Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]CS([O-])(=O)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:19]([NH:26][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(CCCS(=O)(=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(CCNCc2ccccc2)cc1

Procedure:
2-(4-Methanesulfonamidophenyl)ethylmethanesulfonate (XXXII) (20 g), benzylamine (7.0 g) and triethylamine (15 ml) were combined in dimethylformamide (75 ml) and heated 18 hours at 100°. The solvent was evaporated and the residue was dissolved in EtOAc, which was washed with saturated NaHCO3, dried (MgSO4) and evaporated to give a dark oil. This was chromatographed on a silica column, eluting 8.0 g of solid product with CHCl3 /MeOH/concentrated NH4OH (15:1:0.1). This solid was treated with MeOH/concentrated HCl (10:1), causing precipitation of 4'-(2-benzylaminoethyl)methanesulfonanilide.HCl (XXIX.HCl), m.p. 244°-245°, whose NMR was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:13]>>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH2:12][CH3:13])=[CH:15][CH:16]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(Nc2nc(Cl)ccc2[N+](=O)[O-])cc1

Procedure:
From 2,6-dichloro-3-nitropyridine and 4-ethylaniline, prepared in a similar manner as the one described in Example 1.21 with the exception that the reaction was performed at 65° C., the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[CH:11]=[CH:10][N:9]=N[C:7]=2[O:6][CH2:5]1.O1C2=CN=CC=C2C(=O)[CH2:14]1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:14][N:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: CON=C1COc2nnccc21
Reactant: O=C1COc2cnccc21
Product: CON=C1COc2cnccc21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), furo[2,3-c]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as brown solid;
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[C:7](Cl)=[C:8]([Cl:18])[C:9]2[O:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][C:10]=2[CH:17]=1)=O.[O:24]1C2C=CC=CC=2C(C2C(Cl)=C(Cl)C3OC(C(O)=O)CC=3C=2)=[N:25]1.S(=O)(=O)(O)O>C(O)C>[Cl:18][C:8]1[C:7]2[O:24][N:25]=[C:4]([C:3]3[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=3[Cl:1])[C:6]=2[CH:17]=[C:10]2[CH2:11][CH:12]([C:14]([OH:16])=[O:15])[O:13][C:9]=12
Reactant: O=C(O)C1Cc2cc(-c3noc4ccccc34)c(Cl)c(Cl)c2O1
Reactant: O=C(c1ccccc1Cl)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Agent: O=S(=O)(O)O
Solvent: CCO
Product: O=C(O)C1Cc2cc3c(-c4ccccc4Cl)noc3c(Cl)c2O1

Procedure:
8-Chloro-3-(o-chlorophenyl)-5,6-dihydrofuro[3,2-f]-1,2-benzisoxazole-6-carboxylic acid (4d) was prepared from (3d) using the procedure above; the product contained a significant impurity, presumably the countercyclized 5-(3-benzisoxazolyl)-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid. The mixture was dissolved in 200 ml. absolute ethanol and treated with 0.5 ml. concentrated sulfuric acid overnight. The solution was then evaporated to dryness, redissolved in ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and re-evaporated. Chromatography of the ester on silica gel with chloroform and n-hexane in a 3:1 ratio gave a solid, m.p. 136° C., which was determined by detailed mass spectral analysis to be the desired isomer. Hydrolysis at 60° C. in 25 ml. absolute ethanol and 200 ml. aqueous 1M sodium hydroxide for 20 minutes furnished a white precipitate which was distributed between ethyl acetate and 4.0M aqueous hydrochloric acid, washed with brine, dried over anhydrous magnesium sulfate, and evaporated. Recrystallization from ethyl acetate with n-hexane gave (4d), m.p. 224°-225° C., in 8.1% yield. Analysis (C16H9Cl2NO4) C,H,N,Cl.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[Cl:20].[CH3:21][Si:22]([CH3:39])([CH3:38])[C:23]#[C:24][Sn](CCCC)(CCCC)CCCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:24]#[C:23][Si:22]([CH3:39])([CH3:38])[CH3:21])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[Cl:20]
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: COC(=O)c1nc(-c2ccc(I)cc2)c(C)c(N)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2ccc(C#C[Si](C)(C)C)cc2)c(C)c(N)c1Cl
Temperature: 90 °C
Yield: 21.1 %

Procedure:
A mixture of methyl 4-amino-3-chloro-6-(4-iodophenyl)-5-methylpicolinate (264 mg, 0.66 mmol), trimethyl((tributylstannyl)ethynyl)silane (280 mg, 0.72 mmol), tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol) in anhydrous DMF (1.3 mL) was heated at 90° C. for 16 h. The reaction was cooled, diluted water, and extracted with ethyl acetate (2×). The organic layers were dried over anhydrous magnesium sulfate, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-100% ethyl acetate/hexanes) afforded the title compound as a brown solid (52 mg, 21%): mp 158-164° C.; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 4.83 (s, 2H), 3.96 (s, 3H), 2.14 (s, 3H), 0.26 (s, 9H); IR (neat film) 3325, 3227, 2955, 2157, 1729, 1629, 1246 cm−1; ESIMS m/z 372 ([M]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:15][C:16]([Cl:21])([Cl:20])[C:17]([N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)=[O:18]
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of 1-(2-methoxyphenyl) piperazine (7.0 g) in dichloromethane (30 ml) was added over 0.25 h to a stirred solution of trichloroacetyl chloride (4.06 ml) in dichloromethane (40 ml) at room temperature under argon. Diisopropylethylamine (5.95 ml) was then added and the whole was stirred for 18 h. The reaction mixture was washed with water (2×100 ml), dried (Na2SO4) and concentrated to give the title compound (D3) as an oil (11.2 g, 91%). MH+337/339.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[CH:33][C:32]([F:49])=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[CH:33][C:32]([F:49])=[CH:31][C:30]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one (130c) (240 mg, 0.636 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (336 mg, 0.763 mmol), Pd(PPh3)4 (37 mg, 0.0318 mmol), Na2CO3 aqueous solution (1.0 N, 2.1 mL, 2.1 mmol), 1,2-dimethoxyethane (4.2 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (3×30 mL), brine (30 mL), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 242a.
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([N+:19]([O-:21])=[O:20])[C:10]=1N>CN(C)C=O>[F:17][C:14]1[C:13]([F:18])=[C:12]([N+:19]([O-:21])=[O:20])[CH:10]=[C:9]([F:8])[C:15]=1[CH3:16]
Reactant: Cc1c(F)c(N)c([N+](=O)[O-])c(F)c1F
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: Cc1c(F)cc([N+](=O)[O-])c(F)c1F
Temperature: 0 °C
Yield: 36.8 %

Procedure:
To a solution of t-butyl nitrite (1.87 g) in anhydrous dimethylformamide (10.9 ml) is added dropwise a solution of 2,4,5-trifluoro-3-methyl-6-nitroaniline (2.05 g) in anhydrous dimethylformamide (16.4 ml) with stirring at 50°-52° C. and the mixture is stirred at the same temperature for 30 minutes. After cooling, the reaction mixture is poured into ice-water, extracted with diethyl ether, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the obtained residue is purified by silica-gel column-chromatography (eluent; dichloromethane: n-hexane=1:4) to give 2,3,6-trifluoro-4-nitrotoluene (0.7 g).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CN(C)C=O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:23]
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1c2ccccc2Oc2ccccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
A solution of phenoxazine (10 g, 54.6 mmol) in dry dimethyl formamide (15 ml) was added slowly to a stirred ice cooled suspension of sodium hydride (60% dispersion in oil) (2.88 g, 60.1 mmol) in dimethyl formamide (10 ml), under an atmosphere of nitrogen. The mixture was stirred at 80° C. for 2 h and cooled to 0° C. and ethyl bromoacetate (12.78 g, 76.50 mmol) was added dropwise and stirring was continued for 12 h at 25° C. (TLC monitored). Water (50 ml) was added and the aqueous phase extracted with ethyl acetate (2×75 ml). The combined organic phases were washed with water (50 ml), brine (5 ml), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel (100-200 mesh) using a mixture of benzene and petroleum ether (1:1) to afford the title compound (5.7 g, 39%) as a pale bluish green solid. mp: 96-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:7]=1.[Cl-].[NH4+].C(OCC)(=O)C>C(O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1-c1ccc(F)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(Cl)cc1-c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a solution of the above 5-chloro-4′-fluoro-2-nitrobiphenyl (4.20 g, 15.7 mmol) and iron powder (2.75 g, 49.3 mmol) in ethanol (20 mL), a saturated aqueous ammonium chloride solution (aq., 8.0 mL) was added, and the mixture was stirred at 90° C. for 30 minutes. After the reaction, the reaction mixture was cooled to room temperature and ethyl acetate (30 mL) was added. After the organic phase was washed with water (30 mL), it was dried with sodium sulfate. After the filtration and concentration, the residue was purified by silica gel column chromatography (ethyl acetate/hexane, 1:20-1:3, v/v) to give the title compound (2.43 g, 11.0 mmol, 67%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8](C3CCCCO3)[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[C:18]([NH:23][C:24]3[C:25]4[C:29]([CH:30]=[CH:31][CH:32]=3)=[N:28][N:27](C3CCCCO3)[CH:26]=4)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl.CO>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([C:17]2[C:18]([NH:23][C:24]3[C:25]4[CH:26]=[N:27][NH:28][C:29]=4[CH:30]=[CH:31][CH:32]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: Cc1nc(-c2cccnc2Nc2cccc3nn(C4CCCCO4)cc23)c2cnn(C3CCCCO3)c2n1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2cccnc2Nc2cccc3[nH]ncc23)c2cn[nH]c2n1
Reaction time: 16 h
Yield: 92.1 %

Procedure:
A solution of N-(3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (56.9 mg, 111 μmol) in DCM (1 mL) and MeOH (2 mL) was treated with (+/−)-10-camphorsulfonic acid (57 mg, 2.2 equiv.) and stirred for 16 h. LCMS indicated clean monodeprotection with only a small amount of the fully deprotected compound. Additional (+/−)-10-camphorsulfonic acid (57 mg, 2.2 equiv.) was added and the solution stirred at 60° C. for 1 h after which time reaction was complete. The mixture was concentrated and purified by SCX ion exchange chromatography washing with MeOH and eluting off with 2N NH3/MeOH to give N-(3-(6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-1H-indazol-4-amine (35 mg, 87% yield) as a brown solid. 1H NMR of free base thus obtained gives broad signals, so a small amount was converted to the HCl salt for better 1H NMR analysis by dissolving in MeOH containing 2 drops 2 M aqueous HCl followed by concentration to dryness. HCl salt: 1H NMR (400 MHz, d6-DMSO) δ 14.18 (br. s., 1H); 11.38 (s, 1H); 10.43 (s, 1H); 9.76 (s, 1H); 9.42 (d, 1H); 9.04 (s, 1H); 8.64 (d, 1H); 8.46 (s, 1H); 7.85-7.98 (m, 2H); 7.69 (d, J=9.54 Hz, 1H); 2.14 (s, 3H). m/z (ESI, +ve) 343.0 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH3:1][NH:2][C:3]([CH:5]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9][CH2:8][N:7]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=2)[CH2:6]1)=[O:4]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CNC(=O)C1CNCCc2c1[nH]c1ccccc21
Product: CNC(=O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using N-methyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carbamide and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 9.49 (1H, br s), 7.35 (3H, m), 7.24 (1H, m), 7.14 (4H, m), 4.30 (2H, m), 4.19 (1H, m), 3.69 (2H, m), 3.07 (1H, m), 2.91 (1H, m), 2.78 (3H, br s); MS (ES): 366.2 (MH+).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C[N+]([O-])=O.[F:9][C:10]1[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:26][CH:25]=[C:24]([F:35])[C:11]=1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[CH:23]=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1)=[O:13].[Cl:36][CH2:37][C:38](Cl)=[O:39]>C(Cl)Cl.[Cl-].[NH4+]>[Cl:36][CH2:37][C:38]([C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[C:24]([F:35])=[CH:25][CH:26]=[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[C:10]=3[F:9])[CH:16]=2)[NH:21][CH:22]=1)=[O:39]
Reactant: O=C(Cl)CCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 49.3 %

Procedure:
A solution of aluminum trichloride (0.266 g, 2.00 mmol) in 1:1 DCM:CH3NO2 (5 mL) was added slowly to a slurry of 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.100 g, 0.254 mmol) in 1:1 DCM:CH3NO2 (2 mL) at 0° C. The solution was stirred at 0° C. for 40 minutes. A solution of 2-chloroacetyl chloride (0.0307 mL, 0.380 mmol) in DCM (1 mL) was added, and the reaction mixture was allowed to warm to room temperature overnight. Additional 2-chloroacetyl chloride (5 eq.) was added, and the reaction mixture was warmed to 50° C. for 20 hours. The solution was cooled and diluted with saturated aqueous ammonium chloride and extracted with EtOAc (3 X). The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. They were then purified via column chromatography (5% MeOH/DCM) to afford N-(3-(2-chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (59 mg, 50%) as a solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>O.C(OCC)C>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:18][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: Oc1cccc(F)c1
Reactant: CC(Br)CCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: OCCCCCCOc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1 M NaOH (17.8 mL) was added to a refluxing mixture of 3-fluorophenol (2 g, 17.8 mmol) and 5-bromo-1-hexanol (3.23 g, 17.8 mmol) in water (20 mL). After 3 h, the resulting mixture was cooled to room temperature and diluted with diethyl ether. The layers were separated, the organic layer was washed sequentially with 1N NaOH and water, then dried (Na2SO4) and concentrated to yield 6-(3-fluorophenoxy)hexan-1-ol as an oil. A solution of 6-(3-fluorophenoxy)hexan-1-ol (2.9 g, 13.67 mmol) was added dropwise to a mixture of 1,1,1-tris(acetyloxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one (7.0 g, 16.4 mmol) with ice-bath cooling. The resulting solution was stirred for 2.5 h at room temperature, then poured into a solution of sodium thiosulfate in saturated aqueous sodium bicarbonate. After 0.5 h, the layers were separated and the aqueous layer was extracted with CH2Cl2. The organic phase was dried (Na2SO4) filtered and concentrated to yield 6-(3-fluorophenoxy)hexanal. A solution of 6-(3-fluorophenoxy)hexanal (2.9 g, 13.8 mmol) in ethyl acetate (20 mL) and water (20 mL) containing NaCN (2 g, 41.4 mmol) was stirred vigorously overnight. After 20 h, the phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water, dried (Na2SO4) and concentrated to yield 7-(3-fluorophenoxy)-2-hydroxyheptanenitrile, which was dissolved in methanol (40 mL) and cooled to −78° C. The solution was saturated with HCl (g) and stored at −10° C. for 18 h. The resulting mixture was concentrated, diluted with ethyl acetate (40 mL) and water (40 mL), then stirred overnight. The layers were separated and the organic phase was dried (Na2SO4) and concentrated to yield the corresponding methyl ester which was dissolved in 9:1 dioxane:water (20 mL) and treated with a solution of LiOH (1.4 g, 58 mmol). The resulting solution was stirred for 4 h then acidified to pH˜3 with 1N HCl. The mixture was then extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with water, dried (Na2SO4) and concentrated to yield 7-(3-fluorophenoxy)-2-hydroxyheptanoic acid as a white solid. (MS m/z=257 MH+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:2]1.[CH3:27][CH2:28][CH2:29]CCC.C(Br)C=C>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:29][CH:28]=[CH2:27])[CH:19]=3)[CH2:16][CH2:17]2)=[CH:2]1
Reactant: CCCCCC
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCc2csc3ccccc23)C1
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCn1cc(C2=CCN(CCc3csc4ccccc34)CC2)c2ccccc21
Reaction time: 5.5 h

Procedure:
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (358 mg, 1 mmol) (obtained from example 29, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 330 min and allyl bromide (183 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Yellow semi-solid. Yield: 195 mg (48%); 399 (M+H); 1HNMR (400 MHz, CDCl3): δ 7.99˜7.87 (m, 3H); 7.42˜6.99 (m, 6H); 6.22˜6.21 (s, 1H); 5.22˜5.21 (d, J=1.3 Hz, 2H); 5.20˜5.19 (d, J=1.3 Hz, 2H); 4.71˜4.65 (d, 1.6 Hz, 2H); 3.49˜2.67 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH:9]=2)=[O:4].[C:26]([Cu])#[N:27].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:26]#[N:27])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH:9]=2)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(I)c2cc(Oc3ccccc3OC)ccc2c1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
4-Hydroxy-1-iodo-7-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (150 mg, 0.33 mmol) and CuCN (60 mg, 0.67 mmol) were suspended in DMF (1.3 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 100 mg. MS: (−) m/z 349.28 (M−1).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:6]=[C:5]([CH2:17]O)[CH:4]=1)[CH3:2].CN(C)C=O.P(Cl)(Cl)([Cl:26])=O>C(Cl)Cl>[Cl:26][CH2:17][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=[C:7]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:6]=1
Reactant: CCc1cc(CO)cc(Nc2ncc(C#N)s2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cc(CCl)cc(Nc2ncc(C#N)s2)n1
Reaction time: 2.5 h

Procedure:
2-{[6-Ethyl-4-(hydroxymethyl)pyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile (12-3, 0.146 g, 0.56 mmol) was stirred in anhydrous CH2Cl2 (2.5 mL) under N2. N,N-Dimethylformamide (0.043 mL, 0.56 mmol) was added followed by phosphorous oxychloride (0.209 mL, 2.24 mmol). After 2.5 hours, the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to afford 2-{[4-(chloromethyl)-6-ethylpyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile as an orange solid. 1H NMR (DMSO-d6) δ 12.32 (s, 1H), 8.28 (s, 1H), 7.00 (d, 2H, J=3.66 Hz), 4.77 (s, 2H), 2.83 (q, 2H, J=7.63 Hz), 1.34 (t, 3H, J=7.63 Hz).