193.0 (C4), 163.6 (CO2Me), 153.8 (d, JF-C=251 Hz, C2′), 147.9 (C2), 144.6 (d, JF-C=13 Hz, C3′), 128.6 (d, JF-C=3 Hz, C1′/C4′), 126.8 (d, JF-C=11 Hz, C1′/C4′), 125.5 (d, JF-C=3 Hz, C5′), 121.5 (d, JF-C=4 Hz, C6′), 102.0 (C3), 61.6 (d, JF-C=5 Hz, OMe), 53.4, 50.8, 42.0; HRMS-ESI (m/z): calcd for C14H13ClFNO4, 313.0512. found, 313.0511. Anal. Calcd for C14H13ClFNO4: C, 53.60; H, 4.18; N, 4.46. Found: C, 53.30; H, 4.14; N, 4.35.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]#[C:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])([OH:9])[CH2:5][CH2:4]1.I[C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C(=O)([O-])[O-].[Na+].[Na+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-2](Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:27][N:2]([CH3:1])[C:3]1([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:32]3[C:30](=[CH:29][CH:35]=[CH:34][CH:33]=3)[NH:31][C:14]=2[Si:15]([CH2:18][CH3:19])([CH2:20][CH3:21])[CH2:16][CH3:17])([OH:9])[CH2:5][CH2:4]1
Reactant: CC[Si](C#CCCCC1(O)CCC(c2cccs2)(N(C)C)CC1)(CC)CC
Reactant: Nc1ccccc1I
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-2](Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC[Si](CC)(CC)c1[nH]c2ccccc2c1CCCC1(O)CCC(c2cccs2)(N(C)C)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 4-dimethylamino-4-(thiophen-2-yl)-1-(5-(triethylsilyl)pent-4-inyl)cyclohexanol (3.00 g, 7.4 mmol), 2-iodoaniline (1.94 g, 8.9 mmol), [1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene]-(3-chloropyridyl)palladium(II)-chloride (PEPPSI, 503 mg, 0.74 mmol) and sodium carbonate (3.92 g, 37 mmol) was evacuated for 30 min (oil pump). It was then flushed with argon and absolute N,N-dimethylformamide (10 mL, previously flushed for 1 h with argon) was added by syringe via a Schlenk tube. The reaction mixture was stirred for 18 h at 100° C. and changed colour to dark brown during this. The reaction mixture was then concentrated to low volume in a vacuum, the residue taken up several times in toluol (3×30 mL) and concentrated to low volume again in each case. The residue was distributed between water and ethyl acetate (100 mL each), the phases were separated and the aqueous phase extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with 1 M sodium thiosulphate solution and saturated sodium chloride solution (50 mL each), dried with sodium sulphate and concentrated to low volume in a vacuum. The residue (4.40 g) was purified by means of flash chromatography (200 g, 20×5.7 cm) with dichloromethane/methanol (95:5).
Reaction SMILES: BrC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[Br:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1>C1(C)C=CC=CC=1.C(O)C>[Br:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1.[Br:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=1)[C:40]([NH:42][C:43]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[CH:27][CH:28]=1)=[S:44])=[O:41]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccc(Br)c1
Agent: O=C(N=C=S)c1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Br)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
3-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (67 mg, yield 74%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Br:12])[C:3]=1N.C(O)(C)C.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Br:12])[CH:3]=1
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cc(Br)c1
Yield: 99 %

Procedure:
296 parts of 2,6-dibromo-4-nitro-aniline are introduced into 400 parts of isopropanol and 750 parts of water and 130 parts of concentrated sulfuric acid (98 percent strength by weight) are then added to the mixture. A solution of 105 parts of NaNO2 in 150 parts of water is run in at 70° C. as described in Example 1. The mixture is cooled, 300 parts of water are added and the product is filtered off. 278 parts of 3,5-dibromo-nitro-benzene (99% of theory), of melting point 102°-104° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:13]([C:4]1[CH:5]=[N:6][C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[C:2]([CH3:1])[CH:3]=1)[CH3:14])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(-n2cccn2)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1-n1cccn1
Yield: 79 %

Procedure:
The title compound is prepared in 79% yield (1.11 g, colorless oil) from 1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanone (920 mg, 4.57 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (665 mg, 5.49 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([OH:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].CCN(CC)CC>C(Cl)Cl>[F:1][C@H:2]1[C@H:8]([O:9][S:26]([C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)CC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
trans-tert-butyl 4-fluoro-5-hydroxyazepane-1-carboxylate (12.36 g, 52.98 mmol) was dissolved in CH2Cl2 (110 mL). The solution was cooled to 0° C., 4-nitrobenzene-1-sulfonyl chloride (14.09 g, 63.58 mmol) was added and the mixture was stirred for 10 minutes. NEt3 (11.08 mL, 79.48 mmol) was added and the mixture was slowly warmed to ambient temperature over 1 hour and stirred for an additional 2 hours. The mixture was diluted with CH2Cl2 and washed with water followed by 1N KHSO4 (2×50 mL), then with saturated aqueous NaHCO3 (50 mL) and brine, and the combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (10 to 70% MTBE/hexanes) to provide 18.4 g of the product (84%) as a single isomer and as a faint orange powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([NH:41]C(OC(C)(C)C)=O)=[CH:37][CH:36]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C(O)(C(F)(F)F)=O>CO>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][CH2:31][C:25]2[S:24][C:23]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[C:13]([C:11](=[O:12])[NH:10][C:2]5[S:1][C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=6[N:3]=5)[CH:14]=[CH:15][CH:16]=4)[CH2:21]3)=[N:27][C:26]=2[C:28]([OH:30])=[O:29])=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound 5-(3-(4-aminophenoxy)propyl)-2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylic acid (6) was prepared by the following procedure: To 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(tert-butoxycarbonylamino)phenoxy)propyl)thiazole-4-carboxylic acid (4) (20 mg, 0.029 mmol) in MeOH (1 mL) was added TFA (1 mL, 13 mmol) and stirred at rt for 2 hours. The reaction mixture was purified by HPLC (Preparative reverse phase HPLC was performed on an automated Gilson HPLC system, using a SymmetryPrep Shield RP18 prep cartridge, 250 mm×21.20 mm i.d., 10 um, and a flow rate of 25 mL/min; λ=214, 245 nm; mobile phase A, 0.1% TFA in H2O; mobile phase B, CH3CN; linear gradient 0-70% of B in 40 minutes) to provide the desired product 5-(3-(4-aminophenoxy)propyl)-2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylic acid in 48% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (1H, s), 9.04 (1H, s), 8.03 (1H, d), 7.79 (1H, d), 7.67 (1H, d), 7.47 (2H, m), 7.37 (2H, m), 7.09 (2H, d), 6.92 (2H, m), 4.83 (2H, s), 3.95 (2H, t), 3.72 (2H, t), 3.17 (2H, m), 3.03 (2H, t), 1.99 (2H, m). MS (ESI(+)): m/z 586 (M+H).
Reaction SMILES: [Cl:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].[C:17]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25]Br)([CH3:20])([CH3:19])[CH3:18]>C(#N)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:17]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25][N:6]1[CH:5]=[C:4]([C:7]#[N:8])[C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:2]1[Cl:1])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: N#Cc1c[nH]c(Cl)c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCn1cc(C#N)c(-c2ccccc2)c1Cl
Yield: 77.3 %

Procedure:
To a solution of 51.6 g (254 mmol) of 5-chloro-4-phenyl-1H-pyrrole-3-carbonitrile in 400 ml of acetonitrile are added 20.4 g (509 mmol) of finely ground sodium hydroxide and 3.46 g (10.2 mmol) of tetrabutylammonium hydrogen sulfate, and the mixture is stirred vigorously for a few minutes, followed by adding 68.5 g (255 mmol) of tert-butyl(2-bromo-ethyl)carbamate (CAS 39684-80-5), and the mixture is then stirred for 4 hours at reflux. [After cooling, the solvent is evaporated off under reduced pressure, the residue is taken up in water and the product is extracted with ethyl acetate.] The organic phase is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 67.9 g of tert-butyl{2-[2-chloro-4-cyano-3-phenyl-1H-pyrrol-1-yl]ethyl}carbamate in the form of a white powder after recrystallizing from acetonitrile, filtering off and drying.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1[CH2:50][CH2:49][CH2:48][C@H]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][C@H:36]([CH3:37])[C:49]([CH3:48])([CH3:50])[CH3:2])[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: NC[C@@H]1CCCO1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN[C@H](C)C(C)(C)C)c4)cc23)CC1
Yield: 43.6 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (2R)-3,3-dimethyl-2-butanamine (52 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 24.9 mg of the title compound (43.6%).
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([OH:23])=[CH:15][CH:14]=1)(=[O:3])[CH3:2].[Br:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:23][CH2:26][CH2:25][Br:24])=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: BrCCBr
Reactant: CC(=O)c1c(-c2ccc(O)c3ccccc23)oc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1c(-c2ccc(OCCBr)c3ccccc23)oc2ccccc12

Procedure:
To a solution of 11.9 g. (0.039 mol.) of 3-acetyl-2-(4-hydroxynaphthyl)benzofuran in 400 ml. of 2-butanone was added 100 ml. (0.24 mol.) of 1,2-dibromoethane and 22 g. (0.16 mol.) of anhydrous potassium carbonate. The reaction mixture was refluxed for 8 hours, then the solvent was evaporated and the excess 1,2-dibromoethane was removed by distillation in vacuo. The residue was chromatographed on silica with 10% hexane in methylene chloride as eluant to give 3-acetyl-2-[4-(2-bromoethoxy)naphthyl]benzofuran, m.p. 115°-117°.