Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[C:9]2[C:10]([NH:15]C(=O)C(C)(C)C)=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[NH2:15][C:10]1[C:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:22])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ncccc1C(O)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
To a solution of N-{3-[(4-fluoro-phenyl)-hydroxy-methyl]-pyridin-2-yl}pivalamide (890 mg, 2.94 mmol) in ethanol (44 mL) was added 2 N aqueous sodium hydroxide solution (7.36 mL, 14.7 mmol). The reaction was heated to 100° C. for 5 hours. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield the title compound as a as a light yellow solid (548 mg, 85%) without further purification.
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]([CH:31]=[O:32])=[C:29]([CH:33]([CH3:35])[CH3:34])[CH:28]=[C:27]3[C:22]=2[C:23](=[O:38])[CH2:24][C:25]([CH3:37])([CH3:36])[O:26]3)=[CH:17][CH:16]=1.FC1C=CC(C2C(C=O)=C(CCC)C=C3C=2C(=O)CC(C)(C)O3)=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]([CH:31]([OH:32])[C:3]3[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)=[C:29]([CH:33]([CH3:34])[CH3:35])[CH:28]=[C:27]3[C:22]=2[C:23](=[O:38])[CH2:24][C:25]([CH3:36])([CH3:37])[O:26]3)=[CH:17][CH:16]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC(C)(C)O2
Reactant: FC(F)(F)Oc1ccc([Mg]Br)cc1
Agent: CCCc1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC(C)(C)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 0.75 h

Procedure:
At −78° C., 2.35 ml (1.19 mmol) of a freshly prepared 0.5 M solution of bromo[4-(trifluoromethoxy)phenyl]magnesium in tetrahydrofuran are slowly added dropwise to a solution of 338 mg (990 μmol) of a 2:1 mixture of rac-5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 20A) and rac-5-(4-fluorophenyl)-7-n-propyl-2,2-dimethyl-4-oxochroman-6-carbaldehyde in 8 ml of tetrahydrofuran. The mixture is then allowed to thaw slowly to −20° C. and stirred at this temperature for 45 min. 10% strength sodium bicarbonate solution is then added, the mixture is extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. The organic phases are dried over magnesium sulfate, the solvent is then removed under reduced pressure and the residue is purified by preparative HPLC (method 1).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[O:3]1.C(N(CC)CC)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:6]2[CH2:5][C:4]3([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)[O:3][CH:2]2[CH3:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: CC1NCC2(CCN(C)CC2)O1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1OC2(CCN(C)CC2)CN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
2,8-Dimethyl-1-oxa-3,8-diaza-spiro[4.5]decane (1.42 g, 8.38 mmol) was dissolved in dry dichloromethane (5 ml) under argon atmosphere. Distilled triethylamine (1.75 ml, 12.57 mmol) was added and the resulted solution was cooled to 0° C. p-Fluorobenzenesulfonyl chloride (1.63 gr, 8.37 mmol) was added and the reaction flask was allowed to warm to room temperature with stirring, and a white solid started to precipitate. After 30 min of stirring, dichloromethane (90 ml) was added and the resulting solution was washed with water (2×10 ml). The organic phase was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 140/10/1) to give AF715 (1.23 g, 98.7% chemical purity) as an off-white powder. 1H NMR. (CDCl3, 500 MHz) δ 7.89-7.87 (m, 2H, CHCSO2), 7.27-7.22 (m, 2H, CHCF), 5.05 (q, J=5.23, 1H, CHCH3), 3.33 (d, J=10.26 Hz, 1H, CHHNS), 3.19 (d, J=10.26 Hz, 1H, CHHNS), 2.52-2.42 (m, 114), 2.34-2.25 (m, 2H), 2.23 (s, 3H, NCH3), 2.18-2.09 (m, 1H), 1.77-1.72 (m, 2H), 1.52 (d, J=5.23 Hz, 3H, CH3CH), 1.25-1.18 (m, 1H), 1.10-1.03 (m, 1H) ppm; 13C NMR (CDCl3, 500 MHz) δ 166.45 and 164.42 (C), 134.0 (C), 130.37 (CH), 130.29 (CH), 116.68 (CH), 116.50 (CH), 86.95 (CH), 66.30 (C), 55.48 (CH2), 52.57 (CH2), 52.11 (CH2), 46.04 (CH3), 35.64 (CH2), 32.84 (CH2), 22.95 (CH3) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[NH:10][CH2:9]2)=[CH:4][C:3]=1[C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1.[C:21]([C:23]1[N:24]=[C:25]([C:36](O)=[O:37])[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=1)#[N:22].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N>>[C:15]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][NH:10][C:11](=[O:14])[NH:12][CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:36]([C:25]2[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=[C:23]([C:21]#[N:22])[N:24]=2)=[O:37])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Reactant: Nc1ccc(C2CNC(=O)NC2)cc1C1=CCCCC1
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNC(=O)NC2)cc1C1=CCCCC1

Procedure:
5-(4-Amino-3-cyclohex-1-enyl-phenyl)-tetrahydro-pyrimidin-2-one (22 mg, as prepared in the previous step) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d), 27.2 mg, 0.0890 mmol) as described in Example 1, step (1) to obtain the title compound (14 mg, over two steps) after purification on silica (3% MeOH-EtOAc): Mass spectrum (ESI, m/z): Calcd. for C27H36N6O3Si, 521.2 (M+H). found 521.1.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:18]1.C(O)(=O)C(O)=O.S1C2C=CC=CC=2C(N2CCN(CCCC(C3SC4SCCNC(=O)C=4C=3)=O)CC2)=N1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:29]3[CH2:30][CH2:31][N:26]([C:19]4[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[S:17][N:18]=4)[CH2:27][CH2:28]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCl)C1
Agent: O=C(CCCN1CCN(c2nsc3ccccc23)CC1)c1cc2c(s1)SCCNC2=O
Agent: O=C(O)C(=O)O
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCN(c3nsc4ccccc34)CC2)C1
Yield: 58.5 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 14 using 1.0 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.88 g of 1-(1,2-benzoisothiazol- 3-yl)piperazine to give 1.0 g of 6-acetyl-3-(2-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 190°-192° C. (decomposition) as an oxalate 1/2 hydrate thereof.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:20])([CH3:19])[C:13]=2[CH:21]=1.[Cl:22][C:23]1[CH:24]=[C:25]([SH:30])[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:20])([CH3:19])[C:13]=3[CH:21]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCCBr)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(6-bromohexyloxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichlorothiophenol.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:29])[C:20]3[O:24][C:23]([C:25](O)=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].C(Cl)CCl.Cl.[CH3:39][NH:40][CH3:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][N:40]([CH3:41])[C:25]([C:23]1[O:24][C:20]2[C:19]([CH3:29])=[CH:18][C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:31])[C:2]([CH3:33])([CH3:32])[CH3:1])=[C:7]([CH3:30])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:28][C:21]=2[CH:22]=1)=[O:26]
Reactant: CNC
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)O)cc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)N(C)C)cc2c1
Yield: 97.9 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carboxylic acid (270 mg, 0.599 mmol) in CH2Cl2 (10 mL) and DMAP (220 mg, 1.80 mmol), EDC (172 mg, 0.898 mmol), and dimethyl amine hydrochloride (73 mg, 0.90 mmol) are reacted analogous to Example 5 to yield title compound (280 mg, 98%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)=[CH:4][CH:3]=1.[C:22]([Zn]C#N)#[N:23]>CN(C=O)C>[CH3:8][C:6]1[N:7]=[C:2]([C:22]#[N:23])[CH:3]=[CH:4][C:5]=1[C:9]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][NH:13]2
Reactant: N#C[Zn]C#N
Reactant: Cc1nc(Cl)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Solvent: CN(C)C=O
Product: Cc1nc(C#N)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Temperature: 120 °C
Reaction time: 24 h
Yield: 34 %

Procedure:
A mixture of 4-(6-chloro-2-methylpyridin-3-yl)-6-(trifluoromethyl)-1H-indazole (0.97 g, 3.11 mmol), dicyanozinc (1.462 g, 12.45 mmol), and tetrakis(triphenylphoshine)palladium(0) (0.360 g, 0.311 mmol) in DMF (15 mL) was thoroughly degassed by nitrogen and stirred at 120° C. for 24 hours. The reaction mixture was subsequently cooled and diluted with EtOAc then washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by CombiFlash® chromatography, eluting with a gradient of 0-100% EtOAc in hexane. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a white solid (0.32 g, 34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39 (s, 3H), 7.45 (d, J=1.01 Hz, 1H), 7.90-8.16 (m, 4H), 13.81 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C15H9F3N4, 303.1. found 303.18.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:16][NH2:17])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:18]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:28]=O)[C:22]=2[CH:21]=[CH:20][N:19]=1.CC(O)=O>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:16]/[N:17]=[CH:28]/[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:22]=2[CH:21]=[CH:20][N:19]=[CH:18]3)=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cccc2cnccc12
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)NN)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)c1ccc(C2CC2C(=O)N/N=C/c2cccc3cnccc23)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a room temperature solution of 2-(4-tert-butylphenyl)cyclopropanecarbohydrazide (200 mg, 0.86 mmol) in ethanol (10 mL) were added isoquinoline-5-carbaldehyde (162 mg, 1.0 mmol) and a catalytic amount of glacial AcOH (0.4 mL) under an inert atmosphere. The reaction mixture was then stirred at 90° C. for 4 h, concentrated in vacuo, and the residue was then dissolved in DCM (50 mL). The organic layer was washed with saturated NaHCO3 solution (15 mL) and brine (15 mL). The organic layer was then separated, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 1% MeOH in dichloromethane to afford (E)-2-(4-tert-butylphenyl)-N′-(isoquinolin-5-ylmethylene) cyclopropanecarbohydrazide (160 mg, 50%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 11.60 (s, 1H), 9.38 (s, 1H), 8.71-8.56 (m, 2H), 8.25-8.12 (m, 2H), 8.11-7.99 (m, 2H), 7.39-7.29 (m, 2H), 7.19-7.06 (m, 2H), 2.41-2.33 (m, 1H), 1.95-1.90 (m, 1H), 1.42-1.34 (m, 2H), 1.25 (s, 9H). MS: M m/z=372.2 HPLC: 96%, (Condition-A).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH3:11]I>CCCCCC.CN(C)C=O>[CH3:11][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: CI
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To sodium hydride (50% oil dispersion, 43.2 g, 21.6 g of active NaH, 900 mmol), prewashed in dry hexane, in 800 ml of dimethylformamide (DMF) is added 5-hydroxy-2-methylpyridine (98.8 g, 906 mmol) in 700 ml of DMF at 15° and over 0.75 hour. The reaction is allowed to warm to RT and is stirred for 2 hours. It is then cooled to 10°, and methyliodide is added over 0.5 hour. The reaction is again allowed to warm to RT and is stirred overnight. It is then filtered through celite, and the solid is washed with chloroform, filtered and rotoevaporated. The resulting solid is washed with chloroform 3X, and is stirred with chloroform overnight. It is filtered and rotoevaporated, after which ether is added, followed by 10% sodium hydroxide and water. The mixture is extracted with ether (3X). The combined ether extracts are washed with water and with brine, dried over calcium sulfate, filtered and rotoevaporated to give 5-methoxy-2 -methylpyridine.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].[OH-].[K+].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[S:18]>O.C1COCC1.[OH-].[Na+]>[C:2]([C:4]1[CH:12]=[CH:11][C:9]([O:10][C:17](=[S:18])[N:16]([CH3:20])[CH3:15])=[C:6]([O:7][CH3:8])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CN(C)C(=S)Cl
Reactant: COc1cc(C(C)=O)ccc1O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(C)=O)ccc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of acetovanillone (8.31 g, 50 mmol) and 2.81 g KOH (50 mmol) in H2O (34 mL), at 0°, is added a solution of dimethylthiocarbamoyl chloride (8.28 g, 67 mmol) in THF (14 mL), dropwise, at such a rate as to keep the reaction temperature below 12°. The reaction mixture is warmed to room temperature, and stirred for 30 minutes. It is then diluted with 1 N NaOH (100 mL) and extracted with EtOAc (3×80 mL). The combined organic phase is washed with H2O (1×100 mL) and brine (1×50 mL), dried over MgSO4, and concentrated in vacuo to give dimethylthiocarbamic acid O-(4-acetyl-2-methoxy-phenyl) ester. To a thick walled pyrex tube is aded dimethylthiocarbamic acid O-(4-acetyl-2-methoxy-phenyl) ester (9.81 g, 38.77 mmol). The tube is flushed with nitrogen, sealed, and then heated to 250° for 1 hour. After cooling, the residue is chromatographed (silica gel, 1:1 EtOAc/hexane) to yield dimethylthiocarbamic acid S-(4-acetyl-2-methoxy-phenyl) ester.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([CH2:38][CH2:39]Br)=[CH:36][CH:35]=1)([O-:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[C:24]([CH2:23][N:16]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:22][CH2:21][CH2:20][N:19]([CH2:39][CH2:38][C:37]2[CH:36]=[CH:35][C:34]([N+:31]([O-:33])=[O:32])=[CH:42][CH:41]=2)[CH2:18][CH2:17]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)CN1CCCNCCN(CC(=O)OC(C)(C)C)CCCNCC1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN1CCCN(CCc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OC(C)(C)C)CCCNCC1
Yield: 68.4 %

Procedure:
A solution of compound (5) (1.37 g, 3.19 mmol), 4-nitrophenethyl bromide (1.47 g, 6.38 mmol), anhydrous K2CO3 (1.32 g, 9.57 mmol) and KI (1.59 g, 9.57 mmol) dissolved in dry toluene (150 ml) was stirred under reflux for 24 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and CH2Cl2 (250 ml) was added thereto. The resultant brown slurry was filtered through a celite pad, and washed with CH2Cl2 (2×30 ml). The solvent was evaporated from the combined filtrate under reduced pressure. The residue thus obtained was purified via alumina (basic) column chromatography using EtOAc/methanol (10:2) as an eluent to provide compound (8) as a yellow oil (1.26 g, 68% yield). 1H NMR (500 MHz, CDCl3): δ 8.07-8.06 (dd, 2H), 7.35-7.33 (dd, 2H), 3.23-3.20 (dd, 4H), 2.97 (brs, 4H), 2.87-2.82 (m, 4H), 2.71-2.51 (m, 12H), 1.88 (brs, 2H), 1.61 (brs, 2H), 1.39-1.37 (dd, 18H); 13C NMR (125 MHz, CDCl3): δ 170.7, 170.5, 148.6, 146.3, 129.5, 123.5, 81.3, 81.1, 55.7, 55.3, 55.0, 52.5, 52.0, 50.2, 49.5, 48.4, 46.1, 32.0, 28.1, 24.4, 24.3, 23.2; HRMS (FAB) calculated for C30H52N5O6: 578.3918 [(M+H)+], measured value: 578.3915 [(M+H)+].
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(OC([N:46]1[C:54]2[C:49](=[CH:50][C:51]([O:55][CH3:56])=[CH:52][CH:53]=2)[CH:48]=[C:47]1B(O)O)=O)(C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:47]1[NH:46][C:54]2[C:49]([CH:48]=1)=[CH:50][C:51]([O:55][CH3:56])=[CH:52][CH:53]=2)(=[O:21])=[O:20])(=[O:29])=[O:30]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Reactant: COc1ccc2c(c1)cc(B(O)O)n2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(-c3n[nH]c4ccc(NS(=O)(=O)c5ccccc5S(C)(=O)=O)cc34)cc2c1
Yield: 19.3 %

Procedure:
2-Methylsulfonyl-N-[3-(5-methoxy-1H-indol-2-yl)-1H-indazol-5-yl]benzenesulfonamide can be obtained as described in Example 47 from 1.77 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)-indazole-1-carboxylate, 1.52 g 1-(tert-butoxycarbonyl)-5-methoxy-indole-2-boronic acid, 70 ml of dimethyl-formamide, 5.65 ml of a saturated aqueous sodium hydrogencarbonate solution and 151 mg of tetrakis(triphenylphosphine)palladium[0]. 250 mg of 2-methylsulfonyl-N-[3-(5-methoxy-1H-indol-2-yl)-1H-indazol-5-yl]benzenesulfonamide are thus obtained in the form of an amorphous cream solid (LC/MS analysis: Tr 3.52 minutes MH+=497).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([O:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7](=[O:19])[CH2:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([CH:8]2[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([O:20][C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]2=[O:19])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: O=C(CS(=O)(=O)c1ccc(F)cc1)N(CCCCBr)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C(S(=O)(=O)c2ccc(F)cc2)CCCCN1OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
N-(4-Bromo-butyl)-2-(4-fluoro-benzenesulfonyl)-N-trityloxy-acetamide prepared from step E (170.2 mg, 0.279 mmol) and Cs2CO3 (187.3 mg, 0.575 mmol) in anhydrous DMF (6 mL) was stirred at room temperature for overnight.). The reaction mixture was diluted with EtOAc and washed sequentially with water and saturated NaCl solution. The organic phase was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to gave a crude material, which was then purified by a column chromatography (0˜30% EtOAc in hexane). MS: 552.2 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22]O)[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9]C)[CH2:7]C)=[O:5].NC1C=CC(Br)=C2C=1[C:32](=[O:34])N(C)C2.CC1(C)C(C)(C)OB(C2C=NN(CCCCO)C=2)O1>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:32][OH:34])[CH:19]=2)=[C:11]2[C:3]=1[C:4](=[O:5])[N:6]([CH3:7])[CH2:9]2
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Reactant: CN1Cc2c(Br)ccc(N)c2C1=O
Agent: CC1(C)OB(c2cnn(CCCCO)c2)OC1(C)C
Product: CN1Cc2c(-c3cnn(CCCCO)c3)ccc(N)c2C1=O
Yield: 22 %

Procedure:
Prepared analogously to Compound 3C using 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 17D, 300 mg, 1.24 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-1-ol (Compound 14C, 364 mg, 1.37 mmol) to afford 81 mg of the title compound (22%). 1H NMR (400 MHz, CDCl3) d 7.65 (s, 1H), 7.50 (s, 1H), 7.36 (d, J=8.3 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H), 5.25 (br. s., 2H), 4.38 (s, 2H), 4.23 (t, J=7.0 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 3.18 (s, 3H), 1.98-2.08 (m, 2H), 1.60-1.66 (m, 2H) [OH obscured].
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:2][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:3])=[CH:27][CH:26]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Clc1ccc(CBr)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCc3ccc(Cl)cc3)(CC1)CC2
Yield: 61.4 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 4-chlorobenzyl bromide (21.0 mg) were used to obtain (2S,4S)-1-[[N-[4-(4-chlorobenzyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (25.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH:4][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1F
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Nc2ccccc2)c(F)cc1F
Temperature: 25 °C
Reaction time: 50 h
Yield: 90.9 %

Procedure:
A mixture of 2,4-difluoro-5-nitroaniline (3.00 g, 17.23 mmol) (see EP0379894 A3), phenylboronic acid (6.30 g, 51.69 mmol), copper(II) acetate (3.13 g, 17.23 mmol) and 4 Å molecular sieves (3.0 g) in dichloromethane (170.0 mL) and triethylamine (12.01 mL, 43.08 mmol) was placed in a round bottomed flask. The resulting suspension was stirred under at room temperature under a dry ambient atmosphere 50 h. The mixture was filtered through diatomaceous earth and the solvent was evaporated. Additional phenylboronic acid (6.30 g, 51.69 mmol), copper(II) acetate (3.13 g, 17.23 mmol), molecular sieves (3.00 g) triethylamine (12.01 mL, 43.08 mmol), and dichloromethane (170.00 mL) were added and the slurry was stirred for 12 h. The mixture was again filtered through diatomaceous earth and the solvent was evaporated. The resulting residue was re-dissolved in EtOAc, adsorbed on silica and flash chromatographed (15% EtOAc/hexanes) to give 2,4-difluoro-5-nitro-N-phenylaniline as an orange solid (3.92 g, 91% yield).